Comparison of busulfan pharmacokinetics between four-times-daily and once-daily administration in pediatric patients: a preliminary prospective observational trial
Atsushi Yamaguchi, Shinsuke Hirabayashi, Kazuko Niki, Keisuke Kagami, Yukayo Terashita, Yuko Cho, Atsushi Manabe, Mitsuru Sugawara, Yoh Takekuma
International Journal of Hematology, Springer Science and Business Media LLC, 2024年12月03日
研究論文（学術雑誌）

Validated UPLC-MS/MS method for quantification of melatonin receptor agonists and dual orexin receptor antagonists in human plasma and breast milk: Application to quantify suvorexant and lemborexant in clinical samples
Hina Ishikawa, Ayako Furugen, Ayako Nishimura, Takeshi Umazume, Shuhei Ishikawa, Ryoichi Aoyagi, Katsuya Narumi, Keisuke Okamoto, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi
Journal of Pharmaceutical and Biomedical Analysis, 251, 116432, 116432, Elsevier BV, 2024年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Pharmaceutical care is important for mental health during the perinatal period, which is often characterized by insomnia. In recent years, prescriptions of melatonin receptor agonists (MRAs) and dual orexin receptor antagonists (DORAs) for insomnia have increased; however, their use during the perinatal period has scarcely been reported. In the present study, we developed a UPLC-MS/MS method for the quantification of ramelteon, its metabolite M-II, suvorexant, and lemborexant in human plasma and breast milk to accumulate information on the safety and transfer of MRAs and DORAs into breast milk. Samples of MRAs (ramelteon and M-II) in plasma and breast milk were prepared using liquid-liquid extraction (LLE) with ethyl acetate. For DORAs (suvorexant and lemborexant), LLE with ethyl acetate was applied to plasma samples. For breast milk samples, significant ion suppression was observed for LLE with ethyl acetate. Solid-phase extraction (SPE) cartridges capable of removing phospholipids improved the matrix effects. Finally, protein precipitation with methanol and an SPE cartridge, InertSep® Phospholipid Remover, were selected for breast milk sample preparation. An ACQUITY UPLC BEH C18 column was used for analyte separation. MRAs and DORAs were eluted using isocratic and gradient elution, respectively, and analyzed using electrospray ionization in the positive mode with multiple reaction monitoring. The range of calibration curve for MRAs and DORAs was 0.1-25 and 0.5-50 ng/ml, respectively. Both the plasma and breast milk samples exhibited good linearity over this range. The method was validated by evaluating its accuracy and precision, matrix effect, recovery, carry-over, stability, and dilution integrity. The validated method was successfully applied to clinical samples donated by breastfeeding women and the milk/plasma (M/P) ratio and relative infant dose (RID) of lemborexant (one case) and suvorexant (two cases) were estimated. The M/P ratio of lemborexant was <1, and the RID was 1.05 %. The M/P ratio of suvorexant was <0.1, and RID was 0.11-0.20 %. This method will be useful for future studies evaluating the safety of these drugs during breastfeeding.

Impact of baseline renal impairment on severe neutropenia development in pemetrexed and carboplatin thoracic cancer treatment.
Yoshitaka Saito, Osamu Taniguchi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32, 12, 829, 829, 2024年11月27日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Carboplatin (CBDCA) plus pemetrexed (PEM) is a commonly-used thoracic cancer treatment. As both CBDCA and PEM are excreted via the kidneys, renal impairment (RI) can lead to severe neutropenia, the most typical adverse event in the treatment. We aimed to determine the impact of baseline RI on the development of severe neutropenia following real-world CBDCA + PEM-containing treatments. METHODS: Patients with thoracic cancer receiving CBDCA + PEM-containing treatments (n = 155) were divided into a control group (baseline creatinine clearance [CCr] ≥ 60 mL/min) and an RI group (baseline CCr < 60 mL/min) and retrospectively evaluated. The primary endpoint was the incidence of severe neutropenia during the first cycle. We also assessed factors associated with the development of severe neutropenia. RESULTS: Severe neutropenia during the first cycle was confirmed in 41.2% of the patients in the RI group, which was significantly higher than that in the control group (20.7%, P = 0.02). Additionally, severe neutropenia during all evaluation periods was also more prevalent in the RI group compared to the control group (47.1% vs. 24.8%, P = 0.02). In contrast, the incidence of severe thrombocytopenia was not different. Multivariate logistic regression analyses identified RI as a risk factor for severe neutropenia (adjusted odds ratio 2.71; 95% confidence interval 1.18-6.21, P = 0.02 for the first cycle; 2.62, 1.17-5.84, P = 0.02 for all evaluation periods). CONCLUSION: Our study revealed that patients with baseline RI exhibited severe neutropenia after CBDCA + PEM-containing treatments.

Effects of famotidine use during pregnancy: an observational cohort study.
Ayako Nishimura, Ayako Furugen, Masaki Kobayashi, Yoh Takekuma, Naho Yakuwa, Mikako Goto, Masahiro Hayashi, Atsuko Murashima, Mitsuru Sugawara
Journal of pharmaceutical health care and sciences, 10, 1, 70, 70, 2024年11月08日, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Famotidine, a histamine2-receptor antagonist (H2Ras), is widely used to treat and prevent gastrointestinal symptoms during pregnancy. Although several studies have reported the use of H2Ras during pregnancy, limited data on famotidine were included in these reports. Therefore, we analyzed pregnancy outcome data to evaluate the effects of famotidine use during pregnancy on the fetus. METHODS: Pregnancy outcome data were used for females enrolled in two Japanese facilities that provided counseling on drug use during pregnancy between April 1988 and December 2017. For the primary endpoint, the incidence of congenital malformations was calculated from the data of live birth to pregnant women who took famotidine (n = 330) or drugs considered to exert no teratogenic risk (control, n = 1,407) during the first trimester of pregnancy. Considering secondary endpoints, the incidence of obstetric outcomes, including preterm delivery, was calculated from data on the use of famotidine (n = 347) and controls (n = 1,476) during the entire pregnancy. The crude odds ratios (cORs) for the incidence of congenital malformations were calculated using univariate logistic regression analysis, with the control group used as the reference. Adjusted ORs (aORs) were calculated using multivariate logistic regression analysis adjusted for various other factors. RESULTS: The incidences of congenital malformations in the famotidine and control groups were 3.9% and 2.8%, respectively. There was no significant difference between the famotidine and control groups (cOR: 1.40 [95% CI:0.68-2.71], aOR: 1.06 [95% CI:0.51-2.16]). Conversely, the preterm delivery rates were 8.1% and 3.8% in the famotidine and control groups, respectively, indicating a significant difference (cOR: 2.00 [95% CI:1.20-3.27]). However, the multivariate analysis eliminated famotidine use as a confounding factor. CONCLUSIONS: This observational cohort study revealed that exposure to famotidine during the first trimester of pregnancy was not associated with an increased risk of congenital malformations in infants. Although a higher rate of preterm delivery was detected in famotidine users when compared with controls, this could be attributed to confounding factors, such as complications.

Impact of renal impairment on early development of severe neutropenia with trifluridine/tipiracil treatment for metastatic colorectal cancer.
Yoshitaka Saito, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Scientific reports, 14, 1, 26990, 26990, 2024年11月06日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Trifluridine/tipiracil (FTD/TPI) with or without bevacizumab is an effective treatment for metastatic colorectal cancer (mCRC). As this agent is mainly excreted via the kidney, we aimed to evaluate the impact of renal impairment (RI) on the early development of severe neutropenia, a dose-limiting toxicity and whose development reflects better treatment outcomes, in patients with mCRC treated with FTD/TPI. Patients with mCRC receiving FTD/TPI ± bevacizumab (n = 100) were divided into the RI group (creatinine clearance [CCr] < 90 mL/min) or control group (CCr ≥ 90 mL/min), and retrospectively evaluated. Severe neutropenia during the first two cycles occurred in 57.6% and 34.2% of patients in the RI and control groups, respectively, which was significantly different (P = 0.03) and met our primary endpoint. Furthermore, the incidence during the first cycle also differed significantly (52.5% in the RI group and 17.1% in the control group, P = 0.0004). Multivariate logistic regression analysis suggested that baseline RI and neutropenia were significant risk factors for early severe neutropenia (adjusted odds ratio and 95% confidence interval: 3.07, 1.24-7.59, P = 0.02 for RI, and 9.76, 1.08-88.11, P = 0.04 for neutropenia). In conclusion, our study suggested that patients with RI can exhibit early severe neutropenia during real-world FTD/TPI treatment for mCRC.

Development and validation of the prediction score for augmented renal clearance in critically Ill Japanese adults.
Ryusei Mikami, Shungo Imai, Mineji Hayakawa, Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Mitsuru Sugawara, Yoh Takekuma
Journal of pharmaceutical health care and sciences, 10, 1, 69, 69, 2024年11月06日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Augmented renal clearance (ARC) decreases the therapeutic concentration of drugs excreted by the kidneys in critically ill patients. Several ARC prediction models have been developed and validated; however, their usefulness in Japan has not been comprehensively investigated. Thus, we developed a unique ARC prediction model for a Japanese mixed intensive care unit (ICU) population and compared it with existing models. METHODS: This retrospective study enrolled a mixed ICU population in Japan from January 2019 and June 2022. The primary outcome was the development and validation of a model to predict ARC onset based on baseline information at ICU admission. Patients admitted until May 2021 were included in the training set, and external validation was performed on patients admitted thereafter. A multivariate logistic regression model was used to develop an integer-based predictive scoring system for ARC. The new model (the JPNARC score) was externally validated along with the ARC and Augmented Renal Clearance in Trauma Intensive Care (ARCTIC) scores. RESULTS: A total of 2,592 critically ill patients were enrolled initially, with 651 patients finally included after excluding 1,941 patients. The training and validation datasets comprised 456 and 195 patients, respectively. Multivariate analysis was performed to develop the JPNARC score, which incorporated age, sex, serum creatinine, and diagnosis upon ICU admission (trauma or central nervous system disease). The JPNARC score had a larger area under the receiver operating characteristic curve than the ARC and ARCTIC scores in the validation dataset (0.832, 0.633, and 0.740, respectively). CONCLUSIONS: An integer-based scoring system was developed to predict ARC onset in a critically ill Japanese population and showed high predictive performance. New models designed to predict the often-unrecognized ARC phenomenon may aid in the decision-making process for upward drug dosage modifications, especially in resource- and labor-limited settings.

Reply to Accurate Risk Prediction Model for Surgical Site Infection After Lower Third Molar Surgery.
Akira Yamagami, Katsuya Narumi, Yoshitaka Saito, Ayako Furugen, Shungo Imai, Yoshimasa Kitagawa, Yoichi Ohiro, Ryo Takagi, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi
Oral diseases, 2024年11月03日, ［査読有り］, ［国際誌］
英語

Effect of baseline anemia on the efficacy of docetaxel and ramucirumab for advanced non-small cell lung cancer treatment.
Yoshitaka Saito, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
BMC cancer, 24, 1, 1301, 1301, 2024年10月21日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Docetaxel (DOC) and ramucirumab (RAM) is one of the most effective regimens for advanced non-small cell lung cancer (NSCLC) treatment. In our previous study, baseline anemia was identified as a preventive factor against the development of severe adverse effects during the first treatment cycle. It was hypothesized that anemia directly promotes tumor angiogenesis, leading to the elevation of RAM efficacy with increased DOC delivery to tumors, while reducing DOC delivery to other organs, potentially mitigating severe adverse effects. If this hypothesis is correct, patients with baseline anemia may have better clinical outcomes than those with normal hemoglobin levels. In this study, we aimed to investigate the effect of baseline anemia on the efficacy of DOC + RAM in treating advanced NSCLC in a real-word setting. METHODS: Patients with advanced NSCLC receiving DOC + RAM (n = 72) were retrospectively assessed. They were categorized into a control group with normal baseline hemoglobin levels and an anemia group with baseline anemia. The primary endpoint was progression-free survival (PFS) evaluation. RESULTS: Patients in the anemia group had a significantly shorter PFS than that of patients in the control group (median PFS: 3.2 and 6.2 months; 95% confidence interval [CI]: 2.2-4.8 and 4.3-9.9 months, respectively;P = 0.008). In addition, the disease control rate in the anemia group was 65.8%, which was significantly lower than that in the control group (93.6%; P = 0.007). Overall survival tended to be shorter in patients with anemia than in controls, although the difference was not statistically significant (P = 0.07). Multivariate Cox hazard analysis suggested that baseline anemia was a singular risk factor for poor PFS (adjusted hazard ratio 1.84, 95% CI 1.08-3.13; P = 0.02). The incidence of severe adverse effects did not differ between the two groups. CONCLUSIONS: This study suggests that the PFS of patients with anemia treated with DOC + RAM for advanced NSCLC is shorter than that of those without the symptoms.

Clinical research for saliva-based therapeutic drug monitoring of linezolid.
Yuki Inoue, Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Tsutomu Endo, Masahiko Takahata, Miki Komatsu, Mitsuru Sugawara, Yoh Takekuma
British journal of clinical pharmacology, 2024年10月10日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Linezolid is primarily used to treat of methicillin-resistant Staphylococcus aureus and multidrug-resistant tuberculosis infections. Thrombocytopenia due to linezolid usage is a concern, and therapeutic drug monitoring has been reported to be effective in its prevention. Plasma concentrations provide valuable information for treatment decisions; however, collecting plasma samples can be burdensome for both patients and healthcare providers. Therefore, there is interest in saliva as an alternative for monitoring, considering its potential to replace plasma samples. METHODS: Patients hospitalized at Hokkaido University Hospital and Hokkaido Spinal Cord Injury Center between April 2022 and July 2024, who received oral or intravenous linezolid treatment, were enrolled. The concentrations of linezolid were simultaneously measured in plasma and saliva samples. We determined the concentration profiles of linezolid in the saliva and examined the correlation between saliva and plasma linezolid concentrations. RESULTS: Eighteen patients receiving linezolid were enrolled. The average of saliva/plasma (S/P) concentration ratios of linezolid were 1.018. A strong correlation was found between the salivary and plasma concentrations of linezolid (R = .833, P < .001). Notably, in patients receiving intravenous administration of linezolid, the correlation was even more pronounced (R = .885, P < .001). Additionally, when focusing on the S/P ratio of the trough concentrations in the morning and at night, the S/P ratios at night were much closer to 1.0. CONCLUSION: The concentrations of linezolid in plasma and saliva were similar, indicating their potential applicability in clinical settings. The monitoring of linezolid concentrations in saliva has been shown to be particularly suitable for patients receiving intravenous administration.

Exploring the impact of baseline platelet count on linezolid-induced thrombocytopenia: a retrospective single-center observation study.
Yuki Inoue, Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Mitsuru Sugawara, Yoh Takekuma
International journal of clinical pharmacy, 2024年10月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Patients treated with linezolid (LZD) frequently develop thrombocytopenia, and previous studies have identified the risk factors for this condition. However, the relationship between the development of LZD-induced thrombocytopenia and baseline platelet count has varied according to different reports. AIM: To explore the relationship between platelet count and the development of LZD-induced thrombocytopenia. METHOD: Patients who underwent LZD at Hokkaido University Hospital in Japan from September 2008 to March 2023 were included. We collected data on patient characteristics and platelet counts at baseline and during LZD therapy from the electronic medical records. Thrombocytopenia was defined as a decrease in platelet count by 30% or more from baseline, or a platelet level < 100,000/µL. RESULTS: Two hundred and ninety-five patients who received LZD were included in this study, of whom 34.9% developed thrombocytopenia. In the early days of LZD treatment, the thrombocytopenia group showed a nearly 5% decrease in platelet count, while the non-thrombocytopenia group exhibited an increase of over 5%. Additionally, focusing on early onset thrombocytopenia (within 5 days), a baseline platelet count of < 150,000/µL was identified as a risk factor for early thrombocytopenia. Conversely, it was also observed that 24.7% of patients with a baseline platelet count ≥ 150,000/µL still developed early thrombocytopenia. CONCLUSION: Our findings suggest that while a baseline platelet count of < 150,000/µL is a risk factor for the early onset of thrombocytopenia, vigilant monitoring of platelet counts by clinical pharmacists in the early stages of LZD treatment is essential, regardless of baseline platelet levels.

The crucial relationship between vancomycin minimum inhibitory concentration and therapeutic efficacy against methicillin-resistant coagulase-negative staphylococci.
Yusuke Niinuma, Keisuke Kagami, Mitsuru Sugawara, Yoh Takekuma
Journal of chemotherapy (Florence, Italy), 1, 8, 2024年08月26日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio was used as an indicator of the clinical efficacy of vancomycin. However, the target AUC/MIC has not been set for methicillin-resistant coagulase-negative staphylococci (MR-CNS), and the effectiveness of vancomycin in strains with high MIC is unknown. Therefore, we aimed to investigate the relationship between the vancomycin MIC and therapeutic efficacy in patients with MR-CNS bacteremia. The primary outcome was the difference in treatment failure rate when the MR-CNS vancomycin MIC was 1 or 2 µg/mL. The treatment failure rate did not significantly differ between the two groups (MIC 1 vs. MIC 2: 27.0% vs. 31.0%; p = 0.779). As a result of multivariate analysis, AUC/MIC0-24 h ≤230 was extracted as risk factor for treatment failure, suggesting the importance of a sufficient initial loading dose and early blood concentration monitoring to increase AUC/MIC0-24 h for successful treatment.

Association of oral mucositis induced by anthracycline-cyclophosphamide and subsequent docetaxel treatment for perioperative breast cancer.
Yoshitaka Saito, Yoh Takekuma, Masato Takahashi, Tomohiro Oshino, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32, 8, 513, 513, 2024年07月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy is effective for perioperative breast cancer treatment. However, these treatments frequently induce oral mucositis (OM), with an incidence ranging from 20 to 50%. The association of OM development between different chemotherapeutic treatments remains unclear. Consequently, this study aimed to compare OM development during docetaxel-containing chemotherapy between patients with and without OM experience during previous anthracycline-cyclophosphamide treatments to assess the association between OM development and treatment regimens. METHODS: Seventy-two patients with breast cancer receiving anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy as a perioperative treatment were categorized into the control (no prior OM experience with anthracycline-cyclophosphamide) and OM-experience (OM development during previous treatment) groups and retrospectively evaluated. The primary endpoint was the incidence of all-grade OM in the first docetaxel-containing chemotherapy cycle. Additionally, the incidences of OM and dysgeusia during all treatment cycles and factors associated with the incidence of OM were evaluated. RESULTS: The incidence of all-grade OM in the first cycle was significantly higher in the OM-experience group (54.2%) than in the control group (10.4%; P < 0.0001). Furthermore, its incidence in all treatment cycles was higher in the OM-experience group (66.7%) than in the control group (12.5%, P < 0.0001). However, the incidence of dysgeusia did not differ between the groups. Multivariate logistic regression analysis revealed OM experience during previous anthracycline-cyclophosphamide treatment and concomitant pertuzumab use as independent risk factors for OM development in subsequent docetaxel-containing chemotherapy. CONCLUSION: Our study suggests that patients experiencing OM with anthracycline-cyclophosphamide during perioperative breast cancer treatment exhibit symptoms following subsequent docetaxel-containing chemotherapy.

Evaluation of the impact of systemic dexamethasone dosage on docetaxel-induced hand-foot syndrome in patients with breast cancer.
Yoshitaka Saito, Yoh Takekuma, Masato Takahashi, Tomohiro Oshino, Mitsuru Sugawara
Scientific reports, 14, 1, 14083, 14083, 2024年06月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents the other docetaxel-induced adverse inflammatory effects in a dose-dependent manner. This study aimed to evaluate the dose-dependent efficacy of systemic DEX in attenuating HFS in patients with breast cancer receiving docetaxel. Patients with breast cancer receiving docetaxel (75 mg/m2)-containing regimens (n = 111) were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2-4, and analyzed retrospectively. Development of all-grade HFS in all treatment cycles was significantly lower in the 8 mg group (50.0%) than in the 4 mg group (73.0%, P = 0.03), with primary endpoint accomplishment. Moreover, its development in the first cycle was also lower in the 8 mg group than in the 4 mg group. These results were confirmed in a propensity score-matched population. Logistic regression analysis suggested higher DEX dosage as an independent preventive factor (adjusted odds ratio 0.35; 95% confidence interval 0.14-0.86, P = 0.02 for all cycles; 0.26, 0.11-0.63, P = 0.003 for the first cycle). Our study suggests that systemic DEX prevents the occurrence of docetaxel-induced HFS in patients with breast cancer in a dose-dependent manner in a real-world setting.

Development of an Evaluation System Using Intestinal Organoids for Drug Efflux Transport Analysis by an Imaging Approach
Chihiro Koseki, Takehiko Ishikawa, Yuki Sato, Mikiko Shimada, Yuki Yokoi, Kiminori Nakamura, Naoyuki Honma, Takanori Moriyama, Hitoshi Kashiwagi, Mitsuru Sugawara
Journal of Pharmaceutical Sciences, Elsevier BV, 2024年06月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, There are several in vitro systems that enable evaluation of the absorption direction, but there are few quantitative systems that enable easy evaluation of the excretion direction. Enteroids, organoids derived from intestine, have been frozen and passaged for various research. But it is not clear how the freezing and passaging affect the expression and function of transporters. We investigated the effects of passage and cryopreservation of enteroids. We focused on P-gp (P-glycoprotein) and compared the transfer rates of rhodamine 123 (Rh123) into the lumen of enteroids with and without a P-gp inhibitor. mRNA expression levels did not change significantly before and after passage and cryopreservation. Accumulation of Rh123 in the lumen of enteroids was observed. With some P-gp inhibitors, excretion of Rh123 into the lumen of enteroids was inhibited and the nonexcreted Rh123 accumulated in enteroids epithelial cells. The transfer rate of Rh123 into the lumen of enteroids with a P-gp inhibitor was significantly decreased compared to that of without a P-gp inhibitor. Before and after passage and cryopreservation, the transfer rate was almost the same as that of primary cultured enteroids. We succeeded in easily evaluating whether a component is a substrate of P-gp using enteroids.

Immunoregulatory Effects of Elemental Diet and Its Ingredient, Tryptophan, via Activation of the Aryl Hydrocarbon Receptor in Mice
Atsuhito Kubota, Shungo Imai, Ryoichi Aoyagi, Wataru Murase, Masaru Terasaki, Mitsuru Sugawara, Yoh Takekuma, Hiroyuki Kojima
International Journal of Molecular Sciences, 25, 6, 3448, 2024年03月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation and its treatment varies widely; however, when inflammation is high, a complete nutrient containing pre-digested elemental diet (ED) is used to preserve the intestinal tract. In this study, we investigated the mechanisms underlying the effectiveness of EDs for IBD using mice. C57BL/6 mice were orally treated with the ED (5 mL/day) and its ingredient L-tryptophan (Trp) (1-100 mg/kg), respectively. Flow cytometry analysis revealed that treatment with the ED and Trp (10 and 100 mg/kg) significantly increased the percentage of splenic CD4+-/CD25+-/Foxp3+ regulatory T cells (Tregs). In the 2% DSS-induced colitis-mouse model, Trp administration (100 mg/kg) led to a significant decrease in TNF-α and increase in IL-10 in the serum as well as a significant decrease in the inflammation score. Furthermore, the aryl hydrocarbon receptor (AhR) agonistic activity, which is a key function of Treg induction, of Trp and 15 Trp metabolites was characterized using a highly sensitive DR-EcoScreen cell assay. Five Trp metabolites, including L-kynurenine, acted as AhR agonists, while Trp did not. Taken together, these results suggest that the ED treatment has a Trp-dependent immunoregulatory effect, and several Trp metabolites that activate the AhR might contribute to induction of remission in patients with IBD.

Evaluation of the risk factors for the failure of a single prophylactic dose of anticholinergic drugs for irinotecan-induced cholinergic symptoms.
Takuya Watanabe, Yoshitaka Saito, Yoh Takekuma, Yasushi Shimizu, Ichiro Kinoshita, Yoshito Komatsu, Mitsuru Sugawara
International journal of clinical pharmacology and therapeutics, 62, 5, 213, 221, 2024年03月03日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Irinotecan (IRI) is an anticancer drug that is frequently used to treat colorectal, gastric, and pancreatic cancers. Its side effects include cholinergic symptoms, such as diarrhea, abdominal pain, nausea, and hyperhidrosis. Anticholinergic medicines are frequently used for treatment or prophylaxis; however, the risk factors for the failure of a single prophylactic anticholinergic administration remain unclear. Moreover, an appropriate anticholinergic drug for prophylaxis remains unknown. Thus, we aimed to identify the risk factors associated with the failure of a single prophylactic dose of anticholinergic drugs for IRI-induced cholinergic symptoms and to evaluate the usefulness of multiple prophylactic doses of anticholinergic drugs. MATERIALS AND METHODS: Patients who underwent IRI treatment for colorectal, gastric, or pancreatic cancer and received prophylactic anticholinergic drugs for IRI-induced cholinergic symptoms (n = 135) were retrospectively evaluated. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for failure of a single prophylactic dose of anticholinergic drugs. We also evaluated the efficacy of multiple prophylactic anticholinergic drug administration. RESULTS: Based on univariate and multivariate analyses, colorectal cancer, female sex, and prophylactic use of scopolamine butyl bromide were identified as risk factors for failure of a single prophylactic dose of anticholinergic drugs. The efficacy of multiple prophylactic doses was confirmed to be 95% of the patients who had a single prophylactic failure due to temporary effect but symptom appearance after a certain period of time (wearing-off). CONCLUSION: We determined that colorectal cancer, female sex, and prophylactic use of scopolamine butyl bromide were risk factors associated with the failure of a single prophylactic dose of anticholinergic drugs, and that multiple prophylactic doses for wearing-off can be a promising method.

Impact of preexisting proteinuria on the development of regorafenib-induced problematic proteinuria in real-world metastatic colorectal cancer treatment.
Yoshitaka Saito, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Scientific reports, 14, 1, 5153, 5153, 2024年03月02日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Regorafenib is the first multikinase inhibitor for treating metastatic colorectal cancer (mCRC). Proteinuria is a frequently encountered adverse effect, regardless of prior administration of vascular endothelial growth factor inhibitors. Herein, we aimed to assess the impact of baseline preexisting proteinuria on regorafenib-induced problematic proteinuria during real-world mCRC therapy. Patients with mCRC receiving regorafenib (n = 100) were retrospectively assessed and divided into control and preexisting proteinuria (baseline grade of 1-2) groups. The primary endpoint was the development of grade ≥ 2 (grade ≥ 3 in case of baseline grade 2 patients) proteinuria. Propensity score-matching was performed to confirm the robustness of primary analyses. Defined proteinuria occurred in 30.7 and 57.9% of patients in the control and preexisting proteinuria groups, respectively, with significant differences in the all-patient population (P = 0.01). The preexisting proteinuria group exhibited significant defined proteinuria development within 7 days of regorafenib initiation, grade ≥ 3 symptoms, and treatment suspension owing to proteinuria. Similar results were obtained in the propensity score-matched population. According to multivariate logistic regression analysis, baseline proteinuria was a singular risk factor for defined proteinuria development (adjusted odds ratio; 3.76, 95% confidence interval; 1.45-9.75, P = 0.007). Collectively, our study revealed that patients with preexisting proteinuria develop regorafenib-induced proteinuria degradation.

Evaluation of Prediabetes in Cisplatin-induced Nephrotoxicity in the Short Hydration Method: A Subgroup Analysis
YOSHITAKA SAITO, TATSUHIKO SAKAMOTO, MASAKI KOBAYASHI, YOH TAKEKUMA, ISSEI HIGUCHI, KEISUKE OKAMOTO, JUN SAKAKIBARA-KONISHI, YASUSHI SHIMIZU, ICHIRO KINOSHITA, MITSURU SUGAWARA
In Vivo, 38, 2, 800, 806, Anticancer Research USA Inc., 2024年02月28日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Cisplatin-induced nephrotoxicity (CIN) is one of the most attention-requiring adverse effects. We have reported that diabetes mellitus significantly increases the incidence of CIN in a short hydration method in real-world lung cancer treatment. However, the effect of prediabetes on CIN development remains unclear. This study investigated whether patients with prediabetes exhibit CIN at a greater rate during real-world cisplatin-including treatments as a subgroup analysis. PATIENTS AND METHODS: This retrospective observational study enrolled patients with lung cancer receiving cisplatin treatment (≥75 mg/m2) from May 2014 to January 2021 (n=169). Patients were divided into a prediabetes group (baseline HbA1c 5.7-6.4%) and a control group (baseline HbA1c <5.7%). The primary endpoint of this study was the incidence of CIN in all treatment cycles between the two groups. We also assessed variations in serum creatinine (SCr) levels and creatinine clearance (CCr). RESULTS: CIN occurred in 4.7% of controls and 8.3% of patients with prediabetes in all cycles, with no significant difference (p=0.37). In contrast, variation of SCr levels and CCr was significantly worse in the prediabetes group [median variation level (range) 0.11 mg/dl (-0.11-0.46 mg/dl) and 0.12 mg/dl (-0.02-1.08 mg/d) in controls and prediabetes, p=0.04 for SCr; -12.9 ml/min (-54.1-4.9 ml/min) and -16.3 ml/min (-49.4-3.0 ml/min), p=0.02 for CCr, respectively]. These results were also confirmed during the first cycle of treatment. CONCLUSION: Patients with prediabetes did not develop problematic CIN, although they exhibited significant increases in SCr and decreases in CCr.

Association Between Multisystem Immune-related Adverse Events and Progression-free Survivals in PD-1/PD-L1 Inhibitor Monotherapy.
Atsushi Yamaguchi, Yoshitaka Saito, Keisuke Okamoto, Ayako Furugen, Katsuya Narumi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara, Masaki Kobayashi
In vivo (Athens, Greece), 38, 6, 2886, 2896, 2024年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Immune-related adverse events (irAEs) occur in various organs, and sometimes multiply following treatment with immune checkpoint inhibitors (ICIs). This study aimed to determine the association between the number of irAEs and clinical outcomes. PATIENTS AND METHODS: This was a retrospective study that included patients with lung cancer, melanoma, and head and neck cancer who were treated with anti-programmed cell death (ligand) 1 (PD-1/PD-L1) monotherapy. We evaluated the association between the number of irAEs and progression-free survival (PFS) in the simple Cox regression analysis. To eliminate the immortal-time bias, an additional landmark analysis was performed. RESULTS: In total, 92, 69, and 37 patients were allocated to the no, single, and multisystem irAEs groups, respectively. The multisystem irAEs were associated with better PFS compared to the no irAE group. In contrast, at the 12-week landmark, multisystem irAEs were associated with poor PFS compared to the no irAEs group. Furthermore, the rate of treatment suspension owing to irAEs in the multisystem irAEs group (62.5%) was higher than that in the single irAE group (17.3%) at the 12-week landmark. CONCLUSION: The incidence of multisystem irAEs was associated with improved clinical outcomes in patients with lung cancer, melanoma, and head and neck cancer treated with PD-1/PD-L1 inhibitor monotherapy. However, these results may be influenced by a potential immortal-time bias. When accounting for this bias, the early development of multisystem irAEs within 12 weeks was linked to treatment suspension and poorer clinical outcomes.

Risk Factor Analysis for Anti-epidermal Growth Factor Receptor Monoclonal Antibody-induced Problematic Skin Toxicities in Patients With Liver Metastatic Colorectal Cancer.
Yoshitaka Saito, Kazuki Uchiyama, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
In vivo (Athens, Greece), 38, 5, 2390, 2398, 2024年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: We previously reported that patients with metastatic colorectal cancer (mCRC) and baseline liver metastasis are at a higher risk of developing grade ≥2 overall skin toxicities when treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibody. This study aimed to identify additional factors associated with skin toxicities induced by anti-EGFR treatment in patients with liver metastatic CRC. PATIENTS AND METHODS: Patients with liver metastatic CRC who initially received anti-EGFR monoclonal antibody-containing treatment (n=77) were retrospectively assessed. The primary endpoint was to identify the factor(s) responsible for the development of grade ≥2 overall skin toxicities. Additionally, factors for grade ≥2 rash and paronychia were evaluated. RESULTS: The incidence of grade ≥2 overall skin symptoms, rash, and paronychia was 62.3%, 31.2%, and 28.6%, respectively. Multivariate Cox proportional hazard regression analyses revealed that age <65 years and anemia were independent baseline risk factors for grade ≥2 overall skin toxicities (adjusted hazard ratio 2.09, 95% confidence interval=1.10-3.97, p=0.02 for age; 2.36, 1.20-4.61, p=0.01 for anemia). In contrast, combination prophylaxis using systemic minocycline and corticosteroid ointment was a preventive factor (0.47, 0.25-0.88, p=0.02). Males and age <65 years were baseline risk factors for grade ≥2 rash, and combination prophylaxis was identified as a preventive factor. No factors were identified for paronychia. CONCLUSION: Age <65 years and anemia were identified as independent baseline risk factors. Additionally, combination prophylaxis was found to be a preventive factor against anti-EGFR monoclonal antibody-induced grade ≥2 overall skin toxicities in patients with liver metastatic CRC.

Evaluation of Efficacy of Adding Aprepitant to Palonosetron and Dexamethasone in Carboplatin and Etoposide Therapy.
Tatsuhiko Sakamoto, Moeko Kado, Yoshitaka Saito, Kazuki Uchiyama, Ryota Kanno, Osamu Taniguchi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 47, 6, 1189, 1195, 2024年, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in addition to a 5-hydroxytryptamine type 3 receptor antagonist with dexamethasone (DEX) for CBDCA-containing chemotherapy because of its higher emetogenic risk. However, the additional efficacy of aprepitant (APR) in CBDCA-containing treatment remains controversial, and data on multiple-day treatments are limited. Etoposide (ETP) was administered on days 1-3 in the CBDCA + ETP regimen, and it is important to evaluate suitable antiemetic therapy for the regimen. Therefore, we evaluated the efficacy of additional APR in CBDCA + ETP. Patients were divided into two groups and retrospectively evaluated. One was the control group, which was prophylactically administered palonosetron (PALO) and DEX, and the other was the APR group, which received APR orally with PALO and DEX. The primary endpoint was complete response (CR) between the groups. The overall CR rates were 75.0 and 76.4% in the control and APR groups, respectively, with no significant difference (p = 1.00). In the acute phase, it was 88.9 and 97.2%, respectively, and 86.1 and 79.2% in the delayed phase, respectively, without significant differences (p = 0.10 and 0.38, respectively). The incidence and severity of nausea, vomiting, and anorexia were not significantly different between the two groups in the acute and delayed phases. Our findings suggest that combining APR with PALO and DEX does not improve the CR rate in CBDCA + ETP therapy.

Platelets Affect the Activity of Amino Acid Transporter SNAT4 in HuH-7 Human Hepatoma Cells.
Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Shungo Imai, Yoh Takekuma, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 47, 3, 652, 659, 2024年, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Platelets have been reported to exert diverse actions besides hemostasis and thrombus formation in the body. However, whether platelets affect transporter activity remains to be determined. In this study, we examined the effects of platelets on the activity of amino acid transporter system A, which is known to be changed by various factors, and we clarified the mechanism by which platelets affect system A activity. Among system A subtypes, we found that sodium-coupled neutral amino acid transporter (SNAT) 4 played a central role in the transport activity of system A in HuH-7 human hepatoma cells. Interestingly, platelets showed a biphasic effect on system A activity: activated platelet supernatants (APS) including the granule contents released from platelets downregulated system A activity at lower concentrations and the downregulation was suppressed at higher concentrations. The downregulation was due to a decrease in the affinity of SNAT4 for its substrate and not a decrease in the SNAT4 abundance on the plasma membrane. In addition, APS did not decrease the expression level of SNAT4 mRNA. On the other hand, platelets did not affect system A activity when the platelet suspension was added to HuH-7 cells. These results indicate that platelets indirectly affect the transport activity of system A by releasing bioactive substances but do not directly affect it by binding to HuH-7 cells.

Decrease in Mycophenolic Acid Plasma Level by Sacubitril/Valsartan in a Lupus Nephritis Patient: A Case Report.
Shunsuke Nashimoto, Masashi Miyamae, Issei Higuchi, Michihito Kono, Maria Tada, Tatsuya Atsumi, Mitsuru Sugawara, Yoh Takekuma
Case reports in nephrology and dialysis, 14, 1, 30, 35, 2024年, ［査読有り］, ［国際誌］
英語, INTRODUCTION: Mycophenolate mofetil (MMF), an inactive prodrug of mycophenolic acid (MPA), is an immunosuppressive drug used widely in the treatment of lupus nephritis. In this case report, the area under the blood concentration time curve (AUC) of MPA was significantly decreased by the concomitant use of sacubitril/valsartan. CASE PRESENTATION: The patient was a man in his 40s with a diagnosis of lupus nephritis class IVa/c+V. MMF dose was 1.5 g/day at admission, and AUC of MPA on day 14 was 25.1 μg⋅h/mL. Owing to poor blood pressure control, sacubitril/valsartan was initiated at 97/103 mg/day on day 29. On day 37, AUC of MPA was significantly decreased to 8.7 μg⋅h/mL, suggesting drug interaction with the newly initiated sacubitril/valsartan. Sacubitril/valsartan was decreased to 49/51 mg/day, and AUC of MPA on day 67 was 37.6 μg⋅h/mL, achieving the target range. The final MMF dose was set at 1.75 g/day. A possible mechanism of drug interaction between sacubitril/valsartan and MPA involves an organic anion transporting polypeptide (OATP). The inhibition of OATPs by sacubitril may have interrupted the enterohepatic circulation of MPA, resulting in a lower plasma concentration. CONCLUSION: Since lupus nephritis is often associated with hypertension, the drug interaction observed in this report may also occur in other cases. However, it is impossible to conclude that the decrease in plasma MPA levels was due to the concomitant use of sacubitril/valsartan, and more cases and basic findings are needed.

Significantly Delayed Development of Polyarthritis with Active Tenosynovitis after Possible Temporary Neutropenic Immune-Related Adverse Events Caused by Atezolizumab Treatment: A Novel Case Report.
Yoshitaka Saito, Yoh Takekuma, Hajime Asahina, Ryo Hisada, Mitsuru Sugawara
Case reports in oncological medicine, 2024, 1566299, 1566299, 2024年, ［査読有り］, ［最終著者］, ［国際誌］
英語, Immune checkpoint inhibitors have drastically improved cancer treatment. However, they may induce immune-related adverse events (irAEs). Here, we report a case of significantly delayed rheumatic irAEs (Rh-irAEs) with prior possible temporary neutropenic irAEs in a patient with atezolizumab-treated non-small-cell lung cancer and its management. A man in his sixties received atezolizumab monotherapy as the sixth-line treatment. He experienced an infusion-related reaction (fever) during the first cycle. On day 22 of cycle 2, grade 4 neutropenia suddenly appeared, but it disappeared on the next day. Cycle 3 was initiated after seven days; the patient did not exhibit any symptoms for approximately 500 days. However, on day 534 (day 1 of cycle 21), the patient complained of pain in the shoulders, back, and wrists. On day 644, the shoulder and back pain worsened with obvious swelling of the fingers. We thus suspended treatment and consulted a rheumatologist. A diagnosis of polyarthritis with active tenosynovitis was made based on joint ultrasound and laboratory tests. Prednisolone 15 mg attenuated the symptoms, allowing suspension of analgesics; however, dose reduction from 15 mg/day was difficult because of symptom flares. Finally, iguratimod 25 mg twice daily was initiated on day 764; prednisolone was reduced to 10 mg without flares, and its dosage was slowly reduced to 5 mg/day. Although irAEs exhibit multisystem features, delayed development of polyarthritis with active tenosynovitis after possible temporary neutropenic irAEs is rare. Thus, irAEs need to be monitored for a long time in patients with suspected irAE development even if it appears transiently.

Comparison of the incidence of nausea and vomiting between linezolid and vancomycin using claims database: a retrospective cohort study.
Takezo Tsutsumi, Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma
International journal of clinical pharmacy, 46, 2, 421, 428, 2023年12月29日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Nausea and vomiting during linezolid therapy have been reported as part of safety analyses in clinical trials. We have previously examined the incidence of vomiting during linezolid therapy (18.1%). A previous study conducted at a single hospital showed low external validity. It is necessary to verify whether these results can be reproduced using generalizable data sources. AIM: To evaluate the incidence of nausea and vomiting during linezolid therapy compared with vancomycin using a Japanese claims database. METHOD: Patients administered linezolid or vancomycin were selected from the database between January 2005 and June 2017. The primary endpoint was the comparison of nausea and vomiting between the linezolid and vancomycin groups. We conducted propensity score matching (PSM) to adjust for patient characteristics. To assess risk factors for nausea and vomiting, logistic regression was conducted as the secondary endpoint. We defined nausea and vomiting as the first prescription of antiemetics during linezolid or vancomycin therapy as a surrogate endpoint. RESULTS: In total, 1215 patients were enrolled. After PSM, the number of patients in the linezolid and vancomycin groups was 241. Nausea and vomiting were observed in 11.2% and 5.0% of patients in the linezolid and vancomycin groups, respectively (p < 0.05). Linezolid administration was extracted as a risk factor for nausea and vomiting (odds ratio, 2.09; 95% confidence interval, 1.02-4.30). CONCLUSION: This study clarified the relationship between linezolid and nausea and vomiting using a Japanese claims database. Further studies are required to elucidate the unknown mechanisms of linezolid-induced nausea and vomiting.

Palonosetron for prevention of delayed chemotherapy-induced nausea and vomiting in pediatric patients: a meta-analysis
Atsushi Yamaguchi, Yoshitaka Saito, Yoh Takekuma, Mitsuru Sugawara
Supportive Care in Cancer, 32, 1, 58, 58, Springer Science and Business Media LLC, 2023年12月26日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) are common adverse events in patients undergoing emetogenic chemotherapy. Palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA), has demonstrated non-inferiority to first-generation 5-HT3 RAs for CINV in pediatric patients. Although palonosetron has a long half-life and prolonged antiemetic action, its efficacy against delayed CINV in pediatric patients is not well understood. Therefore, this meta-analysis of randomized controlled trials (RCTs) aimed to evaluate the efficacy of palonosetron for delayed CINV in pediatric patients. METHODS: A literature search of MEDLINE/PubMed, Embase, Cochrane Library, and Web of Science databases was performed. A meta-analysis was performed using forest plots, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. A funnel plot was constructed to explore publication bias. RESULTS: The literature search retrieved 842 records, of which 23 full-text articles were assessed, including six RCTs. Meta-analysis of four RCTs that reported on the complete response (CR: defined as no emesis and no rescue medication) rate for delayed CINV revealed that palonosetron was statistically superior to first-generation 5-HT3 RAs (RR = 1.21 [95% CI 1.09-1.35]; p < 0.01). Although the number of studies included was small, no publication bias was observed in the funnel plots. In addition, the CR rate for overall and acute CINV was also significantly higher for palonosetron (RR = 1.25 [95% CI 1.01-1.54]; p = 0.04 and RR = 1.06 [95% CI 1.01-1.12]; p = 0.03, respectively). CONCLUSION: Palonosetron is effective in the prophylaxis of delayed CINV in pediatric patients.

Evaluation of the additional prophylactic effect of topical steroid ointment to systemic minocycline against anti-epidermal growth factor antibody-induced skin toxicities in metastatic colorectal cancer treatment.
Yoshitaka Saito, Kazuki Uchiyama, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32, 1, 8, 8, 2023年12月06日, ［査読有り］, ［最終著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Anti-epidermal growth factor receptor (EGFR) antibodies often cause skin toxicities. Preemptive skin treatments using systemic antibiotics with or without topical steroid are reportedly effective although the most suitable method remains unclear. This study aimed to determine whether combination prophylaxis using systemic minocycline and topical steroid is superior to minocycline alone in a real-world metastatic colorectal cancer (mCRC) treatment. METHODS: Patients with mCRC (n = 87) who received anti-EGFR monoclonal antibodies were retrospectively assessed. The primary objective was to compare the incidence of grade ≥ 2 overall skin toxicities during all treatment periods between the control group receiving prophylactic minocycline 100 mg/day, and the combination prophylaxis group receiving minocycline 100 mg/day + topical steroid. The incidence of each skin symptom was also evaluated. RESULTS: The incidence of grade ≥ 2 overall skin toxicities was 63.6% in the control and 56.9% in the combination groups, with no significant difference (P = 0.63). Similarly, the incidence of grade ≥ 2 dry skin, fissures, paronychia, and pruritus did not significantly differ. In addition, incidence of all-grade skin toxicities was not different. However, the incidence of grade ≥ 2 papulopustular rashes was significantly lower in the combination group (23.1% vs. 50.0%, P = 0.03). Propensity score-matched analysis supported these results. Multivariate logistic regression analysis showed no significant association between combination prophylaxis and grade ≥ 2 overall skin toxicities, but it did show a reduction in grade ≥ 2 papulopustular rashes. CONCLUSION: Adding topical steroids to systemic minocycline did not mitigate grade ≥ 2 overall skin toxicities induced by anti-EGFR antibodies; however, it significantly improved papulopustular rashes.

Detection of factors related to treatment reduction in docetaxel and ramucirumab for non-small cell lung cancer treatment.
Yoshitaka Saito, Shinya Tamaki, Daisuke Hirate, Shinya Takada, Kenta Takahashi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
Scientific reports, 13, 1, 19457, 19457, 2023年11月09日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Treatment using docetaxel (DOC) and ramucirumab (RAM) is an effective regimen in second or later line advanced non-small cell lung carcinoma (NSCLC) treatment. However, it induces severe adverse effects, resulting in treatment reduction such as dose reduction and/or discontinuation. This study aimed to reveal the factor(s) associated with treatment reduction in DOC + RAM. We retrospectively evaluated patients with advanced NSCLC (n = 155). Treatment reduction of the second course due to severe adverse effects was conducted in 25.8% of the participants, and relative dose intensity at the second course was 95.7 ± 8.4% for DOC and 91.9 ± 24.8% for RAM. Multivariate logistic regression analyses identified that baseline anemia and prophylactic granulocyte colony-stimulating factor (G-CSF) administration are preventive factors for the reduction (adjusted odds ratio, 0.29; 95% confidence interval, 0.12-0.66; P = 0.004 for baseline anemia, 0.18; 0.08-0.42; P < 0.0001 for prophylactic G-CSF administration). The primary cause of the reduction was febrile neutropenia, and the same factors were identified. Our study revealed that patients with baseline anemia and prophylactic G-CSF administration have less risk for treatment reduction in DOC + RAM for NSCLC treatment.

Risk factor analysis for cisplatin-induced nephrotoxicity with the short hydration method in diabetic patients.
Yoshitaka Saito, Masaki Kobayashi, Shinya Tamaki, Katsuyuki Nakamura, Daisuke Hirate, Kenta Takahashi, Yoh Takekuma, Jun Sakakibara-Konishi, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
Scientific reports, 13, 1, 17126, 17126, 2023年10月10日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, The occurrence of cisplatin (CDDP)-induced nephrotoxicity (CIN) has decreased with advancements in supportive care. In contrast, we reported that baseline diabetes mellitus (DM) complications significantly worsen CIN. This study aimed to determine further risk factors associated with CIN development in DM patients. Patients with thoracic cancer requiring DM pharmacotherapy, who received CDDP (≥ 60 mg/m2)-containing regimens using the short hydration method (n = 140), were enrolled in this retrospective multicenter observational study. The primary endpoint of the present study was the elucidation of risk factors (patient factors, DM medication influence, and treatment-related factors) associated with CIN development in patients with DM. Cisplatin-induced nephrotoxicity occurred in 22.1% of patients with DM. The median worst variation of serum creatinine levels and creatinine clearance (worst level - baseline level) was 0.16 mg/dL (range: - 0.12-1.41 mg/dL) and - 15.9 mL/min (- 85.5-24.3 mL/min), respectively. Multivariate logistic regression analyses identified female sex as the singular risk factor for CIN development in the DM population (adjusted odds ratio; 2.87, 95% confidence interval; 1.08-7.67, P = 0.04). Diabetes mellitus medication and treatment-related factors did not affect CIN development. In conclusion, our study revealed that female sex is significantly associated with CIN development in patients with DM and thoracic cancer.

Quantitative analysis of communication changes in online medication counseling -Using the Roter Interaction Analysis System.
Ayako Mori, Izumi Kato, Katsuya Narumi, Yoh Takekuma, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Masaki Kobayashi
Research in social & administrative pharmacy : RSAP, 20, 1, 36, 42, 2023年10月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Quantitative analysis and objective evaluation of communication play an important role in medical communication education. In the process of developing an online methodology for medication counseling practice, we felt the necessity of conducting a quantitative evaluation to enhance its effectiveness. OBJECTIVES: This study aimed to quantitatively evaluate the communication in each scenario to comprehensively identify the differences between face-to-face and online communication in medication counseling practicum. In addition, we examined how patient satisfaction changes between face-to-face and online interactions. METHODS: Face-to-face and online role-playing were conducted between simulated patients (SPs) and students acting as pharmacists, and their dialogues were videotaped. The utterances in each recorded dialogue were categorized and analyzed by the Roter interaction analysis system (RIAS). The Japanese version of the Medical Interview Satisfaction Scale (MISS-21J) responses of the SPs were analyzed for the patient satisfaction survey. RESULT: The results of the RIAS analysis revealed that the socio-emotional category appeared significantly more frequently in face-to-face communication, with more utterances that were more attuned to the feelings of the other person and more considerate of his or her feelings. The ratio of the number of utterances between students and SPs suggested that the communication was more interactive. CONCLUSION: Based on the respective communication tendencies may have led to higher satisfaction in face-to-face than in online patient satisfaction surveys, less anxiety about illness and medications, and easier trusting relationships. Since it is difficult to grasp the mood of the other party and to open up to them due to the lack of nonverbal information in online dialogue, it is necessary to be more conscious of conversations that capture the feelings of patients in online medication counseling.

Development of a risk prediction model for surgical site infection after lower third molar surgery.
Akira Yamagami, Katsuya Narumi, Yoshitaka Saito, Ayako Furugen, Shungo Imai, Yoshimasa Kitagawa, Yoichi Ohiro, Ryo Takagi, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi
Oral diseases, 2023年09月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There is little evidence regarding risk prediction for surgical site infection (SSI) after lower third molar (L3M) surgery. METHODS: We conducted a nested case-control study to develop a multivariable logistic model for predicting the risk of SSI after L3M surgery. Data were obtained from Hokkaido University Hospital from April 2013 to March 2020. Multiple imputation was applied for the missing values. We conducted decision tree (DT) analysis to evaluate the combinations of factors affecting SSI risk. RESULTS: We identified 648 patients. The final model retained the available distal space (Pell & Gregory II [p = 0.05], Pell & Gregory III [p < 0.01]), depth (Pell & Gregory B [p < 0.01], Pell & Gregory C [p < 0.01]), surgeon's experience (3-10 years [p = 0.25], <3 years [p < 0.01]), and simultaneous extraction of both L3M [p < 0.01]; the concordance-statistic was 0.72. The DT analysis demonstrated that patients with Pell and Gregory B or C and simultaneous extraction of both L3M had the highest risk of SSI. CONCLUSIONS: We developed a model for predicting SSI after L3M surgery with adequate predictive metrics in a single center. This model will make the SSI risk prediction more accessible.

Factors associated with household transmission of SARS-CoV-2 omicron variant to health care workers: A retrospective cohort study.
Keisuke Kagami, Reiko Oyamada, Tsubasa Watanabe, Sho Nakakubo, Takahiro Hayashi, Sumio Iwasaki, Tatsuya Fukumoto, Takayuki Usami, Kasumi Hayasaka, Shinichi Fujisawa, Chiaki Watanabe, Mutsumi Nishida, Takanori Teshima, Yusuke Niinuma, Isao Yokota, Yoh Takekuma, Mitsuru Sugawara, Nobuhisa Ishiguro
International journal of nursing practice, 29, 5, e13195, 2023年08月24日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIM: The aim of this study was to determine the risk factors for household transmission of the omicron variant of SARS-CoV-2. BACKGROUND: The household infection rate has been reported to be higher for the omicron variant than for non-omicron variants of SARS-CoV-2. Determination of the risk factors for household transmission of the omicron variant is therefore important. DESIGN: A Retrospective Cohort Study was conducted. METHODS: When family members of health care workers (HCWs) were found to be infected with SARS-CoV-2, the HCWs had to receive two nucleic acid amplification tests for SARS-CoV-2: immediately after and 5 to 10 days after the onset of COVID-19 in the family members. Risk factors of household transmission were analysed by comparing cases (HCWs infected with SARS-CoV-2) and controls (HCWs not infected with SARS-CoV-2) using multivariable analysis. RESULTS: Unvaccinated status (OR: 3.97), age of index cases (≤6 years) (OR: 1.94) and staying at home with index cases (OR: 10.18) were risk factors for household transmission. CONCLUSION: If there is a strong desire to avoid household infection, family members infected with SARS-CoV-2 should live separately during the period of viral shedding.

Risk factor analysis for anti-epidermal growth factor receptor monoclonal antibody-induced skin toxicities in real-world metastatic colorectal cancer treatment.
Yoshitaka Saito, Kazuki Uchiyama, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 31, 8, 504, 504, 2023年08月02日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are effective in treating RAS wild-type metastatic colorectal cancer (mCRC). However, their administration induces skin toxicity, markedly reducing patients' quality of life. This study is aimed at identifying the risk factors associated with anti-EGFR monoclonal antibody-induced skin toxicities. METHODS: Patients with mCRC (n = 116) who received anti-EGFR monoclonal antibody treatment were retrospectively evaluated. Primary endpoint was evaluation of the risk factors for grade ≥ 2 overall skin toxicities during all the treatment periods. Furthermore, factors associated with each grade ≥ 2 skin symptoms were assessed. RESULTS: Incidence of total grade ≥ 2 skin toxicity symptoms was 61.2%, and those of grade ≥ 2 rash, dry skin, fissures, and paronychia were 34.5%, 25.9%, 20.7%, and 25.0%, respectively. Multivariate logistic regression analyses revealed that liver metastasis was an independent risk factor for overall grade ≥ 2 skin toxicities (adjusted odds ratio [OR], 2.88; 95% confidence interval [CI], 1.22-6.78; P = 0.02) and prophylactic administration of antibiotics as a preventive factor (OR 0.10; 95%CI 0.01-0.91; P = 0.04). For grade ≥ 2 rash, prophylactic use of systemic antibiotics and topical steroid ointment was a preventive factor (OR 0.37; 95%CI 0.16-0.89; P = 0.03). Moreover, liver metastasis (OR 8.37; 95%CI 1.98-35.47; P = 0.004) and prophylactic administration of antibiotics (OR 0.15; 95%CI 0.03-0.76; P = 0.02) were significantly associated with grade ≥ 2 paronychia. CONCLUSION: Liver metastasis was suggested to be a risk factor for the incidence of overall grade ≥ 2 skin toxicities; moreover, preemptive systemic antibiotic administration drastically decreased this risk during all periods of anti-EGFR treatment for mCRC.

Correlation between antibiotic use and resistance of gram-negative bacteria at a university hospital in Japan from 2013 to 2021: a study using the Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system.
Keisuke Kagami, Nobuhisa Ishiguro, Sumio Iwasaki, Keisuke Taki, Tatsuya Fukumoto, Kasumi Hayasaka, Reiko Oyamada, Tsubasa Watanabe, Sho Nakakubo, Yusuke Niinuma, Mitsuru Sugawara, Yoh Takekuma
European journal of hospital pharmacy : science and practice, 2023年07月12日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVES: The Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system aggregates information related to antimicrobial resistance (AMR) measures. We aimed to investigate the correlation between antibiotic use and AMR at a university hospital from 2013 to 2021 in a time series analysis using the J-SIPHE system. We also studied this correlation in each ward (inter-ward analysis). METHODS: Data on antibiotic use and resistance rates were collected from the J-SIPHE system, except for the resistance rate in each ward, which was calculated from the source data prepared for this system. RESULTS: Piperacillin/tazobactam use was positively correlated with piperacillin/tazobactam resistance in Escherichia coli and Klebsiella pneumoniae in the inter-ward analysis, and in Pseudomonas aeruginosa in both analyses. Carbapenem use was positively correlated with meropenem resistance in Enterobacter cloacae in the time series analysis and in P. aeruginosa in both analyses, and imipenem/cilastatin resistance in P. aeruginosa in inter-ward analysis. Quinolone use was positively correlated with levofloxacin resistance in E. coli in both analyses, and in K. pneumoniae in inter-ward analysis. CONCLUSIONS: This is the first study to investigate the correlation between antibiotic use and AMR at a single hospital in time series and inter-ward analyses using the J-SIPHE system and data prepared for this system, suggesting that this system may be useful for promoting AMR measures.

Acid suppressants reduce the therapeutic effect of immune checkpoint inhibitors and increase the risk of acute kidney injury: a meta-analysis
Keisuke Okamoto, Yoshitaka Saito, Atsushi Yamaguchi, Yoh Takekuma, Mitsuru Sugawara
International Journal of Clinical Oncology, 28, 10, 1343, 1353, Springer Science and Business Media LLC, 2023年07月08日, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Immune checkpoint inhibitors (ICIs) are used in cancer immunotherapy; however, they can lead to immune-related adverse events (irAEs) through immune function of patients. Therefore, this meta-analysis aimed to assess the concomitant effect of acid suppressants (ASs) on ICIs, including several subgroup analyses. METHODS: We identified related studies and generated the forest plot. The primary endpoint was defined as the change in progression free survival (PFS) and overall survival (OS) with or without ASs administration. We also evaluated the effect of ASs on the incidence of irAEs. RESULTS: The total hazard ratio (HR) of ASs on PFS with ICI treatment was 1.39 and the 95% confidence interval (95% CI) was 1.21-1.59 (Z: p < 0.00001). Moreover, the total HR of ASs on OS was 1.40 and the 95% CI was 1.21-1.61 (Z: p < 0.00001), suggesting that ASs reduced ICI's therapeutic effect. The total odds ratio (OR) for evaluating the effect of ASs on irAEs was 1.23 with a 95% CI of 0.81-1.88 (Z: p = 0.34). However, ASs significantly worsened acute kidney injury (AKI) (total OR 2.10; 95% CI 1.74-2.53 (Z, p < 0.00001)). Furthermore, although proton pump inhibitors (PPIs) reduced ICI's therapeutic effect, histamine H2-receptor antagonists (H2RAs) did not affect OS. CONCLUSIONS: It was shown that ASs, especially PPIs, reduced ICI's therapeutic effect, while H2RAs had no effect, and ASs did not affect irAEs; however, it is a risk factor for ICIs-induced AKI.

Monitoring Salivary Concentrations of Tedizolid and Linezolid Using Rats
Yuki Inoue, Yuki Sato, Hitoshi Kashiwagi, Shunsuke Nashimoto, Mitsuru Sugawara, Yoh Takekuma
European Journal of Drug Metabolism and Pharmacokinetics, 48, 4, 387, 395, Springer Science and Business Media LLC, 2023年06月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND AND OBJECTIVE: Therapeutic drug monitoring (TDM) is an effective tool for the management of patients who are administered linezolid. The use of saliva for TDM has potential advantages over the use of plasma; however, only a few reports have compared drug concentrations in the saliva and plasma. Moreover, there are no reports on the salivary concentration of tedizolid, an oxazolidinone antibiotic similar to linezolid. In the present study, the concentrations of tedizolid and linezolid in rat submandibular saliva were compared with those measured in the plasma. METHODS: Tedizolid (10 mg/kg, n = 6) and linezolid (12 mg/kg, n = 5) were administered via the rat tail vein. Submandibular saliva and plasma samples were collected for up to 8 h after the initiation of drug administration, and assayed for the concentrations of tedizolid and linezolid. RESULTS: A strong correlation was found between the saliva and plasma concentrations of tedizolid (r = 0.964, p < 0.001) and linezolid (r = 0.936, p < 0.001). The value of tedizolid maximum concentration of drug (Cmax) was 0.99 ± 0.08 µg/mL in the saliva and 14.46 ± 1.71 µg/mL in the plasma. Meanwhile, the Cmax of linezolid was 8.01 ± 1.42 µg/mL in the saliva and 13.00 ± 1.90 µg/mL in the plasma. According to these results, the saliva/plasma concentration ratios of tedizolid and linezolid in rats were 0.0513 ± 0.0080 and 0.6341 ± 0.0339, respectively. CONCLUSIONS: Considering the correlation between saliva and plasma concentrations of tedizolid and linezolid, as well as the characteristics of saliva, the results of this study suggest that saliva is a useful matrix for TDM.

Impact of systemic dexamethasone dosage on docetaxel-induced oral mucositis in patients with breast cancer.
Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Tomohiro Oshino, Mitsuru Sugawara
Scientific reports, 13, 1, 10169, 10169, 2023年06月22日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Oral mucositis (OM) is a common adverse effect of docetaxel-containing treatment. This study aimed to assess whether dexamethasone (DEX) dose-dependently attenuates docetaxel-induced OM and dysgeusia. We retrospectively analyzed medical records of patients with breast cancer receiving docetaxel-containing regimens at Hokkaido University Hospital between June 2015 and June 2022. The patients were divided into low-dose and high-dose groups (DEX 4 or 8 mg/day on days 2-4, respectively), and incidence of OM and dysgeusia, and risk factor(s) for OM incidence were evaluated. The incidence of all-grade OM in the first cycle was 57.8% in the low-dose group and 19.2% in the high-dose group (P = 0.0002), which met our primary endpoint. The incidence of OM in all treatment cycles was also significantly lowered by DEX-dose increase (P = 0.01). In contrast, the incidence of dysgeusia was similar between the two groups in the first and all cycles (P = 0.50 and P = 0.28, respectively). These results were also confirmed in a propensity score-matched population. Multivariate logistic regression analysis also suggested that lower DEX dosage was a singular risk factor for all-grade OM incidence. In conclusion, our study suggests that DEX dose-dependently reduces the incidence of OM in docetaxel-containing regimens for breast cancer treatment.

Severe hypertension development significantly improves progression-free survival in regorafenib treatment for metastatic colorectal cancer.
Yoshitaka Saito, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
International journal of clinical oncology, 28, 9, 1183, 1190, 2023年06月15日, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, PURPOSE: Regorafenib is the first multikinase inhibitor used for metastatic colorectal cancer (mCRC) treatment. Reports regarding other multikinase inhibitors have suggested that the development of hypertension is associated with improved clinical benefits. We aimed to reveal the relationship between the development of severe hypertension and regorafenib efficacy in an mCRC real-world setting. METHODS: Patients with mCRC (n = 100) who received regorafenib were assessed retrospectively. The primary endpoint was a comparison of progression-free survival (PFS) between patients with and without ≥ grade 3 hypertension. The secondary endpoints were overall survival (OS), disease control rate (DCR), and adverse effects. RESULTS: Patients developing ≥ grade 3 hypertension accounted for 30%, and obtained significantly longer PFS than control patients (median PFS of 53 and 56 days, 95% confidence interval [CI] of 46-144 and 49-63 days, respectively; P = 0.04). In contrast, OS and DCR were not statistically different between the groups (P = 0.13 and P = 0.46, respectively). The incidence and severity of adverse effects were not significantly different, except for hypertension. Treatment interruption was significantly more frequent in patients with hypertension (P = 0.04). Multivariate Cox hazard analysis suggested that the development of ≥ grade 3 severe hypertension was an independent factor for improved PFS (adjusted hazard ratio 0.57, 95% CI 0.35-0.93; P = 0.02). In contrast, baseline hypoalbuminemia was associated with a worse PFS (1.85, 1.14-3.01; P = 0.01). CONCLUSION: We have revealed that patients who develop severe hypertension after regorafenib treatment for mCRC have improved PFS. Management of hypertension is important for effective treatment with less burden; therefore, further evaluation is needed.

High dose of dexamethasone attenuates docetaxel-induced fluid retention in breast cancer treatment.
Yoshitaka Saito, Ryota Kanno, Yoh Takekuma, Takashi Takeshita, Tomohiro Oshino, Mitsuru Sugawara
Scientific reports, 13, 1, 9247, 9247, 2023年06月07日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Docetaxel-induced fluid retention (DIFR) cumulatively occurs and is one of the most troublesome adverse effects. This study aimed to determine whether high dose dexamethasone (DEX) could prevent DIFR during breast cancer treatment. Breast cancer patients receiving docetaxel (75 mg/m2)-containing regimens were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2-4 and retrospectively assessed. Incidence of greater than or equal to grade 2 DIFR was significantly lower in the 8 mg group (13.0%) compared to the 4 mg group (39.6%, P = 0.001). All-grade DIFR was also less in the 8 mg group (P = 0.01). Furthermore, the maximum variation of body weight was significantly lower in the 8 mg group (P = 0.0003). These results were also confirmed in the propensity score-matched population. Additionally, time-related DIFR incidence was also significantly delayed in the 8 mg group (P = 0.0005). Our study revealed that high dose DEX prevents DIFR. Therefore, further studies on its management are required for less onerous chemotherapy provision with better DIFR control.

Dexamethasone dose-dependently prevents taxane-associated acute pain syndrome in breast cancer treatment.
Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Tomohiro Oshino, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 31, 6, 372, 372, 2023年06月03日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Taxane-associated acute pain syndrome (T-APS) is one of the most bothersome adverse effects caused by taxanes. We have previously reported the attenuating effect of dexamethasone (DEX) on T-APS and its risk factors under DEX prophylaxis. However, the appropriate DEX dosage administration remains unclear. Therefore, this study aimed to investigate whether DEX dose-dependently prevents T-APS in breast cancer patients. METHODS: We retrospectively evaluated patients with breast cancer who received docetaxel (75 mg/m2)-containing chemotherapy without pegfilgrastim and regular non-steroidal anti-inflammatory drugs. The patients were divided into 4 mg/day and 8 mg/day DEX groups, with each DEX dosage on days 2-4 (n = 68 for each group). Primary endpoint was the comparison of all-grade T-APS incidence between the groups. Propensity score-matching was performed to adjust the baseline factors between the groups, and outcomes in the matched-population were also assessed. RESULTS: The incidence of all-grade T-APS was 72.1% in 4 mg/day group and 48.5% in 8 mg/day group, which was significantly lowered by higher DEX dosage (P = 0.008). The severity of T-APS was also significantly reduced in 8 mg/day group (P = 0.02). These results were confirmed in the propensity score matching. Multivariate logistic analysis showed that higher DEX dosage was an independent T-APS preventive factor, whereas age < 55 years was a risk factor. Moreover, DEX-dosage-associated adverse effects similarly appeared in both groups. CONCLUSION: Our study suggested that DEX dose-dependently prevents T-APS in breast cancer treatment. As understanding of the nature of T-APS and its appropriate management can significantly contribute to less onerous chemotherapy provision, further studies are required.

Cyclosporine A乳剤ならびに自己乳化型製剤の特性と経口吸収性評価　　　　　　　　　　　　　　　
佐藤 夕紀, 木下 祐介, 上村 聡, 丸山 真吾, 武隈 洋, 菅原 満
日本薬剤学会年会講演要旨集, 38年会, 171, 171, (公社)日本薬剤学会, 2023年05月
日本語

医薬品の在庫管理における医療機器の導入効果　　　　　　　　　　　　　　　
山崎 浩二郎, 久保田 康生, 川岸 亨, 武隈 洋, 菅原 満
北海道病院薬剤師会誌, 104, 17, 19, (一社)北海道病院薬剤師会, 2023年04月, ［最終著者, 責任著者］
日本語

Efficacy of antacids for cisplatin-induced gastrointestinal symptoms in the treatment of lung cancer.
Osamu Taniguchi, Yoshitaka Saito, Yoh Takekuma, Hirotoshi Akita, Ichiro Kinoshita, Yasushi Shimizu, Naofumi Shinagawa, Mitsuru Sugawara
International journal of clinical pharmacology and therapeutics, 61, 6, 246, 254, 2023年03月27日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Chemotherapy-induced nausea and vomiting (CINV) and chemotherapy-associated dyspepsia syndrome (CADS) are frequently appearing adverse effects of cisplatin (CDDP)-containing chemotherapy. Antiemetic guidelines suggest that the administration of antacids such as proton pump inhibitors (PPIs) or histamine type-2 receptor antagonists be considered for CADS, although their efficacy for treating these symptoms remains unknown. This study aimed to reveal whether antacids attenuate gastrointestinal symptoms in CDDP-containing chemotherapy. MATERIALS AND METHODS: In total, 138 patients with lung cancer who received ≥ 75 mg/m2 CDDP-containing regimens were enrolled in this retrospective study. Patients were divided into an antacid group including patients administered PPIs or vonoprazan during all chemotherapy periods and controls without antacid administration. The primary endpoint was the comparison of anorexia incidence during the first cycle of chemotherapy. Secondary endpoints were CINV evaluation and risk factor analysis for the incidence of anorexia using logistic regression analysis. RESULTS: The incidence of anorexia during the first cycle was 54.4% in the control group and 60.3% in the antacid group, without significant differences (p = 0.60). The incidence of nausea was also similar between the groups (p = 1.00). Multivariate analysis suggested that antacid administration was not associated with anorexia. CONCLUSION: Baseline antacid administration does not affect gastrointestinal symptoms associated with CDDP-containing treatment in lung cancer.

Onset timing and duration of augmented renal clearance in a mixed intensive care unit.
Ryusei Mikami, Mineji Hayakawa, Shungo Imai, Mitsuru Sugawara, Yoh Takekuma
Journal of intensive care, 11, 1, 13, 13, 2023年03月23日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Augmented renal clearance (ARC) is associated with lower blood plasma concentrations of renally excreted drugs; however, its time course is unknown. The current study aimed to determine the onset timing/duration of ARC, its risk factors, and its association with clinical outcomes by continuous monitoring of urinary creatinine clearance (CrCl) in critically ill patients. METHODS: Data were retrospectively obtained from the medical records of 2592 critically ill patients admitted to the intensive care unit (ICU) from January 2019 to June 2022 at a tertiary emergency hospital. Among these, patients with continuously measured urinary CrCl were selected and observed over time. We evaluated the onset timing and duration of ARC by plotting Kaplan-Meier curves. Furthermore, by multivariate analyses, factors associated with the onset and persistence of ARC were analyzed, and the association between the ARC time course and clinical outcomes was evaluated. RESULTS: The prevalence of ARC was 33.4% (245/734). ARC onset was within 3 days of admission in approximately half of the cases, and within 1 week in most of the other cases. In contrast, the persistence duration of ARC varied widely (median, 5 days), and lasted for more than a month in some cases. Multivariate analysis identified younger age, male sex, lower serum creatinine at admission, admission with central nervous system disease, no medical history, use of mechanically assisted ventilation, and vasopressor use as onset factors for ARC. Furthermore, factors associated with ARC persistence such as younger age and higher urinary CrCl on ARC day 1 were detected. The onset of ARC was significantly associated with reduced mortality, but persistent of ARC was significantly associated with fewer ICU-free days. CONCLUSIONS: Despite the early onset of ARC, its duration varied widely and ARC persisted longer in younger patients with higher urinary CrCl. Since the duration of ARC was associated with fewer ICU-free days, it may be necessary to consider a long-term increased-dose regimen of renally excreted drugs beginning early in patients who are predicted to have a persistent ARC.

Usefulness of the Albumin–Bilirubin Score in Determining the Initial Dose of Voriconazole for Patients with Liver Cirrhosis
Shunsuke Nashimoto, Shungo Imai, Mitsuru Sugawara, Yoh Takekuma
Biological and Pharmaceutical Bulletin, 46, 2, 230, 236, Pharmaceutical Society of Japan, 2023年02月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The Child-Pugh score is widely used to assess liver function and estimate drug clearance in patients with liver cirrhosis. Recently, the albumin-bilirubin (ALBI) score, which objectively assesses liver function based only on albumin and total bilirubin levels, was developed as a new method. The purpose of this study was to analyze the relationship between the liver function assessment method and the plasma concentration of voriconazole (VRCZ), an antifungal drug for patients with liver cirrhosis. This single-center retrospective study enrolled 159 patients who received VRCZ between 2012 and 2020. In patients administered VRCZ orally, the median concentration to dose (C : D) ratio increased with the progression of Child-Pugh and ALBI grades. Positive correlations between the ALBI score and VRCZ C : D ratio were observed in patients with cirrhosis (r = 0.52 (95% confidence interval, 0.069-0.79); p < 0.05). In addition, a highly negative correlation was observed between the ALBI score and VRCZ daily maintenance dose (r=-0.79 (95% confidence interval, -0.92 to -0.50); p < 0.0001). In contrast, for patients administered VRCZ intravenously, no increase in C : D ratio was observed for both Child-Pugh and ALBI scores compared to the non-liver cirrhosis group. This may be because the injection is often used in severely ill patients, and factors other than impaired liver function may affect the plasma concentrations of VRCZ. In conclusion, the ALBI score was shown to be useful in predicting VRCZ clearance as well as the Child-Pugh score, and the initial dose of VRCZ might be determined according to the ALBI score.

Use of Japanese big data from electronic medical records to investigate risk factors and identify their high-risk combinations for linezolid-induced thrombocytopenia.
Yuki Inoue, Yoh Takekuma, Takayuki Miyai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Shungo Imai
European journal of clinical pharmacology, 79, 3, 415, 425, 2023年01月30日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Thrombocytopenia is a major event associated with linezolid (LZD) therapy. Factors affecting LZD-induced thrombocytopenia (LIT) have been reported in previous studies. However, several issues pertaining to LIT have not yet been clarified. In the present study, we used Japanese big data to investigate associated factors and their high-risk combinations that influence LIT. METHODS: Patients administered LZD between May 2006 and October 2020 were included in this study. LIT was defined as either a 30% or more reduction from the baseline platelets or platelet values of < 100,000/µL. We evaluated factors affecting LIT and combinations of factors that alter LIT risk according to a decision tree (DT) analysis, a typical machine learning method. RESULTS: We successfully enrolled 1399 patients and LIT occurred in 44.7% of the patients (n = 626). We classified the laboratory data on renal function, LZD duration, age, and body weight (BW) into smaller categories. The results of multivariate analysis showed that prolonged LZD therapy, BW < 45 kg, estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, and dialysis were risk factors for LIT. The DT analysis revealed that the highest risk was a combination of LZD duration ≥ 14 days and eGFR < 30 mL/min/1.73 m2. CONCLUSIONS: The present study extracted four risk factors and identified high-risk combinations for LIT. Patients with these risk factors should be closely monitored.

Prediction and Implications of Edoxaban-Associated Bleeding in Patients after Critical Illness
Ryusei Mikami, Mineji Hayakawa, Shungo Imai, Kunihiko Maekawa, Kojiro Yamazaki, Mitsuru Sugawara, Yoh Takekuma
Journal of Clinical Medicine, 12, 3, 860, 860, MDPI AG, 2023年01月21日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, In this retrospective study, we aimed to identify the risk factors for bleeding in patients after critical illness during edoxaban treatment. Data from patients who received edoxaban after critical illness at the Emergency Department at a tertiary care hospital were obtained from the hospital medical records. Multivariate analysis revealed the risk factors for edoxaban-associated bleeding. Additionally, we developed an edoxaban-associated bleeding score (EAB score) based on these results. The derived EAB score was compared with the HAS-BLED score using receiver operating characteristic (ROC) curve analysis. Bleeding was observed in 42 of 114 patients (36.8%). We identified the following bleeding predictors (odds ratios, 95% confidence interval, score points) using multivariate analysis: concomitant use of antiplatelet agents (6.759, 2.047–22.32, 2 points), concomitant use of P-glycoprotein inhibitors (3.825, 1.484–9.856, 1 point), prothrombin time (PT)% following edoxaban administration of <75% and ≥60% (2.507, 0.788–7.970, 1 point), and PT% following edoxaban administration of <60% (11.23, 3.560–35.42, 3 points). The ROC curve analysis revealed an area under the curve of 0.826 for the EAB score and 0.625 for the HAS-BLED score. Under appropriate edoxaban dosing regimens in patients after critical illness, a combination of antiplatelet agents, P-gp inhibitors, and a low PT% following edoxaban administration were identified as strong risk factors for bleeding.

Effects of Body Composition on Renal Function Estimates in Older Patients.
Soyoko Kaburaki, Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma
Biological & pharmaceutical bulletin, 46, 11, 1609, 1618, 2023年, ［国内誌］
英語, 研究論文（学術雑誌）, The modified Cockcroft-Gault (CG) equation, previously developed for an aged-oriented cohort, was validated in a newly obtained dataset. Estimates of creatinine clearance (CCr) using this equation were found to be more accurate than those determined using the conventional CG equation, particularly for patients exceeding 65 years of age. We identified a subset of patients in this cohort whose estimates were inadequate. Using statistical analysis, we found that the deviation from estimates was attributed to a decreased albumin level. In addition, we determined a reduced albumin cutoff value for the modified CG equation to obtain a good estimate. Univariate linear regression analysis was applied to measure the CCr in this cohort and identify parameters related to body composition, and we found that extracellular water (ECW)/total body water (TBW) and body fat (%) were relevant. Using measured values of ECW/TBW and body fat (%), a multivariate linear regression (MLR) estimating equation was developed based on the modified CG equation. This equation was applied to a cohort over 65 years of age, and it was found that a good estimate was obtained for older patients with low albumin levels. Thus, we propose a flow diagram that illustrates conditions for selecting an appropriate estimating equation from among the CG, modified CG, and MLR equations.

Temporary Severe Neutropenia during Administration of Atezolizumab: A Novel Case Report.
Ryota Kanno, Yoshitaka Saito, Yoh Takekuma, Hajime Asahina, Mitsuru Sugawara
Case reports in oncology, 16, 1, 372, 377, 2023年, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, Here, we describe a case of temporary severe neutropenia after atezolizumab monotherapy and its treatment course. Atezolizumab monotherapy was introduced as a 6th-line treatment for a man in his late 60s, who was diagnosed with stage Ⅳ lung adenocarcinoma. The first treatment cycle was administered during hospitalization, and the patient presented with a fever of 37.8°C on the first day. The fever resolved after the administration of acetaminophen and naproxen, and the white blood cell count, neutrophil count, and other white blood cell fractions were normal. However, grade 3 leukopenia and grade 4 neutropenia appeared at the beginning of the third cycle, and treatment was discontinued. After treatment, monocyte count in the leukocyte fraction increased from approximately 10% to 25.6%. Lenograstim 100 μg subcutaneous injection and oral levofloxacin 500 mg once daily were started of onset of neutropenia, and he was hospitalized the next day. Laboratory findings upon admission showed a significant improvement to 5,300/µL for leukocytes and 3,376/µL for neutrophils. Lenograstim was discontinued, with no further decrease in the neutrophil count. Atezolizumab therapy was resumed, and there was no further reduction in leukocyte, neutrophil, or leukocyte fractions over about a 2-year period. Concomitant drugs were maintained during the atezolizumab treatment, suggesting that they did not induce neutropenia. In conclusion, we observed temporary severe neutropenia during atezolizumab monotherapy. Neutrophil recovery with cautious monitoring has enabled longer efficacy. We should consider temporary symptom occurrence in cases of haematological immune-related adverse events.

Gefitinib-induced Myositis: A Novel Case Report.
Tatsuhiko Sakamoto, Yoshitaka Saito, Yoh Takekuma, Eiki Kikuchi, Mitsuru Sugawara
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 143, 7, 617, 620, 2023年, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Chemotherapy-induced myositis is a severe adverse event caused by chemotherapeutic agents such as immune checkpoint inhibitors (ICIs) or cytotoxic agents. We experienced a patient with gefitinib-induced myositis with symptoms of muscle cramps and stiffness in the limbs, and reported the treatment process. A 70-year-old woman received four courses of carboplatin (CBDCA)+pemetrexed (PEM)+gefitinib (intravenous CBDCA area under the curve (AUC) 5 and PEM 500 mg/m2, every 3 weeks, and oral gefitinib 250 mg daily), for epidermal growth factor receptor (EGFR) mutation-positive stage IV lung cancer treatment; followed by seven courses of PEM+gefitinib, and continued gefitinib monotherapy thereafter. Myositis occurred 5 months after the initiation of gefitinib monotherapy. She developed strong limb cramps despite regular oral administration of 400 mg acetaminophen three times a day and complained of pain on a numeric rating scale of 10/10. Her creatine kinase (CK) was elevated from the second course of CBDCA+PEM+gefitinib but was stable at grade 1-2 thereafter. However, the muscle symptoms disappeared with CK normalization within a few days of gefitinib discontinuation due to disease progression. The Naranjo Adverse Drug Reaction Scale score was 6, suggesting a probable association. Osimertinib (an EGFR tyrosine kinase inhibitor)-induced myositis has been reported, but similar events were first observed with gefitinib in this case. Consequently, when treating with gefitinib, myositis, including the CK variation, should be monitored and appropriately managed with multidirectional treatment.

Risk Factor Analysis of Vancomycin-Induced Nephrotoxicity in Paediatric Patients Aged 0-1 Year Using Japanese Medical Database.
Takayuki Miyai, Yoh Takekuma, Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Mitsuru Sugawara, Shungo Imai
Biological & pharmaceutical bulletin, 46, 6, 817, 823, 2023年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Vancomycin (VCM)-induced nephrotoxicity (VIN) is a major side effect in paediatric patients. However, most studies are limited to patients aged 0-18 years. We evaluated the risk factors of VIN in patients aged 0-1 year using Japanese electronic medical record database. We used RWD database which was contained electronic medical records and claims data of approximately 20 million people from 160 medical institutions. We targeted hospitalized patients who were administered VCM between June 2000 and December 2020. VIN was defined by two criteria: Criterion 1 was an increase in serum creatinine (Scr) ≥ 0.5 mg/dL or 50% during VCM treatment period compared to the Scr baseline; and criterion 2 was an increase in Scr ≥50% within seven days or Scr ≥0.3 mg/dL within two days during VCM treatment. The risk factors of VIN were evaluated using multivariate logistic regression analysis. We analysed 446 patients; patients with VIN in Criteria 1 and 2 were 33 and 58, respectively. In Criterion 1, multivariate logistic regression analysis identified four independent factors with p-value <0.05 (VCM concentration ≥20 mg/L, amphotericin B (AMPH-B), piperacillin-tazobactam (TAZ/PIPC), and vasopressor drugs). In Criterion 2, multivariate logistic regression analysis identified concomitant use of vasopressor drugs with p-value <0.05. Therefore, concomitant use of vasopressor drugs was suggested to affect the risk of VIN in patients aged 0-1 year. The findings may help in developing estimation models to assess the risk of VIN in paediatric patients.

Therapeutic Drug Monitoring of Oral Voriconazole in an Infant Less than Six Months of Age and Pharmacokinetics Changes Induced by Development of CYP2C19 in the Growth Process: A Novel Case Report.
Atsushi Yamaguchi, Yuki Tazawa, Masashiro Ueki, Masafumi Yamada, Atsushi Manabe, Mitsuru Sugawara, Yoh Takekuma
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 143, 6, 545, 549, 2023年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Therapeutic drug monitoring (TDM) is recommended for voriconazole (VRCZ) to avoid adverse events and maximize antifungal efficacy. Currently, the appropriate dose for patients under the age of 2 years is unknown. Here, we report the case of a 1.5-month-old infant with inborn errors of immunity who was orally administered VRCZ. This patient's plasma concentration decreased significantly from 3.8 µg/mL (day 6) to 0.09 µg/mL (day 21), leading to repeated dose escalations to achieve the target concentration (1.38 µg/mL, day 58). The signal intensity ratio of VRCZ to its main metabolite, N-oxide VRCZ, in LC/MS/MS also decreased from 5.30 (day 6) to 0.57 (day 64). Consequently, we suspected that VRCZ metabolism may be enhanced during infant growth. To our knowledge, this is the first report of remarkable changes in VRCZ pharmacokinetics with metabolic activity enhanced by the growth process. In conclusion, we propose that frequent TDM helped to maintain adequate VRCZ plasma concentration in a infants less than 6 months of age.

Diabetes mellitus degenerates cisplatin-induced nephrotoxicity in short hydration method: a propensity score-matching analysis
Yoshitaka Saito, Tatsuhiko Sakamoto, Yoh Takekuma, Masaki Kobayashi, Keisuke Okamoto, Naofumi Shinagawa, Yasushi Shimizu, Ichiro Kinoshita, Mitsuru Sugawara
Scientific Reports, 12, 1, 21819, 21819, Springer Science and Business Media LLC, 2022年12月17日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Abstract

Cisplatin (CDDP)-induced nephrotoxicity (CIN) is dose-limiting. We revealed that co-administration of non-steroid anti-inflammatory drugs and baseline comorbidity of diabetes mellitus (DM) are associated with CIN development in the short hydration method; however, the results were accessorily obtained without appropriate power calculation. This study aimed to demonstrate the influence of DM complications on CIN incidence in a real-world setting. Lung cancer patients receiving CDDP (≥ 75 mg/m²)-containing regimens with a short hydration method (n = 227) were retrospectively evaluated. The patients were divided into control and baseline DM complication groups. The primary endpoint was the evaluation of CIN incidence between the groups. Propensity score-matching was performed to confirm the robustness of the primary analysis results. CIN occurred in 6.8% of control and 27.0% of DM patients, respectively, with a significant difference in all-patient populations (P = 0.001). In addition, variation of serum creatinine and creatinine clearance significantly worsened in DM patients. Similar results were obtained in a propensity-matched population. Multivariate logistic regression analysis found that DM complication is a singular risk factor for CIN development (adjusted odds ratio; 4.31, 95% confidence interval; 1.62–11.50, P = 0.003). In conclusion, our study revealed that baseline DM complications significantly worsen CIN.

Association between skin immune-related adverse events (irAEs) and multisystem irAEs during PD-1/PD-L1 inhibitor monotherapy.
Atsushi Yamaguchi, Yoshitaka Saito, Katsuya Narumi, Ayako Furugen, Yoh Takekuma, Naofumi Shinagawa, Yasushi Shimizu, Hirotoshi Dosaka-Akita, Mitsuru Sugawara, Masaki Kobayashi
Journal of cancer research and clinical oncology, 149, 4, 1659, 1666, 2022年11月08日, ［査読有り］, ［国際誌］
英語, PURPOSE: Patients treated with immune checkpoint inhibitors (ICIs) often develop immune-related adverse events (irAEs) in various organs of the body. However, the patient factors associated with the development of multisystem irAEs are not well known. Skin irAEs most frequently occur and appear early after ICI treatment initiation. They may be a predictive marker for the development of multisystem irAEs, and their occurrence should be evaluated. METHODS: Data of patients receiving ICI monotherapy for lung cancer, melanoma, and head and neck cancer treatment were retrospectively evaluated (n = 207); the single irAE development group (n = 69) was compared with the multisystem irAE development group (n = 37). The primary endpoint was the comparison of the incidence of skin irAEs between the two groups. RESULTS: Skin, thyroid, and hepatic irAEs were associated with the development of multisystem irAEs (odds ratio: 3.30, 95% confidence interval: 1.27-8.52, p = 0.01 for skin; 5.07, 2.09-12.3, p = 0.0003 for thyroid; 10.63, 1.19-94.7, p = 0.03 for hepatic). Skin irAEs were the most common type (65.0% of total participants) and appeared earlier than other irAEs, except for gastrointestinal and ocular irAEs (median time to onset of skin irAEs: 7.5 weeks). Skin irAEs occurred more frequently in the multisystem irAE group (81.0%) than in the single irAE group (56.5%, p = 0.02). CONCLUSION: Skin irAEs can be a useful predictive marker for multisystem irAE development due to ICI treatment. Consequently, patients with skin irAEs should be treated and monitored for other types of irAEs.

Risk factor analysis for regorafenib-induced severe hypertension in metastatic colorectal cancer treatment.
Yoshitaka Saito, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 30, 12, 10203, 10211, 2022年10月11日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Regorafenib, a multikinase inhibitor, is effective in treating metastatic colorectal cancer (mCRC). Hypertension is a frequently occurring adverse effect caused by regorafenib regardless of previous treatment with vascular endothelial growth factor (VEGF) inhibitors in almost all patients. We identified the risk factors associated with regorafenib-induced severe hypertension. Patients with mCRC (n = 100) who received regorafenib were evaluated retrospectively. The primary endpoint was the evaluation of the risk factors for grade ≥ 3 hypertension. The association between pre-existing hypertension at baseline and grade ≥ 3 hypertension symptoms was also assessed. Patients with pre-existing hypertension at baseline accounted for 55% of the total patients. The starting doses of regorafenib were 160 mg (49.0% of patients), 120 mg (29.0%), and 80 mg (22.0%). The incidence of grade ≥ 3 hypertension was 30.0%. The median time to grade ≥ 3 symptom development was 7 days (range: 1-56 days). Additional antihypertensive treatment was administered to 83.6% of patients who developed hypertension. Logistic regression analyses revealed that baseline pre-existing hypertension complications and previous anti-VEGF treatment for ≥ 700 days were independent risk factors for grade ≥ 3 hypertension development. Further analyses revealed that pre-existing hypertension before anti-VEGF treatment (primary hypertension) was significantly related to the symptom development (adjusted odds ratio, 8.74; 95% confidence interval, 2.86-26.72; P = 0.0001). Our study suggests that pre-existing primary hypertension and previous anti-VEGF treatment for ≥ 700 days are independent risk factors for regorafenib-induced severe hypertension. Deeper understanding of the symptom nature and management can significantly contribute to safer interventions, necessitating further studies.

妊娠中にラコサミドを使用し、健児を得た一症例
北村 聖花, 西村 あや子, 武隈 洋, 齋藤 佳敬, 馬詰 武, 菅原 満
薬学雑誌, 142, 9, 1031, 1035, (公社)日本薬学会, 2022年09月
日本語, 症例は33歳女性で、24歳時に症候性部分てんかんを発症した。第一子、第二子の妊娠、出産まではレベチラセタムを漸増しながら使用し、第二子出産後にラコサミド100mg/日の内服が開始された。今回、ペランパネルの開始14日後(妊娠7週2日)に第三子の妊娠が判明したためラコサミド単剤で妊娠経過をみる方針となり、ペランパネルは同日に中止された。妊娠中はラコサミド400mg/日の内服を継続し、軽度の発作は繰り返し出現したものの、重篤な症状の出現は認められなかった。妊娠37週2日に選択的帝王切開での分娩となり、児は男児、体重3025g、Apgar score 1分8点、5分9点、臍帯動脈血pH 7.348であった。出生時に児に先天異常は認められず、新生児薬物離脱症状もなかった。1ヵ月検診においても児に異常はなかった。

妊娠中にラコサミドを使用し、健児を得た一症例　　　　　　　　　　　　　　　
北村 聖花, 西村 あや子, 武隈 洋, 齋藤 佳敬, 馬詰 武, 菅原 満
薬学雑誌, 142, 9, 1031, 1035, (公社)日本薬学会, 2022年09月, ［査読有り］, ［責任著者］
日本語

薬局薬剤師を対象としたメディアによる「くすりの危険性」に関する報道に起因する患者からの相談応需の実態調査
今井 俊吾, 阿部 真也, 松井 洸, 柏木 仁, 佐藤 夕紀, 武隈 洋, 吉町 昌子, 菅原 満
医薬品情報学, 24, 2, 75, 87, (一社)日本医薬品情報学会, 2022年08月, ［査読有り］, ［最終著者］
日本語

Impact of systemic dexamethasone administration on oral mucositis induced by anthracycline-containing regimens in breast cancer treatment.
Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Tomohiro Oshino, Mitsuru Sugawara
Scientific reports, 12, 1, 12587, 12587, 2022年07月22日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Oral mucositis (OM) is one of the most common complications associated with chemotherapy. Here, we evaluated whether systemic dexamethasone (DEX) dosage in prophylactic antiemetics affected the incidence of OM in anthracycline-containing regimens. Patients receiving anthracycline-containing regimens for breast cancer were divided into high- and low-DEX dose groups and retrospectively evaluated. The incidence of all-grade OM in the first cycle in the high- and low-dose groups was 27.3% and 53.5%, respectively, and was significantly lowered by increasing the DEX dose (P < 0.01); thus, the study met its primary endpoint. The result in all treatment cycles was also significant (P = 0.02). In contrast, the incidence of dysgeusia was similar between the high- and low-dose groups in the first and all cycles (13.6% and 16.3% in the first cycle [P = 0.79] and 27.3% and 34.9% in all cycles [P = 0.42], respectively). Multivariate analysis revealed that low DEX dosage was an independent risk factor for all-grade OM development. In conclusion, our study suggests that DEX attenuates OM in anthracycline-containing regimens for breast cancer treatment in a dose-dependent manner. Further evaluation of OM prophylaxis, including DEX administration, is required for better control.

Influence of Dose Reduction of Prophylactic Dexamethasone on Chemotherapy-induced Nausea and Anorexia in Patients Under 55 Years Old Treated With Anthracycline-containing Regimens.
Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Mitsuru Sugawara
Anticancer research, 42, 7, 3753, 3758, 2022年07月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: The incidence of acute nausea in patients treated with anthracycline-containing regimens for breast cancer, was significantly increased by dose reduction of prophylactic antiemetic dexamethasone on day 1, whilst reducing it on days 2-4 did not affect delayed nausea. We also found that patients <55 years old were at higher risk of developing nausea. In this retrospective study, we evaluated the influence of dexamethasone dosage on gastrointestinal symptoms in patients <55 years old. PATIENTS AND METHODS: Patients (20-54 years old) who had received anthracycline-containing regimens for breast cancer were divided into reduced dose (6.6 mg dexamethasone on day 1, and 4 mg on days 2-4) and control (9.9 mg and 8 mg, respectively) groups and retrospectively evaluated. The incidence and severity of nausea, vomiting and anorexia were compared. Risk factors associated with nausea were also assessed. RESULTS: The incidence of acute nausea was significantly higher in the reduced dosage group than in the control group (75.0% and 45.2%, respectively; p=0.02). In contrast, the rate of delayed nausea was not different (p=0.41); the incidence of vomiting and anorexia, and the severity of nausea and anorexia were also not statistically different. Multivariate logistic analysis suggested that patients with no-to-low alcohol consumption and those administered 6.6 mg dexamethasone on day 1 were at a higher risk of acute nausea. CONCLUSION: Our study suggests that dexamethasone dose reduction on day 1 in patients treated with anthracycline-containing regimens is not suitable for acute nausea management, and that the dosage can be reduced to at least 4 mg on days 2-4, even in patients under 55 years of age.

Risk Factor Analysis for the Occurrence of Severe Adverse Effects in Eribulin Treatment.
Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Takuro Noguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Mitsuru Sugawara
Anticancer research, 42, 7, 3693, 3700, 2022年07月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. PATIENTS AND METHODS: Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. RESULTS: SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. CONCLUSION: Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Combination of Mirogabalin and Duloxetine Attenuates Peripheral Neuropathy by Eribulin: A Novel Case Report
Yoshitaka Saito, Yoh Takekuma, Tomohiro Oshino, Mitsuru Sugawara
Case Reports in Oncology, 15, 2, 606, 610, S. Karger AG, 2022年06月10日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most severe complications associated with chemotherapy for breast cancer. We encountered a case in which mirogabalin initially ameliorated, and additional duloxetine further attenuated eribulin-induced CIPN. Herein, we report its management. A 53-year-old woman received eribulin treatment as third-line chemotherapy for recurrent breast cancer. She experienced grade 2 CIPN with adjuvant docetaxel and cyclophosphamide treatment (worst numeric rating scale (NRS) 6/10 for numbness and 6/10 for pain) and had baseline grade 1 symptoms only in the hands (NRS 1/10 for each). CIPN in the hands and feet worsened to NRS 3/10 on day 1 of cycle 4. Mirogabalin (5 mg twice daily) was initiated, resulting in stable symptoms for approximately 6 weeks with grade 1 somnolence and heaviness of the head. The dosage was increased with careful attention to adverse effects to 22.5 mg per day, and the NRS was reduced from 5/10 to 3/10 for numbness and from 8/10 to 5/10 for pain. We administered duloxetine 20 mg with domperidone (10 mg three times a day) for further pain attenuation on day 1 of cycle 15, decreasing the NRS to 1/10 for numbness and 3/10 for pain. Duloxetine was increased due to CIPN degradation (NRS 3/10 and 5/10), resulting in a significant pain attenuation to 1/10. As the CIPN-attenuating mechanisms of mirogabalin and duloxetine are different, we consider that the additive and synergetic effects of this combination affected the results. Combination therapy with these drugs may be a promising strategy.

Correlation between antibiotic use and antibiotic resistance: A multicenter study using the Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system in Hokkaido, Japan.
Keisuke Kagami, Nobuhisa Ishiguro, Sumio Iwasaki, Takayuki Usami, Tatsuya Fukumoto, Kasumi Hayasaka, Reiko Oyamada, Tsubasa Watanabe, Sho Nakakubo, Yusuke Niinuma, Takashi Hagino, Yoshifumi Abe, Ikuya Fujimoto, Hideki Maekawa, Ryo Fujibayashi, Satoshi Fuke, Kuniko Asahi, Shuichi Ota, Tatsuya Nagakura, Toshinari Okubo, Hideomi Asanuma, Toshihiro Ito, Sho Okano, Erika Komatsu, Kota Sasaki, Kei Hashimoto, Kazutoshi Washiya, Yumiko Kato, Katsunori Kusumi, Yasufumi Asai, Yuichi Saito, Yoshiyuki Sakai, Minoru Sakurada, Yuji Sakimoto, Yukari Ichikawa, Takahiro Kinebuchi, Dai Kondo, Syuhei Kanno, Minoru Kobayashi, Kagami Hirabayashi, Shinako Saitou, Katsuhiko Saito, Yuuki Ebina, Yuusuke Koshizaki, Makoto Chiba, Atsushi Yasuda, Toshiya Sato, Atsuo Togashi, Takashi Abe, Takahiro Fujita, Kengo Umehara, Masaru Amishima, Nobuo Murakami, Tetsuya Yagi, Shuhei Fujimoto, Taichi Tajima, Mitsuru Sugawara, Yoh Takekuma
American journal of infection control, 51, 2, 163, 171, 2022年06月04日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system aggregates information related to antimicrobial resistance (AMR) measures in participating medical institutions nationwide and is intended to be used for promotion of AMR measures in participating facilities and their communities. This multicenter study aimed to determine the usefulness of the J-SIPHE system for evaluating the correlation between antibiotic use and antibiotic resistance in Hokkaido, Japan. METHODS: Data on antibiotic use and detection rate of major resistant Gram-negative bacteria at 19 hospitals in 2020 were collected from the J-SIPHE system, and data correlations were analyzed using JMP Pro. RESULTS: The detection rate of carbapenem-resistant Pseudomonas aeruginosa was significantly positively correlated with carbapenem use (Spearman's ρ = 0.551; P = 0.015). There were significant positive correlations between the detection rate of fluoroquinolone-resistant Escherichia coli and the use of piperacillin/tazobactam, carbapenems, and quinolones [ρ = 0.518 (P = 0.023), ρ = 0.76 (P < 0.001), and ρ = 0.502 (P = 0.029), respectively]. CONCLUSION: This is the first multicenter study to investigate the correlation between antibiotic use and antibiotic resistance using the J-SIPHE system. The results suggest that using this system may be beneficial for promoting AMR measures.

週刊誌に掲載された「危ないクスリ」に関する情報の整理とその適切性評価　　　　　　　　　　　　　　　
今井 俊吾, 柏木 仁, 佐藤 夕紀, 武隈 洋, 菅原 満
日本医薬品情報学会総会・学術大会講演要旨集, 24回, 91, 91, (一社)日本医薬品情報学会, 2022年06月
日本語

Suitability of Oral Rehydration Solution (ORS) for Use in the Cisplatin Short Hydration Method.
Yoshitaka Saito, Yoh Takekuma, Masaki Kobayashi, Naofumi Shinagawa, Takuro Noguchi, Satoshi Takeuchi, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Mitsuru Sugawara
Anticancer research, 42, 6, 3185, 3193, 2022年06月, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Short hydration is a method to change partial intravenous hydration to oral to administer cisplatin (CDDP); however, the most suitable form of oral hydration is unknown. This study aimed to determine whether oral rehydration solution (ORS) affects CDDP-induced nephrotoxicity (CIN) and electrolyte imbalance. PATIENTS AND METHODS: Lung cancer patients (n=200) who had received CDDP-including regimens (CDDP dosage ≥75 mg/m2) were retrospectively evaluated. We used logistic analysis to evaluate whether ORS intake could be a preventive factor for CIN (≥grade 2 serum creatinine elevation). Moreover, incidence of CIN and electrolyte imbalance and the variation in serum creatinine and electrolyte levels were compared between ORS and non-ORS (control) patients. RESULTS: CIN occurred in 9.8% of ORS patients, and 7.5% of non-ORS patients (p=0.79). The variation in serum creatinine level was also similar in both groups. Multivariate analysis suggested that ORS intake does not affect CIN, although CIN was associated with the coadministration of non-steroidal anti-inflammatory drugs and the presence of diabetes mellitus. The variations in serum electrolyte levels did not differ, and incidence of hyponatremia, hypokalemia, and hypochloremia was also similar between the groups. Moreover, patients in ORS group experienced significantly more anorexia compared to controls, and approximately 40% of the patients were unable to continue ORS intake. CONCLUSION: ORS intake in CDDP short hydration regimens does not affect CIN and CDDP-induced electrolyte imbalance; however, its intake is associated with the incidence of anorexia suggesting that ORS should not be used for oral hydration.

週刊誌に掲載された「危ないクスリ」に関する情報の整理とその適切性評価
今井 俊吾, 柏木 仁, 佐藤 夕紀, 武隈 洋, 菅原 満
医薬品情報学, 24, 1, 1, 10, (一社)日本医薬品情報学会, 2022年05月
日本語, 週刊誌に記載された処方箋の「危険性」に関する記事の適切性を、オーストラリアで開発されたマスメディアによる医療・健康記事の質を評価するための指標である「メディアドクター指標」を処方箋等に適用できるよう改変したものを用いて明らかにすることを目的に、2018年1月1日から2021年5月24日までに発行された「週刊朝日」「サンデー毎日」など週刊誌10誌を対象に、「薬剤名や薬効分類を特定可能」かつ「当該薬剤・薬効分類におけるヒトに対する具体的な副作用・有害事象に関して記述」している記事19本(週刊誌6誌)を2名の評価者により評価した。その結果、19本の記事のうち10本はB誌に掲載されたもので、計179種類の薬剤(薬効分類で34種類)の危険性について言及されていた。対象となった19本の記事の内容を9項目について評価者2人が評価した結果、11本で2名とも不満足とした評価項目が半数を超えていた。

週刊誌に掲載された「危ないクスリ」に関する情報の整理とその適切性評価
今井 俊吾, 柏木 仁, 佐藤 夕紀, 武隈 洋, 菅原 満
医薬品情報学, 24, 1, 1, 10, (一社)日本医薬品情報学会, 2022年05月, ［査読有り］
日本語, 週刊誌に記載された処方箋の「危険性」に関する記事の適切性を、オーストラリアで開発されたマスメディアによる医療・健康記事の質を評価するための指標である「メディアドクター指標」を処方箋等に適用できるよう改変したものを用いて明らかにすることを目的に、2018年1月1日から2021年5月24日までに発行された「週刊朝日」「サンデー毎日」など週刊誌10誌を対象に、「薬剤名や薬効分類を特定可能」かつ「当該薬剤・薬効分類におけるヒトに対する具体的な副作用・有害事象に関して記述」している記事19本(週刊誌6誌)を2名の評価者により評価した。その結果、19本の記事のうち10本はB誌に掲載されたもので、計179種類の薬剤(薬効分類で34種類)の危険性について言及されていた。対象となった19本の記事の内容を9項目について評価者2人が評価した結果、11本で2名とも不満足とした評価項目が半数を超えていた。

Hepatic drug metabolism in older people with body composition changes.
Soyoko Kaburaki, Eri Yoshimura, Yasushi Miyamoto, Shungo Imai, Hitoshi Kashiwagi, Hidefumi Ueno, Mitsuru Sugawara, Yoh Takekuma
Geriatrics & gerontology international, 22, 5, 449, 454, 2022年05月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, AIM: Dosage adjustment is essential in older individuals because they are prone to experience a decline in liver function and changes in body composition. However, quantitative tests or equations for evaluating the activity of hepatic drug metabolism have not yet been clearly established. We examined hepatic drug metabolism activities in older individuals, focusing on changes in body composition parameters. METHODS: Lansoprazole and nifedipine, substrates of the metabolic enzymes cytochrome P450 (CYP) 2C19 and 3A4, respectively, were selected to study hepatic drug metabolism. Residual samples from blood test for older patients were evaluated to determine drug metabolism. The body composition of relevant patients was determined by analyzing characteristic parameters of skeletal muscle mass index (SMI), handgrip strength (HGS) and hepatic steatosis index (HSI). The differences in hepatic drug metabolism were studied statistically among categories in terms of the cut-off value of these parameters. RESULTS: Older male patients receiving lansoprazole and nifedipine in the low SMI (<7.0 kg/m2 ) category showed an 85-90% reduction in respective CYP2C19 and CYP3A4 metabolic activities compared with the normal SMI category. For the female patients, CYP2C19 and CYP3A4 metabolic activities showed no significant correlation with SMI and HGS. Fatty liver disease (HSI ≥36) was found to reduce CYP2C19 metabolic activity particularly in older female patients. CONCLUSIONS: Low CYP2C19 metabolic activity was statistically correlated with low SMI in male patients and high HSI in female patients, whereas low CYP3A4 metabolic activity was statistically correlated with low HGS in male patients. Geriatr Gerontol Int 2022; 22: 449-454.

医療の質向上、臨床の薬剤師による研究推進を目指した医療ビッグデータの活用 大規模レセプトデータベースを用いた臨床研究
武隈 洋, 今井 俊吾, 菅原 満
薬学雑誌, 142, 4, 331, 336, (公社)日本薬学会, 2022年04月, ［査読有り］
日本語

Evaluation of the strategies to reduce third-generation oral cephalosporins in dentistry at a Japanese academic hospital: An interrupted time series analysis.
Akira Yamagami, Katsuya Narumi, Yoshitaka Saito, Ayako Furugen, Shungo Imai, Yoshimasa Kitagawa, Yoichi Ohiro, Ryo Takagi, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi
Journal of clinical pharmacy and therapeutics, 47, 7, 1010, 1019, 2022年03月07日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, WHAT IS KNOWN AND OBJECTIVE: Third-generation oral cephalosporins, especially cefcapene-pivoxil (CFPN-PI), have been used frequently in the Japanese dental field. In December 2014 and April 2016, the newly published clinical guidelines recommended the use of amoxicillin (AMPC). Thus, it is important to evaluate the impact of these guidelines on the prescription profiles of prophylactic antibiotics, clinical outcomes and cost-effectiveness of antibiotics. METHODS: We conducted a retrospective study to analyse an interrupted time series analysis from April 2013 to March 2020 at the Department of Dentistry of Hokkaido University Hospital. A segmented regression model was used to estimate the changes in the incidence of infectious complications following tooth extraction. Prescribed antibiotic data were evaluated via days of therapy (DOT). Antibiotic costs were calculated in terms of the Japanese yen (JPY). RESULTS AND DISCUSSION: We identified 17,825 eligible patients. The incidence rates of infectious complications (SSI + dry socket) and SSI after tooth extraction were 3.2% and 2.2%, respectively, during the entire period. The extraction of impacted third molars corresponded to 5.0% and 3.4%, respectively. However, their incidence rates were not significantly different during this period. The use of prophylactic antibiotics and antibiotic cost showed consistent trends following the implementation of guidelines. The mean DOT of CFPN-PI decreased (ranging from 4893.6 DOTs/1000 patients [March 2013 to November 2014] to 3856.4 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3856.4 DOTs/1000 patients [December 2014 to March 2016] to 2293.9 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). In contrast, the mean DOT of AMPC was found to be increased (ranging from 1379.7 DOTs/1000 patients [March 2013 to November 2014] to 3236.3 DOTs/1000 patients [December 2014 to March 2016]; p < 0.001, and from 3236.3 DOTs/1000 patients [December 2014 to March 2016] to 4597.8 DOTs/1000 patients [April 2016 to March 2020]; p < 0.001). The mean monthly cost was decreased (ranging from 905.3 JPY [March 2013 to November 2014] to 788.7 JPY [December 2014 to March 2016]; p = 0.003, and from 788.7 JPY [December 2014 to March 2016] to 614.0 JPY [April 2016 to March 2020]; p < 0.001). WHAT IS NEW AND CONCLUSION: After December 2014, prophylactic antibiotics were switched from CFPN-PI to AMPC, and the incidence rate of infectious complications was not significantly different over time. However, changing antibiotics is useful from a cost-effectiveness perspective.

大規模レセプトデータベースを用いたボリコナゾールの治療薬物モニタリング実施に関する実態調査　　　　　　　　　　　　　　　
宮井 貴之, 今井 俊吾, 百 賢二, 柏木 仁, 佐藤 夕紀, 菅原 満, 武隈 洋
日本薬学会年会要旨集, 142年会, 27G, am09S, (公社)日本薬学会, 2022年03月
日本語

がんの多剤耐性を克服する新規エトポシド誘導体の探索　　　　　　　　　　　　　　　
山田 隼大, 王子谷 健太, 柏木 仁, 佐藤 夕紀, 今井 俊吾, 宮地 弘幸, 武隈 洋, 菅原 満
日本薬学会年会要旨集, 142年会, 28C, pm04S, (公社)日本薬学会, 2022年03月
日本語

ビッグデータとデータマイニング手法を用いたリネゾリド誘発性血小板減少症の要因分析　　　　　　　　　　　　　　　
井上 優希, 武隈 洋, 宮井 貴之, 柏木 仁, 佐藤 夕紀, 菅原 満, 今井 俊吾
日本薬学会年会要旨集, 142年会, 28H, pm13S, (公社)日本薬学会, 2022年03月
日本語

Using Japanese big data to investigate novel factors and their high-risk combinations that affect vancomycin-induced nephrotoxicity.
Shungo Imai, Shota Kadomura, Takayuki Miyai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma
British journal of clinical pharmacology, 88, 7, 3241, 3255, 2022年02月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Several factors related to vancomycin-induced nephrotoxicity (VIN) have not yet been clarified. In the present study, we used Japanese big data to investigate novel factors and their high-risk combinations that influence VIN. METHODS: We employed a large Japanese electronic medical record database and included patients who had been administered intravenous vancomycin between June 2000 and December 2020. VIN was defined as an increase in serum creatinine ≥0.5 mg/dL or 1.5-fold higher than the baseline. The outcomes were: (1) factors affecting VIN that were identified using multiple logistic regression analysis, and (2) combinations of factors that affect the risk of VIN according to a decision tree analysis, which is a typical machine learning method. RESULTS: Of the 7,306 patients that were enrolled, VIN occurred in 14.2% of them (1,035). A multivariate analysis extracted 22 variables as independent factors. Concomitant ramelteon use (odds ratio; 0.701, 95% confidence interval; 0.512-0.959), ward pharmacy service (0.741, 0.638-0.861), duration of VCM <7 days (0.748, 0.623-0.899) and trough concentrations 10-15 mg/L (0.668, 0.556-0.802) reduce the risk of VIN. Meanwhile, concomitant piperacillin-tazobactam use (2.056, 1.754-2.409) and piperacillin use (2.868, 1.298-6.338) increase the risk. The decision tree analysis showed that a combination of vancomycin trough concentrations ≥20 mg/L and concomitant piperacillin-tazobactam use was associated with the highest risk. CONCLUSIONS: We revealed that the concomitant ramelteon use and ward pharmacy service may decrease the risk of VIN, while the concomitant use of not only piperacillin-tazobactam but also piperacillin may increase the risk.

Evaluation of risk factors associated with carboplatin and nab-paclitaxel treatment suspension in patients with non-small cell lung cancer.
Yoshitaka Saito, Yoh Takekuma, Naofumi Shinagawa, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 30, 5, 4081, 4088, 2022年01月23日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Carboplatin (CBDCA) + nanoparticle albumin-bound paclitaxel (nab-PTX) is one of the most effective chemotherapeutic regimens for advanced non-small cell lung cancer (NSCLC) treatment. However, neutropenia and neuropathy are well-known dose-limiting toxicities associated with this regimen, frequently resulting in treatment suspension and dose reduction. In the present study, we aimed to identify risk factors associated with CBDCA + nab-PTX treatment suspension. METHODS: Patients with NSCLC who received CBDCA + nab-PTX ± atezolizumab or pembrolizumab regimens were retrospectively evaluated. The risk factor(s) for treatment suspension and primary causes underlying suspension during the first course were assessed; the relative dose intensity (RDI) was compared between patients with and without identified factors. RESULTS: The frequency of treatment suspension was determined as 55%. The causes for suspension were neutropenia (65.2%), infection (24.2%), thrombocytopenia (6.1%), and other conditions. The calculated RDI was 98.5% for CBDCA and 79.3% for nab-PTX. Based on univariate and multivariate analyses, grade 1 or higher liver dysfunction was identified as a risk factor for treatment suspension. We determined primary causes for treatment suspension as neutropenia and/or infection, as they are closely related. Next, we evaluated associated factors and determined age ≥65 years and performance status (PS) 2 as potential factors, in addition to liver dysfunction. CONCLUSION: We observed that liver dysfunction at baseline is a risk factor for treatment suspension. In addition, age ≥65 years and PS 2 can result in treatment suspension owing to neutropenia and/or infection during CBDCA + nab-PTX treatment.

がん治療医・緩和ケアスタッフを対象としたターミナルケア態度尺度を用いた意識調査
熊井 正貴, 加藤 信太郎, 小柳 遼, 敦賀 健吉, 伊藤 陽一, 山田 武宏, 武隈 洋, 菅原 満, 川本 泰之, 小松 嘉人
Palliative Care Research, 17, 2, 51, 58, (NPO)日本緩和医療学会, 2022年
日本語, 【目的】緩和ケアに携わる医療提供者のターミナルケア態度の実態とそれに関連する要因を明らかにすることを目的とした.【方法】がん治療医と緩和ケア医を含む緩和ケアに携わる医療提供者を対象にFrommelt Attitude Toward Care Of Dying Scale Form B日本語版(FATCOD B-J)を用いて質問紙調査を実施した.【結果】解析対象は223例であった(回収率42.2%).FATCOD B-J総得点を目的変数とした重回帰分析の結果,偏回帰係数は年代で40代と比較して30代以下が低く(-3.8),業務から得られる満足感を感じているほうが高く(+5.7),緩和ケアへの関心が強いほうが高かった(+6.2).【考察】緩和ケアへの関心と業務から得られる満足感がターミナルケア態度の涵養に重要である可能性がある.(著者抄録)

Chronic Maxillary Atelectasis without Obstruction of the Maxillary Ostium - A Case Report.
Yuki Numano, Kazuhiro Nomura, Tomotaka Hemmi, Jun Suzuki, Risako Kakuta, Mitsuru Sugawara
Annals of maxillofacial surgery, 12, 2, 224, 226, 2022年, ［国際誌］
英語, RATIONALE: Chronic maxillary atelectasis (CMA) is assumed to be caused by negative pressure in the maxillary sinus secondary to the obstruction of the ostiomeatal complex. PATIENT CONCERNS: A 49-year-old female patient first presented to our hospital complaining of right nasal congestion, rhinorrhoea and cheek pain. DIAGNOSIS: Computed tomography (CT) accidentally revealed the inward bowing of the left maxillary sinus, which is a typical sign of CMA or silent sinus syndrome despite the maxillary ostium being potent. TREATMENT: We did not consider any intervention for CMA because she had no symptoms related to it. OUTCOMES AND TAKE-AWAY LESSONS: No progression was noted clinically or on CT at the 6-month follow-up. The pathogenesis of CMA in our patient was not explainable by the commonly accepted theory. Apparent hypertrophy of the left maxillary bone was confirmed on CT, thus osteitis with chronic rhinosinusitis might be the potential cause of CMA in the open maxillary sinus.

がん治療医・緩和ケアスタッフを対象としたターミナルケア態度尺度を用いた意識調査　　　　　　　　　　　　　　　
熊井 正貴, 加藤 信太郎, 小柳 遼, 敦賀 健吉, 伊藤 陽一, 山田 武宏, 武隈 洋, 菅原 満, 川本 泰之, 小松 嘉人
Palliative Care Research, 17, 2, 51, 58, (NPO)日本緩和医療学会, 2022年, ［査読有り］
日本語, 【目的】緩和ケアに携わる医療提供者のターミナルケア態度の実態とそれに関連する要因を明らかにすることを目的とした.【方法】がん治療医と緩和ケア医を含む緩和ケアに携わる医療提供者を対象にFrommelt Attitude Toward Care Of Dying Scale Form B日本語版(FATCOD B-J)を用いて質問紙調査を実施した.【結果】解析対象は223例であった(回収率42.2%).FATCOD B-J総得点を目的変数とした重回帰分析の結果,偏回帰係数は年代で40代と比較して30代以下が低く(-3.8),業務から得られる満足感を感じているほうが高く(+5.7),緩和ケアへの関心が強いほうが高かった(+6.2).【考察】緩和ケアへの関心と業務から得られる満足感がターミナルケア態度の涵養に重要である可能性がある.(著者抄録)

Machine Learning-Based Model for Estimating Vancomycin Maintenance Dose to Target the Area under the Concentration Curve of 400-600 mg·h/L in Japanese Patients.
Takayuki Miyai, Shungo Imai, Eri Yoshimura, Hitoshi Kashiwagi, Yuki Sato, Hidefumi Ueno, Yoh Takekuma, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 45, 9, 1332, 1339, 2022年, ［査読有り］, ［最終著者, 責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, In therapeutic drug monitoring of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to clinical efficacy and toxicity. Determining the maintenance for patient is necessary since VCM concentrations are affected by factors such as renal function. We constructed a machine learning-based model to estimate the maintenance dose to target an AUC of 400-600 mg⋅h/L in each combination of patient's factors. This retrospective observational study was conducted at two hospitals. Patients who received VCM intravenously with measured trough and another point (e.g., peak) concentrations within the November 2011 to March 2019 period were enrolled. We extracted the factors that affect VCM concentration and constructed a decision tree model using a classification and regression tree algorithm. Of the 1380 patients, 822 were included. Training data were split up to four times and included 24 subgroups. The average corrected VCM daily doses ranged 17.6-59.4 mg/kg. Estimated glomerular filtration rate, age, and body mass index were selected as predictive variables that affected the recommended daily dose. In the validation data, our model had slightly higher proportions of AUC of 400-600 mg⋅h/L than other nomograms. However, our model was based only on limited patients. Thus, further clinical studies are needed to develop a general-purpose model in the future. We successfully constructed a model that recommends VCM maintenance daily doses with AUC of 400-600 mg⋅h/L for each combination of independent variables. Our model has the potential for application as a simple decision-making tool for medical staff.

[Case Report on a Woman with Epilepsy Who Took Lacosamide during Pregnancy and Gave Birth to a Healthy Infant].
Seika Kitamura, Ayako Nishimura, Yoh Takekuma, Yoshitaka Saito, Takeshi Umazume, Mitsuru Sugawara
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 142, 9, 1031, 1035, 2022年, ［査読有り］, ［責任著者］, ［国内誌］
日本語, 研究論文（学術雑誌）, Lacosamide is a novel antiepileptic drug. Although many antiepileptic drugs reportedly pose a risk to fetuses, patients with epilepsy are advised to continue their medications during pregnancy. There have been few reports on lacosamide use during pregnancy, and its effects on the fetus remain unclear. Here, we report a case of lacosamide use during pregnancy. The 33-year-old patient was treated with oral lacosamide (400 mg/d) for symptomatic partial epilepsy. She was concomitantly treated with folic acid (5 mg/d) beginning 4 days before her last menstrual cycle. She was also concomitantly treated with oral perampanel (2 mg/d) at 5-7 weeks' gestation for seizure control but discontinued perampanel after the pregnancy was discovered. She progressed through her pregnancy with only mild seizures. Fetal growth was normal and ultrasonography revealed no external malformations. The patient had an elective cesarean section at 37 weeks and 2 days owing to a previous post-cesarean pregnancy. Her baby boy weighed 3025 g; his Apgar score was 8 and 9, 1 and 5 min, respectively, and his umbilical artery blood pH was 7.348. He had no congenital anomalies and no neonatal drug withdrawal symptoms. This suggests that lacosamide may have a low risk of teratogenicity and fetal toxicity. Thus, this case is valuable for clinicians who are considering the administration of antiepileptic drugs during pregnancy. In the future, more reports on the use of lacosamide during pregnancy should be collected.

Performance Status不良群におけるナルデメジンの有効性の検証
加藤 信太郎, 齋藤 佳敬, 小野田 紘子, 熊井 正貴, 今井 俊吾, 敦賀 健吉, 武隈 洋, 菅原 満
薬学雑誌, 142, 7, 755, 760, (公社)日本薬学会, 2022年, ［査読有り］, ［責任著者］, ［国内誌］
日本語, 研究論文（学術雑誌）, performance status(PS)不良患者におけるナルデメジン(Nal)の有効性を検証した。対象期間にNalが投与された383例のうち解析対象患者は141例であり、そのうちPS良好群は113例、PS不良群は28例であった。投与1日目から7日目までにおけるNalの有効率はPS良好群が71.7%、PS不良群が71.4%であり、有意な差は認められなかった。Nal投与前後の1週間当たりの自発排便回数の変化はPS良好群が2.8回/週の増加、PS不良群が3.6回/週の増加であり、ともに有意に増加していた。治療早期におけるNalの有効率はPS良好群が61.1%、PS不良群が57.1%、治療効果判定期間における有効率は各々60.2%、71.4%であり、ともに有意な差は認められなかった。Nalの効果はPS不良群においてもPS良好群と差が認められないことが明らかとなった。

Prescription and Therapeutic Drug Monitoring Status of Valproic Acid among Patients Receiving Carbapenem Antibiotics: A Preliminary Survey Using a Japanese Claims Database
Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Annals of Clinical Epidemiology, 4, 1, 6, 10, Society for Clinical Epidemiology, 2022年, ［査読有り］
研究論文（学術雑誌）

[Clinical Research Using the Large Health Insurance Claims Database].
Yoh Takekuma, Shungo Imai, Mitsuru Sugawara
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 142, 4, 331, 336, 2022年, ［査読有り］, ［国内誌］
日本語, 研究論文（学術雑誌）, The JMDC Claims Database® contains completely anonymized receipt information on the insured members of health insurance associations. The number of registered users is approximately 9.6 million (6% of the population) as of May 2020. In this database, it is possible to track even outpatient treatment, even if the patient changes the medical facility, as long as the insurer of the subscriber's health insurance does not change, so that long-term medical treatment could be targeted as a research theme. However, as the data do not contain medical record information, it is not possible to obtain laboratory values, although it is possible to know whether clinical tests have been performed. For pharmaceutics-related research, the most suitable use of the receipt database like JMDC Claims Database® seems to be the investigation of actual prescriptions. However, the research topics that pharmacists are interested in are probably comparisons of drug effects, drug-drug interactions, or causal analysis of drugs and side effects. However, laboratory data for evaluating drug efficacy is not available in the receipt database, and the accuracy of the disease name in the database becomes problematic when using the disease name as information indicating the occurrence of side effects. In this review, we introduce our studies performed by using JMDC Claims Database® and how to manage the above-described problems. We hope that this study will be helpful to those who are going to engage in research using medical big data.

Development of a Method of Liquid Chromatography Coupled with Tandem Mass Spectrometry for Simultaneous Determination of Linezolid and Tedizolid in Human Plasma.
Yuki Sato, Yoh Takekuma, Takayuki Daisho, Hitoshi Kashiwagi, Shungo Imai, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 45, 4, 421, 428, 2022年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, It is important to select appropriate antibiotics for infection control. Linezolid and tedizolid are newly developed and synthesized oxazolidinone antibacterial agents. It has been pointed out that there is a relationship between a high plasma concentration of the target drug and incidence of adverse effects, although it has been reported that neither linezolid nor tedizolid requires dose adjustment according to renal function. Due to the high incidence of adverse effects, both are often switched. Precise plasma concentration control by therapeutic drug monitoring (TDM) is desirable for reducing the adverse effects of both drugs and obtaining a better therapeutic effect. In this study, we aimed to establish a method for simultaneous quantification of linezolid and tedizolid in human plasma using LC coupled with tandem mass spectrometry. Sample preparation was performed by a simple operation with acetonitrile. Linezolid and tedizolid were separated by an octadecylsilyl column using a gradient elution of acetonitrile in aqueous 0.1% formic acid solution and were detected in the positive ion electrospray mode with multiple reaction monitoring. Quantification of linezolid and tedizolid ranged from 0.5 to 50 and 0.5 to 20 µg/mL, respectively. The intra-day and inter-day precision and accuracy of data were assessed and found to be acceptable. The developed method was successfully applied to measurement of the concentrations of linezolid and tedizolid. This simple method, which can simultaneously quantify both drug concentrations for daily TDM, could contribute to safer treatment of patients.

A 5% Glucose Solution for the Liquid Formulation Gemcitabine Solvent Decreases Gemcitabine-induced Vascular Pain.
Kazuki Uchiyama, Yoshitaka Saito, Tatsuhiko Sakamoto, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Anticancer research, 42, 1, 343, 348, 2022年01月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND/AIM: Gemcitabine (GEM)-induced vascular pain often occurs in patients. A 5% glucose solution for the lyophilized formulation of GEM solvent is known to decrease the frequency of GEM-induced vascular pain compared with saline. In this study, we aimed to examine the availability of glucose for a liquid formulation GEM solvent for the prevention of GEM-induced vascular pain. PATIENTS AND METHODS: In total, 214 patients with bile tract or pancreatic cancer, who received GEM-containing regimens, were enrolled in this retrospective study. The patients were divided into a glucose group, which was administered the liquid formation GEM diluted with glucose, and a saline group. The frequency of GEM-induced vascular pain was compared between them. RESULTS: Glucose significantly decreased the frequency of GEM-induced vascular pain during the first GEM administration (36% vs. 55%, p=0.005). CONCLUSION: Switching the solution for liquid formulation GEM from saline to glucose significantly decreased the frequency of vascular pain.

Therapeutic drug monitoring-enabled long-term use of linezolid for the successful treatment of refractory pyogenic spondylodiscitis without development of thrombocytopenia: A case report.
Takayuki Daisho, Keisuke Kagami, Koujiro Yamazaki, Nobuhisa Ishiguro, Tsutomu Endo, Masahiko Takahata, Hisataka Suzuki, Mitsuru Sugawara, Yoh Takekuma
Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association, 2021年12月15日, ［査読有り］, ［国内誌］
英語

Impact of reducing day 1 dexamethasone dose in anthracycline-containing regimens on acute gastrointestinal symptoms associated with breast cancer treatment.
Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Mitsuru Sugawara
Scientific reports, 11, 1, 23298, 23298, 2021年12月02日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, The potential of steroid sparing from day 2 onward is reported in anthracycline-containing regimens for breast cancer treatment. We evaluated whether the reduction of dexamethasone (DEX) dose from 9.9 to 6.6 mg on day 1 is possible in anthracycline-containing treatments. Patients receiving anthracycline-containing regimens were divided into control (9.9 mg DEX on day 1) and reduced (6.6 mg DEX on day 1) groups, and retrospectively evaluated. The complete response (CR) rate and the incidence and severity of nausea, vomiting, anorexia, and fatigue were evaluated. The CR rate in the acute phase (day 1) was 63.1% and 38.1% in the control and reduced groups, respectively, with significant difference (P = 0.01) between the groups. However, no difference was found in the delayed phase (days 2-7). The incidence of anorexia and vomiting during treatment was not statistically different. Severity of nausea tended to, but not statistically, worsen while anorexia significantly worsened in the reduced group. Multivariate analysis suggested that patients < 55 years, with non- or less-alcohol drinking habit (< 5 days/week), and administered reduced-DEX dosage on day 1, have a higher risk of acute nausea development. Thus, reducing day 1 DEX dose in anthracycline-containing regimens is not suitable for acute nausea management.

Clinical applicability of urinary creatinine clearance for determining the initial dose of vancomycin in critically ill patients.
Ryusei Mikami, Shungo Imai, Mineji Hayakawa, Mitsuru Sugawara, Yoh Takekuma
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 28, 2, 199, 205, 2021年10月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: The purpose of this study was to evaluate the clinical applicability of urinary creatinine clearance (CrCl) for determining the initial dose of vancomycin (VCM) in critically ill patients and to assess VCM trough plasma concentration/maintenance daily dose (C/D) ratio in patients with augmented renal clearance (ARC). METHODS: As the primary outcome measure, correlations between estimated renal function and the VCM C/D ratio were compared using the following formulas: CrCl, Cockcroft-Gault equation (eCrClC-G) and KineticGFR equation (KeGFR). Patients were divided into those with or without changes in renal function. The patients were further classified based on the presence or absence of ARC. The secondary outcome was the comparison of VCM C/D ratio between ARC and Non-ARC patients. RESULTS: A total of 65 patients were enrolled for analysis. In all groups, CrCl tended to correlate better with the VCM C/D ratio than eCrClC-G and KeGFR. A significantly lower VCM C/D ratio was observed in patients with persistent ARC than in the Non-ARC group (0.24 versus 0.52 kg/L). CONCLUSIONS: The clinical applicability of CrCl for the initial dosing design of VCM in critically ill patients was shown. Furthermore, the results indicated that patients with persistent ARC required a higher VCM dose than Non-ARC patients. Although our findings are limited, they have a value for further verification.

Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.
Shota Kadomura, Shungo Imai, Kenji Momo, Yuki Sato, Hitoshi Kashiwagi, Tatsuya Itoh, Mitsuru Sugawara, Yoh Takekuma
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 28, 7, 10781552211034703, 10781552211034703, 2021年10月18日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

Pregabalin Attenuates Carboplatin-Induced Akathisia-Like Neuropathy: A Novel Case Report
Yoshitaka Saito, Yoh Takekuma, Megumi Furuta, Mitsuru Sugawara
Case Reports in Oncology, 14, 3, 1418, 1421, S. Karger AG, 2021年10月04日, ［査読有り］, ［責任著者］
研究論文（学術雑誌）, Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most serious adverse effects of chemotherapy. We experienced carboplatin (CBDCA)-induced akathisia-like CIPN, which was significantly attenuated by pregabalin administration, and report its treatment. A man in his 40s was administered CBDCA + pemetrexed (PEM) as the third-line treatment for recurrent malignant pleural mesothelioma. He rarely experienced mild akathisia-like symptoms on his feet before the diagnosis. The patient claimed that he exhibited mild degradation of the symptoms in the previous cisplatin (CDDP) + PEM treatment without the need for pharmacotherapy. Symptoms notably worsened approximately 7 days after the first cycle of CBDCA + PEM and did not disappear. Furthermore, symptoms worsened during the daytime and became milder at night. Lorazepam (0.5 mg) was administered 3 times a day from day 14 but was not effective. Finally, we evaluated the symptoms to be derived from CBDCA-induced neuropathy as he experienced the same symptoms in CDDP + PEM and did not have suspicious pathology or medicines for akathisia development. We decided to administer 75 mg pregabalin twice daily, resulting in significant symptom improvement. He also complained that he felt the symptoms 10 h after the previous pregabalin dose, suggesting that pregabalin was effective, and its effect weakened or disappeared as time progressed. Akathisia-like symptoms caused by CBDCA-induced CIPN are rare, but they significantly reduce the quality of life. Pregabalin was significantly effective in this case; therefore, we suggest that a detailed symptom interview and selection of the medicine, based upon the action mechanism, are necessary.

Investigation of the risk factors of vomiting during linezolid therapy: a retrospective observational study.
Takezo Tsutsumi, Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma
European journal of clinical pharmacology, 78, 2, 279, 286, 2021年09月28日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Some clinical studies have reported the occurrence of nausea and vomiting with linezolid (LZD) administration. However, no studies have evaluated nausea and vomiting as primary endpoints. In a previous study, we noted a possible relationship between LZD and vomiting, but risk factors were not identified. Therefore, the aim of the present study was to identify them. METHODS: Patients who received LZD 600 mg twice daily at Hokkaido University Hospital from September 2008 to April 2019 were enrolled in this retrospective observational study. Patient characteristics, concomitant medications, laboratory data, and the occurrence of vomiting were obtained from electronic medical records. Logistic regression analysis was performed to identify risk factors for vomiting, including age, sex, body weight, concomitant medications, and surgeries. RESULTS: A total of 496 patients were included in this study, of which 90 experienced vomiting. By multivariate logistic regression analysis, female sex (adjusted odds ratio [aOR], 2.69; 95% confidence interval [CI], 1.62-4.47), ≥ 10 days of LZD administration (aOR, 2.57; CI, 1.46-4.50), and hyponatraemia (aOR, 2.96; CI, 1.72-5.10) were identified as independent risk factors for vomiting; administration of serotonergic agents (aOR, 0.23; CI, 0.07-0.82) was negatively associated. CONCLUSIONS: This study is the first to successfully identify risk factors for LZD-induced vomiting. Careful monitoring of patients with these risk factors may lead to safer and sustainable LZD administration.

Severe hypertriglyceridemia induced by S-1: Subsequent case series of four patients and further review of the literature.
Yoshitaka Saito, Yoh Takekuma, Satoshi Takeuchi, Yoshito Komatsu, Mitsuru Sugawara
International journal of clinical pharmacology and therapeutics, 59, 12, 787, 793, 2021年09月10日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: We previously reported a case where S-1, containing tegafur, gimeracil, and oteracil potassium, induced severe hypertriglyceridemia. After the case, we regularly monitored serum lipid levels and surprisingly observed an additional 4 cases within 1.5 years. We here report the treatment process. CASE REPORT: At least 3 patients exhibited hyperlipidemia at baseline; in 2 of them, this was caused by previous fluoropyrimidine treatment. One patient experienced grade 4 hypertriglyceridemia, and the other 3 grade 3 hypertriglyceridemia. One patient developed temporary serum triglyceride elevation during the S-1 administration period, and the 3 experienced persistent elevation. The severity of serum triglyceride level worsened with increasing administration and peaked in cycles 2 - 6. Fenofibrate 80 - 160 mg/day and S-1 dose reduction were effective, with some significantly and others gradually decreasing to grade 0 - 1. DISCUSSION: The summarized clinical features are as follows: (1) Severe hypertriglyceridemia tends to appear after several treatment cycles and worsens with increasing administration. (2) It tends to occur in patients with hyperlipidemia at baseline. (3) Patients previously affected with fluoropyrimidines-induced hypertriglyceridemia can experience S-1 symptoms. (4) In some cases, it might decrease after the S-1 suspension period. (5) Fibrates and S-1 dose reductions were effective. As the final fluoropyrimidine product is fluorouracil, its presence or that of its metabolizing enzymes and the genetic background of the patients might have affected the results. We should be aware of the risk of temporal and asymptomatic occurrence of S-1-induced hypertriglyceridemia for early detection with appropriate treatment.

Severe Hypertriglyceridemia Induced by Docetaxel: A Novel Case Report
Yoshitaka Saito, Yoh Takekuma, Takashi Takeshita, Mitsuru Sugawara
Case Reports in Oncology, 14, 3, 1277, 1282, S. Karger AG, 2021年09月09日, ［査読有り］, ［最終著者, 責任著者］
研究論文（学術雑誌）, Docetaxel (DOC) is one of the most effective agents for breast cancer treatment. Here, we report docetaxel-induced severe hypertriglyceridemia in a patient previously diagnosed with hyperlipidemia and corresponding therapeutic intervention. A postmenopausal woman, with previously controlled hyperlipidemia using rosuvastatin 5 mg daily, was diagnosed with stage IIB breast cancer with human epidermal growth factor receptor-2 overexpression; she received DOC (75 mg/m²), pertuzumab, and trastuzumab treatment as neoadjuvant chemotherapy. The serum triglyceride level was mildly higher than normal, and cholesterol level was normal at baseline. The serum triglyceride level was almost stable after chemotherapy initiation but suddenly increased to grade 3 (770 mg/dL) after the third cycle of the treatment without any symptoms. Sustained-release bezafibrate 400 mg was administered, resulting in a significant decrease to the baseline level; bezafibrate was discontinued on day 28 of the fourth chemotherapy as neoadjuvant chemotherapy was completed. The level was stable around the baseline level during adjuvant chemotherapy with pertuzumab and trastuzumab. Therefore, DOC-induced severe hypertriglyceridemia was strongly indicated in this case. The mechanism underlying the symptoms remains unclear; we speculate that it could be a resultant of a decrease in lipid metabolism as the patient had grade 2 diarrhea. Moreover, her backgrounds, such as mild hypertriglyceridemia, postmenopausal, diabetes, and obesity, in addition to DOC administration might have affected the outcome. Fibrate administration and cessation of treatment were as effective as in previous reports. DOC-induced hypertriglyceridemia presents with the possibility of severe complications. Elucidation of the exact mechanisms and epidemiological features is required for better management.

大規模レセプトデータベースを用いたボリコナゾールの治療薬物モニタリング実施に関する実態調査
宮井 貴之, 今井 俊吾, 百 賢二, 柏木 仁, 佐藤 夕紀, 菅原 満, 武隈 洋
TDM研究, 38, 3, 39, 48, (一社)日本TDM学会, 2021年09月, ［査読有り］
日本語, ポリコナゾール(voriconazole;VRCZ)は深在性真菌症治療や造血幹細胞移植後の真菌症予防を目的に処方される。その有効性と副作用リスクは血漿中濃度に相関し、治療薬物モニタリング(therapeutic drug monitoring;TDM)が推奨されるが、処方患者数に対する実施割合の報告はない。そこで、大規模レセプトデータベースを利用し、患者数に基づくVRCZのTDM実施割合を特定薬剤治療管理料から評価した。ただし、VRCZ以外の算定対象薬を併用時、VRCZのTDMによる算定か否かを特定できないため、対象薬としてVRCZのみ処方された例(併用除外例)を評価した。2012年4月から2017年3月までにVRCZを処方された患者は417例、併用除外例は290例であった。併用除外例の32.8%、全例の37.4%でTDMが実施され、実施日の中央値はそれぞれ7日目、6日目であった。TDM実施に関連する要因として病棟薬剤業務、年齢、処方期間が見出された。TDM非実施例のうち、真にTDMの必要な患者がどの程度含まれているかを評価することが今後の課題である。(著者抄録)

Factors affecting creatine phosphokinase elevation during daptomycin therapy using combination of machine learning and conventional methods.
Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
British journal of clinical pharmacology, 88, 3, 1211, 1222, 2021年08月26日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, AIMS: Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP-induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods. METHODS: A population-based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and > 200 IU/L, and (2) > 1,000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree (DT) analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk. RESULTS: Of the 2,970 patients who received DAP, 706 were included. Elevation of CPK values > 200 IU/L and > 1,000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In DT analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high-risk group. CONCLUSIONS: Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high-risk patients require frequent CPK monitoring.

Clinical outcomes of intervention for carbapenems and anti-methicillin-resistant Staphylococcus aureus antibiotics by an antimicrobial stewardship team.
Keisuke Kagami, Nobuhisa Ishiguro, Takehiro Yamada, Yusuke Niinuma, Sumio Iwasaki, Keisuke Taki, Tatsuya Fukumoto, Kasumi Hayasaka, Mutsumi Nishida, Junichi Sugita, Takanori Teshima, Mitsuru Sugawara, Yoh Takekuma
American journal of infection control, 49, 12, 1493, 1498, 2021年08月17日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: There are no reports on the effects of interventions, such as discontinuation and change/de-escalation of carbapenems and anti-methicillin-resistant Staphylococcus aureus (MRSA) antibiotics by an antimicrobial stewardship team focusing on detailed patient outcomes. This study aimed to evaluate these effects. METHODS: This retrospective cohort study was conducted at a tertiary care hospital from December 2018 to November 2019. RESULTS: Favorable clinical responses were obtained in 165/184 cases (89.7%) in the intervention-accepted group, higher than those in the not accepted group (14/19 cases, 73.7%; P=0.056). All-cause 30-day mortality was lower in the accepted group than in the not accepted group (1.1% and 10.5%, respectively; P=0.045). The microbiological outcomes were similar between the two groups. Duration of carbapenem and anti-MRSA antibiotic use in the accepted group was significantly lower than that in the not accepted group (median [interquartile range]: 8 days [5-13] versus 14 days [8-15], respectively, P=0.026 for carbapenem; 10 days [5.3-15] versus 15.5 days [13.8-45.3], respectively, P=0.014 for anti-MRSA antibiotic). CONCLUSION: This is the first study to investigate the effects of interventions such as discontinuation and change/de-escalation of antibiotics on detailed outcomes. Our intervention could reduce the duration of carbapenem and anti-MRSA antibiotic use without worsening clinical and microbiological outcomes.

A cross-sectional survey of hospitalization and blood tests implementation status in patients who received tolvaptan under 75 years of age using a Japanese claims database.
Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Expert opinion on drug safety, 20, 10, 1, 10, 2021年07月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Hypernatremia and liver injury are typical adverse effects of tolvaptan. Therefore, hospitalization and frequent monitoring of serum sodium concentration and liver function are necessary for tolvaptan initiation. We performed a cross-sectional survey to evaluate these situations. RESEARCH DESIGN AND METHODS: We employed the Japanese claims database, which contains data of patients aged < 75 years. Patients who were newly prescribed tolvaptan for fluid accumulation induced by chronic heart failure (FA-CHF) or liver cirrhosis (FA-LC) from January 2011 to June 2017 were included. We evaluated the hospitalization status and implementation of serum sodium and liver function tests in the evaluation period, based on the Japanese package insert. RESULTS: Of 1,173 patients, 347 and 117 were enrolled in FA-CHF and FA-LC groups, respectively. Among them, 10.7% (FA-CHF group) and 5.13% (FA-LC group) were prescribed tolvaptan without hospitalization. In the FA-CHF group, 11.0% and 17.6% did not undergo serum sodium and liver function tests even once in the evaluation period, respectively, compared with 12.0% and 12.8% in the FA-LC group. CONCLUSIONS: Our results highlight the deviation from Japanese package insert recommendations. This approach can be applied to other drugs and provides important perspectives on pharmacovigilance research.

Risk factor analysis for taxane-associated acute pain syndrome under the dexamethasone prophylaxis.
Yoshitaka Saito, Yoh Takekuma, Masaki Kobayashi, Tatsuhiko Sakamoto, Hiroko Yamashita, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 29, 12, 8059, 8067, 2021年07月06日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Taxane-associated acute pain syndrome (T-APS) reportedly occurs in approximately 70% of patients undergoing therapy. We have previously reported that additional dexamethasone (DEX) administration attenuates T-APS. The aim of this study was to reveal risk factor(s) associated with the incidence of T-APS under prophylactic DEX administration. METHODS: In total, 143 patients with breast cancer who received docetaxel (75 mg/m2) or paclitaxel (175 mg/m2)-containing treatment regimens were enrolled. DEX (4-8 mg) was orally administered on days 2-4. Risk factors for the incidence of ≥ G2 and all-grade T-APS, as well as T-APS incidence between taxane-containing regimens in the first cycle, were retrospectively evaluated. RESULTS: Approximately 90% of the patients received taxanes for adjuvant or neoadjuvant chemotherapy. Overall, 55% of patients administered 4 mg DEX, whereas 45% received 8 mg DEX. Pegfilgrastim was administered in 27% of patients. Incidence of ≥ G2 and all-grade T-APS was 23.8%, and 69.2%, respectively. Univariate and multivariate analyses revealed that administration of pegfilgrastim is an independent risk factor for the incidence of ≥ G2 and all-grade T-APS; age younger than 55 years is also a risk factor for all-grade T-APS. Moreover, the incidence of ≥ G2 and all-grade T-APS was 45.5% and 81.8% in a paclitaxel regimen, and 22.0% and 68.2% in docetaxel-including regimens, respectively, revealing increased tendency with paclitaxel administration, with no significant differences. CONCLUSION: Pegfilgrastim co-administration is an independent risk factor for ≥ G2 and all-grade T-APS, and age younger than 55 years is a risk factor of all-grade T-APS under prophylactic DEX administration.

Preexisting autoimmune disease is a risk factor for immune-related adverse events: a meta-analysis.
Atsushi Yamaguchi, Yoshitaka Saito, Keisuke Okamoto, Katsuya Narumi, Ayako Furugen, Yoh Takekuma, Mitsuru Sugawara, Masaki Kobayashi
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 2021年06月23日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Patients with preexisting autoimmune disease (PAD) are often excluded from clinical trials assessing immune checkpoint inhibitors (ICIs). Therefore, the safety of ICI therapy in patients with PAD remains unclear. Herein, we evaluated the incidence of immune-related adverse events (irAEs) in patients with PAD when compared with non-PAD patients. METHODS: We searched MEDLINE/PubMed, Web of Science, and Google Scholar for eligible studies from inception to January 2021. Observational studies reporting the incidence of irAEs in patients with and without PAD were included. We then performed a meta-analysis of eligible studies using forest plots. The primary endpoint of this study was the incidence rate of irAEs between patients with and without PAD. RESULTS: We identified three prospective and three retrospective studies involving 206 patients with PAD and 3078 patients without PAD. In the meta-analysis, 128 patients with PAD (62.1%) experienced irAEs, which occurred in 51.9% of non-PAD patients, resulting in an odds ratio (OR) of 2.14 (95% confidence interval [CI] 1.58-2.89). In the subgroup analysis, the incidence of irAEs was significantly higher in patients with PAD (OR = 2.19, 95% CI [1.55-3.08]). Furthermore, no significant heterogeneity or publication bias was detected, indicating that our meta-analysis could be generalized to clinical settings. CONCLUSION: This meta-analysis demonstrated that PAD was a risk factor for irAE incidence. These results suggest that monitoring the occurrence of irAEs in patients with PAD is required to manage irAEs appropriately.

Alleviation of Abdominal Pain due to Irinotecan-Induced Cholinergic Syndrome Using Loperamide: A Case Report
Kazuki Uchiyama, Yoshitaka Saito, Yoh Takekuma, Satoshi Yuki, Mitsuru Sugawara
Case Reports in Oncology, 14, 2, 806, 811, 2021年06月10日, ［査読有り］, ［責任著者］
研究論文（学術雑誌）, Irinotecan hydrochloride (irinotecan) is a chemotherapeutic agent used in the treatment of solid tumors. In addition to severe neutropenia and delayed diarrhea, irinotecan causes cholinergic syndrome, characterized by abdominal pain and acute diarrhea. The latter symptoms are frequently observed during and after irinotecan treatment. Here, we have discussed the case of a patient who completely recovered from abdominal pain following the administration of loperamide hydrochloride (loperamide) at a dose of 2 mg, before infusing irinotecan. In contrast, anticholinergic drugs were not as effective in alleviating symptoms. A 28-year-old man with stage IV rectal cancer with peritoneal metastasis was prescribed with fluorouracil, irinotecan, and levofolinate calcium (FOLFIRI), in addition to cetuximab. Anticholinergic drugs, such as scopolamine butylbromide (scopolamine) or atropine sulfate (atropine), were administered to treat abdominal pain that was considered as irinotecan-induced cholinergic syndrome, but monotherapy was not effective. Thereafter, oral loperamide (2 mg) with atropine (0.25 mg) was prescribed before irinotecan infusion. Consequently, the patient did not experience any abdominal pain during and after irinotecan treatment. Loperamide is an opioid receptor agonist and decreases the activity of the myenteric plexus of the intestinal wall. It also inhibits the release of both acetylcholine and prostaglandins, resulting in decreased inhibition of peristaltic movement. We assumed that its mechanism solely or in combination contributed to symptom relief. We hypothesized that the synergistic anticholinergic interaction between loperamide and atropine resulted in marked suppression of irinotecan-induced cholinergic syndrome compared to loperamide alone. Thus, loperamide may improve abdominal pain attributed to irinotecan-induced cholinergic syndrome.

Adding aprepitant to palonosetron does not decrease carboplatin-induced nausea and vomiting in patients with gynecologic cancer.
Yuko Watanabe, Yoshitaka Saito, Takashi Mitamura, Yoh Takekuma, Mitsuru Sugawara
Journal of pharmaceutical health care and sciences, 7, 1, 21, 21, 2021年06月01日, ［査読有り］, ［最終著者, 責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Recently, aprepitant has been recommended in carboplatin-based regimens, but there are limited reports on the efficacy of administering aprepitant, palonosetron, and dexamethasone (DEX) in carboplatin-containing regimens. Moreover, because aprepitant is an expensive drug, confirming its effectiveness is very important from the medical cost perspective. In this study, we examined the efficacy of prophylactically administered aprepitant, palonosetron and DEX, in paclitaxel and carboplatin (TC) combination chemotherapy. METHODS: Patients with gynecologic cancer who were treated with paclitaxel (175 mg/m2) and carboplatin (area under the curve, AUC = 5-6) combination chemotherapy were retrospectively evaluated. The complete response (CR) rate, severity of nausea, and incidence of anorexia in the first course were compared between patients who did not receive aprepitant (control group) and those who received (aprepitant group). RESULTS: The 106 patients were divided into two groups, consisting of 52 and 54 the control and aprepitant groups, respectively, and the patient background showed no significant difference between both groups. The CR rate of the overall phase between the control and aprepitant groups was 73.1 vs. 74.1%, that in the acute phase was 98.1 vs. 100%, and in the delayed phase was 75.0 vs. 74.1%, respectively, without any significant difference. The severity of nausea and incidence of anorexia were also not significantly different between both groups. CONCLUSIONS: The results of the study suggest that adding aprepitant to palonosetron and DEX does not prevent carboplatin-induced nausea and vomiting in gynecologic cancer patients. Therefore, adding aprepitant to palonosetron does not decrease carboplatin-induced nausea and vomiting in patients with gynecologic cancer.

Detection of risk factors related to administration suspension and severe neutropenia in gemcitabine and nab-paclitaxel treatment.
Yoshitaka Saito, Yoh Takekuma, Masaki Kobayashi, Yoshito Komatsu, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 29, 6, 3277, 3285, 2021年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The combination of gemcitabine (GEM) and nanoparticle albumin-bound paclitaxel (nab-PTX) is an effective chemotherapeutic regimen for locally advanced and metastatic pancreatic cancer. The dose-limiting toxicities (DLTs) of this treatment are sepsis and neutropenia, while the relative dose intensity (RDI) of GEM is approximately 75% and of nab-PTX is 70-80%. In this study, we evaluated the risk factor(s) regarding treatment suspension, which leads to reduction in the RDI of these agents, enabling appropriate schedule management. METHODS: Two hundred patients with pancreatic cancer who received GEM + nab-PTX were retrospectively investigated. Frequency and risk factor(s) of suspension of the treatment and grade 3/4 neutropenia in the first course were evaluated. RESULTS: The frequency of treatment suspension in the first course was 61%. The frequency of grade 3/4 neutropenia was 51%, while that of thrombocytopenia was 7.5%. The RDI was 78.0% for GEM and 77.7% for nab-PTX. Univariate and multivariate analyses to identify risk or preventive factors related to treatment suspension suggested that low platelet count at baseline was a risk factor, whereas dose reduction from the treatment initiation was a preventive factor. The most common cause of abeyance was grade 3/4 neutropenia (83.6%), the risk factors of which were low platelet count and age ≥ 65 years at baseline, while dose reduction was a preventive factor. CONCLUSION: We found that a low platelet level at baseline was a risk factor, whereas dose reduction from initiation was a preventive factor in regard to treatment suspension and severe neutropenia occurrence in GEM + nab-PTX treatment.

Hypertriglyceridemia induced by S-1: A novel case report and review of the literature.
Yoshitaka Saito, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 27, 4, 1020, 1025, 2021年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, INTRODUCTION: S-1, a compounding agent of tegafur, gimeracil, and oteracil potassium, is one of the most effective chemotherapeutic agents for colorectal cancer. In this case, following S-1 administration, we observed predominant elevation of serum triglyceride. CASE REPORT: A 49-year-old man with stage IV transverse colon adenocarcinoma received S-1 + irinotecan + bevacizumab. At the end of the S-1 administration period in every course, his serum triglyceride level was found to be elevated. Finally, it reached grade 4, without any symptoms of acute pancreatitis in the fifth course, and fenofibrate 80 mg once a day was administered.Management & outcome: Interestingly, the elevation spontaneously normalized without any pharmacotherapy 14 days after S-1 withdrawal, and this elevation did not occur when S-1 was not administered. Further, fenofibrate administration attenuated the hypertriglyceridemia to grades 1-3, with no complications. DISCUSSION: S-1 administration induced hypertriglyceridemia owing to the elevated serum triglyceride; however, a contrasting result was observed in the S-1 withdrawal period and during the S-1-cessation cycle. Since dietary intake was poorer during the S-1 administration period, it is considered that S-1 might have disturbed lipid metabolism. Further, we know that capecitabine, which is a prodrug of fluorouracil, also induces hypertriglyceridemia. As the end product of these medicines is fluorouracil, the presence of fluorouracil or its metabolizing enzymes, the genetic background of the patient might have affected the results. We have to be aware of the risk of asymptomatic and temporal occurrence of hypertriglyceridemia by S-1 administration for the early detection with appropriate pre-emptive treatment.

Benzodiazepine Concentrations in the Breast Milk and Plasma of Nursing Mothers: Estimation of Relative Infant Dose.
Ayako Nishimura, Ayako Furugen, Takeshi Umazume, Seika Kitamura, Mayuko Soma, Kiwamu Noshiro, Yoh Takekuma, Mitsuru Sugawara, Ken Iseki, Masaki Kobayashi
Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine, 16, 5, 424, 431, Mary Ann Liebert Inc, 2021年05月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Objective: Benzodiazepines are common therapies for mental illness and insomnia, and are used during pregnancy and lactation. Although benzodiazepines have been shown to be transferred into breast milk, the amount transferred is small and compatible with breastfeeding. However, information is not available for all drugs. Therefore, we aimed to determine the milk to plasma (M/P) ratio and relative infant dose (RID), which are used as indicators of drug transfer to breast milk, to determine the safety of such drugs for lactating women and breastfeeding infants. Methods: The study comprised of 11 pregnant women who visited the obstetrics department of Hokkaido University Hospital (approval number: 017-0131) and Tenshi Hospital (approval number: 103) for childbirth. The samples were analyzed using liquid chromatography-tandem mass spectrometry, and the M/P ratio and RID were calculated. The condition of the mother and baby at 1 month after delivery was determined from the clinical information. The target benzodiazepines were alprazolam, brotizolam, clonazepam, clotiazepam, etizolam, ethyl loflazepate, flunitrazepam, and lorazepam. Results: For all drugs, the M/P ratios were <1 and remained constant over time. For drugs other than ethyl loflazepate, the RID values were <10%, which are considered safe; however, even with ethyl loflazepate, it was only slightly >10%. No abnormalities were found in breastfeeding infants whose mothers were receiving these medications. Conclusions: The RID results of this study suggest that drug exposure through breast milk is small; thus, maternal drug treatment and breastfeeding are compatible.

Sarcopenia in a patient with most serious complications after highly invasive surgeries treated with nutrition, rehabilitation, and pharmacotherapy: a case report.
Michiyo Tatsumi, Satomi Kumagai, Takahiro Abe, Soichi Murakami, Hiroshi Takeda, Toshiaki Shichinohe, Yuko Watanabe, Shinsuke Katayama, Shiaki Hirai, Aiko Honda, Yoh Takekuma, Mitsuru Sugawara
Journal of pharmaceutical health care and sciences, 7, 1, 16, 16, 2021年04月06日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: Several studies have reported the implementation of nutrition therapy and rehabilitation for acute and critical illnesses. However, rehabilitation nutrition for elderly sarcopenia patients with extremely severe postoperative complications during hospitalization has not yet been established. CASE PRESENTATION: We report the case of a 70-year-old man with sarcopenia that developed as a postoperative complication of the surgical resection of perihilar cholangiocarcinoma and left the patient bedridden from prolonged malnutrition and muscle weakness. The patient's general condition improved after a nearly 6-month intervention by our Nutrition Support Team (NST) that combined nutrition, exercise, and pharmacotherapy. CONCLUSIONS: The appropriate timing and order of pharmacotherapy, nutrient administration, exercise therapy, and team collaboration may enable elderly patients with severe (secondary) sarcopenia and postoperative complications to regain self-sustained walking.

北海道大学病院における新型コロナウイルス感染症の流行に伴う職務上の影響にかかわる調査結果
阿部 結希, 清水 薫子, 中司 展人, 船木 典子, 長堀 紀子, 菅原 満, 澁谷 斉, 高橋 久美子, 北川 善政, 今野 哲, 渥美 達也
日本医師会雑誌, 150, 1, 95, 100, (公社)日本医師会, 2021年04月, ［査読有り］
日本語, 新型コロナウイルス感染症(COVID-19)流行による業務への影響を把握し、今後の方策を提案することを目的とし、北海道大学病院に勤務する職員を対象に、2020年2月28日〜5月31日の業務についてアンケート調査を実施した。医育機関という観点から、診療・研究・教育という多面的な評価を行い、欠勤とその理由についても調査した。いずれの業務においても、多様な影響が見られた。欠勤はすべての職種に認められ、主な理由は、家族の一斉休校、休園や自粛要請であった。職場の雰囲気や理解、体制の構築を望む回答者が多く見られ、オンライン化や在宅・分散勤務、感染対策の徹底など、継続が有効と思われる変化も見られた。特に感染対策として、本人あるいは家族の体調不良時の欠勤、復職基準の徹底は重要であり、同時に職員がスムーズに出欠勤できる支援体制が必要と思われた。(著者抄録)

レセプトデータに基づくクローン病新規ブデソニド徐放性製剤の実態調査
窪田 篤人, 今井 俊吾, 百 賢二, 菅原 満, 武隈 洋
薬局薬学, 13, 1, 54, 61, (一社)日本薬局学会, 2021年04月, ［査読有り］
日本語, 【背景】クローン病(CD)は,主として全消化管に非連続性の慢性肉芽腫性炎症などを生じる原因不明の炎症性疾患である.昨今,生体内利用率の低いブデソニド徐放性製剤(当製剤)が高い治療成績を収めているが,本邦における使用経験は少ないのが現状である.【目的】当製剤使用患者の併用薬,検査項目を抽出し,その特徴を明らかにすることを目的とした.【方法】JMDC Claims Databaseより2016年11月から2017年6月30日までにCDと診断された患者のうち,当製剤を処方された患者51名を抽出した.【結果・考察】当製剤使用患者は,使用前に比べ5-ASA,PSLの使用率が低く,他剤無効による治療薬変更の可能性が示された.また,B型肝炎ウイルス(HBV)再活性化リスク患者(N=41)のうち,HBs,c抗体検査の頻度が少なく(N=17),適切な検査が行われていない可能性が示された.(著者抄録)

薬局薬剤師による「患者への聞き取り」に基づいて実施された疑義照会の実態解明と医療安全への貢献度評価
今井 俊吾, 難波 正志, 柏木 仁, 佐藤 夕紀, 武隈 洋, 菅原 満
薬局薬学, 13, 1, 68, 78, (一社)日本薬局学会, 2021年04月, ［査読有り］, ［責任著者］
日本語, 薬剤師は安全な薬物療法の提供のために,患者から必要な情報を「聞き取る」ことが重要である.しかし,薬局薬剤師の「聞き取り」に対し,一部の一般市民は厳しい視線を投げかけており,患者の理解を促すためのエビデンス構築が急務である.本研究は「患者への聞き取り」に基づき実施された疑義照会に着目し,その実態解明と医療安全への貢献度評価を試みた.解析には北海道大学病院の近隣薬局の疑義照会データを用いた.その結果,聞き取りに基づく疑義照会は「薬学的疑義照会の33.3%を占め,高い許諾割合(98.5%)を有し,用法や用量などの疑義照会分類において,医療安全への貢献度が高い」ことが見いだされた.また,このうち「医師からの説明と処方内容が食い違う」ことが発端となった事例が,特に医療安全へ貢献していることが示された.「患者への聞き取り」に基づく疑義照会の有用性を広く調査するための基礎となる知見が創出された.(著者抄録)

Efficacy and safety of colistin for the treatment of infections caused by multidrug-resistant gram-negative bacilli.
Keisuke Kagami, Nobuhisa Ishiguro, Takehiro Yamada, Yusuke Niinuma, Sumio Iwasaki, Keisuke Taki, Tatsuya Fukumoto, Kasumi Hayasaka, Reiko Oyamada, Tsubasa Watanabe, Mutsumi Nishida, Junichi Sugita, Takanori Teshima, Mitsuru Sugawara, Yoh Takekuma
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 27, 3, 473, 479, 2021年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: The efficacy and safety of colistin for the treatment of infections caused by multidrug-resistant gram-negative bacilli have been poorly investigated in Japanese patients. This study was performed to investigate the efficacy and safety of colistin in Japanese patients by analyzing a considerable number of cases. Furthermore, we evaluated the relationship between the plasma concentration and efficacy and safety of colistin in some cases. METHODS: A retrospective cohort study was conducted at Hokkaido University Hospital, analyzing patients treated with colistin (colistimethate sodium) during the period from January 2007 to December 2019. RESULTS: Overall, 42 cases were enrolled. Favorable clinical response was observed in 25 cases (59.5%), with an all-cause 30-day mortality of 33.3% (14/42 cases). Microbiological eradication was achieved in 18 cases (42.9%). Nephrotoxicity was observed in 20 cases (47.6%) and was mild and reversible in all cases. Plasma trough concentrations of colistin determined in nine patients correlated with changes in serum creatinine concentration (⊿) and creatinine clearance (%). The cutoff value of colistin trough concentration for nephrotoxicity was 2.02 μg/mL. CONCLUSION: Our results showed approximately 60% clinical efficacy of colistin therapy against infections caused by multidrug-resistant gram-negative bacilli in the patients. Further studies with larger populations are needed to elucidate the efficacy and safety of colistin in Japanese patients.

Impact of histamine type-2 receptor antagonists on the anticancer efficacy of gefitinib in patients with non-small cell lung cancer.
Yoshitaka Saito, Yoh Takekuma, Masaki Kobayashi, Naofumi Shinagawa, Yasushi Shimizu, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Ken Iseki, Mitsuru Sugawara
European journal of clinical pharmacology, 77, 3, 381, 388, 2021年03月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Gefitinib is one of the standard treatments for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor mutations. It has been reported that acid suppressants (AS) decrease the anti-tumor effect of gefitinib by reducing its solubility. AS is sometimes necessary in cancer patients; however, previous reports have not shown the most compatible AS with gefitinib administration in cancer patients. This study was conducted to determine if histamine type 2 receptor antagonists (H2RAs) can affect the anti-tumor efficacy of gefitinib. METHODS: Eighty-seven patients with NSCLC who were administered gefitinib were retrospectively investigated. Patients who were co-administered H2RA were compared with non-AS control patients. H2RA was administered once a day at about 3-5 or 8-12 h after gefitinib intake. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR), and adverse effects. RESULTS: Median PFS in H2RA group and control group was 8.0 months and 9.0 months, respectively, with no significant difference (p = 0.82). The incidence of liver dysfunction was significantly less in patients administered H2RA, whereas there were no differences between the two groups with regard to skin toxicity and diarrhea. Multivariate analysis suggested that H2RA co-administration is not a risk factor for worse PFS and OS (hazard ratio of 0.95, 0.86; 95% confidence interval of 0.60-1.48, 0.52-1.43; p = 0.82 and 0.60, respectively). CONCLUSION: This study demonstrated that concomitant administration of H2RA with gefitinib does not affect the efficacy of gefitinib.

A new system to evaluate characteristics of Niemann-Pick C1 Like 1-mediated cholesterol transport using Xenopus laevis oocytes.
Shunsuke Nashimoto, Saori Yagi, Naoki Takeda, Miku Nonaka, Yoh Takekuma, Mitsuru Sugawara, Yuki Sato
Biochimica et biophysica acta. Biomembranes, 1863, 2, 183508, 183508, 2021年02月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Niemann-Pick C1 Like 1 (NPC1L1) is known to be involved in the intestinal absorption of cholesterol. For evaluating the function of NPC1L1, cell lines such as Caco-2, Madin-Darby canine kidney (MDCK) II, and McA-RH7777 have been used in previous studies, but the detailed molecular mechanism of transport has not been elucidated. In this study, the characteristics of cholesterol transport via NPC1L1 were investigated using a Xenopus laevis oocyte expression system in addition to a conventional cell line with stable expression. The transport activity of cholesterol uptake was increased in NPC1L1-overexpressed MDCK cells compared with that in mock cells, but MDCK cells expressed endogenous NPC1L1 and had high cholesterol transport activity. On the other hand, cRNA-injected oocytes expressed NPC1L1 after culturing for 5-6 days. The transport activity of cholesterol uptake was increased in NPC1L1 cRNA-injected oocytes compared with that in water-injected oocytes. In addition, the uptake of cholesterol was decreased in the presence of ezetimibe, an NPC1L1 inhibitor, in cRNA-injected oocytes but not in control oocytes, indicating that endogenous NPC1L1 is not expressed in oocytes. Furthermore, cholesterol uptake was substantially decreased in NPC1L1 L216A cRNA-injected oocytes compared with that in NPC1L1 cRNA-injected oocytes, indicating that leucine at position 216 of NPC1L1 is important for cholesterol transport and that an oocyte expression system is useful for mutant analysis. These results indicate that the oocyte expression system is useful for evaluating the characteristics of NPC1L1-mediated cholesterol transport and may contribute to the elucidation of the detailed molecular mechanism of cholesterol transport via NPC1L1.

Risk Analysis of Denosumab-Induced Hypocalcemia in Bone Metastasis Treatment: Renal Dysfunction Is Not a Risk Factor for Its Incidence in a Strict Denosumab Administration Management System with Calcium/Vitamin D Supplementation.
Yoshitaka Saito, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 44, 12, 1819, 1823, 2021年, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, We have reported that a strict denosumab administration management system with oral calcium/vitamin D supplementation attenuates denosumab-induced hypocalcemia in 158 cancer patients with bone metastasis. In this report, 27.8% of the patients experienced hypocalcemia, including 0.6% with grade 2. So far, the risk factors for ≥grade 2 hypocalcemia incidence have been identified in denosumab-treated cancer patients, including patients without calcium/vitamin D supplementation. Therefore, the present study aimed to reveal the factors that affect all-grade hypocalcemia incidence with calcium/vitamin D supplementation and team medical care according to the management system. A receiver operating characteristic curve analysis suggested that the cutoff of baseline serum calcium level for all-grade hypocalcemia incidence was 9.3 mg/dL. Multivariate analysis revealed that age ≥65 years (odds ratio, 95% confidence interval: 2.57, 1.11-5.95, p = 0.03), grade 1 or higher serum alkaline phosphatase elevation (3.70, 1.71-8.00, p < 0.01), an adjusted serum calcium level of less than 9.3 mg/dL (3.21. 1.25-8.24, p = 0.02) at baseline, and co-administration of cytotoxic agents (2.33, 1.06-7.11, p = 0.03) are risk factors for the incidence of all-grade hypocalcemia. However, renal dysfunction, which has been suggested to be a risk factor in previous reports, was not a factor. In conclusion, we revealed the risk factors for all-grade hypocalcemia in calcium/vitamin D supplementation and awareness, as demonstrated by the management system. Moreover, renal dysfunction was not a risk factor in our strict denosumab administration management system. Our results support the value of early detection of hypocalcemia incidence to guide the selection of an appropriate management strategy.

Hypertriglyceridemia Induced by Fluorouracil: A Novel Case Report
Yoshitaka Saito, Yoh Takekuma, Satoshi Yuki, Yoshito Komatsu, Mitsuru Sugawara
Case Reports in Oncology, 14, 1, 207, 211, 2021年01月, ［査読有り］, ［責任著者］
研究論文（学術雑誌）, We had previously reported on S-1-induced hypertriglyceridemia. Here, we report fluorouracil-induced hypertriglyceridemia in a patient with capecitabine-induced hypertriglyceridemia and the corresponding therapeutic process. A woman in her forties who had experienced grade 3 hypertriglyceridemia due to oxaliplatin + capecitabine was administered fluorouracil ± oxaliplatin + levofolinate calcium + panitumumab; however, grade 4 hypertriglyceridemia occurred after the thirteenth administration. Bezafibrate normalized the elevation. Chemotherapy cessation resulted in its decrease to normal, and bezafibrate was stopped. Nine months after cessation, treatment with fluorouracil + irinotecan + levofolinate calcium + ramucirumab was initiated. After four cycles of treatment, her serum triglyceride levels increased again to grade 3, and then, fenofibrate was administered, resulting in a significant decrease to grade 1-2. Serum triglyceride levels significantly reduced after cessation of the prior fluorouracil-containing regimen, although its elevation was observed again following the latter treatment. Therefore, fluorouracil-induced hypertriglyceridemia was strongly speculated in this case. We have speculated that the most probable cause of tegafur and capecitabine-induced hypertriglyceridemia is fluorouracil or its metabolic enzymes since their end product is fluorouracil in the previous report. Results from this patient suggest that our supposition was correct. Fibrates administration, cessation of the treatment, and monitoring of serum triglyceride level was effective in this case as well as previous reports. Fluorouracil-induced hypertriglyceridemia is associated with the one caused by tegafur and capecitabine and presents the possibility of severe complications. Elucidation of its exact mechanism and epidemiological features is needed for better understanding.

Implementation Status of Liver Function Tests for Monitoring Benzbromarone-Induced Hepatotoxicity: An Epidemiological Survey Using the Japanese Claims Database.
Shungo Imai, Yasuyuki Nasuhara, Kenji Momo, Hiromitsu Oki, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Biological & pharmaceutical bulletin, 44, 10, 1499, 1505, 2021年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, A major adverse effect of benzbromarone is hepatotoxicity. Therefore, periodic liver function tests are required at least for the first 6 months of benzbromarone administration. However, it is not clear whether the relevant blood tests are implemented appropriately. Here, we performed a cross-sectional survey of the implementation status of liver function tests in patients who were newly prescribed benzbromarone, using the Japanese large claims database. Male patients who were newly prescribed benzbromarone from January 2010 to December 2016 were included. We targeted patients who continued benzbromarone during the observation period (up to 180 d from the start of administration). The primary endpoint was the proportion of patients in whom periodic liver function tests were implemented. A periodic liver function test was defined as one or more liver function tests performed during both 1-90 and 91-180 d of initial benzbromarone administration. We labeled the tests as a "periodic test" or "non-periodic test" based on whether periodic liver function tests were performed or not, respectively. Furthermore, factors influencing non-periodic test were analyzed. Periodic testing was implemented only in 28.7% of patients. Additionally, factors such as number of hospital beds ≤19 (compared to 100-199 beds) and duration of the first prescription of benzbromarone were associated with non-periodic testing. Our study revealed that periodic liver function tests are not performed sufficiently in Japan. Thus, clinicians prescribing benzbromarone should be educated about the test. Our blood-test-based approach should be applied to other drugs and countries in future research.

cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability.
Tsuyoshi Aoyama, Hiroki Kuriyama, Yuki Sato, Shungo Imai, Hitoshi Kashiwagi, Mitsuru Sugawara, Yoh Takekuma
Biological & pharmaceutical bulletin, 44, 8, 1101, 1110, 2021年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Dasatinib is a first-line pharmacotherapeutic treatment for chronic myeloid leukemia (CML). It is more effective than traditional treatments but causes adverse effects such as pleural effusion that limits its effective treatment cycle. Since pleural effusion is caused by vascular hyperpermeability and causes discontinuation of treatment with dasatinib, it is important to explore the mechanism of pleural effusion caused by dasatinib and how to prevent it. In this study, we investigated how dasatinib increase vascular permeability, and how it can be prevented. Cytotoxicity was observed in vascular endothelial cells or epithelial cells were exposed to high concentrations of dasatinib. Thus, it was observed in vascular endothelial cells such as human umbilical vascular endothelial cell (HUVEC). Vascular endothelial (VE)-cadherin is one of the important factors that control vascular permeability. When VE-cadherin expression decreases, vascular permeability increases, but it did not change with tyrosine kinase inhibitor exposure. Monolayer permeability significantly increased only with high concentration of dasatinib, but this increase was prevented by cAMP activation. Furthermore, dasatinib affects the cell morphology of HUVEC, with increased inter celluar space compared to control and bosutinib, which were also attenuated by cAMP activation. Dasatinib significantly affected permeability control of vascular endothelial cells compared to bosutinib and imatinib. These results indicated that the cAMP signaling pathway may be involved in the pleural effusion caused by dasatinib in CML patients.

Investigation of the Real-World Situation and Risk Factors Associated with Olanzapine Prescribed to Diabetes Patients by Using a Japanese Claims Database.
Shinsuke Yamashita, Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Mitsuru Sugawara, Yoh Takekuma
Biological & pharmaceutical bulletin, 44, 8, 1151, 1155, 2021年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Olanzapine is effective for schizophrenia management; however, it is contraindicated in diabetes patients. In addition, olanzapine is useful for treating nausea and vomiting, such as in the case of chemotherapy-induced nausea and vomiting (CINV). Therefore, we hypothesized that the contraindicated prescription of olanzapine likely occurs among cancer patients with diabetes, especially by non-psychiatric physicians. Hence, we conducted a nationwide survey to elucidate the situation of such contraindicated prescriptions and the associated risk factors. We extracted the data of patients who were newly prescribed olanzapine between April 2015 and March 2017 from the health insurance claims database developed by JMDC, Inc., Tokyo. The patients who were prescribed contraindicated olanzapine were defined as those who were prescribed olanzapine after a diagnosis of diabetes and diabetes drug prescription. In all, the data of 7181 patients were analyzed. We evaluated the proportion of diabetes patients who were prescribed contraindicated olanzapine from among those who were prescribed olanzapine. Furthermore, we investigated the background of patients who were prescribed olanzapine for information such as olanzapine prescribers and history of cancer chemotherapy. In all, 100 diabetes patients (1.39%) were prescribed olanzapine. In these patients, the frequency of olanzapine prescription was higher by non-psychiatry/neurology physicians than by psychiatry/neurology physicians (3.25 and 0.85%, respectively). Additionally, all olanzapine prescriptions in cancer chemotherapy-treated diabetes patients were issued by non-psychiatry/neurology physicians. Thus, our study revealed there were diabetes patients who were prescribed olanzapine. Additionally, olanzapine for CINV management was more likely to be a contraindicated prescription.

[Pharmaceutical Intervention According to Strict Management System Can Normalize Decreased Serum Calcium Level by Denosumab and Prevent Its Aggravation].
Yoshitaka Saito, Kazuki Uchiyama, Tatsuhiko Sakamoto, Kojiro Yamazaki, Kosei Kubota, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan, 141, 8, 1023, 1030, 2021年, ［査読有り］, ［責任著者］, ［国内誌］
日本語, 研究論文（学術雑誌）, Denosumab is a fully monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL), and prevents skeletal-related events by bone metastasis. Hypocalcemia is the most typical adverse effect of denosumab use. We have developed a management system for the more efficient and safer management of denosumab administration, and evaluated pharmaceutical interventions for the better control of hypocalcemia. All pharmaceutical interventions in the system from April 2016 to March 2020 were retrospectively evaluated. We have also assessed the incidence of hypocalcemia in 158 patients who were administered denosumab for six months or more in the period. A total of 282 pharmaceutical interventions (7.0% of the total administration) were conducted. The most conducted intervention was regarding hypocalcemia, which involved the suspension of the injection and/or the increase of calcium and vitamin D supplement with 65% adoption and 17% temporary treatment suspensions. Other interventions were about hypercalcemia, request of laboratory examination and ordering supplements, dental consultation, and poor renal function. A total of 199 interventions (70.6%) were adopted, with 33 administrations suspended. The frequency of hypocalcemia was 27.8% with just one patient having grade 2 hypocalcemia, suggesting that there were no severe cases. Moreover, hypocalcemia was significantly normalized following pharmaceutical intervention and/or handling by physicians (p=0.02) according to the system. Conversely, the normalization rate in hypercalcemia did not differ according to the countermeasures. In conclusion, pharmaceutical interventions according to our management system benefit safe denosumab treatment, especially in severe hypocalcemia prevention.

An imaging approach for determining the mechanism of enhancement of intestinal absorption of an L-theanine supplement.
Yuki Sato, Kazuki Yamaguchi, Mikako Ogawa, Yoh Takekuma, Mitsuru Sugawara
PloS one, 16, 6, e0253066, 2021年, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND & OBJECTIVE: Theanine (L-glutamylethylamide) contained in green tea is a functional food component that has been attracting attention due to its relaxation effect. It was shown that the ingredients added to the theanine formulations increased the absorption of theanine. If this mechanism can be elucidated, it would be possible to contribute to development of evidence-based formulations. In this study, we investigated the effect of ingredients in the formulations on the absorption of theanine in detail. MAIN METHODS: After oral administration of a mixture of theanine and additional components to Wistar rats the plasma concentration was determined by an HPLC and the pharmacokinetic parameters were calculated. In addition, a new system for evaluating intestinal blood flow was developed since the involvement of intestinal blood flow was considered as a factor that increased absorption of theanine. KEY FINDINGS: Plasma concentration of theanine increased significantly in the combined use group with eight ingredients containing piperine as compared with theanine only group. Piperine would increase theanine absorption by increased blood flow, not an inhibition of metabolism. We succeeded to develop a visual and quantitative system to evaluate the effect of these ingredients directly including piperine on the intestinal blood flow using indocyanine green while maintaining physiological conditions. SIGNIFICANCE: Increased intestinal blood flow by these ingredients including piperine enhanced the absorption of theanine. Other mechanisms may also be considered as the mechanism by which theanine absorption is increased in addition to increased blood flow.

Safety Evaluation of Initial CT-P6 Administration for 30 min during the Switch from Reference Trastuzumab in Maintenance Infusion: A Multicenter Observational Study.
Yoshitaka Saito, Shinya Tamaki, Haruka Hasegawa, Kenta Takahashi, Akira Tokutome, Yoh Takekuma, Hiroko Yamashita, Yoshito Komatsu, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 44, 4, 474, 477, 2021年, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, CT-P6 is a biosimilar of trastuzumab and is recommended to be administered for 30-90 min in subsequent maintenance infusions to prevent infusion-related reactions (IRRs). We administered CT-P6 for 30 min as the first injection and as an alternative to reference trastuzumab in the maintenance infusion and evaluated the safety of the administration. A total of 140 patients with breast or gastric cancer, who received a switch from tri-weekly reference trastuzumab to CT-P6 for 30 min in maintenance infusions, were retrospectively evaluated. Premedication was administered prior to an infusion of CT-P6 and a cytotoxic agent. However, premedication was not provided when CT-P6 was co-administered with pertuzumab or administered alone. The primary endpoint was the incidence of IRRs. The secondary endpoint was the incidence of diarrhea and skin toxicity. Ninety-five percent of the patients had breast cancer, and 44.3% had advance-stage cancer. The treatment included CT-P6 alone (17.9%) or with cytotoxic agents (23.6%), antihormonal drugs (25.7%), and pertuzumab (62.9%). Median administration time of trastuzumab at the switch was 13 administrations (range 2-140). Premedication was administered to 20.7% patients. One patient (0.7%) experienced grade 3 IRR. The frequency of diarrhea in the reference trastuzumab group and the CT-P6 group was 7.1 and 6.4%, respectively, and that of skin toxicity was 6.4 and 5.0%, respectively, without differences. In conclusion, we first demonstrated that an initial CT-P6 administration for 30 min during the switch from reference trastuzumab in maintenance infusion is an acceptable administration method.

Construction of a Risk Prediction Model of Extended Release Oxycodone Tablet-Induced Nausea and Clarification of Predictive Factors.
Masayoshi Kumai, Shungo Imai, Shintaro Kato, Ryo Koyanagi, Kenkichi Tsuruga, Takehiro Yamada, Yoh Takekuma, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 44, 4, 593, 598, 2021年, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Nausea is a typical adverse event associated with opioids. In this study, we performed logistic regression analysis with the aim of clarifying the risk factors for nausea induced by extended-release oxycodone (ER-OXY). Furthermore, we constructed a decision tree (DT) model, a typical data mining method, to estimate the risk of oxycodone-induced nausea by combining multiple factors. A retrospective study was conducted on patients who newly received ER-OXY for cancer pain during hospitalization at Hokkaido University Hospital in Japan from April 2015 to March 2018. In logistic regression and DT analyses, the dependent variable was the presence or absence of nausea. Independent variables were the potential risk factors. First, univariate analyses were performed to screen potential factors associated with oxycodone-induced nausea. Then, multivariate and DT analyses were performed using factors with p-values <0.1 in the univariate analysis. Of 267 cases included in this study, nausea was observed in 30.3% (81/267). In multivariate logistic regression analysis, only female sex was extracted as an independent factor affecting nausea (odds ratio, 1.98). In the DT analysis, we additionally revealed that an age <50 years was a risk factor for nausea in female patients. Thus, our DT model indicated that the risk of ER-OXY-induced nausea was highest in the subgroup comprising females <50 years of age (66.7%) and lowest in male patients (25.1%). The DT model suggested that the factor of young women may be an increased risk of ER-OXY-induced nausea.

Evaluation of Chemotherapy Regimen Management Practice by Oncology-Specialized and Non-specialized Pharmacists Collaboration.
Yoshitaka Saito, Kazuki Uchiyama, Tatsuhiko Sakamoto, Kosei Kubota, Hiromitsu Oki, Miwako Iwai, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 44, 3, 293, 297, 2021年, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, Chemotherapy regimen management is one of the most important oncology pharmacy practices, because chemotherapy is conducted according to the registered regimens. In this study, we evaluated the pharmaceutical practice that assumes the initial confirmation of chemotherapy regimens and the quality of practice sharing between oncology-specialized and non-specialized pharmacists in regimen management committee. Pharmacists initially confirmed the applied regimen prescribed by physicians regarding chemotherapeutic agents and prophylactic supportive care medicines. Following confirmation, the regimens were reviewed by the Hokkaido University Hospital Regimen Management Committee. A total of 233 regimens were reviewed by the committee over three years. In total, 110 pharmaceutical inquiries were conducted, 45% of inquiries were concerning chemotherapeutic agents, of which approximately half were regarding supportive care medicines. Most inquiries were regarding premedication, followed by those on administration time, solvent of infusion medicines, and dosage. Correction was performed for 84.5% of inquiries. There was no significant difference in inquiry rates between practice and trial regimens. We have entrusted the first basic regimen review according to the checklist, creation of the chemotherapy plan document, and registry of the adopted regimens in the ordering system from oncology-certified pharmacists to non-certified pharmacists. Basic regimen review was well conducted by a non-certified pharmacist, and a more advanced review was additionally performed by certified pharmacists. In conclusion, we demonstrated the utility of pharmaceutical confirmation in a chemotherapeutic regimen review, suitable review coverage, and quality practice sharing between oncology-certified and non-certified pharmacists, which is one of the recommended methods in chemotherapy regimen review.

Probiotic Prescription Status of Pediatric Patients with Otitis Media Receiving Oral Amoxicillin or Amoxicillin/Clavulanate from April 2016 to March 2017 Using a Japanese Health Insurance Claims Database.
Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Biological & pharmaceutical bulletin, 44, 3, 448, 452, 2021年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Antibiotic-associated diarrhea (AAD) is a typical side effect of antibiotic treatment, especially in children. Amoxicillin (AMPC) and amoxicillin/clavulanate (AMPC/CVA) are associated with high risk of AAD; however, these antibiotics are important in the pediatric field. Recent research suggests that probiotics prevent pediatric AAD, including that caused by AMPC and AMPC/CVA. Indeed, guidelines for acute otitis media in children recommend the concomitant use of probiotics. However, the prescription status of probiotics for pediatric patients with otitis media receiving oral AMPC and AMPC/CVA remains unknown. We therefore conducted a survey to clarify the current status of these prescriptions and, in particular, to identify specific populations with a low proportion of probiotic prescriptions. Pediatric patients (≤15 years of age) newly prescribed oral AMPC or AMPC/CVA for otitis media between April 2016 and March 2017 were identified from a Japanese health insurance claims database. Eligible patients were divided into the AMPC (1303 patients) and AMPC/CVA (424 patients) groups, in which 659 (50.6%) and 293 (69.1%) patients were prescribed probiotics, respectively. Of the patients receiving probiotic prescriptions in the AMPC and AMPC/CVA groups, 632 (95.9%) and 286 (97.6%) patients received antibiotic-resistant probiotic prescriptions, respectively. When classified by the prescribing clinical department and patient age, the proportions of probiotic prescriptions in Internal Medicine and Pediatrics departments were lower than those in the Otorhinolaryngology department regardless of age. These results indicate the probability of insufficient probiotic prescriptions for pediatric patients with otitis media. Solving this issue may lead to the provision of safer antimicrobial therapy.

Pharmacokinetics of mycophenolic acid after haplo-hematopoietic stem cell transplantation in Japanese recipients.
Kazuki Uchiyama, Yoshitaka Saito, Yoh Takekuma, Junichi Sugita, Takanori Teshima, Mitsuru Sugawara
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 28, 1, 1078155220980815, 1078155220980815, SAGE Publications, 2020年12月22日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Mycophenolate mofetil (MMF), a mycophenolic acid (MPA) prodrug, is used to prevent graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation (HSCT). Although previous studies have reported that enterohepatic circulation (EHC) of MPA, which is usually observed in MMF-treated patients, does not occur in HSCT patients, it is unclear what happens in haploidentical-HSCT (haplo-HSCT) patients, who are using post-transplant cyclophosphamide. This study was conducted to investigate MPA pharmacokinetics in haplo-HSCT patients. METHODS: Seventeen haplo-HSCT patients, who received MMF for GVHD prophylaxis, were enrolled in this study. We collected blood samples on days 14 and 28, and plasma MPA concentrations were measured by high-performance liquid chromatography; pharmacokinetic parameters such as area under the curve (AUC), mean residence time (MRT), and apparent oral clearance (CL/F) were measured with moment analysis. We also evaluated EHC as AUC6-12h/AUC0-12h. RESULTS: There was no significant difference in MPA pharmacokinetic parameters between days 14 and 28. There was also no difference between the pharmacokinetic parameter changes and diarrhea. Additionally, varying plasma MPA concentrations suggested that MPA EHC did not occur. CONCLUSION: In this study, we revealed the pharmacokinetics of MMF in Japanese haplo-HSCT recipients. Additionally, our study demonstrated that MPA EHC might not occur in Japanese haplo-HSCT recipients.

A Risk Prediction Flowchart of Vancomycin-Induced Acute Kidney Injury to Use When Starting Vancomycin Administration: A Multicenter Retrospective Study.
Takayuki Miyai, Shungo Imai, Hitoshi Kashiwagi, Yuki Sato, Shota Kadomura, Kenji Yoshida, Eri Yoshimura, Toshiaki Teraya, Takashi Tsujimoto, Yukari Kawamoto, Tatsuya Itoh, Hidefumi Ueno, Yoshikazu Goto, Yoh Takekuma, Mitsuru Sugawara
Antibiotics (Basel, Switzerland), 9, 12, 1, 12, 2020年12月18日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, We previously constructed a risk prediction model of vancomycin (VCM)-associated nephrotoxicity for use when performing initial therapeutic drug monitoring (TDM), using decision tree analysis. However, we could not build a model to be used at the time of initial administration due to insufficient sample size. Therefore, we performed a multicenter study at four hospitals in Japan. We investigated patients who received VCM intravenously at a standard dose from the first day until the initial TDM from November 2011 to March 2019. Acute kidney injury (AKI) was defined according to the criteria established by the "Kidney disease: Improving global outcomes" group. We extracted potential risk factors that could be evaluated on the day of initial administration and constructed a flowchart using a chi-squared automatic interaction detection algorithm. Among 843 patients, 115 (13.6%) developed AKI. The flowchart comprised three splitting variables (concomitant drugs (vasopressor drugs and tazobactam/piperacillin) and body mass index ≥ 30) and four subgroups. The incidence rates of AKI ranged from 9.34 to 36.8%, and they were classified as low-, intermediate-, and high-risk groups. The accuracy of flowchart was judged appropriate (86.4%). We successfully constructed a simple flowchart predicting VCM-induced AKI to be used when starting VCM administration.

救急/集中治療領域における薬剤師介入の実態と有害事象回避による潜在的な医療経済評価
小林 洋平, 山岡 怜央, 三上 龍生, 山崎 浩二郎, 熊井 正貴, 山田 武宏, 武隈 洋, 菅原 満, 井関 健
日本臨床救急医学会雑誌, 23, 6, 771, 779, (一社)日本臨床救急医学会, 2020年12月, ［査読有り］
日本語, 目的:救急/集中治療室(以下、ICU)における薬剤師介入の実態や医療経済効果を明らかにすることを目的とした。方法:2017年7、8月に、救急科に入院した患者を対象とし、疑義照会記録を用いて後方視的に調査した。薬学的知識を要しない介入を単純エラー、薬学的知識を要する介入を薬学的介入と定義し、介入の内容および処方反映率を調査した。また、能動的な薬学的介入(薬剤師からの提案)に関して医療経済効果を算出した。結果:介入は391件あり、そのうち76%(297件)が薬学的介入であった。薬学的介入では、抗微生物薬関係の介入がもっとも多く117件(反映率91%)であった。また、医療経済効果は、2ヵ月間で3,832,000円であった。結論:薬剤師の救急/ICUへの参画は、医療経済的に有益であることが明らかとなった。また抗微生物薬関係の介入が多く、今後プロトコル作成などにより適正使用推進に寄与できると示唆された。(著者抄録)

オピオイド使用患者の眠気に対する安息香酸ナトリウムカフェイン散の効果　　　　　　　　　　　　　　　
熊井 正貴, 山田 武宏, 敦賀 健吉, 武隈 洋, 菅原 満
日本緩和医療薬学雑誌, 13, 4, 119, 125, (一社)日本緩和医療薬学会, 2020年12月, ［査読有り］, ［責任著者］
日本語, 安息香酸ナトリウムカフェイン散は眠気、倦怠感の適応を有するが、オピオイド使用患者における眠気改善には十分なエビデンスがない。われわれは、オピオイド使用患者の眠気に対する安息香酸ナトリウムカフェイン散の効果を検証するために後ろ向きカルテ調査を行った。眠気はNumeric Rating Scale(NRS)、Epworth Sleepiness Scale日本語版(JESS)を用いて評価し、倦怠感もNRSを調査した。調査対象4例すべてで眠気NRS(0〜10)は1〜5ポイント、JESSスコア(24点満点)は2〜14点の低下がみられた。倦怠感NRS(0〜10)は1例で5ポイント、1例で3ポイントの低下がみられたが、2例は不変であった。1例はせん妄、1例はイレウスにより休薬した。安息香酸ナトリウムカフェイン散は安全性に関して検証を行う必要があるが、オピオイド使用患者の眠気に対して有効である可能性が示された。(著者抄録)

Transport via Niemann-Pick C1 Like 1 contributes to the intestinal absorption of ubiquinone.
Shunsuke Nashimoto, Yuto Takekawa, Yoh Takekuma, Mitsuru Sugawara, Yuki Sato
Drug metabolism and pharmacokinetics, 35, 6, 527, 533, 2020年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Ubiquinone, which is a component in the electron-transport systems of mitochondria, is essential for various activities related to energy metabolism, but the detailed absorption mechanism of ubiquinone is not clear. On the other hand, Niemann-Pick C1 Like 1 (NPC1L1) is involved in the intestinal absorption of fat-soluble components such as cholesterol. In this study, we investigated whether the intestinal absorption of ubiquinone was transported by NPC1L1 as is cholesterol. In this study, coenzyme q10 (CoQ10) and coenzyme q9 (CoQ9) were used as models of ubiquinone. The transport activity of ubiquinone was increased significantly in NPC1L1-overexpressed Madin-Darby canine kidney (MDCK) cells compared with that in pMAM2-BSD vector-transfected MDCK cells and the uptake of ubiquinone was decreased in the presence of ezetimibe, an inhibitor of NPC1L1. These results indicate that NPC1L1 mediates the transport of ubiquinone. Furthermore, to clarify the effect of NPC1L1 on the intestinal absorption of CoQ10, emulsified CoQ10 was orally administered to Wistar rats, and the plasma concentration was measured. The plasma concentration of CoQ10 was significantly decreased by coadministration of ezetimibe and CoQ10 compared to that with administration of only CoQ10. This result indicates that the intestinal absorption of CoQ10 is mediated by NPC1L1.

Comparison of interactions between warfarin and cephalosporins with and without the N-methyl-thio-tetrazole side chain.
Shungo Imai, Shota Kadomura, Kenji Momo, Hitoshi Kashiwagi, Yuki Sato, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 26, 11, 1224, 1228, Elsevier BV, 2020年11月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Cephalosporins with an N-methyl-thio-tetrazole (NMTT) side chain interact with warfarin by reducing the production of blood clotting factors. However, cephalosporins without the NMTT side chain also enhance the effects of warfarin. Thus, we aimed to compare the effects of warfarin modified by cephalosporins with and without the NMTT side chain, using a Japanese health insurance claims database. The inclusion criteria were patients who (1) intravenously received second- or third-generation cephalosporins between April 2010 and March 2017 and (2) received warfarin during cephalosporin therapy. Patients were administered either cephalosporins with the NMTT side chain (NMTT group) or those without NMTT (non-NMTT group). After matching patient data by propensity score, the following outcomes were compared between the two groups: (1) proportion of patients administered vitamin K, (2) proportion of bleeding events, and (3) changes in the daily dose of warfarin. Among 203 patients, 100 patients (50 per group) were matched by the propensity score. The proportion of patients administered vitamin K was 6.0% in both groups. These patients intravenously received a single dose of menatetrenone; no bleeding was observed. The proportion of patients subjected to a reduction in the daily dose of warfarin was 6.5% and 4.3% in the NMTT and non-NMTT groups, respectively. As our study had a small sample size, we could not determine whether the risk of over anticoagulation of warfarin is affected by cephalosporins with or without NMTT side chain. However, we showed the bleeding risk was sufficiently low regardless of the presence/absence of the NMTT side chain.

A cross-sectional exploratory survey on occurrence of triple-whammy prescription pattern in Japan.
Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
International journal of clinical pharmacy, 42, 5, 1369, 1373, Springer Science and Business Media LLC, 2020年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background The concurrent use of nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system blockers, and diuretics, known as a "triple-whammy," is related to the occurrence of acute kidney injury. However, there are few reports regarding the prescription pattern of the triple-whammy. Objective To elucidate the patterns of the triple-whammy prescription in Japan. Methods A cross-sectional study was performed using a health-insurance-claims database that included Japanese people under 75 years of age, and enrolled outpatients that were prescribed any nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system blockers, and diuretics between April 2017 and June 2017. As an outcome, the proportion of triple-whammy prescriptions was evaluated. Among the patients who received triple-whammy prescriptions, we evaluated the prevalence of chronic kidney disease and the proportion of prescriptions provided for these three drugs from different clinical departments and institutions. Results Overall, 730 of 246,721 (0.3%) patients received triple-whammy prescriptions. Among these patients, 13.3% had underlying chronic kidney disease. The proportions of any of the three drug types prescribed by different clinical departments and institutions was 48.2% and 61.8%, respectively. Conclusions We examined the patterns of triple-whammy prescriptions and concluded that pharmacists need to pay attention to triple-whammy prescriptions if the prescriptions are provided by multiple clinical departments or institutions.

Transfer of orally administered hyaluronan to the lymph.
Yuki Sato, Tatsuru Joumura, Yoh Takekuma, Mitsuru Sugawara
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 154, 210, 213, 2020年09月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Hyaluronan (HA) has been widely used in medicines, cosmetics and supplements for health and beauty maintenance. Oral administration is the most desirable and convenient means for consumers. The intestine plays an important role in immune system. We hypothesized that orally administered HA would be transferred to both blood and lymph. In this study, we investigated how orally administered HA was absorbed from the gastrointestinal tract and how much HA was incorporated. Four HA formulations, HA-2,000, 8,000, 50,000 and 300,000, were administered to rats, and concentrations of HA in blood and lymph were determined. In the HA-2,000 group, the HA plasma concentration increased after oral administration. The highest lymph concentration of HA was also obtained by administration of HA-2,000. The plasma and lymph concentrations slightly increased after oral administration in the HA-8,000 group. On the other hand, little absorption was found in the HA-50,000 and 300,000 groups. It is speculated that smaller molecules of HA are more easily absorbed. HA-2,000 was absorbed mainly through the portal vein and through the lymph in gastrointestinal absorption. This is the first report showing that HAs, large molecular weight and water-soluble molecules, after oral administration are transferred not only into blood but also into lymph.

Nonsteroidal anti-inflammatory drugs use in patients with chronic kidney disease are often prescribed from different clinicians than those who diagnosed them.
Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Pharmacoepidemiology and drug safety, 29, 8, 873, 880, 2020年08月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: When prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) for chronic kidney disease (CKD), patients' pathology and concomitant medications should be considered. In our pharmaceutical experience, NSAIDs are often prescribed by departments that are different from those that diagnosed CKD. That is, NSAIDs may be prescribed for patients without the advice of the clinicians who diagnosed them. In this study, we aimed to elucidate how frequently such cases occur. METHODS: We used the large health insurance claims database constructed by JMDC Inc., Tokyo. We evaluated the proportions of CKD diagnosis and NSAID prescription by different clinical departments and institutions. RESULTS: A total of 224 014 out-patients were included in the analysis; they were divided into CKD (n = 1501) and non-CKD groups (n = 222 513). The internal medicine departments diagnosed CKD most frequently (74.8% of the patients) and surgical departments rarely diagnosed CKD. However, the proportion of prescribed NSAIDs was high in other departments, especially surgical departments. In the CKD group, 50.4% of the patients received CKD diagnosis and NSAID prescription from different clinical departments; 72.8% of the patients received a diagnosis and prescription from different medical institutions. CONCLUSION: Our study revealed that NSAIDs are often prescribed to patients with CKD from different clinicians than those who diagnosed them.

Effect of palonosetron and dexamethasone administration on the prevention of gastrointestinal symptoms in hepatic arterial chemoembolization with epirubicin.
Tatsuhiko Sakamoto, Yoshitaka Saito, Masaki Kobayashi, Takehiro Yamada, Yoh Takekuma, Masato Nakai, Koji Ogawa, Ken Iseki, Mitsuru Sugawara
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 28, 7, 3251, 3257, 2020年07月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: There are several studies on premedication to prevent postembolization syndromes which occurs after transcatheter arterial chemoembolization (TACE), but the medication to be used is still not established. This study aimed to examine the effect of palonosetron and dexamethasone on the prevention of gastrointestinal symptoms induced by TACE. METHODS: Patients with hepatocellular carcinoma who were treated with TACE with epirubicin were retrospectively evaluated. The complete response rate of antiemetic drugs and incidence and severity of gastrointestinal symptoms were compared between the antiemetic group (AE group), which includes 51 patients prophylactically administered with palonosetron 0.75 mg and dexamethasone 9.9 mg intravenously before TACE on day 1 and dexamethasone 6.6 mg intravenously on days 2 and 3, and control group with 101 patients without antiemetic premedication. RESULTS: Complete response rate in the entire evaluation period was significantly higher in the AE group compared with that in the control group. In the acute phase, the incidence and severity of nausea, vomiting, and anorexia significantly decreased in the AE group, but only anorexia improved in the delay phase. Additionally, postembolization syndromes, such as abdominal pain and fever, were significantly attenuated in the AE group; however, constipation worsened in this group. CONCLUSIONS: Premedication of palonosetron and dexamethasone significantly prevents the incidence and reduces the severity of gastrointestinal symptoms especially in the acute phase. Further studies will be needed to determine the most recommended 5-HT3 antagonist or dosage of dexamethasone in establishing the optimal antiemetic regimen.

Possibility for Dose Optimization of Pazopanib from Its Plasma Concentration in Japanese Patients with Cancer.
Hiroyuki Tanaka, Hiroaki Hiraga, Yoh Takekuma, Toru Harabayashi, Satoshi Nagamori, Masayuki Endo, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 43, 5, 762, 766, 2020年05月01日, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, The currently approved dose of pazopanib (800 mg) is being re-examined owing to its adverse effects. The aim of this study was to evaluate the relationships among starting or maintenance doses of pazopanib, estimated pazopanib Cmin, and other clinical factors, including albumin and α-1 acid glycoprotein levels, in soft-tissue sarcoma and renal cell carcinoma. We also determined whether therapeutic drug monitoring of pazopanib concentrations may be used to improve its therapeutic efficacy and prevent adverse effects. Forty patients who received pazopanib for renal cancer or soft-tissue sarcoma at the Hokkaido Cancer Center were evaluated prospectively. Cmin for pazopanib was calculated based on the measured values from the plasma samples. The efficacy and time to treatment failure were then assessed. The pazopanib maintenance doses were 200 (n = 4), 400 (n = 34), 600 (n = 4), and 800 mg (n = 1). Most patients (65%) who received a 400 mg dose had an effective pazopanib concentration (≧20 µg/mL), whereas 35% of patients who received the 400 mg dose had ineffective concentrations (<20 µg/mL). Logistic regression analysis revealed that only the albumin level was significantly associated with effective pazopanib concentrations (odds ratio: 1.37, p = 0.0234). In conclusion, a dose of 400 mg had been effective and well tolerated in more than half of patients in this study. However, therapeutic drug monitoring is necessary during pazopanib therapy.

Serotonin Syndrome Developing Immediately after the Initiation of Low-Dose Methadone Therapy: A Case Report
Masayoshi Kumai, Yosuke Maeda, Mototsugu Miura, Kenkichi Tsuruga, Takehiro Yamada, Yoh Takekuma, Mitsuru Sugawara
Case Reports in Oncology, 13, 1, 281, 284, S. Karger AG, 2020年03月24日, ［査読有り］, ［責任著者］
研究論文（学術雑誌）, We present a case in which serotonin syndrome developed immediately after the initiation of low-dose methadone following an increase in oxycodone dose and the initiation of duloxetine. The symptoms of serotonin syndrome were alleviated and later disappeared upon cessation of methadone alone. The case was a 47-year-old woman with a desmoid tumor. The administration of duloxetine (20 mg/day) was initiated while the patient took oxycodone sustained-release tablets (40 mg/day). The following day, excessive perspiration, chills, and tremors appeared after the initiation of 15 mg/day methadone. Discontinuation of methadone led to an alleviation of the symptoms which completely disappeared 3 days later. The results suggest that low-dose methadone can trigger serotonin syndrome as early as after the first dose. Thus, it is important to be aware of the risks and to immediately take action if symptoms appear.

Interaction Between Piperacillin/Tazobactam and Warfarin: a Single-Center Retrospective Single-Arm Cohort Study　　　　　　　　　　　　　　　
Shota Kadomura, Yoh Takekuma, Shungo Imai, Hitoshi Kashiwagi, Kotaro Kawamoto, Tatsuya Itoh, Mitsuru Sugawara
BPB Reports, 3, 2, 65, 69, 2020年03月, ［査読有り］, ［責任著者］

Influence of gastrointestinal activity on the absorption of nilotinib.
Maaya Sasaki, Tsuyoshi Aoyama, Mitsuru Sugawara, Yoh Takekuma
Drug metabolism and pharmacokinetics, 35, 1, 102, 110, 2020年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Nilotinib has bioavailability (BA) of only about 25% or less. The purpose of this study was to evaluate the influence of gastrointestinal activity on the absorption of nilotinib. In order to change gastrointestinal activity, mosapride was used for enhancement and butylscopolamine was used for suppression. Experiments on oral administration of nilotinib using rats whose gastrointestinal activity was altered by mosapride or butylscopolamine were carried out. The results of oral administration of acetaminophen to rats with peristalsis movement changed showed that the effects of peristalsis and gastric emptying rate (GER) on drug absorption could be evaluated in this experimental system. Similarly, even with nilotinib, no change in Tmax was observed, but Cmax increased and decreased significantly. Due to the change in gastrointestinal activity, Cmax of nilotinib changed greatly. This showed that gastrointestinal activity affected the emulsifying action of bile and that the absorbability changed. As a result of examining the contribution to the emulsifying action, it was found that when the bile does not exist in the gastrointestinal tract, absorption of nilotinib did not change even when gastrointestinal motility was enhanced. Therefore, the results suggested that gastrointestinal activity influenced the emulsifying action of bile and the absorption of nilotinib was changed.

Enhancement of intestinal absorption of coenzyme Q10 using emulsions containing oleyl polyethylene acetic acids.
Yuki Sato, Sayaka Yokoyama, Yoshiaki Yamaki, Yuta Nishimura, Mami Miyashita, Shingo Maruyama, Yoh Takekuma, Mitsuru Sugawara
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 142, 105144, 105144, 2020年01月15日, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Emulsions have often been prepared to improve absorption of lipophilic compounds that have poor solubility. Coenzyme Q10 (CoQ10) is a lipophilic compound that has been used as an anti-aging supplement. We focused on oleyl polyethyleneoxy acetic acid, an oxa acid derivative, to prepare emulsions of CoQ10 with the expectation of application to oral pharmaceutics. Oxa acids were purified and classified into four groups based on the average length of the ethylene oxide chain. The emulsion that were prepared using the four oxa acid groups were administered to rats and the plasma concentration profiles of CoQ10 were analyzed. The absorption of CoQ10 was improved in all emulsion groups compared with that in the powder group. The emulsion using oxa acid (n = 9.0) greatly increased the plasma concentration of CoQ10. Absorption was also improved by using emulsions containing larger percentage of oxa acids (6%, 15% and 23%) to compared with the same oxa acid (n = 9.0). The effects of oxa acids on cell viability were almost the same as those of conventional surfactants such as polyoxyethylene (20) sorbitan monooleate (Tween 80). The results showed that oxa acids are useful to prepare emulsions for oral administration and that the absorption of CoQ10 using oxa acids is significantly improved by using our formulations.

Pharmaceutical Care Contributes to the Advanced Management of Patients Receiving Immune Checkpoint Inhibitors.
Yoshitaka Saito, Kazuki Uchiyama, Tatsuhiko Sakamoto, Kojiro Yamazaki, Kosei Kubota, Yoh Takekuma, Yoshito Komatsu, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 43, 12, 1969, 1974, Pharmaceutical Society of Japan, 2020年, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, We previously reported that successive pharmaceutical care by oncology pharmacy specialists contributes to quality outpatient chemotherapy. However, there are a few reports regarding such care during immune checkpoint inhibitors (ICIs) treatment, despite increasing patients being treated with ICIs and the profile of immune-related adverse events being quite different from that of the adverse effects of cytotoxic agents. We retrospectively evaluated the effectiveness of continuous pharmaceutical care in outpatient ICI treatment, focusing especially on the period of providing pharmaceutical recommendations. The adoption rate, efficacy, and period of pharmaceutical interventions, such as prescription questions and pharmaceutical recommendations, were evaluated. A total of 3597 ICI administrations (366 patients) were evaluated. We performed 2625 face-to-face medication counseling. A total of 282 prescription questions and 147 pharmaceutical recommendations were conducted. Approximately 70% of the questions were regarding ordering of laboratory examination, and 86.5% of these questions were adopted. Pharmaceutical recommendations were categorized into medication recommendations (81.1%), examination recommendations (10.8%), and recommendation of expert consultation (8.1%). The adoption rate of pharmaceutical recommendations was 96.0, and 70% of the medication recommendations attenuated the symptoms. Finally, the provision rate of pharmaceutical recommendations was significantly higher in the first 3 months after ICI treatment initiation. We found that pharmaceutical care contributes to an improved quality of outpatient ICI treatment, and face-to-face pharmaceutical counseling up to 3 months after ICI treatment initiation is the most important.

Prescription of Colchicine with Other Dangerous Concomitant Medications: A Nation-Wide Survey Using the Japanese Claims Database.
Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Biological & pharmaceutical bulletin, 43, 10, 1519, 1525, 2020年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, The anti-inflammatory agent colchicine may cause toxic effects such as rhabdomyolysis, pancytopenia, and acute respiratory distress syndrome in cases of overdose and when patients have renal or liver impairment. As colchicine is a substrate for CYP3A4 and P-glycoprotein (P-gp), drug-drug interactions are important factors that cause fatal colchicine-related side effects. Thus, we conducted a nation-wide survey to determine the status of inappropriate colchicine prescriptions in Japan. Patients prescribed the regular use of colchicine from April 2014 to March 2017 were identified using the Japanese large health insurance claims database. As the primary endpoint, we evaluated the concomitant prescription proportions of strong CYP3A4 and/or P-gp inhibitors classified as "contraindications for co-administration" with colchicine in patients with renal or liver impairment. We defined these cases as "inappropriate colchicine prescriptions." Additionally, factors affecting inappropriate colchicine prescriptions were analyzed. Among the 3302 enrolled patients, 43 (1.30%) were inappropriately prescribed colchicine. Of these 43 patients, 11 had baseline renal and/or liver impairment. By multiple regression analysis, the primary diseases "gout" and "Behçet's disease" were extracted as independent factors for inappropriate colchicine prescriptions with odds ratios of 0.40 (95% confidence interval: 0.19-0.84) and 4.93 (95% confidence interval: 2.12-11.5), respectively. We found that approximately 1% of patients had important colchicine interactions. Particularly, Behçet's disease was a risk factor for inappropriate prescriptions, with approximately 25% of patients showing renal and/or liver impairment (classified as "contraindications for co-administration"). These findings may be useful for medical professionals who prescribe colchicine therapy.

Association of the ward pharmacy service with active implementation of therapeutic drug monitoring for vancomycin and teicoplanin-an epidemiological surveillance study using Japanese large health insurance claims database.
Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Sugawara, Yoh Takekuma
Journal of pharmaceutical health care and sciences, 6, 1, 18, 18, 2020年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Ward pharmacists are required for the active implementation of therapeutic drug monitoring (TDM). This epidemiological study verified whether Japanese ward pharmacists contribute to improving the TDM implementation proportions of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents using the large health insurance claims database. Methods: The patients who received intravenous anti-MRSA agents from April 2012 to March 2017 were enrolled. We defined ward pharmacy service as the "drug management and guidance fee" and/or "inpatient pharmaceutical services premium". In addition, implementation of TDM was identified by "the specific drug treatment management fee". We compared the proportions of TDM implementation for vancomycin (VCM), teicoplanin (TEIC), and arbekacin (ABK) in the ward and non-ward pharmacy service groups. To avoid confounding, the propensity score method was employed. Moreover, the clinical variables affecting TDM implementation in each anti-MRSA agent were analyzed by using a multiple logistic regression model. Results: The following number of patients were included in the study: VCM (n = 2138), TEIC (n = 596), and ABK (n = 142). After propensity score matching, the proportions of TDM implementation for VCM and TEIC were higher in the ward pharmacy service group than in the non-ward pharmacy service group (VCM: 69.2% vs 60.3%, TEIC: 51.4% vs 34.7%), while no significant difference was observed for ABK (21.2% vs 23.1%). As independent clinical variables affecting TDM implementation for VCM and TEIC, several clinical variables, including ward pharmacy services, were extracted. In contrast, no clinical variables were extracted for ABK. Conclusions: We found that the ward pharmacy service is associated with the active implementation of TDM for anti-MRSA agents, such as VCM and TEIC.

Validation of the usefulness of artificial neural networks for risk prediction of adverse drug reactions used for individual patients in clinical practice.
Shungo Imai, Yoh Takekuma, Hitoshi Kashiwagi, Takayuki Miyai, Masaki Kobayashi, Ken Iseki, Mitsuru Sugawara
PloS one, 15, 7, e0236789, 2020年, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Artificial neural networks are the main tools for data mining and were inspired by the human brain and nervous system. Studies have demonstrated their usefulness in medicine. However, no studies have used artificial neural networks for the prediction of adverse drug reactions. We aimed to validate the usefulness of artificial neural networks for the prediction of adverse drug reactions and focused on vancomycin -induced nephrotoxicity. For constructing an artificial neural network, a multilayer perceptron algorithm was employed. A 10-fold cross validation method was adopted for evaluating the resultant artificial neural network. In total, 1141 patients who received vancomycin at Hokkaido University Hospital from November 2011 to February 2019 were enrolled. Among these patients, 179 (15.7%) developed vancomycin -induced nephrotoxicity. The top three risk factors of vancomycin -induced nephrotoxicity which are relatively important in the artificial neural networks were average vancomycin trough concentration ≥ 13.0 mg/L and concomitant use of piperacillin-tazobactam and vasopressor drugs. The predictive accuracy of the artificial neural network was 86.3% and that of the multiple logistic regression model (conventional statistical method) was 85.1%. Moreover, area under the receiver operating characteristic curve (AUROC) of the artificial neural network was 0.83. In the 10-fold cross-validation, the accuracy obtained was 86.0% and AUROC was 0.82. The artificial neural network model predicting the vancomycin -induced nephrotoxicity showed good predictive performance. This appears to be the first report of the usefulness of artificial neural networks for an adverse drug reactions risk prediction model.

A New Algorithm Optimized for Initial Dose Settings of Vancomycin Using Machine Learning.
Shungo Imai, Yoh Takekuma, Takayuki Miyai, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 43, 1, 188, 193, 2020年, ［査読有り］, ［責任著者］, ［国内誌］
英語, 研究論文（学術雑誌）, This study aimed to construct an optimal algorithm for initial dose settings of vancomycin (VCM) using machine learning (ML) with decision tree (DT) analysis. Patients who were administered intravenous VCM and underwent therapeutic drug monitoring (TDM) at the Hokkaido University Hospital were enrolled. The study period was November 2011 to March 2019. In total, 654 patients were included in the study. Patients were divided into two groups, training (patients who received VCM from November 2011 to December 2017; n = 496) and testing (patients who received VCM from January 2018 to March 2019; n = 158) groups. For the training group, DT analysis of the classification and regression tree algorithm was performed to construct an algorithm (called DT algorithm) for the initial dose settings of VCM. For the testing group, the rates of attaining the VCM therapeutic range (trough value = 10-15 and 10-20 mg/L) with the DT algorithm and three conventional dose-setting methods were compared for model evaluation. The DT algorithm was constructed to be used for patients with estimated glomerular filtration rate ≥50 mL/min and body weight ≥40 kg. As a result, the recommended daily doses ranged from 20.0 to 58.1 mg/kg. In model evaluation, the DT algorithm obtained the highest rates of attaining the VCM therapeutic range compared to conventional dose-setting methods. Therefore, our DT algorithm can be applied to clinical practice. In addition, ML is useful for setting drug doses.

Continuous Cytostatic Effects of BCR-ABL Tyrosine Kinase Inhibitors (TKIs) after Washout in Human Leukemic K562 Cells.
Tsuyoshi Aoyama, Yoshihiko Shibayama, Tatsuhiko Furukawa, Mitsuru Sugawara, Yoh Takekuma
Biological & pharmaceutical bulletin, 42, 11, 1805, 1813, 2019年11月01日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Tyrosine kinase inhibitors (TKIs) are used as the first choice for chronic myeloid leukemia (CML) pharmacotherapeutics. Some patients taking these drugs showed good therapeutic reactivity despite the disappearance of drugs from blood. We investigated whether these drugs have sustained effects even after their disappearance and whether their effects depend on their amounts of intracellular accumulation. Cell proliferation after exposure of K562 cells or Multidrug resistance-1 (MDR-1)-transfected K562 cells was determined by a cell counting kit-8 assay. The intracellular accumulation amount of the drug showing a sustained cytostatic effect was measured by ultra high performance liquid chromatography mass spectrometry. Cell viability decreased in a culture time-dependent manner after washing out nilotinib and dasatinib. The sustained cytostatic effect of dasatinib, but not that of nilotinib, correlated with the intracellular accumulation level. In contrast, imatinib showed continuous a cytostatic effect after drug washout for long-term exposure but not after drug washout for short-term exposure. These results suggest that a good response in patients with a low serum concentration of imatinib, nilotinib or dasatinib may be due to the cytostatic effect of that drug continues even after its disappearance in plasma.

Comparison of predictive performance of drug dose settings using renal function estimation equations based on the Japanese population: a preliminary retrospective study using vancomycin dosing data.　　　　　　　　　　　　　　　
Shungo Imai, Soyoko Kaburaki, Takayuki Miyai, Hitoshi Kashiwagi, Mitsuru Sugawara, Yoh Takekuma
BPB Reports, 2, 5, 80, 85, 2019年10月, ［査読有り］
英語, 研究論文（学術雑誌）

レビー小体型認知症に対してリバスチグミンからの切り替えで低用量長期間ガランタミン投与が有効だった1症例
濱野 宏美, 土井 正剛, 武隈 洋, 菅原 満, 一木 崇宏
日本老年薬学会雑誌, 2, 2, 27, 34, (一社)日本老年薬学会, 2019年09月, ［査読有り］
日本語, 症例は70歳代女性で、かかりつけ医が当該患者を引き継ぐ前、アルツハイマー型認知症(AD)の診断にてドネペジル5mg/日を服用していた。その後、ドネペジル5mg/日からガランタサミン(GAL)8mg/日へ変更された。数ヵ月後に無症候性脳梗塞を発症し、近隣脳外科の退院後、ニセルゴリン錠5mg、レボドパ・カルビドパ配合錠、リバスチグミンパッチ4.5mg/日が開始された。貼付開始後から皮膚炎を発症し、ステロイド外用薬を使用したが改善しなかった。皮膚炎のためやむを得ずGAL服用へ処方が変更され、会話にはならないが発語が増加し、右手でコップを掴めるようになった。しかし、強い嘔気をきたして近隣病院へ入院しGAL服用は中止されたが、クロピドグレルとレボドパ・カルビドパ配合錠服用は継続されていた。高齢者施設に再入居後にGAL 4mg/日服用を開始したところ、悪化していた覚醒レベルは徐々に回復し、寝床上のみでの生活から車椅子に座り、リビングで過ごせるようになった。

Higher incidence of acute kidney injury in patients treated with piperacillin/tazobactam than in patients treated with cefepime: a single-center retrospective cohort study.
Shota Kadomura, Yoh Takekuma, Yuki Sato, Masato Sumi, Kotaro Kawamoto, Tatsuya Itoh, Mitsuru Sugawara
Journal of pharmaceutical health care and sciences, 5, 13, 13, 2019年, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Background: Piperacillin/tazobactam (PIPC/TAZ) and cefepime (CFPM) are commonly used for the treatment of nosocomial and healthcare-associated infections. Recent reports have suggested that the incidence of acute kidney injury (AKI) in patients treated with a combination of vancomycin (VCM) and PIPC/TAZ is higher than that in patients treated with CFPM. However, there have been few reports on a comparison of the incidences of AKI in patients treated with PIPC/TAZ monotherapy and patients treated with CFPM. In this study, we investigated whether the incidence of AKI in patients treated with PIPC/TAZ is higher than that in patients treated with CFPM. Methods: This study was a single-center retrospective observational study. Patients who died during the therapeutic period, patients younger than 18 years of age, and patients undergoing hemodialysis were excluded. Primary outcomes were the incidence of AKI and the AKIN stages defined by the Acute Kidney Injury Network. Secondary outcomes were discontinuation and/or change of antibiotics and initiation of dialysis due to AKI. We also investigated the time to onset and the risk factors of AKI in this population. Results: There were 163 patients in the PIPC/TAZ group and 103 patients in the CFPM group. The incidence of AKI in patients treated with PIPC/TAZ (8.6%) was significantly higher than that in patients treated with CFPM (0.9%) (odds ratio (OR), 9.53; 95% confidence interval (CI), 1.41-408; p= 0.011). AKI severity was mostly stage 1 in both groups. There was no discontinuation and/or changes of antibiotics and there was no initiation of dialysis in either group. The onset of AKI in the PIPC/TAZ group (median period of 4 days) was earlier than that in the CFPM group. PIPC/TAZ was determined to be an independent risk factor of AKI in multivariate analysis (adjusted OR, 9.56; 95% CI, 1.21-75.3; p = 0.032). Conclusions: This study showed that the incidence of AKI in patients who received PIPC/TAZ was higher than that in patients who received CFPM. Furthermore, the onset of AKI was earlier in patients who received PIPC/TAZ than in patients who received CFPM. PIPC/TAZ was an independent risk factor of AKI in this study population.

Improvement of renal function estimation equations for elderly Japanese people.
Soyoko Kaburaki, Eri Yoshimura, Nozomi Kojima, Hidefumi Ueno, Mitsuru Sugawara, Yoh Takekuma
Health science reports, 1, 10, e85, 2018年10月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Background and aim: The Cockcroft-Gault (C-G) equation for estimation of creatinine clearance (CCr) is still used in a clinical setting for drug dosage adjustment. Because differences between measured and estimated CCr values have been reported, particularly for Japanese elderly people, the aim of this study was to improve the accuracy of CCr estimation equations, such as C-G and Orita-Horio, by fitting to newly obtained data. Also, glomerular filtration rate (GFR) estimation equations, such as the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and the eGFR equation for Japanese people, were studied to compare with measured CCr. Method: Data from 313 subjects over the age of 40 years with laboratory data available were used for analysis in this study. Special attention was paid to elderly people, and approximately 70% of the subjects were over the age of 65 years. Results: The accuracy of estimation by the two conventional (C-G, Orita-Horio) CCr estimation equations was greatly improved by introducing adjusted body weight for which the degree of obesity is over 30% instead of measured body weight. By fitting the coefficients of the estimation equations to the present population, the mean error was reduced by almost half, particularly for people over the age of 75. Although all the values calculated by the GFR estimation equations were underestimated compared with measured CCr due to secretion, a coefficient of determination of above 0.65 was obtained for all GFR estimation equations. Conclusions: Improvement of the fitted CCr estimation equations suggests that reconstruction of renal function estimation equations is required, especially for old people. Further work is required to find optimal renal function (CCr and/or GFR) estimation equations for drug dosage adjustment.

Enhancement of lymphatic transport of lutein by oral administration of a solid dispersion and a self-microemulsifying drug delivery system.
Yuki Sato, Tatsuru Joumura, Shunsuke Nashimoto, Sayaka Yokoyama, Yoh Takekuma, Hideto Yoshida, Mitsuru Sugawara
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 127, 171, 176, 2018年06月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Lutein is located in the macula lutea in the human eye. Since humans cannot synthesize lutein de novo, it must be digested as food. Some studies including our previous study showed very low absorption of lutein after oral administration. These studies also suggested that the absorption route of lutein from the small intestine involves not only the blood but also the lymph. The aim of this study was to clarify the transfer of lutein into lymph and the tissue distribution after oral administration of a solid dispersion (SD) and a self-microemulsifying drug delivery system (SMEDDS) for improvement of the absorption. We used thoracic lymph-cannulated rats. It was shown that the plasma concentrations of lutein in the SD and SMEDDS groups were increased compared with that in the powder group. The absorption of lutein after oral administration of each formulation was clearly evaluated by its cumulative amount in lymph. Our data clearly showed that lutein is transferred into the lymph stream from the small intestine.

Plasma and intracellular concentrations in an elderly patient with chronic myeloid leukemia receiving low-dose dasatinib therapy.
Masahiro Imamura, Yusuke Nakamura, Mitsuru Sugawara
Geriatrics & gerontology international, 18, 3, 505, 507, 2018年03月, ［査読有り］, ［国内誌］
英語

薬学実務実習前後における薬学生のコミュニケーション分析 Roter method of interaction process analysis(RIAS)を用いて
武隈 洋, 森 綾子, 小林 正紀, 山田 勇磨, 佐藤 夕紀, 鳴海 克哉, 古堅 彩子, 菅原 満
薬学雑誌, 138, 12, 1579, 1586, (公社)日本薬学会, 2018年, ［査読有り］, ［責任著者］, ［国内誌］
日本語, 研究論文（学術雑誌）, 病院・薬局実務実習を履修する前の薬学部内での事前実習において模擬患者を相手に行ったロールプレイと、実務実習後に同じシナリオで行ったロールプレイとをRIASによって比較し、コミュニケーション能力がどのように変化しているか検討した。対象は、本学薬学部薬学科の学生で、4年次の事前実習時と6年次の実務実習後に同じ服薬指導のシナリオでロールプレイを行った19名とした。検討の結果、学生は実務実習を経てコミュニケーションへの慣れや知識の増加により発話が流暢になったことが示唆された。また、4年次に比べて6年次には、「単純な相槌」(Back-channel responses)が減少し、「同意・理解」(Shows agreement or understanding)が増加していたことから、相手に対する理解の姿勢を表現できるようになったものと思われた。発話内容をみると、4年次に比べて6年次には「聞き取り」の割合が減少し、「相手への気持ちの寄り添い」や「助言」の割合が増加していた。

パゾパニブの血中濃度に影響する因子の探索
田中 寛之, 平賀 博明, 武隈 洋, 橋下 浩紀, 三浪 圭太, 原林 透, 永森 聡, 遠藤 雅之, 菅原 満
TDM研究, 34, 3, 140, 140, (一社)日本TDM学会, 2017年09月, ［査読有り］, ［責任著者］
日本語

小学校の授業を通して見えてきたことと今後の課題　　　　　　　　　　　　　　　
佐藤夕紀, 宮下元樹, 菅原満
道学薬, 13, 37, 40, 2017年05月, ［招待有り］
日本語, 研究論文（研究会，シンポジウム資料等）

Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between α-tocopherol and ezetimibe.
Nashimoto S, Sato Y, Takekuma Y, Sugawara M
Biopharmaceutics & drug disposition, 38, 4, 280, 289, WILEY, 2017年05月, ［査読有り］, ［責任著者］, ［国際誌］
英語, 研究論文（学術雑誌）, Tocopherol is used not only as an ethical drug but also as a supplement. In 2008, it was reported that α-tocopherol is partly transported via an intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Ezetimibe, a selective inhibitor of NPC1L1, is administered for a long time to inhibit cholesterol absorption and there is a possibility that the absorption of α-tocopherol is also inhibited by ezetimibe. This study investigated the influence of ezetimibe on the absorption of α-tocopherol with single administration and long-term administration. An approach to avoid its undesirable consequence was also examined. α-Tocopherol (10 mg/kg) and ezetimibe (0.1 mg/kg) were administered to rats, and the plasma concentration profiles of α-tocopherol and tissue concentrations were investigated. The plasma concentration of α-tocopherol was decreased by the combination use of ezetimibe in the case of concurrent single administration. On the other hand, inhibition of the absorption of α-tocopherol was prevented by an administration interval of 4 h. In a group of rats administered for 2 months with a 4 h interval, not only the plasma concentration but also the liver concentration was increased compared with those in a group with concurrent combination intake of α-tocopherol and ezetimibe. The absorption of α-tocopherol was inhibited by ezetimibe. The inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h, although ezetimibe is a medicine of enterohepatic circulation. Attention should be paid to the use of ezetimibe and components of NPC1L1 substrates such as α-tocopherol. Copyright © 2016 John Wiley & Sons, Ltd.

耳鼻咽喉科領域におけるアレルギー性咳嗽症状を有する患者に対する抗アレルギー薬併用の実態調査
武隈 洋, 石坂 悠, 高地 里佳, 吉村 恵理, 小嶋 希望, 上野 英文, 平野 卓哉, 野田 敏宏, 熊井 惠美, 菅原 満
薬局薬学, 9, 1, 159, 168, (一社)日本薬局学会, 2017年04月, ［査読有り］
日本語, 耳鼻咽喉科領域のアレルギー性咳嗽患者への抗アレルギー薬の使用実態を調査した。対象は市中保険薬局で抗アレルギー薬を交付された外来患者(耳鼻咽喉科受診)および総合病院内科を受診し抗アレルギー薬が処方された患者とした。抗アレルギー薬およびその併用薬からアレルギー性咳嗽症状を有すると推察される患者を選択し、アレルギー性咳嗽患者の割合および抗アレルギー薬の処方頻度を調査した。患者を湿性咳嗽と乾性咳嗽に分類し、咳症状に関する主訴と服用薬から治療効果を評価した。その結果、両施設ともにLTRA(ロイコトリエン受容体拮抗薬)および第二世代抗ヒスタミン薬の使用頻度が高かった。市中保険薬局では両者の併用頻度が最も高く、内科では単剤使用の頻度が最も高かった。湿性咳嗽および乾性咳嗽ともに症状が改善した60〜70%の患者でLTRAが使用されていた。乾性咳嗽を有する患者の多くが2剤以上の抗アレルギー薬を必要とした。(著者抄録)

Guidelines for Therapeutic Drug Monitoring of Cardiovascular Drugs Clinical Use of Blood Drug Concentration Monitoring (JCS 2015) - Digest Version.
Kazutaka Aonuma, Tsuyoshi Shiga, Hirotsugu Atarashi, Kosuke Doki, Hirotoshi Echizen, Nobuhisa Hagiwara, Junichi Hasegawa, Hideharu Hayashi, Kenzo Hirao, Fukiko Ichida, Takanori Ikeda, Yorinobu Maeda, Naoki Matsumoto, Toshiyuki Sakaeda, Wataru Shimizu, Mitsuru Sugawara, Kyoichi Totsuka, Yoshimasa Tsuchishita, Kazuyuki Ueno, Eiichi Watanabe, Masayuki Hashiguchi, Sumio Hirata, Hidefumi Kasai, Yoshiaki Matsumoto, Akihiko Nogami, Yukio Sekiguchi, Tokuko Shinohara, Atsushi Sugiyama, Naokata Sumitomo, Atsushi Suzuki, Naohiko Takahashi, Eiji Yukawa, Masato Homma, Minoru Horie, Hiroshi Inoue, Hiroshi Ito, Takanori Miura, Tohru Ohe, Kimikazu Shinozaki, Kazuhiko Tanaka
Circulation journal : official journal of the Japanese Circulation Society, 81, 4, 581, 612, JAPANESE CIRCULATION SOC, 2017年03月24日, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）

Simple blood sample pre-treatment to remove DAMPA in ARCHITECT® for methotrexate　　　　　　　　　　　　　　　
Tanaka H, Sako M, Morioka Y, Motoshige H, Takekuma Y, Kawamoto H, Sugawara M, Hiraga H
TDM研究, 34, 1, 1, 7, 2017年03月, ［査読有り］
英語, 研究論文（学術雑誌）

Difference in the Dissolution Behaviors of Tablets Containing Polyvinylpolypyrrolidone (PVPP) Depending on Pharmaceutical Formulation After Storage Under High Temperature and Humid Conditions
Yoh Takekuma, Haruka Ishizaka, Masato Sumi, Yuki Sato, Mitsuru Sugawara
JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 19, 4, 511, 519, CANADIAN SOC PHARMACEUTICAL SCIENCES, 2016年, ［査読有り］
英語, 研究論文（学術雑誌）, PURPOSE. Storage under high temperature and humid conditions has been reported to decrease the dissolution rate for some kinds of tablets containing polyvinylpolypyrrolidone (PVPP) as a disintegrant. The aim of this study was to elucidate the properties of pharmaceutical formulations with PVPP that cause a decrease in the dissolution rate after storage under high temperature and humid conditions by using model tablets with a simple composition. METHODS. Model tablets, which consisted of rosuvastatin calcium or 5 simple structure compounds, salicylic acid, 2-aminodipheny lmethane, 2-aminobiphenyl, 2-(p-tolyl) benzoic acid or 4.4'-biphenol as principal agents, cellulose, lactose hydrate, PVPP and magnesium stearate as additives, were made by direct compression. The model tables were wrapped in paraffin papers and stored for 2 weeks at 40 degrees C/75% relative humidity (RH). Dissolution tests were carried out by the paddle method in the Japanese Pharmacopoeia 16th edition. RESULTS. Model tablets with a simple composition were able to reproduce a decreased dissolution rate after storage at 40 degrees C/75% RH. These tablets showed significantly decreased water absorption activities after storage. In the case of tablets without lactose hydrate by replacing with cellulose, a decreased dissolution rate was not observed. Carboxyl and amino groups in the structure of the principal agent were not directly involved in the decreased dissolution. 2-Benzylaniline tablets showed a remarkably decreased dissolution rate and 2-aminobiphenyl and 2-(p-tolyl) benzoic acid tablets showed slightly decreased dissolution rates, though 4,4'-biphenol tablets did not show a decrease dissolution rate. CONCLUSIONS. We demonstrated that additives and structure of the principal agent were involved in the decreased in dissolution rate for tablets with PVPP. The results suggested that one of the reasons for a decreased dissolution rate was the inclusion of lactose hydrate in tablets. The results also indicated that compounds as principal agents with low affinity for PVPP may be easily affected by airborne water under high temperature and humid conditions.

Pharmacokinetics and dose adjustment of etoposide administered in a medium-dose etoposide, cyclophosphamide and total body irradiation regimen before allogeneic hematopoietic stem cell transplantation.
Yuki Tazawa, Akio Shigematsu, Kumiko Kasashi, Junichi Sugita, Tomoyuki Endo, Takeshi Kondo, Takanori Teshima, Ken Iseki, Mitsuru Sugawara, Yoh Takekuma
Journal of pharmaceutical health care and sciences, 2, 18, 18, 2016年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, BACKGROUND: We investigated the pharmacokinetics of etoposide (ETP) to reduce the inter-individual variations of ETP concentrations in patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation. We also carried out an in vivo study using rats to verify the dose adjustment. METHODS: This study included 20 adult patients. ETP was administered intravenously at a dose of 15 mg/kg once daily for 2 days (total dose: 30 mg/kg) combined with standard conditioning of cyclophosphamide and total body irradiation. In an in vivo study using rats, ETP was administered intravenously at a dose of 15 mg/kg or an adjusted dose. The ETP plasma concentration was determined by using HPLC. The pharmacokinetic parameters were estimated by using a 1-compartment model. RESULTS: The peak concentration (Cmax) of ETP and the area under the plasma concentration-time curve (AUC) of ETP differed greatly among patients (range of Cmax, 51.8 - 116.5 μg/mL; range of AUC, 870 - 2015 μg · h/mL). A significant relationship was found between Cmax and AUC (R = 0.85, P < 0.05). Distribution volume (Vd) was suggested to be one of the factors of inter-individual variation in plasma concentration of ETP in patients (range of Vd, 0.13 - 0.27 L/kg), and correlated with Alb and body weight (R = 0.56, P < 0.05; R = 0.40, P < 0.05 respectively). We predicted Vd of rats by body weight of rats (with normal albumin levels and renal function), and the dose of ETP was adjusted using predicted Vd. In the dose adjustment group, the target plasma ETP concentration was achieved and the variation of plasma ETP concentration was decreased. CONCLUSION: The results suggested that inter-individual variation of plasma concentration of ETP could be reduced by predicting Vd. Prediction of Vd is effective for reducing individual variation of ETP concentration and might enable a good therapeutic effect to be achieved.

An Approach to Improve Intestinal Absorption of Poorly Absorbed Water-Insoluble Components via Niemann-Pick C1-Like 1.
Yuto Takekawa, Yuki Sato, Yoshiaki Yamaki, Mei Imai, Kazuma Noto, Masato Sumi, Yoh Takekuma, Ken Iseki, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 39, 3, 301, 7, PHARMACEUTICAL SOC JAPAN, 2016年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Dietary and biliary cholesterol absorption contributes to the maintenance of tight control of cholesterol homeostasis. Cholesterol is present as mixed micelles formed by bile salts and phospholipids in the intestinal lumen. Recently, Niemann-Pick C1-Like 1 (NPC1L1) transporter was identified as being critical for cholesterol absorption. However, the uptake mechanism of an enveloped substrate of NPC1L1 in whole lipid emulsion particles remains unclear. In this study, we investigated the uptake mechanism of a substrate of NPC1L1 in lipid emulsion particles. We also investigated whether these particles containing cholesterol can improve the intestinal absorption of other lipophilic components via NPC1L1. The uptake of lysophosphatidylcholine (LPC)-4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-propionic acid saccinimidyl ester (BODIPY), a fluorescently labeled phospholipid, in lipid emulsion particles containing cholesterol (1 µM) was significantly increased compared to that without cholesterol in Caco-2 cells. On the other hand, its increased uptake was significantly inhibited by ezetimibe, a selective inhibitor of NPC1L1. These results suggested that not only cholesterol but also some components in lipid emulsion particles are taken up into enterocytes via NPC1L1. We also examined an approach to improve intestinal absorption of a poorly absorbed water-insoluble component, coenzyme Q10 (CoQ10), by this mechanism. The uptake of CoQ10 in lipid emulsion particles containing cholesterol was significantly increased compared to that without cholesterol. Its increased uptake was significantly inhibited by ezetimibe. Though it is still not clear whether CoQ10 is a substrate of NPC1L1, there is a potential for improvement of the absorption of poorly absorbed components by lipid emulsion particles containing cholesterol.

開封後のスタチン製剤の安定性に及ぼす光・温度・湿度の影響
武隈 洋, 高地 里佳, 石坂 悠, 佐藤 夕紀, 鷲見 正人, 菅原 満
医療薬学, 40, 3, 135, 146, (一社)日本医療薬学会, 2014年03月, ［査読有り］
日本語, 開封後のスタチン製剤の安定性に及ぼす光・温度・湿度の影響について検討した。安定性評価の対象とした薬剤は、ロスバスタチン製剤1銘柄2規格、シンバスタチン製剤4銘柄、プラバスタチン製剤4銘柄である。安定性評価の対象薬剤を、一包化した状態を想定してPTPシートから出し、薬包紙を用いて1錠ずつ包んだ。また、散光条件下のみセロポリ分包紙を用いて1錠ずつ分包した。ロスバスタチン製剤はPTPから開封しても室温散光条件下で1年間安定で、一包化調剤後でも患者が通常家庭内で保存する分には大きな問題は生じないことが示唆されたが、粉砕調剤時には遮光保存が必須条件であることが示された。シンバスタチン製剤は、6ヵ月間保存した場合、すべての条件下で安定であったのは1製剤のみであった。プラバスタチン製剤は、すべての製剤において室温遮光条件下で6ヵ月間安定であることが示されたが、散光条件下では一部の製剤に変色が確認された。

Schedule-dependent cytotoxicity of Etoposide and cyclophosphamide in P-glycoprotein-expressing human leukemic K-562 cells.
Yuki Tazawa, Ippei Usukubo, Kazuki Takada, Yoh Takekuma, Yoshihiro Shibayama, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 37, 8, 1323, 9, PHARMACEUTICAL SOC JAPAN, 2014年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Combination chemotherapy is often used to treat cancer. Many studies have shown schedule-dependent effects between anticancer drugs. Our previous studies showed that K-562 cells pretreated with non-cytotoxic concentrations of 4-hydroperoxycyclophosphamide (4-HPC), which is a preactivated analog of cyclophosphamide (CY), enhanced the cytotoxicity of etoposide (VP-16). The appearance of cellular resistance to anticancer drugs is a major problem in cancer chemotherapy. P-Glycoprotein (P-gp) plays an important role in drug resistance, and VP-16 is a substrate for this efflux pump. In the present study, we demonstrated schedule-dependent cytotoxicity of VP-16 and CY in P-gp-overexpressed K-562/P-gp cells. Cytotoxicity of VP-16 was enhanced in K-562/P-gp cells that were pretreated with a non-cytotoxic concentration of 4-HPC compared to that of cells not treated with 4-HPC. 4-HPC arrested the cell cycle at S phase. Cells in S phase are most sensitive to VP-16. The results suggest that cell cycle arrest by 4-HPC pretreatment may be responsible for the enhanced cytotoxicity of VP-16. The findings in this study should lead to improvements in clinical combination chemotherapy.

Emulsification using highly hydrophilic surfactants improves the absorption of orally administered coenzyme Q10.
Yuki Sato, Hanami Mutoh, Mika Suzuki, Yoh Takekuma, Ken Iseki, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 36, 12, 2012, 7, PHARMACEUTICAL SOC JAPAN, 2013年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Coenzyme Q10 (CoQ10) is an essential component in the electron-transport systems of mitochondria and bacteria and is often used as a supplementary treatment for some diseases. We previously reported that the bioavailability of CoQ10 powder was less than 10%. In this study, we investigated various preparations to improve the intestinal absorption of CoQ10 with focus on the effect of emulsification. We prepared a suspension and some emulsions with four types of surfactants and investigated the plasma concentration profile after oral administration to rats. The absorption of CoQ10 was improved by an emulsion formulation although there was little absorption of CoQ10 when a suspension was administered. However, little CoQ10 was absorbed in the bile duct-ligated group even when the emulsion formulation was administered (about 50% of the control group). Bile and emulsion formulation are essential for absorption of CoQ10. When the preparations containing Tween20 (polysorbate (20) sorbitan monolaurate) and Tween80 (polyoxyethylene (20) sorbitan monooleate) were administered, plasma concentrations of CoQ10 were higher than those obtained with preparations containing Tween65 (polyoxyethylene (20) sorbitan tristearate) and Span20 (sorbitan monolaurate). Tween20 and Tween80 have higher hydrophile-lipophile balance (HLB) values than those Tween65 and Span20. Our study suggests that highly lipophilic compounds like CoQ10 would diffuse the unstirred water layer and would easily access the intestinal apical membrane by an emulsion containing a surfactant with a high HLB value. Attention must be given to CoQ10 supplementation for patients whose bile is not excreted to the intestine such as patients with cholestasis.

Intracellular uptake mechanism of lutein in retinal pigment epithelial cells.
Yuki Sato, Yu Kondo, Masato Sumi, Yoh Takekuma, Mitsuru Sugawara
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques, 16, 3, 494, 501, CANADIAN SOC PHARMACEUTICAL SCIENCES, 2013年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. It has received much attention recently due to its preventive effect on age-related macular degeneration, and it has been consumed as a supplement. However, little information about the pharmacokinetic properties of lutein is available. Detailed knowledge of pharmacokinetic properties of lutein is needed for the development of pharmaceutics. In this study, we focused on the macular accumulation of lutein and investigated the uptake mechanism into human retinal pigment epithelial cells. METHODS: ARPE-19 cells were used for the study on the accumulation mechanism of lutein. The concentration of lutein was determined using an HPLC system. Involvement of scavenger class B type 1 (SR-B1) in the accumulation of lutein in ARPE-19 cells was suggested from the results of an inhibition study using block lipid transport 1 (BLT-1), a selective inhibitor of SR-B1. To investigate the involvement of SR-B1 in more detail, small interfering RNA (siRNA) was transfected and the mRNA and protein expression levels of SR-B1 were assessed by quantitative real-time reverse transcription polymerase chain reaction and Western blotting, respectively. RESULTS: We confirmed a sufficient siRNA knockdown effect in both mRNA and protein expression levels of SR-B1. We then found that lutein uptake was significantly decreased by siRNA knockdown of SR-B1. CONCLUSION: The uptake of lutein was significantly decreased by 40% compared with the control uptake level. This suggested that active transport of lutein into ARPE-19 cells is mainly via SR-B1, given the result that lutein uptake at 4ºC was about 40% less that that at 37ºC.

Estimation of the duration after methamphetamine injection using a pharmacokinetic model in suspects who caused fatal traffic accidents.
Kazuo Matsubara, Masaru Asari, Manabu Suno, Toshio Awaya, Mitsuru Sugawara, Tomohiro Omura, Joe Yamamoto, Chikatoshi Maseda, Yoshikazu Tasaki, Hiroshi Shiono, Keiko Shimizu
Legal medicine (Tokyo, Japan), 14, 4, 191, 6, ELSEVIER IRELAND LTD, 2012年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, When the population parameters of drug pharmacokinetics in the human body system are known, the time-course of a certain drug in an individual can generally be estimated by pharmacokinetics. In the present two cases where methamphetamine abusers were suspected to have inflicted mortalities in traffic accidents, the time-elapse or duration immediately after methamphetamine injection to the time when the accidents occurred became points of contention. In each case, we estimated the time-course of blood methamphetamine after the self-administration in the suspects using a 2-compartment pharmacokinetic model with known pharmacokinetic parameters from the literatures. If the injected amount can be determined to a certain extent, it is easy to calculate the average time-elapse after injection by referring to reference values. However, there is considerable individual variability in the elimination rate based on genetic polymorphism and a considerably large error range in the estimated time-elapse results. To minimize estimation errors in such cases, we also analyzed genotype of CYP2D6, which influenced methamphetamine metabolism. Estimation based on two time-point blood samples would usefully benefit legal authorities in passing ruling sentences in cases involving similar personalities and circumstances as those involved in the present study.

Successful transplantation of rat hearts subjected to extended cold preservation with a novel preservation solution.
Kenji Wakayama, Moto Fukai, Kenichiro Yamashita, Taichi Kimura, Gentaro Hirokata, Susumu Shibasaki, Daisuke Fukumori, Sanae Haga, Mitsuru Sugawara, Tomomi Suzuki, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michitaka Ozaki, Toshiya Kamiyama, Satoru Todo
Transplant international : official journal of the European Society for Organ Transplantation, 25, 6, 696, 706, WILEY-BLACKWELL, 2012年06月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Since prolonged cold preservation of the heart deteriorates the outcome of heart transplantation, a more protective preservation solution is required. We therefore developed a new solution, named Dsol, and examined whether Dsol, in comparison to UW, could better inhibit myocardial injury resulting from prolonged cold preservation. Syngeneic heterotopic heart transplantation in Lewis rats was performed after cold preservation with UW or Dsol for 24 or 36 h. In addition to graft survival, myocardial injury, ATP content, and Ca(2+) -dependent proteases activity were assessed in the 24-h preservation group. The cytosolic Ca(2+) concentration of H9c2 cardiomyocytes after 24-h cold preservation was assessed. Dsol significantly improved 7-day graft survival after 36-h preservation. After 24-h preservation, Dsol was associated with significantly faster recovery of ATP content and less activation of calpain and caspase-3 after reperfusion. Dsol diminished graft injury significantly, as revealed by the lower levels of infarction, apoptosis, serum LDH and AST release, and graft fibrosis at 7-day. Dsol significantly inhibited Ca(2+) overload during cold preservation. Dsol inhibited myocardial injury and improved graft survival by suppressing Ca(2+) overload during the preservation and the activation of Ca(2+) -dependent proteases. Dsol is therefore considered a better alternative to UW to ameliorate the outcome of heart transplantation.

効果発現パターンにより抗がん薬を分類するための基礎的検討
高橋 夏子, 小林 正紀, 板垣 史郎, 平野 剛, 武隈 洋, 菅原 満, 井関 健
薬学雑誌, 132, 6, 777, 783, (公社)日本薬学会, 2012年06月, ［査読有り］, ［国内誌］
日本語, ヒト肺癌由来株化細胞A549およびヒト乳癌由来株化細胞MCF-7を用い、作用発現が明確な4種の薬物(シスプラチン(CDDP)、カルボプラチン(CBDCA)、パクリタキセル(PTX)、ゲムシタビン(GEM))を使用し、より簡便な抗癌薬の効果の判定と、投与設計への寄与を目的とし、in vitroでの抗癌薬の分類について基礎的検討を行った。CDDP、CBDCAは濃度依存的に抗腫瘍効果を発現する薬物として分類されることが推測された。一方、PTX、GEMについては細胞生存曲線の低濃度側へのシフトおよびIC 50値の著しい低下がみられことから、時間依存的に抗腫瘍効果を発揮する薬物として、分類可能であることが示唆された。更にCDDP、CBDCAの濃度依存性をより確実なものとするため、IC 50値を基準として前後10倍の濃度を設定し、濃度依存性を評価した結果、薬物濃度に比例した細胞生存率の低下がみられたことから、CDDP、CBDCAは濃度依存的に抗腫瘍効果を発揮する傾向の強い薬物であることが判明した。また、納所依存性の検討においても、用いた2種の細胞間で各抗癌薬の効果発現の様式に同様な傾向がみられた。研究結果より、細胞生存曲線及びIC 50値の変化を指標とし、作用の異なる抗癌薬を濃度依存的薬物および時間依存的薬物に分類できる可能性が示唆された。

国立大学における「実践的医療薬学教育プログラム」の現状
小澤 光一郎, 菅原 満, 関根 祐子, 中嶋 幹郎
薬学雑誌, 132, 3, 345, 350, (公社)日本薬学会, 2012年03月, ［査読有り］, ［国内誌］
日本語, The six-year pharmacy program started in April 2006 in Japan. In the new program, students in the fifth year of the pharmacy course undergo a long-term practice experience (pharmacy clerkship) in community pharmacy and hospital pharmacy settings as compulsory 20 course credits. The new pharmacy practice experience started in May 2010. A start of the new system was a chance as for beginning movement, thus we conducted the questionnaire survey for the following steps. The finding obtained from our questionnaires indicated that many universities had already planned to execute new approaches, such as an advanced practice at outpatient units, an with medical students, and so on.

オピオイドによる難治性の嘔気とめまいに対してヒスタミンH1受容体拮抗薬とペロスピロンの併用が有効であった2症例
長田 貴之, 柴山 良彦, 熊井 正貴, 山田 武宏, 笠師 久美子, 倉本 倫之介, 洲崎 真吾, 赤澤 茂, 真栄田 浩行, 坂下 智博, 折舘 伸彦, 本間 明宏, 福田 諭, 菅原 満, 井関 健
医療薬学, 38, 1, 51, 55, (一社)日本医療薬学会, 2012年01月, ［査読有り］
日本語, 研究論文（学術雑誌）, オピオイドによる難治性の嘔気とめまいに対してヒスタミンH1受容体拮抗薬とペロスピロンの併用が有効であった2例を経験した。症例1は50歳代女で、舌癌の診断で、舌半側切除+両頸部郭清後、術後放射線治療の方針となった。放射線照射部位である舌根周辺に疼痛の増悪を認め、硫酸モルヒネを開始した。しかし、めまいと嘔気が発現し摂食困難となったため、オピオイドローテーションの方針となった。塩酸ペロスピロン錠を処方を開始すると、嘔吐、嘔気は消失し、摂食も可能となった。めまいもほぼ消失した。症例2は30歳代女で、中咽頭癌の診断で、シスプラチン超選択的動注併用放射線治療の方針となった。舌根部に疼痛を訴え、塩酸オキシコドン水和物徐放錠で疼痛をコントロールした。舌根の疼痛が増悪し、塩酸モルヒネ液を開始したが、嘔吐したためオピオイドローテーションの方針となった。塩酸ペロスピロン錠に変更し、嘔吐、嘔気とめまいは消失した。

Mutual inhibition between carvedilol enantiomers during racemate glucuronidation mediated by human liver and intestinal microsomes.
Yoh Takekuma, Keiji Yagisawa, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 35, 2, 151, 63, PHARMACEUTICAL SOC JAPAN, 2012年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Carvedilol is administered orally as a racemic mixture of R(+)- and S(-)-enantiomers for treatment of angina pectoris, hypertension and chronic heart failure. We have reported that enzyme kinetic parameters for carvedilol glucuronidation by human liver microsomes (HLM) differed greatly depending on the substrate form, namely, racemic carvedilol and each enantiomer. These phenomena were thought to be caused by mutual inhibition between carvedilol enantiomers during racemate glucuronidation. The aim of this study was to clarify the mechanism of these phenomena in HLM and human intestinal microsomes (HIM) and its relevance to uridine 5'-diphosphate (UDP)-glucuronosyl transferase (UGT) 1A1, UGT2B4 and UGT2B7, which mainly metabolize carvedilol directly in phase II enzymes. HLM apparently preferred metabolizing (S)-carvedilol to (R)-carvedilol in the racemate, but true activities of HLM for both glucuronidation were approximately equal. By determination of the inhibitory effects of (S)-carvedilol on (R)-carvedilol glucuronidation and vice versa, it was shown that (R)-carvedilol glucuronidation was more easily inhibited than was (S)-carvedilol glucuronidation. UGT2B7 was responsible for (S)-carvedilol glucuronidation in HLM. Ratios of contribution to (R)-carvedilol glucuronidation were approximately equal among UGT1A1, UGT2B4 and UGT2B7. However, enzyme kinetic parameters were different between the two lots of HLM used in this study, depending on the contribution ratio of UGT2B4, in which (R)-glucuronidation was much more easily inhibited by (S)-carvedilol than was (S)-glucuronidation by (R)-carvedilol. Meanwhile, HIM preferred metabolizing (R)-carvedilol, and this tendency was not different between the kinds of substrate form.

Involvement of cholesterol membrane transporter Niemann-Pick C1-like 1 in the intestinal absorption of lutein.
Yuki Sato, Risa Suzuki, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Toshihiro Noda, Satoshi Mizuno, Mitsuru Sugawara, Ken Iseki
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques, 15, 2, 256, 64, CANADIAN SOC PHARMACEUTICAL SCIENCES, 2012年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. Since humans cannot synthesize lutein de novo, it must be digested as food. The physiological importance of an orally administered compound depends on its interaction with target tissues. It is therefore important to clarify the absorption mechanism in the intestine. Cholesterol membrane transporters Niemann-Pick C1 Like 1 (NPC1L1) and scavenger receptor class B type 1 (SR-B1) are involved in the intestinal absorption of highly lipophilic compounds including cholesterol. Ezetimibe, a selective inhibitor of intestinal NPC1L1, is the widespread lipid-lowering agent. It is important to investigate the possibility of food-drug interactions in order to prevent undesirable and harmful clinical consequences. The aim of this work was to determine whether NPC1L1, SR-B1 and other transporters are involved in absorption of lutein. METHODS: Caco-2 cells were used for accumulation and permeability study of lutein. Lutein concentration was determined by an HPLC system. The cDNA of transporters was isolated from total RNA of Caco-2 cells, and the expression of these transporters was confirmed by RT-PCR (reverse transcription-polymerase chain reaction). RESULTS: Ezetimibe inhibited up to 40% of lutein accumulation by Caco-2 cell monolayers. Block lipid transport 1 (BLT-1), a selective chemical inhibitor of SR-B1, also inhibited lutein accumulation by Caco-2 cells. On the other hand, ATP-depletion reagents (sodium fluoride and sodium azide or carbonyl cyanide m-chlorophenylhydrazone) did not influence the accumulation or permeation of lutein significantly. CONCLUSIONS: The results show that lutein absorption is, at least in part, mediated by influx transporters NPC1L1 and SR-B1 rather than mediated by efflux transporters such as ABC (ATP-binding cassette) transporters.

Schedule-dependent cytotoxicity of etoposide (VP-16) and cyclophosphamide in leukemia cell line K-562.
Yuki Tazawa, Kazunori Matsumura, Yoh Takekuma, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 35, 7, 1132, 6, PHARMACEUTICAL SOC JAPAN, 2012年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, In allogeneic bone marrow transplantation (allo-BMT) in patients with leukemia, the combination of VP-16 and cyclophosphamide (CY) is commonly used for the conditioning regimen. In the present study, we demonstrated schedule-dependent cytotoxicity of VP-16 and CY in K-562 cells. K-562 cells were pretreated with low concentrations (2.5 and 5 µg/mL) of 4-hydroperoxycyclophosphamide (40487S), which is a preactivated analog of CY. It was confirmed that these concentrations did not influence cell viability. Cells subsequently exposed to 0.5-100 µg/mL of VP-16 showed reduced the viability compared to that of control cells not treated with 40487S. In contrast, there was no change in the viability of K-562 cells pretreated with low concentrations (0.5 and 1 µg/mL) of VP-16. It was confirmed that these concentrations did not influence cell viability. Viability of subsequently exposed to 1-20 µg/mL was not different from that of control cells not treated with VP-16. VP-16 caused cell cycle arrest at G₂/M phase. On the other hand, 40487S arrested the cell cycle at S phase. Thymidine-synchronized cells, VP-16 showed cell cycle specificity for cell killing from early-S to mid-S phase. On the other hand, 40487S showed cell cycle-independent cytotoxicity. Exposure of cells to VP-16 after 40487S induced a greater cytotoxic effect on K-562 cells. The findings may lead to improvements in clinical combination chemotherapy.

Protective effect of lutein after ischemia-reperfusion in the small intestine.
Yuki Sato, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Toshihiro Noda, Satoshi Mizuno, Mitsuru Sugawara, Ken Iseki
Food chemistry, 127, 3, 893, 8, ELSEVIER SCI LTD, 2011年08月01日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Lutein is a carotenoid mainly found in green leafy vegetables and is located in the macula lutea in the human eye. Since humans cannot synthesise lutein de novo, it must be digested as food. The physiological importance of an orally administered compound depends on its interaction with target tissues. There is little information about the effects of intake of lutein in tissues other than the eyes. The aim of this study was to clarify the protective effect of lutein against oxidative injury using ischemia-reperfusion (I/R) model rats and to determine the relationship between pharmacokinetics and antioxidant activity of lutein. Intestinal I/R was induced by 30-min occlusion of the superior mesenteric artery followed by 60-min reperfusion. After 60min of reperfusion, intestinal tissue was used for analysis of Evans blue dye extravasation, lipid peroxidation and myeloperoxidase activity. Lutein administered before I/R had a significant protective effect against oxidative injury.

Pharmacokinetic properties of lutein emulsion after oral administration to rats and effect of food intake on plasma concentration of lutein.
Yuki Sato, Masaki Kobayashi, Shirou Itagaki, Takeshi Hirano, Toshihiro Noda, Satoshi Mizuno, Mitsuru Sugawara, Ken Iseki
Biopharmaceutics & drug disposition, 32, 3, 151, 8, WILEY-BLACKWELL, 2011年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Lutein is a carotenoid found mainly in green leafy vegetables and is located in the macula lutea in the human eye. An intake of lutein as food is needed since humans cannot synthesize it de novo. Although lutein has received much attention recently due to its antioxidant activities, little information about the pharmacokinetic properties of lutein is available. Lutein emulsion formulation was used and the pharmacokinetics of lutein emulsion after oral administration to rats was investigated. The bioavailability of lutein using this formulation was calculated to be 5.20%. It was found that a large amount of lutein was accumulated in the intestinal mucosa. The absorption of orally administered compounds in the intestine can be enhanced by interaction with food or food components. Thus, the effect of food intake on the intestinal absorption of lutein was investigated. The plasma concentration of lutein after oral administration of the emulsion formulation was improved significantly by food intake. It is possible that the absorption of lutein in the intestine is improved significantly by some food components. Bile acids may also play important roles in the intestinal absorption of lutein since the absorption of lipophilic compounds such as cholesterol is related to bile acids. The results of these studies should contribute to an improvement of lutein absorption and provide important information for obtaining more effective pharmacological effects of lutein.

In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid.
Yuki Sato, Shirou Itagaki, Toshimitsu Kurokawa, Jiro Ogura, Masaki Kobayashi, Takeshi Hirano, Mitsuru Sugawara, Ken Iseki
International journal of pharmaceutics, 403, 1-2, 136, 8, ELSEVIER SCIENCE BV, 2011年01月17日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Dietary polyphenols are thought to be beneficial for human health as antioxidants. Coffee beans contain a common polyphenol, chlorogenic acid. Chlorogenic acid is the ester of caffeic acid and quinic acid. Although these polyphenols have received much attention, there is little evidence indicating a relationship between the effect and the rate of absorption. In this study, we focused on the beneficial effects of chlorogenic acid and caffeic acid, a major metabolite of chlorogenic acid. We carried out in vitro and in vivo experiments. In the in vitro study, caffeic acid had stronger antioxidant activity than that of chlorogenic acid. The uptake of chlorogenic acid by Caco-2 cells was much less than that of caffeic acid. The physiological importance of an orally administered compound depends on its availability for intestinal absorption and subsequent interaction with target tissues. We then used an intestinal ischemia-reperfusion model to evaluate antioxidant activities in vivo. We found that both chlorogenic acid and caffeic acid had effects on intestinal ischemia-reperfusion injury. Since caffeic acid has a stronger antioxidant activity than that of chlorogenic acid and chlorogenic acid is hydrolyzed into caffeic acid in the intestine, it is possible that caffeic acid plays a major role in the protective effect of chlorogenic acid against ischemia-reperfusion injury.

Multidrug resistance protein 2 implicates anticancer drug-resistance to sorafenib.
Yoshihiko Shibayama, Kou Nakano, Hiroshi Maeda, Miyuki Taguchi, Ryuji Ikeda, Mitsuru Sugawara, Ken Iseki, Yasuo Takeda, Katsushi Yamada
Biological & pharmaceutical bulletin, 34, 3, 433, 5, PHARMACEUTICAL SOC JAPAN, 2011年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Sorafenib and sunitinib is a small molecule inhibitor of certain receptor tyrosine kinases, and have improved outcomes for patients with advanced renal cell carcinoma. Inhibitory concentration of 50% cell growth of sorafenib significantly rose to 6.4-fold in a multidrug resistance protein 2 (MRP2) transfected cell line versus control cell line. The concentration of sorafenib was significantly decreased to 74% of control cells after 3 h treatment. In contrast, a tyrosine kinase inhibitor sunitinib did not show alteration of inhibitory concentration of 50% cell growth and accumulation into the cells of MRP2 transfected cells. The present study suggest that sorafenib is a substrate for MRP2, suggesting that MRP2 may implicate drug resistance to sorafenib.

Effect of 5-fluorouracil treatment on SN-38 absorption from intestine in rats.
Yoshihiko Shibayama, Yoshitaka Iwashita, Yoshimi Yoshikawa, Tomoko Kondo, Ryuji Ikeda, Yasuo Takeda, Takayuki Osada, Mitsuru Sugawara, Katsushi Yamada, Ken Iseki
Biological & pharmaceutical bulletin, 34, 9, 1418, 25, PHARMACEUTICAL SOC JAPAN, 2011年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, 5-Fluorouracil (5-FU)-based chemotherapies with irinotecan have been applied for the treatment of cancers, and a common dose-limiting toxicity is neutropenia and diarrhea. In this study, we investigated the effect of 5-FU treatment on expression levels of drug transporters for SN-38 transportation and SN-38 absorption from the intestine following 5-FU treatment. Expression levels of several drug transporters and nuclear receptors in rats after 5-FU treatment were evaluated. SN-38 absorption from the intestine was evaluated by SN-38 concentration levels in serum following SN-38 injection into the intestine of 5-FU treated rats. The levels of renal multidrug resistance protein 2 (Mrp2) on day 4 after treatment (400 mg/kg) showed significant upregulation, 359.2 ± 33.2% (mean ± S.E.) of control. Mrp2 levels in the intestine were downregulated to 26.2 ± 8.4% of control. 5-FU treatment (400 mg/kg) also significantly downregurated expression levels of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) to 41.2 ± 14.7%, 15.7 ± 4.3% of control, respectively. To evaluate SN-38 absorption from the intestine, SN-38 was loaded in to the intestine on day 4 after 5-FU treatment. Pretreatment with 5-FU significantly increased SN-38 concentration in the blood 30, 60 and 90 min after SN-38 administration. The area under the curve for SN-38 in the 5-FU group was significantly higher than in vehicle groups. 5-FU treatment decreased expression levels of P-glycoprotein and Bcrp in intestine. The present study suggests that combination chemotherapy of 5-FU with irinotecan (CPT-11) may elevate SN-38 absorption from intestine.

Protective effect of soy isoflavone genistein on ischemia-reperfusion in the rat small intestine.
Yuki Sato, Shirou Itagaki, Setsu Oikawa, Jiro Ogura, Masaki Kobayashi, Takeshi Hirano, Mitsuru Sugawara, Ken Iseki
Biological & pharmaceutical bulletin, 34, 9, 1448, 54, PHARMACEUTICAL SOC JAPAN, 2011年, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Ischemia-reperfusion (I/R) injury of the intestine is an important factor associated with high rates of morbidity and mortality. Intestinal I/R is a common clinical problem in the settings of severe burns, circulatory shock and strangulation ileus. Intestinal I/R damages remote organs and promotes multi-organ failure. It has been shown that enteral feeding before ischemic insults is beneficial for reducing organ injury and improving survival after intestinal I/R. In that study, the authors used a standard complex enteral diet and they suggested that it is important to find new nutrient formulas. Since reactive oxygen species are responsible for intestinal I/R injury, we focused on a dietary polyphenol, the soy isoflavone genistein. Genistein has a wide spectrum of biochemical and pharmacological activities. However, the possibility of a protective effect of genistein as enteral nutrition on I/R injury has not been investigated. We therefore investigated the protective effect of genistein on oxidative injury using intestinal I/R model rats. We found that genistein, which has combined antioxidant activity from radical scavenging, xanthine oxidase inhibition and chain-breaking effects, exhibits a protective effect on intestinal I/R injury. The results suggest that genistein, a soy isoflavone, has the possibility as a new nutrient formula of enteral feeding.

Penetration of linezolid into rabbit intervertebral discs and surrounding tissues.
Miki Komatsu, Masahiko Takahata, Mitsuru Sugawara, Yoh Takekuma, Takashi Kato, Manabu Ito, Yuichiro Abe, Tohru Irie, Norimasa Iwasaki, Akio Minami
European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society, 19, 12, 2149, 55, SPRINGER, 2010年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Linezolid belongs to a new class of synthetic antimicrobial agent that is effective for a variety of methicillin-resistant Staphylococcus aureus (MRSA) infections including bone and joint MRSA infections, but the effectiveness of linezolid for the treatment of MRSA spine infection remains controversial. In this study, we investigated the diffusion of linezolid or vancomycin into normal rabbit spinal tissues to determine the adequacy of linezolid for the treatment of spinal infection. The penetration efficacy of linezolid into the annulus fibrosus, nucleus pulposus, and vertebral bone (10, 8, and 10%, respectively) was lower than that of vancomycin (27, 11, and 14%, respectively). The penetration efficacy of linezolid into the bone marrow and iliopsoas muscle (88 and 84%, respectively), however, was higher than that of vancomycin (67 and 9%, respectively). These results suggest that linezolid is inadequate for the treatment of spine infection limited to the intervertebral disc, but may be effective for the treatment of infection extending into the muscle and bone marrow, such as in vertebral osteomyelitis, iliopsoas abscess, and postsurgical infection.

放射線治療に伴う口腔粘膜障害に対する予防・軽減効果が期待される物質の探索
板垣 史郎, 中田 千絵, 平野 剛, 鷹野 瑠美, 笠師 久美子, 菅原 満, 高橋 夏子, 小林 正紀, 井関 健
医療薬学, 36, 9, 696, 702, (一社)日本医療薬学会, 2010年09月, ［査読有り］
日本語, 放射線台療に伴う口腔粘膜障害に対する予防・軽減効果が期待される物質を探索した。16Gyの放射線照射を行った後、5日間培養したHO-1-N-1細胞を用いて、種々の化合物の障害抑制効果について検討した。抗酸化作用を有するN-アセチルシステイン(NAC)およびカテキン類に着目し、その障害抑制効果について検討した。高濃度のNACの添加により、放射線照射による細胞生存率の低下が有意に抑制された。カテキン類の添加により、放射線照射による細胞生存率の低下は有意に抑制された。NACおよびカテキン類の添加により、放射線照射による蛍光強度の増大は抑制された。HO-1-N-1細胞に放射線を照射したところ、アポトーシスに特徴的なDNAの断片化が観察され、アポトーシスが誘導されていることが示された。一方、NACおよびカテキン類の添加により、DNAの断片化は顕著に抑制された。

Grapefruit juice enhance the uptake of coenzyme Q10 in the human intestinal cell-line Caco-2
Shirou Itagaki, Akiko Ochiai, Masaki Kobayashi, Mitsuru Sugawara, Takeshi Hirano, Ken Iseki
FOOD CHEMISTRY, 120, 2, 552, 555, ELSEVIER SCI LTD, 2010年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Coenzyme Q10 (CoQ10) is very widely consumed by humans as a food supplement. However, CoQ10 is taken up from the intestine into the circulation at a low rate. The absorption of compounds from the gastrointestinal tract is one of the important determinants for oral bioavailability. Secretory transport limits the Oral bioavailability of compounds. It has been reported that efflux transport of CoQ10 is mediated by P-glycoprotein (P-gp) in Caco-2 cells. We tried to improve intestinal absorption of CoQ10 by modulating P-gp. Since grapefruit juice (GFJ) is reported to inhibit P-gp function, we investigated the effect of GFJ on the transport of CoQ10 by Caco-2 cells. In the presence of GFJ, the basal-to-apical transport of CoQ10 was decreased and the uptake of CoQ10 was increased. These findings suggest that the combined administration of CoQ10 and GFJ could enhance CoQ10 absorption. (C) 2009 Elsevier Ltd. All rights reserved.

In vitro実験系による肺がん化学療法レジメンの抗腫瘍効果の評価
斎藤 由起子, 平野 剛, 沖 洋充, 笠師 久美子, 菅原 満, 小林 正紀, 高橋 夏子, 板垣 史郎, 井関 健
医療薬学, 36, 4, 220, 226, (一社)日本医療薬学会, 2010年04月, ［査読有り］
日本語, In vitro実験系による肺がん化学療法レジメンの抗腫瘍効果について検討した。肺がんのモデルとしてヒト肺扁平上皮がん由来A549細胞を使用した。CDDP+CPT-11(IP)療法において、CDDPは長期間にわたって抗腫瘍効果を示すことが示唆された。SN-38はday2からday5にかけて細胞生存率の回復を認め、CPT-11の1回日の投与により死滅したがん細胞が回復してきたところを再投与によりさらに攻撃するというレジメンの投与スケジュールに相関した。CDDP+VP-16(EP)療法において、各々の単剤のときと比較して抗腫瘍効果が増大することが示された。

Heavy Water Containing Solution Ameliorates Cold Preservation Injury of the Rat Heart
Kenji Wakayama, Moto Fukai, Kenichiro Yamashita, Daisuke Fukumori, Mitsuru Sugawara, Susumu Shibasaki, Gentaro Hirokata, Masaaki Zaitsu, Yusuke Tsunetoshhi, Michitaka Ozaki, Satoru Todo
AMERICAN JOURNAL OF TRANSPLANTATION, 10, 494, 494, WILEY-BLACKWELL PUBLISHING, INC, 2010年04月, ［査読有り］
英語

気分障害圏患者における副作用に対する認知とコンプライアンスへの影響、および心理検査との相関性の検討
久保田 康生, 木村 俊也, 渡邉 紀子, 大崎 明美, 鈴木 克治, 菅原 満, 小山 司, 井関 健
日本病院薬剤師会雑誌, 46, 3, 359, 362, (一社)日本病院薬剤師会, 2010年03月, ［査読有り］
日本語, 研究論文（学術雑誌）, 気分障害圏の患者において薬物治療は症状・機能回復、再発予防のため重要であるが、拒薬に至る患者は4割といわれている。今回、患者に対し薬物療法への認識や考え方についてアンケート調査を行った結果、41%の患者にて拒薬の経験が認められた。理由として、副作用を避けるためなど認識の低さが原因であった。薬剤師が伝えた情報と患者の理解に差がみられる場合もある。そこで、患者の認知や思考の特性を知ることは服薬指導を充実させる方法として重要と考え、認知や思考を含め広く心理機能を測定できるロールシャッハテストに着目した。ロールシャッハテストは7つのクラスターを基に解釈される心理検査であるが、そのなかから認知や思考に関与するZd、X-%、HVIの3種の指標を選択した。HVI陽性において、拒薬との相関性が認められた。HVI陰性においてもZd、X-%が期待値外の場合、治療薬の理解に影響を与える可能性が考えられた。(著者抄録)

Kinetic study of anti-viral ribavirin uptake mediated by hCNT3 and hENT1 in Xenopus laevis oocytes.
Takashi Yamamoto, Mitsuru Sugawara, Takashi Kikukawa, Seiji Miyauchi, Masahiro Yamaguchi, Atsushi Tero, Seiji Takagi, Toshiyuki Nakagaki
Biophysical chemistry, 147, 1-2, 59, 65, ELSEVIER SCIENCE BV, 2010年03月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Transport across the cell membrane is crucial in drug delivery. However, the process is complicated because nucleoside derivatives that are commonly used as anti-viral drugs are transported through two different types of specific transporters: concentrative transporters and equilibrative transporters. Cross-disciplinary approaches involving both biological experiments and theoretical considerations are therefore necessary to study the transport of nucleoside analogues such as ribavirin. Here we constructed an experimental model system using the Xenopus laevis oocyte that expressed examples of both types of transporters: human concentrative nucleoside transporter 3 and human equilibrative transporter 1. We also performed a kinetic study. Experimental results showed that the transport of ribavirin could be reduced by inhibiting one of the two types of transporters, which seems to be counterintuitive. We therefore designed a simple mathematical model of the dynamics of ribavirin uptake and analyzed the model behaviors using a numerical simulation. The theoretical results reproduced the experimentally observed phenomena and suggested a possible mechanism for the process. Based on this mechanism, we predicted some potential methods for the effective uptake of ribavirin from a dynamics point of view.

高度腎機能障害患者におけるリネゾリドの体内動態
山崎 浩二郎, 武隈 洋, 西村 あや子, 宮本 剛典, 菅原 満, 井関 健
TDM研究, 26, 4, 137, 141, (一社)日本TDM学会, 2009年10月, ［査読有り］
日本語, オキサゾリジノン系合成抗菌薬リネゾリド(LZD)は、2006年4月にMRSAに対する適応が追加された。LZDは腎機能低下例においても用法・用量の調節の必要がないと考えられており、血中濃度の測定もほとんど実施されていないのが現状である。今回、高度腎機能障害患者にLZDを投与した症例を経験し、その血中濃度を測定することによりLZDの体内動態への腎機能および透析の影響を検討したので報告する。MRSAによる菌血症の症例では、LZD投与中に腎機能が悪化し透析導入となった。そこで、透析時および非透析時の血中濃度を測定したところ、非透析時のLZDの排泄は健常人と比較して4倍程度遅延し、透析による除去率は50%程度であった。植皮部にMRSA感染がみられた症例では、透析は導入されていないが高度腎機能障害を有していた。LZD投与開始時より血中濃度を測定し、排泄への影響を確認し、その後の投与設計を行った。LZDの排泄は健常人と比較して2倍程度遅延しており、1回600mg1日2回の投与を1日1回へ減量した。その後の経過は良好であった。本検討により、少なくも高度腎機能障害患者においてはLZDの排泄遅延が起こり、LZDの血中濃度が非常に高く推移する可能性があることが明らかとなった。高度腎機能障害患者、透析患者においては血中濃度を測定することが非常に重要であり、今後のLZDの適正使用に貢献できるものと考えられる。(著者抄録)

がん化学療法に伴う口内炎の予防・改善に有効な抗酸化物質の探索
鷹野 瑠美, 平野 剛, 中田 千絵, 笠師 久美子, 菅原 満, 小林 正紀, 板垣 史郎, 井関 健
医療薬学, 35, 4, 247, 253, (一社)日本医療薬学会, 2009年04月, ［査読有り］
日本語, 癌化学療法に伴う口内炎の予防・改善に有効な抗酸化物質を探索するため、種々の化合物についてスーパーオキシドアニオン消去作用を評価した。対象物は含嗽として汎用されている3薬剤、抗酸化作用が記載されている8薬剤、カテキンのEGCgを用いた。その結果、含嗽剤ではアロプリノールの消去作用がレバミピドと比較して非常に強く、カモスタットはほとんど消去作用を示さなかった。他剤ではトラニラスト、メサラジン、ピロキシカムは作用が強く、ガベキサート、L-カルボシステインは弱かった。また、EGCgはアロプリノールと同等の強い消去作用を示した。次いで、組織障害に関与するラジカル連鎖反応停止作用を調べた結果、含嗽3薬剤には同作用は認めず、メサラジン、EGCgには強力な作用を認めた。更に、酸化障害性口内炎モデルに対する細胞障害抑制作用を調べたところ、EGCgは強力な効果を、アロプリノール、メサラジンは弱い効果を示し、レバミピド、カモスタットには効果を認めなかった。

多発性骨髄腫における同種造血幹細胞移植後の慢性消化管GVHDに対しベクロメタゾン腸溶性製剤を投与した症例
久保田 康生, 小林 正紀, 笠師 久美子, 高畑 むつみ, 菅原 満, 橋野 聡, 井関 健
医療薬学, 35, 3, 213, 218, (一社)日本医療薬学会, 2009年03月, ［査読有り］
日本語, 研究論文（学術雑誌）, 57歳女。多発性骨髄腫を発症した。MP(メルファラン+プレドニゾロン)療法を開始し、ビスホスホネート製剤を併用したが、病勢のコントロールが不良であった。サリドマイド+デキサメタゾン療法を開始したが奏効しなかった。自己末梢血幹細胞移植は、十分なCD34陽性細胞数を得ることができず施行できなかった。サリドマイド併用によるCP(シクロホスファミド+プレドニゾロン)療法、サリドマイド併用による少量のシクロホスファミドの内服治療を順次施行したが、出血性膀胱炎などの副作用により継続できなかった。非血縁者間同種造血幹細胞移植を施行し、GVHD予防としてFK506の持続点滴を開始した。内視鏡検査と病理検査により回盲部と結腸における急性消化管GVHDの発症を確認した。プロピオン酸ベクロメタゾン(BDP)腸溶性カプセル剤を投与し、改善傾向を認めた。

Regulatory mechanisms of SNAT2, an amino acid transporter, in L6 rat skeletal muscle cells by insulin, osmotic shock and amino acid deprivation.
Hitoshi Kashiwagi, Kojiro Yamazaki, Yoh Takekuma, Vadivel Ganapathy, Mitsuru Sugawara
Amino acids, 36, 2, 219, 30, SPRINGER, 2009年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Several studies have demonstrated that the activity of system A is upregulated by insulin, osmotic shock and amino acid deprivation. However, the mechanisms are not clear. We carried out studies using L6 rat skeletal muscle cells to clarify the mechanisms of upregulation of system A activity by insulin, osmotic shock and amino acid deprivation. The upregulation was found to be due to an increase in Vmax, not Km. Chloroquine and wortmannin inhibited the upregulation induced by insulin stimulation and amino acid deprivation but not that induced by osmotic shock. On the other hand, cycloheximide and actinomycin D inhibited the upregulation by each stimulation. Moreover, PD98059 and SP600125 inhibited only amino acid deprivation-induced upregulation and SB202190 inhibited only insulin-induced upregulation. Our findings indicate that the mechanisms of upregulation of system A activity by insulin, osmotic shock and amino acid deprivation are different in L6 cells. Western blot and RT-PCR analysis showed an increase in system A at the protein and mRNA levels with each stimulation.

Improvement of renal function estimation equations for elderly Japanese people　　　　　　　　　　　　　　　
Kaburaki, S, Yoshimura, E, Kojima, N, Ueno, H, Sugawara, M, Takekuma, Y
Health Science Reports, 2008年09月, ［査読有り］

Interaction of coenzyme Q10 with the intestinal drug transporter P-glycoprotein.
Shirou Itagaki, Akiko Ochiai, Masaki Kobayashi, Mitsuru Sugawara, Takeshi Hirano, Ken Iseki
Journal of agricultural and food chemistry, 56, 16, 6923, 7, AMER CHEMICAL SOC, 2008年08月27日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, In clinical trials, patients usually take many kinds of drugs at the same time. Thus, drug-drug interactions can often directly affect the therapeutic safety and efficacy of many drugs. Oral delivery is the most desirable means of drug administration. Changes in the activity of drug transporters may substantially influence the absorption of administered drugs from the intestine. However, there have been a few studies on food-drug interactions involving transporters. It is important to be aware of the potential of food-drug interactions and to act in order to prevent undesirable and harmful clinical consequences. Coenzyme Q10 (CoQ10) is very widely consumed by humans as a food supplement because of its recognition by the public as an important nutrient in supporting human health. Since intestinal efflux transporter P-glycoprotein (P-gp) is one of the major factors in drug-drug interactions, we focused on this transporter. We report here for the first time that CoQ10, which is widely used as a food supplement, affects the transport activity of P-gp.

MRSA感染症治療におけるteicoplaninの投与設計の検討
菅原 満, 山澤 裕司, 齋藤 嘉津彦, 小林 道也, 田中 寛之, 唯野 貢司
TDM研究, 25, 1, 28, 36, (一社)日本TDM学会, 2008年01月, ［査読有り］
日本語, 研究論文（学術雑誌）, MRSA感染症治療を目的にTDM施行下にTEICが投与された症例の前向き調査を2005年12月から2007年3月の期間、北海道TDM研究会に所属する17施設で実施した。調査に先立ち、TEICの基本投与法は添付文書に記載されている用法用量、初日800mgの負荷投与、2日目以降は400mgの維持用量投与とし、目標トラフ濃度は10μg/mLに設定した。調査票が回収された102例について、TEICの適正な投与法および目標トラフ濃度10μg/mLの妥当性について検討を行った。その結果、TDM実施によりほぼ全例が最終的には10μg/mLの目標トラフ濃度にコントロールされたが、その到達時期はさまざまであった。臨床所見(体温、CRP、白血球数)はTEIC投与前後で有意な改善を認め、細菌学的有効率は75.9%だった。投与早期に目標トラフ濃度を確保しそれを維持した症例群は、それ以外の症例群に比べて細菌学的効果が優れていた。投与開始3日間に基本投与法より多い投与量が使用された症例群は全例が目標トラフに到達したが、基本投与法の症例群では約半数例が目標トラフ濃度に到達しなかった。TEICの添付文書に記載されている用法用量、初日400mg、2日目以降200mgの維持用量投与をした症例群では全例が目標トラフ濃度に到達しなかった。TEICの投与早期の血中濃度と肝・腎機能の検査値との関係を調べたところ、相関性は認められなかった。今回の検討では、TEICはTDMを施行し投与早期からトラフ濃度を10μg/mL上に確保、維持することが効果的な使用法であると考えられ、そのための投与法を再検討する必要があると思われた。(著者抄録)

心臓血管造影剤による急性腎機能低下に対するアセチルシステインの予防効果および製剤の評価
清川 真美, 澤口 利香, 須田 範行, 武隈 洋, 菅原 満, 相馬 孝光, 川嶋 望, 筒井 裕之, 井関 健
医療薬学, 34, 1, 20, 25, (一社)日本医療薬学会, 2008年01月, ［査読有り］
日本語, 研究論文（学術雑誌）, 造影剤投与を受けた患者に発現する造影剤腎症に対するN-アセチルシステイン(NAC)の予防効果を検討した。また、従来のNAC液の不快な臭いと味覚を改善したNACゼリー製剤の服用性を評価した。腎症予防効果の対象はNACを服用した造影剤投与患者(NAC群)67名と、それ以前に検査を受けたNAC非服用造影剤投与患者(対照群)81名で、腎障害の有無を血清クレアチニン値で評価した。NACゼリー製剤の服用感はNAC群の35名を対象としてアンケート調査を行った。その結果、NAC群の腎障害は対照群に比べて有意に低く、NACは腎機能低下を予防することが示唆された。また、種々の合併症を持つ患者の造影剤腎症に起因する腎機能悪化を予防する可能性が示された。一方、NACゼリー製剤はNAC液の不快な臭いや味覚を改善するが、その味付けには改善の余地があると思われた。

Functional analysis of phenolsulfonphthalein transport system in Long-Evans Cinnamon rats.
Shirou Itagaki, Makoto Chiba, Masaki Kobayashi, Mitsuru Sugawara, Michiya Kobayashi, Takeshi Hirano, Ken Iseki
Biochimica et biophysica acta, 1778, 1, 270, 5, 1, 2008年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, It has been reported that the transport function for organic anions on the kidney is maintained in multidrug resistance-associated protein 2 (Mrp2)-deficient rats. Different from Mrp2-deficient rats, Long-Evans Cinnamon (LEC) rats have impaired urinary excretion of Mrp2-substrate, phenolsulfonphthalein (PSP). PSP is transported by the potential-sensitive urate transport system in rat brush-border membranes. We analyzed the function of PSP transport system in LEC rats. Unlike Long-Evans Agouti (LEA) rats, the initial uptake of PSP and urate into the renal brush-border membrane vesicles of LEC rats were not significantly enhanced in the presence of positive intravesicular potential, suggesting that the potential-sensitive urate transport system is impaired in LEC rats. LEC rats should be useful for elucidating the potential-sensitive urate transport system in rats at the molecular level.

Functional analysis of phenolsulfonphthalein transport system in Long-Evans Cinnamon rats
Shirou Itagaki, Makoto Chiba, Masaki Kobayashi, Mitsuru Sugawara, Michlya Kobayashi, Takeshi Hirano, Ken Iseki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1778, 1, 270, 275, ELSEVIER SCIENCE BV, 2008年01月, ［査読有り］
英語, 研究論文（学術雑誌）, It has been reported that the transport function for organic anions on the kidney is maintained in multidrug resistance-associated protein 2 (Mrp2)-deficient rats. Different from Mrp2-deficient rats, Long-Evans Cinnamon (LEC) rats have impaired urinary excretion of Mrp2-substrate, phenolsulfonphthalein (PSP). PSP is transported by the potential-sensitive urate transport system in Tat brush-border membranes. We analyzed the function of PSP transport system in LEC rats. Unlike Long-Evans Agouti (LEA) rats, the initial uptake of PSP and urate into the renal brush-border membrane vesicles of LEC rats were not significantly enhanced in the presence of positive intravesicular potential, suggesting that the potential-sensitive urate transport system is impaired in LEC rats. LEC rats should be useful for elucidating the potential-sensitive urate transport system in rats at the molecular level. (c) 2007 Elsevier B.V. All rights reserved.

Stereoselective metabolism of racemic carvedilol by UGT1A1 and UGT2B7, and effects of mutation of these enzymes on glucuronidation activity.
Yoh Takekuma, Toru Takenaka, Koujiro Yamazaki, Kazuyuki Ueno, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 30, 11, 2146, 53, PHARMACEUTICAL SOC JAPAN, 2007年11月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, Carvedilol, an alpha- and beta-adrenergic blocking drug, is mainly metabolized by CYP2D6, UGT1A1, UGT2B4 and UGT2B7. This drug is administered orally as a racemic mixture of R(+)- and S(-)-enantiomers. It has been reported that CYP2D6 prefers metabolizing S-carvedilol to R-carvedilol stereoselectively. On the other hand, stereoselective metabolism of carvedilol by UGTs is still unclear. Moreover, we have reported that patients with chronic heart failure who had polymorphism in CYP2D6, UGT1A1 and/or UGT2B7 had lower metabolic activity and oral clearance than did patients with no polymorphism. The aim of this study was to clarify stereoselective metabolism of carvedilol by UGT1A1 and UGT2B7 and to determine by using a recombinant enzyme-introduced mutation whether genetic mutation in UGT1A1 and UGT2B7 causes reduction in metabolic activity for carvedilol. A glucuronidation assay using human liver microsomes and recombinant UGT1A1 and UGT2B7 expressed in HeLa cells demonstrated that UGT1A1 prefers metabolizing R-carvedilol to S-carvedilol. On the other hand, UGT2B7 prefers metabolizing S-carvedilol to R-carvedilol. Moreover, G71R mutation of UGT1A1 reduced both affinity and capacity but did not affect stereoselective metabolism. On the other hand, both A71S and H268Y mutations of UGT2B7 reduced capacity but did not affect affinity and, as a result, the efficiency of metabolism was remarkably reduced. However, as in the case of UGT1A1, neither of the mutations affected stereoselective metabolism.

Evaluation of effects of polymorphism for metabolic enzymes on pharmacokinetics of carvedilol by population pharmacokinetic analysis.
Yoh Takekuma, Toru Takenaka, Masami Kiyokawa, Koujiro Yamazaki, Hiroshi Okamoto, Akira Kitabatake, Hiroyuki Tsutsui, Mitsuru Sugawara
Biological & pharmaceutical bulletin, 30, 3, 537, 42, PHARMACEUTICAL SOC JAPAN, 2007年03月, ［査読有り］, ［国内誌］
英語, 研究論文（学術雑誌）, In our previous study it was observed that the frequencies of UGT1A1*6, UGT2B7*3 and CYP2D6*10 in patients who have a low level ability of glucuronidation were significantly higher than those in patients with a high level of ability of glucuronidation. The same tendency was found in the frequency of CYP2D6*5, though there was no significant difference. The purpose of this study was to evaluate the effects of the polymorphism on pharmacokinetics of carvedilol by population pharmacokinetic analysis. Population pharmacokinetic analysis was performed using 373 plasma concentrations from 41 patients with chronic heart failure or angina pectoris. A one compartment pharmacokinetic model with first-order absorption (for oral dosing) was used to describe the concentration-versus-time data for carvedilol. We examined the effects of various clinical and genetic covariables in the regression models for clearance and volume of distribution. The results suggested that the factors of interindividual variation for carvedilol clearance were creatinine clearance and polymorphisms of UGT2B7 and CYP2D6 in the Japanese population with heart disease. It was estimated that UGT2B7*3 decreased the clearance of carvedilol by 37%, but UGT2B7*2 did not show any effect. Clearance in the patients who have intermediate activity of CYP2D6 was decreased by 39%.

Ribavirin uptake by cultured human choriocarcinoma (BeWo) cells and Xenopus laevis oocytes expressing recombinant plasma membrane human nucleoside transporters.
Takashi Yamamoto, Kenichi Kuniki, Yoh Takekuma, Takeshi Hirano, Ken Iseki, Mitsuru Sugawara
European journal of pharmacology, 557, 1, 1, 8, ELSEVIER SCIENCE BV, 2007年02月14日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We investigated the mechanism of the transport of ribavirin (1-beta-D-ribofuranosyl-1,2,4-trizole-3-carboxamide) into placental epithelial cells using human choriocarcinoma (BeWo) cells and Xenopus oocytes expressing human nucleoside transporters. In BeWo cells, when a relatively low concentration (123 nM) of ribavirin was used, both Na(+)-dependent uptake and -independent uptake of ribavirin were observed. On the other hand, when a higher concentration (100 microM) of ribavirin was used, Na(+)-independent uptake was observed, but there was only a slight Na(+)-dependent uptake. In Xenopus oocytes, influxes of ribavirin mediated by hCNT2 (concentrative nucleoside transporter 2), hCNT3 (concentrative nucleoside transporter 3), hENT1 (equilibrative nucleoside transporter 1) and hENT2 (equilibrative nucleoside transporter 2) were saturable, and apparent K(m) values were 18.0 microM, 14.2 microM, 3.46 mM and 3.71 mM, respectively. These data indicate that hCNT2 and hCNT3 have higher affinity for ribavirin than do hENT1 and hENT2. Moreover, analysis by RT-PCR showed that BeWo cells express mRNA of hCNT3, hENT1 and hENT2. These results suggest that ribavirin is taken up by BeWo cells via both the high-affinity Na(+)-dependent transporter hCNT3 and the low-affinity Na(+)-independent transporters hENT1 and hENT2.

外来化学療法における服薬指導の充実のための病棟-外来間連携ツールの構築
久保田 康生, 中里 恭子, 須田 範行, 沖 洋充, 菅原 満, 小林 道也, 齊藤 浩司, 井関 健
医療薬学, 33, 2, 152, 158, (一社)日本医療薬学会, 2007年02月, ［査読有り］
日本語, 研究論文（学術雑誌）, 患者の入院中の各種状況を把握し、それに応じたテーラーメイド的な服薬指導を行うため、病棟担当薬剤師からセンター担当薬剤師向けへの患者情報伝達手段の方法・内容の検討とその評価を行った。外来治療センターで抗がん剤調製業務および服薬指導を担当しているセンター担当薬剤師5例を対象とし、選択・記述併用形式のアンケート調査を行った。センター担当薬剤師が必要としている情報のアンケート調査結果を基に、病棟担当薬剤師から提供可能な情報を抽出し、外来治療センターへの連絡表を作成した。外来治療センターでの治療患者のおよそ30%の患者に対し、連絡表を使用しており、その有用性が見出されてきている。

Difference between pharmacokinetics of mycophenolic acid (MPA) in rats and that in humans is caused by different affinities of MRP2 to a glucuronized form.
Yoh Takekuma, Haruka Kakiuchi, Koujiro Yamazaki, Seiji Miyauchi, Takashi Kikukawa, Naoki Kamo, Vadivel Ganapathy, Mitsuru Sugawara
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques, 10, 1, 71, 85, CANADIAN SOC PHARMACEUTICAL SCIENCES, 2007年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: Mycophenolic acid (MPA), an immunosuppressant, is excreted as its glucuronized form, MPAG. In humans, MPAG is mostly excreted into urine, whereas more than 80% of the dose is excreted into bile in rats. The aim of this study was to clarify the cause of the species difference. We investigated whether MPAG is a substrate of human organic anion transporters (hOATs), and we compared the affinities of multi-drug resistance-associated protein 2 (MRP2) for MPAG in rats and humans. METHODS: The inhibitory effects of MPAG on the uptake of typical substrates via hOAT1 and hOAT3 were determined using HeLa cells heterologously expressing hOAT1 and Xenopus laevis oocytes heterologously expressing hOAT3. MPAG transport activity via hOAT1 and hOAT3 was determined by the two-microelectrode voltage-clamp technique using Xenopus laevis oocytes expressing hOAT1 and hOAT3. The affinities of MPAG for hMRP2 and rMrp2 were determined by the inhibitory effects of MPAG on p-aminohippuric acid (a typical substrate) uptake using membrane vesicles expressing hMRP2 or rMrp2. RESULTS: MPAG inhibited the uptake of PAH via hOAT1 and hOAT3, and calculated IC50 values were 222.6+/-26.6 microM and 41.5+/-11.5 microM, respectively. However, MPAG was not transported by hOAT1 and hOAT3. MPAG strongly inhibited the uptake of PAH via both rMrp2 and hMRP2. However, the magnitudes of inhibitory effects were different. The calculated IC50 values were 286.2+/-157.3 microM and 1036.8+/-330.5 microM, respectively. CONCLUSION: MPAG is not a substrate but is an inhibitor of hOAT1 and hOAT3. The affinity of rMRP2 to MPAG was about 3.6 times as high as that of hMRP2. Therefore, the difference of affinity between hMRP2 and rMrp2 is a possible mechanism of the difference of excretion ratio of MPAG between rats and human.

神経因性疼痛に対する酢酸フレカイニドの鎮痛効果と血中濃度の関係
山崎 浩二郎, 武隈 洋, 志賀 弘康, 菅原 満, 小澤 剛久, 柴田 万里子, 橋本 聡一, 森本 裕二
TDM研究, 23, 4, 253, 256, (一社)日本TDM学会, 2006年10月, ［査読有り］
日本語, 研究論文（学術雑誌）, 酢酸フレカイニド(FLC)は、Vaughan Williams分類のI c群に属する抗不整脈薬である。近年、抗不整脈薬は鎮痛補助薬としても有効であることが示され、特に神経因性疼痛(ニューロパシックペイン)に対して鎮痛効果があるとされている。そこで著者らは、神経因性疼痛に対するFLCのドラッグチャレンジテストを設計し、その鎮痛効果とFLCの血中濃度との関係について検討した。対象は、帯状疱疹後神経痛、複雑型局部疼痛症候群、難治性神経因性疼痛などの診断を受け、既存の治療法で疼痛軽減が得られなかった、または効果が頭打ちになり罹患より3ヵ月以上経過した症例とした。5名中4名においてVisual analog scale(VAS)の低下が認められた。また、その5名において、FLCの血中濃度に大きな個体差は認められず、投与終了5分後で200〜400ng/mL、30分後で140〜180ng/mL、120分後で100ng/mL付近で推移した。この血中濃度推移とVASの推移の関係より、FLCの神経因性疼痛に対する最低有効血中濃度は140〜180ng/mL付近であることが示唆された。(著者抄録)

患者の健康食品摂取状況および意識調査と健康食品データベース構築
久保田 康生, 沖 洋充, 山崎 浩一, 菅原 満, 西村 正治, 井関 健
日本病院薬剤師会雑誌, 42, 7, 927, 929, (一社)日本病院薬剤師会, 2006年07月, ［査読有り］
日本語, 研究論文（学術雑誌）, 入院患者を73例を対象として,健康食品に関する認識や摂取状況を調査し,特に,化学療法施行患者への服薬指導における健康食品摂取に対する薬剤師としての対応を検証した.また,これらの調査から得られた情報を基に,健康食品に関するデータベースの構築を行った.57.5%が健康食品を摂取し,特にがん患者の摂取率が高かった.摂取群,非摂取群ともに健康被害や相互作用の可能性を疑う頻度に差は見られなかった.既知の健康被害や相互作用だけでも回避できるよう,摂取状況は医療従事者へ報告してもらうよう促すため「患者用注意書き」を作成した.医療従事者へ可能な限りの正確な情報をいち早く提供できるようデータベースを構築した

Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol.
Yoh Takekuma, Toru Takenaka, Masami Kiyokawa, Koujiro Yamazaki, Hiroshi Okamoto, Akira Kitabatake, Hiroyuki Tsutsui, Mitsuru Sugawara
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques, 9, 1, 101, 12, CANADIAN SOC PHARMACEUTICAL SCIENCES, 2006年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: It has been reported that carvedilol, which has beta-adrenergic blocking and vasodilating activities, is mainly metabolized by UDP-glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B7 and CYP2D6. The aim of this study was to determine whether the activity of glucuronidation has an influence on the area under the curve (AUC) of carvedilol and whether polymorphisms in UGTs and CYP2D6 contribute to individual variation in disposition of carvedilol in Japanese. METHODS: Plasma concentrations of carvedilol and its glucuronide were determined by reversed-phase high-performance liquid chromatography (HPLC). Genotyping of UGT1A1, UGT2B4 and UGT2B7 genes was carried out by the direct sequence method. CYP2D6 genotyping was carried out using an amplification refractory mutation system (ARMS) assay and PCR-restriction fragment length polymorphism (RFLP). RESULTS: The level of carvedilol glucuronidation ability in the high-level AUC group was significantly lower than that in the low-level group. The frequencies of UGT1A1*6, UGT2B7*3 and CYP2D6*10 in the low level ability of glucuronidation group were significantly higher than those in the high level group, and the same tendency was found in the frequency of CYP2D6*5, though there was no significant difference. CONCLUSION: Polymorphisms of UGT1A1, UGT2B7 and CYP2D6 strongly affect the pharmacokinetics and disposition of carvedilol in Japanese.

30P3-019 ポリアクリル酸ナトリウム(PANA)人工唾液の使用動向とその評価(院内製剤(薬局製剤),医療薬学の扉は開かれた)
笠師 久美子, 須田 範行, 鄭 漢忠, 菅原 満, 井関 健
日本医療薬学会年会講演要旨集, 16, 0, 435, 435, 一般社団法人 日本医療薬学会, 2006年, ［査読有り］
日本語

麻薬管理の一元化を可能とした麻薬オーダリングシステムの構築と運用
志賀 弘康, 川合 真次, 荻野 修, 菅原 満, 遠藤 晃, 櫻井 恒太郎, 宮崎 勝巳
医療薬学, 31, 12, 1027, 1035, (一社)日本医療薬学会, 2005年12月, ［査読有り］
日本語, 研究論文（学術雑誌）, より正確に,かつ効率的に麻薬を管理することを目的として,麻薬オーダリングシステム(麻薬オーダ)を構築した.各種オーダ(処方,注射,物流)と連動させることにより,麻薬帳票類の自動作成を可能とした麻薬オーダの詳細と,その運用方法,さらにはその有用性を検討した.オーダの麻薬データを利用し,各種麻薬の入出庫データ,廃棄データ等をあらためて手入力することなく,麻薬帳票・届け出類の自動作成が可能となった.これにより麻薬使用量等の集計業務は簡便になり,各種帳票類の作成に要する時間も大幅に短縮し,麻薬受払簿の正確性の向上で,システム導入前と比較して在庫確認作業も簡便になった

外来治療センターにおける薬剤師業務
瀬戸 恵介, 須田 範行, 荻野 修, 菅原 満
日本病院薬剤師会雑誌, 41, 11, 1407, 1409, (一社)日本病院薬剤師会, 2005年11月, ［査読有り］
日本語, 研究論文（学術雑誌）, 外来治療センターを利用している患者49名を対象に,がん化学療法の現状と問題点についてアンケート調査を行った.その結果,約70%の患者が薬についての注意事項や副作用についてのパンフレットを希望していた.また,多くの患者が薬の名前や副作用を知っているのに対し,その対処法や治療後に注意すべき点を知っているのは約1/3と少なかった.現在,このアンケート結果を基に患者向け情報提供用紙を作成し,外来治療センターを初めて利用した患者にこの情報提供用紙を用い,患者個別に注射剤や副作用の説明を行っている

The use of an in vitro dissolution and absorption system to evaluate oral absorption of two weak bases in pH-independent controlled-release formulations.
Mitsuru Sugawara, Shota Kadomura, Xin He, Yoh Takekuma, Naonori Kohri, Katsumi Miyazaki
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 26, 1, 1, 8, ELSEVIER SCIENCE BV, 2005年09月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The aim of this study was to compare the oral absorption of two weak bases including their pH-independent controlled-release preparations using an in vitro evaluation system. This system is able to simulate dissolution of drugs, pH change and permeation of drugs through the epithelial cell membrane in the gastrointestinal tract. Albendazole-polymers solid dispersion and pH-independent sustained-release granules of dipyridamole were prepared by using a solvent method. Elution profiles and predicted absorption of these preparations in gastric pH conditions similar to those in healthy subjects and patients with achlorhydria were compared with those of a physical mixture and commercial tablets. When a physical mixture or commercial tablets were used, the elution profile and predicted absorption of both albendazole and dipyridamole were extremely pH-dependent. On the other hand, when a solid dispersion and granules were used, elution and predicted absorption were not affected by changes in pH of the flowing solution in a drug-dissolving vessel. These results are in agreement with the results of our previous in vivo study using gastric acidity-controlled rabbits. Our results suggest that this in vitro system is useful for the evaluation of oral absorption of pH-independent controlled-release preparations.

Phenolsulfonphthalein transport by potential-sensitive urate transport system.
Shirou Itagaki, Soji Shimamoto, Mitsuru Sugawara, Michiya Kobayashi, Katsumi Miyazaki, Takeshi Hirano, Ken Iseki
European journal of pharmacology, 518, 2-3, 83, 9, ELSEVIER SCIENCE BV, 2005年08月22日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The purpose of this study was to elucidate the transporter-mediated secretion systems for phenolsulfonphthalein in brush-border membranes. In human and rat renal brush-border membranes, a potential-sensitive transport system has been shown to be involved in the efflux of organic anions. The uptake of phenolsulfonphthalein into rat renal brush-border membrane vesicles was stimulated by an inside-positive membrane potential. This potential-sensitive uptake of phenolsulfonphthalein was inhibited by probenecid, pyrazinoate and urate. p-Aminohippurate had no effect on the potential-sensitive uptake of phenolsulfonphthalein. Moreover, urate competitively inhibited the uptake of phenolsulfonphthalein. On the other hand, the uptake of phenolsulfonphthalein was slightly increased in the presence of an outward Cl- gradient. These results suggest that phenolsulfonphthalein has high affinity for the potential-sensitive urate transport system but has low affinity for an anion exchanger.

Structure-affinity relationship in the interactions of human organic anion transporter 1 with caffeine, theophylline, theobromine and their metabolites.
Mitsuru Sugawara, Takahiro Mochizuki, Yoh Takekuma, Katsumi Miyazaki
Biochimica et biophysica acta, 1714, 2, 85, 92, 2, 2005年08月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, It is well known that human organic anion transporter 1 (hOAT1) transports many kinds of drugs, endogenous compounds, and toxins. However, little is known about the structure-affinity relationship. The aim of this study was to elucidate the structure-affinity relationship using a series of structurally related compounds that interact with hOAT1. Inhibitory effects of xanthine- and uric acid-related compounds on the transport of p-aminohippuric acid were examined using CHO-K1 cells stably expressing hOAT1. The order of potency for the inhibitory effects of xanthine-related compounds on PAH uptake was 1-methyl derivative>7-methyl derivative>3-methyl derivative falling dotsxanthine>1,3,7-trimethyl derivative (caffeine). The order of potency of the inhibition was 1,3,7-trimethyluric acid>1,3-dimethyluric acid>1,7-dimethyluric acid>1-methyluric acid>uric acid. A significant correlation between inhibitory potency and lipophilicity of the tested uric acid-related compounds was observed. The main determinant of the affinity of xanthine-related compounds is the position of the methyl group. On the other hand, lipophilicity is the main determinant of the affinity of uric acid-related compounds.

Structure-affinity relationship in the interactions of human organic anion transporter 1 with caffeine, theophylline, theobromine and their metabolites
M Sugawara, T Mochizuki, Y Takekuma, K Miyazaki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1714, 2, 85, 92, ELSEVIER SCIENCE BV, 2005年08月, ［査読有り］
英語, 研究論文（学術雑誌）, It is well known that human organic anion transporter 1 (hOAT1) transports many kinds of drugs, endogetious compounds, and toxins. However, little is known about the structure-affinity relationship. The aim of this study was to elucidate the structure-affinity relationship using a series of structurally related compounds that interact with hOAT1 Inhibitory effects of xanthine-and uric acid-related compounds on the transport of p-aminohippuric acid were examined using CHO-K1 cells stably expressing hOAT1 The order of potency for the inhibitory effects of xanthine-related compounds on PAH uptake was 1-methyl defivative > 7-methyl derivative > 3-methyl derivative(.)=(.) xanthine > 1,3,7-trimethyl derivative (caffeine). The order of potency of the inhibition was 1,3,7-trimethyluric acid > 1,3-dimethyluric acid > 1,7-dimethyluric acid > 1-methyluric acid > uric acid. A significant correlation between inhibitory potency and lipophilicity of the tested uric acid-related compounds was observed. The main determinant of the affinity of xanthine-related compounds is the position of the methyl group. On the other hand, lipophilicity is the main determinant of the affinity of uric acid-related compounds. (c) 2005 Elsevier B.V All rights reserved.

がん化学療法の調剤業務支援のためのプロトコールデータベースの構築と運用
武隈 洋, 岩井 美和子, 藤原 俊恵, 川岸 亨, 熊井 正貴, 松浦 麻耶, 馬渕 朋美, 須田 範行, 宮本 剛典, 荻野 修, 菅原 満, 宮崎 勝巳
医療薬学, 31, 7, 575, 584, (一社)日本医療薬学会, 2005年07月, ［査読有り］
日本語, 研究論文（学術雑誌）, がん化学療法における調剤および処方鑑査を知識や経験年数の差によらず,正確かつ円滑に行うために,全診療科のがん化学療法プロトコールを収集し,そのデータベースを構築・運用した.構築したデータベースの使用マニュアルを作成した.疾患を12に分類し,必要な情報をプロトコール名,対象診療科,対象疾患,薬品名,投与量,単位,投与日,投与経路の項目に沿って,表形式に整理・電子データ化した.データベースシステムは独自の特化したものではなく,他の施設でも内容のメンテナンスを行えば利用可能な汎用データベースシステムとしたため,多くの施設へ提供が可能となり,情報発信基地としての大学病院の役割を果たし得たと考えた

造影剤による腎機能低下の予防を目的としたアセチルシステインゼリーの調製と評価
須田 範行, 新里 利香, 清川 真美, 金内 美妃, 菅原 満, 郡 修徳, 宮崎 勝巳
医療薬学, 31, 5, 355, 359, (一社)日本医療薬学会, 2005年05月, ［査読有り］
日本語, 研究論文（学術雑誌）, 患者のコンプライアンスの向上を目的として内用液に代わる剤形としてゲル化剤を用いたゼリー製剤の調製を試みた.アセチルシステイン(AC)は市販の内用液剤,ゲル化剤はゼラチンあるいは寒天を用いた.矯味剤にはアミノレバンEN専用フレーバーミックスを用いた.ゲル化剤にはゼラチンが適切であった.3種の矯味剤のうち被験者50%がリンゴ味を選択した.ミルクコーヒー味,抹茶味を選択した者はおのおの25%であった.AC水と比較し,ACジュース,ACゼリーは評価が高かった.すべての項目でゼラチンゼリーの評価は最も高く,特に,においの項目では被験者の90%が最もよいと答えた.ACゼリーの服用感はAC内用液と比較し著しく優れていることが示唆された.ゼラチンゼリーは第1液,第2液ともに試験開始後約10分で100%の溶出率を示した.少なくとも7日間は品質を保証できた

Characterization of secretory intestinal transport of phenolsulfonphthalein.
Shirou Itagaki, Makoto Chiba, Soji Shimamoto, Mitsuru Sugawara, Michiya Kobayashi, Katsumi Miyazaki, Takeshi Hirano, Ken Iseki
Drug metabolism and pharmacokinetics, 20, 1, 72, 8, Japanese Society for the Study of Xenobiotics, 2005年02月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, It is known that secretory transport limits the oral bioavailability of certain drugs. However, there is little information on the secretion of anionic compounds in the intestine. Phenolsulfonphthalein (PSP) and p-aminohippuric acid (PAH) have been used widely as substrates for organic anion transport systems. PAH is transported in the secretory direction in the intestine. It is possible that PSP and PAH share the same transport system at the mucosal membrane. The purpose of this study was to characterize the transport system for PSP in the intestine. In the jejunum, the serosal-to-mucosal permeation rate of PSP was significantly reduced in an ATP-depleted condition, whereas a significant difference was not observed in the ileum. Some multidrug resistance-associated protein 2 (Mrp2) inhibitors inhibited PSP permeation in the jejunum. However, pravastatin, a substrate of Mrp2, did not inhibit the PSP permeation. The jejunal secretory transport of pravastatin was significantly reduced in an ATP-depleted condition and by addition of probenecid, but PSP did not affect the jejunal permeation of pravastatin. These results suggest that PSP is secreted into the intestinal lumen by Mrp2-like transporter and that two Mrp2 substrates, PSP and pravastatin, are likely to be transported by different transport systems at the mucosal membrane.

Expression of slc5a8 in kidney and its role in Na(+)-coupled transport of lactate.
Elangovan Gopal, You-Jun Fei, Mitsuru Sugawara, Seiji Miyauchi, Lina Zhuang, Pamela Martin, Sylvia B Smith, Puttur D Prasad, Vadivel Ganapathy
The Journal of biological chemistry, 279, 43, 44522, 32, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2004年10月22日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We report here on the expression of slc5a8 in kidney and its relevance to Na(+)-coupled reabsorption of lactate. slc5a8 is the murine ortholog of SLC5A8, a candidate tumor suppressor gene, which we recently cloned from human intestine and demonstrated its functional identity as a Na(+)-coupled transporter for short-chain fatty acids and lactate. The slc5a8 cDNA, cloned from mouse kidney, codes for a protein consisting of 611 amino acids. When expressed heterologously in mammalian cells or Xenopus oocytes, slc5a8 mediates Na(+)-coupled electrogenic transport of lactate/pyruvate as well as short-chain fatty acids (e.g. acetate, propionate, and butyrate). The Na+/fatty acid stoichiometry varies depending on the fatty acid substrate (2:1 for lactate and 4:1 for propionate). This phenomenon of variable Na+/substrate stoichiometry depending on the fatty acid substrate is also demonstrable with human SLC5A8. In situ hybridization with sagittal sections of mouse kidney demonstrates abundant expression of the transcripts in the cortex as well as the medulla. Brush border membrane vesicles prepared from rabbit kidney are able to transport lactate in a Na(+)-coupled manner. The transport process exhibits the overshoot phenomenon, indicating uphill lactate transport in response to the transmembrane Na+ gradient. The Na(+)-coupled lactate transport in these membrane vesicles is inhibitable by short-chain fatty acids. We conclude that slc5a8 is expressed abundantly in the kidney and that it plays a role in the active reabsorption of lactate. slc5a8 is the first transporter known to be expressed in mammalian kidney that has the ability to mediate the Na(+)-coupled reabsorption of lactate.

Comparison of urinary excretion of phenolsulfonphthalein in an animal model for Wilson's disease (Long-Evans Cinnamon rats) with that in normal Wistar rats: involvement of primary active organic anion transporter.
Shirou Itagaki, Soji Shimamoto, Takeshi Hirano, Ken Iseki, Mitsuru Sugawara, Sachiho Nishimura, Michio Fujimoto, Michiya Kobayashi, Katsumi Miyazaki
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques, 7, 2, 227, 34, 2, 2004年07月13日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, PURPOSE: The aim of this study was to determine the cause of the decline in phenolsulfonphthalein (PSP) excretion in Long-Evans Cinnamon (LEC) rats. METHODS: The uptake of PSP into rat renal basolateral membrane vesicles (BLMV) was studied. Cyclosporin A (CYA) was used to modulate an ATP-dependent primary active transporter. PSP was intravenously injected into rats with or without CYA. The transcellular transport of PSP was examined by using primary cultured renal proximal tubule cells (PTC). RESULTS: No significant difference was found between the uptake of PSP into renal BLMV of Wistar rats and that into renal BLMV of LEC rats. In the presence of CYA, the urinary excretion and the plasma concentrations of PSP in Wistar rats were decreased and increased, respectively. In primary cultured renal PTC from Wistar rats, the basal-to-apical transport of PSP was greater than that in the opposite direction and the basal-to-apical transport of PSP was substantially reduced by the addition of CYA. However, CYA did not affect the basal-to-apical transport of PSP in PTC from LEC rats. CONCLUSIONS: The results suggest that PSP is transported by primary active organic anion transporter and that the activity level of this transporter is reduced in LEC rats.

Absorption of ester prodrugs in Caco-2 and rat intestine models.
Xin He, Mitsuru Sugawara, Yoh Takekuma, Katsumi Miyazaki
Antimicrobial agents and chemotherapy, 48, 7, 2604, 9, AMER SOC MICROBIOLOGY, 2004年07月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The aim of this study was to elucidate the absorption mechanism in Caco-2 and rat intestine models in order to improve the accuracy of prediction of oral absorption of ester prodrugs. Pivampicillin and cefcapene pivoxil hydrochloride (CFPN-PI), ester-type oral antibiotics, were chosen as model ester prodrugs. The level of esterase activity in Caco-2 cells was lower than that measured in the rat jejunum when p-nitrophenyl acetate was used as a substrate. Almost complete ester hydrolysis occurred before the ester prodrugs reached the basolateral side of the monolayer, and the disappearance of prodrugs was thought to be due to metabolism or transport after addition to the apical side of the monolayer. When pivampicillin and CFPN-PI were used, the amounts of ampicillin and cefcapene (CFPN) produced by hydrolysis of prodrugs were increased because intracellular degradation of prodrugs resulted in intracellular accumulation. On the other hand, when ampicillin or CFPN was used, only a small amount of the drug reached the basolateral side of the monolayers and no intracellular accumulation was observed. The permeability of CFPN-PI, the solubility of which is dependent on the acidity of gastric juice, across a Caco-2 monolayer or rat intestine, was also investigated by using an in vitro system that mimics the physiological state of the human gastrointestinal tract. The oral absorption of CFPN-PI in humans is predicted to be good either in the Caco-2 model or in the rat intestine model. It is concluded that our system may be a valuable tool for evaluation of oral absorption of ester prodrugs metabolized during permeation through the intestinal epithelium. Broader evaluation of such a system is warranted.

The variability of liver graft function and urinary 6beta-hydroxycortisol to cortisol ratio during liver regeneration in liver transplant recipients.
Satoshi Kishino, Maki Ogawa, Yoh Takekuma, Mitsuru Sugawara, Tsuyoshi Shimamura, Hiroyuki Furukawa, Satoru Todo, Katsumi Miyazaki
Clinical transplantation, 18, 2, 124, 9, BLACKWELL MUNKSGAARD, 2004年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The urinary ratio of 6beta-hydroxycortisol to cortisol (6beta-OHF/F) is considered to be the simplest and most practical method for estimation of hepatic cytochrome P450 3A4 (CYP3A4) activity as a non-invasive marker of human in vivo CYP3A4 activity. However, the inter- and intra-individual variability of the urinary 6beta-OHF/F ratio during liver regeneration and the effect of variability on optimal dose of tacrolimus have not yet been clarified. The objective of this study was to clarify the change in the urinary 6beta-OHF/F ratio during liver regeneration and to determine the effect of the liver graft function on the optimal tacrolimus dose in liver transplant recipients. Two liver transplant recipients (one male and one female) and eight healthy volunteers (five males and three females) were enrolled in this study. Urine samples were collected from the recipients from 08.00 hours for 24 h on post-transplant period, 1-10 and 21-30 days postoperatively. In the healthy volunteers, morning spot urine samples were collected at 08.00 hours. The mean urinary 6beta-OHF/F ratio in the immediate postoperative period was significantly low (p < 0.05). However, a marked difference in the regulation of CYP3A4 activity during liver regeneration was found in the two recipients. A significant correlation was found between the urinary 6beta-OHF/F ratio and the C/D ratio of tacrolimus (R = 0.658, p < 0.05). The urinary 6beta-OHF/F ratio is a useful probe for estimating the variability of CYP3A4 activity in liver transplant recipients in early postoperative phase. Future studies should evaluate the clinical usefulness of the urinary 6beta-OHF/F ratio as a predictor of tacrolimus pharmacokinetics in liver transplantation.

Comparison of the disposition behavior of organic anions in an animal model for Wilson's disease (Long-Evans Cinnamon rats) with that in normal Long-Evans Agouti rats.
Shirou Itagaki, Mitsuru Sugawara, Michiya Kobayashi, Katsumi Miyazaki, Takeshi Hirano, Ken Iseki
Drug metabolism and pharmacokinetics, 19, 2, 150, 4, Japanese Society for the Study of Xenobiotics, 2004年04月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Long-Evans Cinnamon (LEC) rats have an abnormality similar to that observed in Wilson's disease in humans and are therefore a good animal model for the study of Wilson's disease. LEC rats develop hereditary hepatitis and severe jaundice. Mutant animals with hyperbilirubinemia have been widely used as animal models for human diseases. Among these mutant animals, Eisai hyperbilirubinemic rats (EHBR) have defective biliary excretion of organic anions. Thus, biliary excretion of sulfobromophthalein (BSP) and urinary excretion of phenolsulfonphthalein (PSP) in LEC rats were compared with those in Long-Evans Agouti (LEA) rats. In LEC rats, the excretion of BSP, a multidrug resistance-associated protein 2 (Mrp2/Abcc2) substrate, was significantly decreased compared to that in LEA rats. It has been reported that the transport function for organic anions on the kidney is maintained in EHBR. However, the urinary excretion of PSP is impaired in LEC rats. It is possible that organic anion transporters responsible for the urinary excretion of PSP in LEA rats and EHBR are impaired in LEC rats. It is important to elucidate the relationship between organic anion secretion and Wilson's disease.

Erratum: Differential binding of disopyramide and warfarin enantiomers to human x1-acid glycoprotein variants (British Journal of Clinical Pharmacology (2003) 56:6 (664-669))
T. Nakagawa, S. Kishino, S. Itoh, M. Sugawara, K. Miyazaki
British Journal of Clinical Pharmacology, 57, 2, 226, 2004年02月, ［査読有り］
研究論文（学術雑誌）

生体部分肝移植患者におけるLinezolid(Zyvox)の体内動態
岸野 吏志, 馬渕 朋美, 武隈 洋, 菅原 満, 嶋村 剛, 古川 裕之, 藤堂 省, 宮崎 勝巳
TDM研究, 21, 1, 21, 25, (一社)日本TDM学会, 2004年01月, ［査読有り］
日本語, 研究論文（学術雑誌）, 38歳男性生体部分肝移植患者におけるリネゾリド(LZD)連続投与中の血中動態を検討した.LZDは,1回600mg(点滴時間2時間),1日2回連続投与とした.総(結合型+非結合型)薬物の最高血中濃度は31.70μg/ml,トラフ濃度は10.75±3.76μg/mlであり,非結合型薬物の最高血中濃度は25.29μg/ml,トラフ濃度は8.97±2.84μg/mlであった.また,消失半減期は7.46hr,分布容積は5.54L,Vssは30.63Lであり,健常人と異なる傾向が認められた.一方,総薬物,および非結合型薬物の血中濃度曲線面積は,それぞれ228.21μg/ml・hr,210.72μg/ml・hrと,健常人と比較して増加する傾向が認められた.また,肝移植患者の血漿蛋白結合率は13.18±4.67%であり,健常人の平均結合率に比べて顕著に低下していることが明らかになった.この症例では副作用が認められなかったことから,LZDは臓器移植患者においても比較的安全に使用可能であることが示唆された

A new system for the prediction of drug absorption using a pH-controlled Caco-2 model: evaluation of pH-dependent soluble drug absorption and pH-related changes in absorption.
Xin He, Shota Kadomura, Yoh Takekuma, Mitsuru Sugawara, Katsumi Miyazaki
Journal of pharmaceutical sciences, 93, 1, 71, 7, JOHN WILEY & SONS INC, 2004年01月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, One purpose of this study was to develop a new system for the prediction of pH-dependent soluble drug absorption that takes into account the physiological condition of the gastrointestinal tract. Another purpose was to establish several models of different gastric acidities: a normal gastric acidity model, a low gastric acidity model (a model of achlorhydria), a temporarily elevated gastric acidity model (a model of a case in which an acidic drug was coadministered to temporarily elevate gastric acidity in the case of low gastric acidity), a weak antacid model (a model of a case in which a weak antacid drug, such as an H(2) receptor antagonist, was coadministered to temporarily elevate pH up to 6), and a strong antacid model (a model of a case in which a strong antacid drug, such as magnesium hydroxide, was coadministered to temporarily elevate pH up to 8.0). These models were used to evaluate variation in pH-related absorption in humans. Dipyridamole preparation (Persantin tablets) and glibenclamide preparation (Euglucon tablets), both poorly water-soluble and pH-dependent soluble drugs, were chosen as model drugs to determine whether absorption is altered by changes in levels of gastric acid. The extent of absorption of dipyridamole was remarkably lower when gastric pH was continuously elevated to 6.0, whereas it was increased when gastric pH temporarily decreased to 1.8. The extent of absorption of glibenclamide increased dramatically when gastric pH temporarily increased to 8.0, but did not change when gastric pH temporarily increased to 6.0. These results are consistent with reported results obtained in clinical studies. The results suggest that pH-related variations in absorption in humans can be accurately predicted using our new system.

Differential binding of disopyramide and warfarin enantiomers to human alpha(1)-acid glycoprotein variants
T Nakagawa, S Kishino, S Itoh, M Sugawara, K Miyazaki
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 56, 6, 664, 669, BLACKWELL PUBLISHING LTD, 2003年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Aims The F1S and A genetic variants of alpha(1)-acid glycoprotein (AAG) change under various physiological and pathological conditions. They also vary in their drug binding abilities. We have studied the stereoselective binding ability of each of the AAG variants using enantiomers of disopyramide (DP) and warfarin (WR).
Methods The AAG variants were separated by hydroxyapatite chromatography. Binding of drug enantiomers to the AAG variants was studied by the Hummel-Dreyer method. The characteristics of the binding activities were examined by Scatchard plot analysis. The first five amino-terminal amino acids (residues 112-116) of the cyanogen bromide (CNBr) fragment (residues 112-181) of each of the separated AAG fractions were elucidated by Edman degradation.
Results Commercial AAG was separated into two main fractions. Residues 112-116 of fraction 2 were identical to the amino acid sequences predicted from the AAG A gene, LAFDV, and encode the F1S variant. In fraction 3, the deduced amino acid sequence of the AAG B gene, FGSYL, was established, and encodes the A variant. The binding affinities of both DP enantiomers in fraction 3 were significantly higher than those in fraction 2. The differences between dissociation constants (Kd) in fractions 2 and 3 were 5.2-fold for (S)-DP (P < 0.05) and 3.7-fold for (R)-DP (P < 0.001). The dissociation constant of (S)-DP (0.39 +/- 0.08 muM) was lower than that of (R)-DP (0.53 +/- 0.10 muM) in fraction 3 [95% confidence interval (CI) - 0.282, - 0.010; P < 0.05], although the binding activities of the DP enantiomers were almost the same in fraction 2. By contrast WR enantiomers had a higher binding affinity in fraction 2 than in fraction 3, the differences in dissociation constants between fractions 2 and 3 being 12.6-fold for (S)-WR (P < 0.001) and 8.3-fold for (R)-WR (P < 0.001). The dissociation constant of (S)-WR (0.28 +/- 0.10 muM) was significantly lower than that of (R)-WR (0.48 +/- 0.08 muM) in fraction 2 (95% CI - 0.369, - 0.028; P < 0.05), but there were no significant differences between the binding activities of WR enantiomers in fraction 3.
Conclusions DP and WR enantiomers bind preferentially to fraction 3 and fraction 2, respectively. Fractions 2 and 3 are encoded by the AAG A and the AAG B genes, respectively.

癌化学療法時にみられる口内炎発症予防を目的としたメシル酸カモスタット口腔内崩壊錠の調製と評価
須田 範行, 今野 安大, 森田 豊, 中田 宏, 菅原 満, 宮崎 正三, 宮崎 勝巳
医療薬学, 29, 6, 705, 710, (一社)日本医療薬学会, 2003年12月, ［査読有り］
日本語, 研究論文（学術雑誌）, メシル酸カモスタット口腔内停留性を調整し,その物理的性質及び口腔内停留性について検討した.20名の健康成人被験者に対するアンケートから矯味としてミククコーヒー味を選択し,D-マンニトールを賦形剤としPVPを結合剤として錠剤を調整し,十分な硬度と口腔内崩壊性を持つことを確かめた.口腔内停留性実験の結果,この口腔内崩壊錠はメシル酸カモスタットの粘膜付着性及び口腔内停留性が含嗽剤よりも優れていることが明らかとなり,口に含むだけで唾液で速やかに崩壊し,水を用いなくても容易に服用でき,服薬コンプライアンスの向上が期待できる

Influence of continuous venovenous haemodiafiltration on the pharmacokinetics of tacrolimus in liver transplant recipients with small-for-size grafts
S Kishino, Y Takekuma, M Sugawara, T Shimamura, H Furukawa, S Todo, K Miyazaki
CLINICAL TRANSPLANTATION, 17, 5, 412, 416, BLACKWELL MUNKSGAARD, 2003年10月, ［査読有り］
英語, 研究論文（学術雑誌）, In adult-to-adult living donor liver transplantation (LDLT), the graft volume is inevitably much smaller than the ideal liver mass ( standard liver volume) for the recipient's metabolic demand. Patients with small-for-size grafts are treated with continuous venovenous haemodiafiltration (CVVHD) for the artificial liver support. However, little is known about the influence of CVVHD on the elimination of tacrolimus. The objective of this study was to elucidate the effect of CVVHD on the pharmacokinetics of tacrolimus in recipients of LDLT with small-for-size grafts. Three liver transplant recipients ( one male and two females) and donors ( two males and one female) were enrolled in this study. Blood samples from inflow port and outflow port were obtained on the first day at the start of CVVHD. Whole-blood concentrations of tacrolimus were measured immediately using the microparticle enzyme immunoassay (MEIA; Abbott Laboratories). There was no significant difference between concentrations of tacrolimus in blood sampled at inflow port and outflow port sites and t(1/2)-values of tacrolimus in the three recipients were 29.9, 63.6 and 28.8 h. CVVHD did not cause a decrease in the blood tacrolimus concentration. Adjustment to the dose or dosing interval is not required for patients treated with tacrolimus during CVVHD.

An in vitro system for prediction of oral absorption of relatively water-soluble drugs and ester prodrugs.
Xin He, Mitsuru Sugawara, Michiya Kobayashi, Yoh Takekuma, Katsumi Miyazaki
International journal of pharmaceutics, 263, 1-2, 35, 44, ELSEVIER SCIENCE BV, 2003年09月16日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We developed an in vitro system simulating the physiological condition in the gastrointestinal (GI) tract for prediction of oral absorption of relatively water-soluble drugs and ester prodrug pivampicillin. This evaluation system includes a drug-dissolving vessel (DDV, assumed stomach), a pH adjustment vessel (PAV, assumed intestine) and a side-by-side diffusion chamber that is mounted by a Caco-2 monolayer, which is grown on a polycarbonate filter, or by a rat intestine between the donor and receiver compartments. Our proposed system can accommodate large amounts of solid drugs, simulating a drastic pH change process in GI tract, that is, an orally administered solid drug is dissolved in the stomach (pH 1-2) and transferred to the intestine (pH 6), and that dissolution process can also be monitored. The optimal flow rates for our system are 0.35-1.10 ml/min. Using this system, cumulative permeations of eight relatively water-soluble drugs were compared, and these cumulative permeations indicated the ability of drug absorption in humans. Drugs that permeated across a Caco-2 monolayer at cumulative permeation of more than 0.03% or over 0.04% in rat intestine can be almost completely absorbed in humans. If the cumulative permeation across a Caco-2 monolayer is lower than 0.03% or below 0.04% in the rat intestine, there was a good linear correlation between cumulative permeation across a Caco-2 monolayer and oral absorption in humans, or between cumulative permeation across a rat intestine and oral absorption in humans. In the case of relatively water-soluble drugs, a good linear correlation was obtained between cumulative permeation across a Caco-2 monolayer and cumulative permeation across a rat intestine. This result indicates that it is possible to predict the oral absorption of a relatively water-soluble drug in humans based on the cumulative permeation of the drug across a Caco-2 monolayer and/or a rat intestine. The time course of permeation of the ester prodrug pivampicillin, which is metabolized in a Caco-2 monolayer or in a rat intestine, was also evaluated. It stated clearly that it is also possible to predict the oral absorption of pivampicillin in humans based on the cumulative permeation across a Caco-2 monolayer or rat intestine. Our newly developed system enables more kinds of oral preparations and also pH-dependent soluble drugs to be evaluated.

Major role of organic anion transporters in the uptake of phenolsulfonphthalein in the kidney.
Shirou Itagaki, Mitsuru Sugawara, Michiya Kobayashi, Sachiho Nishimura, Michio Fujimoto, Katsumi Miyazaki, Ken Iseki
European journal of pharmacology, 475, 1-3, 85, 92, ELSEVIER SCIENCE BV, 2003年08月15日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Phenolsulfonphthalein is used for testing renal function. However, its excretion mechanism has not been elucidated. The purpose of this study was therefore to elucidate the transporter-mediated excretion system for phenolsulfonphthalein. p-Aminohippuric acid, a substrate of rat organic anion transporter1 (rOat1), and cimetidine, a substrate of rOat3, reduced the urinary excretion of phenolsulfonphthalein. The uptake of phenolsulfonphthalein by kidney slices was found to consist of two components. The IC50 values of rOat1 substrates were higher than those of rOat3 substrates. In the presence of cimetidine, the Eadie-Hofstee plot gave a single straight line. The profile of the phenolsulfonphthalein uptake component in the presence of cimetidine was similar to that of the low-affinity component in the absence of cimetidine. We conclude that rOat1 and rOat3 are involved in the renal uptake of phenolsulfonphthalein and that phenolsulfonphthalein is a high-affinity substrate for rOat3 but is a relatively low-affinity substrate for rOat1.

循環器系薬剤に関する総合的な医薬品情報データベースの構築
笠原 勇太, 高田 陽美, 小林 道也, 川合 真次, 荻野 修, 菅原 満, 関川 彬, 宮崎 勝巳
医療薬学, 29, 2, 165, 172, (一社)日本医療薬学会, 2003年04月, ［査読有り］
日本語, 研究論文（学術雑誌）

Uptake of dipeptide and beta-lactam antibiotics by the basolateral membrane vesicles prepared from rat kidney.
Mitsuru Sugawara, Toru Ogawa, Michiya Kobayashi, Katsumi Miyazaki
Biochimica et biophysica acta, 1609, 1, 39, 44, 1, 2003年01月10日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The transport of dipeptides and beta-lactam antibiotics across the rat renal basolateral membrane was examined. The initial uptake of glycylsarcosine and cefadroxil by rat renal basolateral membrane vesicles was inhibited by the presence of all the di- and tripeptides and beta-lactam antibiotics that were tested in this study. However, the uptake of both substrates was not inhibited by glycine, an amino acid. The initial uptake of zwitterionic beta-lactam antibiotics, cefadroxil, cephradine, and cephalexin, was stimulated by preloaded glycylsarcosine (countertransport effect). On the other hand, the uptake of dianionic beta-lactam antibiotics, ceftibuten and cefixime, was not affected. A concentration-dependent initial uptake of glycylsarcosine and cefadroxil suggested the existence of a carrier-mediated mechanism, whereas the transport of ceftibuten did not show any saturated uptake. The transporter that participates in the permeation of dipeptides and beta-lactam antibiotics across basolateral membranes showed lower affinity than did PEPT1 and PEPT2. This is the first study that showed an evidence for a peptide transporter, expressed in the rat renal basolateral membrane, that recognizes zwitterionic beta-lactam antibiotics using basolateral membrane vesicles isolated from normal rat kidney.

生体肝移植患者における持続血液濾過透析(CHDF)施行時のタクロリムスの血中動態
岸野 吏志, 越浪 由加, 菅原 満, 丸藤 哲, 古川 博之, 藤堂 省, 宮崎 勝巳
TDM研究, 20, 1, 24, 29, (一社)日本TDM学会, 2003年01月, ［査読有り］
日本語, 研究論文（学術雑誌）, 生体部分肝移植後患者3例を対象に標題の血中動態を検討した.CHDF施行時と非施行時の全血中タクロリムス濃度に有意な違いは認めなかった.ダイアライザーの流入側,流出側のタクロリムス濃度にも違いは認められなかった.又,CHDF非施行例との間に体内動態パラメーターの有意な違いは認めなかった.これらより,CHDFの血中タクロリムス濃度への影響は極めて小さいと考えられた

Inhibitory Effects of Basic Drugs on the Sodium-Dependent Transport of L-Alanine via System B^0 in the Small Intestine
SUGAWARA Mitsuru, KATO Masaya, KITAKUBO Mayumi, TAKEKUMA Yoh, GANAPATHY Vadivel, MIYAZAKI Katsumi
Drug metabolism and pharmacokinetics, 18, 3, 186, 93, 日本薬物動態学会, 2003年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, To elucidate the mechanism of the interaction of basic drugs with Na⁺-dependent L-alanine absorption from the small intestine, we investigated the effect of imipramine on the transport of L-alanine via system B⁰, which is thought to be one of the main Na⁺-dependent systems for intestinal absorption of short-chain neutral amino acids, including L-alanine. The uptake of L-alanine by cells that express hATB⁰ (human amino acid transporter B⁰) was inhibited in the presence of imipramine. The Eadie-Hofstee plot showed that the inhibition was not competitive with the substrate (L-alanine) but competitive with Na⁺. When rat intestinal brush border membrane vesicles were used, several basic drugs had inhibitory effects. Inhibition was also observed in intestinal absorption evaluated by an in situ single-pass perfusion technique. However, the potencies of inhibition were different. The potency of inhibition was dependent on the lipophilicity of the drugs.

Mechanism of active secretion of phenolsulfonphthalein in the liver via Mrp2 (abcc2), an organic anion transporter.
Shirou Itagaki, Mitsuru Sugawara, Michiya Kobayashi, Katsumi Miyazaki, Ken Iseki
Drug metabolism and pharmacokinetics, 18, 4, 238, 44, 4, 2003年, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, Phenolsulfonphthalein (PSP) has been selected as a model drug that is eliminated from both the kidney and liver in rats. Although the renal PSP transport system has been studied, few details of the biliary excretion of PSP have been reported. We investigated the biliary excretion system for PSP in rats. It has been reported that the biliary excretion of many organic anions from hepatocytes into bile is mediated by a primary active transporter, referred to as multidrug resistance-associated protein 2 (Mrp2/abcc2). The biliary excretion of PSP in SD rats was significantly decreased in the presence of Mrp2 inhibitors. The biliary excretion of PSP in Eisai hyperbilirubinemic rats (EHBR), hereditarily Mrp2-defective rats, was significantly lower than that in SD rats. Moreover, an efflux experiment using Caco-2 cells was carried out to confirm Mrp2-mediated PSP transport. Mrp2 inhibitors significantly decreased PSP efflux from Caco-2 cells. These results suggest that Mrp2 contributes to the biliary excretion of PSP in SD rats.

Uptake of dipeptide and beta-lactam antibiotics by the basolateral membrane vesicles prepared from rat kidney
M Sugawara, T Ogawa, M Kobayashi, K Miyazaki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1609, 1, 39, 44, ELSEVIER SCIENCE BV, 2003年01月, ［査読有り］
英語, 研究論文（学術雑誌）, The transport of dipeptides and beta-lactam antibiotics across the rat renal basolateral membrane was examined. The initial uptake of glycylsarcosine and cefadroxil by rat renal basolateral membrane vesicles was inhibited by the presence of all the di- and tripeptides and beta-lactam antibiotics that were tested in this study. However, the uptake of both substrates was not inhibited by glycine, an amino acid. The initial uptake of zwitterionic beta-lactam antibiotics, cefadroxil, cephradine, and cephalexin, was stimulated by preloaded glycylsarcosine (countertransport effect). On the other hand, the uptake of dianionic beta-lactam antibiotics, ceftibuten and cefixime, was not affected. A concentration-dependent initial uptake of glycylsarcosine and cefadroxil suggested the existence of a carrier-mediated mechanism, whereas the transport of ceftibuten did not show any saturated uptake. The transporter that participates in the permeation of dipeptides and beta-lactam antibiotics across basolateral membranes showed lower affinity than did PEPT1 and PEPT2. This is the first study that showed an evidence for a peptide transporter, expressed in the rat renal basolateral membrane, that recognizes zwitterionic beta-lactam antibiotics using basolateral membrane vesicles isolated from normal rat kidney. (C) 2002 Elsevier Science B.V. All rights reserved.

Age- and gender-related differences in carbohydrate concentrations of alpha1-acid glycoprotein variants and the effects of glycoforms on their drug-binding capacities.
Satoshi Kishino, Akikazu Nomura, Shin Itoh, Tsutomu Nakagawa, Yoh Takekuma, Mitsuru Sugawara, Hiroyuki Furukawa, Satoru Todo, Katsumi Miyazaki
European journal of clinical pharmacology, 58, 9, 621, 8, SPRINGER-VERLAG, 2002年12月, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, OBJECTIVE: Alpha(1)-acid glycoprotein (AAG) is a major binding protein for neutral and basic drugs because of its great drug affinity. AAG has three main genetic variants--F1, S, and A variants. Several attempts have been made to elucidate the differences in compositions of the carbohydrate moiety and structure-function relationships such as drug-binding differences. However, there have been few reports on age- and gender-related differences in compositions or concentrations of the carbohydrate moiety of AAG variants. The aim of this study was to clarify the age- and gender-related differences in carbohydrate concentrations and in drug-binding capacities of AAG glycoforms. METHODS: The sera used in this study were obtained from 32 healthy subjects (17 men and 15 women, aged 16-84 years). The AAG glycoforms were isolated by hydroxyapatite chromatography. The binding capacity of AAG to disopyramide (DP), which is a basic drug, was determined using the ultrafiltration method. The concentrations of N-acetylneuraminic acid (NeuAc) and monosaccharides in AAG were determined using high-pH anion-exchange chromatography with pulsed-amperometric detection. RESULTS: The mean plasma AAG concentration in the female subjects was significantly lower than that in the male subjects (0.67 +/- 0.12 mg/ml, mean +/- SD, in females, n = 15, versus 0.81 +/- 0.17 mg/ml in males, n = 17, P < 0.05), but no age-related differences were found (0.75 +/- 0.18 mg/ml in young subjects, n = 24, versus 0.77 +/- 0.12 mg/ml in older subjects, n = 8, n.s.). However, the degree of branching of the glycan chain in the female subjects was significantly lower than that in the male subjects (1.61 +/- 0.17 mol/mol, mean +/- SD, in females, n = 15, versus 1.75 +/- 0.23 mol/mol in males, n = 17, P < 0.05). There was a significant inverse relationship between the binding capacity of AAG to DP (Cb/AAG) and the degree of branching of the glycan chain. The binding capacity (Cb/AAG) decreased as the degree of branching in AAG glycans increased. The binding capacity (Cb/AAG) in the female subjects was significantly higher than that in the male subjects (2.79 +/- 0.59 mg/g AAG in females, mean +/- SD, n = 15, versus 2.37 +/- 0.29 mg/g AAG in males, n = 17, P < 0.05). CONCLUSION. The degree of branching of the glycan chain in AAG plays an important role in drug-binding capacity. Gender-related differences in drug-binding capacity (Cb/AAG) may be caused by differences in the ratios of the extent of branching of the glycan chain in AAG.

Liquid chromatographic method for the determination of ganciclovir and/or acyclovir in human plasma using pulsed amperometric detection.
Satoshi Kishino, Yoh Takekuma, Mitsuru Sugawara, Tsuyoshi Shimamura, Hiroyuki Furukawa, Satoru Todo, Katsumi Miyazaki
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 780, 2, 289, 94, ELSEVIER SCIENCE BV, 2002年11月25日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, We have developed a simple, rapid and highly sensitive method for determining plasma concentrations of ganciclovir and/or acyclovir by using reversed-phase chromatography followed by pulsed amperometric detection. A linear relationship between the amount of ganciclovir (0.05-10 microg/ml plasma) or acyclovir (0.1-20 microg/ml plasma) and peak height ratio was obtained. The relative standard deviations of all standard curves were greater than or equal to 0.999. The limits of detection for ganciclovir and acyclovir quantitation were 10 ng/ml and 50 ng/ml (signal/noise >3), respectively. Daily fluctuations of plasma standard curves (n=5) for the ganciclovir and acyclovir samples were small, with relative standard deviations (RSD) of 3.3 and 4.5% (n=5), respectively. The intra-assay precision for the ganciclovir and acyclovir samples were 6.9 (n=5) and 5.5% (n=5), respectively. Inter-assay precision of ganciclovir (n=3) and acyclovir (n=3) ranged from 2.6 to 6.8% and 3.5 to 5.0%, respectively. Using this method, the pharmacokinetics and removal of ganciclovir during continuous hemodiafiltration (CHDF) in a liver transplant recipient being treated for severe cytomegalovirus infection was investigated. The mean (+/-SD) ratio of ganciclovir concentrations at the inlet and outlet of the dialyzer (C(outlet)/C(inlet)) was 0.56+/-0.09. The areas under the curves of ganciclovir up to 12 h postdosing (AUC(0-->12)) at the inlet and outlet of the dialyzer were 12.54 microg h/ml and 7.16 microg h/ml, respectively. The ultrafiltrate of ganciclovir was 16.6 mg. The terminal elimination half-life (T(1/2)) of ganciclovir during CHDF was 3.6 h. These results demonstrate that CHDF effectively removes ganciclovir. Until formal guidelines have been established, ganciclovir or acyclovir dosage should be adjusted according to the results of monitoring of plasma drug concentration. The method described here is suitable for clinical monitoring of plasma ganciclovir or acyclovir levels in solid organ transplant recipients and for use in studies involving pharmacokinetics.

Ionic strength has a greater effect than does transmembrane electric potential difference on permeation of tryptamine and indoleacetic acid across Caco-2 cells.
Mitsuru Sugawara, Megumi Kurosawa, Kasumi Sakai, Michiya Kobayashi, Ken Iseki, Katsumi Miyazaki
Biochimica et biophysica acta, 1564, 1, 149, 55, 1, 2002年08月19日, ［査読有り］, ［国際誌］
英語, 研究論文（学術雑誌）, The effects of transmembrane electric potential difference and ionic strength on the permeation of tryptamine and indoleacetic acid across a Caco-2 cell monolayer were examined. A decrease in the transmembrane electric potential difference caused by the addition of potassium ion to the transport buffer had no effect on the permeation rate of either compound. On the other hand, an increase in ionic strength resulted in a decrease in the permeation rate of tryptamine and an increase in the permeation rate of indoleacetic acid. The changes in the permeation rate with changes in the ionic strength were correlated with the membrane surface potential monitored by 1-anilino-8-naphthalenesulfonic acid (ANS), a fluorescent probe. We tested these effects using several other cationic and anionic compounds. These effects of ionic strength were found to be common to all drugs tested. The compound that showed a relatively lower permeation rate was given relatively stronger effect. The possibility of overestimation or underestimation caused by these effects should be considered when the permeation of an ionic compound is evaluated using a cell monolayer system.

Ionic strength has a greater effect than does transmembrane electric potential difference on permeation of tryptamine and indoleacetic acid across Caco-2 cells
M Sugawara, M Kurosawa, K Sakai, M Kobayashi, K Iseki, K Miyazaki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1564, 1, 149, 155, ELSEVIER SCIENCE BV, 2002年08月, ［査読有り］
英語, 研究論文（学術雑誌）, The effects of transmembrane electric potential difference and ionic strength on the permeation of tryptamine and indoleacetic acid across a Caco-2 cell monolayer were examined. A decrease in the transmembrane electric potential difference caused by the addition of potassium ion to the transport buffer had no effect on the permeation rate of either compound. On the other hand, an increase in ionic strength resulted in a decrease in the permeation rate of tryptamine and an increase in the permeation rate of indoleacetic acid. The changes in the permeation rate with changes in the ionic strength were correlated with the membrane surface potential monitored by 1-anilino-8-naphthalenesulfonic acid (ANS), a fluorescent probe. We tested these effects using several other cationic and anionic compounds. These effects of ionic strength were found to be common to all drugs tested. The compound that showed a relatively lower permeation rate was given relatively stronger effect. The possibility of overestimation or underestimation caused by these effects should be considered when the permeation of an ionic compound is evaluated using a cell monolayer system. (C) 2002 Elsevier Science B.V. All rights reserved.

ザイボックス錠を粉砕して製した懸濁液の安定性に関する検討
菅原 満, 萩野 修, 宮崎 勝巳
医療薬学, 28, 3, 256, 258, (一社)日本医療薬学会, 2002年06月, ［査読有り］
日本語, 研究論文（学術雑誌）

胃癌患者における胃切除術後の薬物吸収動態
井藤達也, 福田由布子, 竹本 功, 斉藤正信, 松岡伸一, 秦 温信, 平野 剛, 井関 健, 菅原 満, 宮崎勝巳
臨床薬理, 33, 3, 67, 72, Japanese Society of Clinical Pharmacology and Therapeutics, 2002年, ［査読有り］
日本語, 研究論文（学術雑誌）, We investigated the absorption rates of acetaminophen, theophyline and lansoprazole after pylorus preserving-gastrectomy (PPG) with preservation of the vagal nerve as a treatment for patients with early gastric cancer. Postoperative functioning of the residual stomach 6 months after the operation in patients with early gastric cancer who had undergone PPG (PPG group, n=5) was compared with that in patients who had undergone distal gastrectomy (DG group, n=4). We also investigated recovery of body weight, findings in a series of gastrointestinal x-rays, gastroscopic findings, hormonal secretion and digestive and absorbtive abilities. The postoperative absorption rates of acetaminophen in the PPG group were almost the same as those before the operation, but they were slower in the PPG group than in the DG group. The absorption rate of theophyline from a sustained release formulation was faster in the DG group, and slower in the PPG group compared to the preoperative absorption rates. In the DG group, the absorption rate of an enteric-coated preparation of lansoprazole did not differ greatly from that before the operation. In the PPG group, however, there were large individual differences and a notable delay in absorption and reduction in the amount of absorption in the early stage. Recovery of body weight at 6 months after the operation was not significantly different in the PPG and DG groups. In the PPG group, postoperative gastrointestinal x-rays showed that the pyloric form had been retained, and gastroscopic examination showed that there had been no reflux gastritis or esophagitis. The rates of digestion and absorption were faster in the DG group than in the PPG group, and the plasma levels of glucose were higher but the serum levels of gastrin were lower in the DG group than in the PPG group. Furthermore, hormonal secretion in the PPG group was close to the normal physiological range. These results indicate that the rate of absorption was faster in the DG group and slower in the PPG group. The absorbability of drugs following gastric resection varies depending on the type of operation and the properties of the drug preparation.

肺癌患者における塩酸イリノテカン(CPT-11)の胸水中および心嚢液中への移行性
井藤達也, 高岡和夫, 竹本 功, 秦 温信, 井上勝一, 佐々木健太郎, 平野 剛, 井関 健, 菅原 満, 宮崎勝巳
臨床薬理, 33, 2, 47, 52, Japanese Society of Clinical Pharmacology and Therapeutics, 2002年, ［査読有り］
日本語, 研究論文（学術雑誌）, The purpose of this study was to evaluate the distribution of CPT-11 and its active metabolite, SN-38, in pleural and pericardial fluid after intravenous administration. Two patients with lung cancer were treated with intravenous CPT-11 (60 mg/m2) on days 1, 8, and 15. The CPT-11 was detected in the pleural fluid 1.5 hr after the begining of intravenous infusion, and the level reached the maximum 24 hrs later. Similarly, the active metabolite SN-38 was detected in the pleural fluid 1.5 hr after the begining of intravenous infusion, and SN-38 concentration in the pleural fluid was almost as high as that in plasma 24 hrs later. These results suggest that intravenously administered CPT-11 may penetrate the thoracic cavity and may be metabolized to SN-38 there. The proportions of maximum concentrations of CPT-11 and SN-38 in the pleural fluid to the corresponding plasma levels were 20.4% and 28.5%, respectively. In addition, the AUCs of the lactone form SN-38 were much lower than those of the carboxyl form in the pleural fluid. CPT-11, SN-38 and SN-38 glucronide showed similar pharmacokinetics in the pericardium as that in plasma.

Cloning and functional characterization of a new subtype of the amino acid transport system N
T Nakanishi, R Kekuda, YJ Fei, T Hatanaka, M Sugawara, RG Martindale, FH Leibach, PD Prasad, Ganapathy, V
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 281, 6, C1757, C1768, AMER PHYSIOLOGICAL SOC, 2001年12月, ［査読有り］
英語, 研究論文（学術雑誌）, We have cloned a new subtype of the amino acid transport system N2 (SN2 or second subtype of system N) from rat brain. Rat SN2 consists of 471 amino acids and belongs to the recently identified glutamine transporter gene family that consists of system N and system A. Rat SN2 exhibits 63% identity with rat SN1. It also shows considerable sequence identity (50-56%) with the members of the amino acid transporter A subfamily. In the rat, SN2 mRNA is most abundant in the liver but is detectable in the brain, lung, stomach, kidney, testis, and spleen. When expressed in Xenopus laevis oocytes and in mammalian cells, rat SN2 mediates Na+-dependent transport of several neutral amino acids, including glycine, asparagine, alanine, serine, glutamine, and histidine. The transport process is electrogenic, Li+ tolerant, and pH sensitive. The transport mechanism involves the influx of Na+ and amino acids coupled to the efflux of H+, resulting in intracellular alkalization. Proline, alpha-(methylamino) isobutyric acid, and anionic and cationic amino acids are not recognized by rat SN2.

Development of a new system for prediction of drug absorption that takes into account drug dissolution and pH change in the gastro-intestinal tract
M Kobayashi, N Sada, M Sugawara, K Iseki, K Miyazaki
INTERNATIONAL JOURNAL OF PHARMACEUTICS, 221, 1-2, 87, 94, ELSEVIER SCIENCE BV, 2001年06月, ［査読有り］
英語, 研究論文（学術雑誌）, A new system for prediction of drug absorption that takes into account drug dissolution and pH change in the gastro-intestinal tract was developed. In this new system, a drug (solid form) is added into a drug-dissolving vessel (pH 1.0) and the dissolved drug is transferred to a pH adjustment vessel (pH 6.0). Then the drug solution is transferred to the apical surface of Caco-2 cells, and the permeation rate of the: drug across a Caco-2 monolayer is determined. This system was able to predict the oral absorption ratios of ten water-soluble drugs in humans. Using this system, it was predicted that drugs that permeated Caco-2 at a rate of more than 0.1%, of the dose in 200 min would be almost completely absorbed after oral administration in humans. For a drug whose permeation ratio was less than 0.03%, the absorption ratio was predicted to be less than 30%,. This system also enabled prediction of the absorption rate and variability in the absorption of albendazole, a drug with poor water solubility. It also enabled assessment of the improvement in absorption using a solid dispersion of albendazole-polymers that improved the water solubility. The results suggest that this system is useful for oral absorption screening of new drugs and pharmaceutical products. (C) 2001 Elsevier Science B.V. All rights reserved.

Involvement of transporter recruitment as well as gene expression in the substrate-induced adaptive regulation of amino acid transport system A
R Ling, CC Bridges, M Sugawara, T Fujita, FH Leibach, PD Prasad, Ganapathy, V
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1512, 1, 15, 21, ELSEVIER SCIENCE BV, 2001年05月, ［査読有り］
英語, 研究論文（学術雑誌）, We investigated the molecular mechanism involved in the adaptive regulation of the amino acid transport system Al a process in which amino acid starvation induces the transport activity. These studies were done with rat C6 glioma cells. System A activity in these cells is mediated exclusively by the system A subtype, amino acid transporter A2 (ATA2). The other two known system A subtypes, ATA1 and ATA3, are not expressed in these cells. Exposure of these cells to an amino acid-free medium induces system A activity. This process consists of an acute phase and a chronic phase. Laser-scanning confocal microscopic immunolocalization of ATA2 reveals that the acute phase is associated with recruitment of preformed ATA2 from an intracellular pool to the plasma membrane. In contrast, the chronic phase is associated with an induction of nta gene expression as evidenced from the increase in the steady-state levels of ATA2 mRNA, restoration of the intracellular pool of ATA2 protein, and blockade of the induction by cycloheximide and actinomycin D. The increase in system A activity induced by amino acid starvation is blocked specifically by system A substrates, including the non-metabolizable alpha-(methylamino)isobutyric acid. (C) 2001 Elsevier Science B.V. All rights reserved.

Structure, function, and tissue expression pattern of human SN2, a subtype of the amino acid transport system N
T Nakanishi, M Sugawara, W Huang, RG Martindale, FH Leibach, ME Ganapathy, PD Prasad, Ganapathy, V
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 281, 5, 1343, 1348, ACADEMIC PRESS INC, 2001年03月, ［査読有り］
英語, 研究論文（学術雑誌）, We have cloned a new subtype of the amino acid transport system N from a human liver cell line. This transporter, designated SN2, consists of 472 amino acids and exhibits 62% identity with human SN1 at the level of amino acid sequence. SN2-specific transcripts are expressed predominantly in the stomach, brain, liver, lung, and intestinal tract. The sizes of the transcripts vary in different tissues, indicating tissue-specific alternative splicing of the SN2 mRNA. In contrast, SN1 is expressed primarily in the brain and liver and there is no evidence for the presence of multiple transcripts of varying size for SN1. When expressed in mammalian cells, the cloned human SN2 mediates Na+-coupled transport of system N-specific amino acid substrates (glutamine, asparagine, and histidine). In addition, SN2 also transports serine, amino, and glycine. Anionic amino acids, cationic amino acids, imino acids, and N-alkylated amino acids are not recognized as substrates by human SN2. The SN2-mediated transport process is Li+ tolerant and highly pH-dependent. The Michaelis-Menten constant for histidine uptake via human SN2 is 0.6 +/- 0.1 mM, The gene coding for SN2 is located on human chromosome Xp11.23. Successful cloning of SN2 provides the first molecular evidence for the existence of subtypes within the amino acid transport system N in mammalian tissues. (C) 2001 Academic Press.

Evidence for the transport of neutral as well as cationic amino acids by ATA3, a novel and liver-specific subtype of amino acid transport system A
T Hatanaka, W Huang, R Ling, PD Prasad, M Sugawara, FH Leibach, Ganapathy, V
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1510, 1-2, 10, 17, ELSEVIER SCIENCE BV, 2001年02月, ［査読有り］
英語, 研究論文（学術雑誌）, We report here on the cloning and functional characterization of the third subtype of amino acid transport system A, designated ATA3 (amino acid transporter A3), from a human liver cell line. This transporter consists of 547 amino acids and is structurally related to the members of the glutamine transporter family. The human ATA3 (hATA3) exhibits 88% identity in amino acid sequence with rat ATA3. The gene coding for hATA3 contains 16 exons and is located on human chromosome 12q13. It is expressed almost exclusively in the liver. hATA3 mediates the transport of neutral amino acids including alpha-(methylamino)isobutyric acid (MeAIB), the model substrate for system A, in a Na+-coupled manner and the transport of cationic amino acids in a Na+-independent manner. The affinity of hATA3 for cationic amino acids is higher than for neutral amino acids. The transport function of hATA3 is thus similar to that of system y(+)L. The ability of hATA3 to transport cationic amino acids with high affinity is unique among the members of the glutamine transporter family. hATA1 and hATA2, the other two known members of the system A subfamily, show little affinity toward cationic amino acids. hATA3 also differs from hATA1 and hATA2 in exhibiting low affinity for MeAIB. Since liver does not express any of the previously known high-affinity cationic amino acid transporters, ATA3 is likely to provide the major route for the uptake of arginine in this tissue. (C) 2001 Elsevier Science B.V. All rights reserved.

Structure and function of ATA3, a new subtype of amino acid transport system A, primarily expressed in the liver and skeletal muscle
M Sugawara, T Nakanishi, YJ Fei, RG Martindale, ME Ganapathy, FH Leibach, Ganapathy, V
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1509, 1-2, 7, 13, ELSEVIER SCIENCE BV, 2000年12月, ［査読有り］
英語, 研究論文（学術雑誌）, To date, two different transporters that are capable of transporting alpha-(methylamino)isobutyric acid, the specific substrate for amino acid transport system A, have been cloned. These two transporters are known as ATA1 and ATA2. We have cloned a third transporter that is able to transport the system A-specific substrate. This new transporter, cloned from rat skeletal muscle and designated rATA3, consists of 547 amino acids and has a high degree of homology to rat ATA1 (47% identity) and rat ATA2 (57% identity). rATA3 mRNA is present only in the liver and skeletal muscle. When expressed in Xenopus laevis oocytes, rATA3 mediates the transport of alpha-[C-14](methylamino)isobutyric acid and [H-3]alanine. With the two-microelectrode voltage clamp technique, we have shown that exposure of rATA3-expressing oocytes to neutral, short-chain aliphatic amino acids induces inward currents. The amino acid-induced current is Na+-dependent and pH-dependent. Analysis of the currents with alanine as the substrate has shown that the K-0.5 for alanine (i.e., concentration of the amino acid yielding half-maximal current) is 4.2 +/- 0.1 mM and that the Na+:alanine stoichiometry is 1:1. (C) 2000 Elsevier Science B.V. All rights reserved.

イリノテカンと活性代謝物のラクトン体・カルボキシル体およびその抱合体のHPLC同時定量法の確立
井藤達也, 竹本 功, 秦 温信, 高岡和夫, 菅原 満, 井関 健, 宮崎勝巳
TDM研究, 17, 4, 383, 389, 2000年10月, ［査読有り］
日本語, 研究論文（学術雑誌）

Primary structure, genomic organization, and functional and electrogenic characteristics of human system N 1, a Na+- and H+-coupled glutamine transporter
YJ Fei, M Sugawara, T Nakanishi, W Huang, HP Wang, PD Prasad, FH Leibach, Ganapathy, V
JOURNAL OF BIOLOGICAL CHEMISTRY, 275, 31, 23707, 23717, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2000年08月, ［査読有り］
英語, 研究論文（学術雑誌）, We have cloned the human Na+- and H+-coupled amino acid transport system N (hSN1) from HepG2 liver cells and investigated its functional characteristics. Human SN1 protein consists of 504 amino acids and shows high homology to rat SN1 and rat brain glutamine transporter (GlnT). When expressed in mammalian cells, the transport function of human SN1 could be demonstrated with glutamine as the substrate in the presence of LiCl (instead of NaCl) and cysteine. The transport activity was saturable, pH-sensitive, and specific for glutamine, histidine, asparagine, and alanine. Analysis of Li+ activation kinetics showed a Li+:glutamine stoichiometry of 2:1. When expressed in Xenopus laevis oocytes, the transport of glutamine or asparagine via human SN1 was associated with inward currents under voltage-clamped conditions. The transport function, monitored as glutamine- or asparagine-induced currents, was saturable, Na+-dependent, Li+-tolerant, and pH-sensitive. The transport cycle was associated with the involvement of more than one Na+ ion. Uptake of asparagine was directly demonstrable in these oocytes by using radiolabeled substrate, and this uptake was inhibited by membrane depolarization. In addition, simultaneous measurement of asparagine influx and charge influx in the same oocyte yielded an asparagine:charge ratio of 1. These data suggest that SN1 mediates the influx of two Na+ and one amino acid substrate per transport cycle coupled to the efflux of one H+, rendering the transport process electrogenic.

Cloning of an Amino Acid Transporter with Functional Characteristics and Tissue Expression Pattern Identical to That of System A
Sugawara M, Nakanishi T, Fei Y.-J, Huang W, Ganapathy M. E, Leibach F. H, Ganapathy V
J. Biol. Chem., 275, 22, 16473, 16477, 2000年08月, ［査読有り］
英語, 研究論文（学術雑誌）, We report here on the cloning and functional characterization of the protein responsible for the system A amino acid transport activity that is known to be expressed in most mammalian tissues. This transporter, designated ATA2 for amino acid transporter A2, was cloned from rat skeletal muscle. It is distinct from the neuron-specific glutamine transporter (GlnT/ATA1). Rat ATA2 consists of 504 amino acids and bears significant homology to GlnT/ATA1 and system N (SN1). ATA2-specific mRNA is ubiquitously expressed in rat tissues. When expressed in mammalian cells, ATA2 mediates Na+dependent transport of α-(methylamino)isobutyric acid, a specific model substrate for system A. The transporter is specific for neutral amino acids. It is pH- sensitive and Li+-intolerant. The Na+:amino acid stoichiometry is 1:1. When expressed in Xenopus laevis oocytes, transport of neutral amino acids via ATA2 is associated with inward currents. The substrate-induced current is Na+-dependent and pH-sensitive. The amino acid transport system A is particularly known for its adaptive and hormonal regulation, and therefore the successful cloning of the protein responsible for this transport activity represents a significant step toward understanding the function and expression of this transporter in various physiological and pathological states.

Primary Structure, Functional Characteristics and Tissue Expression Pattern of Human ATA2, a Subtype of Amino Acid Transport System
Hatanaka T, Huang W, Wang H, Sugawara M, Prasad P. D, Leibach F. H, Ganapathy V
Biochim. Biophys. Acta, 1467, 1, 1, 6, 2000年07月, ［査読有り］
英語, 研究論文（学術雑誌）

Cloning and functional expression of ATA1, a subtype of amino acid transporter A, from human placenta
HP Wang, W Huang, M Sugawara, LD Devoe, FH Leibach, PD Prasad, Ganapathy, V
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 273, 3, 1175, 1179, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2000年07月, ［査読有り］
英語, 研究論文（学術雑誌）, This report describes the primary structure and functional characteristics of human ATA1, a subtype of the amino acid transport system A. The human ATA1 cDNA was isolated from a placental cDNA library. The cDNA codes for a protein of 487 amino acids with 11 putative transmembrane domains. The transporter mRNA (similar to 9.0 kb) is expressed most prominently in the placenta and heart, but detectable level of expression is evident in other tissues including the brain. When expressed heterologously in mammalian cells, the cloned transporter mediates Na+-coupled transport of the system A-specific model substrate alpha-(methylamino)isobutyric acid. The transport process is saturable with a Michaelis-Menten constant of 0.89 +/- 0.12 mM. The Na+:amino acid stoichiometry is 1:1 as deduced from the Na+-activation kinetics. The transporter is specific for small short-chain neutral amino acids. The gene for the transporter is located on human chromosome 12, (C) 2000 Academic Press.

Primary structure, functional characteristics and tissue expression pattern of human ATA2, a subtype of aminoacid transport system A
T Hatanaka, W Huang, HP Wang, M Sugawara, PD Prasad, FH Leibach, Ganapathy, V
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1467, 1, 1, 6, ELSEVIER SCIENCE BV, 2000年07月, ［査読有り］
英語, 研究論文（学術雑誌）, We report here on the primary structure and functional characteristics of the protein responsible for the system A amino acid transport activity that is known to be expressed in most human tissues. This transporter, designated ATA? for amino acid transporter A2, was cloned from the human hepatoma cell line HepG2. Human ATA2 (hATA2) consists of 506 amino acids and exhibits a high degree of homology to rat ATA2. hATA2-specific mRNA is ubiquitously expressed in human tissues. When expressed in mammalian cells, hATA2 mediates Na+-dependent transport of alpha-(methylamino)isobutyric acid, a specific model substrate for system A. The transporter is specific for neutral amino acids. It is pH-sensitive and Li+-intolerant. The Na+-amino acid stoichiometry is 1:1. (C) 2000 Elsevier Science B.V. All rights reserved.

cDNA structure, genomic organization, and promoter analysis of the mouse intestinal peptide transporter PEPT1
YJ Fei, M Sugawara, JC Liu, HW Li, Ganapathy, V, ME Ganapathy, FH Leibach
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1492, 1, 145, 154, ELSEVIER SCIENCE BV, 2000年06月, ［査読有り］
英語, 研究論文（学術雑誌）, We describe in this report the cDNA structure, functional characteristics, genomic organization, and promoter analysis of the mouse H+-coupled low-affinity peptide transporter PEPT1. The mouse PEPT1 cDNA cloned from a kidney cDNA library is similar to 3.1 kb long and encodes a protein of 709 amino acids. When expressed heterologously in mammalian cells and in Xenopus laevis oocytes, mouse PEPT1 mediates H+-coupled electrogenic transport of the dipeptide glycylsarcosine. The mouse pept1 gene, cloned from a genomic DNA library in bacterial artificial chromosome, is similar to 38 kb long and consists of 23 exons and 22 introns. 5'-Rapid amplification of cDNA ends with poly(A)(+) RNA from mouse intestine has identified the transcription start site that lies 31 bp upstream of the translation start site. The promoter region upstream of the transcription start site does not contain the TATA box but possesses three GC boxes which are the binding sites for the transcription activator SP1. Functional analysis of the promoter region using the luciferase reporter assay in Caco-2 cells (a human intestinal cell line that express PEPT1 constitutively) and five different 5'-deletion fragments of the promoter has shown that essential promoter/enhancer elements are present within 1140 bp upstream of the transcription start site. (C) 2000 Elsevier Science B.V. All rights reserved.

Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2
M Sugawara, W Huang, YL Fei, FH Leibach, Ganapathy, V, ME Ganapathy
JOURNAL OF PHARMACEUTICAL SCIENCES, 89, 6, 781, 789, JOHN WILEY & SONS INC, 2000年06月, ［査読有り］
英語, 研究論文（学術雑誌）, In clinical trials, valganciclovir, the valyl ester of ganciclovir, has been shown to enhance the bioavailability of ganciclovir when taken orally by patients with cytomegalovirus infection. We investigated the role of the intestinal peptide transporter PEPT1 in this process by comparing the interaction of ganciclovir and valganciclovir with the transporter in different experimental systems. We also studied the interaction of these two compounds with the renal peptide transporter PEPT2. In cell culture model systems using Caco-2 cells for PEPT1 and SKPT cells for PEPT2, valganciclovir inhibited glycylsarcosine transport mediated by PEPT1 and PEPT2 with Ki values (inhibition constant) of 1.68 +/- 0.30 and 0.043 +/- 0.005 mM, respectively. The inhibition by valganciclovir was competitive in both cases. Ganciclovir did not interact with either transporter. Similar studies done with cloned PEPT1 and PEPT2 in heterologous expression systems yielded comparable results. The transport of valganciclovir via PEPT1 was investigated directly in PEPT1-expressing Xenopus laevis oocytes with an electrophysiological approach. Valganciclovir, but not ganciclovir, induced inward currents in PEPT1-expressing oocytes. These results demonstrate that the increased bioavailability of valganciclovir is related to its recognition as a substrate by the intestinal peptide transporter PEPT1. This prodrug Is also recognized by the renal peptide transporter PEPT2 with high affinity. (C) 2000 Wiley-Liss, Inc.

β-Lactam Antibiotics as Substrates for OCTN2, an Organic Cation/Carnitine Transporter
Ganapathy M. E, Huang W, Rajan D. P, Carter A. L, Sugawara M, Iseki K, Leibach F. H, Ganapathy V
J. Biol. Chem., 275, 3, 1699, 1707, AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2000年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is associated with carnitine deficiency. A potential mechanism for the development of carnitine deficiency is competition between cephaloridine and carnitine for the renal reabsorptive process. OCTN2 is an organic cation/carnitine transporter that is responsible for Na+-coupled transport of carnitine in the kidney and other tissues. We investigated the interaction of several beta-lactam antibiotics with OCTN2 using human cell lines that express the transporter constitutively as well as using cloned human and rat OCTN2s expressed heterologously in human cell lines. The beta-lactam antibiotics cephaloridine, cefoselis, cefepime, and cefluprenam were found to inhibit OCTN2-mediated carnitine transport, These antibiotics possess a quaternary nitrogen as does carnitine, Several other beta-lactam antibiotics that do not possess this structural feature did not interact with OCTN2, The interaction of cephaloridine with OCTN2 is competitive with respect to carnitine, Interestingly, many of the beta-lactam antibiotics that were not recognized by OCTN2 were good substrates for the H+-coupled peptide transporters PEPT1 and PEPT2, In contrast, cephaloridine, cefoselis, cefepime, and cefluprenam, which were recognized by OCTN2, did not interact with PEPT1 and PEPT2, The interaction of cephaloridine with OCTN2 was Na+-dependent, whereas the interaction of cefoselis and cefepime with OCTN2 was largely Na+-independent, Furthermore, the Na+-dependent, OCTN2-mediated cellular uptake of cephaloridine could be demonstrated by direct uptake measurements, These studies show that OCTN2 plays a crucial role in the pharmacokinetics and therapeutic efficacy of certain beta-lactam antibiotics such as cephaloridine and that cephaloridine-induced carnitine deficiency is likely to be due to inhibition of carnitine reabsorption in the kidney.

Effects of interactions between drugs on the renal excretion of trientine in rats - Acetazolamide and furosemide increase trientine excretion
M Kobayashi, H Fujisaki, M Sugawara, K Iseki, K Miyazaki
PHARMACEUTICAL RESEARCH, 16, 12, 1888, 1892, SPRINGER/PLENUM PUBLISHERS, 1999年12月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose. To elucidate the effects of drug interactions on the urinary excretion of trientine in rats.
Method. Trientine and various other drugs were intravenously administered to rats and the urinary excretion of trientine was investigated. To clarify the mechanisms of drug-drug interactions, we also investigated the effects of various drugs on spermine uptake by rat renal brush-border membrane vesicles.
Results. Cimetidine, a substrate of the H+/organic cation antiporter, and aminoglycoside antibiotics did not affect trientine excretion, while acetazolamide: and furosemide. which increase the concentration of sodium ions in renal proximal tubules, increased the excretion of trientine. However, trichlormethiazide, which acts in renal distal tubules, did not affect trientine excretion. Acetazolamide and furosemide did not directly affect the Na+/spermine transporter because these diuretics had no effect on the uptake of spermine into the rat renal brush-border membrane vesicles.
Conclusions. There is no interaction between trientine and the substrate of the H+/organic cation antiporter or aminoglycoside antibiotics. However, drugs that change the concentration of sodium ions in renal proximal tubules, such as diuretics, can increase the trientine excretion since the increase in the luminal concentration of sodium ion accelerates the Na+/spermine antiporter.

高速液体クロマトグラフィーによる血清中ピルニカイジド定量法の確立と有効濃度の検討　　　　　　　　　　　　　　　
井藤達也, 福島紘司, 尾形仁子, 中川英久, 渡辺 晃, 菅原 満, 井関 健, 宮崎勝巳
TDM研究, 16, 3, 273, 278, 1999年07月, ［査読有り］
日本語, 研究論文（学術雑誌）

Multiplicity of the H+-Dependent Transport Mechanism of Dipeptide and Anionic β-Lactam Antibiotic Ceftibuten in Rat Intestinal Brush-Border Membrane
Iseki K, Sugawara M, Sato K, Naasani I, Hayakawa T, Kobayashi M, Miyazaki K
J. Pharmacol. Exp. Ther., 289, 1, 66, 71, AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 1999年04月, ［査読有り］
英語, 研究論文（学術雑誌）, To elucidate the transport characteristics of the H+/dipeptide carrier that recognizes the orally active beta-lactam antibiotic ceftibuten, the uptake behaviors were compared of ceftibuten and Gly-Sar by rat intestinal brush-border membrane vesicles. The results show that 1) both the uptake of ceftibuten and that of Gly-Sar were dependent on an inwardly directed H+ gradient; 2) anionic compounds such as hippurylphenyllactic acid competitively inhibited ceftibuten uptake in the presence of H+ gradient, whereas this anion did not inhibit Gly-Sar uptake; and 3) the carrier-mediated uptake of ceftibuten did not disappear even in the presence of 20 mM Gly-Sar. The results provide an evidence that several transporters with different features are potentially responsible for the uptake of beta-lactam antibiotics into the intestinal cells. It is suggested that the dianionic beta-lactam antibiotics that carry a net negative charge such as ceftibuten use multiple H+-dependent transport systems for absorption.

The presence of an Na+/spermine antiporter in the rat renal brush-border membrane
M Kobayashi, H Fujisaki, M Sugawara, K Iseki, K Miyazaki
JOURNAL OF PHARMACY AND PHARMACOLOGY, 51, 3, 279, 284, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1999年03月, ［査読有り］
英語, 研究論文（学術雑誌）, This study was aimed at determining the driving force for spermine transport in rat renal proximal tubular brush-border membrane.
The uptake of spermine and trientine, a spermine-like drug used for treating Wilson's disease, into rat renal brush-border membrane vesicles was significantly stimulated by an outwardly directed Na+ gradient. The Na+-dependent uptake was temperature dependent and saturable. A kinetic analysis of the initial uptake of spermine with an Na+ gradient gave a K-m value of 1.44 mu M and a V-max value of 6.31 pmol (mg protein)(-1)/30 s. The Na+-dependent uptake of [H-3]spermine was inhibited by spermine, trientine and tetraethylenepentamine. Substrates of the H+/organic cation transporter (cimetidine and tetraethylammonium), physiological polyamines (putrescine and spermidine) with 2 or 3 amino groups and aminoglycosides (amikacin and tobramicin) with 4 or 5 cationic amines did not affect the uptake of spermine in the presence of an outwardly directed Na+ gradient.
These results suggest that the renal tubular secretion of spermine is mediated by an Na+/spermine antiport system which is specific for a straight-chain polyamine compound with more than 4 amino groups.

A general approach for the prediction of the intestinal absorption of drugs: Regression analysis using the physicochemical properties and drug-membrane electrostatic interaction
M Sugawara, Y Takekuma, H Yamada, M Kobayashi, K Iseki, K Miyazaki
JOURNAL OF PHARMACEUTICAL SCIENCES, 87, 8, 960, 966, AMER PHARMACEUTICAL ASSN, 1998年08月, ［査読有り］
英語, 研究論文（学術雑誌）, A general method for predicting the intestinal absorption of a wide range of drugs using multiple regression analysis of their physicochemical properties and the drug-membrane electrostatic interaction was developed. The absorption rates of tested drugs from rat jejunum were measured by the in situ single-pass perfusion technique. The drugs used in this study were divided into three groups for regression analysis, and a smaller "test" set of compounds was used to assess the predictive capacity of the regression equation. When the analysis was applied to each respective group of drugs (i.e., anionic, cationic, and nonionized compounds), obtained regression coefficients were 0.569, 0.821, 0.728 by using the organic solvent (n-octanol)/buffer partition coefficient, 0.730, 0.734, 0.914 using the permeation rate across a silicon membrane, and 0.790, 0.915, 0.941 using an EVA membrane, respectively. However, smaller regression coefficients of 0.377, 0.468, and 0.718 were obtained when these three groups of drugs were put together for prediction. Meanwhile, correlation was improved remarkably when drug-membrane electrostatic interactions, namely, hydrogen-bonding donor (H-alpha) and acceptor (H-beta) activity or index of electricity (E-c), were added to the other parameters of lipophilicity and permeation rate across the EVA membrane (r = 0.880 and 0.883, respectively). Moreover, the equation obtained from these regression analyses was applicable even to the prediction of the absorption of the zwitterionic drugs. These results suggest that including the electrostatic interaction parameters in addition to lipophilicity and permeability across artificial membranes would afford a better prediction for the intestinal absorption of the vast majority of drugs.

血液透析患者におけるランソプラゾールの薬物動態　　　　　　　　　　　　　　　
井藤達也, 稲垣真実子, 福島紘司, 岡本延彦, 安田卓二, 布施川尚, 菅原 満, 井関 健, 宮崎勝巳
ＴＤＭ研究, 15, 3, 259, 265, 1998年07月, ［査読有り］
日本語, 研究論文（学術雑誌）

Ionic-diffusion potential-dependent transport of a new quinolone, sparfloxacin, across rat intestinal brush-border membrane
K Iseki, T Hirano, K Tsuji, S Miyazaki, M Takada, M Kobayashi, M Sugawara, K Miyazaki
JOURNAL OF PHARMACY AND PHARMACOLOGY, 50, 6, 627, 634, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1998年06月, ［査読有り］
英語, 研究論文（学術雑誌）, The mechanism of uptake of sparfloxacin, a new quinolone, by intestinal brush-border membrane vesicles was investigated to clarify whether there is a common transport process for new quinolones mediated by the diffusion potential across the intestinal membrane bilayer.
Sparfloxacin was taken up pH-dependently by rat intestinal brush-border membrane vesicles, behaviour analogous to that of organic cations including enoxacin and ciprofloxacin. Transient overshooting uptake of this quinolone was observed in the presence of an outward H+ gradient. Momentary dissipation of the H+ gradient by addition of carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone did not affect the uptake of sparfloxacin, and a marked but incomplete reduction in the H+-sensitive overshooting uptake of sparfloxacin was apparent in the voltage-clamped brush-border membrane vesicles. Furthermore, a valinomycin-induced K+-diffusion potential (interior negative) and an inward Cl(-)diffusion potential stimulated the initial uptake of sparfloxacin at pH 5.5. Sparfloxacin uptake was inhibited by tetracaine and imipramine. The inhibitory effect of these cations correlated well with changes in membrane surface charges induced by the presence of tetracaine or imipramine.
These results indicate that sparfloxacin transport across the brush-border membrane depends upon the inside-negative ionic diffusion potential, that the H+ - or K+-diffusion-potential-dependent uptake of sparfloxacin by intestinal brush-border membrane vesicles is affected by the membrane surface potential and that inhibition of sparfloxacin uptake originates from changes in the membrane surface potential caused by the organic cations.

Mechanism of the inhibitory effect of imipramine on the Na+-dependent transport of L-glutamic acid in rat intestinal brush-border membrane
M Sugawara, M Kato, M Kobayashi, K Iseki, K Miyazaki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1370, 2, 252, 258, ELSEVIER SCIENCE BV, 1998年03月, ［査読有り］
英語, 研究論文（学術雑誌）, The mechanism of the inhibitory effect of imipramine, a lipophilic organic cation on the Na+-dependent transport of L-glutamic acid across intestinal brush-border membrane was investigated. The uptake of L-glutamic acid by intestinal brush-border membrane vesicles was dependent on the concentration of Na+. Fitting of the uptake; data in the presence of various concentrations of Na+ using Hill equation yielded a Hill coefficient of 2.18. This result suggest that the carrier system of L-glutamic acid has at least two sites for Na+-binding. By the analysis of double reciprocal plot and Dixon-type plot, it was found that imipramine inhibits the transport of L-glutamic acid by interacting competitively with the binding sites of Na+, but not inhibit L-glutamic acid binding site. Moreover, the effect of imipramine on the transport of L-alanine and D-glucose which are co-transported with only one Na+ molecule was also suggestive of interaction with the Na+-binding sites on the carrier. These results indicate that the mechanism of the inhibitory effect of imipramine on the Na+-dependent carrier systems is common for all systems regardless of the stoichiometry or substrates. (C) 1998 Elsevier Science B.V.

Purification by ceftibuten-affinity chromatography and the functional reconstitution of oligopeptide transporter(s) in rat intestinal brush-border membrane
K Iseki, K Yonemura, T Kikuchi, Naasani, I, M Sugawara, M Kobayashi, N Kohri, K Miyazaki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1370, 1, 161, 168, ELSEVIER SCIENCE BV, 1998年03月, ［査読有り］
英語, 研究論文（学術雑誌）, The transport activity of ceftibuten, a dianionic peptide-like compound, was extracted from rat intestinal brush-border membrane by iz-octylglucoside and reconstituted into asolectin liposomes by dialysis. The proteoliposomes prepared from the membrane extract showed an inward H+-gradient-dependent uptake of ceftibuten and glycylsarcosine. Ceftibuten-immobilized affinity chromatography of the membrane extract permitted the isolation of two polypeptides (apparent molecular mass of 117 and 127 kDa) that can recognize the dianionic peptide structure of ceftibuten. Proteoliposomes prepared from reconstituting the isolated proteins into asolectin vesicles showed an overshooting uptake of ceftibuten in the presence of an inwardly directed H+ gradient, and this uptake could be inhibited by L-valyl-L-proline. N-glycanase digestion of the isolated proteins, 117 and 127 kDa, trimmed them into 78 and 120 kDa products, respectively. The protein core size of the smaller protein was in agreement with the calculated molecular mass of similar to 79 kDa for the rat PepT1 transporter obtained by other investigators. (C) 1998 Elsevier Science B.V.

Purification and liposomal reconstitution of the oligopeptide transport activity in rat renal cortex using ceftibuten-affinity chromatography
K Iseki, Naasani, I, T Kikuchi, M Sugawara, M Kobayashi, N Kohri, K Miyazaki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1368, 2, 329, 337, ELSEVIER SCIENCE BV, 1998年01月, ［査読有り］
英語, 研究論文（学術雑誌）, The carrier protein(s) responsible for the transport of ceftibuten, a peptide-like dianionic cefem, in rat renal brush-border membrane were solubilized and purified by a ceftibuten-ligand specific affinity chromatography technique. The proteoliposomes reconstituted from the solubilized brush-border membrane proteins by dialysis had H+-sensitive uptake of ceftibuten and trans-stimulative effect by cephalexin. A specific uptake activity for ceftibuten was found in the 3.5 M-eluted fraction but not the flowthrough and the 0.5 M-eluted fraction of the affinity chromatography. Analyzing this active fraction by SDS/PAGE after reconstituting into liposomes gave two major proteins (approx. molecular masses of 130 and 107 kDa). The purification protocol presented in this study permitted an efficient isolation of the carrier proteins responsible for the transport of ceftibuten and other peptide-like compounds. (C) 1998 Elsevier Science B.V.

Single-step isolation method for six glycoforms of human α1-acid glycoprotein by hydroxylapatite chromatography and study of their binding capacities for disopyramide
Satoshi Kishino, Akikazu Nomura, Michiyo Saitoh, Mitsuru Sugawara, Ken Iseki, Akira Kitabatake, Katsumi Miyazaki
Journal of Chromatography B: Biomedical Applications, 703, 1-2, 1, 6, 1997年12月05日, ［査読有り］
英語, 研究論文（学術雑誌）, A single-step isolation method for the glycoforms of human serum α1- acid glycoprotein (AAG) using a hydroxylapatite column under a gradient elution program was developed. The concentrations of N-acetylneuraminic acid and monosaccharides (fucose, N-acetylglucosamine, galactose and mannose) of six AAG glycoforms were determined by the pulsed-amperometric detection method. For each AAG glycoform, significant sex-related differences in carbohydrate content have been observed only for AAG glycoforms two and six, and not for each AAG glycoform. The relationship between the extent of the branch in the glycan chain and the binding capacity to disopyramide were examined. Female AAG contained highly sialylated AAG glycoforms compared to male glycoforms. Conversely, male AAG was rich in the lower sialylated AAG glycoform. Furthermore, it was found that the drug binding capacity decreases with increasing branching of the glycan chain. This suggests that the binding sites of AAG are hindered by a relatively large carbohydrate moiety, such as tetraantennary structures.

Single-Step Isolation Method for Six Glycoforms of Human α1-Acid Glycoprotein by Hydroxylapatite Chromatography and Study of Their Binding Capacities for Disopyramide
Kishino S, Nomura A, Saitoh M, Sugawara M, Iseki K, Kitabatake A, Miyazaki K
J. Chromatogr. B, 703, 1-2, 1, 6, ELSEVIER SCIENCE BV, 1997年12月, ［査読有り］
英語, 研究論文（学術雑誌）, A single-step isolation method for the glycoforms of human serum alpha(1)-acid glycoprotein (AAG) using a hydroxylapatite column under a gradient elution program was developed. The concentrations of N-acetylneuraminic acid and monosaccharides (fucose, N-acetylglucosamine, galactose and mannose) of six AAG glycoforms were determined by the pulsed amperometric detection method, For each AAG glycoform, significant sex-related differences in carbohydrate content have been observed only for AAG glycoforms two and six, and not for each AAG glycoform. The relationship between the extent of the branch in the glycan chain and the binding capacity to disopyramide were examined. Female AAG contained highly sialylated AAG glycoforms compared to male glycoforms. Conversely, male AAG was rich in the lower sialylated AAG glycoform. Furthermore, it was found that the drug binding capacity decreases with increasing branching of the glycan chain. This suggests that the binding sites of AAG are hindered by a relatively large carbohydrate moiety, such as tetraantennary structures.

The effect of membrane surface potential on the permeability of anionic compounds across the apical membrane in human intestinal epithelial (Caco-2) cells
K Iseki, K Kaido, M Kobayashi, M Sugawara, K Miyazaki
BIOLOGICAL & PHARMACEUTICAL BULLETIN, 20, 7, 794, 799, PHARMACEUTICAL SOC JAPAN, 1997年07月, ［査読有り］
英語, 研究論文（学術雑誌）, The effect of membrane surface potential of the apical side on the intracellular uptake of ionic compounds was investigated using the human colon adenocarcinoma cell line (Caco-2). The transepithelial transport of indolepropionic acid and tryptamine was consistent with the uptake behavior shown by rat intestinal brush-border membrane (BBM) vesicles. Imipramine, which diminished the negative charge of the membrane surface (for both Caco-2 and BBM), acted to increase the uptake of the anionic compounds, indolepropionic acid and ceftibuten, and to decrease that of tryptamine (cationic compound) by both the Caco-2 monolayer and the intestinal BBM vesicles at a pH of 7.5. These results suggest that the effects of membrane surface potential on the permeability of ionic compounds were detectable on the Caco-2 cell line as well as the BBM vesicles. On the other hand, the inhibition of H+-linked transport and the stimulation of the surface charge-regulated uptake of ceftibuten have occurred simultaneously on the Caco-2 cell line in the presence of imipramine. It seems that the membrane surface charge (negative) plays an important role in the transport process of ionic compounds across the intestinal epithelium.

Structure-relationship study of the uptake of aliphatic polyamine compounds by rat intestinal brush-border membrane vesicles
M Kobayashi, S Suruga, H Takeuchi, M Sugawara, K Iseki, K Miyazaki
JOURNAL OF PHARMACY AND PHARMACOLOGY, 49, 5, 511, 515, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1997年05月, ［査読有り］
英語, 研究論文（学術雑誌）, The effects of lipophilicity, ion-diffusion potential and membrane surface potential on the uptake of various aliphatic polyamine compounds by rat intestinal brush-border membrane vesicles (BBMV) have been investigated.
A valinomycin-induced potassium-diffusion potential (inside-negative) stimulated the initial uptake of diamine compounds, and good correlation was observed between lipophilicity and the amount of diffusion potential-dependent transport of the diamines. In contrast, because of their much lower lipophilicity, tri- and tetraamine compounds were not affected by the diffusion potential. Tetracaine, which can make the membrane surface potential more positive, inhibited the transport rate of 1,9-nonanediamine, spermidine and spermine by the BBMV.
These data suggest that the transport mechanism of diamines is similar to that of monoamine compounds in respect to its dependence on ion-diffusion potential and on the membrane surface potential. The extent of the effect of ion-diffusion potential on the rate of transport of the diamines was closely related to the lipophilicity of the diamine. In contrast, only the surface potential contributed to the transport mechanism of lower lipophilic tri- and tetraamine compounds.

The mechanism of excretion of trientine from the rat kidney: Trientine is not recognized by the H+ organic cation transporter
M Kobayashi, R Tanabe, M Sugawara, K Iseki, K Miyazaki
JOURNAL OF PHARMACY AND PHARMACOLOGY, 49, 4, 426, 429, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1997年04月, ［査読有り］
英語, 研究論文（学術雑誌）, Trientine dihydrochloride is used to treat Wilson's disease by chelating copper and increasing its urinary excretion. The mechanism of renal excretion of trientine has been investigated in-vivo and in-vitro.
Trientine clearance in the rat was significantly faster than creatinine clearance. When trientine and the same number of moles of copper ions were administered simultaneously to the rat, however, trientine clearance decreased to almost the same level as the creatinine clearance. To clarify this active excretion system for trientine, the uptake of trientine and a physiological polyamine compound, spermine, was investigated using rat renal brush-border membrane vesicles. Although, because trientine and spermine are organic cations, the H+/organic cation transporter is expected to recognize these compounds, neither an outwardly directed H+ gradient nor an inward Na+ gradient stimulated trientine uptake. [C-14]Spermine uptake was, nevertheless, trans-stimulated by both unlabelled spermine and trientine and the trans-stimulating effect of spermine on trientine uptake was, furthermore, completely abolished by addition of copper ions to the incubation medium.
These results suggest that there is a specific transport system for spermine and trientine on the renal brush-border membrane. This transport system contributes to the secretion of trientine in the kidney proximal tubule but does not recognize the trientine-copper complex.

Solubilization and reconstitution characteristics of the carrier protein(s) responsible for the transport of ceftibuten, a substrate for the oligopeptide transporters, in rat renal brush-border membrane
Naasani, I, T Kikuchi, M Sugawara, M Kobayashi, K Iseki, K Miyazaki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1283, 2, 185, 191, ELSEVIER SCIENCE BV, 1996年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Optimal procedures for the reconstitution of the transport activity of ceftibuten, a dianionic beta-lactam antibiotic, from rat kidney brush-border membrane were developed. The uptake activity into reconstituted proteoliposomes appeared to be particularly sensitive to the extraction conditions, and to the lipid composition used for reconstitution. Changes in the concentration of octyl glucoside significantly affected the extraction of ceftibuten transport activity, and optimal extraction was achieved at a concentration of 60 mM. Optimal reconstitution was achieved using a lipid composition of asolectin, cholesterol and phosphatidylserine in a w/w percent ratio of 60:30:10, respectively, and with a lipid-to-protein ratio of 10. The uptake of ceftibuten into the resulting proteoliposomes showed temperature and pH dependency, was inhibitable by a range of cephem antibiotics, oligopeptides and the organic anion PAH, and was trans-stimulated by cephalexin and dipeptides. This reconstitution system will likely prove useful in future studies on the functional analysis of the peptide transport system in a purified form.

Uptake mechanism of trientine by rat intestinal brush-border membrane vesicles
R Tanabe, M Kobayashi, M Sugawara, K Iseki, K Miyazaki
JOURNAL OF PHARMACY AND PHARMACOLOGY, 48, 5, 517, 521, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1996年05月, ［査読有り］
英語, 研究論文（学術雑誌）, The uptake characteristics of trientine by rat intestinal brush-border membrane vesicles were studied.
The uptake characteristics of trientine were similar to those of the physiological polyamines with respect to the excessive accumulation in vesicles, the pH dependency, the temperature dependency and the ineffectiveness of K+ diffusion potential (inside negative). The initial uptake of trientine was saturable with a K-m value of 1.13 mM, which was larger than that of spermine and spermidine. Furthermore, the uptake rate of trientine was dose-dependently inhibited by spermine and spermidine. Spermine competitively inhibited the uptake of trientine with a K-i value of 18.6 mu M, and it was close to the K-m value for spermine (30.4 mu M).
These data suggested that the uptake of trientine was similar to that of spermine and spermidine in rat small intestinal brush-border membrane vesicles, and these polyamines seem to inhibit the absorption of trientine from the gastrointestinal tract.

理論式による多剤配合時のpH予測方法
井関 健, 中垣 悌, 小林道也, 菅原 満, 荻野 修, 宮崎勝巳
病院薬学, 22, 2, 183, 188, 日本病院薬剤師会, 1996年03月, ［査読有り］
日本語, 研究論文（学術雑誌）, A method for predicting pH changes in multiple admixtures was designed on the basis of the acid-base equilibrium theory. The pH's of transfusions mixed with the various injections were estimated by solving a general theoretical equation for proton concentrations in the multicomponents-blended aquaous solution obtained using a dichotomy as the algorithm. Eighty-two transfusions and parenteral solution mixture combinations were examined for the efficacy of the predicted equation. As a result, the estimated pH was in good agreement with the measured pH in all examinations, and a good corelation existed between the measured and calculated values of pH. Furthermore, the incompatibility of the parenteral admixture can be easily predicted using the present estimation-program for pH changes without any preliminary pH titration tests. These results suggest that this prediction method will be a useful tool for constructing and handling database incompatipility.

Transport Mechanisms of Nucleosides and the Derivative, 6-Mercaptopurine Riboside across Rat Intestinal Brush-border Membranes
Iseki K, Sugawara M, Fujiwara T, Naasani I, Kobayashi M, Miyazaki K
Biochim. Biophys. Acta, 1278, 1, 105, 110, 1996年01月, ［査読有り］
英語, 研究論文（学術雑誌）

Transport mechanisms of nucleosides and the derivative, 6-mercaptopurine riboside across rat intestinal brush-border membranes
K Iseki, M Sugawara, T Fujiwara, Naasani, I, M Kobayashi, K Miyazaki
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1278, 1, 105, 110, ELSEVIER SCIENCE BV, 1996年01月, ［査読有り］
英語, 研究論文（学術雑誌）, Na+-driven nucleoside transport processes across rat intestinal brush-border membrane vesicles were investigated. 6-Mercaptopurine riboside (6-MPR), an analogue of purine-nucleoside such as adenosine and inosine, was recognized by its purine- and pyrimidine-nucleosides transport system, but their nucleo-bases did not entirely inhibit the 6-MPR transport. The analysis according to the Hill equation of the curve for Na+ activation of 6-MPR uptake was consistent with the notion of a Na+/6-MPR coupling stoichiometry of 1:1. The expressed transport activities of adenosine, uridine, and 6-MPR were Na+-dependent and saturable, and their affinity constants (K-m value) obtained by Eadie-Hofstee analysis were approx. 20, 15 and 100 mu M. Moreover, the uptake of radiolabeled adenosine and uridine was trans-stimulated by 6-MPR inside vesicles in the absence of an inwardly directed Na+-gradient. On the other hand, uridine did not exhibit any inhibitory effects on the uptake of adenosine despite the fact that adenosine was a potent inhibitor for uridine uptake by intestinal brush-border membrane vesicles. These differences in the inhibition may be explained by the multiplicity of the nucleoside transport systems.

Purification Method for α-1-Acid Glycoprotein with Subsequent High-Performance Liquid Chromatographic Determination of Monosaccharides in Plasma of Healthy Subjects and Patients with Renal Insufficiency
Kishino S, Nomura A, Sugawara M, Iseki K, Kakinoki S, Kitabatake A, Miyazaki K
J. Chromatogr. B, 672, 2, 199, 205, ELSEVIER SCIENCE BV, 1995年10月, ［査読有り］
英語, 研究論文（学術雑誌）, A simple purification method for human plasma alpha-1-acid glycoprotein (AAG) using an ion-exchange and hydroxyapatite column was developed. The recovery of the method was found to be high. We also improved a determination method for N-acetylneuraminic acid and monosaccharides in the carbohydrate moiety of AAG by using an ion-exchange column and pulse-amperometric detection. By this method, a composition analysis of the carbohydrate moiety of AAG (N-acetylneuraminic acid, fucose, N-acetyl glucosamine, galactose and mannose) was possible with 1.0 ml of plasma. We compared these carbohydrate concentrations in the AAG of patients with renal insufficiency with those of healthy subjects. In the AAG of the patients, the concentrations of N-acetylglucosamine, galactose and mannose were significantly higher than those in the AAG of the healthy subjects.

CHANGES IN THE BINDING-CAPACITY OF ALPHA-1-ACID GLYCOPROTEIN IN PATIENTS WITH RENAL-INSUFFICIENCY
S KISHINO, A NOMURA, ZS DI, M SUGAWARA, K ISEKI, S KAKINOKI, A KITABATAKE, K MIYAZAKI
THERAPEUTIC DRUG MONITORING, 17, 5, 449, 453, LIPPINCOTT-RAVEN PUBL, 1995年10月, ［査読有り］
英語, 研究論文（学術雑誌）, The elevation of alpha-1-acid glycoprotein (AAG) concentration and the binding characteristics of disopyramide (DP) to AAG in patients with renal insufficiency were investigated. The serum AAG concentration and protein binding of DP in patients were significantly greater than those in healthy subjects. However, in both the serum and the purified AAG, Scatchard analysis showed that the number of binding sites per molecule of AAG in patients was significantly lower than that in healthy subjects, although there was no difference in the dissociation constant (K-d). These results suggest that the AAG induced in renal insufficiency is qualitatively different from normal AAG. Moreover, the change of the unbound DP fraction when DP concentration was increased was larger in the patients than in the healthy controls. Therefore, monitoring of the unbound DP would be important for therapeutic drug monitoring in patients with renal insufficiency.

THE INTESTINAL TRANSPORT MECHANISM OF FLUOROQUINOLONES - INHIBITORY EFFECT OF CIPROFLOXACIN, AN ENOXACIN DERIVATIVE, ON THE MEMBRANE POTENTIAL-DEPENDENT UPTAKE OF ENOXACIN
T HIRANO, K ISEKI, SATO, I, S MIYAZAKI, M TAKADA, M KOBAYASHI, M SUGAWARA, K MIYAZAKI
PHARMACEUTICAL RESEARCH, 12, 9, 1299, 1303, PLENUM PUBL CORP, 1995年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Purpose. To clarify the absorption-structure relationship for the fluoroquinolones from the point of view of inhibitory behavior. Methods, The inhibitory effects of ciprofloxacin on the transport process of enoxacin across the rat intestinal blush-border membrane was examined. Results, Ciprofloxacin, which has a similar structure to enoxacin, exhibited a pH-dependent interference with enoxacin absorption from rat jejunal loops. The uptake experiments using BBM vesicles showed that ciprofloxacin significantly reduced not only the initial binding of enoxacin to the membrane surface, hut also the K+- or H+-diffusion potential-dependent transport across the membrane. Furthermore, an H+-diffusion potential (interior negative) also exhibited a stimulative uptake of ciprofloxacin. Conclusions. These results suggest that the inhibition behavior of ciprofloxacin from the jejunal loop was closely related to the ionic diffusion potential-dependent uptake of enoxacin across the brush-border membrane.

COMPARISON OF THE TRANSPORT CHARACTERISTICS OF CEFTIBUTEN IN RAT RENAL AND INTESTINAL BRUSH-BORDER MEMBRANES
NAASANI, I, K SATO, K ISEKI, M SUGAWARA, M KOBAYASHI, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS, 1231, 2, 163, 168, ELSEVIER SCIENCE BV, 1995年09月, ［査読有り］
英語, 研究論文（学術雑誌）, The transport characteristics of ceftibuten, a dianionic cephem antibiotic, in rat renal and intestinal brush-border membranes were compared. Ceftibuten transport was mediated by two transport systems in the renal brush-border membrane and by one transport system in the intestinal brush-border membrane. The apparent kinetic parameters for the uptake of ceftibuten by the renal brush-border membrane vesicles, respectively, were: K-m1, K-m2 values of 26 and 1946 mu M and V-max1, V-max2 values of 105 and 1400 pmol/mg protein per 30 s. The apparent kinetic parameters for the uptake by the intestinal brush-border membrane vesicles were: K-m of 425 mu M and V-max of 1701 pmol/mg protein per 30 s. In the renal brush-border membrane, L-Ala-L-Pro was partially competitive and competitive inhibitor for the uptake by the high and low affinity systems, respectively. However, L-Ala-L-Pro was a non-competitive inhibitor for the uptake by the intestinal brush-border membrane vesicles. L-Carnosine was a specific and competitive inhibitor for the high affinity system in the renal brush-border membrane, while it had no effect on the low affinity system of the kidney or on the transport system of the intestine. It was concluded that the transport characteristics of ceftibuten in the renal and intestinal brush-border membranes are similar in some aspects but they are not identical.

ALPHA-1-ACID GLYCOPROTEIN CONCENTRATION AND THE PROTEIN-BINDING OF DISOPYRAMIDE IN HEALTHY-SUBJECTS
S KISHINO, A NOMURA, ZS DI, M SUGAWARA, K ISEKI, S KAKINOKI, A KITABATAKE, K MIYAZAKI
JOURNAL OF CLINICAL PHARMACOLOGY, 35, 5, 510, 514, LIPPINCOTT-RAVEN PUBL, 1995年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Age- and gender-related changes in serum alpha(1)-acid glycoprotein (AAG) concentration and the serum protein binding of disopyramide were examined after intensive medical examination. Based on the clinical chemistry tests over 51 points, 245 subjects were diagnosed as healthy and 71 subjects (22.5%) revealed an abnormal value for at least one item, In the healthy subjects, serum AAG concentration in men was significantly higher than in women (men, 0.78 +/- 0.18 mg/mL, mean +/- SD; women, 0.67 +/- 0.16 mg/mL. In contrast, there were no significant differences in the AAG concentration between age groups for men and women and in the unbound fraction of disopyramide. Gender changes AAG concentration. Age, however, does not change AAG concentration and the protein binding of the basic drug.

TRANSPORT MECHANISM OF CEFTIBUTEN, A DIANIONIC CEPHEM, IN RAT RENAL BRUSH-BORDER MEMBRANE
NAASANI, I, M SUGAWARA, M KOBAYASHI, K ISEKI, K MIYAZAKI
PHARMACEUTICAL RESEARCH, 12, 4, 605, 608, PLENUM PUBL CORP, 1995年04月, ［査読有り］
英語, 研究論文（学術雑誌）, The uptake mechanism of ceftibuten by rat renal brush-border membrane vesicles was investigated. Uptake was found to be independent of a Na+ gradient and partially dependent on an inwardly directed H+-gradient. Competition experiments between ceftibuten and several compounds demonstrated that the peptide-like structural features of inhibitors are more essential than their charge properties for inhibiting uptake. Anionic compound, such as p-aminohippuric acid, also inhibited ceftibuten uptake by renal brush-border membrane vesicles in the presence of an H+-gradient. We conclude that ceftibuten, in spite of its anionic structure, is transported via the dipeptide transport systems, rather than the organic anion transport system.

Effect of Membrane Surface Potential on the Uptake and Inhibition of Cationic Compounds in Rat Intestinal Brush-Border Membrane Vesicles and Liposomes
Sugawara M, Oikawa H, Kobayashi M, Iseki K, Miyazaki K
Biochim. Biophys. Acta, 1234, 1, 22, 28, 1995年03月, ［査読有り］
英語, 研究論文（学術雑誌）

EFFECT OF MEMBRANE-SURFACE POTENTIAL ON THE UPTAKE AND THE INHIBITION OF CATIONIC COMPOUNDS IN RAT INTESTINAL BRUSH-BORDER MEMBRANE-VESICLES AND LIPOSOMES
M SUGAWARA, H OIKAWA, M KOBAYASHI, K ISEKI, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1234, 1, 22, 28, ELSEVIER SCIENCE BV, 1995年03月, ［査読有り］
英語, 研究論文（学術雑誌）, The effect of membrane surface potential on the uptake of tryptamine, an organic cation, by rat intestinal brush-border membrane vesicles was investigated. In the presence of an inside-negative K+-diffusion potential, the manner of initial uptake of tryptamine appeared to be pi-I-dependent and the uptake in the acidic medium was lower than that in the neutral medium. Changes in surface potential of brush-border membrane vesicles were monitored using 8-anilino-1-naphthalenesulfonic acid (ANS) and the results suggested that the membrane surface potential (negative charge on the membrane surface) decreased in the acidic medium. A good correlation was observed between the K+-diffusion potential-dependent uptake of tryptamine and membrane surface potential monitored by ANS at various pH levels. The uptake of tryptamine by liposomes (large unilamellar vesicles), which contained various amounts of dipalmitoylphosphatidylserine (DPPS), was also examined. The uptake of tryptamine decreased with a decrease of DPPS content in the liposomes, and was correlated with the membrane surface potential monitored by ANS. Moreover, the effect of organic cations on the uptake of tryptamine by intestinal brush-border membrane vesicles was examined. The uptake of tryptamine was inhibited by tetracaine and imipramine. The inhibitory effect of these cations was well correlated with changes in the membrane surface potential in the presence of tetracaine or imipramine. These results suggest that the Kf-diffusion potential-dependent uptake of tryptamine by intestinal brush-border membrane vesicles is affected by membrane surface potential, and the inhibition of tryptamine uptake originates in changes in the membrane surface potential caused by the organic cations.

TRANSPORT MECHANISMS OF ENOXACIN IN RAT BRUSH-BORDER MEMBRANE OF RENAL-CORTEX - INTERACTION WITH ORGANIC CATION-TRANSPORT SYSTEM AND IONIC-DIFFUSION POTENTIAL-DEPENDENT UPTAKE
T HIRANO, K ISEKI, M SUGAWARA, S MIYAZAKI, M TAKADA, K MIYAZAKI
BIOLOGICAL & PHARMACEUTICAL BULLETIN, 18, 2, 342, 346, PHARMACEUTICAL SOC JAPAN, 1995年02月, ［査読有り］
英語, 研究論文（学術雑誌）, The mechanism of the renal transport of enoxacin (ENX) has been investigated using brush-border membrane vesicles (BBMV's) isolated from the rat renal cortex. The initial rate and time-course of ENX uptake were quite dependent upon the medium pH (pH 5.5 > pH 7.5). The pH dependence was in accordance with the degree of cationic form. Carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) affected the transient uphill transport of ENX across the renal brush-border membrane in the presence of an outward-directed H+-gradient. The initial uptake Has saturable, and transport kinetic parameters were given for a K-m and V-max of 0.59 mM and 1.37 nmol/(mg protein)/30 s, respectively. On the other hand, an outward H+-gradient (pH(in)=5.5, (out)=7.5) dependent uptake of ENX was partially decreased by the voltage-clamped BBMVs. Furthermore, a valinomycin-induced K+-diffusion potential (interior negative) was found to increase the uptake of ENX at pH 5.5,, which is cationic form-rich. These results suggest that ENX uptake participates in not only the H+/organic cation antiport system for organic cation secretion but also the ionic diffusion potential (interior negative) dependent permeation through the membrane.

Predicting the Intestinal Absorption of Anionic Drugs from Their Physicochemical Properties
Mitsuru Sugawara, Yoh Takekuma, Michiya Kobayashi, Ken Iseki, Katsumi Miyazaki
Pharmacy and Pharmacology Communications, 1, 10, 491, 493, 1995年, ［査読有り］
英語, 研究論文（学術雑誌）, A method for predicting the intestinal absorption of anionic drugs by measuring their physicochemical properties (organic solvent/buffer partition coefficients, hydrogen bonding and diffusion rate across silicone membrane) was investigated. The absorption rates of ten anionic drugs, which were mainly non‐steroidal anti‐inflammatory agents, were measured in‐situ by a rat intestinal single‐pass perfusion technique. A poor correlation between the absorption rate and the partition into octanol was observed, although the absorption rate showed a tendency to increase when the partition coefficient increased. On the other hand, the technique of determining the permeation rate across silicon membrane, which comprises a diffusion process, gave a good correlation with the in‐situ absorption results. The effects of permeant size (molecular volume or molecular weight) and hydrogen bonding were also investigated. When these two factors were considered together with the permeation rate across a silicone membrane, excellent regression coefficients were obtained. These results suggest that the permeation rate across a silicone membrane, permeant size and hydrogen bonding are valuable measures for predicting the absorption behaviour of anionic drugs. 1995 Royal Pharmaceutical Society of Great Britain

Sodium‐dependent Putrescine Transport in Rat Intestinal Basolateral Membrane
MICHIYA KOBAYASHI, RYOU TANABE, MITSURU SUGAWARA, KEN ISEKI, KATSUMI MIYAZAKI
Pharmacy and Pharmacology Communications, 1, 7, 337, 339, 1995年, ［査読有り］
英語, 研究論文（学術雑誌）, The uptake characteristics of polyamines were investigated using basolateral membrane vesicles isolated from rat small intestine. Only putrescine uptake was stimulated by an inward Na+ gradient. A kinetic analysis of the initial uptake of putrescine with Na+ gradient gave a Km value of 1.95 μm and a Vmax value of 6.01 pmol (mg protein)−130s. Several diamine compounds including methylglyoxal bis‐(guanyl)hydrazone, an antileukemia reagent, inhibited the putrescine uptake. However, tri‐ and tetraamine compounds such as spermine and spermidine did not. These results suggested that there is a specific carrier for putrescine in the basolateral membrane of rat small intestinal epithelial cells. This carrier recognizes some compounds with two cationic amino groups. Taking into account the difference of the concentration of sodium ion between the intra‐ and the extra‐cellular spaces, this carrier will transport putrescine from the blood to the intestinal cells. 1995 Royal Pharmaceutical Society of Great Britain

Uptake of 6‐Mercaptopurine Riboside via the Nucleoside Transporter in the Human Intestinal Brush‐border Membrane
KEN ISEKI, IMAD NAASANI, MITSURU SUGAWARA, TOSHIE FUJIWARA, MICHIYA KOBAYASHI, KATSUMI MIYAZAKI
Pharmacy and Pharmacology Communications, 1, 3, 127, 129, 1995年, ［査読有り］
英語, 研究論文（学術雑誌）, The transport systems of 6‐mercaptopurine riboside (6‐MPR), a nucleoside analogue, in the human jejunal brush‐border membrane and in the human epithelial cell line, Caco‐2, were investigated. The transport activities of 6‐MPR were found to be dependent upon an inward Na+‐gradient at pH 5·5. Trans‐stimulation studies indicated that the uptakes of both [3H]adenosine and [3H]uridine were significantly increased by the presence of 6‐MPR inside the human brush‐border membrane vesicles. The uptake of 6‐MPR from the apical side of Caco‐2 monolayer was sensitive for an inward‐directed Na+‐gradient, and a greater uptake was observed at an acidic medium (pH 5·5>
7·5). Moreover, both adenosine and uridine were significantly effective in inhibiting the 6‐MPR uptake by Caco‐2. These results indicate that an analogue of adenosine, 6‐MPR, is able to be taken up via the Na+‐gradient‐dependent purine‐ and pyrimidine‐nucleosides transport systems in the human intestinal brush‐border membrane. 1995 Royal Pharmaceutical Society of Great Britain

THE STIMULATIVE EFFECT OF DIFFUSION POTENTIAL ON ENOXACIN UPTAKE ACROSS RAT INTESTINAL BRUSH-BORDER MEMBRANES
T HIRANO, K ISEKI, S MIYAZAKI, M TAKADA, M KOBAYASHI, M SUGAWARA, K MIYAZAKI
JOURNAL OF PHARMACY AND PHARMACOLOGY, 46, 8, 676, 679, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1994年08月, ［査読有り］
英語, 研究論文（学術雑誌）, Evidence of a membrane potential dependence for enoxacin uptake by rat intestinal brush-border membrane vesicles has been found. The transient overshooting uptake of enoxacin disappeared in the voltage-clamped brush-border membrane vesicles in the presence of an outward H+-gradient. Momentary dissipation of the H+-gradient itself by carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) did not affect the uptake of enoxacin. In contrast, enoxacin uptake was depressed by an interior positive K+-diffusion potential induced by valinomycin. Furthermore, not only the outward H+-gradient but also an inward Cl--gradient caused a stimulating effect on enoxacin uptake, and the stimulation by the Cl--gradient was dissipated by using voltage-clamped membrane vesicles. These results indicate that enoxacin transportation across the brush-border membrane is dependent on the ionic diffusion potential. On the other hand, neither Gly-Gly nor guanidine had any effect on enoxacin uptake by the membrane vesicles in the presence of an inward (for Gly-Gly) or outward (for guanidine) H+-gradient as a driving force for each transport system. Therefore, it seems that enoxacin transport through the intestinal epithelia does not participate in the carrier-mediated transport systems for Gly-Gly and guanidine.

THE INHIBITORY EFFECTS OF CEPHALOSPORIN AND DIPEPTIDE ON CEFTIBUTEN UPTAKE BY HUMAN AND RAT INTESTINAL BRUSH-BORDER MEMBRANE-VESICLES
M SUGAWARA, T TODA, M KOBAYASHI, K ISEKI, K MIYAZAKI, H SHIROTO, JI UCHINO, Y KONDO
JOURNAL OF PHARMACY AND PHARMACOLOGY, 46, 8, 680, 684, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1994年08月, ［査読有り］
英語, 研究論文（学術雑誌）, The types of inhibitory effects caused by compound V (an analogue of ceftibuten) and alanylproline (dipeptide) on the uptake of ceftibuten by brush-border membrane vesicles (BBMV) prepared from human and rat small intestine were analysed. In the presence of an inward H+-gradient, the initial uptake rate of ceftibuten by both human and rat intestinal BBMV was concentration-dependent with apparent K-m and V-max values of 0.35 mM and 2.052 nmol (mg protein)(-1) min(-1) for human BBMV, and 0.50 mM and 3.056 nmol (mg protein)(-1) min(-1) for rat BBMV, respectively. For both human and rat BBMV, kinetic analysis by Dixon and Lineweaver-Burk plots demonstrated that the uptake of ceftibuten was competitively inhibited by compound V, whereas inhibition by alanylproline was noncompetitive or partially competitive. These results suggest that there is a stereospecific transport system which is common to ceftibuten and compound V, and that this system is not identical to the carrier system for the dipeptide, alanylproline.

Effect of Membrane Surface Potential on the Uptake of Anionic Compounds by Liposomes
Sugawara M, Hashimoto A, Kobayashi M, Iseki K, Miyazaki K
Biochim. Biophys. Acta, 1192, 2, 241, 246, 1994年06月, ［査読有り］
英語, 研究論文（学術雑誌）

EFFECT OF MEMBRANE-SURFACE POTENTIAL ON THE UPTAKE OF ANIONIC COMPOUNDS BY LIPOSOMES
M SUGAWARA, A HASHIMOTO, M KOBAYASHI, K ISEKI, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1192, 2, 241, 246, ELSEVIER SCIENCE BV, 1994年06月, ［査読有り］
英語, 研究論文（学術雑誌）, The effect of membrane surface potential on the uptake of several anionic compounds by liposomes (large unilamellar vesicles), which contain various amounts of dipalmitoylphosphatidylserine (DPPS), was investigated. The uptake amount of four tested anionic compounds (cefixime, benzyioxyindoleacetic acid (BOIAA), ceftibuten and S-1006) decreased with an increase in the DPPS content of liposomes, and was correlated with the membrane surface potential monitored using a fluorescent dye, 8-anilino-1-naphthalene sulfonate (ANS). Moreover, for all of the tested anionic compounds, a good correlation was observed between the ratio of the uptake value (5 min) by each of the liposomes comprising various amounts of DPPS to the uptake value by liposomes containing 10% DPPS and a relative membrane surface potential monitored by ANS. On the other hand, the uptake of zwitterionic compounds (enoxacin, cephradine and benzyloxytryptophan (BOTP)) was independent of DPPS content. These results suggest that the uptake of tested anionic compounds by large unilamellar lipid vesicles is dependent on the membrane surface potential which originates in the surface negative charge.

経口セフェム系抗生物質の消化管吸収に及ぼすペプチド結腸栄養剤エンテルード(R)併用の影響
井関 健, 佐藤 佳子, 菅原 満
薬学雑誌, 114, 4, 233, 240, (公社)日本薬学会, 1994年04月, ［査読有り］
日本語, 研究論文（学術雑誌）, 1)ペプチド製剤エンテルード(R)は,CETBの吸収を顕著に遅らせた。しかし,CEXの吸収には何ら変化が認められなかったことより,両薬物の消化管吸収に違いのあることが明らかになった。2)エンテルード(R)の吸収抑制効果は,主成分であるペプチドによる輸送担体の阻害ではなく,その他の構成成分によって生じることが認められた

EFFECT OF ENTERUED(R) ADMINISTRATION ON THE INTESTINAL-ABSORPTION OF ORALLY-ACTIVE CEFEM ANTIBIOTICS
K ISEKI, Y SATOH, M SUGAWARA, K MIYAZAKI
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 114, 4, 233, 240, PHARMACEUTICAL SOC JAPAN, 1994年04月, ［査読有り］
日本語, 研究論文（学術雑誌）, The effect of simultaneous administration of Enterued (R), an elemental diet, which is composed of oligopeptides (egg white hydrolyzate), on the orally active cefems was investigated. Ceftibuten (CETB) administered together with Enterued (R) to man was excreted slower in the urine. AUC from the plasma concentrations of CETB after the oral administration with Enterued (R) was markedly decreased compared to that without Enterued (R) in rat. In contrast, neither urinary excretion of cephalexin (CEX) in man nor the AUC from the plasma profile of CEX in rat was changed by Enterued (R). Furthermore, the disappearance, tissue accumulation, net absorption of CETB from the rat jejunal loop were significantly inhibited by Enterued (R). However, the net absorption of CEX has no alternation in the presence of Enterued (R), although the apparent disappearance decreased on the basis of the diminishment of tissue accumulation. Additionally, Hepan ED (R), which is an elementary diet composed of amino acids, and the mineral solution containing neither peptides nor vitamins have also exhibited the decreasing effect on the CETB absorption behaviour. These results suggested that the inhibitory effects of Enterued (R) on the absorption of these antibiotics were not due to the inhibition of peptide-transport systems.

Changes in the Permeation Rate of Organic Anions through the Intestinal Brush-Border Membrane with Membrane Surface Potential
Sugawara M, Hashimoto A, Toda T, Takahashi M, Kobayashi M, Iseki K, Miyazaki K
Biochim. Biophys. Acta, 1190, 1, 85, 90, 1994年02月, ［査読有り］
英語, 研究論文（学術雑誌）

CHANGES IN THE PERMEATION RATE OF ORGANIC-ANIONS THROUGH THE INTESTINAL BRUSH-BORDER MEMBRANE WITH MEMBRANE-SURFACE POTENTIAL
M SUGAWARA, A HASHIMOTO, T TODA, M TAKAHASHI, M KOBAYASHI, K ISEKI, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 1190, 1, 85, 90, ELSEVIER SCIENCE BV, 1994年02月, ［査読有り］
英語, 研究論文（学術雑誌）, The effects of membrane surface potential on the uptake of anionic compounds by rat intestinal brush-border membrane vesicles were investigated. The uptake amount of all tested anionic compounds (ceftibuten, cefixime, benzylpenicillin, s-1006 and rentiapril) in the neutral medium (pH 7.5) was lower than that in the acidic medium (pH 5.5). Changes in surface potential of brush-border membrane vesicles were monitored using a fluorescence dye, 8-anilino-1-naphthalenesulfonate (ANS), and the results suggested an increase of a negative charge on the membrane surface proportional to the increase of the pH of medium. A good correlation was observed between the initial uptake rate of all tested anionic compounds and relative membrane surface potential monitored by ANS. Moreover, the uptake of cefixime by artificial liposome made from PC containing various amount of DPPS was measured. The uptake value of cefixime was decreased in proportion to an increase of DPPS content. These results suggest that the permeation of anionic compounds across intestinal brush-border membrane is dependent on surface potential originate in the surface negative charge.

The transport mechanisms of organic cations and their zwitterionic derivatives across rat intestinal brush-border membrane. II. Comparison of the membrane potential effect on the uptake by membrane vesicles
Ken Iseki, Mitsuru Sugawara, Nobutaka Saitoh, Katsumi Miyazaki
BBA - Biomembranes, 1152, 1, 9, 14, 1993年10月10日, ［査読有り］
英語, 研究論文（学術雑誌）, Further investigation of organic cation transport mechanisms were continued using rat intestinal brush-border membranes following our previous report [1,2]. The net uptake of organic cations was superior to that of their zwitterionic derivatives. This result agreed with the absorption behaviour of these compounds from rat intestinal loop. The uptake of tyramine and 5-benzyloxytryptamine was significantly stimulated by the valinomycin-generated K+-diffusion potential (inside-negative). On the other hand, the uptake of zwitterionic derivatives was not affected by the valinomycin-induced K+-diffusion potential. The voltage-clamped brush-border membrane vesicles exhibited a complete disappearance of the overshoot-uptake of organic cations. Therefore, this permeation mechanism across the intestinal brush-border membrane seems to be different from the well-known H+-antiport system of organic cation found in other organs such as kidney and liver, and depends upon an inside-negative H+- or K+-diffusion potential. © 1993.

The Transport Mechanisms of Organic Cations and Their Zwitterionic Derivatives across Rat Intestinal Brush-Border Membrane. 2. Comparison of the Membrane Potential Effect on the Uptake by Membrane Vesicles
Iseki K, Sugawara M, Saitoh N, Miyazaki K
Biochim. Biophys. Acta, 1152, 1, 9, 14, 1993年10月, ［査読有り］
英語, 研究論文（学術雑誌）

THE TRANSPORT MECHANISMS OF ORGANIC CATIONS AND THEIR ZWITTERIONIC DERIVATIVES ACROSS RAT INTESTINAL BRUSH-BORDER MEMBRANE .2. COMPARISON OF THE MEMBRANE-POTENTIAL EFFECT ON THE UPTAKE BY MEMBRANE-VESICLES
K ISEKI, M SUGAWARA, N SAITOH, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA, 1152, 1, 9, 14, ELSEVIER SCIENCE BV, 1993年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Further investigation of organic cation transport mechanisms were continued using rat intestinal brush-border membranes following our previous report [1,2]. The net uptake of organic cations was superior to that of their zwitterionic derivatives. This result agreed with the absorption behaviour of these compounds from rat intestinal loop. The uptake of tyramine and 5-benzyloxytryptamine was significantly stimulated by the valinomycin-generated K+-diffusion potential (inside-negative). On the other hand, the uptake of zwitterionic derivatives was not affected by the valinomycin-induced K+-diffusion potential. The voltage-clamped brush-border membrane vesicles exhibited a complete disappearance of the overshoot-uptake of organic cations. Therefore, this permeation mechanism across the intestinal brush-border membrane seems to be different from the well-known H+-antiport system of organic cation found in other organs such as kidney and liver, and depends upon an inside-negative H+- or K+-diffusion potential.

The diversity of Na+-independent uptake systems for polyamines in rat intestinal brush-border membrane vesicles
Michiya Kobayashi, Ken Iseki, Mitsuru Sugawara, Katsumi Miyazaki
BBA - Biomembranes, 1151, 2, 161, 167, 1993年09月19日, ［査読有り］
英語, 研究論文（学術雑誌）, Na+-independent uptake rate and binding to the membrane surface of polyamines (spermine, spermidine and putrescine) have been characterized using rat small intestinal brush-border membrane vesicles. The uptake of spermine and spermidine was saturable (Km 30.4 μM and 148.1 μM, respectively), however, putrescine uptake was not saturable up to 8 mM. In contrast, the values of binding to the membrane surface of all polyamines were not saturable in the present studies. In Dixon plot analysis, spermine competitively inhibited the uptake rate of spermidine with a Ki value of 33.8 μM, while the putrescine inhibitory effect on the spermidine uptake rate was non-competitive (Ki 3.28 mM). These uptake systems were not affected by the valinomycin-induced K+-diffusion potential (inside negative). These results suggested that there were two different Na+-independent uptake systems for spermine and spermidine, as well as for putrescine, on this membrane. However, they were not the same as the electric potential-dependent uptake system for monocationic compounds. Furthermore, this uptake system for spermine and spermidine might not be a carrier protein, because the intravesicular spermine exhibited no trans-stimulation effect on the uptake of spermidine. © 1993.

The Diversity of Na+-Independent Uptake Systems for Polyamines in Rat Intestinal Brush-border Membrane Vesicles
Kobayashi M, Iseki K, Sugawara M, Miyazaki K
Biochim. Biophys. Acta, 1151, 2, 161, 167, 1993年09月, ［査読有り］
英語, 研究論文（学術雑誌）

THE DIVERSITY OF NA+-INDEPENDENT UPTAKE SYSTEMS FOR POLYAMINES IN RAT INTESTINAL BRUSH-BORDER MEMBRANE-VESICLES
M KOBAYASHI, K ISEKI, M SUGAWARA, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA, 1151, 2, 161, 167, ELSEVIER SCIENCE BV, 1993年09月, ［査読有り］
英語, 研究論文（学術雑誌）, Na+-independent uptake rate and binding to the, membrane surface of polyamines (spermine, spermidine and putrescine) have been characterized using rat small intestinal brush-border membrane vesicles. The uptake of spermine and spermidine was saturable (K(m) = 30.4 muM and 148.1 muM, respectively), however, putrescine uptake was not saturable up to 8 mM. In contrast, the values of binding to the membrane surface of all polyamines were not saturable in the present studies. In Dixon plot analysis, spermine competitively inhibited the uptake rate of spermidine with a K(i) value of 33.8 muM, while the putrescine inhibitory effect on the spermidine uptake rate was non-competitive (K(i) = 3.28 mM). These uptake systems were not affected by the valinomycin-induced K+-diffusion potential (inside negative). These results suggested that there were two different Na+-independent uptake systems for spermine and spermidine, as well as for putrescine, on this membrane. However, they were not the same as the electric potential-dependent uptake system for monocationic compounds. Furthermore, this uptake system for spermine and spermidine might not be a carrier protein, because the intravesicular spermine exhibited no trans-stimulation effect on the uptake of spermidine.

THE TRANSPORT MECHANISM OF AN ORGANIC CATION, DISOPYRAMIDE, BY BRUSH-BORDER MEMBRANES - COMPARISON BETWEEN RENAL-CORTEX AND SMALL-INTESTINE OF THE RAT
Y TAKAHASHI, T ITOH, M KOBAYASHI, M SUGAWARA, H SAITOH, K ISEKI, K MIYAZAKI, S MIYAZAKI, M TAKADA, Y KAWASHIMA
JOURNAL OF PHARMACY AND PHARMACOLOGY, 45, 5, 419, 424, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1993年05月, ［査読有り］
英語, 研究論文（学術雑誌）, The characteristics of disopyramide uptake in brush-border membrane vesicles isolated from rat renal cortex and small intestine were investigated. Transport of disopyramide into an osmotically reactive intravesicular space was observed with notable binding to the membrane surface. An outwardly directed H+ gradient stimulated disopyramide uptake, resulting in a transient uphill transport in both brush-border membranes. As for the renal brush-border membrane, the H+ gradient itself appeared to be the driving force for this stimulation of uptake. These findings suggest that disopyramide-H+ antiport is the mechanism of disopyramide action in renal cell membrane. The initial uptake was saturable (K(m) and V(max) of 68.0 muM and 1.25 nmol (mg protein)-1/30 s, respectively). The stimulation of disopyramide uptake by an outward H+ gradient in rat intestinal brush-border membrane was due to an interior negative H+-diffusion potential. A K+-diffusion potential (interior negative) enhanced disopyramide uptake. These results suggest that there are different mechanisms of disopyramide uptake for renal and intestinal brush-border membrane vesicles.

ウィルソン病治療薬トリエンチンの患者における血清中濃度推移と尿中排泄挙動
小林 道也, 長原 しのぶ, 菅原 満
TDM研究, 10, 2, 166, 171, (一社)日本TDM学会, 1993年04月, ［査読有り］
日本語, 研究論文（学術雑誌）

The transport mechanisms of organic cations and their zwitterionic derivatives across rat intestinal brush-border membrane. 1. Binding characteristics to the bio- and lipid-membranes
Ken Iseki, Mitsuru Sugawara, Nobutaka Saitoh, Katsumi Miyazaki
BBA - Biomembranes, 1146, 1, 121, 126, 1993年02月23日, ［査読有り］
英語, 研究論文（学術雑誌）, The uptake mechanisms of organic cations such as tryptamine, tyramine, 5-benzyloxytryptamine (BOTA) and their zwitterionic derivatives (tyrosine, tryptophan, 5-benzyloxytryptophan (BOTP)) by rat intestinal brush-border membrane vesicles and liposome containing phosphatidylserine were studied and compared. As compared to their zwitterionic derivatives, uptake rates by rat intestinal brush-border membrane of these three cations were far superior. The binding of cationic compounds to the brush-border membrane was also higher than those of their zwitterionic derivatives. Furthermore, the binding behaviour of BOTA and tryptamine to phospholipid liposome clearly amplified with increasing amounts of phosphatidylserine. In contrast, the contents of phosphatidylserine, a negatively charged phospholipid, exhibited no effects on the binding of zwitterionic derivatives (tryptophan and BOTP). The double-reciprocal plot of tryptamine binding with BOTA to liposome showed competitive inhibition. These results suggest that the binding of organic cations to the membrane lipid has a relatively high specificity despite the absence of membrane protein such as a transport-carrier in the liposome, and that the binding of cationic compounds plays an important role in the uptake to the cell membrane systems. © 1993.

THE TRANSPORT MECHANISMS OF ORGANIC CATIONS AND THEIR ZWITTERIONIC DERIVATIVES ACROSS RAT INTESTINAL BRUSH-BORDER MEMBRANE .1. BINDING CHARACTERISTICS TO THE BIO-MEMBRANES AND LIPID-MEMBRANES
K ISEKI, M SUGAWARA, N SAITOH, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA, 1146, 1, 121, 126, ELSEVIER SCIENCE BV, 1993年02月, ［査読有り］
英語, 研究論文（学術雑誌）, The uptake mechanisms of organic cations such as tryptamine, tyramine, 5-benzyloxytryptamine (BOTA) and their zwitterionic derivatives (tyrosine, tryptophan, 5-benzyloxytryptophan (BOTP)) by rat intestinal brush-border membrane vesicles and liposome containing phosphatidylserine were studied and compared. As compared to their zwitterionic derivatives, uptake rates by rat intestinal brush-border membrane of these three cations were far superior. The binding of cationic compounds to the brush-border membrane was also higher than those of their zwitterionic derivatives. Furthermore, the binding behaviour of BOTA and tryptamine to phospholipid liposome clearly amplified with increasing amounts of phosphatidylserine. In contrast, the contents of phosphatidylserine, a negatively charged phospholipid, exhibited no effects on the binding of zwitterionic derivatives (tryptophan and BOTP). The double-reciprocal plot of tryptamine binding with BOTA to liposome showed competitive inhibition. These results suggest that the binding of organic cations to the membrane lipid has a relatively high specificity despite the absence of membrane protein such as a transport-carrier in the liposome, and that the binding of cationic compounds plays an important role in the uptake to the cell membrane systems.

TRANSPORT CHARACTERISTICS OF CEPHALOSPORIN ANTIBIOTICS ACROSS INTESTINAL BRUSH-BORDER MEMBRANE IN MAN, RAT AND RABBIT
M SUGAWARA, T TODA, K ISEKI, K MIYAZAKI, H SHIROTO, Y KONDO, JI UCHINO
JOURNAL OF PHARMACY AND PHARMACOLOGY, 44, 12, 968, 972, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1992年12月, ［査読有り］
英語, 研究論文（学術雑誌）, The uptake of orally active cephalosporins, ceftibuten and cephradine, by intestinal brush-border membrane vesicles isolated from man, rat and rabbit was studied. In the presence of an inward H+ gradient, ceftibuten but not cephradine was taken up into intestinal brush-border membrane vesicles of man and rat against the concentration gradient (overshoot phenomenon). In rabbit jejunal brush-border membrane vesicles, the uptake of both cephalosporins in the presence of an inward H+ gradient exhibited the overshoot phenomenon. In human and rat vesicles, the initial uptake of ceftibuten was strongly inhibited by compound V, an analogue of ceftibuten, but the uptake of cephradine was not affected by any of the cephalosporins tested, whereas in the rabbit brush-border membrane vesicles, initial uptake of both ceftibuten and cephradine were markedly inhibited by all cephalosporins and dipeptides used. These results suggest that the transport characteristics of human and rat intestinal brush-border membrane for cephalosporins are comparable, and that rabbit is an inadequate animal for investigating the transport characteristics of beta-lactam antibiotics.

Carrier-mediated transport system for choline and its related quaternary ammonium compounds on rat intestinal brush-border membrane
Hiroshi Saitoh, Michiya Kobayashi, Mitsuru Sugawara, Ken Iseki, Katsumi Miyazaki
BBA - Biomembranes, 1112, 1, 153, 160, 1992年11月23日, ［査読有り］
英語, 研究論文（学術雑誌）, The characteristics of the intestinal transport system for choline were investigated using isolated brush-border membrane vesicles from rat small intestine. In spite of the diminutive lipid solubility, the uptake of choline by membrane vesicles reflected smooth permeation into intravesicular space rather than the binding to the membrane surface. Physiological conditions, present in the intact intestine, such as an inward-directed Na+ or H+ gradient and inside negative membrane potentials, didn't directly involve in choline transport across the brush-border membrane. Moreover, an outward-directed H+ gradient had no significant effect on the time course of choline transport. However, in the absence of a driving-force, the initial uptake of choline exhibited a saturable manner. A kinetic analysis of the initial uptake rate gave an apparent Km of 159 μM. Furthermore, unlabeled choline caused both cis-inhibition and trans-stimulation for labeled choline transport, suggesting the existence of a carrier-mediated transport system for choline, classified as so-called 'facilitated diffusion'. Since tetramethylammonium, acetylcholine, and N1-methylnicotinamide caused both cis-inhibition and trans-stimulation, they appear to be accepted as the substrate of choline carrier. On the other hand, quaternary ammonium compounds (QACs) such as those which possessed hydrophobic parts in their molecules exhibited only cis-inhibition. They also inhibited Na+-dependent d-glucose transport, indicating that they influenced various carrier-mediated transport systems non-specifically due to interaction with the membrane. These findings strongly suggest that the choline transport system on the brush-border membrane of rat intestine recognizes only small molecular QACs as its substrate. © 1992.

Membrane-potential-dependent uptake of tryptamine by rat intestinal brush-border membrane vesicles
Mitsuru Sugawara, Makoto Sasaki, Ken Iseki, Katsumi Miyazaki
BBA - Biomembranes, 1111, 2, 145, 150, 1992年11月09日, ［査読有り］
英語, 研究論文（学術雑誌）, The effect of membrane potential on the uptake of tryptamine, an organic cation, by rat intestinal brush-border membrane vesicles was studied. In the presence of an outwardly directed H+-gradient, the initial uptake of tryptamine was stimulated remarkably and the overshoot phenomenon was observed. In contrast, the uptake was depressed by an inwardly-directed H+-gradient. The effect of H+-gradient on the uptake of tryptamine was maintained in the presence of FCCP, whereas it vanished when voltage-clamped vesicles were used. Moreover, the uptake of tryptamine was linearly augmented with increase of the valinomycin-induced inside-negative K+ diffusion potential. These results suggest that tryptamine is taken up into intestinal brush-border membrane vesicles depends upon the ionic diffusion potential. The effect of several indole derivatives and amine compounds on the uptake of tryptamine was also examined. The uptake of tryptamine was inibited by all amine compounds used, but anionic and zwitterionic compounds had no effect, suggesting that these amines amines interact on brush-border membrane and cause an inhibitory effect. © 1992.

CARRIER-MEDIATED TRANSPORT-SYSTEM FOR CHOLINE AND ITS RELATED QUATERNARY AMMONIUM-COMPOUNDS ON RAT INTESTINAL BRUSH-BORDER MEMBRANE
H SAITOH, M KOBAYASHI, M SUGAWARA, K ISEKI, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA, 1112, 1, 153, 160, ELSEVIER SCIENCE BV, 1992年11月, ［査読有り］
英語, 研究論文（学術雑誌）, The characteristics of the intestinal transport system for choline were investigated using isolated brush-border membrane vesicles from rat small intestine. In spite of the diminutive lipid solubility, the uptake of choline by membrane vesicles reflected smooth permeation into intravesicular space rather than the binding to the membrane surface. Physiological conditions, present in the intact intestine, such as an inward-directed Na+ or H+ gradient and inside negative membrane potentials, didn't directly involve in choline transport across the brush-border membrane. Moreover, an outward-directed H+ gradient had no significant effect on the time course of choline transport. However, in the absence of a driving-force,the initial uptake of choline exhibited a saturable manner. A kinetic analysis of the initial uptake rate gave an apparent K(m) of 159 muM. Furthermore, unlabeled choline caused both cis-inhibition and trans-stimulation for labeled choline transport, suggesting the existence of a carrier-mediated transport system for choline, classified as so-called 'facilitated diffusion'. Since tetramethylammonium, acetylcholine, and N1-methylnicotinamide tinamide caused both cis-inhibition and trans-stimulation, they appear to be accepted as the substrate of choline carrier. On the other hand, quaternary ammonium compounds (QACs) such as those which possessed hydrophobic parts in their molecules exhibited only cis-inhibition. They also inhibited Na+-dependent D-glucose transport, indicating that they influenced various carrier-mediated transport systems non-specifically due to interaction with the membrane. These findings strongly suggest that the choline transport system on the brush-border membrane of rat intestine recognizes only small molecular QACs as its substrate.

Membrane-Potential-Dependent Uptake of Tryptamine by Rat Intestinal Brush-Border Membrane Vesicles
Sugawara M, Sasaki M, Iseki K, Miyazaki K
Biochim. Biophys. Acta, 1111, 2, 145, 150, 1992年11月, ［査読有り］
英語, 研究論文（学術雑誌）

Rapid and Simple Method for the Determination of α1-Acid Glycoprotein in Serum By Liquid Chromatography
Kishino S, Zai D.S, Sugawara M, Iseki K, Miyazaki K
J. Chromatogr., 582, 1-2, 246, 248, ELSEVIER SCIENCE BV, 1992年11月, ［査読有り］
英語, 研究論文（学術雑誌）, A rapid and simple method for the determination of alpha1-acid glycoprotein (AAG) in serum was developed by using an anion-exchange column for clean-up of serum and a hydroxyapatite column for high-performance liquid chromatography (HPLC). A good correlation was observed between this HPLC method and the conventional radial immunodiffusion method. The method may also be used to determine the AAG concentration in the serum of experimental animals.

MEMBRANE-POTENTIAL-DEPENDENT UPTAKE OF TRYPTAMINE BY RAT INTESTINAL BRUSH-BORDER MEMBRANE-VESICLES
M SUGAWARA, M SASAKI, K ISEKI, K MIYAZAKI
BIOCHIMICA ET BIOPHYSICA ACTA, 1111, 2, 145, 150, ELSEVIER SCIENCE BV, 1992年11月, ［査読有り］
英語, 研究論文（学術雑誌）, The effect of membrane potential on the uptake of tryptamine, an organic cation, by rat intestinal brush-border membrane vesicles was studied. In the presence of an outwardly directed H+-gradient, the initial uptake of tryptamine was stimulated remarkably and the overshoot phenomenon was observed. In contrast, the uptake was depressed by an inwardly-directed H+-gradient. The effect of H+-gradient on the uptake of tryptamine was maintained in the presence of FCCP, whereas it vanished when voltage-clamped vesicles were used. Moreover, the uptake of tryptamine was linearly augmented with increase of the valinomycin-induced inside-negative K+ diffusion potential. These results suggest that tryptamine is taken up into intestinal brush-border membrane vesicles depends upon the ionic diffusion potential. The effect of several indole derivatives and amine compounds on the uptake of tryptamine was also examined. The uptake of tryptamine was inhibited by all amine compounds used, but anionic and zwitterionic compounds had no effect, suggesting that these amines interact on brush-border membrane and cause an inhibitory effect.

ニコランジルの血中微量定量法と血中動態　　　　　　　　　　　　　　　
岸野 吏志, 菅原 満, 井関 健
TDM研究, 9, 2, 94, 100, (一社)日本TDM学会, 1992年09月, ［査読有り］
日本語, 研究論文（学術雑誌）

THE PH DEPENDENT UPTAKE OF ENOXACIN BY RAT INTESTINAL BRUSH-BORDER MEMBRANE-VESICLES
K ISEKI, T HIRANO, Y FUKUSHI, Y KITAMURA, S MIYAZAKI, M TAKADA, M SUGAWARA, H SAITOH, K MIYAZAKI
JOURNAL OF PHARMACY AND PHARMACOLOGY, 44, 9, 722, 726, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1992年09月, ［査読有り］
英語, 研究論文（学術雑誌）, The mechanism of the intestinal transport of enoxacin, an orally active fluoroquinolone antibiotic, has been investigated using brush-border membrane vesicles isolated from rat small intestine. The initial rate and time-course of enoxacin uptake were considerably dependent upon the medium pH (pH 5.5 > pH 7.5) and upon the percent ionization of the carboxyl group (pK(a) 6.2, anionic charge), namely, the degree of uptake of cationic form was higher than that of the zwitterionic form. There was evidence of transport into the intravesicular space as shown by the effect of extravesicular medium osmolarity on enoxacin uptake at steady state (30 min). This transport across the brush-border membrane was stimulated by the valinomycin-induced K+-diffusion potential (interior negative) and an outward H+-diffusion potential. Furthermore, changing the pH of the medium from 5-5 to 7-5 significantly decreased the effect of valinomycin-induced K+ -diffusion potential on the enoxacin uptake. These results suggest that the uptake behaviour of the cationic form of enoxacin plays an important role in the intestinal absorption process of enoxacin.

UPTAKE CHARACTERISTICS OF POLYAMINES INTO RAT INTESTINAL BRUSH-BORDER MEMBRANE-VESICLES
M KOBAYASHI, M SUGAWARA, K ISEKI, K MIYAZAKI
JOURNAL OF PHARMACOBIO-DYNAMICS, 15, 6, S67, S67, PHARMACEUTICAL SOC JAPAN, 1992年06月, ［査読有り］
英語, 研究論文（学術雑誌）

TRANSPORT CHARACTERISTICS OF CEFTIBUTEN, CEFIXIME AND CEPHALEXIN ACROSS HUMAN JEJUNAL BRUSH-BORDER MEMBRANE
M SUGAWARA, K ISEKI, K MIYAZAKI, H SHIROTO, Y KONDO, JI UCHINO
JOURNAL OF PHARMACY AND PHARMACOLOGY, 43, 12, 882, 884, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1991年12月, ［査読有り］
英語, 研究論文（学術雑誌）, The transport characteristics of orally active cephalosporins, ceftibuten, cefixime and cephalexin have been examined using brush border membrane vesicles isolated from human jejunum. In the initial uptake of ceftibuten, the stimulation and overshoot phenomena were observed in the presence of an inward H+ gradient. Effects of H+ gradient on the uptake of cefixime and cephalexin were low and no overshoot was observed. These transport characteristics, especially uphill transport phenomena, were in agreement with previous results obtained from rat intestinal brush-border membrane vesicles and suggest that these beta-lactam antibiotics are absorbed by different transport systems, despite their similar molecular structures.

H+ Coupled Transport of Orally Active Cephalosporins Lacking an α-Amino Group across Brush-Border Membrane Vesicles from Rat Small Intestine
Sugawara M, Iseki K, Miyazaki K
J. Pharm. Pharmacol., 43, 6, 433, 435, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1991年06月, ［査読有り］
英語, 研究論文（学術雑誌）, The effect of an inwardly directed H+ gradient on the transport characteristics of ceftibuten, cefixime and analogues of ceftibuten in rat intestinal brush-border membrane vesicles have been investigated. In the presence of a transmembrane H+ gradient, ceftibuten and its analogues exhibited a peak to equilibrium overshoot and an accumulation in the vesicles against the concentration gradient. However, the uptake of cefixime and S-1006 [ (6R, 7R)-(7-[ (Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-8-oxo-3-carbamoyloxy-methyl-5-thia-1-azabicyclo [4,2,0]oct-2-ene-2-carboxylic acid), which lacks a carboxyl group at position 4 of carboxyethylidene structure, exhibited no overshoot, although the equilibrium uptake was increased by a H+ gradient. The equilibrium uptake was dependent on the pH of the final incubation medium and the H+ gradient. These data suggested that the orally active cephalosporins were transported into rat intestinal brush-border membrane by the transmembrane H+ gradient and the pH of the medium.

ウィルソン病治療薬トリエチレンテトラミンのラットにおける消化管吸収と尿中排泄
小林 道也, 菅原 満, 斎藤 浩司
薬学雑誌, 110, 10, 759, 763, (公社)日本薬学会, 1990年10月, ［査読有り］
日本語, 研究論文（学術雑誌）, トリエンチンのより有効な投与方法を確立するための基礎的知見を得ることを目的として,ラットにおける消化管吸収および尿中排泄について検討を行った.小腸からの吸収では,トリエンチンの1時間における平均吸収率は空腸上部で42.0%,回腸部で22.5%であった.tight junction blockerであるTAPの共存下では空腸上部でのみ吸収が阻害され,回腸部では全く影響なかった.が,空腸上部でも阻害率は全吸収量の27%であり,消化管でのトリエンチンの吸収過程は小腸の上皮細胞膜の透過が主であることが示唆された.小腸刷子縁膜(BBM)に対する結合を調べると,トリエンチンは無機イオン(Na+, K+, Ca2+, Mg2+, Cu2+)非存在下ではアミノ糖抗生物質アミカシンと同程度に強く結合した.が,無機イオン存在下では結合は強く阻害され,トリエンチンのBBMに対する結合が静電気的なものであることを示唆する.食餌による吸収挙動の変化では,非絶食時の血中濃度推移は絶食時と比較して有意に低かった.トリエンチン経口投与後24時間に排泄された尿中未変化体は投与量の3%であったが,加水分解尿中のトリエンチンの総量は約35%と多く,トリエンチンの経口投与後の低い血漿中濃度は吸収性が低いことによるだけでなく,代謝を受けることにもよると考えられた.以上からトリエンチンの経口投与後の吸収は食餌内容により大きく変動すると考えられた

INTESTINAL-ABSORPTION AND URINARY-EXCRETION OF TRIETHYLENETETRAMINE FOR WILSONS-DISEASE IN RAT
M KOBAYASHI, M SUGAWARA, H SAITOH, K ISEKI, K MIYAZAKI
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, 110, 10, 759, 763, PHARMACEUTICAL SOC JAPAN, 1990年10月, ［査読有り］
日本語, 研究論文（学術雑誌）

Contribution of Passive Transport Mechanisms to the Intestinal Absorption of β-Lactam Antibiotics
Sugawara M, Saitoh H, Iseki K, Miyazaki K, Arita T
J. Pharm. Pharmacol., 42, 5, 314, 318, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1990年05月, ［査読有り］
英語, 研究論文（学術雑誌）, Abstract— The transport characteristics of aminopenicillins (ampicillin and amoxicillin), aminocephalosporins (cephalexin, cephradine and cefadroxil) and cefazolin have been compared with those of an actively transported substance (D‐glucose) and a passively transported substance (L‐glucose). Although the initial uptake of the aminocephalosporins was stimulated in the presence of an inward H+ gradient, there was no overshoot in the uptake of any of the drugs tested, even in the presence of an H+ gradient. Also, the time course and the degree of uptake of these drugs were similar to those of L‐glucose, especially in the absence of an H+ gradient. These results suggest that the β‐lactam antibiotics tested, like L‐glucose, pass through the rat intestinal brush border membrane mainly by passive diffusion. However, the differences in absorption between these drugs, like the differences in their disappearance from a proximal loop of rat intestine, cannot be explained by a simple permeation process alone. 1990 Royal Pharmaceutical Society of Great Britain

Mechanism of gastrointestinal absorption of β-lactam antibiotics - contribution of passive diffusion to the BBM permeation process -
M. Sugawara, K. Iseki, H. Saitoh, K. Miyazaki, T. Arita
Journal of Pharmacobio-Dynamics, 13, 4, 1990年, ［査読有り］, ［筆頭著者］
研究論文（国際会議プロシーディングス）

Comparison of Transport Characteristics of Amino β-Lactam Antibiotics and Dipeptides across Rat Intestinal Brush Border Membrane
Iseki K, Sugawara M, Saitoh H, Miyazaki K, Arita T
J. Pharm. Pharmacol., 41, 9, 628, 632, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1989年09月, ［査読有り］
英語, 研究論文（学術雑誌）, The transport characteristics of amino β‐lactam antibiotics, ampicillin and cephradine, have been examined and compared with that of glycylglycine using brush border membrane vesicles isolated from rat small intestine. The initial rate of glycylglycine uptake was markedly stimulated in the presence of an inward H + gradient compared with the uptake rates in the absence of an H + gradient. With the same H + gradient the stimulation of cephradine uptake was lower and ampicillin uptake was not altered. Cephradine uptake, however, was greater than that of glycylglycine in both vesicular conditions ((pH)i > (pH)0 and (pH)i = (pH)0). Inhibitory effects of dipeptides, ampicillin and cephradine on the initial uptake of glycylglycine were also examined. Glycylglycine uptake was significantly decreased in the presence of L‐phenylalanylglycine or carnosine. Ampicillin and cephradine did not alter the uptake of glycylglycine. These results suggest that the contribution of the inward H+ gradient to the permeation of ampicillin, cephradine and glycylglycine across the rat small intestinal brush border membranes is different for each of the substances examined. 1989 Royal Pharmaceutical Society of Great Britain

Effect of Chlorpromazine on the Permeability of β-Lactam Antibiotics across Rat Intestinal Brush Border Membrane Vesicles
Iseki K, Sugawara M, Saitoh H, Miyazaki K, Arita T
J. Pharm. Pharmacol., 40, 10, 701, 705, ROYAL PHARMACEUTICAL SOC GREAT BRITAIN, 1988年10月, ［査読有り］
英語, 研究論文（学術雑誌）, Abstract— The effect of chlorpromazine on the membrane permeability of β‐lactam antibiotics (benzylpenicillin, ampicillin, cephradine and cephalexin) and actively transported substances (glycylglycine and D‐glucose) has been studied using rat intestinal brush border membrane vesicles. Except for cephalexin, the initial uptakes at 25°C of these antibiotics were significantly enhanced in the presence of chlorpromazine. In contrast, the transport of glycylglycine and D‐glucose was significantly inhibited. These results suggest that the two groups, drugs and actively transported substances, have a different permeation process. The effect of chlorpromazine concentration on membrane lipid fluidity, as assessed by the fluorescence polarization of 1,6‐diphenyl‐1,3,5‐hexatriene (DPH) and 1‐anilino‐8‐naphthalene sulphonate (ANS), was also examined. The fluorescence polarization of ANS decreased with increasing concentration of chlorpromazine, while that of DPH increased suggesting an increase of membrane surface fluidity might affect the permeation of β‐lactam antibiotics and actively transported substances in a different manner. 1988 Royal Pharmaceutical Society of Great Britain

オレキシン受容体拮抗薬のUPLC/MS/MS定量法構築とヒト乳汁移行性評価への応用　　　　　　　　　　　　　　　
石川 陽菜, 古堅 彩子, 西村 あや子, 馬詰 武, 青柳 亮一, 石川 修平, 鳴海 克哉, 岡本 敬介, 武隈 洋, 菅原 満, 小林 正紀, TDM研究, 41, 2, 149, 149, 2024年07月
(一社)日本TDM学会, 日本語

ヒアルロン酸4,6,8糖の同時定量法の確立　　　　　　　　　　　　　　　
佐藤 夕紀, 高林 直央, 青柳 空馬, 梨本 俊亮, 柏木 仁, 武隈 洋, 菅原 満, 日本薬剤学会年会講演要旨集, 39年会, 201, 201, 2024年05月
(公社)日本薬剤学会, 日本語

新たなTDM対象抗菌薬の最前線 オキサゾリジノン系抗菌薬のTDM　　　　　　　　　　　　　　　
武隈 洋, 井上 優希, 菅原 満, 日本化学療法学会雑誌, 72, 1, 61, 61, 2024年01月
(公社)日本化学療法学会, 日本語

食道胃接合部癌術後に食道狭窄を繰り返す症例に対して持効性注射薬カボテグラビル+リルピビリン(CAB+RPV)を導入した一例　　　　　　　　　　　　　　　
田澤 佑基, 遠藤 知之, 武隈 洋, 菅原 満, 日本エイズ学会誌, 25, 4, 483, 483, 2023年11月
(一社)日本エイズ学会, 日本語

医療事故の再発防止への提言(第3号)に対する取り組み(第2報) アドレナリン注射液0.3mg製剤の院内配置　　　　　　　　　　　　　　　
植田 孝介, 沖 洋充, 宮前 祐士, 久保田 康生, 岡本 千秋, 三上 薫子, 藤原 晶, 根岸 淳, 菅原 満, 南須原 康行, 医療の質・安全学会誌, 18, Suppl., 348, 348, 2023年11月
(一社)医療の質・安全学会, 日本語

採血に依らないTDM～Alternative samplingによるTDMに関する最新知見～ 唾液サンプリングに基づくTDMの実際
武隈 洋, 井上 優希, 菅原 満, TDM研究, 40, 2, 80, 80, 2023年06月
(一社)日本TDM学会, 日本語

肝機能障害患者に対するボリコナゾールの初期投与設計におけるAlbumin-Bilirubinスコアの有用性検証
梨本 俊亮, 今井 俊吾, 菅原 満, 武隈 洋, TDM研究, 40, 2, 175, 175, 2023年06月
(一社)日本TDM学会, 日本語

ブスルファンの著しい薬物動態変動が認められた小児の1例
山口 敦史, 武隈 洋, 仁木 加寿子, 平林 真介, 寺下 友佳代, 長谷河 昌孝, 長 祐子, 真部 淳, 菅原 満, TDM研究, 40, 2, 212, 212, 2023年06月
(一社)日本TDM学会, 日本語

マスメディアによる「くすりの危険性」に関する報道に起因した患者相談の実態調査　　　　　　　　　　　　　　　
今井 俊吾, 阿部 真也, 松井 洸, 柏木 仁, 佐藤 夕紀, 武隈 洋, 吉町 昌子, 菅原 満, 日本医薬品情報学会総会・学術大会講演要旨集, 25回, 132, 132, 2023年06月
(一社)日本医薬品情報学会, 日本語

肝機能障害患者に対するボリコナゾールの初期投与設計におけるAlbumin-Bilirubinスコアの有用性検証
梨本 俊亮, 今井 俊吾, 菅原 満, 武隈 洋, TDM研究, 40, 2, 175, 175, 2023年06月
(一社)日本TDM学会, 日本語

ブスルファンの著しい薬物動態変動が認められた小児の1例
山口 敦史, 武隈 洋, 仁木 加寿子, 平林 真介, 寺下 友佳代, 長谷河 昌孝, 長 祐子, 真部 淳, 菅原 満, TDM研究, 40, 2, 212, 212, 2023年06月
(一社)日本TDM学会, 日本語

医薬品の在庫管理における医療機器の導入効果　　　　　　　　　　　　　　　
山崎 浩二郎, 久保田 康生, 川岸 亨, 武隈 洋, 菅原 満, 北海道病院薬剤師会誌, 104, 17, 19, 2023年04月
近年バイオ医薬品の開発が進み、高額な医薬品が次々に上市されている。当院のような急性期病院においては、治療の変更や中止により、その高額な医薬品を使用しなくなることがあり、使用しなかった医薬品は不動在庫となり期限切れを起こすことがあり、これは病院経営的に大きな損失となる。そこで当院では、特に高額な冷所保管医薬品をリフレッシュできる医薬品専用保冷庫「Cubixx」(スズケングループ)を2019年2月に導入した。また、治療の変更や中止により投与中止となった一包化の内服薬を分別し再利用する目的で「TABSORT」(YUYAMA社)を2021年3月に導入した。Cubixx導入後3年間の各年度に7～9種類の医薬品をリフレッシュし、その効果として、薬価にして合計100万円以上の損失を未然に防ぐことができた。TABSORT導入後1年間に再利用することができた錠剤は延べ66701剤(薬価にして252万円)であった。, (一社)北海道病院薬剤師会, 日本語

Enterobacter cloacae感染症に対する第3世代セファロスポリンの有効性調査　　　　　　　　　　　　　　　
新沼 悠介, 鏡 圭介, 武隈 洋, 菅原 満, 日本化学療法学会雑誌, 71, 2, 181, 182, 2023年03月
(公社)日本化学療法学会, 日本語

【STOP!AMR 抗菌薬の適正使用を考える】歯科における最適な抗菌薬に関する考察　　　　　　　　　　　　　　　
山神 彰, 菅原 満, DENTAL DIAMOND, 48, 3, 46, 50, 2023年02月
(株)デンタルダイヤモンド社, 日本語

中分子創薬の課題克服を指向した構造-物性相関解析:光学活性シクロプロパン含有環状ペプチド類の構造と溶解性,受動拡散性,細胞膜透過性,P-gp基質性相関
宮地弘幸, 金光佳世子, 石井真由美, 渡邊恵里, 佐藤優希菜, 長田貴行, 山崎祐季, 柏木仁, 菅原満, 周東智, 重田育照, 渡邉瑞貴, 前仲勝実, 日本薬学会年会要旨集(Web), 143rd, 2023年

Cyclosporine A乳剤ならびに自己乳化型製剤の特性と経口吸収性評価
佐藤夕紀, 木下祐介, 上村聡, 丸山真吾, 武隈洋, 菅原満, 菅原満, 日本薬剤学会年会講演要旨集(CD-ROM), 38th, 2023年

大規模レセプトデータベースを活用した炎症性腸疾患患者におけるHBVスクリーニング検査と核酸アナログ製剤の医療経済学的検討
青柳亮一, 窪田篤人, 窪田篤人, 今井俊吾, 今井俊吾, 八木澤啓司, 沖洋充, 山崎浩二郎, 小島弘幸, 菅原満, 菅原満, 武隈洋, 日本薬学会年会要旨集(Web), 143rd, 2023年

成分栄養療法の制御性T細胞誘導に及ぼす抗菌薬併用の影響
窪田篤人, 村瀬渉, 今井俊吾, 菅原満, 武隈洋, 小島弘幸, 日本免疫毒性学会学術年会講演要旨集, 30th, 2023年

長時間作用型ベンゾジアゼピン(BZD)系薬のMilk/Plasma ratio(M/P比)およびRelative Infant Dose(RID)の算出
西村あや子, 古堅彩子, 馬詰武, 北村聖花, 武隈洋, 菅原満, 菅原満, 小林正紀, 医療薬学フォーラム講演要旨集, 31st, 2023年

経口投与されたヒアルロン酸オリゴ糖の同時定量法開発
高林直央, 佐藤夕紀, 柏木仁, 梨本俊亮, 武隈洋, 菅原満, 菅原満, バイオメディカル分析科学シンポジウム講演要旨集, 35th, 2023年

ドルテグラビル/アバカビル/ラミブジン(DTG/ABC/3TC)からDTG/3TCへの薬剤変更における薬剤師介入効果の検証　　　　　　　　　　　　　　　
田澤 佑基, 遠藤 知之, 武隈 洋, 菅原 満, 日本エイズ学会誌, 24, 4, 383, 383, 2022年11月
(一社)日本エイズ学会, 日本語

週刊誌に掲載された「危ないクスリ」に関する情報の整理とその適切性評価　　　　　　　　　　　　　　　
今井 俊吾, 柏木 仁, 佐藤 夕紀, 武隈 洋, 菅原 満, 日本医薬品情報学会総会・学術大会講演要旨集, 24回, 91, 91, 2022年06月
(一社)日本医薬品情報学会, 日本語

サーベイランスシステムJ-SIPHE(感染対策連携共通プラットフォーム)を用いた多施設解析-抗菌薬使用量と耐性菌の関連　　　　　　　　　　　　　　　
鏡 圭介, 石黒 信久, 新沼 悠介, 武隈 洋, 菅原 満, 日本化学療法学会雑誌, 70, Suppl.A, 311, 311, 2022年05月
(公社)日本化学療法学会, 日本語

重症病態後の患者におけるエドキサバン関連出血の予測モデルの構築　　　　　　　　　　　　　　　
三上 龍生, 早川 峰司, 今井 俊吾, 前川 邦彦, 山崎 浩二郎, 菅原 満, 武隈 洋, 日本血栓止血学会誌, 33, 2, 269, 269, 2022年05月
(一社)日本血栓止血学会, 日本語

機械学習を活用した定常状態のAUC400-600mg・h/Lを目標とするバンコマイシン投与量推定モデルの構築
宮井 貴之, 今井 俊吾, 吉村 理恵, 柏木 仁, 佐藤 夕紀, 上野 英文, 武隈 洋, 菅原 満, TDM研究, 39, 2, 128, 128, 2022年05月
(一社)日本TDM学会, 日本語

乳児へのボリコナゾール投与中に、代謝機能の発達によると考えられる著しい血中濃度低下が認められた1例
山口 敦史, 田澤 佑基, 武隈 洋, 植木 将弘, 山田 雅文, 真鍋 淳, 菅原 満, TDM研究, 39, 2, 136, 136, 2022年05月
(一社)日本TDM学会, 日本語

重症患者におけるバンコマイシンの初期投与量決定のための実測クレアチニンクリアランスの臨床適用性　　　　　　　　　　　　　　　
三上 龍生, 今井 俊吾, 早川 峰司, 菅原 満, 武隈 洋, 日本薬学会年会要旨集, 142年会, 27G, am10, 2022年03月
(公社)日本薬学会, 日本語

大規模レセプトデータベースを用いたボリコナゾールの治療薬物モニタリング実施に関する実態調査　　　　　　　　　　　　　　　
宮井 貴之, 今井 俊吾, 百 賢二, 柏木 仁, 佐藤 夕紀, 菅原 満, 武隈 洋, 日本薬学会年会要旨集, 142年会, 27G, am09S, 2022年03月
(公社)日本薬学会, 日本語

がんの多剤耐性を克服する新規エトポシド誘導体の探索　　　　　　　　　　　　　　　
山田 隼大, 王子谷 健太, 柏木 仁, 佐藤 夕紀, 今井 俊吾, 宮地 弘幸, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 142年会, 28C, pm04S, 2022年03月
(公社)日本薬学会, 日本語

ビッグデータとデータマイニング手法を用いたリネゾリド誘発性血小板減少症の要因分析　　　　　　　　　　　　　　　
井上 優希, 武隈 洋, 宮井 貴之, 柏木 仁, 佐藤 夕紀, 菅原 満, 今井 俊吾, 日本薬学会年会要旨集, 142年会, 28H, pm13S, 2022年03月
(公社)日本薬学会, 日本語

レセプトデータベースを用いた糖尿病患者へのオランザピンの処方実態調査
山下慎介, 山下慎介, 今井俊吾, 今井俊吾, 百賢二, 百賢二, 柏木仁, 佐藤夕紀, 菅原満, 菅原満, 武隈洋, 日本医療薬学会年会講演要旨集(Web), 32, 2022年

LC/MS/MSを用いたリネゾリドならびにテジゾリドのヒト血漿中濃度同時定量法の確立
佐藤夕紀, 大聖貴之, 柏木仁, 今井俊吾, 武隈洋, 菅原満, 菅原満, 日本医療薬学会年会講演要旨集(Web), 32, 2022年

リネゾリド投与患者における嘔吐発現要因の探索
堤竹蔵, 堤竹蔵, 今井俊吾, 今井俊吾, 柏木仁, 佐藤夕紀, 菅原満, 菅原満, 菅原満, 武隈洋, 日本医療薬学会年会講演要旨集(Web), 32, 2022年

歯科領域における経口第3世代セフェム系抗菌薬減少戦略の評価:中断時系列分析
山神彰, 鳴海克哉, 齋藤佳敬, 古堅彩子, 今井俊吾, 北川善政, 大廣洋一, 高木諒, 武隈洋, 菅原満, 菅原満, 小林正紀, 小林正紀, 医療薬学フォーラム講演要旨集, 30th, 2022年

炎症性腸疾患の病態制御に対する免疫学的アプローチ
窪田 篤人, 寺崎 将, 小林 正紀, 室本 竜太, 青栁 亮一, 武隈 洋, 菅原 満, 小島 弘幸, 日本毒性学会学術年会, 49.1, Suppl., S39-5, S70, 2022年
はじめに

炎症性腸疾患（IBD）は、腸管の慢性炎症を呈する自己免疫疾患である。本邦における患者数は、近年増加の一途を辿り患者数は30万人を超えると推測されている。これまでの報告からIBDの病態形成には、遺伝的要因を基盤とした免疫機能、環境因子、腸内細菌叢など様々な因子が関与している。治療は内科的療法が主軸となり、抗炎症作用を有する 5-アミノサリチル酸（5-ASA）や免疫抑制剤などが用いられる。我々は、本邦における最大の疫学レセプトデータベースである JMDC Claims Database （累積母集団数1400万人）の2016年4月から2021年3月までの5年間に IBD と診断された全患者 44,328 名のデータを用い、治療傾向を調査した。その結果、頻度の高い治療として5-ASAや経口成分栄養（ED）療法が抽出された。



IBDと制御性T細胞

近年5-ASAは、既存の抗炎症機序の他に芳香族炭化水素受容体（AhR）を介して制御性T細胞（Treg）を誘導することが示唆された。更に、演者らは5-ASAがAhRの直接的なリガンドとなり、その結合部位について報告している（Kubota et al., Pharmacol. 2022）。そこで処方頻度の高いED療法についてもAhRに着目し、種々検討を行った。その結果、IBDモデルマウスに対するED療法は、腸管の炎症を抑制し、脾臓Tregの比率を有意に上昇させた。また、ED療法に含まれるトリプトファン（Trp）は、腸内細菌叢で代謝されAhRリガンドとなる事が知られていることから、Trpを強化したED療法をIBDモデルマウスに投与した。その結果、腸管の炎症抑制効果に加え、血中IL-10の上昇、TNF-αの抑制、脾臓Tregの上昇が認められた。本演題ではAhRに着目した免疫学的アプローチがIBDの病態制御の一助となることを紹介したい。, 日本毒性学会, 日本語

がん治療医・緩和ケアスタッフを対象としたターミナルケア態度尺度を用いた意識調査　　　　　　　　　　　　　　　
熊井 正貴, 加藤 信太郎, 小柳 遼, 敦賀 健吉, 伊藤 陽一, 山田 武宏, 川本 泰之, 武隈 洋, 菅原 満, 小松 嘉人, Palliative Care Research, 16, Suppl._Hokkaido, S492, S492, 2021年10月
(NPO)日本緩和医療学会, 日本語

がん治療医・緩和ケアスタッフを対象としたターミナルケア態度尺度を用いた意識調査　　　　　　　　　　　　　　　
熊井 正貴, 加藤 信太郎, 小柳 遼, 敦賀 健吉, 伊藤 陽一, 山田 武宏, 川本 泰之, 武隈 洋, 菅原 満, 小松 嘉人, Palliative Care Research, 16, Suppl._Hokkaido, S492, S492, 2021年10月
(NPO)日本緩和医療学会, 日本語

北海道版・令和元年度次世代薬剤師指導者研修会における研修6ヵ月後のアンケート調査による行動変容からの研修効果評価　　　　　　　　　　　　　　　
片山 真二, 伊藤 優, 岩尾 一生, 前田 直大, 宇野 雅樹, 野田 敏宏, 山田 武志, 五十君 篤哉, 菅原 満, 竹内 伸仁, 令和元年度次世代薬剤師指導者研修会WG, 日本薬剤師会学術大会講演要旨集, 54回, 214, 214, 2021年09月
(公社)日本薬剤師会, 日本語

北海道版・令和元年度次世代薬剤師指導者研修会における研修6ヵ月後のアンケート調査による行動変容からの研修効果評価　　　　　　　　　　　　　　　
片山 真二, 伊藤 優, 岩尾 一生, 前田 直大, 宇野 雅樹, 野田 敏宏, 山田 武志, 五十君 篤哉, 菅原 満, 竹内 伸仁, 令和元年度次世代薬剤師指導者研修会WG, 日本薬剤師会学術大会講演要旨集, 54回, 214, 214, 2021年09月
(公社)日本薬剤師会, 日本語

大規模レセプトデータベースを用いた日本におけるTriple Whammy処方の実態解明　　　　　　　　　　　　　　　
今井 俊吾, 百 賢二, 柏木 仁, 宮井 貴之, 菅原 満, 武隈 洋, 日本医薬品情報学会総会・学術大会講演要旨集, 23回, 78, 78, 2021年06月
(一社)日本医薬品情報学会, 日本語

オキシコドン徐放錠による悪心危険因子の解明と機械学習を用いたリスク推定モデルの構築
熊井 正貴, 今井 俊吾, 加藤 信太郎, 小柳 遼, 敦賀 健吉, 山田 武宏, 武隈 洋, 菅原 満, 日本臨床腫瘍薬学会雑誌, 20, 3, 3, 2021年05月
(一社)日本臨床腫瘍薬学会, 日本語

医療の質向上、臨床の薬剤師による研究推進を目指した医療ビッグデータの活用 JMDCレセプトデータベースを用いた臨床研究　　　　　　　　　　　　　　　
武隈 洋, 今井 俊吾, 菅原 満, 日本薬学会年会要旨集, 141年会, S13, 3, 2021年03月
(公社)日本薬学会, 日本語

若手薬学研究者で加速させる感染症トランスレーショナルリサーチ バンコマイシンによる腎機能障害リスクを投与開始前に推定するためのフローチャートの構築 感染症診療におけるデータマイニング手法の活用　　　　　　　　　　　　　　　
宮井 貴之, 今井 俊吾, 菅原 満, 日本薬学会年会要旨集, 141年会, GS01, 6, 2021年03月
(公社)日本薬学会, 日本語

卵黄レシチンを用いた乳剤化に適した化合物の物理化学的特性　　　　　　　　　　　　　　　
鳥山 竜也, 佐藤 夕紀, 柏木 仁, 今井 俊吾, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 141年会, 28V11, pm06S, 2021年03月
(公社)日本薬学会, 日本語

吸収トランスポーターの機能解析へのエンテロイドの応用　　　　　　　　　　　　　　　
島田 美紀子, 佐藤 夕紀, 柏木 仁, 今井 俊吾, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 141年会, 29V07, am05S, 2021年03月
(公社)日本薬学会, 日本語

医療の質向上、臨床の薬剤師による研究推進を目指した医療ビッグデータの活用 JMDCレセプトデータベースを用いた臨床研究　　　　　　　　　　　　　　　
武隈 洋, 今井 俊吾, 菅原 満, 日本薬学会年会要旨集, 141年会, S13, 3, 2021年03月
(公社)日本薬学会, 日本語

若手薬学研究者で加速させる感染症トランスレーショナルリサーチ バンコマイシンによる腎機能障害リスクを投与開始前に推定するためのフローチャートの構築 感染症診療におけるデータマイニング手法の活用　　　　　　　　　　　　　　　
宮井 貴之, 今井 俊吾, 菅原 満, 日本薬学会年会要旨集, 141年会, GS01, 6, 2021年03月
(公社)日本薬学会, 日本語

卵黄レシチンを用いた乳剤化に適した化合物の物理化学的特性　　　　　　　　　　　　　　　
鳥山 竜也, 佐藤 夕紀, 柏木 仁, 今井 俊吾, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 141年会, 28V11, pm06S, 2021年03月
(公社)日本薬学会, 日本語

吸収トランスポーターの機能解析へのエンテロイドの応用　　　　　　　　　　　　　　　
島田 美紀子, 佐藤 夕紀, 柏木 仁, 今井 俊吾, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 141年会, 29V07, am05S, 2021年03月
(公社)日本薬学会, 日本語

日本におけるコルヒチンと強力なCYP3A4阻害薬/P糖蛋白質阻害薬の併用実態の解明　　　　　　　　　　　　　　　
今井 俊吾, 百 賢二, 柏木 仁, 宮井 貴之, 菅原 満, 武隈 洋, 日本腎臓病薬物療法学会誌, 9, 特別号, S140, S140, 2020年11月
日本腎臓病薬物療法学会, 日本語

ASTによるカルバペネム系抗菌薬および抗MRSA薬のdaily reviewが抗菌薬使用量および患者アウトカムに与える影響　　　　　　　　　　　　　　　
鏡 圭介, 石黒 信久, 山田 武宏, 新沼 悠介, 武隈 洋, 菅原 満, 小山田 玲子, 渡邊 翼, 早坂 かすみ, 福元 達也, 岩崎 澄央, 瀧 圭介, 日本化学療法学会雑誌, 68, Suppl.A, 333, 333, 2020年09月
(公社)日本化学療法学会, 日本語

院内製造18F-FDGのエンドトキシン試験における反応干渉因子に関する検討　　　　　　　　　　　　　　　
小林 准, 西嶋 剣一, 大曲 茂生, 山崎 純一, 菊池 康子, 久下 裕司, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 140年会, 26I, pm21, 2020年03月
(公社)日本薬学会, 日本語

BCR-ABLチロシンキナーゼ阻害剤(TKI)の一時的曝露による持続的細胞増殖抑制効果の検討　　　　　　　　　　　　　　　
青山 剛, 武隈 洋, 今井 俊吾, 柏木 仁, 菅原 満, 日本薬学会年会要旨集, 140年会, 27Y, am01, 2020年03月
(公社)日本薬学会, 日本語

高齢者における肝薬物代謝能低下時の体組成変化　　　　　　　　　　　　　　　
蕪木 素代子, 吉村 恵理, 宮本 康史, 今井 俊吾, 柏木 仁, 上野 英文, 菅原 満, 武隈 洋, 日本薬学会年会要旨集, 140年会, 27Z, am11S, 2020年03月
(公社)日本薬学会, 日本語

シクロプロパン鎖導入環状ペプチド化合物の膜透過性および吸収性の評価　　　　　　　　　　　　　　　
加藤 七海, 植村 真衣, 松井 耕平, 渡邉 瑞貴, 武隈 洋, 周東 智, 菅原 満, 日本薬学会年会要旨集, 140年会, 27Z, pm13, 2020年03月
(公社)日本薬学会, 日本語

下顎埋伏智歯抜歯術におけるセフカペンピボキシルとアモキシシリンの手術部位感染予防効果の比較　　　　　　　　　　　　　　　
山神 彰, 小林 正紀, 山田 武宏, 北川 善政, 大廣 洋一, 佐藤 淳, 石黒 信久, 今井 俊吾, 武隈 洋, 菅原 満, 井関 健, 日本薬学会年会要旨集, 140年会, 28Z, am10S, 2020年03月
(公社)日本薬学会, 日本語

院内製造18F-FDGのエンドトキシン試験における反応干渉因子に関する検討　　　　　　　　　　　　　　　
小林 准, 西嶋 剣一, 大曲 茂生, 山崎 純一, 菊池 康子, 久下 裕司, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 140年会, 26I, pm21, 2020年03月
(公社)日本薬学会, 日本語

BCR-ABLチロシンキナーゼ阻害剤(TKI)の一時的曝露による持続的細胞増殖抑制効果の検討　　　　　　　　　　　　　　　
青山 剛, 武隈 洋, 今井 俊吾, 柏木 仁, 菅原 満, 日本薬学会年会要旨集, 140年会, 27Y, am01, 2020年03月
(公社)日本薬学会, 日本語

高齢者における肝薬物代謝能低下時の体組成変化　　　　　　　　　　　　　　　
蕪木 素代子, 吉村 恵理, 宮本 康史, 今井 俊吾, 柏木 仁, 上野 英文, 菅原 満, 武隈 洋, 日本薬学会年会要旨集, 140年会, 27Z, am11S, 2020年03月
(公社)日本薬学会, 日本語

シクロプロパン鎖導入環状ペプチド化合物の膜透過性および吸収性の評価　　　　　　　　　　　　　　　
加藤 七海, 植村 真衣, 松井 耕平, 渡邉 瑞貴, 武隈 洋, 周東 智, 菅原 満, 日本薬学会年会要旨集, 140年会, 27Z, pm13, 2020年03月
(公社)日本薬学会, 日本語

下顎埋伏智歯抜歯術におけるセフカペンピボキシルとアモキシシリンの手術部位感染予防効果の比較　　　　　　　　　　　　　　　
山神 彰, 小林 正紀, 山田 武宏, 北川 善政, 大廣 洋一, 佐藤 淳, 石黒 信久, 今井 俊吾, 武隈 洋, 菅原 満, 井関 健, 日本薬学会年会要旨集, 140年会, 28Z, am10S, 2020年03月
(公社)日本薬学会, 日本語

Xenopus laevis oocyteを用いたコレステロールトランスポーターNiemann-Pick C1-Like1(NPC1L1)発現系の構築
梨本俊亮, 八木沙織, 武田直樹, 野中美玖, 武隈洋, 菅原満, 菅原満, 佐藤夕紀, トランスポーター研究会年会抄録集, 15th, 2020年

医療事故の再発防止への提言(第3号)に対する取り組み アドレナリン注射液0.3mg製剤の院内配置　　　　　　　　　　　　　　　
沖 洋充, 山崎 浩二郎, 熊井 正貴, 古藤 幸子, 本田 秀子, 根岸 淳, 菅原 満, 南須原 康行, 医療の質・安全学会誌, 14, Suppl., 498, 498, 2019年11月
(一社)医療の質・安全学会, 日本語

外来化学療法における検査オーダ項目の事前確認及び提案の有益性　　　　　　　　　　　　　　　
大聖貴之, 西村紗綾, 山﨑浩二郎, 志賀弘康, 齋藤佳敬, 内山数貴, 坂本達彦, 武隈洋, 菅原満, 第24回 札幌病院薬剤師会会員発表会講演要旨集, 2019年11月

牛車腎気丸によるドセタキセル誘発性末梢神経障害の予防効果　　　　　　　　　　　　　　　
菅野 亮太, 齋藤 佳敬, 山下 啓子, 武隈 洋, 菅原 満, 第24回 札幌病院薬剤師会会員発表会講演要旨集, 2019年11月

monthlyTC施行時のアプレピタントによる消化器症状予防・軽減効果の評価　　　　　　　　　　　　　　　
渡辺祐子, 齋藤佳敬, 武隈洋, 菅原満, 第24回 札幌病院薬剤師会会員発表会講演要旨集, 2019年11月

Performance Status 不良群におけるナルデメジンの有効性の検証．
加藤信太郎, 小野田紘子, 今井俊吾, 熊井正貴, 武隈洋, 菅原満, 日本緩和医療学会 第2回関西支部学術大会, 142, 7, 755, 760, 2019年10月
performance status(PS)不良患者におけるナルデメジン(Nal)の有効性を検証した。対象期間にNalが投与された383例のうち解析対象患者は141例であり、そのうちPS良好群は113例、PS不良群は28例であった。投与1日目から7日目までにおけるNalの有効率はPS良好群が71.7%、PS不良群が71.4%であり、有意な差は認められなかった。Nal投与前後の1週間当たりの自発排便回数の変化はPS良好群が2.8回/週の増加、PS不良群が3.6回/週の増加であり、ともに有意に増加していた。治療早期におけるNalの有効率はPS良好群が61.1%、PS不良群が57.1%、治療効果判定期間における有効率は各々60.2%、71.4%であり、ともに有意な差は認められなかった。Nalの効果はPS不良群においてもPS良好群と差が認められないことが明らかとなった。, (公社)日本薬学会, 日本語

バンコマイシンの初回投与設計ノモグラム(抗菌薬TDMガイドライン2016)の臨床的検証
田中 寛之, 森岡 悠紀, 武隈 洋, 藤田 崇宏, 遠藤 雅之, 菅原 満, TDM研究, 36, 2, 179, 179, 2019年05月
(一社)日本TDM学会, 日本語

臨床製剤と薬学教育をめぐる現状と課題 薬剤学から臨床製剤を考える　　　　　　　　　　　　　　　
菅原 満, 日本薬学会年会要旨集, 139年会, 1, 258, 258, 2019年03月
(公社)日本薬学会, 日本語

門脈およびリンパ管への薬物移行を考慮した消化管吸収の評価
定村 樹, 佐藤 夕紀, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 139年会, 4, 61, 61, 2019年03月
(公社)日本薬学会, 日本語

エンテロイドを用いた薬物排出トランスポーターの機能解析
小関 千尋, 石川 岳彦, 佐藤 夕紀, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 139年会, 4, 68, 68, 2019年03月
(公社)日本薬学会, 日本語

Xenopus laevis oocytesを用いたNiemann-Pick C1-Like 1(NPC1L1)発現系の最適化
八木 沙織, 梨本 俊亮, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 139年会, 4, 68, 68, 2019年03月
(公社)日本薬学会, 日本語

薬学実務実習前後における薬学生のコミュニケーション分析 RIAS(Roter method of interaction process analysis)を用いて　　　　　　　　　　　　　　　
武隈 洋, 森 綾子, 小林 正紀, 山田 勇磨, 佐藤 夕紀, 鳴海 克哉, 古堅 彩子, 菅原 満, 日本薬学会年会要旨集, 139年会, 4, 212, 212, 2019年03月
(公社)日本薬学会, 日本語

エンテロイドは薬物排出トランスポーターの機能解析ツールになり得るか　　　　　　　　　　　　　　　
小関千尋, 石川岳彦, 佐藤夕紀, 武隈 洋, 菅原 満, 第32回北海道薬物作用談話会, 2018年07月
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

消化管活動性がニロチニブの吸収性に及ぼす影響
佐々木真彩, 青山剛, 佐藤夕紀, 武隈洋, 菅原満, 医療薬学フォーラム講演要旨集, 26th, 249, 2018年06月
日本語

テアニンの製剤に含有される成分によるテアニンの消化管吸収増大機構の解明　　　　　　　　　　　　　　　
佐藤 夕紀, 山口 和奎, 小川 美香子, 武隈 洋, 足立 知基, 櫻田 剛史, 中川 公太, 本城 政稔, 菅原 満, 日本薬剤学会年会講演要旨集, 33年会, 184, 184, 2018年05月
(公社)日本薬剤学会, 日本語

オキサ酸を用いた乳剤化によるクルクミンの吸収改善と消化管への影響の評価　　　　　　　　　　　　　　　
西村悠汰, 八巻義朗, 佐藤夕紀, 武隈 洋, 丸山真吾, 菅原 満, 日本薬学会北海道支部第145 回例会, 2018年05月
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

肝遊離細胞サンドイッチ培養法を用いたカルベジロールの輸送および代謝における光学異性体間相互作用の解析　　　　　　　　　　　　　　　
伊藤 圭祐, 佐々木 萌子, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 138年会, 4, 51, 51, 2018年03月
(公社)日本薬学会, 日本語

オキサ酸を乳化剤として用いたCoenzyme Q10乳剤の性質とその消化管吸収性　　　　　　　　　　　　　　　
八巻 義朗, 西村 悠汰, 横山 さや香, 佐藤 夕紀, 武隈 洋, 丸山 真吾, 菅原 満, 日本薬学会年会要旨集, 138年会, 4, 86, 86, 2018年03月
(公社)日本薬学会, 日本語

後期高齢者における腎機能推定式の乖離とその補正法の確立　　　　　　　　　　　　　　　
蕪木 素代子, 吉村 恵理, 小嶋 希望, 上野 英文, 菅原 満, 武隈 洋, 日本薬学会年会要旨集, 138年会, 4, 174, 174, 2018年03月
(公社)日本薬学会, 日本語

シクロプロパンの構造特性に基づく膜透過性環状ペプチドの設計と合成
植村 真衣, 加藤 七海, 松井 耕平, 桑原 智希, 渡邉 瑞貴, 福田 隼, 武隈 洋, 菅原 満, 周東 智, 日本薬学会年会要旨集, 138年会, 2, 116, 116, 2018年03月
(公社)日本薬学会, 日本語

肝遊離細胞サンドイッチ培養法を用いたカルベジロールの輸送および代謝における光学異性体間相互作用の解析
伊藤圭祐, 佐々木萌子, 佐藤夕紀, 鷲見正人, 武隈洋, 菅原満, 日本薬学会年会要旨集(CD-ROM), 138th, 4, ROMBUNNO.27C‐am03, 51, 2018年03月
(公社)日本薬学会, 日本語

小腸オルガノイドを利用した排出系トランスポータの基質関与探索ツールの構築
佐藤夕紀, 中村公則, 小関千尋, 石川岳彦, 島田美紀子, 横井友樹, 本間直幸, 森山隆則, 菅原満, トランスポーター研究会年会抄録集, 13th, 2018年

新しい錠剤包装ESOP(easy seal open pack)の使用感とその改良に向けた調査研究
佐藤夕紀, 梨本俊亮, 武隈洋, 平野卓哉, 野田敏宏, 須田範行, 井関健, 盛本修司, 菅原満, 日本医療薬学会年会講演要旨集(Web), 28, 2018年

高齢者における腎機能推定式の補正法の確立　　　　　　　　　　　　　　　
蕪木素代子, 武隈 洋, 吉村恵理, 小嶋希望, 上野博文, 菅原 満, 第31回北海道TDM研究会研究発表会, 2017年11月
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

ヒトK562細胞に対するBCR-ABLチロシンキナーゼインヒビター(TKIs)Washout後持続的細胞増殖抑制効果の検証　　　　　　　　　　　　　　　
青山 剛, 武隈 洋, 佐藤夕紀, 鷲見正人, 菅原 満, 第31回北海道TDM研究会研究発表会, 2017年11月
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

脳梗塞を合併したレビー小体型認知症に対してリバスチグミンからの切り替えで低用量長期間投与ガランタミンが有効だった1症例　　　　　　　　　　　　　　　
濱野 宏美, 土井 正剛, 武隈 洋, 菅原 満, 一木 崇宏, 日本薬剤師会学術大会講演要旨集, 50回, [P, 418], 2017年10月
(公社)日本薬剤師会, 日本語

【臓器摘出・切除の晩期合併症 手術歴のある患者で考慮すべきポイント総まとめ】臓器摘出・切除後の薬物動態!どこに注意すべきか?! 胃腸摘出・切除術後の薬物動態学的注意点
菅原 満, 薬局, 68, 9, 3026, 3031, 2017年08月
＜Key Points＞胃や小腸の切除やそれに伴う再建術により、薬物の消化管吸収に変動を及ぼす生理機能が影響を受ける。吸収やバイオアベイラビリティの増大や減少が認められている薬物があることから、それらの薬物では、治療効果の変動や副作用発現などを注意深くモニターする必要がある。(著者抄録), (株)南山堂, 日本語

ルテインの製剤化による消化管吸収改善　　　　　　　　　　　　　　　
定村樹, 佐藤夕紀, 梨本俊亮, 鷲見正人, 武隈洋, 菅原満, 日本薬学会北海道支部第144 回例会, 2017年05月
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

実務実習前後における薬学生のRIASによるコミュニケーション分析　　　　　　　　　　　　　　　
森 綾子, 武隈 洋, 小林正紀, 山田勇磨, 佐藤夕紀, 鳴海克哉, 古堅彩子, 菅原 満, 総合技術研究会2017東京大学, 2017年03月08日
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

オキサ酸を乳化剤として用いたCoenzyme Q10の乳剤化と消化管吸収改善　　　　　　　　　　　　　　　
横山 さや香, 宮下 真美, 佐藤 夕紀, 武隈 洋, 丸山 真吾, 菅原 満, 日本薬学会年会要旨集, 137年会, 4, 67, 67, 2017年03月
(公社)日本薬学会, 日本語

テアニン錠剤(速放錠・徐放錠)の溶出性および吸収性の変動要因　　　　　　　　　　　　　　　
山口 和奎, 佐藤 夕紀, 武隈 洋, 櫻田 剛史, 中川 公太, 本城 政稔, 菅原 満, 日本薬学会年会要旨集, 137年会, 4, 67, 67, 2017年03月
(公社)日本薬学会, 日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

シクロプロパンの構造特性に基づく環状ペプチド膜透過性の飛躍的向上
植村 真衣, 松井 耕平, 桑原 智希, 渡邉 瑞貴, 福田 隼, 加藤 七海, 武隈 洋, 菅原 満, 周東 智, 日本薬学会年会要旨集, 137年会, 2, 120, 120, 2017年03月
(公社)日本薬学会, 日本語

卵黄レシチンを用いた自己乳化製剤によるクルクミンの消化管吸収改善
宮下 真美, 横山 さや香, 佐藤 夕紀, 武隈 洋, 吉田 英人, 菅原 満, 日本薬学会年会要旨集, 137年会, 4, 67, 67, 2017年03月
(公社)日本薬学会, 日本語

肝遊離細胞サンドイッチ培養法を用いたカルベジロールのグルクロン酸抱合反応に及ぼす光学異性体相互作用の評価
佐々木 萌子, 武隈 洋, 佐藤 夕紀, 鷲見 正人, 菅原 満, 日本薬学会年会要旨集, 137年会, 4, 63, 63, 2017年03月
(公社)日本薬学会, 日本語

慢性骨髄性白血病治療薬ダサチニブの消化管吸収に及ぼす消化管内pHおよびトランスポーターの影響
助畑 歩, 武隈 洋, 鷲見 正人, 佐藤 夕紀, 菅原 満, 日本薬学会年会要旨集, 137年会, 4, 66, 66, 2017年03月
(公社)日本薬学会, 日本語

ダサチニブの週2回投与で分子遺伝学寛解に達成した一症例　　　　　　　　　　　　　　　
中村雄亮, 齊藤嘉津彦, 青山剛, 武隈 洋, 菅原 満, 第30回北海道TDM研究会研究発表会, 2016年11月26日
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

piperacillin/tazobactamとcefepimeの急性腎障害発症に関する後ろ向き観察 比較研究　　　　　　　　　　　　　　　
門村将太, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満, 福田由布子, 井藤達也, 第30回北海道TDM研究会研究発表会, 2016年11月26日
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

日本循環器学会/日本TDM学会合同ガイドライン(2013-2014年度合同研究班報告)【ダイジェスト版】 2015年版 循環器薬の薬物血中濃度モニタリングに関するガイドライン
青沼 和隆, 志賀 剛, 新 博次, 池田 隆徳, 市田 蕗子, 上野 和行, 越前 宏俊, 栄田 敏之, 清水 渉, 菅原 満, 土下 喜正, 土岐 浩介, 戸塚 恭一, 萩原 誠久, 長谷川 純一, 林 秀晴, 平尾 見三, 前田 頼伸, 松本 直樹, 渡邉 英一, 笠井 英史, 篠原 徳子, 杉山 篤, 鈴木 敦, 住友 直方, 関口 幸夫, 高橋 尚彦, 野上 昭彦, 橋口 正行, 平田 純生, 松本 宜明, 湯川 栄二, 伊藤 宏, 井上 博, 大江 透, 篠崎 公一, 田中 一彦, 本間 真人, 堀江 稔, 三浦 崇則, 日本循環器学会, 日本TDM学会, TDM研究, 33, 3, 123, 157, 2016年09月
(一社)日本TDM学会, 日本語

日本循環器学会/日本TDM学会合同ガイドライン(2013-2014年度合同研究班報告)【ダイジェスト版】 2015年版 循環器薬の薬物血中濃度モニタリングに関するガイドライン　　　　　　　　　　　　　　　
青沼 和隆, 志賀 剛, 新 博次, 池田 隆徳, 市田 蕗子, 上野 和行, 越前 宏俊, 栄田 敏之, 清水 渉, 菅原 満, 土下 喜正, 土岐 浩介, 戸塚 恭一, 萩原 誠久, 長谷川 純一, 林 秀晴, 平尾 見三, 前田 頼伸, 松本 直樹, 渡邉 英一, 笠井 英史, 篠原 徳子, 杉山 篤, 鈴木 敦, 住友 直方, 関口 幸夫, 高橋 尚彦, 野上 昭彦, 橋口 正行, 平田 純生, 松本 宜明, 湯川 栄二, 伊藤 宏, 井上 博, 大江 透, 篠崎 公一, 田中 一彦, 本間 真人, 堀江 稔, 三浦 崇則, 日本循環器学会, 日本TDM学会, TDM研究, 33, 3, 123, 157, 2016年09月
(一社)日本TDM学会, 日本語

パゾパニブの投与量と推定血中トラフ濃度の関連性の評価
田中 寛之, 平賀 博明, 武隈 洋, 三浪 圭太, 原林 透, 永森 聡, 遠藤 雅之, 菅原 満, 日本整形外科学会雑誌, 90, 6, S1214, S1214, 2016年06月
(公社)日本整形外科学会, 日本語

コレステロールを含有する乳剤によるコエンザイムQ10の吸収改善　　　　　　　　　　　　　　　
佐藤 夕紀, 八巻 義朗, 竹川 悠人, 武隈 洋, 菅原 満, 日本薬剤学会年会講演要旨集, 31年会, 186, 186, 2016年05月
(公社)日本薬剤学会, 日本語

イマチニブのTDMにより副作用軽減と治療継続が可能となった二重癌の一症例
元茂 拓法, 田中 寛之, 森岡 悠紀, 武隈 洋, 遠藤 雅之, 菅原 満, 黒澤 光俊, TDM研究, 33, 2, 194, 194, 2016年05月
(一社)日本TDM学会, 日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

先導的薬剤師養成に向けた実践的アドバンスト教育プログラムの共同開発 国立大学における実践的医療薬学教育プログラム及びチーム医療・地域医療プログラムの開発　　　　　　　　　　　　　　　
小澤 光一郎, 中嶋 幹郎, 菅原 満, 関根 祐子, 日本薬学会年会要旨集, 136年会, 1, 213, 213, 2016年03月
(公社)日本薬学会, 日本語

脂質異常症治療薬エゼチミブによるα-トコフェロールの消化管吸収抑制とその回避策　　　　　　　　　　　　　　　
梨本 俊亮, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 136年会, 4, 55, 55, 2016年03月
(公社)日本薬学会, 日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

小腸コレステロールトランスポーターNPC1L1 (Niemann-Pick C1-Like 1)を介したCoenzyme Q10の消化管吸収改善　　　　　　　　　　　　　　　
佐藤夕紀, 八巻義朗, 横山さや香, 竹川悠人, 鷲見正人, 武隈洋, 菅原満, 第13回日本コエンザイムQ協会研究会, 2016年02月02日
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

日本循環器学会/日本TDM学会合同ガイドライン(2013-2014年度合同研究班報告) 2015年版 循環器薬の薬物血中濃度モニタリングに関するガイドライン　　　　　　　　　　　　　　　
青沼 和隆, 志賀 剛, 新 博次, 池田 隆徳, 市田 蕗子, 上野 和行, 越前 宏俊, 栄田 敏之, 清水 渉, 菅原 満, 土下 喜正, 土岐 浩介, 戸塚 恭一, 萩原 誠久, 長谷川 純一, 林 秀晴, 平尾 見三, 前田 頼伸, 松本 直樹, 渡邉 英一, 笠井 英史, 篠原 徳子, 杉山 篤, 鈴木 敦, 住友 直方, 関口 幸夫, 高橋 尚彦, 野上 昭彦, 橋口 正行, 平田 純生, 松本 宜明, 湯川 栄二, 伊藤 宏, 井上 博, 大江 透, 篠崎 公一, 田中 一彦, 本間 真人, 堀江 稔, 三浦 崇則, 日本循環器学会, 日本TDM学会, 循環器病ガイドシリーズ, 2015, 循環器薬の薬物血中濃度モニタリングに関するガイドライン, 3, 54, 2016年02月
(一社)日本循環器学会, 日本語

日本循環器学会/日本TDM学会合同ガイドライン(2013-2014年度合同研究班報告)【ダイジェスト版】2015年版 循環器薬の薬物血中濃度モニタリングに関するガイドライン　　　　　　　　　　　　　　　
青沼 和隆, 志賀 剛, 新 博次, 池田 隆徳, 市田 蕗子, 上野 和行, 越前 宏俊, 栄田 敏之, 清水 渉, 菅原 満, 土下 喜正, 土岐 浩介, 戸塚 恭一, 萩原 誠久, 長谷川 純一, 林 秀晴, 平尾 見三, 前田 頼伸, 松本 直樹, 渡邉 英一, 笠井 英史, 篠原 徳子, 杉山 篤, 鈴木 敦, 住友 直方, 関口 幸夫, 高橋 尚彦, 野上 昭彦, 橋口 正行, 平田 純生, 松本 宜明, 湯川 栄二, 伊藤 宏, 井上 博, 大江 透, 篠崎 公一, 田中 一彦, 本間 真人, 堀江 稔, 三浦 崇則, 日本循環器学会, 日本TDM学会, 循環器病ガイドシリーズ, 2015, 循環器薬の薬物血中濃度モニタリングに関するガイドライン, 55, 89, 2016年02月
(一社)日本循環器学会, 日本語

α-トコフェロールの吸収動態に及ぼすエゼチミブの影響　　　　　　　　　　　　　　　
佐藤夕紀, 梨本俊亮, 武隈洋, 菅原満, 第27回ビタミンE研究会, 2016年01月08日
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

クロスポビドンを含む錠剤の製剤処方による溶出性の違い
武隈洋, 石坂悠, 佐藤夕紀, 鷲見正人, 菅原満, 日本医療薬学会年会講演要旨集(Web), 26, 2016年

薬剤師会と大学の連携が保険調剤薬局での無菌調剤業務の推進に及ぼす効果　　　　　　　　　　　　　　　
柴山 良彦, 竹内 伸仁, 菅原 満, 井関 健, 日本薬剤師会学術大会講演要旨集, 48回, 421, 421, 2015年11月
(公社)日本薬剤師会, 日本語

可溶性ローヤルゼリー蛋白質MRJP1の腸管透過性評価と吸収成分の生理機能の解析
本間 直幸, 山日 千明, 面 すみれ, 佐藤 夕紀, 菅原 満, 森山 隆則, 日本未病システム学会学術総会抄録集, 22回, 119, 119, 2015年09月
(一社)日本未病学会, 日本語

テアニン製剤(速放錠・徐放錠)を用いた溶出性および吸収性の検討　　　　　　　　　　　　　　　
山口和奎, 佐藤夕紀, 武隈 洋, 中川公太, 大野智弘, 本城政稔, 菅原 満, 第29回北海道薬物作用談話会, 2015年08月09日
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

アレルギー性咳嗽患者に対する抗アレルギー薬の適用と治療効果に関する疫学研究　　　　　　　　　　　　　　　
石坂 悠, 武隈 洋, 平野 卓哉, 野田 敏宏, 熊井 恵美, 菅原 満, 日本医薬品情報学会総会・学術大会講演要旨集, 18回, 73, 73, 2015年06月
(一社)日本医薬品情報学会, 日本語

造血幹細胞移植時の抗がん剤併用療法における投与量および薬物曝露順序の最適化
武隈 洋, 田澤 佑基, 臼窪 一平, 高田 一輝, 柴山 良彦, 重松 明男, 笠師 久美子, 豊嶋 崇徳, 井関 健, 菅原 満, 臨床薬理の進歩, 36, 142, 152, 2015年06月
造血幹細胞移植時の抗がん剤併用療法における投与量および薬物曝露順序の最適化について検討した。成人急性リンパ性白血病(ALL)およびその類縁疾患に対し、中等量エトポシド(VP-16)/シクロホスファミド(CY)/全身放射線照射(TBI)前処置を用いた同種造血幹細胞移植を施行した21例を対象とした。VP-16の薬物動態は個体差が大きく、最高血中濃度(Cmax)とサイトメガロウイルス(CMV)感染との関建性が示唆された。ROC曲線解析から、Cmaxのカットオフ値は80.8μg/mLと算出した。また、K-562/P-gp細胞への低濃度4-ヒドロペルオキシシクロホスファミドの事前曝露によりVP-16の感受性が高いS期の細胞が増大し、VP-16の殺細胞効果が増強することが示唆された。, (公財)臨床薬理研究振興財団, 日本語

TDMへの応用を目指した3種のチロシンキナーゼ阻害剤の血中濃度測定法の検証　　　　　　　　　　　　　　　
助畑 歩, 武隈 洋, 佐藤夕紀, 鷲見正人, 田中寛之, 遠藤 雅之, 菅原 満, 日本薬学会北海道支部第142回例会（札幌）, 2015年05月16日
日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

実務実習をより良くするために(12)実務実習を効果的に実施するための事前学習と実習後のアドバンストプログラムの開発
菅原 満, 武隈 洋, 柴山 良彦, 医薬ジャーナル, 51, 5, 145, 149, 2015年05月
医薬ジャーナル社, 日本語

実務実習をより良くするために 実務実習を効果的に実施するための事前学習と実習後のアドバンストプログラムの開発
菅原 満, 武隈 洋, 柴山 良彦, 井関 健, 医薬ジャーナル, 51, 5, 1381, 1385, 2015年05月
北海道大学では、薬剤師を対象とした生涯研修プログラム「医療薬学講座〜在宅医療を中心に〜」に参加した学生へのアンケート調査を行った。その結果より、関心の高かったバイタルサインやフィジカルアセスメントに関して、長期実務実習開始前にある程度の知識と技能を習得する必要があると考え、事前実習での学習プログラムについて充実を図ることとした。それに先立ち、附属病院薬剤部が企画した研究会に薬学部教員も参加し、実習に必要な項目と方法について検討、プログラムを作成した。一方、模擬患者養成事業で行っているシナリオ練習に、実務実習終了後の学生(大学院生を含む)が薬剤師役で参加し、より複雑な症例を取り入れることで、アドバンスト医療コミュニケーションプログラムとしてのトライアルとした。(著者抄録), (株)医薬ジャーナル社, 日本語

骨肉腫MAP療法における2-compartment modelによる非タンパク結合Platinum推定CmaxとCDDP腎毒性の予測
田中 寛之, 森岡 悠紀, 深井 雄太, 武隈 洋, 川口 啓之, 平賀 博明, 菅原 満, 遠藤 雅之, TDM研究, 32, 2, 151, 151, 2015年05月
(一社)日本TDM学会, 日本語

エゼチミブ(ゼチーア)が機能性食品成分α-トコフェロールの吸収に与える影響　　　　　　　　　　　　　　　
梨本 俊亮, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬剤学会年会講演要旨集, 30年会, 131, 131, 2015年05月
(公社)日本薬剤学会, 日本語

乳剤化によるコエンザイムQ10の消化管吸収改善　　　　　　　　　　　　　　　
佐藤 夕紀, 竹川 悠人, 能登 数馬, 武隈 洋, 菅原 満, 日本薬剤学会年会講演要旨集, 30年会, 136, 136, 2015年05月
(公社)日本薬剤学会, 日本語

耳鼻咽喉科領域におけるアレルギー性咳嗽患者に対する抗アレルギー薬の適用と治療効果
武隈 洋, 石坂 悠, 平野 卓哉, 野田 敏宏, 熊井 惠美, 菅原 満, アレルギー, 64, 3-4, 576, 576, 2015年04月
(一社)日本アレルギー学会, 日本語

先導的薬剤師養成に向けた実践的アドバンスト教育プログラムの共同開発 国立大学における「実践的医療薬学教育プログラム」および「チーム医療・地域医療プログラム」の開発　　　　　　　　　　　　　　　
小澤 光一郎, 中嶋 幹郎, 菅原 満, 関根 祐子, 日本薬学会年会要旨集, 135年会, 1, 231, 231, 2015年03月
(公社)日本薬学会, 日本語

Niemann-Pick C1 Like-1(NPC1L1)を標的とした乳剤化による難吸収性物質の吸収改善　　　　　　　　　　　　　　　
竹川 悠人, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 135年会, 4, 76, 76, 2015年03月
(公社)日本薬学会, 日本語

2種の血中テイコプラニン濃度測定キット間の測定値の相関性　　　　　　　　　　　　　　　
田中 寛之, 山田 武宏, 戸田 貴大, 小林 道也, 菅原 満, 猪爪 信夫, 日本化学療法学会雑誌, 63, 2, 254, 254, 2015年03月
(公社)日本化学療法学会, 日本語

【妊婦の薬物治療管理 リスクと不安を最小にするための基礎と実践】妊娠による生理変化と薬物動態 吸収過程
菅原 満, 薬局, 66, 1, 34, 35, 2015年01月
＜Key Points＞妊娠時における薬物吸収の変動に関しては、妊娠による生理的諸因子の変動に関連付けて説明されている場合が多い。対象となる薬物の物理化学的な性質や吸収のメカニズムを把握しておくことが重要である。(著者抄録), (株)南山堂, 日本語

ローヤルゼリー機能性成分の腸管透過性評価と吸収成分の生理機能の解析
本間 直幸, 山日 千明, 面 すみれ, 佐藤 夕紀, 菅原 満, 村田 清志, 山口 喜久二, 森山 隆則, 機能性食品と薬理栄養, 8, 5, 436, 436, 2014年12月
(株)インフォノーツパブリッシング, 日本語, 研究発表ペーパー・要旨（全国大会，その他学術会議）

UDP-グルクロン酸転移酵素の生細胞と細胞破砕液での代謝活性の比較　　　　　　　　　　　　　　　
池上由麻, 佐藤夕紀, 鷲見正人, 武隈洋, 菅原満, 第28回北海道TDM研究会研究発表会（札幌）, 2014年11月29日
研究発表ペーパー・要旨（全国大会，その他学術会議）

28-O4PM-10 アレルギー性咳嗽治療に用いられる抗アレルギー薬の使用実態 : 内科と耳鼻咽喉科の比較(薬物療法(その他)3,一般演題(口頭),新時代を拓く医療薬学フロンティア)
石坂 悠, 武隈 洋, 吉村 恵理, 吉田 憲史, 小嶋 希望, 上野 英文, 菅原 満, 日本医療薬学会年会講演要旨集, 24, 244, 244, 2014年08月25日
日本医療薬学会, 日本語

UGT1A1 p.P364L変異体および UGT2B7 p.P366L変異体の光学異性体認識性　　　　　　　　　　　　　　　
依田めぐみ, 佐藤夕紀, 鷲見正人, 武隈洋, 菅原満, 第28回北海道薬物作用談話会（札幌）, 2014年07月19日

抗ウイルス薬 リバビリンのトランスポーターを介した消化管吸収の解析　　　　　　　　　　　　　　　
早風郁美, 佐藤夕紀, 鷲見正人, 武隈洋, 菅原満, 第28回北海道薬物作用談話会（札幌）, 2014年07月19日

中等量エトポシド(VP‐16)/シクロホスファミド(CY)/全身放射線(TBI)前処置レジメンにおけるVP‐16のPK/PD解析による投与量の最適化に関する検討
田澤佑基, 武隈洋, 佐藤夕紀, 鷲見正人, 笠師久美子, 井関健, 菅原満, 医療薬学フォーラム講演要旨集, 22nd, 242, 2014年06月
日本語

細胞周期変化がエトポシド(VP-16)の殺細胞効果に与える影響　　　　　　　　　　　　　　　
田澤佑基, 吉岡美咲, 武隈 洋, 佐藤夕紀, 鷲見 正人, 菅原 満, 日本薬学会北海道支部第141回例会（札幌）, 2014年05月24日

臨床応用を目指したHPLC-UV法による血中imatinib定量法の確立
田中 寛之, 木村 雄太, 川口 啓之, 武隈 洋, 高崎 雅彦, 菅原 満, TDM研究, 31, 3, 169, 169, 2014年05月
(一社)日本TDM学会, 日本語

先導的薬剤師養成に向けた実践的アドバンスト教育プログラムの共同開発 実践的医療薬学教育プログラム及びチーム医療・地域医療プログラム　　　　　　　　　　　　　　　
菅原 満, 日本薬学会年会要旨集, 134年会, 1, 150, 150, 2014年03月
(公社)日本薬学会, 日本語

Coenzyme Q10の消化管吸収改善　　　　　　　　　　　　　　　
佐藤夕紀, 能登数馬, 竹川悠人, 鷲見正人, 武隈 洋, 菅原 満, 特定非営利活動法人 日本コエンザイムQ 協会 第11回研究会プログラム（東京）, 2014年01月28日

Caco-2細胞におけるNPC1L1を介したコレステロール輸送の特徴　　　　　　　　　　　　　　　
阿部沙也華, 佐藤夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 第27回北海道TDM研究会研究発表会（札幌）, 2013年11月30日

薬物曝露による細胞周期変化が細胞周期依存性の抗癌剤の作用に与える影響　　　　　　　　　　　　　　　
吉岡美咲, 田澤佑基, 佐藤夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 第27回北海道TDM研究会研究発表会（札幌）, 2013年11月30日

テアニンの体内動態および吸収機構の解明　　　　　　　　　　　　　　　
亀田佑生, 佐藤夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 第27回北海道TDM研究会研究発表会（札幌）, 2013年11月30日

土-10-O14-09 乳剤化による難吸収性物質の吸収改善 : コレステロール輸送担体NPC1L1の利用(薬物動態,一般演題(口頭)14,再興、再考、創ろう最高の医療の未来)
竹川 悠人, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本医療薬学会年会講演要旨集, 23, 219, 219, 2013年08月28日
日本医療薬学会, 日本語

抗アレルギー薬の使用実態調査およびそのアレルギー性咳嗽への適用に関する疫学的研究　　　　　　　　　　　　　　　
武隈 洋, 高地 里佳, 野田 敏宏, 平野 卓哉, 菅原 満, 日本医薬品情報学会総会・学術大会講演要旨集, 16回, 132, 132, 2013年08月
(一社)日本医薬品情報学会, 日本語

難吸収性ポリフェノールの乳剤化によるバイオアベイラビリティ改善　　　　　　　　　　　　　　　
星山博俊, 佐藤夕紀, 鷲見正人, 武隈洋, 菅原満, 第27回北海道薬物作用談話会（江別）, 2013年07月20日

Niemann-pick C1 Like-1 (NPC1L1) を介した難吸収性物質の吸収改善へのアプローチ　　　　　　　　　　　　　　　
竹川悠人, 佐藤夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬学会北海道支部第140回例会（札幌）, 2013年05月18日

熱力学的手法を用いた多剤排出輸送担体の基質探索の検討　　　　　　　　　　　　　　　
森岡悠紀, 鷲見正人, 佐藤夕紀, 武隈洋, 菅原満, 日本薬学会北海道支部第140回例会（札幌）, 2013年05月18日

hOATPs/rOatps を介するミコフェノール酸グルクロナイドの輸送特性の種差　　　　　　　　　　　　　　　
坂本達彦, 鷲見正人, 佐藤夕紀, 武隈洋, 菅原満, 日本薬学会北海道支部第140回例会（札幌）, 2013年05月

黄斑色素成分ルテインのヒト網膜上皮細胞内への取り込み機構の解明　　　　　　　　　　　　　　　
佐藤 夕紀, 近藤 有, 武隈 洋, 菅原 満, 日本薬剤学会年会講演要旨集, 28年会, 272, 272, 2013年04月
(公社)日本薬剤学会, 日本語

国立大学博士課程における「チーム医療・地域医療モデル教育プログラム」の開発　　　　　　　　　　　　　　　
関根 祐子, 菅原 満, 小澤 光一郎, 中嶋 幹郎, 日本薬学会年会要旨集, 133年会, 1, 270, 270, 2013年03月
(公社)日本薬学会, 日本語

ヌクレオシドトランスポーターの基質輸送に及ぼすエトポシドの影響
高田 一輝, 田澤 佑基, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 133年会, 4, 78, 78, 2013年03月
(公社)日本薬学会, 日本語

一包化調剤時におけるスタチン製剤の保存安定性
高地 里佳, 石坂 悠, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 133年会, 4, 153, 153, 2013年03月
(公社)日本薬学会, 日本語

シタラビンの白血病細胞内移行に対するエトポシドの影響　　　　　　　　　　　　　　　
高田一輝, 田澤佑基, 佐藤夕紀, 鷲見正人, 武隈洋, 菅原満, 第26回北海道TDM研究会研究発表会（札幌）, 2012年12月

テアニンの脳移行に関与するトランスポーター　　　　　　　　　　　　　　　
川守田渉, 亀田佑生, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満, 第26回北海道薬物作用談話会（札幌）, 2012年07月

粒子径に着目した CoQ10 の乳剤化による吸収改善　　　　　　　　　　　　　　　
能登数馬, 佐藤夕紀, 武隈 洋, 菅原 満, 日本薬学会北海道支部第138回例会（札幌）, 2012年06月

先導的薬剤師養成に向けた実践的アドバンスト教育プログラムの共同開発 国立大学における「実践的医療薬学教育プログラム」の開発　　　　　　　　　　　　　　　
中嶋 幹郎, 菅原 満, 関根 祐子, 小澤 光一郎, 日本薬学会年会要旨集, 132年会, 1, 190, 190, 2012年03月
(公社)日本薬学会, 日本語

P糖蛋白質(P-gp)発現白血病由来細胞を用いたエトポシド(VP-16)/シクロホスファミド(CY)曝露順序の殺細胞効果に及ぼす影響
臼窪 一平, 田澤 佑基, 佐藤 夕紀, 鷲見 正人, 柴山 良彦, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 132年会, 4, 200, 200, 2012年03月
(公社)日本薬学会, 日本語

中等量VP‐16/シクロホスファミド(CY)/全身放射線(TBI)前処置レジメンにおけるVP‐16のPK/PD解析
田澤佑基, 松村一仙, 佐藤夕紀, 鷲見正人, 武隈洋, 重松明男, 笠師久美子, 山田武宏, 田中淳司, 橋野聡, 井関健, 今村雅寛, 菅原満, 日本造血細胞移植学会総会プログラム・抄録集, 34th, 224, 2012年02月01日
日本語

エトポシド/シクロホスファミド併用の殺細胞効果に及ぼす曝露順序の影響 ～白血病由来 K-562 細胞及び P-糖タンパク質発現株を用いた検討～　　　　　　　　　　　　　　　
田澤佑基, 臼窪一平, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満, 日本薬学会北海道支部第137回例会（札幌）, 2011年12月

抗酸化作用を有する食品成分ルテインの乳化による消化管吸収改善　　　　　　　　　　　　　　　
佐藤 夕紀, 武隈 洋, 井関 健, 菅原 満, 機能性食品と薬理栄養, 7, 1, 89, 89, 2011年12月
(株)インフォノーツパブリッシング, 日本語

オピオイドによる難治性の嘔気とめまいに対しH₁受容体拮抗薬とペロスピロンの併用が有効であった症例
長田貴之, 柴山良彦, 熊井正貴, 山田武宏, 笠師久美子, 菅原満, 井関健, 医療薬学フォーラム講演要旨集, 19th, 186, 2011年07月
日本語

【授乳期の服薬相談 基礎と臨床からのアプローチ】乳児と成人との薬物動態の違い 吸収過程
菅原 満, 薬局, 62, 7, 2777, 2780, 2011年06月
＜Key Points＞◎乳児の薬物吸収性に関する情報は乏しく、薬物動態に関わる生理機能の新生児・乳児と成人との間の違いを把握する必要がある。◎胃内pHと消化管内の移動速度は、現在までに明らかにされている重要な要因である。◎消化管に発現するトランスポーターと代謝酵素の活性は重要な要因と考えられるが、現在のところ詳細は不明であり、具体的なエビデンスに乏しい。(著者抄録), (株)南山堂, 日本語

同種造血幹細胞移植時における中等量エトポシド(VP-16)/シクロホスファミド(CY)/全身放射線(TBI)前処置レジメンの検討 VP-16のPK/PD解析および培養細胞系を用いたVP-16/CY曝露順序の検討
田澤 佑基, 松村 一仙, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 重松 明男, 笠師 久美子, 山田 武宏, 井関 健, 今村 雅寛, 菅原 満, TDM研究, 28, 3, s203, s203, 2011年06月
(一社)日本TDM学会, 日本語

薬物治療の最適化 アレルギー疾患治療薬の使用適正化を目指したTDM
菅原 満, アレルギー, 60, 3-4, 402, 402, 2011年04月
(一社)日本アレルギー学会, 日本語

先導的薬剤師養成に向けた実践的アドバンスト教育プログラムの共同開発 国立大学における「実践的医療薬学教育プログラム」の現状　　　　　　　　　　　　　　　
小澤 光一郎, 菅原 満, 関根 祐子, 中嶋 幹郎, 日本薬学会年会要旨集, 131年会, 1, 156, 156, 2011年03月
(公社)日本薬学会, 日本語

ルテインの乳化による消化管吸収改善　　　　　　　　　　　　　　　
佐藤 夕紀, 鈴木 里彩, 武隈 洋, 井関 健, 菅原 満, 日本薬学会年会要旨集, 131年会, 4, 165, 165, 2011年03月
(公社)日本薬学会, 日本語

ソラフェニブおよびスニチニブのMRP2(ABCC2)に対する基質特異性　　　　　　　　　　　　　　　
柴山 良彦, 中野 公, 前田 弘志, 田口 美雪, 池田 龍二, 菅原 満, 井関 健, 武田 泰夫, 山田 勝士, 日本薬学会年会要旨集, 131年会, 4, 288, 288, 2011年03月
(公社)日本薬学会, 日本語

乗り物酔い様の浮遊感を伴うオピオイドの難治性嘔気にペロスピロンが有効であった症例
長田 貴之, 熊井 正貴, 柴山 良彦, 山田 武宏, 笠師 久美子, 菅原 満, 井関 健, 日本薬学会年会要旨集, 131年会, 4, 293, 293, 2011年03月
(公社)日本薬学会, 日本語

テアニンの消化管吸収に関与するトランスポーター　　　　　　　　　　　　　　　
川守田 渉, 堀田 雄也, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 131年会, 4, 165, 165, 2011年03月
(公社)日本薬学会, 日本語

白血病由来細胞を用いたエトポシド(VP-16)/シクロホスファミド(CY)曝露順序の殺細胞効果への影響
田澤 佑基, 松村 一仙, 笠師 久美子, 佐藤 夕紀, 鷲見 正人, 武隈 洋, 井関 健, 菅原 満, 日本薬学会年会要旨集, 131年会, 4, 178, 178, 2011年03月
(公社)日本薬学会, 日本語

乳児と成人との薬物動態の違い-① 吸収過程　　　　　　　　　　　　　　　
菅原 満, 薬局別冊, 62, 7, 55, 58, 2011年

医療薬学ブラッシュアップ講座 薬物の体内動態に関する最近の話題-4 腎機能と薬物動態　　　　　　　　　　　　　　　
菅原 満, 道薬誌, 28, 2, 7, 11, 2011年

医療薬学ブラッシュアップ講座 薬物の体内動態に関する最近の話題-3 経口バイオアベイラビリティ　　　　　　　　　　　　　　　
菅原 満, 道薬誌, 28, 1, 32, 37, 2011年

マイクロRNA126、210が抗がん薬感受性に及ぼす影響　　　　　　　　　　　　　　　
柴山 良彦, 田口 深雪, 池田 龍二, 古川 龍彦, 菅原 満, 井関 健, 武田 泰生, 山田 勝士, 臨床薬理, 41, Suppl., S254, S254, 2010年11月
(一社)日本臨床薬理学会, 日本語

薬剤師業務・研究支援ツールとしてのTDM
菅原 満, TDM研究, 27, 3, s56, s56, 2010年06月
(一社)日本TDM学会, 日本語

TDM実践シリーズ プレアボイド報告　　　　　　　　　　　　　　　
小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2628, 2628, 9, 12, 2010年05月
(株)薬事新報社, 日本語

A Novel Solution for Rat Liver Preservation Composed of Heavy Water and Swan Buffer; a Pilot Study
Daisuke Fukumori, Moto Fukai, Kenji Wakayama, Kenichiro Yamashita, Shinya Ueki, Mitsuru Sugawara, Sanae Haga, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo, AMERICAN JOURNAL OF TRANSPLANTATION, 10, 496, 497, 2010年04月
WILEY-BLACKWELL PUBLISHING, INC, 英語, 研究発表ペーパー・要旨（国際会議）

Heavy Water (D2O) Universally Ameliorates Cold Preservation Injury: Precise Analyses of Cytoprotective Mechanisms In Vitro
Moto Fukai, Kenji Wakayama, Daisuke Fukumori, Kenichiro Yamashita, Mitsuru Sugawara, Sanae Haga, Ueki Gentaro Hirokata, Hiroyuki Furukawa, Michitaka Ozaki, Satoru Todo, AMERICAN JOURNAL OF TRANSPLANTATION, 10, 492, 493, 2010年04月
WILEY-BLACKWELL, 英語, 研究発表ペーパー・要旨（国際会議）

TDM実践シリーズ 免疫抑制剤ミコフェノール酸モフェチル　　　　　　　　　　　　　　　
武隈 洋, 菅原 満, 小林 道也, 唯野 貢司, 野村 憲和, 北海道TDM研究会, 薬事新報, 2623, 345, 350, 2010年04月
(株)薬事新報社, 日本語

テアニンの消化管吸収に関与するトランスポーター
堀田 雄也, 武隈 洋, 菅原 満, 薬剤学: 生命とくすり, 70, Suppl., 117, 117, 2010年04月
(公社)日本薬剤学会, 日本語

TDM実践シリーズ 免疫抑制剤 シクロスポリン・タクロリムス　　　　　　　　　　　　　　　
菅原 満, 武隈 洋, 小林 道也, 唯野 貢司, 野村 憲和, 薬事新報, 2626, 2626, 31, 36, 2010年04月
(株)薬事新報社, 日本語

カルベジロールのグルクロン酸抱合に及ぼすエナンチオマー間の相互作用　　　　　　　　　　　　　　　
八木澤 啓司, 武隈 洋, 菅原 満, 日本薬学会年会要旨集, 130年会, 4, 200, 200, 2010年03月
(公社)日本薬学会, 日本語

PK/PD概念に基づいた抗がん剤の分類
高橋 夏子, 武隈 洋, 小林 正紀, 板垣 史郎, 菅原 満, 井関 健, 日本薬学会年会要旨集, 130年会, 4, 298, 298, 2010年03月
(公社)日本薬学会, 日本語

北海道大学薬学部における実務実習事前実習の取り組みとその評価
武隈 洋, 小林 正紀, 山田 勇磨, 板垣 史郎, 吉田 和幸, 井関 健, 菅原 満, 日本薬学会年会要旨集, 130年会, 4, 346, 346, 2010年03月
(公社)日本薬学会, 日本語

TDM実践シリーズ(その他4) ワルファリン　　　　　　　　　　　　　　　
山崎 将英, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 薬事新報, 2621, 2621, 9, 15, 2010年03月
(株)薬事新報社, 日本語

TDM実践シリーズ その他 精神疾患治療薬　　　　　　　　　　　　　　　
岩尾 一生, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2619, 2619, 9, 13, 2010年03月
(株)薬事新報社, 日本語

TDM実践シリーズ(その他2) 塩酸イリノテカンとTDM　　　　　　　　　　　　　　　
田中 寛之, 小林 道也, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2617, 2617, 9, 12, 2010年02月
(株)薬事新報社, 日本語

TDM実践シリーズ その他 抗がん剤　　　　　　　　　　　　　　　
井藤 達也, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 薬事新報, 2615, 2615, 9, 14, 2010年02月
(株)薬事新報社, 日本語

医療薬学ブラッシュアップ講座 薬物の体内動態に関する最近の話題-2 薬物の消化管吸収とトランスポーター　　　　　　　　　　　　　　　
菅原 満, 道薬誌, 27, 12, 4, 9, 2010年

医療薬学ブラッシュアップ講座 薬物の体内動態に関する最近の話題-1 薬物の消化管吸収性予測と経口製剤の評価　　　　　　　　　　　　　　　
菅原 満, 道薬誌, 27, 11, 4, 9, 2010年

TDM実践シリーズ（17）免疫抑制剤①ミコフェノール酸モフェチル　　　　　　　　　　　　　　　
武隈 洋, 菅原 満, 小林道也, 唯野貢司, 野村憲和, 薬事新報, 2623, 9, 14, 2010年

TDM実践シリーズ 抗真菌薬　　　　　　　　　　　　　　　
野田 久美子, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 薬事新報, 2613, 2613, 27, 31, 2010年01月
(株)薬事新報社, 日本語

TDM実践シリーズ 抗生物質製剤(2)　　　　　　　　　　　　　　　
横山 敏紀, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2611, 2611, 9, 14, 2010年01月
(株)薬事新報社, 日本語

TDM実践シリーズ 抗生物質製剤(1)　　　　　　　　　　　　　　　
國本 雄介, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2608, 2608, 9, 13, 2009年12月
(株)薬事新報社, 日本語

TDM実践シリーズ 抗不整脈薬(2)　　　　　　　　　　　　　　　
後藤 仁和, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2606, 2606, 9, 13, 2009年12月
(株)薬事新報社, 日本語

ボリコナゾールの血漿中濃度および髄液移行性をモニタリングした脳クリプトコックス症例　　　　　　　　　　　　　　　
田島宏恵, 武隈 洋, 沖 洋充, 八島萌美, 秋本幸子, 菅原 満, 井関 健, 第23回北海道TDM研究会研究発表会（札幌）, 2009年11月

腎移植患者において腎機能の変動がミコフェノール酸体内動態に与える影響　　　　　　　　　　　　　　　
大谷 薫, 武隈 洋, 原田幸子, 福澤信之, 下田直彦, 三浦正義, 菅原 満, 野々村克也, 井関 健, 第23回北海道TDM研究会研究発表会（札幌）, 2009年11月

TDM実践シリーズ 抗不整脈薬(1)　　　　　　　　　　　　　　　
中村 寛, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2604, 2604, 9, 13, 2009年11月
(株)薬事新報社, 日本語

TDM実践シリーズ ジギタリス製剤　　　　　　　　　　　　　　　
今田 愛也, 野村 憲和, 小林 道也, 唯野 貢司, 菅原 満, 薬事新報, 2602, 2602, 9, 13, 2009年11月
(株)薬事新報社, 日本語

TDM実践シリーズ テオフィリン　　　　　　　　　　　　　　　
相馬 まゆ子, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2600, 2600, 9, 14, 2009年10月
(株)薬事新報社, 日本語

TDM実践シリーズ 抗てんかん薬　　　　　　　　　　　　　　　
山田 和範, 河内 邦仁, 山澤 裕司, 小林 道也, 唯野 貢司, 菅原 満, 野村 憲和, 北海道TDM研究会, 薬事新報, 2597, 2597, 31, 37, 2009年10月
(株)薬事新報社, 日本語

O13-003 北海道大学病院における内服薬疑義照会率の傾向と分析(一般演題 口頭発表,調剤・処方鑑査・リスクマネジメント/医薬品情報・データベース/有害事象・副作用,医療薬学の創る未来 科学と臨床の融合)
齋藤 佳敬, 志賀 弘康, 小林 正紀, 須田 範行, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 19, 0, 281, 281, 2009年09月15日
日本医療薬学会, 日本語

TDM実践シリーズ TDMの基礎 血中濃度解析とシミュレーションの概要とそのソフトウェア　　　　　　　　　　　　　　　
齊藤 嘉津彦, 野村 憲和, 小林 道也, 唯野 貢司, 菅原 満, 薬事新報, 2595, 2595, 9, 12, 2009年09月
(株)薬事新報社, 日本語

TDM実践シリーズ TDMの基礎(3)　　　　　　　　　　　　　　　
板垣 史郎, 菅原 満, 唯野 貢司, 小林 道也, 野村 憲和, 北海道TDM研究会, 薬事新報, 2593, 2593, 9, 14, 2009年09月
(株)薬事新報社, 日本語

TDM実践シリーズ TDMの基礎 PK-PD　　　　　　　　　　　　　　　
戸田 貴大, 野村 憲和, 小林 道也, 唯野 貢司, 菅原 満, 北海道TDM研究会, 薬事新報, 2591, 896, 901, 2009年08月
(株)薬事新報社, 日本語

抗MRSA薬リネゾリドとバンコマイシンの脊椎組織への移行性の違い
武隈 洋, 加藤 貴志, 漆畑 英樹, 小松 幹, 高畑 雅彦, 菅原 満, 三浪 明男, 井関 健, TDM研究, 26, 3, s149, s149, 2009年06月
(一社)日本TDM学会, 日本語

テイコプラニン初期投与設計への薬剤師介入の効果
李 暁光, 武隈 洋, 山崎 浩二郎, 西村 あや子, 菅原 満, 井関 健, TDM研究, 26, 3, s170, s170, 2009年06月
(一社)日本TDM学会, 日本語

テイコプラニンのローディングドーズがもたらす血中トラフ濃度と有効性の検討 第2次研究中間報告
野田 久美子, 田中 寛之, 山澤 裕司, 齊藤 嘉津彦, 小林 道也, 菅原 満, 唯野 貢司, TDM研究, 26, 3, s173, s173, 2009年06月
(一社)日本TDM学会, 日本語

ミコフェノール酸モフェチルの大量投与によっても目標AUCに到達しなかった小児生体腎移植患者の1症例
大谷 薫, 武隈 洋, 原田 幸子, 下田 直彦, 三浦 正義, 菅原 満, 野々村 克也, 井関 健, TDM研究, 26, 3, s208, s208, 2009年06月
(一社)日本TDM学会, 日本語

難水溶性薬物の乳剤化とその消化管吸収性に及ぼす胆汁の影響　　　　　　　　　　　　　　　
武藤花見, 今井智子, 中山淳司, 鈴木美香, 武隈 洋, 井関 健, 菅原 満, 日本薬学会北海道支部第132回例会（札幌）, 2009年05月

Na+/モノカルボン酸共輸送担体(SMCT1)の基質認識機構における構造活性相関　　　　　　　　　　　　　　　
宮内 正二, 駄馬崎 泰洋, 菅原 満, Gopal Elangovan, Ganapathy Vadivel, 日本薬学会年会要旨集, 129年会, 4, 260, 260, 2009年03月
(公社)日本薬学会, 日本語

新規開発臓器保存液を用いた心冷保存限界延長の試み
若山 顕治, 深井 原, 山下 健一郎, 後藤 了一, 植木 伸也, 福森 大介, 柴崎 晋, 大浦 哲, 廣方 玄太郎, 芳賀 早苗, 谷口 雅彦, 鈴木 友己, 嶋村 剛, 松下 道明, 古川 博之, 尾崎 倫孝, 藤堂 省, 小野 太祐, 絹川 真太郎, 筒井 裕之, 菅原 満, 日本外科学会雑誌, 110, 臨増2, 709, 709, 2009年02月
(一社)日本外科学会, 日本語

頭頸部放射線治療において使用される鎮痛薬と腫瘍部位の関連性に関する後ろ向き観察研究
長田貴之, 熊井正貴, 山田武宏, 笠師久美子, 鈴木章之, 本間明宏, 福田諭, 菅原満, 井関健, 井関健, 日本緩和医療薬学会年会プログラム・要旨集, 3rd, 2009年

返品麻薬再利用のためのオーダリングシステム構築と運用後の現状
熊井正貴, 志賀弘康, 笠師久美子, 菅原満, 井関健, 井関健, 日本緩和医療学会学術大会プログラム・抄録集, 14th, 2009年

O11-006 気分障害圏患者の副作用への認知とコンプライアンスへの影響 : 心理検査との相関性(一般演題 口頭発表,精神科領域,医療薬学の創る未来 科学と臨床の融合)
久保田 康生, 木村 俊也, 渡邉 紀子, 大崎 明美, 笠師 久美子, 菅原 満, 小山 司, 井関 健, 日本医療薬学会年会講演要旨集, 19, 277, 277, 2009年
一般社団法人 日本医療薬学会, 日本語

Extended Preservation of Rat Hearts with Novel Organ Preservation Solution: Role of Actin Cytoskeleton and ATP Maintenance.
Kenji Wakayama, Moto Fukai, Kenichiro Yamashita, Daisuke Fukumori, Susumu Shibasaki, Gentaro Hirokata, Tomohiro Shibata, Tetsu Oura, Ryoichi Goto, Masahiko Taniguchi, Tomomi Suzuki, Tsuyoshi Shimamura, Michiaki Matsushita, Hiroyuki Furukawa, Michitaka Ozaki, Taisuke Ono, Mitsuru Sugawara, Satoru Todo, AMERICAN JOURNAL OF TRANSPLANTATION, 9, 491, 491, 2009年
WILEY-BLACKWELL PUBLISHING, INC, 英語, 研究発表ペーパー・要旨（国際会議）

Re-Evaluation of Heavy Water for Organ Preservation Solution; In Vitro Study.
Moto Fukai, Kenichiro Yamashita, Kenji Wakayama, Daisuke Fukumori, Ryoichi Goto, Sanae Haga, Gentaro Hirokata, Shigeru Nakakimura, Mitsuru Sugawara, Hirofumi Kamachi, Tomomi Suzuki, Tsuyoshi Shimamura, Hiroyuki Furukawa, Michiaki Matsushita, Michitaka Ozaki, Satoru Todo, AMERICAN JOURNAL OF TRANSPLANTATION, 9, 581, 581, 2009年
WILEY-BLACKWELL PUBLISHING, INC, 英語, 研究発表ペーパー・要旨（国際会議）

造血幹細胞移植における栄養指標と口内症状の評価(第二報)　　　　　　　　　　　　　　　
笠師 久美子, 柏崎 晴彦, 阿部 貴恵, 重松 明男, 池田 陽子, 上野 あさひ, 菅原 満, 井関 健, 静脈経腸栄養, 24, 1, 345, 345, 2009年01月
(株)ジェフコーポレーション, 日本語

TDM実践シリーズ（２）TDMの基礎②PK-PD　　　　　　　　　　　　　　　
戸田貴大, 野村憲和, 小林道也, 唯野貢司, 菅原 満, 薬事新報, 2591, 25, 30, 2009年

処方せん発行時の抗MRSA薬初期投与設計による医師への情報提供の有用性　　　　　　　　　　　　　　　
木村俊也, 山崎浩二郎, 西村あや子, 横田亜季, 小笠原貴子, 大崎由美子, 執行聡美, 清川真美, 宮本剛典, 菅原 満, 井関 健, 北海道病院薬剤師会誌, 76, 27, 30, 2009年

カルベジロールの体内動態に及ぼす UGT遺伝子多型およびエナンチオマー間の 相互阻害作用の影響　　　　　　　　　　　　　　　
武隈 洋, 武中 徹, 八木澤啓司, 井幡圭佑, 菅原 満, UGT研究会（福岡）, 2008年10月

21C-12 消化管吸収予測システムを用いた後発医薬品の薬剤学的同等性評価(1)(後発医薬品,来るべき時代への道を拓く)
下山 哲哉, 渡辺 祐子, 山本 千秋, 小林 正紀, 板垣 史郎, 菅原 満, 平野 剛, 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 267, 267, 2008年09月01日
日本医療薬学会, 日本語

20-P1-168 吸収予測システムを用いた後発医薬品の薬剤学的同等性評価(2) : BCS分類class IおよびIIIの製剤における比較(後発医薬品,来るべき時代への道を拓く)
渡辺 祐子, 山本 千秋, 下山 哲哉, 小林 正紀, 板垣 史郎, 菅原 満, 平野 剛, 井関 健, 日本医療薬学会年会講演要旨集, 18, 0, 310, 310, 2008年09月01日
日本医療薬学会, 日本語

感染性脊椎炎をターゲットとした新規抗MRSA薬リネゾリドの脊椎周辺組織への移行性に関する実験的研究
小松 幹, 高畑 雅彦, 武隈 洋, 菅原 満, 加藤 貴志, 入江 徹, 安倍 雄一郎, 伊東 学, 三浪 明男, 日本整形外科学会雑誌, 82, 8, S1248, S1248, 2008年08月
(公社)日本整形外科学会, 日本語

抗MRSA薬テイコプラニンの初期投与設計による適正使用への関わり　　　　　　　　　　　　　　　
木村 俊也, 山崎 浩二郎, 西村 あや子, 坪内 孝敏, 横田 亜季, 小笠原 貴子, 大崎 由美子, 執行 聡美, 清川 真美, 宮本 剛典, 武隈 洋, 菅原 満, 井関 健, TDM研究, 25, 3, s213, s213, 2008年06月
(一社)日本TDM学会, 日本語

BCSクラス4に属する薬物の乳剤化とその消化管吸収性に及ぼす胆汁の影響
武藤 花見, 鈴木 美香, 武隈 洋, 井関 健, 菅原 満, 薬剤学: 生命とくすり, 68, Suppl., 249, 249, 2008年04月
(公社)日本薬剤学会, 日本語

汎用データベースソフトを用いた持参薬識別システムの構築と運用　　　　　　　　　　　　　　　
川岸 亨, 熊井 正貴, 齋藤 京之, 笠師 久美子, 菅原 満, 井関 健, 日本薬学会年会要旨集, 128年会, 4, 207, 207, 2008年03月
(公社)日本薬学会, 日本語

化膿性脊椎炎に対するリネゾリドの臨床効果と脊椎への移行性　　　　　　　　　　　　　　　
加藤 貴志, 菅原 満, 井関 健, 武隈 洋, 高畑 雅彦, 小松 幹, 伊東 学, 三浪 明男, 日本薬学会年会要旨集, 128年会, 4, 85, 85, 2008年03月
(公社)日本薬学会, 日本語

北大病院における内服薬疑義照会率の傾向と分析
齋藤 佳敬, 榊原 則寛, 志賀 弘康, 沖 洋充, 小林 正紀, 川合 真次, 深井 敏隆, 菅原 満, 井関 健, 日本薬学会年会要旨集, 128年会, 4, 163, 163, 2008年03月
(公社)日本薬学会, 日本語

FDG-PET検査における薬剤の影響~院内ガイドライン作成の試み~
新里利香, 笠師久美子, 鐘ケ江香久子, 菅原満, 井関健, 医療薬学フォーラム講演要旨集, 16th, 2008年

当院における緩和ケアチームの活動報告
熊井正貴, 熊井正貴, 田巻知宏, 笠師久美子, 菅原満, 井関健, 井関健, 日本緩和医療薬学会年会プログラム・要旨集, 2nd, 2008年

20C-18 リネゾリドの使用状況調査および有効性、副作用に関する調査(感染対策・ICT,来るべき時代への道を拓く)
山崎 浩二郎, 西村 あや子, 宮本 剛典, 武隈 洋, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 18, 245, 245, 2008年
一般社団法人 日本医療薬学会, 日本語

20E-03 マイクロエマルジョン型シクロスポリン製剤の先発医薬品と後発医薬品の製剤学的な比較(後発医薬品,来るべき時代への道を拓く)
植田 孝介, 武隈 洋, 沖 洋充, 須田 範行, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 18, 253, 253, 2008年
一般社団法人 日本医療薬学会, 日本語

20I-04 高齢透析患者の栄養管理におけるNST薬剤師のあり方(栄養管理・NST,来るべき時代への道を拓く)
清川 真美, 上野 あさひ, 池田 陽子, 須田 範行, 渡邊 昌也, 石川 康暢, 菅原 満, 武田 宏司, 井関 健, 日本医療薬学会年会講演要旨集, 18, 262, 262, 2008年
一般社団法人 日本医療薬学会, 日本語

21C-03 頭頸部癌に対するシスプラチン超選択的動注における副作用調査(がん薬物療法(副作用対策),来るべき時代への道を拓く)
熊井 正貴, 浅野 順次, 笠師 久美子, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 18, 266, 266, 2008年
一般社団法人 日本医療薬学会, 日本語

EVALUATION OF KETOPROFEN ABSORPTION IN TWO PREPARATIONS WITH AN IN VITRO SYSTEM
Xin He, Mitsuru Sugawara, Xingbin Zhu, Shota Kadomura, Yang Wang, Yoh Takekuma, Changxiao Liu, DRUG METABOLISM REVIEWS, 40, 31, 32, 2008年
TAYLOR & FRANCIS INC, 英語, 研究発表ペーパー・要旨（国際会議）

造血幹細胞移植における栄養指標と口内症状の評価　　　　　　　　　　　　　　　
笠師 久美子, 柏崎 晴彦, 阿部 貴恵, 須田 範行, 菅原 満, 井関 健, 静脈経腸栄養, 23, 増刊, 213, 213, 2008年01月
(株)ジェフコーポレーション, 日本語

小腸瘻周囲に皮膚びらんを呈した短腸症候群患者への栄養管理の一例　　　　　　　　　　　　　　　
植田 孝介, 久保 ちづる, 林 みゆき, 須田 範行, 菅原 満, 井関 健, 七戸 俊明, 武田 宏司, 静脈経腸栄養, 23, 増刊, 319, 319, 2008年01月
(株)ジェフコーポレーション, 日本語

20D-30 がん化学療法における口内炎の予防に対する抗酸化物質の応用(がん薬物療法(副作用対策),来るべき時代への道を拓く)
鷹野 瑠美, 平野 剛, 中田 千絵, 笠師 久美子, 菅原 満, 小林 正紀, 板垣 史郎, 井関 健, 大江 利治, 日本医療薬学会年会講演要旨集, 18, 0, 253, 253, 2008年
一般社団法人 日本医療薬学会, 日本語

ビスホスホネート製剤ゾメタの使用状況調査　　　　　　　　　　　　　　　
上野英文, 寺林久幸, 澤口利香, 久保田康生, 須田範行, 沖 洋充, 笠師久美子, 菅原 満, 井関 健, 北海道病院薬剤師会誌, 74, 43, 46, 2008年

北海道大学病院における持参薬確認業務への取り組み　　　　　　　　　　　　　　　
齋藤京之, 熊井正貴, 小田島澄子, 海藤文恵, 鳥飼真之介, 執行聡美, 川岸諭佳, 沖 洋充, 深井敏隆, 荻野 修, 菅原 満, 井関 健, 北海道病院薬剤師会誌, 74, 19, 21, 2008年

Pharmacokineticsの鑑定事例への応用 危険運転行為と覚せい剤摂取　　　　　　　　　　　　　　　
清水 惠子, 松原 和夫, 菅原 満, 浅利 優, 丹 祐夏, 渡邊 智, 塩野 寛, 中毒研究, 20, 4, 438, 438, 2007年10月
(株)へるす出版, 日本語

オピオイド製剤の適正使用に関する調査
斎藤由起子, 沖洋充, 平野剛, 菅原満, 井関健, 日本医療薬学会年会講演要旨集, 17th, 315, 315, 2007年09月01日
一般社団法人 日本医療薬学会, 日本語

29-C1-10-2 Coenzyme Q10の消化管吸収挙動:排出系トランスポーターの関与(薬物相互作用・薬物動態,社会の期待に応える医療薬学を)
落合 彰子, 小林 正紀, 板垣 史郎, 平野 剛, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 17, 0, 196, 196, 2007年09月01日
日本医療薬学会, 日本語

チーム医療に貢献するTDMの実際 地域の中でのチーム医療 北海道TDM研究会の活動を通じて　　　　　　　　　　　　　　　
菅原 満, 唯野 貢司, TDM研究, 24, 3, s56, s57, 2007年07月
(一社)日本TDM学会, 日本語

テイコプラニンのローディングドーズがもたらす血中トラフ濃度と有効性の検討 中間報告　　　　　　　　　　　　　　　
田中 寛之, 山澤 裕司, 齋藤 嘉津彦, 小林 道也, 菅原 満, 唯野 貢司, TDM研究, 24, 3, s135, s135, 2007年07月
(一社)日本TDM学会, 日本語

タクロリムス(TAC)併用腎移植患者におけるミコフェノール酸(MPA)の血中濃度変動要因解析
武隈 洋, 寺岡 栄美, 澤口 利香, 山崎 浩二郎, 森田 研, 下田 直彦, 堀田 記世彦, 岩見 大基, 渡井 至彦, 菅原 満, 野々村 克也, 井関 健, 移植, 42, 2, 194, 195, 2007年04月
(一社)日本移植学会, 日本語

Pharmacokineticsの鑑定事例への応用 危険運転行為と覚せい剤摂取　　　　　　　　　　　　　　　
清水 惠子, 浅利 優, 安積 順一, 松原 和夫, 菅原 満, 塩野 寛, 日本法医学雑誌, 61, 1, 52, 52, 2007年03月
(NPO)日本法医学会, 日本語

ラット及びヒト間のMPA(ミコフェノール酸)体内動態の違いにおけるMRP2(multidrug resistance-associated protein 2)及びOAT(organic anion transporter)の関与　　　　　　　　　　　　　　　
垣内 悠, 武隈 洋, 山崎 浩二郎, 井関 健, 菅原 満, 日本薬学会年会要旨集, 127年会, 3, 84, 84, 2007年03月
(公社)日本薬学会, 日本語

30-B2-14-1 処方オーダによる後発医薬品への変更許可システムとその稼働状況(医薬分業・薬薬連携・治験,社会の期待に応える医療薬学を)
川合 真次, 深井 敏隆, 荻野 修, 菅原 満, 櫻井 恒太郎, 井関 健, 日本医療薬学会年会講演要旨集, 17, 206, 206, 2007年
一般社団法人 日本医療薬学会, 日本語

29-P1-134 テイコプラニン(TEIC)TDM実施患者における血中濃度と疾患別臨床評価(TDM/薬物動態,社会の期待に応える医療薬学を)
西村 あや子, 坪内 孝敏, 山崎 浩二郎, 宮本 剛典, 武隈 洋, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 17, 239, 239, 2007年
一般社団法人 日本医療薬学会, 日本語

29-P1-143 全身性エリテマトーデス(SLE)患者に対するミコフェノール酸モフェチル(MMF)の適用とTDMの有用性(TDM/薬物動態,社会の期待に応える医療薬学を)
武隈 洋, 奥 健志, 小笠原 貴子, 山崎 浩二郎, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 17, 240, 240, 2007年
一般社団法人 日本医療薬学会, 日本語

リネゾリドの椎間板への移行性　　　　　　　　　　　　　　　
加藤貴志, 菅原 満, 井関 健, 武隈 洋, 高畑雅彦, 小松幹, 伊東 学, 三浪明男, 第21回北海道TDM研究会（札幌）, 2007年

29-P1-39 栄養療法における脂肪乳剤の使用に関する意識調査および適正使用の推進(NST,社会の期待に応える医療薬学を)
鷹野 瑠美, 須田 範行, 平野 剛, 笠師 久美子, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 17, 0, 223, 223, 2007年
一般社団法人 日本医療薬学会, 日本語

副作用症状を来した肝移植患者における免疫抑制剤の選択　　　　　　　　　　　　　　　
小笠原貴子, 新沼朋美, 沖 洋充, 深井敏隆, 荻野 修, 武隈 洋, 菅原 満, 井関 健, 北海道病院薬剤師会誌, 72, 35, 37, 2007年

30P1-011 外来化学療法における服薬指導充実のための病棟 : 外来間連携ツールの構築(癌薬物療法(外来化学療法、緩和ケア等),医療薬学の扉は開かれた)
久保田 康生, 中里 恭子, 須田 範行, 沖 洋充, 菅原 満, 小林 道也, 齊藤 浩司, 井関 健, 日本医療薬学会年会講演要旨集, 16, 357, 357, 2006年09月01日
日本医療薬学会, 日本語

01P2-154 テイコプラニン投与時における至適ローディングドーズの検討 : 新旧TDM解析支援ソフトウェア間の有用性の比較(薬物動態(TDM・投与設計等),医療薬学の扉は開かれた)
小笠原 貴子, 武隈 洋, 山崎 浩二郎, 沖 洋充, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 16, 553, 553, 2006年09月01日
日本医療薬学会, 日本語

01P3-001 スルバクタム/セフォペラゾン製剤の後発医薬品導入に際する有効性の比較検討(薬剤疫学,医療薬学の扉は開かれた)
大西 潤, 井藤 達也, 志賀 隆博, 高木 智史, 鈴木 岳, 武隈 洋, 菅原 満, 竹本 功, 井関 健, 日本医療薬学会年会講演要旨集, 16, 555, 555, 2006年09月01日
日本医療薬学会, 日本語

30-F-05 心臓血管造影剤による急性腎機能低下に対するアセチルシステインの予防効果および製剤の評価(服薬指導(入院・外来),医療薬学の扉は開かれた)
清川 真美, 澤口 利香, 須田 範行, 菅原 満, 井関 健, 日本医療薬学会年会講演要旨集, 16, 320, 320, 2006年09月01日
日本医療薬学会, 日本語

コエンザイムQ10の消化管吸収挙動:製剤的工夫による違い
井関健, 落合彰子, 黒川俊光, 板垣史郎, 平野剛, 菅原満, 日本医療薬学会年会講演要旨集, 16th, 433, 433, 2006年09月01日
日本医療薬学会, 日本語

薬物のα1-酸性糖タンパク質への結合と臨床
菅原 満, TDM研究, 23, 2, 55, 56, 2006年04月
(一社)日本TDM学会, 日本語

カルベジロールの体内動態変動に及ぼすグルクロン酸転移酵素およびCYP2D6遺伝子多型の影響
武隈 洋, 武中 徹, 清川 真美, 山崎 浩二郎, 岡本 洋, 菅原 満, 北畠 顕, 筒井 裕之, 宮崎 勝巳, TDM研究, 23, 2, 77, 78, 2006年04月
(一社)日本TDM学会, 日本語

腎移植患者におけるタクロリムス併用時の少数採血点によるミコフェノール酸AUC0-12推定
寺岡 栄美, 武隈 洋, 山崎 浩二郎, 高田 晴美, 菅原 満, 渡井 至彦, 森田 研, 福澤 信之, 野々村 克也, 宮崎 勝巳, TDM研究, 23, 2, 145, 146, 2006年04月
(一社)日本TDM学会, 日本語

注射オーダを利用した特定生物由来製剤の使用管理システム　　　　　　　　　　　　　　　
川合 真次, 山崎 浩二郎, 宮本 剛典, 荻野 修, 菅原 満, 井関 健, 櫻井 恒太郎, 日本薬学会年会要旨集, 126年会, 2, 220, 220, 2006年03月
(公社)日本薬学会, 日本語

ヌクレオシドトランスポーターを介した抗ウイルス薬リバビリンの消化管吸収
國木 賢一, 山本 崇, 武隈 洋, 菅原 満, 井関 健, 薬剤学: 生命とくすり, 66, Suppl., 229, 229, 2006年02月
(公社)日本薬剤学会, 日本語

薬物療法時の血液浄化療法の影響 ～リネゾリド・ガンシクロビルについて～　　　　　　　　　　　　　　　
武隈 洋, 山﨑浩二郎, 宮本剛典, 菅原 満, 井関 健, 第20回北海道TDM研究会（札幌）, 2006年

中性アミノ酸トランスポーターSNAT2の発現変動　　　　　　　　　　　　　　　
柏木 仁, 山﨑 浩二郎, 武隈 洋, 井関 健, 菅原 満, 第20回北海道薬物作用談話会（札幌）, 2006年

血清アルブミンを中心としたMPA血中濃度の変動要因解析　　　　　　　　　　　　　　　
寺岡 栄美, 山﨑浩二郎, 菅原 満, 井関 健, 武隈 洋, 森田 研, 下田直彦, 堀田記世彦, 岩見大基, 渡井 至彦, 野々村克也, 第24回北海道腎移植談話会（札幌）, 2006年

副作用症状を来した肝移植患者に対する免疫抑制剤の選択　　　　　　　　　　　　　　　
小笠原貴子, 新沼朋美, 武隈 洋, 沖 洋充, 深井敏隆, 荻野 修, 菅原 満, 井関 健, 第53回北海道薬学大会（札幌）, 2006年

外来化学療法の取り組み 当院における外来治療センターの現状　　　　　　　　　　　　　　　
須田 範行, 荻野 修, 菅原 満, 井関 健, 薬事新報, 2398, 9, 15, 2005年12月
(株)薬事新報社, 日本語

P-800 健康食品に対する意識と摂取状況およびそのデータベース(DB)化(22.健康食品,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
久保田 康生, 沖 洋充, 菅原 満, 山崎 浩一, 西村 正治, 日本医療薬学会年会講演要旨集, 15, 428, 428, 2005年09月01日
日本医療薬学会, 日本語

P-541 院内LANを用いた情報提供、添付文書閲覧システムの構築(5.医薬品情報・データベース4,医療薬学の未来へ翔(はばた)く-薬剤師の薬剤業務・教育・研究への能動的関わり-)
橋本 純一, 住吉 一宏, 川合 真次, 深井 敏隆, 荻野 修, 菅原 満, 櫻井 恒太郎, 宮崎 勝巳, 日本医療薬学会年会講演要旨集, 15, 364, 364, 2005年09月01日
日本医療薬学会, 日本語

【泌尿器科の化学療法】泌尿器科化学療法で使用される代表薬剤
松浦 麻耶, 菅原 満, 篠原 信雄, 泌尿器ケア, 10, 9, 839, 843, 2005年09月
(株)メディカ出版, 日本語

総合ビタミン剤配合型高カロリー輸液キット製剤「フルカリック」1日用量製剤の有用性の検討
須田 範行, 菅原 満, 新薬と臨牀, 54, 8, 956, 963, 2005年08月
フルカリックは,初めて総合ビタミン剤を配合した高カロリー輸液キット製剤である.今回,1日容量製剤が開発され,有用性について,高カロリー輸液に適用されている処方を用いて検討した.A群(半日容量製剤2袋に薬剤を混注し,遮光タイプのIVHバッグ1袋に注入し1日分にまとめた群),B群(半日容量製剤2袋それぞれに薬剤を混注した群),C群(1日容量製剤1袋に薬剤を混注した群)とした.調剤順序は無作為に割付けを行った.調製時間はA群が640秒,B群が276秒,C群が224秒であった.C群はA群,B群と比較し有意に調製時間が短縮した.アンケート調査では,調製操作時間,調製操作の簡便性,利便性の総合評価の項目で有意差を認めた.半日容量製剤2袋を1日容量製剤1袋に変更可能な処方は97件あり,半日容量製剤194袋を1日容量製剤97袋に変更可能であった.フルカリック1日容量製剤は,臨床現場にとって有用性の高い製剤であることが示唆された, (株)医薬情報研究所, 日本語

神経因性疼痛に対する酢酸フレカイニドの鎮痛効果とTDMの有用性
山崎 浩二郎, 武隈 洋, 志賀 弘康, 菅原 満, 宮崎 勝巳, 小澤 剛久, 柴田 万里子, 橋本 聡一, 森本 裕二, TDM研究, 22, 3, 238, 238, 2005年07月
(一社)日本TDM学会, 日本語

【癌治療の臨床薬理】イリノテカンの至適投与設計と下痢発症メカニズムに関する研究
井関 健, 板垣 史郎, 菅原 満, 宮崎 勝巳, 平野 剛, 臨床薬理の進歩, 26, 20, 29, 2005年07月
(公財)臨床薬理研究振興財団, 日本語

カルベジロール血漿中濃度に及ぼすグルクロン酸抱合能の影響
武隈 洋, 清川 真美, 山崎 浩二郎, 米澤 一也, 岡本 洋, 菅原 満, 北畠 顕, 宮崎 勝巳, TDM研究, 22, 2, 151, 152, 2005年04月
(一社)日本TDM学会, 日本語

ヌクレオシドトランスポーターを介した薬物輸送 CNTとENTの比較　　　　　　　　　　　　　　　
山本 崇, 國木 賢一, 武隈 洋, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 125年会, 2, 112, 112, 2005年03月
(公社)日本薬学会, 日本語

当院における外来治療センターの現状と問題点　　　　　　　　　　　　　　　
須田 範行, 瀬戸 恵介, 熊井 正貴, 岩井 美和子, 志賀 弘康, 宮本 剛典, 荻野 修, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 125年会, 2, 165, 165, 2005年03月
(公社)日本薬学会, 日本語

心疾患患者におけるカルベジロール薬物動態の母集団パラメータ解析　　　　　　　　　　　　　　　
武隈 洋, 清川 真美, 武中 徹, 山崎 浩二郎, 岡本 洋, 菅原 満, 北畠 顕, 筒井 裕之, 宮崎 勝巳, 日本薬学会年会要旨集, 125年会, 2, 181, 181, 2005年03月
(公社)日本薬学会, 日本語

救急・集中治療室12例におけるフレカイニド静注薬の効果解析　　　　　　　　　　　　　　　
松田直之, 大城あき子, 下嶋秀和, 久保田信彦, 星野弘勝, 早川峰司, 澤村 淳, 石川岳彦, 丸藤 哲, 武隈 洋, 菅原 満, 第6回抗不整脈薬TDM研究会（東京）, 2005年

神経因性疼痛に対する酢酸フレカイニドの鎮痛効果の検討　　　　　　　　　　　　　　　
武隈 洋, 山﨑浩二郎, 志賀弘康, 菅原 満, 宮崎勝巳, 小澤剛久, 柴田万里子, 橋本聡一, 森本裕二, 第6回抗不整脈薬TDM研究会（東京）, 2005年

総合ビタミン剤配合型高カロリー輸液キット製剤「フルカリック®」1日容量製剤の有用性の検討　　　　　　　　　　　　　　　
須田範行, 菅原 満, 新薬と臨床, 54, 8, 18, 25, 2005年

【日常診療に用いられる薬剤の上手な使い方と服薬指導】薬物の吸収とその変動要因　　　　　　　　　　　　　　　
菅原 満, 宮崎 勝巳, 成人病と生活習慣病, 35, 1, 9, 16, 2005年01月
経口投与製剤は,その服用しやすさからもっとも汎用される剤形であるが,薬理作用が消化管からの吸収性の変動により影響を受けることが多々ある.薬物の消化管からの吸収に変動を及ぼす生理的要因や,食事や併用薬との相互作用として,(1)消化管運動の亢進・抑制,(2)複合体形成および吸着,(3)消化管内pHの変動,(4)代謝酵素阻害・誘導,(5)トランスポーターの阻害・誘導,(6)腸内細菌叢の変化などがある.これらの要因による薬理効果の変動や副作用の発現を防ぐために,薬剤師による処方監査やコンピュータシステムによる処方チェック,さらには患者への服薬指導が重要な役割を果たす.薬物の消化管吸収における相互作用が生じる組み合わせが入力された時に,相互作用の内容とともに,薬剤を変更する際の代替薬の提示や対処法を併せてコメントとして表示するコンピュータシステムの導入,あるいは薬効や副作用とともに,使用上の注意を記載した情報提供用紙は非常に有用である.副作用や相互作用は,事前の知識によりある程度回避することができる.そのためには,患者や周囲にいる人がその初期症状に気づき,早急に対処することも重要である.薬効や副作用とともに,このような使用上の注意を,専門用語を用いずにわかりやすい表現で記載した情報提供用紙が服薬指導には欠かせない(著者抄録), (株)東京医学社, 日本語

肝のう胞治療時のジソピラミド血中濃度モニタリング エタノール注入療法患者の症例
坪井 瞳, 板垣 まゆこ, 今田 愛也, 阿部 康子, 金重 啓子, 樟本 賢首, 岸野 吏志, 菅原 満, 宮崎 勝巳, TDM研究, 21, 4, 336, 336, 2004年10月
(一社)日本TDM学会, 日本語

【Q&Aで学ぶTDM活用ガイド】TDMを始める準備をする TDMを始める前に知っておきたいこと 特定薬剤治療管理料の算定は薬剤によって異なるそうですね.ややこしいので教えてください　　　　　　　　　　　　　　　
菅原 満, 宮崎 勝巳, 薬局, 55, 10月臨増, 6, 7, 2004年10月
(株)南山堂, 日本語

【Q&Aで学ぶTDM活用ガイド】TDMを始める準備をする TDMを始める前に知っておきたいこと TDMを実施すると経済的なメリットはあるのでしょうか?　　　　　　　　　　　　　　　
菅原 満, 宮崎 勝巳, 薬局, 55, 10月臨増, 8, 10, 2004年10月
(株)南山堂, 日本語

【Q&Aで学ぶTDM活用ガイド】TDMを始める準備をする TDMを始める前に知っておきたいこと 血中濃度は常に有効治療域に入れなければならないのでしょうか?　　　　　　　　　　　　　　　
菅原 満, 宮崎 勝巳, 薬局, 55, 10月臨増, 11, 13, 2004年10月
(株)南山堂, 日本語

P-205 造影剤による腎機能低下の予防を目的としたアセチルシステインゼリーの調製と評価(13.院内製剤(薬局製剤),"薬剤師がつくる薬物治療"-薬・薬・学の連携-)
須田 範行, 新里 利香, 清川 真美, 金内 美妃, 菅原 満, 郡 修徳, 宮崎 勝巳, 日本医療薬学会年会講演要旨集, 14, 268, 268, 2004年09月01日
日本医療薬学会, 日本語

P-231 麻薬オーダリンクシステムの構築とその運用(14.調剤・処方管理・オーダリング(注射剤含む),"薬剤師がつくる薬物治療"-薬・薬・学の連携-)
志賀 弘康, 川合 真次, 荻野 修, 菅原 満, 宮崎 勝巳, 日本医療薬学会年会講演要旨集, 14, 274, 274, 2004年09月01日
日本医療薬学会, 日本語

北海道大学病院における治験実施体制の整備と新たな取り組み　　　　　　　　　　　　　　　
後藤 瑞子, 橋本 あきら, 荻野 修, 菅原 満, 宮崎 勝巳, 亀田 悦子, 奥原 芳子, 河野 敏春, 佐藤 典宏, 遠藤 晃, 櫻井 恒太郎, 小池 隆夫, 臨床薬理, 35, Suppl., S201, S201, 2004年08月
(一社)日本臨床薬理学会, 日本語

生体部分肝移植患者におけるMicafungin(Funguard)の体内動態
岸野 吏志, 馬渕 朋美, 菅原 満, 嶋村 剛, 古川 裕之, 藤堂 省, 宮崎 勝巳, TDM研究, 21, 2, 145, 146, 2004年04月
(一社)日本TDM学会, 日本語

拡張型心筋症患者における遺伝子多型性によるβ遮断薬レスポンダー解析
井上 直樹, 岡本 洋, 福島 新, 本間 恒章, 小松 博史, 長嶋 健一郎, 秋野 正敏, 松井 裕, 小野塚 久夫, 米澤 一也, 北畠 顕, 菅原 満, 東 純一, Circulation Journal, 68, Suppl.II, 758, 758, 2004年04月
(一社)日本循環器学会, 日本語

薬剤師による処方支援(3)薬剤師にできる処方支援法--病棟活動とデータベースの活用
菅原 満, 宮崎 勝巳, 医薬ジャ-ナル, 40, 3, 130, 136, 2004年03月
医薬ジャ-ナル社, 日本語

肝のう胞治療時のジソピラミド血中濃度モニタリング エタノール注入療法患者の症例　　　　　　　　　　　　　　　
坪井 瞳, 板垣 まゆ子, 今田 愛也, 金重 啓子, 樟本 賢首, 岸野 吏志, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 124年会, 4, 184, 184, 2004年03月
(公社)日本薬学会, 日本語

AAG variantに対するクロルプロマジンの結合に及ぼすシアル酸の影響　　　　　　　　　　　　　　　
中川 勉, 佐々木 花, 武隈 洋, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 124年会, 4, 87, 87, 2004年03月
(公社)日本薬学会, 日本語

タキソール注投与時の結晶析出に関する報告　　　　　　　　　　　　　　　
岩井 美和子, 須田 範行, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 124年会, 4, 125, 125, 2004年03月
(公社)日本薬学会, 日本語

癌化学療法の調剤業務支援のためのプロトコールデータベースの構築と運用　　　　　　　　　　　　　　　
武隈 洋, 岩井 美和子, 藤原 俊恵, 川岸 亨, 熊井 正貴, 松浦 麻耶, 前佛 美也子, 高橋 悠子, 相楽 賢一, 馬渕 朋美, 須田 範行, 宮本 剛典, 荻野 修, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 124年会, 4, 150, 150, 2004年03月
(公社)日本薬学会, 日本語

hOAT1を介した有機アニオン輸送に対するキサンチン系薬物の阻害効果　　　　　　　　　　　　　　　
菅原 満, 望月 敬浩, 武隈 洋, 宮崎 勝巳, 日本薬学会年会要旨集, 124年会, 4, 76, 76, 2004年03月
(公社)日本薬学会, 日本語

PSP取り込み過程における有機アニオントランスポーターの寄与
板垣 史郎, 菅原 満, 小林 道也, 平野 剛, 宮崎 勝巳, 井関 健, 日本薬学会年会要旨集, 124年会, 4, 75, 75, 2004年03月
(公社)日本薬学会, 日本語

【抗がん剤の適正使用へのポイント】がん患者における薬物の吸収と排泄
菅原 満, 宮崎 勝巳, 薬局, 55, 3, 1481, 1490, 2004年03月
(株)南山堂, 日本語

薬剤師による処方支援 薬剤師にできる処方支援法 病棟活動とデータベースの活用
菅原 満, 宮崎 勝巳, 医薬ジャーナル, 40, 3, 1012, 1018, 2004年03月
薬剤師による処方支援の例として,病棟活動を通じて薬剤師が処方計画に参画できたケースについて,北海道大学病院において経験した例を紹介する.一方,病棟活動を行っていない診療科においても,何らかの形で処方を支援する方策が必要である.そこで,薬剤部において作成したデータベースを,処方オーダリングシステムにリンクすることにより,処方作成を支援する取り組みについても述べた, (株)医薬ジャーナル社, 日本語

Differential binding of disopyramide and warfarin enantiomers to human alpha(1)-acid glycoprotein variants (vol 56, pg 664, 2003)
T Nakagawa, S Kishino, S Itoh, M Sugawara, K Miyazaki, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 57, 2, 226, 226, 2004年02月
BLACKWELL PUBLISHING LTD, 英語, その他

拡張型心筋症患者におけるβ遮断薬薬剤反応性と遺伝子多型性解析　　　　　　　　　　　　　　　
岡本 洋, 小野塚 久夫, 米澤 一也, 北畠 顕, 菅原 満, 東 純一, 日本内科学会雑誌, 93, Suppl., 170, 170, 2004年02月
(一社)日本内科学会, 日本語

急性腎不全患者におけるフレカイニドの血中濃度と頻脈抑制作用の一例　　　　　　　　　　　　　　　
松田直之, 平安山直美, 早川峰司, 澤村 淳, 亀山 隆, 丸藤 哲, 武隈 洋, 菅原 満, 宮崎勝巳, 第5回抗不整脈薬TDM研究会（福岡）, 2004年

hOAT1の基質認識における構造相関～核酸類似構造化合物を用いた検討～　　　　　　　　　　　　　　　
小田真也, 望月敬浩, 武隈 洋, 菅原 満, 宮崎勝巳, 日本薬学会北海道支部第122回例会（札幌）, 2004年

奥村勝彦監修、Q＆Aで学ぶTDM活用ガイド　　　　　　　　　　　　　　　
菅原 満, 宮崎勝巳, 薬局, 55, 10月臨時増刊号, 6, 13, 2004年

27-02-06 循環器科病棟において TDM を有効利用した症例
清川 真美, 武隈 洋, 岸野 吏志, 深井 敏隆, 高木 眞弓, 米澤 一也, 菅原 満, 宮崎 勝巳, 北畠 顯, 日本医療薬学会年会講演要旨集, 13, 132, 132, 2003年09月01日
日本医療薬学会, 日本語

抗がん剤適正使用を支える医薬品プロフィール　　　　　　　　　　　　　　　
政田 幹夫, 菅原 満, 有吉 範高, 森田 邦彦, 川上 純一, 後藤 伸之, 中村 敏明, 栄田 敏之, 直良 浩司, 井関 健, 黒崎 勇二, 谷川原 祐介, 向山 雄人, 日本癌治療学会誌, 38, 2, 202, 202, 2003年09月
(一社)日本癌治療学会, 日本語

慢性心不全患者における遺伝子多型性解析
岡本 洋, 秋野 正敏, 松井 裕, 米澤 一也, 小野塚 久夫, 北畠 顕, 菅原 満, 東 純一, 日本内分泌学会雑誌, 79, 2, 539, 539, 2003年09月
(一社)日本内分泌学会, 日本語

生体部分肝移植患者におけるLinezolid(Zyvox)の体内動態
岸野 吏志, 馬渕 朋美, 菅原 満, 嶋村 剛, 古川 裕之, 藤堂 省, 宮崎 勝巳, TDM研究, 20, 2, 183, 184, 2003年04月
(一社)日本TDM学会, 日本語

生体肝移植患者におけるタクロリムスの体内動態の変動とその要因
岸野 吏志, 菅原 満, 古川 博之, 藤堂 省, 宮崎 勝巳, 日本外科学会雑誌, 104, 臨増, 434, 434, 2003年04月
(一社)日本外科学会, 日本語

システムB0を介した中性アミノ酸の輸送におよぼす塩基性薬物の影響　　　　　　　　　　　　　　　
北窪 真弓, 武隈 洋, 菅原 満, Ganapathy V., 宮崎 勝巳, 日本薬学会年会要旨集, 123年会, 4, 61, 61, 2003年03月
(公社)日本薬学会, 日本語

α1-酸性糖蛋白質への立体選択的な薬物結合におけるシアル酸の影響　　　　　　　　　　　　　　　
中川 勉, 伊藤 慎, 岸野 吏志, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 123年会, 4, 69, 69, 2003年03月
(公社)日本薬学会, 日本語

消化管内の生理的条件を考慮した薬物消化管吸収評価系の構築 プロドラッグの吸収評価　　　　　　　　　　　　　　　
何 新, 武隈 洋, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 123年会, 4, 101, 101, 2003年03月
(公社)日本薬学会, 日本語

癌化学療法時の口内炎予防を目的としたメシル酸カモスタット口腔内速崩錠の調製とその評価　　　　　　　　　　　　　　　
須田 範行, 今野 安大, 岩井 美和子, 森田 豊, 中田 宏, 菅原 満, 宮崎 正三, 宮崎 勝巳, 日本薬学会年会要旨集, 123年会, 4, 122, 122, 2003年03月
(公社)日本薬学会, 日本語

カルニチントランスポーター（OCTN2）発現細胞を用いた基質認識特性の解明　　　　　　　　　　　　　　　
高野太樹, 武隈 洋, 菅原 満, 宮崎勝巳, 日本薬学会北海道支部第120回例会（札幌）, 2003年

システムＡアミノ酸トランスポーターの活性・発現におよぼすインスリンの影響　　　　　　　　　　　　　　　
柏木 仁, 武隈 洋, 菅原 満, 宮崎勝巳, 日本薬学会北海道支部第120回例会（札幌）, 2003年

抗ウイルス薬リバビリンの胎盤透過機構　　　　　　　　　　　　　　　
森田 崇, 武隈 洋, 菅原 満, 宮崎勝巳, 日本薬学会北海道支部第120回例会（札幌）, 2003年

フェンタニルパッチ連日投与により傾眠が改善された一症例　　　　　　　　　　　　　　　
志賀弘康, 荻野 修, 菅原 満, 宮崎勝巳, 北海道病院薬剤師会誌, 65, 37, 40, 2003年

リスク軽減を目的とした調剤業務のシステム化−薬袋作製機の導入−　　　　　　　　　　　　　　　
橋本純一, 深井敏隆, 荻野 修, 菅原 満, 宮崎勝巳, 北海道病院薬剤師会誌, 64, 53, 56, 2003年

グルタミンの動態と臨床的有用性
菅原 満, 日本医療薬学会会報, 6, 4, 16, 25, 2002年12月
(一社)日本医療薬学会, 日本語

P-47 より充実した情報提供に向けて : 新データシステムの構築
橋本 純一, 山下 恭範, 榊原 則寛, 川合 真次, 深井 敏隆, 荻野 修, 菅原 満, 宮崎 勝巳, 日本医療薬学会年会講演要旨集, 12, 156, 156, 2002年09月24日
日本医療薬学会, 日本語

P-433 肝移植患者における内因性 cortisol の尿中代謝物を用いた薬物代謝能(CYP 3 A 4 活性)評価法の検討
岸野 吏志, 小川 真紀, 菅原 満, 古川 博之, 藤堂 省, 宮崎 勝巳, 日本医療薬学会年会講演要旨集, 12, 253, 253, 2002年09月24日
日本医療薬学会, 日本語

病院における製剤 くる病患者のリン酸補給に対するリン酸バッファー錠の調整と臨在学的評価　　　　　　　　　　　　　　　
岸野 吏志, 菅原 満, 宮崎 勝巳, 郡 修徳, PHARM TECH JAPAN, 18, 8, 1227, 1233, 2002年07月
(株)じほう, 日本語

膜と薬物の相互作用 生物物理化学的アプローチ 薬物-生体膜間の静電的相互作用をファクターとした薬物吸収性予測　　　　　　　　　　　　　　　
菅原 満, 日本薬学会年会要旨集, 122年会, 1, 195, 195, 2002年03月
(公社)日本薬学会, 日本語

消化管内pH変動および腸管代謝を考慮した薬物吸収予測システムの構築　　　　　　　　　　　　　　　
何 新, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 122年会, 4, 51, 51, 2002年03月
(公社)日本薬学会, 日本語

小腸上皮細胞におけるポリアミン取り込み機構　　　　　　　　　　　　　　　
瀬戸 恵介, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 122年会, 4, 63, 63, 2002年03月
(公社)日本薬学会, 日本語

α1-酸性糖蛋白質の不均一性体とPropranolol光学異性体の立体選択的結合性　　　　　　　　　　　　　　　
伊藤 慎, 中川 勉, 岸野 吏志, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 122年会, 4, 71, 71, 2002年03月
(公社)日本薬学会, 日本語

α1-酸性糖蛋白質とその不均一性体の糖鎖構造解析　　　　　　　　　　　　　　　
中川 勉, 越浪 由加, 佐々木 花, 岸野 吏志, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 122年会, 4, 71, 71, 2002年03月
(公社)日本薬学会, 日本語

肝移植患者におけるCHDF(持続血液濾過透析)施行時のGanciclovirの血中動態　　　　　　　　　　　　　　　
岸野 吏志, 菅原 満, 宮崎 勝巳, 古川 博之, 藤堂 省, 日本薬学会年会要旨集, 122年会, 4, 124, 124, 2002年03月
(公社)日本薬学会, 日本語

VRE感染症治療剤ザイボックス錠の粉砕可否に関する検討　　　　　　　　　　　　　　　
菅原 満, 荻野 修, 宮崎 勝巳, 日本薬学会年会要旨集, 122年会, 4, 149, 149, 2002年03月
(公社)日本薬学会, 日本語

薬学部4年生の医薬品情報(DI)実習における修得度のアンケート調査
川合 真次, 平野 剛, 菅原 満, 井関 健, 岸野 吏志, 荻野 修, 野村 靖幸, 宮崎 勝巳, 日本薬学会年会要旨集, 122年会, 3, 203, 203, 2002年03月
(公社)日本薬学会, 日本語

北大病院におけるＣＲＣ業務について　　　　　　　　　　　　　　　
高田陽美, 橋本あきら, 荻野 修, 菅原 満, 宮崎勝巳, 竹内ひとみ, 奥原芳子, 小柳知彦, 北海道病院薬剤師会誌, 62, 63, 68, 2002年

当院薬剤部におけるリスク回避のための対策　　　　　　　　　　　　　　　
久保田康生, 深井敏隆, 荻野 修, 菅原 満, 宮崎勝巳, 北海道病院薬剤師会誌, 62, 35, 38, 2002年

【新薬展望2002】最近のDDSの進歩　　　　　　　　　　　　　　　
菅原 満, 宮崎 勝巳, 医薬ジャーナル, 38, 増刊, 342, 346, 2002年01月
(株)医薬ジャーナル社, 日本語

O-63 薬剤師主導による心不全患者に対するカルベジロール投与プロトコールの構築 (2) : カルベジロール血中濃度測定が処方構築に有用だった例
清川 真美, 岸野 吏志, 深井 敏隆, 高木 眞弓, 米澤 一也, 小林 道也, 菅原 満, 宮崎 勝巳, 北畠 顯, 日本医療薬学会年会講演要旨集, 11, 94, 94, 2001年09月01日
日本医療薬学会, 日本語

P-94 院内製剤 1.0M 安息香酸ナトリウム注射液, 0.25M フェニル酢酸ナトリウム注射液に関する検討 : 製剤の安定性および生体肝移植直前の高アンモニア血症に対する使用例
岩井 美和子, 武隈 洋, 須田 範行, 岸野 吏志, 菅原 満, 古川 博之, 藤堂 省, 宮崎 勝巳, 日本医療薬学会年会講演要旨集, 11, 134, 134, 2001年09月01日
日本医療薬学会, 日本語

β-ラクタム系抗生物質の消化管吸収における重炭酸イオンの影響
山崎 浩二郎, 北窪 真弓, 小林 道也, 菅原 満, 宮崎 勝巳, 薬物動態, 16, Suppl., S309, S309, 2001年09月
(一社)日本薬物動態学会, 日本語

Caco-2細胞における多剤排出蛋白を介したPSP輸送
板垣 史郎, 小林 道也, 井関 健, 菅原 満, 宮崎 勝巳, 薬物動態, 16, Suppl., S243, S243, 2001年09月
(一社)日本薬物動態学会, 日本語

【薬剤の相互作用と副作用 より安全な薬物療法を目指して】内科医がとくに注意すべき相互作用・副作用 症状の捉え方と回避法 抗生物質,抗菌薬
菅原 満, 宮崎 勝巳, 内科, 88, 2, 298, 306, 2001年08月
(株)南江堂, 日本語

肝再生時に活性増大 中性アミノ酸輸送システムA
菅原 満, ファルマシア, 37, 7, 657, 658, 2001年07月
(公社)日本薬学会, 日本語

C6 glioma細胞におけるsystem Aアミノ酸トランスポーターの機能特性　　　　　　　　　　　　　　　
田中 一成, 杉浦 香織, 藤川 世梨, 岡田 直貴, 藤田 卓也, 山本 昌, 菅原 満, Leibach Frederick H., Ganapathy Vadivel, 日本薬学会年会要旨集, 121年会, 3, 83, 83, 2001年03月
(公社)日本薬学会, 日本語

アミノ酸輸送担体システムAのクローニング及び機能解析　　　　　　　　　　　　　　　
菅原 満, Leibach Frederick H., Ganapathy Vadivel, 宮崎 勝巳, 日本薬学会年会要旨集, 121年会, 3, 83, 83, 2001年03月
(公社)日本薬学会, 日本語

α1-酸性糖蛋白質とその不均一性体に対する光学異性体薬物の立体選択的結合性　　　　　　　　　　　　　　　
中川 勉, 伊藤 慎, 岸野 吏志, 小林 道也, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 121年会, 3, 95, 95, 2001年03月
(公社)日本薬学会, 日本語

院内製剤の安定性と使用期限に関する検討　　　　　　　　　　　　　　　
岩井 美和子, 志賀 弘康, 山下 恭範, 須田 範行, 武隈 洋, 岸野 吏志, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 121年会, 3, 139, 139, 2001年03月
(公社)日本薬学会, 日本語

生体肝移植患者におけるタクロリムスの体内動態(2)　　　　　　　　　　　　　　　
岸野 吏志, 志賀 弘康, 山下 恭範, 岩井 美和子, 菅原 満, 古川 博之, 藤堂 省, 宮崎 勝巳, 日本薬学会年会要旨集, 121年会, 3, 141, 141, 2001年03月
(公社)日本薬学会, 日本語

高アンモニア血症に対する院内製剤供給後の治療成績評価　　　　　　　　　　　　　　　
山下 恭範, 岩井 美和子, 志賀 弘康, 岸野 吏志, 菅原 満, 宮崎 勝巳, 窪田 満, 小林 邦彦, 日本薬学会年会要旨集, 121年会, 3, 139, 139, 2001年03月
(公社)日本薬学会, 日本語

薬剤師主導による心不全患者に対するカルベジロール投与プロトコールの構築　　　　　　　　　　　　　　　
清川 真美, 岸野 吏志, 深井 敏隆, 高木 眞弓, 米澤 一也, 小林 道也, 菅原 満, 宮崎 勝巳, 北畠 顯, 日本薬学会年会要旨集, 121年会, 3, 177, 177, 2001年03月
(公社)日本薬学会, 日本語

北大病院における治験コーディネーター業務への取り組み　　　　　　　　　　　　　　　
橋本 あきら, 高田 陽美, 川合 真次, 荻野 修, 菅原 満, 浅野 弘恵, 木下 克恵, 竹内 ひとみ, 奥原 芳子, 宮崎 勝巳, 日本薬学会年会要旨集, 121年会, 3, 157, 157, 2001年03月
(公社)日本薬学会, 日本語

消化管内pH変動を考慮した薬物吸収評価系の改良と消化管内薬物相互作用の評価　　　　　　　　　　　　　　　
小林 道也, 佐田 憲昭, 立浪 綾子, 坪井 瞳, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 121年会, 3, 110, 110, 2001年03月
(公社)日本薬学会, 日本語

病棟業務における薬剤師の職能 循環器科病棟におけるプレアボイド症例　　　　　　　　　　　　　　　
沖 洋充, 清川 真美, 深井 敏隆, 小林 道也, 荻野 修, 菅原 満, 宮崎 勝巳, 日本薬学会年会要旨集, 121年会, 3, 163, 163, 2001年03月
(公社)日本薬学会, 日本語

グルタミントランスポーターの機能解析　　　　　　　　　　　　　　　
菅原 満, 日本薬剤学会会報”生命とくすり”, 17, 4, 6, 7, 2001年

各種イオン型薬物の小腸基底膜透過に及ぼす膜電位の影響　　　　　　　　　　　　　　　
小林 道也, 吉田 英人, 菅原 満, 井関 健, 宮崎 勝巳, 薬物動態, 15, Suppl., S278, S278, 2000年09月
(一社)日本薬物動態学会, 日本語

消化管内pH変動を考慮した吸収評価系によるヒト薬物動態予測　　　　　　　　　　　　　　　
佐田 憲昭, 菅原 満, 小林 道也, 中 正道, 井関 健, 宮崎 勝巳, 薬物動態, 15, Suppl., S278, S278, 2000年09月
(一社)日本薬物動態学会, 日本語

塩酸イリノテカン(CPT-11),SN-38及びSN-38グルクロナイド定量法の確立 高速液体クロマトグラフィーによるラクトン閉環体及び総濃度の分離定量
井藤 達也, 秦 温信, 高岡 和夫, 藤崎 博子, 菅原 満, 井関 健, 宮崎 勝巳, TDM研究, 17, 2, 121, 122, 2000年04月
(一社)日本TDM学会, 日本語

薬物の生体内動態における構造相関(第49報) 消化管内pHの変動を考慮した難溶性薬物の消化管吸収評価法　　　　　　　　　　　　　　　
佐田 憲昭, 菅原 満, 小林 道也, 中 正道, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 120年会, 4, 51, 51, 2000年03月
(公社)日本薬学会, 日本語

ヒト小腸及びCaco-2細胞を用いた薬物吸収性評価 P-glycoproteinによる排出系の異同性　　　　　　　　　　　　　　　
早川 智久, 菅原 満, 井関 健, 宮崎 勝巳, 薬物動態, 14, Suppl., S170, S170, 1999年09月
(一社)日本薬物動態学会, 日本語

消化管内pHの変動を考慮した薬物の消化管吸収評価法の確立　　　　　　　　　　　　　　　
佐田 憲昭, 菅原 満, 小林 道也, 中 正道, 井関 健, 宮崎 勝巳, 薬物動態, 14, Suppl., S217, S217, 1999年09月
(一社)日本薬物動態学会, 日本語

高速液体クロマトグラフィーによる血清中ピルジカイニド定量法の確立　　　　　　　　　　　　　　　
井藤 達也, 新庄 一, 尾形 仁子, 中川 英久, 浜辺 晃, 菅原 満, 井関 健, 宮崎 勝巳, Journal of Cardiology, 34, Suppl.I, 308, 308, 1999年08月
(一社)日本心臓病学会, 日本語

高速液体クロマトグラフィーによる血清中ピルジカイニド定量法の確立と有効濃度の検討
井藤 達也, 福島 紘司, 尾形 仁子, 中川 英久, 浜辺 晃, 菅原 満, 井関 健, 宮崎 勝巳, TDM研究, 16, 2, 149, 150, 1999年04月
(一社)日本TDM学会, 日本語

胃癌患者における胃切除術後の薬物吸収動態　　　　　　　　　　　　　　　
井藤 達也, 福田 由布子, 福島 紘司, 真鍋 邦彦, 秦 温信, 佐野 文男, 斎藤 正信, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 119年会, 4, 146, 146, 1999年03月
(公社)日本薬学会, 日本語

薬物の生体内動態における構造相関(第48報) 多剤排出蛋白を介したPSP(Phenolsulfonphthalein)の腎排泄　　　　　　　　　　　　　　　
小林 道也, 藤本 道夫, 西村 幸穂, 井上 悟, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 119年会, 4, 9, 9, 1999年03月
(公社)日本薬学会, 日本語

イオン型薬物の消化管吸収に及ぼす膜表面電位の影響　　　　　　　　　　　　　　　
黒澤 恵, 菅原 満, 井関 健, 宮崎 勝巳, 薬物動態, 13, Suppl., S219, S219, 1998年10月
(一社)日本薬物動態学会, 日本語

ラット小腸H+依存性輸送タンパクの精製とその機能評価　　　　　　　　　　　　　　　
神谷 あや子, 小林 道也, 菅原 満, 井関 健, 宮崎 勝巳, 薬物動態, 13, Suppl., S268, S268, 1998年10月
(一社)日本薬物動態学会, 日本語

12-4-A4 薬学部 4 年次学生に対する 1 ヶ月間病院実習の実施とその評価
小林 道也, 深井 敏隆, 岸野 吏志, 川合 真次, 菅原 満, 宮本 剛典, 荻野 修, 井関 健, 宮崎 勝巳, 日本病院薬学会年会講演要旨集, 8, 90, 90, 1998年08月17日
日本医療薬学会, 日本語

経腸栄養剤投与時における薬物吸収の変動
井関 健, 浅子 恵, 金内 美妃, 菅原 満, 宮崎 勝巳, 薬剤学, 58, 150, 150, 1998年03月05日
日本語

薬物の生体内動態における構造相関(第43報) LECラットにおけるフェノールスルホンフタレインの腎排泄挙動　　　　　　　　　　　　　　　
藤本 道夫, 小林 道也, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 118年会, 4, 36, 36, 1998年03月
(公社)日本薬学会, 日本語

高アンモニア血症治療薬フェニル酢酸製剤の生体内動態　　　　　　　　　　　　　　　
馬渕 朋美, 板垣 文雄, 橋本 あきら, 岸野 吏志, 菅原 満, 井関 健, 宮崎 勝巳, 郡 修徳, 長坂 博範, 窪田 満, 日本薬学会年会要旨集, 118年会, 4, 150, 150, 1998年03月
(公社)日本薬学会, 日本語

薬物の生体内動態における構造相関(第42報) トリエンチンの尿中排泄におけるスペルミン輸送担体の寄与　　　　　　　　　　　　　　　
藤崎 博子, 小林 道也, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 118年会, 4, 36, 36, 1998年03月
(公社)日本薬学会, 日本語

薬物の生体内動態における構造相関(第44報) 難水溶性薬物の消化管吸収予測　　　　　　　　　　　　　　　
菅原 満, 古居 奈歩, 小林 道也, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 118年会, 4, 7, 7, 1998年03月
(公社)日本薬学会, 日本語

薬物の生体内動態における構造相関(第45報) 薬物の消化管吸収に及ぼす膜表面電位の影響　　　　　　　　　　　　　　　
黒澤 恵, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 118年会, 4, 7, 7, 1998年03月
(公社)日本薬学会, 日本語

最近の文献情報より 薬物相互作用に関する文献情報（6）　　　　　　　　　　　　　　　
小林道也, 平野 剛, 菅原 満, 宮崎勝巳, 日病薬誌, 34, 1559, 1561, 1998年

最近の文献情報より 薬物相互作用に関する文献情報（4）　　　　　　　　　　　　　　　
菅原 満, 岸野吏志, 小林道也, 宮崎勝巳, 日病薬誌, 34, 969, 971, 1998年

最近の文献情報より 薬物相互作用に関する文献情報（3）　　　　　　　　　　　　　　　
平野 剛, 菅原 満, 岸野吏志, 宮崎勝巳, 日病薬誌, 34, 669, 671, 1998年

最近の文献情報より 薬物相互作用に関する文献情報（2）　　　　　　　　　　　　　　　
平野 剛, 小林道也, 菅原 満, 宮崎勝巳, 日病薬誌, 34, 347, 349, 1998年

ペプチド輸送担体の再構築と構造解析
米村 一洋, 神谷 あや子, 菅原 満, 井関 健, 宮崎 勝巳, 薬物動態 = Xenobiotic metabolism and disposition, 12, 195, 195, 1997年10月09日
日本語

薬物の生体内動態における構造相関(第40報) 物理化学的測定値を用いた薬物の消化管吸収予測式の構築　　　　　　　　　　　　　　　
菅原 満, 日本薬学会年会要旨集, 117年会, 4, 13, 13, 1997年03月
(公社)日本薬学会, 日本語

EXCRETION MECHANISM OF POLYAMINE DRUGS FROM THE KIDNEY
小林 道也, 藤崎 博子, 菅原 満, 井関 健, 宮崎 勝巳, 薬物動態, 12, 76, 77, 1997年
The mechanism of renal excretion of polyamine drugs has been investigated in vivo and in vitro. Trientine clearance (CLtri) in the rat was significantly faster than creatinine clearance (CLcr). However, CLtri decreased to almost the same level as the CLcr when trientine and the same number of moles of copper ions were administered simultaneously to the rat. To clarify this active excretion system for trientine, the uptake of trientine and spermine, a physiological polyamine, was investigated using the rat renal proximal tubular brush-border membrane vesicles (BBMV). An outwardly directed Na⁺ gradient remarkably enhanced the uptake of these polyamine compounds, however, it did not affect the uptake of trientine-Cu complex. The Na⁺-dependent uptake of [³H]spermine was completely inhibited by spermine, trientine and tetraethylenepentamine. On the contrary, physiological polyamines (putrescine and spermidine) which have 2 or 3 amino-groups, and aminoglycoside antibiotics which have 4 or 5 cationic amines, did not affect the uptake of spermine in the presence of an outward Na⁺ gradient. These results suggest that the mechanism contribute to the renal tubular secretion of spermine is a Na⁺/spermine antiport system, and this transporter recognizes the straight-chain polyamine drug which has more than 4 amino-groups in its molecule., The Japanese Society for the Study of Xenobiotics, 英語

Effect of cationic drugs on Na⁺-dependent carrier mediated transport and its evaluation
加藤 雅也, 菅原 満, 小林 道也, 井関 健, 宮崎 勝巳, 薬物動態, 12, 74, 75, 1997年
We investigated the effect of cationic drugs on carrier mediated transport using in vitro and in situ techniques. The initial uptake of glucose, alanine and glutamic acid by rat intestinal brush border membrane vesicles(BBMV) was distinctly inhibited by imipramine in the presence of Na⁺ gradient, but not inhibited in the absence of Na⁺ gradient. This result indicates that imipramine inhibited carrier mediated transport. Imipramine exhibited competitive inhibition with respect to Na⁺ concentration, while exhibited non-competitive inhibition with respect to glutamic acid concentration. This finding suggests that imipramine affected carrier mediated transport by competitive inhibition to Na⁺ binding site of the carrier. On the other hand, in situ single pass perfusion method showed that absorption of alanine was also inhibited by imipramine and other cationic drugs in the presence of Na⁺, but not inhibited in the absence of Na⁺. This result is agreement with that of BBMV study. The inhibition of carrier mediated alanine transport by cationic drugs in BBMV corresponded to that in situ. There was a relatively good correlationship between the BBMV study and in situ perfusion study in the inhibitory effects., The Japanese Society for the Study of Xenobiotics, 英語

薬物の物理化学的測定値による新規消化管吸収予測法の検討
武隈 洋, 菅原 満, 山田 晴美, 小林 道也, 井関 健, 宮崎 勝巳, 薬物動態 = Xenobiotic metabolism and disposition, 11, S108, S109, 1996年09月20日
A predicting method for the intestinal absorption of drugs by measuring their physicochemical properties such as organic solvent / buffer partition coefficient, molecular volume (molecular weight), hydrogen bonding and diffusion rate across silicone membrane was investigated. A poor correlation was observed between absorption rate from intestinal lumen and organic solvent / buffer partition coefficient of tested drugs. On the contrary, good regression coefficient (R = 0.801) was obtained when the three factors (molecular weight, hydrogen bonding, and permeation rate across silicone membrane) were used. On the other hand, the excellent regression was observed when the drugs were classified into anionic, cationic, and neutral groups. These results suggest that the permeation rate across silicone membrane, molecular weight, and hydrogen bonding are valuable measures for predicting the absorption behavior of drugs. Moreover, an additional parameter which reflects the effect of the molecular charge will be necessary., The Japanese Society for the Study of Xenobiotics, 日本語

薬物の生体内動態における構造相関(第36報) グルタミン酸の小腸刷子縁膜透過に及ぼすカチオン型薬物の影響　　　　　　　　　　　　　　　
菅原 満, 加藤 雅也, 小林 道也, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 116年会, 4, 38, 38, 1996年03月
(公社)日本薬学会, 日本語

薬物の生体内動態における構造相関(第34報) ポリアミン類のラット腎刷子縁膜透過機構　　　　　　　　　　　　　　　
小林 道也, 田辺 亮, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 116年会, 4, 46, 46, 1996年03月
(公社)日本薬学会, 日本語

薬物の生体内動態における構造相関(第35報) ラット腎セフチブテン輸送担体の再構成　　　　　　　　　　　　　　　
菊地 崇行, Naasani Imad, 菅原 満, 井関 健, 宮崎 勝巳, 日本薬学会年会要旨集, 116年会, 4, 46, 46, 1996年03月
(公社)日本薬学会, 日本語

アニオン型薬物の消化管吸収予測式の構築 物理化学的測定値によるsimulation
菅原 満, 薬物動態, 10, Suppl., 317, 317, 1995年10月
(一社)日本薬物動態学会, 日本語

薬物の生体内動態における構造相関 (第30報) スパルフロキサシンの小腸刷子縁膜透過に及ぼす膜表面電位の効果
辻華里, 平野剛, 宮崎正三, 高田昌彦, 菅原満, 井関健, 宮崎勝巳, 日本薬学会年会要旨集, 115th, Pt 4, 102, 1995年03月
日本語

イオン性薬物の小腸刷子縁膜透過におよぼす膜表面電位の影響
菅原 満, 薬物動態, 9, Suppl., 62, 65, 1994年10月
(一社)日本薬物動態学会, 日本語

キノロン系抗菌剤の消化管吸収および腎排せつ機構
平野剛, 宮崎正三, 高田昌彦, 菅原満, 井関健, 宮崎勝巳, 薬物動態, 9, Suppl, S110-S113, 113, 1994年10月
Transport mechanisms of intestinal absorption and renal excretion for new-quinolone antibactrial agents were investigated. The absorption of enoxacin (ENX) from rat jejunal loop exhibited a pH-dependent profile. The greater absorption at acidic pH of medium was observed, and ciprofloxacin (CPFX) reduced the ENX plasma concentration after simultaeously oral administration to rat. In the uptake experiments by the intestinal brush-border membrane vesicles (BBMV), initial rate and time-course of ENX and sparfioxacin (SPFX) were significantly dependent on the pH of medium (pH5.5 > pH7.5), and CPFX inhibited compleately the pH dependent uptake of ENX. The ion diffusion potential affected the uptake of these drugs by the intestinal BBMV. On the other hand, ENX uptake by the renal BBMV was contributed by not only the ionic diffusion potential but also the cation-H⁺ antiport system of organic cation secretion., The Japanese Society for the Study of Xenobiotics, 日本語

The Transport Mechanism of an Organic Cation, Disopyramide, by Brush-Border Membranes. : Comparison Between Renal Cortex and Small Intestine of the Rat.
TAKAHASHI YASUSHI, ITOH TATSUYA, KOBAYASHI MICHIYA, SUGAWARA MITSURU, SAITOH HIROSHI, ISEKI KEN, MIYAZAKI KATSUMI, MIYAZAKI SHOZO, TAKADA MASAHIKO, KAWASHIMA YOSHIAKI, 岐阜藥科大學紀要, 43, 84, 84, 1994年06月30日
岐阜薬科大学, 英語

EFFECT OF MEMBRANE SURFACE POTENTIAL ON THE PERMEATION OF IONIC DRUGS THROUGH THE INTESTINAL BRUSH-BORDER MEMBRANE
菅原 満, 小林 道也, 井関 健, 宮崎 勝巳, 薬物動態, 9, 62, 65, 1994年
The effect of membrane surface potential on the permeation of ionic compounds through the intestinal brush-border membrane was investigated using uptake experiments by brush-border membrane vesicles (BBMV) and large unilamellar vesicles (LUV). The uptake of anionic compounds (ceftibuten, cefixime, benzylpenicillin etc.) was decreased with increase of membrane surface negativity. On the other hand, the uptake of a cationic compound, tryptamine, was increased with increase of surface negativity. The uptake of these ionic compounds was well correlated with membrane surface potential of BBMV and LUV monitored by ANS. These results suggest that the permeation of ionic compounds through the intestinal brush-border membrane is dependent on the membrane surface potential. The mechanism of inhibitory effect on the uptake among these Ionic compounds was also examined from the viewpoint of changes in the membrane surface potential. The inhibitory effect of tetracaine and imipramine on the uptake of tryptamine was well correlated with changes in the membrane surface potential induced by these organic cations. Similar relation was observed in the inhibitory effect of flufenamic acid on the uptake of cefixime. These results suggest that changes in the membrane surface potential contribute to the inhibitory effect on the uptake of these Ionic compounds., The Japanese Society for the Study of Xenobiotics, 英語

MECHANISM OF POLYAMINES TRANSPORT BY RAT INTESTINAL EPITHELIAL CELL MEMBRANE
小林 道也, 菅原 満, 井関 健, 宮崎 勝巳, 薬物動態, 8, 743, 746, 1993年
The uptake characteristics of polyamines have been investigated using rat intestinal brush-border membrane vesicles (BBMV). The uptake of these polyamines into BBMV was high and the order of uptake activity was spermine > spermidine > putrescine, and the medium pH affected remarkably the uptake of polyamines (pH 7.5 > pH 5.5). We have also examined the binding behavior of polyamines to liposome, and the similar phenomenon such as uptake activity and pH-dependency was observed. An inward Na⁺ gradient did not stimulate the initial uptake of all polyamines. The uptake rate of spermine and spermidine were saturable (Km = 30.4 and 148.1 μM, respectively), but putrescine was not saturable up to 8 mM. Spermine competitively inhibited the uptake rate of spermidine (Ki = 33.8 NM), while putrescine inhibited spermidine non-competitively (Ki = 3.28 mM). However, intravesicular spermine exhibited no trans-stimulation effect on the uptake of spermine and spermidine. Therefore, the polyamines were considered to be taken up via a passive diffusion mechanism rather than the carrier-mediated systems. The interaction between polyamine and inner-layer acidic phospholipids of BBMV might play an important role as a driving force of the polyamine uptake mechanism. Furthermore, the uptake mechanism of polyamine was different from cationic compounds because valinomycin-induced potassium diffusion potential (inside negative) did not affect the uptake of polyamines., The Japanese Society for the Study of Xenobiotics, 英語

薬物の生体内動態における構造相関(第1報) β-ラクタム系抗生物質の消化管吸収機構　　　　　　　　　　　　　　　
菅原 満, 日本薬学会年会要旨集, 111年会, 4, 137, 137, 1991年03月
(公社)日本薬学会, 日本語

βラクタム系抗生物質の小腸刷子縁膜透過性　　　　　　　　　　　　　　　
菅原 満, 日本薬学会年会要旨集, 109年会, 2, 76, 76, 1989年03月
(公社)日本薬学会, 日本語

パートナー薬剤学
原島, 秀吉, 伊藤, 智夫, 寺田, 勝英, 伊藤, 清美
南江堂, 2022年02月, 9784524403875, xiv, 436p, 日本語, ［分担執筆］

薬理学
吉岡, 充弘, 泉, 剛, 井関, 健, 横式, 尚司, 菅原, 満
医学書院, 2022年01月, 9784260047166, 12, 361p, 日本語

臨床薬学テキストシリーズ 循環器/腎・泌尿器/代謝/内分泌
赤池, 昭紀, 伊藤, 貞嘉, 上野, 和行, 乾, 賢一, 虚血性心疾患
中山書店, 2020年01月, 9784521744520, xviii, 381p, 日本語, ［分担執筆］

免疫疾患/骨・関節疾患/血液・造血器疾患/内分泌・代謝疾患
菅原, 満, 石井, 伊都子
南江堂, 2018年03月, 9784524252152, xii, 145p, 日本語

薬理学
吉岡, 充弘, 泉, 剛, 井関, 健, 横式, 尚司, 菅原, 満
医学書院, 2018年, 9784260031844, 10, 352p, 日本語

2015年版 循環器薬の血中濃度モニタリングに関するガイドライン　　　　　　　　　　　　　　　
菅原 満, 血中濃度測定法、各薬の薬物相互作用一覧
一般社団法人日本循環器学会, 2015年, ［共著］

コンパス医薬品情報学 : 理論と演習
菅原 満, 臨床研究の立案と実践
南江堂, 2015年, 9784524403332, ix, 231p, 日本語, ［単著］

Applied 臨床薬物動態学　　　　　　　　　　　　　　　
菅原 満, 臨床薬物動態学総論 薬物の体内動態
京都廣川書店, 2013年, ［分担執筆］

新編 プログラム学習による病態と処方解析　　　　　　　　　　　　　　　
菅原 満, 呼吸器疾患（急性気管支炎，肺炎）
廣川書店, 2013年, ［分担執筆］

実務実習テキストアルティメイト―現場で生きる学問を目指して―　　　　　　　　　　　　　　　
菅原 満, 第５章リスクマネージメント
京都廣川書店, 2010年04月, ［分担執筆］

TDM実践ハンドブック　　　　　　　　　　　　　　　
唯野貢司, 菅原 満, 小林道也, 齊藤嘉津彦, 後藤仁和, 戸田貴大
薬事新報社, 2007年, ［分担執筆］

薬物の胎盤透過に関与するヌクレオシドトランスポーターの同定および機能評価
菅原, 満
[北海道大学病院], 2006年, 41p

表解注射薬の配合変化 : 混注時の留意点
菅原, 満, 宮本, 剛典
じほう, 2005年09月, 4840734682, 17, 543p, 日本語, ［監修］

プログラム学習による処方解析学　　　　　　　　　　　　　　　
菅原 満, 井関 健, 呼吸器疾患
廣川書店, 2004年, ［分担執筆］

最新皮膚科学大系 特別巻１ 新生児・小児・高齢者の皮膚疾患　　　　　　　　　　　　　　　
菅原 満, 宮崎勝巳, 新生児・小児の薬剤使用上の一般的注意、内服薬
中山書店, 2004年, ［分担執筆］

医学書院 医学大事典　　　　　　　　　　　　　　　
菅原 満
医学書院, 2003年, ［分担執筆］

アレルギー性咳嗽患者に対する抗アレルギー薬の適用と治療効果に関する疫学研究　　　　　　　　　　　　　　　
石坂 悠, 武隈 洋, 平野卓哉, 野田敏宏, 熊井恵美, 菅原 満
第18回日本医療薬情報学会総会・学術大会（岡山）, 2015年06月27日
［国内会議］

耳鼻咽喉科領域におけるアレルギー性咳嗽患者に対する抗アレルギー薬の適用と治療効果　　　　　　　　　　　　　　　
武隈 洋, 石坂 悠, 平野卓哉, 野田敏宏, 熊井惠美, 菅原 満
第64回日本アレルギー学会学術大会（東京）, 2015年05月26日
［国内会議］

乳剤化によるコエンザイムQ10の消化管吸収改善　　　　　　　　　　　　　　　
佐藤夕紀, 竹川悠人, 能登数馬, 武隈 洋, 菅原 満
日本薬剤学会第30年会（長崎）, 2015年05月21日
［国内会議］

エゼチミブ（ゼチーア○Rが機能性食品成分α-トコフェノールの吸収に与える影響　　　　　　　　　　　　　　　
梨本俊亮, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
日本薬剤学会第30年会（長崎）, 2015年05月21日
［国内会議］

TDMへの応用を目指した３種のチロシンキナーゼ阻害剤の血中濃度測定法の検証　　　　　　　　　　　　　　　
助畑 歩, 武隈 洋, 佐藤夕紀, 鷲見正人, 田中寛之, 遠藤雅之, 菅原 満
日本薬学会北海道支部第142回例会（札幌）, 2015年05月16日
［国内会議］

「実践的医療薬学教育プログラム」および「チーム医療・地域医療プログラム」の開発～シンポジウム「先導的薬剤師養成に向けた実践的アドバンスト教育プログラムの共同開発」　　　　　　　　　　　　　　　
小澤光一郎, 中嶋幹郎, 菅原 満, 関根祐子
日本薬学会第135年会（神戸）, 2015年03月25日
［国内会議］

Niemann-Pick C1 Like-1 (NPC1L1)を標的とした乳剤化による難吸収性物質の吸収改善　　　　　　　　　　　　　　　
竹川悠人, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
日本薬学会第135年会（神戸）, 2015年03月25日
［国内会議］

ローヤルゼリー機能性成分の腸管 透過性評価と吸収成分の生理機能の解析　　　　　　　　　　　　　　　
本間直幸, 山日千明, 面すみれ, 佐藤夕紀, 菅原 満, 村田清志, 山口喜久二, 森山隆則
第12回日本機能性食品医用学会総会（京都）, 2014年12月14日
［国内会議］

UDP-グルクロン酸転移酵素の生細胞と細胞破砕液での代謝活性の比較　　　　　　　　　　　　　　　
池上由麻, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第28回北海道TDM研究会研究発表会（札幌）, 2014年11月29日
［国内会議］

２種の血中テイコプラニン濃度測定キット間の測定値の相関性　　　　　　　　　　　　　　　
田中寛之, 山田武宏, 戸田貴大, 小林道也, 菅原 満, 猪爪信夫
第63回日本感染症学会東日本地方会総会学術集会・第61回日本化学療法学会東日本支部総会合同学会（東京）, 2014年10月29日
［国内会議］

アレルギー性咳嗽治療に用いられる抗アレルギー薬の使用実態～内科と耳鼻咽喉科の比較～　　　　　　　　　　　　　　　
石坂 悠, 武隈 洋, 吉村恵理, 吉田憲史, 小嶋希望, 上野英文, 菅原 満
第24回日本医療薬学会年会（名古屋）, 2014年09月27日
［国内会議］

UGT1A1 p.P364L変異体およびUGT2B7 p.P366L変異体の光学異性体認識性　　　　　　　　　　　　　　　
依田めぐみ, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第28回北海道薬物作用談話会（札幌）, 2014年07月19日
［国内会議］

抗ウイルス薬リバビリンのトランスポーターを介した消化管吸収の解析　　　　　　　　　　　　　　　
早風郁美, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第28回北海道薬物作用談話会（札幌）, 2014年07月19日
［国内会議］

中等量エトポシド (VP-16)/シクロホスファミド (CY)/全身放射線(TBI)前処置レジメンにおけるVP-16のPK/PD解析による投与量の最適化に関する検討　　　　　　　　　　　　　　　
田澤佑基, 武隈 洋, 佐藤夕紀, 鷲見正人, 笠師久美子, 井関 健, 菅原 満
第22回クリニカルファーマシーシンポジウム/医療薬学フォーラム2014（東京）, 2014年06月28日
［国内会議］

臨床応用を目指したHPLC-UV法による血中imatinib定量法の確立　　　　　　　　　　　　　　　
田中寛之, 木村雄太, 川口啓之, 武隈 洋, 高崎雅彦, 菅原 満
第31回日本TDM学会・学術大会（東京）, 2014年05月31日
［国内会議］

細胞周期変化がエトポシド（VP-16）の殺細胞効果に与える影響　　　　　　　　　　　　　　　
田澤佑基, 吉岡美咲, 武隈 洋, 佐藤夕紀, 鷲見正人, 菅原 満
日本薬学会北海道支部第141回例会（札幌）, 2014年05月24日
［国内会議］

実践的医療薬学教育プログラム及びチーム医療・地域医療プログラム～シンポジウム「先導的薬剤師養成に向けた実践的アドバンスト教育プログラムの共同開発」　　　　　　　　　　　　　　　
菅原 満
日本薬学会第134年会（熊本）, 2014年03月27日
［国内会議］

Coenzyme Q10の消化管吸収改善　　　　　　　　　　　　　　　
佐藤夕紀, 能登一馬, 竹川悠人, 鷲見正人, 武隈 洋, 菅原 満
日本コエンザイムQ協会 第11回研究会（東京）, 2014年01月28日
［国内会議］

薬物曝露による細胞周期変化が細胞周期依存性の抗癌剤の作用に与える影響　　　　　　　　　　　　　　　
吉岡美咲, 田澤佑基, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第27回北海道TDM研究会研究発表会（札幌）, 2013年11月30日
［国内会議］

テアニンの体内動態および吸収機構の解明　　　　　　　　　　　　　　　
亀田佑生, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第27回北海道TDM研究会研究発表会（札幌）, 2013年11月30日
［国内会議］

Caco-2細胞におけるNPC1L1を介したコレステロール輸送の特徴　　　　　　　　　　　　　　　
阿部沙也華, 竹川悠人, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第27回北海道TDM研究会研究発表会（札幌）, 2013年11月30日
［国内会議］

乳剤化による難吸収性物質の吸収改善～コレステロール輸送担体NPC1L1の利用～　　　　　　　　　　　　　　　
竹川悠人, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第23回日本医療薬学会年会（仙台）, 2013年09月21日
［国内会議］

難吸収性ポリフェノールの乳剤化によるバイオアベイラビリティ改善　　　　　　　　　　　　　　　
星山博俊, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第27回北海道薬物作用談話会（江別）, 2013年07月20日
［国内会議］

Intracellular uptake mechanism of lutein in retinal pigment epithelial cells　　　　　　　　　　　　　　　
Sato Y, Kondo Y, Sumi M, Takekuma Y, Sugawara M
5th World Conference on Drug Absorption, Transport and Delivery (WCDATD)（Uppsala, Sweden）, 2013年06月24日

黄斑色素成分ルテインのヒト網膜上非細胞内への取り込み機構の解明　　　　　　　　　　　　　　　
佐藤夕紀, 近藤 有, 武隈 洋, 菅原 満
日本薬剤学会第28年会（名古屋）, 2013年05月23日
［国内会議］

hOATPs/rOatpsを介するミコフェノール酸グルクロナイドの輸送特性の種差　　　　　　　　　　　　　　　
坂本達彦, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
日本薬学会北海道支部第140例会（札幌）, 2013年05月18日
［国内会議］

熱力学的手法を用いた多剤排出輸送担体の基質検索の検討　　　　　　　　　　　　　　　
森岡悠紀, 鷲見正人, 佐藤夕紀, 武隈 洋, 菅原 満
日本薬学会北海道支部第140例会（札幌）, 2013年05月18日
［国内会議］

Niemann-pick C1 Like-1 (NPC1L1)を介した難吸収性物質の吸収改善へのアプローチ　　　　　　　　　　　　　　　
竹川悠人, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
日本薬学会北海道支部第140例会（札幌）, 2013年05月18日
［国内会議］

より服用しやすい製剤を調製するための工夫　　　　　　　　　　　　　　　
菅原 満
第207回薬剤師臨床セミナー（札幌薬剤師会）, 2013年05月16日, 公開講演，セミナー，チュートリアル，講習，講義等
札幌薬剤師会誌，68, 53-68 (2013)

一包化調剤時におけるスタチン製剤の保存安定性　　　　　　　　　　　　　　　
高地里佳, 石坂 悠, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
日本薬学会第133年会（横浜）, 2013年03月27日
［国内会議］

ヌクレオシドトランスポーターの基質輸送に及ぼすエトポシドの影響　　　　　　　　　　　　　　　
高田一輝, 田澤佑基, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
日本薬学会第133年会（横浜）, 2013年03月27日
［国内会議］

シタラビンの白血球細胞内移行に対するエトポシドの影響　　　　　　　　　　　　　　　
高田一輝, 田澤佑基, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第26回北海道TDM研究会研究発表会（札幌）, 2012年12月08日
［国内会議］

一包化調剤時におけるスタチン製剤の保存安定性　　　　　　　　　　　　　　　
高地里佳, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第26回北海道薬物作用談話会（札幌）, 2012年07月28日
［国内会議］

テアニンの脳移行に関与するトランスポーター　　　　　　　　　　　　　　　
川守田渉, 亀田佑生, 佐藤夕紀, 鷲見正人, 武隈 洋, 菅原 満
第26回北海道薬物作用談話会（札幌）, 2012年07月28日
［国内会議］

粒子径に着目したCoQ10の乳剤化による吸収改善　　　　　　　　　　　　　　　
能登数馬, 佐藤夕紀, 武隈 洋, 菅原 満
日本薬学会北海道支部第138回例会（札幌）, 2012年06月16日
［国内会議］

P糖蛋白質（P-gp）発現白血病由来細胞を用いたエトポシド（VP-16）／シクロホスファミド（CY）曝露順序の殺細胞効果に及ぼす影響　　　　　　　　　　　　　　　
臼窪一平, 田澤佑基, 佐藤夕紀, 鷲見正人, 柴山良彦, 武隈 洋, 菅原 満
日本薬学会第132年会（札幌）, 2012年03月28日
［国内会議］

国立大学における「実践的医療薬学教育プログラム」の開発　　　　　　　　　　　　　　　
中嶋幹郎, 菅原 満, 関根祐子, 小澤光一郎
日本薬学会第132年会（札幌）, 2012年03月28日
［国内会議］

Improvement of intestinal absorption of functional foods, lutein and coenzyme Q10　　　　　　　　　　　　　　　
Sato Y, Mutoh H, Takekuma Y, Iseki K, Sugawara M
8th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology（Istanbul, Turkey）, 2012年03月19日

中等量VP-16/シクロホスファミド(CY)/全身放射線(TBI)前処置レジメンにおけるVP-16のPK/PD解析　　　　　　　　　　　　　　　
田澤佑基, 松村一仙, 佐藤夕紀, 鷲見正人, 武隈 洋, 重松明男, 笠師久美子, 山田武宏, 田中淳司, 橋野 聡, 井関 健, 今村雅寛, 菅原 満
第34回日本造血細胞移植学会総会（大阪）, 2012年02月24日
［国内会議］

天然色素成分ルテインの乳化による消化管吸収改善　　　　　　　　　　　　　　　
佐藤夕紀, 武隈 洋, 井関 健, 菅原 満
第9回日本機能性食品医用学会総会（大阪）, 2011年12月10日
［国内会議］

機能性食品成分ルテインの乳化による消化管吸収の改善　　　　　　　　　　　　　　　
佐藤夕紀, 鈴木里彩, 武隈 洋, 井関 健, 菅原 満
医療薬学フォーラム2011／第19回クリニカルファーマシーシンポジウム（旭川）, 2011年07月09日
［国内会議］

オピオイドによる難治性の嘔気とめまいに対しH1受容体拮抗薬とペロスピロンの併用が有効であった症例　　　　　　　　　　　　　　　
長田貴之, 柴山良彦, 熊井正貴, 山田武宏, 笠師久美子, 菅原 満, 井関 健
医療薬学フォーラム2011／第19回クリニカルファーマシーシンポジウム（旭川）, 2011年07月09日
［国内会議］

同種造血幹細胞移植時における中等量エトポシド（VP-16）／シクロホスファミド（CY）／全身放射線（TBI）前処置レジメンの検討～VP-16のPK/PD解析および培養細胞系を用いたVP-16／CY曝露順序の検討　　　　　　　　　　　　　　　
田澤佑基, 松村一仙, 佐藤夕紀, 鷲見正人, 武隈 洋, 重松明男, 笠師久美子, 山田武宏, 井関 健, 今村雅寛, 菅原 満
第28回日本TDM学会・学術大会（広島）, 2011年06月18日
［国内会議］