研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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Effects of α-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport

Takara Kohji, Sakaeda Toshiyuki, Kakumoto Mikio, Tanigawara Yusuke, Kobayashi Hironao, Okumura Katsuhiko, Ohnishi Noriaki, Yokoyama Teruyoshi

Oncology Research 17 （ 11-12 ） 527 - 533 2009年

ISSN 0965-0407

The purpose of this study is to examine the effects of doxazosin, an α-adrenoceptor antagonist, on P-glycoprotein/MDR1-mediated multidrug resistance (MDR) and the transport of anticancer drugs. The effects of doxazosin, prazosin, and terazosin on MDR1-mediated MDR were assessed in human cervical carcinoma HeLa cells and the MDR1-overexpressing derivative Hvr100-6, established by stepwise increases of the vinblastine concentration in the culture medium. The effects of doxazosin on the transcellular transport and intracellular accumulation of [³H]vinblastine, [3H]daunorubicin, and [³H]digoxin, all MDR1 substrates, were evaluated using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK₁ cells. The sensitivity to vinblastine and paclitaxel of Hvr100-6 cells was increased at 3.4- and 17.5-fold, respectively, by the addition of 1 μM doxazosin, whereas prazosin and terazosin had weaker or no such effects. Prazosin at 1 μM had a reversal effect on the sensitivity to vinblastine, whereas terazosin had no effect. In transport experiments, doxazosin concentration dependently increased the apical-to-basal transport of radiolabeled drugs in LLC-GA5-COL150 cells, but did not show remarkable effects on the basal-to-apical transport. In addition, doxazosin restored the intracellular accumulation in a concentration-dependent manner in LLC-GA5-COL150 cells. Doxazosin may partly reverse MDR by inhibiting MDR1-mediated transport, making it a candidate lead compound in the development of a reversing agent for MDR. Copyright © 2009 Cognizant Comm. Corp.

Comparative pharmacodynamics of olmesartan and azelnidipine in patients with hypertension: a population pharmacokinetic/pharmacodynamic analysis

Tanigawara Yusuke, Yoshihara Kazutaka, Kuramoto Kizuku, Arakawa Kikuo

Drug Metabolism and Pharmacokinetics 24 （ 4 ） 376 - 388 2009年

ISSN 1347-4367

The objectives of this study were to identify the factors influencing antihypertensive response to the angiotensin receptor blocker, olmesartan medoxomil, or the calcium channel blocker, azelnidipine, and to discuss the possibility of utilizing them as predictors for drug selection prior to therapy. A two-way crossover study of olmesartan medoxomil and azelnidipine was conducted in 29 patients with mild to moderate essential hypertension. The 24-hour ambulatory blood pressure measurements (ABPM) and plasma drug concentrations were obtained on the first and at the end of each treatment period, and were analyzed using population pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The population PK/PD models considering circadian variations in baseline blood pressure well described the observed plasma drug concentrations and 24-hour ABPM profiles. Pre-treatment plasma renin activity (PRA) was identified as a significant covariate on the maximum drug effect (E_max) of olmesartan, whereas azelnidpine E_max was independent of patient background characteristics investigated. No patient was found to have a high E_max to one agent who also had a high E_max to the other. In conclusion, the effects of olmesartan medoxomil and azelnidipine were modestly correlated with pharmacokinetic profiles, and the pre-treatment PRA level could be a useful determinant of responsiveness in selecting olmesartan medoxomil and azelnidipine.

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血中濃度モニタリングに基づくアミカシン，トブラマイシンの用量最適化と治療効果の向上

武田香陽子，池谷　修，山吉康子，早川智久，青柳修一，森田邦彦，谷川原祐介

ＴＤＭ研究（TDM研究） 25 （ 4 ） 180 - 186 2008年10月

院内製剤「人工髄液CSF-19」の開発と調製実績

山口雅也，市村健一，矢島　茂，佐々木　隆，谷川原祐介

薬剤学 68 （ 5 ） 371-377 2008年10月

研究論文（学術雑誌）, 共著, 査読有り

Single-institute phase 2 study of thalidomide treatment for refractory or relapsed multiple myeloma

Hattori Yutaka, Okamoto Shin Ichiro, Shimada Naoki, Kakimoto Tsunayuki, Morita Kunihiko, Tanigawara Yusuke, Ikeda Yasuo

Cancer Science 99 （ 6 ） 1243 - 1250 2008年06月

ISSN 1347-9032

We previously reported a pilot study of thalidomide monotherapy for Japanese patients with refractory or relapsed multiple myeloma. In the present work, we have extended this clinical trial to a single-institute phase 2 study with a larger number of patients and longer follow-up time. New information on the optimal dose and prognostic factors as well as the correlation of toxicities with treatment schedule was obtained. Fifteen of 56 (27%) patients achieved a partial response, including three cases with near-complete remission. Most patients suffered toxicities at a dose of 400 mg per day, but there was no clear dose-response relationship. Thus, a lower dose such as 200.mg per day or less is considered optimal. Multivariate analyses identified only lack of response to therapy as an adverse prognostic factor for progression-free survival. Chromosomal abnormality, C-reactive protein. >10 mg/L, and more than six previous courses of chemotherapy were significantly associated with shorter overall survival. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 23 and 11% of patients, respectively. Grade 4 interstitial pneumonia and grade 5 pulmonary hypertension were observed; however, no patient suffered deep vein thrombosis, which has frequently been observed in other studies. Duration of therapy was closely related to the development of peripheral neuropathy. The efficacy and prognostic factors of this treatment were confirmed in long-term observation. However, special attention should be paid to toxicities such as hematological and pulmonary complications as well as peripheral neuropathy in long-term users. © 2008 Japanese Cancer Association.

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Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Yamada Y., Tahara M., Miya T., Satoh T., Shirao K., Shimada Y., Ohtsu A., Sasaki Y., Tanigawara Y.

British Journal of Cancer 98 （ 6 ） 1034 - 1038 2008年03月

ISSN 0007-0920

Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35-40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m^-2 (level 1) or 130 mg m^-2 (level 2) on day 1, and S-1 (80-120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2-14), RR of 50% (1 CR and 13 PR: 95% CI 31-69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access. © 2008 Cancer Research UK.

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Greater impact of oral fluconazole on drug interaction with intravenous calcineurin inhibitors as compared with intravenous fluconazole

Mihara Ai, Mori Takehiko, Aisa Yoshinobu, Yamazaki Rie, Iketani Osamu, Tanigawara Yusuke, Ikeda Yasuo, Okamoto Shinichiro

European Journal of Clinical Pharmacology 64 （ 1 ） 89 - 91 2008年01月

ISSN 0031-6970

Objective: Although the drug interaction between fluconazole and calcineurin inhibitors has been established, the influence of the route of fluconazole administration on its drug interaction with calcineurin inhibitors has yet to be fully examined. The aim of the present study is to examine whether different routes of fluconazole administration alter its drug interactions with intravenous calcineurin inhibitors. Methods: In 53 recipients of allogeneic hematopoietic cell transplantation receiving calcineurin inhibitors intravenously, steady-state whole-blood levels of cyclosporine A (CsA) or tacrolimus were measured after the route of fluconazole (200 mg/day) administration was switched from intravenous to oral. Results: The mean steady-state whole-blood level of CsA or tacrolimus significantly increased after the route of fluconazole administration was switched from intravenous to oral (CsA: to 394±28.4 from 362±17.8 ng/mL; tacrolimus: to 18.8±0.64 from 17.4±0.39 ng/mL, P<0.05). Conclusion: This finding strongly suggests that oral fluconazole has a greater impact on its drug interactions with intravenous calcineurin inhibitors than intravenous fluconazole. Monitoring of blood levels of intravenous calcineurin inhibitors is recommended when the route of fluconazole administration is switched from intravenous to oral. © 2007 Springer-Verlag.

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Inflluence of MTHFR and RFC1 polymorphisms on toxicities during maintenance chemotherapy for childhood acute lymphoblastic leukemia of lymphoma

N. Shimasaki, T. Mori, C. Torii, R. Sato, H. Shimada, Y. Tanigawara, K. Kosaki, T. Takahashi

J. Pediatr. Hematol. Oncol. 30 （ 5 ） 347-352 2008年

研究論文（学術雑誌）, 共著, 査読有り

小児深在性真菌症患者におけるmicafunginの有効性，安全性および薬物動態

砂川慶介，月本一郎，豊永義清，恒松由記子，岩井直一，谷川原祐介

日本化学療法学会雑誌 56 （ 2 ） 190-201 2008年

研究論文（学術雑誌）, 単著, 査読有り

呼吸器感染症に対するsitafloxacinの一般臨床試験

齋藤　厚，谷川原祐介，渡辺　彰，青木信樹，二木芳人，河野　茂，賀来満夫，堀　誠治，戸塚恭一

日本化学療法学会雑誌 56 （ S1 ） 63-80 2008年

研究論文（学術雑誌）, 共著, 査読有り

MRSA感染症患者に対するarbekacin 200mg１日１回投与の治療効果－臨床薬理試験－

相川直樹，河野　茂，賀来満夫、渡辺　彰，山口恵三，谷川原祐介

日本化学療法学会雑誌 56 （ 3 ） 299-312 2008年

研究論文（学術雑誌）, 共著, 査読有り

Population pharmacokinetics of landiolol hydrochloride in healthy subjects

Honda Naoki, Nakade Susumu, Kasai Hidefumi, Hashimoto Yoshitaka, Ohno Tomoya, Kitagawa Junsaku, Yamauchi Akinori, Hasegawa Chihiro, Kikawa Shinichi, Kunisawa Takayuki, Tanigawara Yusuke, Miyata Yasuyuki

Drug Metabolism and Pharmacokinetics 23 （ 6 ） 447 - 455 2008年

ISSN 1347-4367

Landiolol hydrochloride is a newly developed cardioselective, ultra short-acting β₁-adrenergic receptor blocking agent used for perioperative arrhythmia control. The objective of this study was to characterize the population pharmacokinetics of landiolol hydrochloride in healthy male subjects. A total of 420 blood concentration data points collected from 47 healthy male subjects were used for the population pharmacokinetic analysis. NONMEM was used for population pharmacokinetic analysis. In addition, the final pharmacokinetic model was evaluated using a bootstrap method and a leave-one-out cross validation method. The concentration time course of landiolol hydrochloride was best described by a two-compartment model with lag time. The final parameters were total body clearance (CL: 36.6 mL/min/kg), distribution volume of the central compartment (V1: 101 mL/kg), inter-compartmental clearance (16.1 mL/min/kg), distribution volume of the peripheral compartment (55.6 mL/kg), and lag time (0.82 min). The inter-individual variability in the CL and V1 were 21.8% and 46.3%, respectively. The residual variability was 22.1%. Model evaluation by the two different methods indicated that the final model was robust and parameter estimates were reasonable. The population pharmacokinetic model for landiolol hydrochloride in healthy subjects was developed and was shown to be appropriate by both bootstrap and leave-one-out cross validation methods.

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慢性呼吸器病変の二次感染患者を対象としたgarenoxacinの臨床第Ⅲ相試験-PK/PD試験-

小林　宏行，谷川原　祐介，渡辺　彰，青木　信樹，佐野　靖之，小田切　繁樹，二木　芳人，河野　茂，斎藤　厚

日本化学療法学会雑誌 55 （ SUPPL. 1 ） 144 - 161 2007年10月

ISSN 1340-7007

The efficacy and safety of garenoxacin mesilate hydrate(GRNX), new oral des-fluoroquinolone antimicrobial, were investigated in patients with secondary infection occurred on chronic respiratory disorders. Patients were treated with GRNX 400 mg once daily for 10 days. Plasma concentration of GRNX in each patient was determined and the obtained clinical results were analysed based on pharmacokinetics(PK) and pharmacokinetics/pharmacodynamics(PK/PD) parameters. Clinical efficacy rates were 87.8% (108/123) at the end of treatment and 83.7% (103/123) at the 7th day of post-treatment. Bacteriological eradication rates were 89.6% (60/67) and 85.1% (57/67) at the above time points. Eradication rates of causative organisms were 100% (13/13) in Streptococcus pneumoniae, 7/8 in Staphylococcus aureus, 100% (28/28) in Haemophilus influenzae and 8/8 in Moraxella (Branhamella) catarrhalis at the end of treatment. All penicillin-resistant S. pneumoniae(PRSP) including penicillin-intermediate resistant S. pneumoniae(PISP) were eradicated. Drug-related adverse events were observed in 19 patients (26 events), the incidence rate was 14.0% (19/136). Gastrointestinal disorders including 4 cases of diarrhea (2.9%), 3 of loose stool (2.2%) and 3 of vomiting (2.2%) were frequently observed. Laboratory abnormalities were observed in 26 patients (19.3%). Frequent abnormalities were 14 cases of AST elevation (10.4%), 13 of ALT elevation (9.6%) and 5 of serum amylase elevation (3.8%). No relationship was observed between PK parameters (AUC_0-24 and Cmax) and incidence of adverse events. 90.9% of patient in this study exceeded the target value of fAUC_0-24/MIC > 50. Clinical efficacy at the 7th day of post-treatment was 91.7% (55/60) in those cases whose target value was more than 50, but it was only 3/6 in those whose target value was less than 50. Similar results were obtained in studies in US and EU. From aboves, it indicates that GRNX is a beneficial antimicrobial agent for secondary infection of chronic respiratory diseases.

Phase II study of oxaliplatin in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines

Boku Narikazu, Ohtsu Atsushi, Hyodo Ichinosuke, Shirao Kuniaki, Miyata Yoshinori, Nakagawa Kazuhiko, Tamura Takao, Hatake Kiyohiko, Tanigawara Yusuke

Japanese Journal of Clinical Oncology 37 （ 6 ） 440 - 445 2007年06月

ISSN 0368-2811

Background: Although oxaliplatin (L-OHP) combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV) is one of the standard chemotherapy regimens for metastatic or recurrent colorectal cancer, its introduction to Japan has been delayed. Phase I studies of L-OHP monotherapy in Japan showed no dose-limiting toxicity at the internationally recommended dose of 130 mg/m² every 3 weeks, as well as no racial differences in pharmacokinetics as compared with Western subjects. This study aimed to clarify the efficacy and safety of L-OHP monotherapy in patients with metastatic colorectal cancer refractory to fluoropyrimidines. Methods: Patients with metastatic colorectal cancer who had failed to respond to fluoropyrimidine-based chemotherapy received L-OHP at a dose of 130 mg/m² every 3 weeks. Results: Sixty patients were enrolled. Two ineligible patients and one untreated patient were excluded from analysis. The median number of treatment cycles was 4 (range, 1 - 6). The overall response rate was 9% (5/57, 95% CI: 4 - 19%). The median time to progression was 2.7 months, and the median survival time was 11.1 months. Grade 3 major toxicity comprised thrombocytopenia (12%) and nausea (11%). There was no grade 4 toxicity. All patients experienced mild to moderate sensory neurotoxicity without functional impairment interfering with activities of daily living. Conclusions: The efficacy and toxicity of L-OHP in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines is apparently similar to those in Western patients. © 2007 Foundation for Promotion of Cancer Research.

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がん化学療法レジメンのエビデンスとなる臨床論文の副作用特性に基づいた「副作用グレード評価シート」の作成

今村知世, 後田奈緒美, 津田壮一郎, 谷川原祐介

日本病院薬剤師会雑誌 43 （ 6 ） 796-799 2007年06月

研究論文（学術雑誌）, 単著

ロラタジンシロップの小児における通年性アレルギー性鼻炎に対する第Ⅲ相二重盲検比較試験－フマル酸ケトチフェンドライシロップに対する非劣性の検討－

石川哮，谷川原祐介，鈴木五男，上埜光紀，橋本紘治，熊井惠美，宗信夫，中島光好

臨床医薬 23 （ 11 ） 965 - 990 2007年

Reversal effects of Ca2+ antagonists on multidrug resistance via down-regulation of MDR1 mRNA.

Komoto Chiho, Nakamura Tsutomu, Yamamori Motohiro, Ohmoto Nobuko, Kobayashi Hironao, Kuwahara Akiko, Nishiguchi Kohshi, Takara Kohji, Tanigawara Yusuke, Okamura Noboru, Okumura Katsuhiko, Sakaeda Toshiyuki

The Kobe journal of medical sciences 53 （ 6 ） 355 - 363 2007年

In previous reports, the effects of 12 Ca2+ antagonists on a multidrug resistant transporter, P-glycoprotein/MDR1, were evaluated in terms of those on MDR1-mediated transport of [3H]digoxin and the sensitivity of vinblastine sulfate or paclitaxel, and they were able to be classified into 4 subgroups based on their actions, as those with transport inhibition and sensitivity recovery, those with or without transport inhibition but marginal sensitivity recovery, and those without both. In this study, our previous findings were confirmed by the resistance against doxorubicin hydrochloride and daunorubicin hydrochloride, and by the recovery of [3H] vinblastine sulfate accumulation. Furthermore, it was found that the effects of 12 Ca2+ antagonists on the sensitivity recovery were also explained by the down-regulation of MDR1 mRNA, suggesting a novel mechanism to reverse the MDR1-mediated multidrug resistance.

ロラタジンドライシロップの小児アトピー性皮膚炎に対する第Ⅲ相二重盲検比較試験－フマル酸ケトチフェンドライシロップに対する非劣性の検討－

川島眞，谷川原祐介，鈴木五男，原田昭太郎，中川秀巳，古江増隆，久木田淳，中島光好

臨床医薬 23 （ 11 ） 991 - 1016 2007年

Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors

Yamada Yasuhide, Tamura Tomohide, Yamamoto Noboru, Shimoyama Tatsu, Ueda Yutaka, Murakami Haruyasu, Kusaba Hitoshi, Kamiya Yoshikazu, Saka Hideo, Tanigawara Yusuke, McGovren J. Patrick, Natsumeda Yutaka

Cancer Chemotherapy and Pharmacology 58 （ 2 ） 173 - 182 2006年08月

ISSN 0344-5704

Purpose: Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors. Experimental design: Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m². Pharmacokinetic assessments were performed during and after the first administration. Results: Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m² dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3-4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C_max values of 103 ± 17 ng/ml at the 13 mg/m² dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1-2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4-3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression ≥50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer. Conclusions: The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m². The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m². The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors. © Springer-Verlag 2005.

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Phase I study of single-dose oxaliplatin in Japanese patients with malignant tumors

Shirao Kuniaki, Matsumura Yasuhiro, Yamada Yasuhide, Muro Kei, Gotoh Masahiro, Boku Narikazu, Ohtsu Atsushi, Nagashima Fumio, Sano Yasushi, Mutoh Manabu, Tanigawara Yusuke

Japanese Journal of Clinical Oncology 36 （ 5 ） 295 - 300 2006年05月

ISSN 0368-2811

Background: Oxaliplatin, a platinum compound, has been commonly used around the world for treating advanced colorectal cancer. The generally recommended dose and schedule of oxaliplatin monotherapy is 130 mg/m² every 3 weeks. This trial was conducted to evaluate the safety and pharmacokinetics of oxaliplatin monotherapy in Japanese patients with solid tumors. Methods: Oxaliplatin was administered as a 2-h intravenous infusion every 3 weeks at a dose of 90 and 130 mg/m². Blood was collected to determine the total platinum and the ultrafiltrate platinum concentrations in plasma in all cycles. Results: Nine patients were enrolled; three were given oxaliplatin monotherapy at 90 mg/m² and six received 130 mg/m². All tumors were colorectal cancer. The major adverse reactions included myelosuppressive, neurological and gastrointestinal toxicities, although most were grades 1 and 2 at both dose levels. Peripheral sensory neuropathy of without movement disturbance (grade 1 or 2) was observed in all patients at both dose levels. The 130 mg/m² dose level was not found to be the maximum tolerated dose, but was judged to be the recommended dose. No objective responses were seen and five cases of no change were observed. A bi-exponential open model best described the disappearance of platinum in the plasma, and a tri-exponential open model best described the disappearance of ultrafilterable platinum in the plasma at both dose levels. No racial difference was suggested in the pharmacokinetics of oxaliplatin. Conclusions: The oxaliplatin monotherapy dose schedule of 130 mg/m² every 3 weeks, recommended worldwide, is acceptable for Japanese patients. © 2006 Oxford University Press.

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