研究者詳細 - 谷川原　祐介

論文 - 谷川原　祐介

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Phase I/II study of oxaliplatin with weekly bolus fluorouracil and high-dose leucovorin (ROX) As first-line therapy for patients with colorectal cancer

Yamada Yasuhide, Ohtsu Atsushi, Boku Narikazu, Miyata Yoshinori, Shimada Yasuhiro, Doi Toshihiko, Muro Kei, Muto Manabu, Hamaguchi Tetsuya, Mera Kiyomi, Yano Tomonori, Tanigawara Yusuke, Shirao Kuniaki

Japanese Journal of Clinical Oncology 36 （ 4 ） 218 - 223 2006年04月

ISSN 0368-2811

Background: Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for the treatment of patients with metastatic colorectal cancer. Weekly bolus 5-FU with high-dose LV (Roswell Park Memorial Institute Regimen: RPMI) is the most commonly used regimen in Japan. The objectives of this study were to determine the recommended dose (RD) of RPMI combined with oxaliplatin and to evaluate the toxicity and efficacy at the RD. Methods: The subjects were 18 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m²) was given intravenously over 2 h on days 1 and 15 with l-LV (250 mg/m²) given intravenously over 2 h and 5-FU as an intravenous bolus on days 1, 8, and 15. This treatment was repeated every 4 weeks. The dose of 5-FU was escalated from 400 mg/m² (level 1) to 500 mg/m² (level 2). Results: A total of 14 patients received level 1, and 4 received level 2. Three of the patients had dose-limiting toxicity (DLT) in cycle 1 of level 2 (grade 3 thrombocytopenia, grade 4 neutropenia and grade 2 neutropenia in one patient each), requiring that treatment was delayed for longer than 7 days. None of the 14 patients given level 1 had DLT or grade 3 or 4 gastrointestinal toxicity. Sensory neuropathy occurred in all patients. Objective response rates were 61% in the 18 patients studied and 64% at level 1. The median time to progression was 171 days, and the median overall survival time was 603 days in the 18 patients studied. Conclusions: Oxaliplatin (85 mg/m²) with weekly bol us 5-FU (400 mg/m²) and high-dose l-LV (250 mg/m²) is recommended for further phase III studies in patients with metastatic colorectal cancer. © 2006 Oxford University Press.

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Thalidomide for the treatment of leptomeningeal multiple myeloma

Hattori Yutaka, Yabe Mariko, Okamoto Shinichiro, Morita Kunihiko, Tanigawara Yusuke, Ikeda Yasuo

European Journal of Haematology 76 （ 4 ） 358 - 359 2006年04月

ISSN 0902-4441

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Effects of methylenetetrahydrofolate reductase and reduced folate carrier 1 polymorphisms on high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia or lymphoma

Shimasaki Noriko, Mori Tetsuya, Samejima Hazuki, Sato Reiko, Shimada Hiroyuki, Yahagi Naohisa, Torii Chiharu, Yoshihara Hiroki, Tanigawara Yusuke, Takahashi Takao, Kosaki Kenjiro

Journal of Pediatric Hematology/Oncology 28 （ 2 ） 64 - 68 2006年02月

ISSN 1077-4114

The authors investigated whether high-dose methotrexate-induced toxicity differed according to the presence of methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier 1 (RFC1) genetic polymorphism. The authors studied 15 children with acute lymphoblastic leukemia or lymphoblastic lymphoma who were treated using protocols that included high-dose methotrexate (3.0 g/m²), for an overall total of 43 courses. Methotrexate-induced toxicities and the plasma methotrexate concentrations were evaluated retrospectively. Hematologic toxicity was the most frequently observed toxicity, appearing in 87% of the patients. In a subset of patients (47%), elevation of liver transaminase levels showed a repeated tendency to develop. High plasma methotrexate concentrations at 48 hours after the methotrexate infusion were not significantly related to methotrexate-induced toxicities except for mucositis. A generalized estimating equation analysis revealed that vomiting during the high-dose methotrexate treatment was more pronounced in patients who had a larger number of G alleles at the RFC1 80G>A polymorphism. No significant differences in the development of other toxicities or in the plasma methotrexate concentrations were observed for the different MTHFR 677C>T or RFC1 80G>A polymorphisms. This study suggests but does not prove that the RFC1 80G>A polymorphism may contribute to interindividual variability in responses to high-dose methotrexate. Copyright © 2006 by Lippincott Williams & Wilkins.

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Population Pharmacokinetic Analysis of Micafungin in Japanese Patients with Fungal Infections

谷川原祐介

Drug Metab. Pharmacokinet. 21 （ 4 ） 324-331 2006年

研究論文（学術雑誌）, 単著

1173C>T polymorphism in VKORC1 modulates the required warfarin dose

K. Kosaki, C. Yamaghishi, R. Sato, H. Semejima, H. Fuijita, K. Tamura, K. Maeyama, H. Yamagishi, A. Sugaya, H. Dodo, Y. Tanigawara, T. Takahashi

Pediatr. Cardiol. 27 （ 6 ） 685-688 2006年

研究論文（学術雑誌）, 共著, 査読有り

Novel application of proteinchip technology exploring acute rejection markers of rat small bowel transplantation

Yamayoshi Yasuko, Watanabe Toshihiko, Tanabe Minoru, Hoshino Ken, Matsumoto Koshi, Morikawa Yasuhide, Shimadzu Motohide, Kitajima Masaki, Tanigawara Yusuke

Transplantation 82 （ 3 ） 320 - 326 2006年

ISSN 0041-1337

BACKGROUND. Because no biomarker that reflects small bowel allograft rejection is available, we applied surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to develop noninvasive markers required for routine diagnosis. METHODS. Heterotopic small bowel transplantation (SBT) was performed in rats, and they were divided into four experimental groups: sham-operated rats (sham), syngeneic transplants (syngeneic), allogeneic transplants (allogeneic), allogeneic transplants received FK506 (allo+FK). Plasma samples were analyzed with SELDI ProteinChip arrays to detect peaks that predominated in the allogeneic model. Possible biomarkers were identified in combination with SELDI retentate chromatography mass spectrometry (RCMS) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). The identified protein was further analyzed by immunohistochemistry. RESULTS. An increase in the level of a 14.8-kDa protein, identified as lysozyme, was observed specifically in the plasma of the allogeneic group; the levels of this protein remained unchanged in the plasma of the other groups. On the other hand, the levels of a 10.1-kDa and a 13.0-kDa protein, identified as migration inhibitory factor-related proteins (MRP), MRP-8 and MRP-14, respectively, began to increase from an early stage of acute rejection. We also observed that lysozyme-positive macrophages had strongly infiltrated the lamina propria during acute rejection. CONCLUSIONS. We identified three plasma proteins-MRP-8, MRP-14, and lysozyme-that increased during small bowel allograft rejection. The identified proteins appeared to be markers for inflammation associated with allograft rejection. This proteomic approach will be useful for the identification of candidate biomarkers. Copyright © 2006 by Lippincott Williams & Wilkins.

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Linear pharmacokinetics of micafungin and its active metabolites in Japanese pediatric patients with fungal infections

Tabata Kenji, Katashima Masataka, Kawamura Akio, Tanigawara Yusuke, Sunagawa Keisuke

Biological and Pharmaceutical Bulletin 29 （ 8 ） 1706 - 1711 2006年

ISSN 0918-6158

The objective of this study was to propose the appropriate dosage regimen of micafungin for pediatric use, considering the effects of dose-linearity, age and other cofactors on the pharmacokinetics. Pharmacokinetic analysis of micafungin and its active metabolites (M1 and M2) after intravenous infusion at doses of 1 to 3 mg/kg was conducted for 19 Japanese pediatric patients (3 infants, 7 toddlers, and 9 pupils) with deep mycosis caused by either Aspergillus or Candida species. One patient was given the maximum dose of 6 mg/kg. The Cmax of micafungin increased in proportion to the dose. The mean values (S.D.) were 5.03 (2.33), 10.25 (4.45), 14.8 (5.52) and 21.1 μg/ml at 1, 2 , 3 and 6 mg/kg, respectively. These parameters were comparable to those seen in adults when the parameter was normalized by body weight. The elimination half life (t_1/2) of micafungin over the dose range was apparently constant with the value of 13.1 h. There was no difference between the age groups observed. In fact, the metabolite concentrations were almost the same as those obtained for non-pediatric patients. Thus, micafungin showed the same dose-proportional pharmacokinetics in pediatric patients as it did in adults. No age dependent pharmacokinetics were observed in this study. It was concluded that the body weight adjustment was adequate for the treatment of micafungin in pediatric patients. © 2006 Pharmaceutical Society of Japan.

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Pharmacokinetic-Pharmacodynamic Relationship of Arbekacin for Treatment of Patients Infected with Methicillin-Resistant Staphylococcus aureus

谷川原祐介

Antimicrobial Agents Chemother. 50 （ 11 ） 3763-3769 2006年

研究論文（学術雑誌）, 単著

Population Pharmacokinetics of Arbekacin in Patients Infected with Methicillin-Resistant Staphylococcus Aureus

谷川原祐介

Antimicrobial Agents Chemother. 50 （ 11 ） 3754-3762 2006年

研究論文（学術雑誌）, 単著

A New Active Vitamin D,ED-71, Increases Bone Mass in Osteoporotic Patients under Vitamin D Supplementation:A randomized, Double-Blind, Placebo-Controlled Clinical Trial

Toshio Matsumoto, Takami Miki, Hiroshi Hagino, Toshitsugu Sugimoto, Sumiaki Okamoto, Takako Hirota, Yusuke Tanigawara, Yasufumi Hayashi, Masao Fukunaga, Masataka Shiraki, and Toshitaka Nakamura,'

J. Clin. Endocrinol. Metab. 90 （ 9 ） 5031-5036 2005年09月

研究論文（学術雑誌）, 共著

Faropenem(ファロム錠®）の健常成人と感染症患者における母集団薬物動態

Hirooka Hideki, Sou Masahiro, Miyata Koji, Shiba Kohya, Tanigawara Yusuke

臨床薬理 36 （ 4 ） 197 - 207 2005年07月

ISSN 0388-1601

Faropenem (FRPM) is an oral penem antibacterial medicine with a high stability to beta-lactamase which has a broad antibacterial spectrum and a strong antibacterial activity to gram positive bacteria, and gram negative bacteria, except for Pseudomonas aeruginosa and anaerobic bacteria. The sale of faropenem was started in 1997. Based on the plasma faropenem concentration vs. time data obtained from clinical trials using healthy adult volunteers and patients, and a post-marketing clinical study using advanced age patients, the population pharmacokinetic analysis of a total of 20 studies was performed. The concentration data of 1,065 points from 218 patients whose creatinine clearances were measured (85 points/12 patients) or estimated (980 points/206 patients) from plasma concentration levels was used for the analysis. A one-compartment model with first-order absorption was used as a pharmacokinetic model where the absorption lag-time was assumed. Among the population pharmacokinetic parameters, the apparent total body clearance (CL), apparent distribution volume (V), first-order absorption rate constant (k_a) and absorption lag-time (t_lag) showed great inter-subject variation. In the final model, creatinine clearance (CLcr) was chosen as the most influential covariate against CL and CL was well correlated with CLcr when CLcr was less than 80 mL/min. The inter-subject variability in CL was explained by considering CLcr as a cofactor. The apparent distribution volume increased in the geriatric patients. Both k_a and t_lag were dependent on meals in all patients. Based on these results, the population pharmacokinetic model of faropenem was made by taking these covariates into consideration. From the results of population pharmacokinetics analysis, the prolongation of the elimination half-life (t_1/2) of faropenem was suggested in the patients with decreased kidney function as previously reported.

Comprehensive screening of the thiopurine methyltransferase polymorphisms by denaturing high-performance liquid chromatography

Udaka Toru, Torii Chiharu, Takahashi Daisuke, Mori Tetsuya, Aramaki Michihiko, Kosaki Rika, Tanigawara Yusuke, Takahashi Takao, Kosaki Kenjiro

Genetic Testing 9 （ 2 ） 85 - 92 2005年06月

ISSN 1090-6576

The drug-metabolizing enzyme thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of thiopurines such as 6-mercaptopurine, 6-thioguanine, and azathiopurine, which are used as immunosuppressants and in the treatment of acute lymphoblastic leukemia and rheumatoid arthritis. TPMT enzymatic activity is a polymorphic trait, and poor metabolizers may develop life-threatening bone marrow failure. To avoid such adverse effects, the TPMT enzymatic activity in patients' red blood cells (RBCs) is routinely measured prior to thiopurine administration in a limited number of oncology clinics. In the present study, we took advantage of a highly sensitive and specific automated denaturing high-performance liquid chromatography (dHPLC) technique that not only detects known polymorphic alleles, but also identifies previously uncharacterized sequence variants. We developed a dHPLC-based protocol to analyze the entire coding region and validated the protocol to detect all 16 previously described variant alleles. We further analyzed the entire coding region of the TPMT gene in 288 control samples collected worldwide and identified two novel amino acid substitutions Arg163Cys (487C>T) and Arg226Gln (677G>A) within exons 7 and 10, respectively. The clinical application of this comprehensive screening system for examining the entire TPMT gene would help to identify patients at risk for bone marrow failure prior to 6-mercaptopurine therapy. © Mary Ann Liebert, Inc.

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がん性疼痛に対して0.1％モルヒネ軟膏が有効であった症例

栗林淳也，小杉志都子，橋口さおり，津崎晃一，武田純三，川北智子，須山郁子，木村理恵子、村松　博，谷川原祐介

ペインクリニック 26 （ 12 ） 1676-1679 2005年

研究論文（学術雑誌）, 共著, 査読有り

血液透析患者におけるテイコプラニンの至適投与法の検討

門川俊明，浅井昌樹，森田邦彦，熊谷祐生，谷川原祐介，林　松彦，猿田享男法

透析会誌 38 （ 3 ） 205 - 211 2005年

Vitreous concentrations of triamcinolone acetonide in human eyes after intravitreal or subtenon injection

Inoue Makoto, Takeda Kayoko, Morita Kunihiko, Yamada Masakazu, Tanigawara Yusuke, Oguchi Yoshihisa

American Journal of Ophthalmology 138 （ 6 ） 1046 - 1048 2004年12月

ISSN 0002-9394

To compare vitreous concentrations of triamcinolone acetonide (TA) achieved by prior therapeutic intravitreal and subtenon injections. Interventional case series. Vitreous samples were collected from patients who required vitreous surgery, six having received a subtenon injection of TA and another six, an intravitreal injection. Vitreous concentrations of TA were measured by high-performance liquid chromatography. Vitreous concentrations of TA after intravitreal injection were 1.22 ± 0.24 μg/ml, significantly higher than those after subtenon injection (<0.001 μg/ml, P =. 003). Vitreous concentrations of TA after subtenon injection and TA-assisted vitrectomy performed in a few patients to visualize the transparent vitreous gel were 0.20 ± 0.11 μg/ml, an intermediate amount between these two groups. Much higher vitreous concentrations of TA after intravitreal injection than subtenon injection may accelerate therapeutic effect when intravitreal injections are given to reduce macular edema. Subtenon injections of TA may act via the sclera as opposed to the vitreous. © 2004 by Elsevier Inc. All rights reserved.

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A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam

Kosaki Kenjiro, Tamura Kazuyo, Sato Reiko, Samejima Hazuki, Tanigawara Yusuke, Takahashi Takao

Brain and Development 26 （ 8 ） 530 - 534 2004年12月

ISSN 0387-7604

N-desmethylclobazam (N-CLB), the major metabolite of clobazam (CLB), exerts a large influence on therapeutic and adverse effects of CLB. A substantial inter-individual variability has been observed in the ratios of N-CLB concentration/CLB dose and of the N-CLB/CLB concentration. We document here a genotype-phenotype correlation between CYP2C19 polymorphisms and those ratios. Patients with two mutated CYP2C19 alleles show significantly higher ratios than those with the wild type genotype: patients with one mutated allele exhibited intermediate trait. That is, the degree of elevation in the ratios was dependent on the number of mutated alleles of CYP2C19 (gene-dose effect). The N-CLB concentration/CLB dose ratio of patients with two mutated alleles was more than six fold higher than that of wild type patients. Thus, the serum N-CLB/CLB concentration ratio may be a valuable parameter to screen for patients at risk for side effects. Such precautions may be clinically relevant in populations where the mutant allele frequency is high, such as in Asian populations (∼35%). Patients co-medicated with CYP3A4 inducer showed lower CLB concentration/CLB dose ratios and higher N-CLB/CLB concentration ratios. The overall effect of CYP3A4 inducer on N-CLB metabolism, however, was small and, thus, we conclude that the CYP2C19 genotype is the major determinant of the N-CLB concentration. For this reason it is crucial for the better management of epilepsy and other chronic illnesses in general to establish the correlation of genotype of CYP enzymes and pharmacokinetics/dynamics of drugs. © 2004 Elsevier B.V. All rights reserved.

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生体部分肝移植の薬理ゲノミクスならびに臨床薬理学的研究に基づくシクロスポリンの至適投与法の開発

森田邦彦，早川智久，池谷　修，野本麻衣子，三原　潔，星野　健，田辺　稔，阿部雄太，河地茂行，若林　剛，島津元秀，森川康英，北島政樹，谷川原祐介

今日の移植 17 （ 6 ） 798-800 2004年11月

研究論文（学術雑誌）, 共著

院内製剤0.05%シクロスポリン点眼液の安定性と有用性の検討

村松博, 我妻秀和, 森田邦彦, 谷川原祐介

日本病院薬剤師会雑誌 40 （ 10 ） 1273 - 1276 2004年10月

共著

Pharmacokinetic comparison of an angiotensin II receptor antagonist, telmisartan, in Japanese and western hypertensive patients using population pharmacokinetic method

S. Tatami, N. Yamamura, A. Sarashina, CL Yong, T. Igarashi, Y. Tanigawara

Drug. Metab. Pharmacokinet. 19 （ 1 ） 15-23 2004年

研究論文（学術雑誌）, 共著, 査読有り

ベンジルアルコールを除去した硝子体内投与用トリアムシノロンアセトニド溶液の作成

井上　真, 植竹美香, 武田香陽子, 磯上一成, 村松博, 山口雅也, 森田邦彦, 谷川原祐介, 山田昌和, 小口芳久

眼紀 55 （ 6 ） 445-449 2004年

研究論文（学術雑誌）, 共著

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谷川原 祐介

論文 - 谷川原 祐介

谷川原　祐介

論文 - 谷川原　祐介