研究者詳細 - 合葉　哲也

論文 - 合葉　哲也

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The Effects of Body Weight and Combination Drug Therapy on the Serum Concentrations of Zonisamide in 94 Epileptic dogs: An Epidemiological Analysis 査読

Koya Fukunaga, Tetsuya Aiba, Miyoko Saito, Makoto Muto, Naoyuki Watanabe, Keiko Uchida, Seiichi Okuno, Takayuki Kobayashi, Kensuke Orito

International Journal of Appled Research in Veterinary Medicine 10 ( 3 ) 258 - 263 2012年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：VETERINARY SOLUTIONS LLC

To clarify the effects of background factors such as body weight, combination drug therapy with phenobarbital (PB) and potassium bromide (KBr), age, gender, neuter status, and blood collection time on the serum concentrations of zonisamide (ZNS) in 94 epileptic dogs, serum ZNS concentrations of 141 samples from 94 epileptic dogs were measured by high-performance liquid chromatography with UV detection. Serum ZNS concentrations were divided by the dosage of ZNS, to obtain normalized ZNS concentrations. Multiple linear regression analysis revealed that body weight and combination therapies with KBr, PB, and KBr + PB affected the normalized ZNS concentrations, and normalized ZNS concentrations were positively correlated with body weight. The normalized ZNS concentrations in dogs with PB combination therapy were lower when compared with those concentrations in dogs receiving ZNS alone, but were higher in dogs receiving KBr combination therapy. These results suggest that serum ZNS concentrations are influenced by body weight and combination drug therapies using KBr, PB, and KBr + PB. This information of ZNS characteristics may be useful in determining the initial and modified doses of ZNS in the therapy of epileptic dogs.

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In Vivo Application of Chitosan to Facilitate Intestinal Acyclovir Absorption in Rats 査読

Ayumi Masuda, Yuko Goto, Yuji Kurosaki, Tetsuya Aiba

Journal of Pharmaceutical Sciences 101 ( 7 ) 2449 - 2456 2012年7月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

The effect of chitosan on the intestinal absorption of acyclovir (ACV) was evaluated in rats, and factors influencing its facilitative effect on the ACV absorption were examined. When ACV solution containing 1% chitosan with an average molecular weight of 150 kDa was administered into the upper jejunum, a significant increase in the plasma ACV concentration was observed, with the peak ACV concentration being eight times greater than that observed with the chitosan-free solution. The chitosan-free ACV solution, whose viscosity was adjusted to remain unchanged with polyethylene glycol, did not cause an increase in the plasma concentration, and neither did the chitosan-free solutions substitutionally containing low molecular cationic compounds, triethanolamine and kanamycin. When chitosan was digested with chitosanase to shorten its polycationic polysaccharide structure, chitosan subjected to 150-min digestion retained its facilitative effect on ACV absorption, but that subjected to 420-min digestion no longer caused facilitation, in which its average molecular weight was reduced to around 10 kDa. It is therefore indicated that intestinal ACV absorption can be facilitated with chitosan, and that it is necessary for chitosan to have a certain length of polycationic polysaccharide structure to exert such facilitation. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2449-2456, 2012

DOI： 10.1002/jps.23170

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Microdialysis法を用いた薬物の筋肉内局所動態評価局所冷却による局所薬物利用率の増大

牧之段敬一, 東恩納司, 崎山達矢, 合葉哲也, 黒崎勇二

日本DDS学会学術集会プログラム予稿集 28回 122 - 122 2012年6月

新規RXRアゴニスト及びその類縁化合物のヒト肝における代謝特性の予測

合葉哲也, 村上由樹, 清水康正, 川田浩平, 中山真理子, 小笠原明美, 岡田淳芳, 黒崎勇二, 加来田博貴

日本薬学会年会要旨集 132年会 ( 2 ) 269 - 269 2012年3月

Comparative study on altered hepatic metabolism of CYP3A substrates in rats with glycerol-induced acute renal failure 査読

Jun-ichi Kusaba, Noriko Kajikawa, Hiromu Kawasaki, Yuji Kurosaki, Tetsuya Aiba

Biopharmaceutics and Drug Disposition 33 ( 1 ) 22 - 29 2012年1月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol-induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis-Menten parameters, Km and Vmax, were examined in the incubation study, the Km values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The Vmax values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased Km values accompanied the decreased Vmax values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the Km value was observed in ARF rats, but it did not accompany the decrease in the Vmax value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti-CYP3A1 and anti-CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats. Copyright (C) 2012 John Wiley & Sons, Ltd.

DOI： 10.1002/bdd.1774

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肺移植患者におけるシクロスポリン経口クリアランスに及ぼす移植後経過日数の影響

土井原夕貴, 上島智, 合葉哲也, 佐藤智昭, 河崎陽一, 山根正修, 大藤剛宏, 松永尚, 黒崎勇二, 三好新一郎, 千堂年昭

臨床薬理 42 ( Suppl. ) S268 - S268 2011年10月

P-0589 経腸栄養剤を用いた疎水性薬剤の簡易懸濁法適用の検討(一般演題ポスター発表,医薬品情報・データベース,Enjoy Pharmacists' Lifestyles)

座間味義人, 松永康臣, 合葉哲也, 天野学, 小山敏広, 四宮一昭, 北村佳久, 黒崎勇二, 佐々木健二, 野田真吾, 千堂年昭, 川崎博己, 五味田裕

日本医療薬学会年会講演要旨集 21 280 - 280 2011年9月

Pharmacodynamic Characterization of Nitric Oxide-Mediated Vasodilatory Activity in Isolated Perfused Rat Mesenteric Artery Bed 査読

Shinsuke Inoue, Tetsuya Aiba, Yasuyuki Masaoka, Keiko Shimizu, Yukiko Komori, Mitsunobu Mio, Shingo Takatori, Hiromu Kawasaki, Yuji Kurosaki

Biological and Pharmaceutical Bulletin 34 ( 9 ) 1487 - 1492 2011年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

Vasodilation profiles following a short-term infusion of nitric oxide (NO), acetylcholine (ACh), and sodium nitroprusside (SNP) into an isolated perfused mesenteric artery bed were analyzed in rats to examine their vasodilatory efficacy under physiological conditions. These compounds commonly increase the intracellular NO concentration to exert vasodilatory activity. In an experiment with exogenous NO infusion where 100 mu l of 1 : 300 diluted NO-saturated solution (approx. 53 pmol of NO) was applied, the infusion caused transient vasodilation in a dose-dependent manner, with the peak vasodilation value being 74.7% of the maximum relaxation value. In experiments with ACh, the peak vasodilation value was 81.5% of the maximum at a dose of 60 pawl. The vasodilation profile of ACh was similar to that of NO infusion, but the ACh-induced vasodilation reduced at a slower rate than that induced by NO infusion. The vasodilatory activity of SNP was less potent than that of ACh, and its peak value was 62.8% of the maximum at a dose of 2000 pmol. However, SNP activity was augmented by removing the vascular endothelia of the mesenteric artery bed, and the peak value reached 67.3% of the maximum at a dose of 60 pmol. Pharmacodynamic analysis indicated that NO and ACh are equivalent regarding their vasodilator), efficacy, while the efficacy of SNP was less than 1% of theirs, as the arterial vascular endothelium impeded intracellular SNP-related NO generation, by which 95% of SNP's vasodilator), efficacy was negated. These findings will be helpful to understand factors influencing the therapeutic efficacy of vasodilators.

DOI： 10.1248/bpb.34.1487

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Pharmacokinetic properties of newly synthesized retinoid X receptor agonists possessing a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton in rats 査読

Akemi Ogasawara, Yoshiki Murakami, Nobumasa Yakushiji, Fuminori Ohsawa, Jun-ichi Kusaba, Tetsuya Aiba, Yuji Kurosaki, Hiroki Kakuta

Drug Development and Industrial Pharmacy 37 ( 9 ) 1060 - 1067 2011年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：INFORMA HEALTHCARE

Objective: The pharmacokinetic properties of three newly synthesized retinoid X receptor (RXR) agonists were evaluated in rats to elucidate the structural factor influencing their pharmacokinetic properties. Material and methods: Three RXR agonists possessing a common 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic acid skeleton and side chain structures that are slightly different from each other were prepared as we previously reported (Takamatsu et al., ChemMedChem, 2008; 3: 780-787). The plasma concentration profiles of these compounds were evaluated following the intravenous and intra-intestinal administrations. Their hepatic metabolism was characterized using rat liver microsomes. Results: Based on the plasma concentration profile, NEt-3IP (3-isopropoxy) was shown to have a distribution volume of 4.53 L/kg, and to be cleared from the body with an elimination half-time of 0.95 h. The bioavailability of NEt-3IP is 16.4%, whereas those of the isobutoxy analog NEt-3IB and the cyclopropylmethoxy analog NEt-3cPM are 46.5% and 22.6%, respectively. Subsequently, in the experiments using rat liver microsomes, the K-m and V-max values of NEt-3IP were determined as 7.85 mu M and 0.48 nmol/min/mg protein, respectively. This K-m value is nearly the same as those of NEt-3IB and NEt-3cPM, but the V-max value is noticeably smaller. Additionally, it was revealed that the CYP family mainly metabolizing NEt-3IP is different from those metabolizing the other analogs. Conclusion: Based on these findings, the pharmacokinetic properties of the compounds possessing this type of the skeleton seem to be largely influenced by a slight modification of the side chain structure.

DOI： 10.3109/03639045.2011.559247

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肺移植患者におけるタクロリムス血中濃度推移の母集団解析

上島智, 合葉哲也, 佐藤智昭, 河崎陽一, 山根正修, 大藤剛宏, 松永尚, 黒崎勇二, 三好新一郎, 千堂年昭

TDM研究 28 ( 3 ) s180 - s180 2011年6月

薬物の筋肉内拡散・分布動態に及ぼす血流量の影響局所冷却時の動態特性

牧之段敬一, 東恩納司, 村上仁美, 合葉哲也, 黒崎勇二

日本薬剤学会年会講演要旨集 26年会 141 - 141 2011年5月

Empirical Approach for Improved Estimation of Unbound Serum Concentrations of Valproic Acid in Epileptic Infants by Considering Their Physical Development 査読

Satoshi Ueshima, Tetsuya Aiba, Tomoaki Sato, Hisashi Matsunaga, Yuji Kurosaki, Yoko Ohtsuka, Toshiaki Sendo

Biological and Pharmaceutical Bulletin 34 ( 1 ) 108 - 113 2011年1月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

The unbound serum concentration of valproic acid (VPA) is closely related to its therapeutic efficacy. In epileptic infants, the unbound VPA concentration varies largely from patient to patient, being difficult to predict using the reported equations for older children. To establish an equation to estimate the unbound concentration in infants, we empirically characterized the relationship between total and unbound VPA concentrations, taking their growth and development into consideration. Data were retrospectively collected from archived clinical records of 30 epileptic infants aged 0-11 months old. The relationship between total and unbound VPA concentrations was analyzed according to the Langmuir equation, in which the patient's body weight, height, and body surface area were considered as physical development indices. Inter- and intra-individual variabilities in the VPA concentrations were also considered. It was shown that the unbound VPA concentration in infants is properly estimated when their body weights are taken into account, in which the parameter for the maximum binding site concentration (Bm) increases as the body weight increases, while that for the dissociation constant (Xd) is unaltered. Additionally, the relationship was shown to slightly change when the infants are concomitantly treated with VPA and the other antiepileptics. These findings provide useful information to adjust the VPA dosage to achieve optimal therapeutic efficacy in epileptic infants.

DOI： 10.1248/bpb.34.108

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いま求められる薬剤師の教育力

調剤と情報 17 ( 1 ) 17 - 18 2011年

ジェネリック医薬品使用・銘柄変更ガイダンス（第二版）査読

合葉哲也, 出石啓治, 飯島康典, 岩月進, 加藤久幸, 小林大高, 坂巻弘之

日本薬剤師会雑誌 63 ( 8 ) 947 - 953 2011年

Altered Electrolyte Handling of the Choroid Plexus in Rats with Glycerol-induced Acute Renal Failure 査読

Atsuko Ishikawa, Kentaro Kono, Rie Sakae, Tetsuya Aiba, Hiromu Kawasaki, Yuji Kurosaki

Biopharmaceutics and Drug Disposition 31 ( 8-9 ) 455 - 463 2010年11月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY

The altered electrolyte handling of the choroid plexus was investigated in rats with acute renal failure (ARF) using lithium and rubidium as surrogate markers for sodium and potassium, respectively. Firstly, the transport of these two markers from the plasma to cerebrospinal fluid (CSF) was evaluated after they were concurrently injected into the femoral vein. As a result, their disposition from the plasma to CSF was shown to decrease in ARF rats, but the relationship profile between those two markers was not different from that observed in normal rats, indicating that the decreased disposition of lithium and rubidium occurs without affecting the stoichiometric balance. To clarify the mechanisms accounting for the decreased disposition, an inhibition study was then performed. When bumetanide, an inhibitor of the Na+/K+/2Cl(-) co-transporter, was directly introduced into the cerebroventricle prior to lithium and rubidium being intravenously administered, a marked increase in the markers' disposition was observed. However, such an increased disposition did not occur when bumetanide was injected into the femoral vein. Other inhibitors, such as amiloride for the Na+/H+ exchanger and ouabain for Na+/K+-ATPase, did not show any effects on marker disposition regardless of the inhibitor being administered into either the cerebroventricle or femoral vein. These findings suggest that the decreased marker disposition in ARF rats is due to an increased efflux process of the choroid plexus mediated by the Na+/K+/2Cl(-) co-transporter. That is, electrolyte efflux from the CSF to plasma increases, and thereby the electrolyte influx from the plasma to CSF is counteracted. Copyright (C) 2010 John Wiley & Sons, Ltd.

DOI： 10.1002/bdd.726

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小児におけるテイコプラニンの母集団薬物動態解析血中濃度に及ぼす基礎疾患の影響

槇田崇志, 上島智, 佐藤智昭, 合葉哲也, 黒崎勇二, 松永尚, 千堂年昭

TDM研究 27 ( 3 ) s155 - s155 2010年6月