研究者詳細 - 合葉　哲也

論文 - 合葉　哲也

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Altered Pharmacological Efficacy of Phenobarbital with the Treatment of 7,8-Dihydroxyflavone, an Agonist of Tropomyosin Receptor Kinase B, in Rats 査読

Keiichiro Suzuki, Kazuya Matsumoto, Misa Takenaka, Tetsuya Aiba

Biological and Pharmaceutical Bulletin 46 ( 1 ) 86 - 94 2023年1月

Acute peripheral inflammation increases plasma concentration of hypoglycemic agent nateglinide with decreased hepatic drug-metabolizing activity in rats. 査読

Kojina M, Suzuki K, Nishiwaki A, Aiba T

Biological and Pharmaceutical Bulletin 44 ( 1 ) 96 - 102 2021年1月

Effects of dexamethasone to reverse decreased hepatic midazolam metabolism in rats with acute renal failure. 査読

Doi M, Kajikawa N, Aiba T

Xenobiotica 50 ( 5 ) 506 - 514 2020年3月

In Vivo Study on Mechanism Underlying Increased Pharmacological Effects of Phenobarbital in Rats with Glycerol-Induced Acute Renal Failure 査読

Atsuyoshi Okada, Keiichiro Suzuki, Keisuke Hara, Moeko Kojina, Tetsuya Aiba

Biological and Pharmaceutical Bulletin 42 ( 3 ) 501 - 506 2019年3月

Altered hepatic drug-metabolizing activity in rats suffering from hypoxemia with experimentally induced acute lung impairment 査読

Yuki Hori, Yasumasa Shimizu, Tetsuya Aiba

Xenobiotica 48 ( 6 ) 576 - 583 2018年6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：Taylor and Francis Ltd

1.Hepatic drug-metabolizing activity was investigated in vitro with liver microsomes prepared from rats suffering from hypoxemia with experimentally induced acute lung impairment (ALI). 2.Male Wistar rats received an intrabronchial administration of dilute hydrochloride solution for ALI induction. Pooled liver microsomes were prepared for the normal and ALI rats, and the hepatic drug metabolism mediated by cytochrome P450 (CYP) 3 A was examined in an incubation study with the microsomes. 3.The NADPH-dependent metabolism of midazolam significantly increases in ALI rats as compared with that in normal rats. Testosterone 6β-hydroxylation was also observed to significantly increase in ALI rats. 4.When the hepatic expression of CYP3A proteins was examined, the protein expression of CYP3A1 was shown to significantly increase and that of CYP3A2 remained unaltered in ALI rats. The hepatic expression of NADPH-cytochrome P450 reductase (POR), a protein mediating electron transfer in CYP-mediated drug metabolism, was also revealed to significantly increases in ALI rats. 5.With the findings regarding the midazolam elimination, the hepatic drug-metabolizing activity seems to increase in response to acute hypoxemia, partly due to an altered expression of the CYP3A enzymes, and an augmented electron transfer with an increased POR expression is probably involved in the increase.

DOI： 10.1080/00498254.2017.1349969

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Bortezomib combined with standard induction chemotherapy in Japanese children with refractory acute lymphoblastic leukemia 査読

Akihiro Iguchi, Yuko Cho, Minako Sugiyama, Yukayo Terashita, Tadashi Ariga, Yosuke Hosoya, Shinsuke Hirabayashi, Atsushi Manabe, Keisuke Hara, Tetsuya Aiba, Tsugumi Shiokawa, Hiroko Tada, Norihiro Sato

International Journal of Hematology 106 ( 2 ) 291 - 298 2017年8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：SPRINGER JAPAN KK

Bortezomib has been shown to be effective and well-tolerated in patients with refractory acute lymphoblastic leukemia (ALL) in the Therapeutic Advances in Childhood Leukemia trial. However, the safety and efficacy of bortezomib have not been evaluated in Japanese pediatric patients. Here, we report the results of a clinical trial designed to evaluate the safety of bortezomib combined with induction chemotherapy in Japanese children with refractory ALL. A total of six patients with B-precursor ALL were enrolled in this study. Four-dose bortezomib (1.3 mg/m(2)/dose) combined with two standard induction chemotherapies was used. Prolonged pancytopenia (grade 4) was observed in all patients. Four of the six patients developed severe infectious complications. Peripheral neuropathy (grade 2) occurred in five patients. The individual plasma bortezomib concentration-time profiles were not related to toxicity and efficacy. Five patients were evaluable for response, and four patients achieved complete response (CR) or CR without platelet recovery (80%). In conclusion, four-dose bortezomib (1.3 mg/m(2)/dose) combined with standard re-induction chemotherapy was associated with a high risk of infectious complications induced by prolonged neutropenia, although high efficacy has been achieved for Japanese pediatric patients with refractory ALL. Attention must be given to severe infectious complications when performing re-induction chemotherapy including bortezomib.

DOI： 10.1007/s12185-017-2235-z

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Correlation between the Efficacy of Lamotrigine and the Serum Lamotrigine Level during the Remission Phase of Acute Bipolar II Depression: A Naturalistic and Unblinded Prospective Pilot Study 査読

Akiyoshi Kikkawa, Yoshihisa Kitamura, Tetsuya Aiba, Koichi Hiraki, Toshiaki Sendo

Biological and Pharmaceutical Bulletin 40 ( 4 ) 413 - 418 2017年4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：PHARMACEUTICAL SOC JAPAN

Lamotrigine has acute antidepressant effects in patients with bipolar disorder. However, there is little information regarding appropriate serum levels of lamotrigine and the time until remission after the start of lamotrigine therapy in patients with bipolar II depression. This was a naturalistic and unblinded prospective pilot study. Twelve patients' depressive symptoms were evaluated using the Montgomery-angstrom sberg Depression Rating Scale (MADRS) at the start of treatment and at the time of remission, and blood samples were obtained at the time of remission. Mahalanobis distance was used to analyze the relationship between the MADRS improvement rate and the serum lamotrigine level. Furthermore, we calculated the Spearman's rank correlation coefficient for the relationship between the MADRS improvement rate and the serum lamotrigine level, and produced box plots of the serum lamotrigine level at remission and the time until remission. The Mahalanobis distance for the patient that was co-administered lamotrigine and valproic acid differed significantly from those of the other patients (p<0.001). There was no linear relationship between the serum lamotrigine level and the MADRS improvement rate among the patients that did not receive valproic acid. The median time from the start of lamotrigine therapy until remission was 6 weeks. The serum lamotrigine level does not have an important impact on the acute therapeutic effects of lamotrigine on bipolar II depression. In addition, we consider that different treatment options should be considered for non-responders who do not exhibit any improvement after the administration of lamotrigine for approximately 6 weeks.

DOI： 10.1248/bpb.b16-00725

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一般向けビタミン主薬製剤及びビタミン含有保健薬の水溶性ビタミン配合量に基づく類似性分析査読

鈴木啓一郎, 神志那萌子, 合葉哲也

137 ( 5 ) 595 - 602 2017年

Altered hepatic drug metabolizing activity in rats with acute lung impairment

Yuki Hori, Yasumasa Simizu, Tetsuya Aiba

Drug Metabolism Reviews 47 89 - 89 2015年11月

In vivo application of chitosan to improve bioavailability of cyanocobalamin, a form of vitamin B-12, following intraintestinal administration in rats 査読

Yuko Goto, Ayumi Masuda, Tetsuya Aiba

International Journal of Pharmaceutics 483 ( 1-2 ) 250 - 255 2015年4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：ELSEVIER SCIENCE BV

The effect of chitosan on the intestinal absorption of cyanocobalamin (VB12), a stable form of vitamin B-12, was investigated in vivo in rats, with the aim of improving the oral bioavailability of VB12 for anemia treatment in patients with gastrectomy. The bioavailability was evaluated based on the plasma concentration profile of VB12 following intraintestinal administration of the VB12 solution containing chitosan at various concentrations. The bioavailability of VB12 was 0.6 +/- 0.2% when the chitosan-free VB12 solution was administered, while it increased to 10.5 +/- 3.3% when chitosan was dissolved in the VB12 solution at a concentration of 1%. The bioavailability of VB12 increases with the chitosan concentration, in which chitosan seems to augment the amount of VB12 absorbed without affecting the absorption rate constant of VB12. It was also shown that the bioavailability of VB12 does not increase further when the degree of chitosan deacetylation is increased from 83 to 100% by substitutively employing the fully deacetylated chitosan. These findings suggest that the oral administration of VB12 with readily available chitosan may be a practical approach for anemia treatment in patients with gastrectomy. (C) 2015 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2015.02.016

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Pharmaceutical properties of a low-substituted hydroxypropyl cellulose (L-HPC) hydrogel as a novel external dressing 査読

Atsushi Ogawa, Sachie Nakayama, Mami Uehara, Yasuhiro Mori, Mai Takahashi, Tetsuya Aiba, Yuji Kurosaki

International Journal of Pharmaceutics 477 ( 1-2 ) 546 - 552 2014年12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：ELSEVIER SCIENCE BV

Controlling the moisture balance between exudates and their transpiration from the surface of wounded skin is important for healing. Low-substituted hydroxypropyl cellulose (L-HPC) hydrogel sheets (HGSs) possessing high water retention and water vapor transmission properties were prepared by neutralizing the highly viscous alkaline liquid of 7-10% L-HPC. Glycerol-impregnated L-HPC hydrogel sheets (L-HPC G-HGSs) were obtained by exchanging aqueous liquid in L-HPC HGSs. The physical characteristics required for wound dressings, i.e., mechanical strength, adhesive strength, and water retention properties, as well as the water vapor transmission (WVT) properties of L-HPC HGSs and L-HPC G-HGSs were evaluated. The mechanical strengths of L-HPC HGSs were enhanced with increases in the L-HPC content. The impregnation of glycerol in L-HPC HGSs yielded a significantly elasticated sheet. The adhesive strengths of L-HPC HGSs were significantly lower than those of commercial medical dressings. Water retention in L-HPC HGSs after being stored for 2 h at 37 degrees C was approximately 50%. The WVT rate of 7% L-HPC HGS was approximately 40 g/m(2)/h, which was markedly higher than that of silicone gel type medical dressings. In conclusion, L-HPC HGSs are promising dressings that maintain an adequate moisture balance by transpiring excessive wound exudates with less damage to the healing wound. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ijpharm.2014.10.043

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双極性障害II型患者のうつ状態急性期に対するラモトリギンの血中濃度と効果との関係および寛解までの服用日数に関する検討

吉川明良, 吉川明良, 北村佳久, 合葉哲也, 和田健, 森田幸孝, 岩本崇志, 開浩一, 千堂年昭

臨床薬理 45 ( Supplement ) S250 - S250 2014年11月

Effect of Carrageenan-induced Acute Peripheral Inflammation on the Pharmacokinetics and Hepatic Metabolism of Midazolam in Rats 査読

Noriko Kajikawa, Masami Doi, Jun-ichi Kusaba, Tetsuya Aiba

Drug Metabolism and Pharmacokinetics 29 ( 5 ) 400 - 406 2014年10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：JAPANESE SOC STUDY XENOBIOTICS

The effect of carrageenan-induced acute peripheral inflammation (API) on the pharmacokinetics of the hepatically metabolizing compound midazolam (MDZ) was investigated in rats. Rats were subcutaneously treated with lambda-carrageenan in the hind paw to induce API. When MDZ was intravenously administered in male rats, it was demonstrated that the plasma concentration profile of MDZ slightly alters in API rats compared with that in normal rats, while the plasma concentrations of its metabolites, 4-hydroxy and 1'-hydroxy MDZ, are markedly reduced with delayed appearances in API rats. In the incubation study with rat liver microsomes, it was clearly indicated that the generation rates of the two metabolites decrease in API rats. Western blot analysis revealed that hepatic CYP3A1 expression increases, while CYP3A2 expression decreases in API rats. In female rats, in which CYP3A2 is barely expressed in the liver, MDZ metabolism is little affected by API. These findings indicate that the hepatic handling of a therapeutic compound varies with API, largely due to altered hepatic expression of the drug-metabolizing enzyme.

DOI： 10.2133/dmpk.DMPK-14-RG-020

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Interspecies comparison of hepatic metabolism of six newly synthesized retinoid X receptor agonistic compounds possessing a 6-[N-ethyl-N-(alkoxyisopropylphenyl)amino]nicotinic acid skeleton in rat and human liver microsomes 査読

Yoshiki Murakami, Yasumasa Shimizu, Akemi Ogasawara, Satoshi Ueshima, Mariko Nakayama, Kohei Kawata, Hiroki Kakuta, Tetsuya Aiba

Drug Development and Industrial Pharmacy 40 ( 8 ) 1065 - 1071 2014年8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：INFORMA HEALTHCARE

Objective: The hepatic metabolism of six compounds newly synthesized as retinoid X receptor agonists was characterized in rat and human liver microsomes to examine the relationship between their hepatic metabolism profiles and side chain structures, considering the interspecies difference.
Materials and methods: The compounds used have a 6-[N-ethyl-N-(3-alkoxy-4-isopropylphenyl)amino]nicotinic or 6-[N-ethyl-N-(4-alkoxy-3-isopropylphenyl)amino]nicotinic acid skeleton, in which the isopropoxy, isobutoxy or cyclopropylmethoxy group is employed for the alkoxy group. These compounds were incubated with the microsomes, and their Michaelis-Menten parameters were determined. The incubation study was also performed with various cytochrome P450 (CYP) inhibitors to examine their susceptibilities to the inhibitors. In addition, a molecular docking simulation was conducted to assess the compound's spatial configuration with the CYP isoform when necessary.
Results: The Michaelis-Menten parameters determined are comparable between rats and humans for the compounds having 3-isobutoxy, 4-isobutoxy, 4-isopropoxy and 4-cyclopropylmethoxy groups. However, it was indicated that all compounds except that having the 3-isobutoxy group are metabolized in a different manner between rats and humans. That is, the extent of the contribution of each CYP isozyme is different between those two species. A molecular docking simulation showed that the spatial configuration of the compound to be associated with CYP2D6 markedly changes depending on whether the isobutoxy group is situated at the 3- or 4-position.
Conclusion: A slight difference in the side chain structures markedly alters the compound's metabolic profile, which amplifies the interspecies difference regarding the profile, increasing the difficulty in characterizing the profile in humans with the structural-property relationship and interspecies extrapolation.

DOI： 10.3109/03639045.2013.807278

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粉砕法による経管投与における薬剤量損失に対する簡易懸濁法の有用性についての検討

座間味義人, 小山敏広, 合葉哲也, 天野学, 安藤哲信, 倉田なおみ, 名和秀起, 名倉弘哲, 北村佳久, 千堂年昭

静脈経腸栄養 29 ( 4 ) 1027-1033 (J-STAGE) - 1033 2014年7月

記述言語：日本語出版者・発行元：(株)ジェフコーポレーション

【目的】従来の薬剤経管投与法である粉砕法は薬効の減少につながる薬剤量の損失が指摘されている。そこで粉砕法による薬剤量損失に対する簡易懸濁法の有用性について検討した。【方法】頻繁に粉砕指示がなされる5種類の薬剤を用いて粉砕・分包による薬物含量減少、薬剤調製時の懸濁性および実際の経管投与を想定した薬物含量について2つの方法を比較した。【結果】薬剤を粉砕・分包するとそれぞれの薬物含量は減少した。またワーファリン錠を粉砕して水に溶解すると完全には懸濁せず、小さな塊が生じたが、簡易懸濁法では均一に懸濁した。ワーファリン錠の経管投与を想定した実験において粉砕法では薬物含量が大幅に減少したが、簡易懸濁法では、ほとんど損失が認められなかった。【結論】簡易懸濁法は粉砕法に比べて薬剤損失の面で有用性が高いことが示唆され、ワーファリン錠のように安定性が悪い薬剤では特に適正な薬物投与に貢献出来ると考えられる。(著者抄録)

DOI： 10.11244/jjspen.29.1027

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Effects of Peritoneal Dialysis on Pharmacotherapy: A Deductive Pharmacokinetic-model Approach to Predict Drug Concentration Profiles in Plasma and Peritoneal Fluid 査読

Mizuki Horiuchi, Soichiro Moriyama, Yukiko Takahata, Tetsuya Aiba, Yuji Kurosaki

Drug Metabolism and Pharmacokinetics 29 ( 2 ) 154 - 161 2014年4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：JAPANESE SOC STUDY XENOBIOTICS

The aim of this study was to present a deductive compartment pharmacokinetic (PK) model to predict the concentration profiles of drugs in plasma and peritoneal fluid in peritoneal dialysis (PD) rats. PK parameters of model drugs in normal and experimentally induced acute renal failure (ARF) rats not undergoing PD were obtained inductively in a common regression manner with a two-compartment model. In PD normal and ARF rats, PK parameters relating to the transfer of drugs to the peritoneal dialysate and the progress of renal failure were deductively modified to simulate the drug concentration-time profiles in plasma and in the peritoneal fluid in PD rats. The deductively introduced modifiers were the volume of distribution in the peripheral compartment, plasma protein binding, and solvent movement factor to the peritoneal fluid. Predicted profiles of tolbutamide, propranolol and cefazolin in PD normal and ARF rats were compared with the corresponding observed data. This minimal deductive approach yielded satisfactory accuracy in the prediction of both the plasma and peritoneal fluid concentrations of tolbutamide and propranolol.

DOI： 10.2133/dmpk.DMPK-13-RG-067

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双極性障害患者に対するラモトリギンの使用実態調査と考察

Akiyoshi Kikkawa, Yoshihisa Kitamura, Ken Wada, Yukitaka Morita, Takashi Iwamoto, Tetsuya Aiba, Kouiti Hiraki, Toshiaki Sendou

日本病院薬剤師会雑誌 50 ( 4 ) 491 - 494 2014年

遮光器具を用いた光に不安定な薬剤の含量減少の抑制について

座間味義人, 座間味義人, 座間味義人, 東恩納司, 安藤哲信, 武藤浩司, 天野学, 倉田なおみ, 合葉哲也, 北村佳久, 千堂年昭

静脈経腸栄養 29 ( 3 ) SUP54(J-STAGE) 2014年

Effect of Carrageenan-Induced Acute Peripheral Inflammation on the Electrolyte Disposition to Cerebrospinal Fluid in Rats 査読

Kentaro Kono, Atsuyoshi Okada, Atsuko Ishikawa, Tetsuya Aiba

Biological and Pharmaceutical Bulletin 36 ( 11 ) 1829 - 1834 2013年11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：PHARMACEUTICAL SOC JAPAN

To clarify whether peripheral inflammation has a remote effect on the central nervous system, the electrolyte disposition between the circulating blood and central nervous system was evaluated in rats with carrageenan-induced acute peripheral inflammation (API). lambda-Carrageenan was subcutaneously injected in the hind paw of the rat, and lithium was utilized as a surrogate marker of sodium. When the plasma and cerebrospinal fluid (CSF) concentrations of lithium were examined following lithium being intravenously administered, it was revealed that the CSF concentration of lithium in API rats is reduced compared to that in normal rats, while the plasma concentration profile of lithium in API rats is indistinguishable from that in normal rats. The pharmacokinetic analysis showed that the lithium disposition from the plasma to CSF markedly decreased by 35.8% in API rats compared to that in normal rats. On the other hand, when lithium was immediately administered into the lateral ventricle, its elimination profiles in CSF were not different between normal and API rats. It is therefore probable that the lithium disposition from the plasma to CSF alters in API rats, reflecting the entry process of electrolytes from the circulating blood to brain tissue being suppressed in response to peripheral inflammation.

DOI： 10.1248/bpb.b13-00531

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双極性障害患者に対するラモトリギンの使用実態調査と考察

吉川明良, 北村佳久, 合葉哲也, 和田健, 森田幸孝, 岩本崇志, 開浩一, 千堂年昭

日本医療薬学会年会講演要旨集 23rd 433 - 433 2013年8月

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