Development of the theory of assessment for the therapeutic and adverse effect of drugs for the purpose of rational drug use

发展药物疗效及不良反应评估理论以促进合理用药

• 批准号: 09672318
• 负责人: YAMADA Yasuhiro
• 金额: $ 1.15万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672318/
• 关键词: cilostazol; sarpogrelate hydrochloride; aspirin; ticlopidine; platelet aggregation; pharmacokinetic-pharmacodynamic model; dosing regimen; 抗血小板率; レセプター; 循環器系薬物; β-遮断薬; 投与計画

Antiplatelet agents (cilostazol, sarpogrelate hydrochloride, aspirin, and ticlopidine) were investigated based on pharmacokinetics and pharmacodynamics. Cilostazol is a potent inhibitor of human platelet aggregation and selectively inhibits human platelet cyclic adenosine monophosphate phosphodiesterase type III.A pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effect of cilostazol considering the reversible inhibition of phosphodiesterase in the platelet was developed. The estimated average inhibition of phosphodiesterase was 59.7% after oral administration of usual dose. A significant linear relationship between the calculated inhibitory effects on phosphodiesterase and inhibitory effects on collagen-induced platelet aggregation was obtained(p<0.05). Based on this finding, a new method for predicting inhibitory effects on collagen-induced platelet aggregation after oral administration of cilostazol was developed. Sarpogrelate and its active metabolite (M-1) ar … More e potent inhibitors of human platelet aggregation, selectively inhibit human platelet 5-HT_2-serotonergic receptor. A pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effect of sarpogrelate and M-1, considering both the competitive reversible inhibition and the association/dissociation process of these drugs at the 5-HT_2 receptor in the platelet was developed. The developed model was well fitted to the actual data, and suggested that M-1 was more effective to the inhibition on platelet aggregation than sarpogrelate. Based on this finding, a new method was developed for predicting inhibitory effects on the platelet aggregation after oral administration of sarpogrelate hydrochloride. The relationship between plasma concentration of ticlopidine and its inhibitory effect on platelet aggregation in human was analyzed using a pharmacokinetic-pharmacodynamic model. Assuming that ticlopidine acts on platelet precursors in the bone marrow, the apparent reaction rate constant of ticlopidine and platelet precursors (K), apparent transformation rate constant of platelet precursors (kr) and apparent elimination rate constant of platelets (ke) were estimated. The antiaggregation effects of ticlopidine on platelets after administration of 100, 200 and 300 mg (b.i.d. for 8 days) were simulated using the pharmacokinetic-pharmacodynamic parameters of K, kr and ke. While the antiaggregation effect reached the steady state within 3-4 days without dose-dependency of the interval, the maximum effect increased with dose. The antiplatelet effects of aspirin (inhibition of thromboxane B_2 (TXB_2) production) after repeated administrations of 40, 80 and 320 mg/day for 8 days were simulated using these pharinacokinetic-pharmacodynamic parameters and compared with those of ticlopidine. The maximum inhibition was reached within 2 days after 40 mg administration of aspirin and even earlier (within 1 day) after 80 mg. The duration of inhibitory effect of aspirin on TBX_2 pThese pharmacokinetic-pharmacodynamic models may be useful for establishing the dosing regimen of antiplatelet drugs in clinical settings. Less

基于药代动力学和药效学研究了抗血小板药物（西洛他唑、盐酸沙格雷酯、阿司匹林和噻氯匹定）。西洛他唑是一种有效的血小板聚集抑制剂，可选择性抑制人血小板环磷酸腺苷磷酸二酯酶III，建立了考虑其可逆性抑制血小板磷酸二酯酶的药代动力学-药效学模型。口服常规剂量后，磷酸二酯酶的估计平均抑制率为59.7%。对磷酸二酯酶的抑制作用与对胶原诱导的血小板聚集的抑制作用呈显著的线性关系（p<0.05）。基于这一发现，开发了一种新的方法来预测口服西洛他唑后对胶原诱导的血小板聚集的抑制作用。沙格雷酯及其活性代谢产物（M-1） ...更多信息 人血小板聚集的有效抑制剂，选择性地抑制人血小板5-HT_2受体。本文建立了沙格雷酯和M-1抗血小板作用的药代动力学-药效学模型，考虑了这两种药物对血小板5-HT_2受体的可逆性竞争抑制和结合/解离过程。模型与实际数据拟合良好，表明M-1对血小板聚集的抑制作用优于沙格雷酯。基于这一发现，开发了一种新的方法来预测口服盐酸沙格雷酯后对血小板聚集的抑制作用。应用药代动力学-药效学模型，分析了噻氯匹定在人体内的血药浓度与其抑制血小板聚集作用的关系。假定噻氯匹定作用于骨髓中的血小板前体，估算了噻氯匹定与血小板前体的表观反应速率常数（K）、血小板前体的表观转化速率常数（kr）和血小板的表观消除速率常数（ke）。噻氯匹定100、200和300 mg（b.i.d.）8天）使用药代动力学-药效学参数K、kr和ke进行模拟。虽然抗聚集作用在3-4天内达到稳态，但无剂量依赖性间隔，最大作用随剂量增加而增加。用这些药代动力学-药效学参数模拟阿司匹林（40、80和320 mg/d，连续8天）的抗血小板作用（抑制血栓素B_2（TXB_2）的产生），并与噻氯匹定进行比较。40 mg阿司匹林给药后2天内达到最大抑制，80 mg阿司匹林给药后甚至更早（1天内）达到最大抑制。阿司匹林对TBX_2 p抑制作用的持续时间这些药代动力学-药效学模型可用于临床抗血小板药物给药方案的制定。少

项目成果

Takako Shimizu, Yasuhiko Yamada, Tatsuji Iga, et al: "Analysis of antiplatelet effect of cirostazol and its application to drug dosage regimen-Modeling besed on reversible inhibition of phosphodiesterase in the platelet-" Jpan.J.Hosp.Pharm.24 (4). 333-339

Takako Shimizu、Yasuhiko Yamada、Tatsuji Iga 等人：“西罗他唑的抗血小板作用分析及其在药物剂量方案中的应用 - 基于血小板中磷酸二酯酶可逆抑制的建模 -”Jpan.J.Hosp.Pharm.24（4

山田 安彦、伊賀 立二、他: "シロスタゾールによる抗血小板作用の解析とその処方設計への応用" 病院薬学. (印刷中).

Yasuhiko Yamada、Tatsuji Iga 等：“西洛他唑的抗血小板作用分析及其在处方设计中的应用”《医院药房》（正在出版）。

山田安彦,伊賀立二 他: "シロスタゾールによる抗血小板作用の解析とその処方設計への応用-血小板中ホスホジエステラーゼの可逆的阻害を考慮したPK/PDモデルの構築-" 病院薬学. 24(4). 333-339 (1998)

Yasuhiko Yamada、Tatsuji Iga 等：“西洛他唑的抗血小板作用分析及其在处方设计中的应用 - 考虑血小板中磷酸二酯酶的可逆抑制的 PK/PD 模型的构建 -”医院药理学 333-。 339 (1998)