Studies on factors contributing adverse drug reactions: establishment of a rational drug dosage system

药物不良反应影响因素研究：建立合理用药剂量体系

• 批准号: 13672393
• 负责人: NAKANO Shigeyuki
• 金额: $ 2.05万
• 依托单位: OITA MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672393/
• 关键词: impaired performance; bromazepam; digoxin; theophylline; quazepam; itraconazole; fluconazole; St John's wort; bromzepam; theophylline; St John's wort; CYP2C9; CYP3A4; マクロライド系抗菌薬; P糖蛋白質; 薬物相互作用; ワープロ法; 日常作業効率; lorazepam

For the purpose of this research, we carried out five clinical studies.(1) A new computerized test battery to evaluate drug effects on psychomotor performance: Lorazepam-induced performance in healthy volunteersLorazepam-induced impaired psychomotor performance was objectively and sensitively detected in healthy subjects with no sujective feeling change using our newly developed computerized test battery. This objective method can be applied to more precisely evaluate the drug induced impaired psychomotor performance.(2) The effect of erythromycin and clarithromycin on the phamacokinetics of intravenous digoxin in healthy volunteersWe observed a significant increase in digoxin renal clearance after coadministration of erythromycin and clarithromycin. However, serum digoxin disposition is not affected by either marcrolide when digoxin is administered intravenouly. These findings do not support the hypothesis that the increase in digoxin concentrations by macrolides is due to reduced ren … More al excretion of digoxin.(3) The effect of itraconazole on the pharmacokinetics and pharmacodynamics of bromazepam in healty volunteersThe inhibition of cytochrome P450(CYP) 3A4 produced by itraconazole did not alter the pharmacokinetics and pharmacodynamics of bromazepam. It is likely that CYP3A4 plays a minor role, if any, in the metabolism of bromazepam. When using benzodiazepiners in patients with altered CYP3A4 activity, bromazepam can be one of the alternatives as well as lorazepam that are metabolized by glucuronidation.(4) Effect of St John's wort (SJW) on the pharmacokinetics of theophylline in health volunteersThe 15-day treatment with SJW produced no significant changes in the pharmcokinetics of theophylline in plasma. However, it is likely that the metabolism of theophylline is affected by SJW as indicated by the change in the urinary metabolite ration of 1-methyluric acid.(5) The effect of itraconazole and fluconazole on the pharmacodynamics of quazepam in healthy volunteersCompared with placebo, impairment of psychomotor performance with quazepam was significantly diminished after coadministration of fluconazole. This is probably due to the inhibition of CYP2C9 and CYP3A4 by fluconazole, which reduces productions of active metabolites of quazepam. Less

为了本研究的目的，我们进行了五项临床研究。（1）一种新的计算机化测试组，用于评估药物对精神运动表现的影响：劳拉西泮在健康志愿者中引起的表现使用我们新开发的计算机化测试组，在健康受试者中客观、灵敏地检测到劳拉西泮引起的精神运动表现受损，没有主观感觉变化。这种客观的方法可以更准确地评估药物引起的精神运动能力受损。(2)红霉素和克拉霉素对健康志愿者静脉注射地高辛药代动力学的影响我们观察到红霉素和克拉霉素合用后地高辛肾清除率显着增加。然而，当静脉内给予地高辛时，血清地高辛的分布不受任一大环内酯的影响。这些结果并不支持大环内酯类药物地高辛浓度增加是由于地高辛排泄减少所致的假设。(3) 伊曲康唑对健康志愿者中溴西泮药代动力学和药效学的影响伊曲康唑对细胞色素 P450(CYP) 3A4 的抑制作用并没有改变 溴西泮的药代动力学和药效学。 CYP3A4 在溴西泮的代谢中可能发挥次要作用（如果有的话）。当CYP3A4活性改变的患者使用苯二氮卓类药物时，溴西泮可以作为替代药物之一，以及通过葡萄糖醛酸化代谢的劳拉西泮。(4)圣约翰草(SJW)对健康志愿者茶碱药代动力学的影响在健康志愿者中，用SJW治疗15天，茶碱的药代动力学没有明显变化。 等离子体。然而，茶碱的代谢很可能受到SJW的影响，如尿中1-甲基尿酸代谢物比率的变化所示。 (5)伊曲康唑和氟康唑对健康志愿者中夸西泮药效学的影响与安慰剂相比，共同给药后夸西泮对精神运动能力的损害显着减轻 氟康唑。这可能是由于氟康唑抑制 CYP2C9 和 CYP3A4，从而减少了夸西泮活性代谢物的产生。较少的

项目成果

Sunami Y, Tsutsumi K, Kotegawa T, Nakamura K, Nakano S: "A new computerized test battery to evaluate drug effects on psychomotor performance: Lorazepam-induced impaired performance in healthy volunteers"Jpn Clin Pharmacol Ther. 33(3). 73-79 (2002)

Sunami Y、Ttsutsumi K、Kotekawa T、Nakamura K、Nakano S：“一种新的计算机化测试电池，用于评估药物对精神运动表现的影响：劳拉西泮导致健康志愿者的表现受损”Jpn Clin Pharmacol Ther。

Sunami Y, Tsutsumi K, Kotegawa T, Nakamura K, Nakano S: "A new computerized test battery to evaluate drug effects on psychomotor performance : Lorazepam-induced impaired perfoemance in healthy volunteers"Jpn J Clin Pharmancel Ther. 33. 73-79 (2002)

Sunami Y、Ttsutsumi K、Kotekawa T、Nakamura K、Nakano S：“一种新的计算机化测试电池，用于评估药物对精神运动表现的影响：劳拉西泮导致健康志愿者的表现受损”Jpn J Clin Pharmancel Ther。

Tsutsumi K, Kotegawa T, Kuranari M, Ohtani Y, Morimoto T, Matsuki S, Nakano S: "The effect of erythromycin and clarithromycin on the pharmacokinetics if intravenous digoxin in healthy volunteers"J Clin Pharmacol. 42(10). 1159-1164 (2002)

Tsutsumi K、Kotekawa T、Kuranari M、Ohtani Y、Morimoto T、Matsuki S、Nakano S：“红霉素和克拉霉素对健康志愿者静脉注射地高辛的药代动力学的影响”J Clin Pharmacol。

Tsutsumi K, Kotegawa T, Kuranari M, Ohtani Y, Moerimoto T, Matsuki S, Nakano S: "The effect of erythromycin and clarithromycin on the pharmacokinetics of intravenous digoxin in healthy volunteers"J Clin Pharmacol. 42. 1159-1164 (2002)

Tsutsumi K、Kotekawa T、Kuranari M、Ohtani Y、Moerimoto T、Matsuki S、Nakano S：“红霉素和克拉霉素对健康志愿者静脉注射地高辛药代动力学的影响”J Clin Pharmacol。

Sunami Y: "A new computerized test battery to evaluate drug effects on psychomotor performance : Lorazepam-induced impaired performance in healthy volunteers"Jpn J Clin Pharmacol Ther. (In Press).

Sunami Y：“一种新的计算机化测试电池，用于评估药物对精神运动表现的影响：劳拉西泮导致健康志愿者的表现受损”Jpn J Clin Pharmacol Ther。