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

为了这项研究的目的，我们进行了五项临床研究。(1)一种新的评价药物对精神运动表现影响的计算机化测试方法：采用新开发的计算机化测试方法，在无主观感觉变化的情况下，客观、灵敏地检测劳拉西泮诱导的健康受试者精神运动表现受损。这种客观的方法可以更准确地评价药物引起的精神运动功能障碍。(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著增加。然而，地高辛静脉注射时，血清地高辛的处置不受任一环内酯的影响。这些发现不支持大环内酯类药物引起地高辛浓度增加是由于地高辛排泄减少的假设。(3)伊曲康唑对溴西泮在健康志愿者体内药代动力学和药效学的影响。伊曲康唑对细胞色素P450(CYP) 3A4的抑制作用没有改变溴西泮的药代动力学和药效学。很可能CYP3A4在溴西泮的代谢中起着次要作用，如果有的话。当对CYP3A4活性改变的患者使用苯二氮卓类药物时，溴西泮和劳拉西泮可作为葡萄糖醛酸化代谢的替代药物之一。(4)圣约翰草（SJW）对健康志愿者体内茶碱药代动力学的影响经15天的圣约翰草治疗后，血浆中茶碱药代动力学无明显变化。然而，从尿中1-甲基尿酸代谢物比例的变化可以看出，SJW可能会影响茶碱的代谢。(5)伊曲康唑和氟康唑对健康志愿者喹西泮药理学的影响：与安慰剂相比，氟康唑联合给药后，喹西泮对精神运动能力的损害明显减轻。这可能是由于氟康唑抑制CYP2C9和CYP3A4，从而减少了喹西泮活性代谢物的产生。少

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