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

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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