Analysis of factors responsible for adverse drug reactions(ADR) : Studies for rational dosage regimen to avoid ADR

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 15590469
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Oita University (2004); 大分医科大学 (2003)
• Principal Investigator: NAKANO Shigeyuki Oita University, Faculty of Medicine, professor, 医学部, 教授 (10033341)
• Co-Investigator(Kenkyū-buntansha): KOTEGAWA Tsutomu Oita University, Faculty of Medicine, associate professor, 医学部, 助教授 (20264343) ; KOTEGAWA Kinimo Oita University, Faculty of Medicine, assistant professor, 医学部, 助手 (20244171)
• Project Period (FY): 2003 – 2004
• Keywords: impaired performance / psychomotor function / loratadine / d-chlorpheniramine / quazepam / itraconazole / fluconazole / adverse drug reaction

Research Abstract

(1)The effect of loratadine on psychomotor function measured using a personal computer in healthy Japanese adult subjects : A comparison with d-chlorpheniramine maleate and placebo in a double-blind 4-way crossover study
The influence of loratadine(10mg or 20mg) on psychomotor function was investigated in healthy adult volunteers using the efficiency of typing figures in a personal computer as an index. The study was performed as a double-blind crossover test using d-chlorpheniramine maleate and placebo as control drugs. The twenty subjects typed figures for 15 minutes after drug administration. Correct typing quantity, total typing quantity and erroneous typing quantity were counted for each subject after each typing job.
In a paired comparison among the groups, the numbers of correct figures typed in the chlorpheniramine group was significantly less than that in the placebo group, 10 mg group and 20 mg group of loratadine. No significant difference was observed among the placebo group, loratadine 10 mg group and loratadine 20 mg groups. In conclusion, unlike d-chlorpheniramine maleate, loratadine did not influence psychomotor function at all at either the usual dose of 10 mg or the double dose of 20 mg after administration.
(2)The effect of itraconazole and fluconazole on the pharmacokinetics and pharmacodynamics of quazepam in healthy volunteers
Nine healthy volunteers(genotyped as wild type CYP2C9) participated in a randomized double-blind, three-way crossover design. The subjects received single oral dose of quazepam 15mg after 4-day pretreatment of oral itraconazole, fluconazole, or placebo. Plasma concentration of quazepam and its metabolites were determined for 96 hours. Pharmacodynamic effects of quazepam were assessed using continuous number addition test(CNAT) and EEG.
Fluconazole caused a significant increase in plasma quazepam concentration, although the EEG change was significantly diminished by fluconazole. This is probably due to the decrease in plasma N-alkyl-2-oxoquazepam(DOQ) concentration. The results suggest that DOQ play a role in the CNS effects of QZP.