健常日本人におけるコンピュータ眼球運動解析とＶｉｓｕａｌ Ａｎａｌｏｇｕｅ Ｓｃａｌｅを用いたＮｉｔｒａｚｅｐａｍの薬物動態 薬力学相関に対する評価

Abstract

The effects of drugs on the central nervous system can be evaluated using a large number of tests in human. Since each test has a different sensitivity, to obtain pharmacodynamic parameters direct comparison of the results obtained by different tests is sometimes misleading. Thus, the choice of methods for evaluation likely affects the results of studies on sedative effects of drugs . Analysis of saccadic eye movement is reported to be a highly selective method to evaluate the sedative effect of benzodiaze-pines. This study was performed using computerized eye movement analysis to validate their application for evaluation of the effects of the anxiolytic, nitrazepam.A randomized, double-blind, placebo-controlled cross-over study was carried out with eight healthy volunteers. Nitrazepam (5 mg) or its placebo was administered in each occasion with a 2 week wash-out period. Pharmacodynamic tests (saccadic eye movement, smooth persuit and VAS) were performed before intake and 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 240, 360 and 480 minutes after the drug administration. Serum nitrazepam concentrations were measured by HPLC. Pharmacokinetic parameters of nitrazepam were as follows: Cmax: 75.78±28.86 ng/ml, tmax: 1.56±1.24 hr, t1/2: 27.10±6.09 hr. The tmax and t1/2 were similar to those reported in Caucasians. However, the Cmax of Japanese subjects was about two-fold higher than that of Caucasians. A significant decrease in saccadic peak velocity was observed in every subject after nitrazepam administration (treatment effect, p=0.002). Saccadic latency was significantly prolonged in the nitrazepam group (treatment effect, p=0.04). No significant effects on smooth pursuit performance were found (p=0.07).The concentration-effects relationship for saccadic peak velocity was described by a linear-model or clock-wise type.Measurement of saccadic peak velocity and saccadic latency have been used successfully to characterize the sedative effects of nitrazepam in healthy subjects. The computerized eye movement analysis is a simple, sensitive and reproducible method without pre-test exercise and can be applied for the evaluation of effects of other CNS acting drugs.