地西泮血药浓度及中枢神经系统效应定量测定

QUANTITATIVE ANALYSIS OF DIAZEPAM'S CENTRAL NERVOUS SYSTEM EFFECTS

对１０名健康男性成人受试者采用双盲随机交叉给药方法给予单剂量７．５ｍｇ，１５ｍｇ地西泮及安慰剂口服，并于服药前后测定地西泮的血药浓度、数字符号匹配测验（ＤＳＳＴ）及脑电图。结果发现，地西泮血药浓度和５ｈ血药浓度曲线下面积与剂量成正比；服用地西泮后各时间快波频率段（１２．８－３０．２Ｈｚ）的脑电振幅占整个频率段（２－３１．２Ｈｚ）的脑电振幅百分比（快波比重）均显著高于服药前测定值（基分）及服安慰剂后各相应时间测定值，且脑电快波活动的增加与地西泮剂量和血药浓度成正比，服安慰剂后各时间的快波比重与基分比较无显著差异；服用两种剂量地西泮后除３０ｍｉｎ外的各时间ＤＳＳＴ得分均显著低于基分和服安慰剂后各相应时间的得分，其分数的下降与地西泮剂量和血药浓度成正比，而服安慰剂后各时间ＤＳＳＴ得分与基分比较无显著差异。地西泮血药浓度，ＤＳＳＴ得分的变化，脑电快波比重的改变三者之间彼此显著相关。上述结果表明ＤＳＳＴ和脑电波幅测试是两种敏感可靠的苯二氮类药物中枢神经系统效应定量分析方法。

Ten healthy male subjects received single oral doses of placebo,7.5mg diazepam,and 15mg diazepam in a double-blind randomized crossover study.Plasma diazepam levels,the Digit Symbol Substitution Test (DSST), and fraction of total electroencephalographic(EEG) amplitude falling in the sigma plus beta(12.8-31.2 Hz)frequency range were determined after drug administration. Plasma diazepam concentration and area under the 5-hour curve were proportional to dose.The percentage of EEG amplitude falling in the 12.8 to 31.2 Hz range did not change over baseline with placebo but were significantly higher than the baseline values and the values with placebo measured at the corresponding times 0. 5 to 5 hours after 7. 5mg and 15mg diazepam.The increase in the percentage of EEG amplitude falling in the 12.8 to 31.2 Hz range was highly correlated with plasma diazepam concentration. DSST scores did not change over baseline for placebo, DSST decrements with 7.5 and 15 mg diazepam paralleled and were correlated with the changes in the percentage of EEG amplitude falling in the 12.8-31.2 Hz range and with plasma diazepam levels.Thus the DSST test and EEG analysis provides sensitive and reliable quantitation of benzodiazepine central nervous system effects.