Saletu B, Grünberger J, Linzmayer L, Taeuber K
Int Pharmacopsychiatry. 1982;17 Suppl 1:43-72. doi: 10.1159/000468601.
Pharmacokinetics and pharmacodynamics of nomifensine infusions as compared with oral preparations were investigated in a double-blind place-controlled crossover study in 10 healthy normal volunteers. They received randomized in weekly intervals 75 mg nomifensine and placebo intravenously as well as placebo, 75 and 150 mg nomifensine orally. Blood samples, quantitative EEG evaluations, psychometric tests, blood pressure, pulse rate and side effects were obtained and monitored at the hours 0, 1, 2, 4, 6 and 8. Nomifensine serum levels were determined by a radioimmunoassay; peak levels occurred within the first 2 h, the elimination half-life was around 2 h, both results indicating fast absorption and elimination. While the evaluation of the total nomifensine demonstrated almost identical bioavailability of the oral and intravenous form, free nomifensine levels after 75 mg i.v. were more similar to those after 150 mg than 75 mg p.o. Digital computer period analysis of the EEG confirmed nomifensine as a drug with a significant effect on the CNS as compared with placebo, showing in fact an antidepressant 'pharmaco-EEG profile' similar to desipramine. Evaluation of dose-effect curves demonstrated that 75 mg i.v. was the most effective drug, being closer to 150 than 75 mg p.o. The latter oral dosage could be discriminated from placebo only in certain variables at certain times. Concerning time-effect, nomifensine was most effective around the 6th hour post-drug, which was similar to the psychometric findings, thus showing a considerable delay compared to the peak serum concentration. Relating pharmacodynamic findings to pharmacokinetic results it became evident that free nomifensine may be of far greater importance for the drugs encephalotropic and psychotropic properties than the total unconjugated and conjugated nomifensine--thus justifying the development of a parenteral preparation. Finally, the relationship of blood levels and CNS effects was found to have a characteristic 'hysteresis loop' shape suggesting a delay of pharmacodynamic effects as opposed to the serum concentrations. This delay may be due to a slowly formed active metabolite, the drug acting on deep compartment receptors or both.
在一项针对10名健康正常志愿者的双盲安慰剂对照交叉研究中，对诺米芬辛静脉输注与口服制剂的药代动力学和药效学进行了研究。他们每周随机接受一次75毫克诺米芬辛和安慰剂静脉注射，以及安慰剂、75毫克和150毫克诺米芬辛口服。在0、1、2、4、6和8小时采集血样、进行定量脑电图评估、心理测试、测量血压、脉搏率并监测副作用。通过放射免疫分析法测定诺米芬辛血清水平；峰值水平在最初2小时内出现，消除半衰期约为2小时，这两个结果表明吸收和消除迅速。虽然对总诺米芬辛的评估显示口服和静脉注射形式的生物利用度几乎相同，但75毫克静脉注射后游离诺米芬辛水平与150毫克口服后更相似，而不是75毫克口服后。脑电图的数字计算机周期分析证实，与安慰剂相比，诺米芬辛是一种对中枢神经系统有显著作用的药物，实际上显示出与地昔帕明相似的抗抑郁“药物脑电图特征”。剂量效应曲线评估表明，75毫克静脉注射是最有效的药物，比75毫克口服更接近150毫克口服。后一种口服剂量仅在特定时间的某些变量中可与安慰剂区分开来。关于时间效应，诺米芬辛在给药后约6小时最有效，这与心理测试结果相似，因此与血清峰值浓度相比有相当大的延迟。将药效学结果与药代动力学结果相关联后发现，游离诺米芬辛对药物的亲脑性和精神性特性可能比总未结合和结合的诺米芬辛重要得多——因此证明了开发肠胃外制剂的合理性。最后，发现血药水平与中枢神经系统效应之间的关系具有特征性的“滞后环”形状，这表明药效学效应相对于血清浓度有延迟。这种延迟可能是由于缓慢形成的活性代谢物、药物作用于深部隔室受体或两者兼而有之。
