Luszczki Jarogniew J, Ratnaraj Neville, Patsalos Philip N, Czuczwar Stanislaw J
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland.
Naunyn Schmiedebergs Arch Pharmacol. 2006 May;373(2):169-81. doi: 10.1007/s00210-006-0055-4. Epub 2006 Apr 8.
This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin--PHT, carbamazepine--CBZ, valproate--VPA and phenobarbital--PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis. Drug-related adverse effects were ascertained by use of the chimney test (motor impairment) and the step-through passive avoidance task (learning and retrieval). It was observed that the combination of LCZ with VPA or PB, at the fixed ratio of 1:1, was supra-additive (synergistic) and the combination of LCZ with CBZ, at all fixed ratios tested (1:3, 1:1 and 3:1), was supra-additive against electroconvulsions. The remaining combinations evaluated, i.e., LCZ with PB or VPA at fixed ratios of 1:3 and 3:1, as well as all fixed-ratio combinations between LCZ and PHT, were additive in the MES test in mice. Pharmacokinetic characterization revealed that LCZ significantly increased both free plasma and brain concentrations of CBZ and PHT, but was without effect on PB. Moreover, a bi-directional pharmacokinetic interaction between LCZ and VPA was observed in that while LCZ increased free plasma, but not total brain VPA concentrations, VPA increased the total brain, but not free plasma LCZ concentrations. Adverse-effect testing revealed that for all antiepileptic drug combinations neither motor performance nor long-term memory was altered. Of the drug combinations investigated, only that of LCZ and PB at the fixed ratio of 1:1 was not associated with any pharmacokinetic interactions, and thus it may be concluded that the supra-additive (synergistic) isobolographic interaction was pharmacodynamic in nature. Furthermore, the fact that LCZ and PB have similar mechanisms of action would suggest that drugs with similar mechanisms of action may provide rational polytherapy regimens.
本研究在小鼠最大电休克（MES）诱导的癫痫模型中，采用等效应线分析法，考察了洛雷唑（LCZ）与多种传统抗癫痫药物（苯妥英 - PHT、卡马西平 - CBZ、丙戊酸盐 - VPA和苯巴比妥 - PB）之间的相互作用特征。通过烟囱试验（运动功能损害）和穿梭箱被动回避任务（学习和记忆恢复）确定药物相关的不良反应。观察到，LCZ与VPA或PB以1:1的固定比例联合使用时具有超相加（协同）作用，并且LCZ与CBZ在所有测试的固定比例（1:3、1:1和3:1）下联合使用时，对惊厥具有超相加作用。评估的其余联合用药，即LCZ与PB或VPA以1:3和3:1的固定比例联合，以及LCZ与PHT之间的所有固定比例联合，在小鼠MES试验中均为相加作用。药代动力学特征显示，LCZ显著提高了CBZ和PHT的游离血浆浓度和脑内浓度，但对PB无影响。此外，观察到LCZ与VPA之间存在双向药代动力学相互作用，即LCZ增加了游离血浆VPA浓度，但未增加脑内总VPA浓度，而VPA增加了脑内总LCZ浓度，但未增加游离血浆LCZ浓度。不良反应测试表明，所有抗癫痫药物联合使用均未改变运动功能或长期记忆。在所研究的药物联合中，只有LCZ与PB以1:1的固定比例联合未出现任何药代动力学相互作用，因此可以得出结论，超相加（协同）等效应线相互作用本质上是药效学的。此外，LCZ和PB具有相似作用机制这一事实表明，作用机制相似的药物可能提供合理的联合治疗方案。
