Luszczki Jarogniew J, Ratnaraj Neville, Patsalos Philip N, Czuczwar Stanislaw J
Department of Pathophysiology, Medical University, Lublin, Poland.
Eur J Pharmacol. 2008 Oct 24;595(1-3):13-21. doi: 10.1016/j.ejphar.2008.07.051. Epub 2008 Jul 31.
The aim of this study was to characterize the pharmacodynamic, pharmacokinetic and adverse-effect profiles of vigabatrin and gabapentin. Isobolographic analysis was used in two mouse experimental models of epilepsy: the maximal electroshock seizure threshold test and pentylenetetrazole-induced seizures. In the maximal electroshock seizure threshold test, electroconvulsions were produced by a current with various intensities whilst in the pentylenetetrazole test a CD(97) dose (100 mg/kg) was used. Potential adverse-effect profiles of interactions of vigabatrin with gabapentin at three fixed-ratios of 1:3, 1:1 and 3:1 from both seizure tests were evaluated in the chimney (motor performance) and grip-strength (skeletal muscular strength) tests. Vigabatrin and gabapentin total brain concentrations were determined with high performance liquid chromatography. Vigabatrin and gabapentin administered singly increased the electroconvulsive threshold (TID(20) - 226.2 and 70.0 mg/kg, respectively). With isobolography, the combination of vigabatrin with gabapentin at the fixed-ratio of 1:3 exerted supra-additive (synergistic) interactions whilst at 1:1 and 3:1 additivity occurred. Similarly, vigabatrin and gabapentin administered singly suppressed the pentylenetetrazole-induced seizures (ED(50) values - 622.5 and 201.1 mg/kg, respectively). Isobolography revealed that vigabatrin with gabapentin in combination at the fixed-ratio of 1:1 produced supra-additive (synergistic) interaction whilst at 1:3 and 3:1 additivity occurred. In combination neither motor coordination nor skeletal muscular strength was affected. Total vigabatrin and gabapentin brain concentrations revealed that neither drug affected the pharmacokinetics of the other. Vigabatrin and gabapentin have a favorable pharmacodynamic interaction in animal seizure models in the absence of acute adverse effects or concurrent pharmacokinetic changes.
本研究的目的是描述氨己烯酸和加巴喷丁的药效学、药代动力学及不良反应特征。采用等效线图分析法，在两种小鼠癫痫实验模型中进行研究：最大电休克惊厥阈值试验和戊四氮诱发惊厥试验。在最大电休克惊厥阈值试验中，通过不同强度的电流诱发惊厥，而在戊四氮试验中，使用CD(97)剂量（100mg/kg）。在烟囱试验（运动性能）和握力试验（骨骼肌力量）中，评估了氨己烯酸与加巴喷丁按1:3、1:1和3:1三种固定比例联合使用时的潜在不良反应特征。采用高效液相色谱法测定氨己烯酸和加巴喷丁在脑中的总浓度。单独给予氨己烯酸和加巴喷丁均可提高电惊厥阈值（TID(20)分别为226.2和70.0mg/kg）。等效线图分析显示，氨己烯酸与加巴喷丁按1:3固定比例联合使用时产生超相加（协同）相互作用，而按1:1和3:1联合使用时则产生相加作用。同样，单独给予氨己烯酸和加巴喷丁均可抑制戊四氮诱发的惊厥（ED(50)值分别为622.5和201.1mg/kg）。等效线图分析表明，氨己烯酸与加巴喷丁按1:1固定比例联合使用时产生超相加（协同）相互作用，而按1:3和3:1联合使用时则产生相加作用。联合使用时，运动协调性和骨骼肌力量均未受影响。氨己烯酸和加巴喷丁在脑中的总浓度表明，两种药物均不影响对方的药代动力学。在动物癫痫模型中，氨己烯酸和加巴喷丁具有良好的药效学相互作用，且无急性不良反应或同时发生的药代动力学变化。
