Luszczki Jarogniew J
Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland.
Naunyn Schmiedebergs Arch Pharmacol. 2007 Apr;375(2):105-14. doi: 10.1007/s00210-007-0144-z. Epub 2007 Mar 1.
The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)-two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose-response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.
本研究的目的是表征托吡酯（TPM）和加巴喷丁（GBP）这两种第二代抗癫痫药物单独及联合给药时，在小鼠最大电休克（MES）诱导的癫痫发作和烟囱试验中的抗惊厥作用及急性不良反应潜力。使用I型等效线图分析法，针对非平行剂量反应关系曲线（DRRC），确定TPM与GBP按1:1固定比例联合用药时的抗惊厥作用和急性不良反应。为确定TPM与GBP之间观察到的相互作用是否存在任何药代动力学影响，测定了两种药物在全脑的浓度。对TPM和GBP进行等效线图相互作用分析，其DRRC在MES和烟囱试验中均不平行，同时给出了所有必要计算结果，以确定相加性的上下限。等效线图分析显示，TPM与GBP按1:1固定比例联合用药在抑制MES诱导的癫痫发作方面呈现超相加（协同）作用，同时，在烟囱试验中，该联合用药在运动协调障碍（不良反应）方面产生相加作用。对TPM与GBP联合用药的药代动力学相互作用特征评估显示，TPM和GBP均未影响实验动物全脑中它们各自的浓度，因此，在MES试验中观察到的相互作用本质上是药效学的。总之，TPM与GBP联合用药，由于在MES试验中具有超相加作用，在烟囱试验中运动协调障碍方面具有相加作用，且药物之间不存在药代动力学相互作用，符合良好联合用药的标准，值得在进一步临床实践中推荐。
