Deckers C L, Czuczwar S J, Hekster Y A, Keyser A, Kubova H, Meinardi H, Patsalos P N, Renier W O, Van Rijn C M
Institute of Neurology and Department of Clinical Pharmacy, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Epilepsia. 2000 Nov;41(11):1364-74. doi: 10.1111/j.1528-1157.2000.tb00111.x.
When monotherapy with antiepileptic drugs (AEDs) fails, combination therapy is tried in an attempt to improve effectiveness by improving efficacy, tolerability, or both. We reviewed the available studies (both animal and human) on AED polytherapy to determine whether AEDs can be selected for combination therapy based on their mechanisms of action, and if so, which combinations are associated with increased effectiveness. Because various designs and methods of analysis were used in these studies, it was also necessary to evaluate the appropriateness of these approaches.
Published papers reporting on AED polytherapy in animals or humans were identified by Medline search and by checking references cited in these papers.
Thirty-nine papers were identified reporting on two-drug AED combinations. Several combinations were reported to offer improved effectiveness, but no uniform approach was used in either animal or human studies for the evaluation of pharmacodynamic drug interactions; efficacy was often the only end point.
There is evidence that AED polytherapy based on mechanisms of action may enhance effectiveness. In particular, combining a sodium channel blocker with a drug enhancing GABAergic inhibition appears to be advantageous. Combining two GABA mimetic drugs or combining an AMPA antagonist with an NMDA antagonist may enhance efficacy, but tolerability is sometimes reduced. Combining two sodium channel blockers seems less promising. However, given the incomplete knowledge of the pathophysiology of seizures and indeed of the exact mechanisms of action of AEDs, an empirical but rational approach for evaluating AED combinations is of fundamental importance. This would involve appropriate testing of all possible combinations in animal models and subsequent evaluation of advantageous combinations in clinical trials. Testing procedures in animals should include the isobologram method, and the concept of drug load should be the basis of studies in patients with epilepsy.
当抗癫痫药物（AEDs）单药治疗失败时，会尝试联合治疗，以期通过提高疗效、耐受性或两者来提升治疗效果。我们回顾了关于AED联合治疗的现有研究（包括动物和人体研究），以确定是否可根据AEDs的作用机制来选择联合治疗药物，若可行，哪些联合用药能提高疗效。由于这些研究采用了各种设计和分析方法，因此还需评估这些方法的适用性。
通过检索Medline并查阅这些论文中引用的参考文献，找出报道动物或人体AED联合治疗的已发表论文。
共识别出39篇报道两种AED联合用药的论文。有几种联合用药被报道可提高疗效，但在动物和人体研究中，评估药效学药物相互作用时未采用统一方法；疗效往往是唯一的终点指标。
有证据表明，基于作用机制的AED联合治疗可能会提高疗效。特别是，将钠通道阻滞剂与增强GABA能抑制的药物联合使用似乎具有优势。联合使用两种GABA模拟药物或联合使用AMPA拮抗剂与NMDA拮抗剂可能会提高疗效，但耐受性有时会降低。联合使用两种钠通道阻滞剂似乎前景不佳。然而，鉴于对癫痫病理生理学以及AEDs确切作用机制的了解尚不完整，则采用经验性但合理的方法来评估AED联合用药至关重要。这将涉及在动物模型中对所有可能的联合用药进行适当测试，并随后在临床试验中评估优势联合用药。动物测试程序应包括等效应线图法，而药物负荷的概念应作为癫痫患者研究的基础。
