Sills G J, Butler E, Thompson G G, Brodie M J
Epilepsy Unit, University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland, UK.
Seizure. 1999 Oct;8(7):404-11. doi: 10.1053/seiz.1999.0326.
In light of theirclosely related mechanisms of action, and preliminary clinical evidence suggesting that they possess similar efficacies, it has been anecdotally suggested that vigabatrin and tiagabine may prove to be therapeutically indistinguishable. As a result, we have conducted a preclinical comparison of their anticonvulsant profile and mechanism of action. Pentylenetetrazol and maximal electroshock seizures were employed to determine the experimental anticonvulsant profile. Mechanisms of action were investigated using assays of gamma -aminobutyric acid (GABA), GABA-transaminase and glutamic acid decarboxylase in mouse brain and GABA uptake and GABA-transaminase in rat astrocyte cultures. Vigabatrin was without effect on either pentylenetetrazol- or maximal electroshock-induced seizures, whereas tiagabine increased the latency to pentylenetetrazol seizures and reduced the incidence of maximal electroshock seizures. In mouse brain assays, tiagabine was without effect, while vigabatrin increased GABA concentrations and reduced GABA-transaminase and glutamic acid decarboxylase activities. In cortical astrocyte cultures, vigabatrin reduced the activities of both GABA uptake and GABA-transaminase, whereas tiagabine blocked GABA uptake alone. These results suggest that vigabatrin and tiagabine have differing efficacy in experimental seizure models and distinct neurochemical effects. It is possible, then, that these drugs will have different spectra of activity and toxicity profiles in human epilepsy.
鉴于加巴喷丁和噻加宾作用机制密切相关，且初步临床证据表明二者疗效相似，有人据此推测，加巴喷丁和噻加宾在治疗上可能并无差异。因此，我们对二者的抗惊厥谱及作用机制进行了临床前比较。采用戊四氮和最大电休克惊厥模型来确定实验性抗惊厥谱。利用小鼠脑内γ-氨基丁酸（GABA）、GABA转氨酶和谷氨酸脱羧酶检测方法以及大鼠星形胶质细胞培养物中的GABA摄取和GABA转氨酶检测方法来研究作用机制。加巴喷丁对戊四氮或最大电休克诱导的惊厥均无影响，而噻加宾可延长戊四氮惊厥的潜伏期，并降低最大电休克惊厥的发生率。在小鼠脑检测中，噻加宾无作用，而加巴喷丁可增加GABA浓度，并降低GABA转氨酶和谷氨酸脱羧酶活性。在皮质星形胶质细胞培养物中，加巴喷丁可降低GABA摄取和GABA转氨酶的活性，而噻加宾仅阻断GABA摄取。这些结果表明，加巴喷丁和噻加宾在实验性惊厥模型中疗效不同，且具有不同的神经化学效应。那么，这两种药物在人类癫痫中可能具有不同的活性谱和毒性谱。
