Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.
Neurotoxicology. 2012 Jan;33(1):127-37. doi: 10.1016/j.neuro.2011.12.011. Epub 2011 Dec 21.
During drug development, seizure threshold tests are widely used to identify potential proconvulsant activity of investigational drugs. The most commonly used tests in this respect are the timed intravenous pentylenetetrazole (PTZ) infusion seizure test and the maximal electroshock seizure threshold (MEST) test in mice or rats. To our knowledge, no study is available in which proconvulsant drug activities in these models are directly compared, which prompted us to perform such experiments in male Wistar rats. Five drugs with reported proconvulsant activity were tested in the two models: d-amphetamine, chlorpromazine, caffeine, theophylline, and tramadol. Furthermore, the anticonvulsant drug phenobarbital was included in the experiments. While phenobarbital exerted anticonvulsant activity in both models, the five proconvulsant drugs markedly differed in their effects. In the dose range tested, d-amphetamine significantly lowered the PTZ seizure threshold but increased the MEST, caffeine and theophylline did not alter the PTZ seizure threshold but decreased the MEST, and tramadol reduced the PTZ threshold but increased the MEST. These marked differences between seizure threshold tests are most likely a consequence of the mechanisms underlying seizure induction in these tests. Our data indicate that using only one seizure threshold model during preclinical drug development may pose the risk that potential proconvulsant activity of an investigational drug is overseen. However, the label "proconvulsant" may be misleading if such activity only occurs at doses high above the therapeutic range, but the drug is not proconvulsant or even exerts anticonvulsant effects at lower, therapeutically relevant doses.
在药物开发过程中，通常会使用惊厥阈测试来识别潜在的致惊厥药物的活性。在这方面最常用的测试是计时静脉注射戊四氮（PTZ）输注惊厥测试和最大电休克惊厥阈（MEST）测试，分别在小鼠或大鼠中进行。据我们所知，目前尚无研究直接比较这两种模型中的致惊厥药物活性，这促使我们在雄性 Wistar 大鼠中进行了这样的实验。在这两种模型中测试了五种具有报道的致惊厥活性的药物：苯丙胺、氯丙嗪、咖啡因、茶碱和曲马多。此外，还在实验中加入了抗惊厥药物苯巴比妥。虽然苯巴比妥在两种模型中均表现出抗惊厥活性，但这五种致惊厥药物的作用明显不同。在测试的剂量范围内，苯丙胺显著降低了 PTZ 惊厥阈，但增加了 MEST；咖啡因和茶碱并未改变 PTZ 惊厥阈，但降低了 MEST；曲马多降低了 PTZ 阈，但增加了 MEST。这些惊厥阈测试之间的显著差异很可能是这些测试中引起惊厥的机制所致。我们的数据表明，在临床前药物开发过程中仅使用一种惊厥阈模型可能会导致潜在的致惊厥药物活性被忽视的风险。然而，如果这种活性仅发生在治疗范围以上的高剂量，而药物在较低的、治疗相关剂量下不是致惊厥的，甚至具有抗惊厥作用，那么“致惊厥”的标签可能会产生误导。
