Löscher Wolfgang
Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany.
Center for Systems Neuroscience, Hannover, Germany.
Epilepsia. 2023 Mar;64(3):553-566. doi: 10.1111/epi.17511. Epub 2023 Jan 26.
There are only a few drugs that can seriously lay claim to the title of "wonder drug," and ivermectin, the world's first endectocide and forerunner of a completely new class of antiparasitic agents, is among them. Ivermectin, a mixture of two macrolytic lactone derivatives (avermectin B and B in a ratio of 80:20), exerts its highly potent antiparasitic effect by activating the glutamate-gated chloride channel, which is absent in vertebrate species. However, in mammals, ivermectin activates several other Cys-loop receptors, including the inhibitory γ-aminobutyric acid type A and glycine receptors and the excitatory nicotinic acetylcholine receptor of brain neurons. Based on these effects on vertebrate receptors, ivermectin has recently been proposed to constitute a multifaceted wonder drug for various novel neurological indications, including alcohol use disorders, motor neuron diseases, and epilepsy. This review critically discusses the preclinical and clinical evidence of antiseizure effects of ivermectin and provides several arguments supporting that ivermectin is not a suitable candidate drug for the treatment of epilepsy. First, ivermectin penetrates the mammalian brain poorly, so it does not exert any pharmacological effects via mammalian ligand-gated ion channels in the brain unless it is used at high, potentially toxic doses or the blood-brain barrier is functionally impaired. Second, ivermectin is not selective but activates numerous inhibitory and excitatory receptors. Third, the preclinical evidence for antiseizure effects of ivermectin is equivocal, and at least in part, median effective doses in seizure models are in the range of the median lethal dose. Fourth, the only robust clinical evidence of antiseizure effects stems from the treatment of patients with onchocerciasis, in which the reduction of seizures is due to a reduction in microfilaria densities but not a direct antiseizure effect of ivermectin. We hope that this critical analysis of available data will avert the unjustified hype associated with the recent use of ivermectin to control COVID-19 from recurring in neurological diseases such as epilepsy.
仅有少数几种药物堪称“神药”，伊维菌素便是其中之一，它是世界上第一种体内外寄生虫杀虫剂，也是全新一类抗寄生虫药物的先驱。伊维菌素是两种大环内酯衍生物（阿维菌素B1a和B1b，比例为80:20）的混合物，通过激活脊椎动物所没有的谷氨酸门控氯离子通道发挥其高效抗寄生虫作用。然而，在哺乳动物中，伊维菌素还能激活其他几种半胱氨酸环受体，包括抑制性γ-氨基丁酸A型和甘氨酸受体以及脑神经元的兴奋性烟碱型乙酰胆碱受体。基于对脊椎动物受体的这些作用，伊维菌素最近被提议作为一种多方面的神药，用于治疗包括酒精使用障碍、运动神经元疾病和癫痫在内的各种新型神经疾病。本综述批判性地讨论了伊维菌素抗癫痫作用的临床前和临床证据，并提供了几个论据，支持伊维菌素并非治疗癫痫的合适候选药物。首先，伊维菌素很难穿透哺乳动物的大脑，因此，除非以高剂量（可能有毒）使用或血脑屏障功能受损，否则它不会通过大脑中的哺乳动物配体门控离子通道发挥任何药理作用。其次，伊维菌素没有选择性，而是激活众多抑制性和兴奋性受体。第三，伊维菌素抗癫痫作用的临床前证据并不明确，至少在部分癫痫模型中，半数有效剂量处于半数致死剂量范围内。第四，唯一有力的抗癫痫作用临床证据来自盘尾丝虫病患者的治疗，其中癫痫发作减少是由于微丝蚴密度降低，而非伊维菌素的直接抗癫痫作用。我们希望，对现有数据的这种批判性分析将避免与最近使用伊维菌素控制新冠疫情相关的不合理炒作在癫痫等神经疾病中再次出现。
