Pranzatelli M R, Nadi N S
Department of Pediatrics, George Washington University, Washington, DC 20010, USA.
Adv Neurol. 1995;67:329-60.
Most drugs used to treat myoclonus are also antiepileptic. The main drugs are the benzodiazepines, valproate, and barbituates. Advances in the understanding of antiepileptic drug mechanisms of action have revealed two main patterns: increasing inhibition either through GABA or glycine, or decreasing excitation due to glutamate. Anticonvulsants such as the benzodiazepines, barbiturates, vigabatrin, tiagabine, or progabide act through GABA. New prototype anticonvulsants such as dizocilpine and remacemide target glutamate receptors or associated ion channels. For some antimyoclonic drugs such as piracetam, many effects are reported but no mechanism of action has been established. Many newer anticonvulsants have not been tested in human myoclonic disorders but efficacy against PTZ-induced seizures suggests antimyoclonic activity. Our ability to improve the treatment of myoclonus requires greater knowledge of the molecular mechanisms of myoclonus and more exact delineation of its relation to epilepsy. Better drugs also will result from refinements from prototype drugs and new concepts about brain function. Most of the discussion has been focused on the use of drugs as symptomatic treatment, but drugs such as glutamate blockers are already having a role in the treatment of degenerative neurological disorders, an important cause of some myoclonic disorders. It also may be possible to improve treatment by focusing on selective regional effects of drugs or drug delivery. The CNS penetration of drugs is often no uniform. For many antimyoclonic and antiepileptic drugs, regional studies have not been performed, especially in humans. Lack of efficacy could therefore be due to lack of drug delivery to myoclonic generators or suppression structures. It is conceivable that drug effects in different brain regions also may be opposing, such as in forebrain and hindbrain structures. Stimulation of the same receptor subtype may have different implications for myoclonus if the sites are pre- or postsynaptically located (as in 5-HTIA sites), or predominantly cerebellar versus hippocampal (as in BDZ I vs II sites). Molecular genetic abnormalities in neurological disease may affect neurotransmission and the action of drug either directly at the receptor site or in other ways such as transduction, translation, or expression. Further insights into these abnormalities may provide new targets for pharmacotherapy. Most antiepileptic and antimyoclonic drugs developed to date have aimed at broad-spectrum treatment of the symptoms, rather than treatment of regional problems such as in the forebrain or the hindbrain. Because of this, the currently available drugs have broad side effects such as cognitive impairment, tremors, teratogenicity, etc. To develop more region-specific and more efficacious drugs, we need to develop a better understanding of local central nervous system problems in myoclonus and epilepsy. The development and application of molecular biological techniques have increased our knowledge of receptors and transporters immensely. It is conceivable that in the near future we will be able to determine whether small mutations affect the structure and function of these molecules. In addition, the glimpses into the process of cell death and sprouting by remaining neurons in the epileptic brain, and perhaps the myoclonic brain, raise the possibility of designing regionally oriented drugs with greater efficacy and fewer side effects. The current developments in the understanding of the central neurons should allow for the development of exciting new pharmacotherapies in the future.
大多数用于治疗肌阵挛的药物也是抗癫痫药。主要药物有苯二氮䓬类、丙戊酸盐和巴比妥类。对抗癫痫药物作用机制认识的进展揭示了两种主要模式：通过γ-氨基丁酸（GABA）或甘氨酸增强抑制作用，或因谷氨酸减少兴奋作用。抗惊厥药如苯二氮䓬类、巴比妥类、氨己烯酸、噻加宾或普罗加比通过GABA起作用。新的原型抗惊厥药如地佐环平及瑞玛西胺作用于谷氨酸受体或相关离子通道。对于某些抗肌阵挛药物如吡拉西坦，虽有多种作用报道，但作用机制尚未明确。许多新型抗惊厥药尚未在人类肌阵挛性疾病中进行测试，但对戊四氮诱发癫痫的疗效提示其有抗肌阵挛活性。我们要改善肌阵挛的治疗，就需要更深入了解肌阵挛的分子机制，并更准确地界定其与癫痫的关系。对原型药物的改进及关于脑功能的新概念也将带来更好的药物。大多数讨论都集中在药物作为对症治疗的应用上，但像谷氨酸阻滞剂这类药物已在退行性神经疾病（某些肌阵挛性疾病的重要病因）的治疗中发挥作用。通过关注药物的选择性区域效应或药物递送，也有可能改善治疗。药物在中枢神经系统的渗透往往不均匀。对于许多抗肌阵挛和抗癫痫药物，尚未进行区域研究，尤其是在人体。因此，疗效不佳可能是由于药物未能输送至肌阵挛的起源部位或抑制结构。可以想象，药物在不同脑区的作用也可能相反，如在前脑和后脑结构中。如果刺激的是突触前或突触后位点（如5-羟色胺1A位点），或者主要是小脑与海马位点（如苯二氮䓬I型与II型位点），刺激相同的受体亚型对肌阵挛可能有不同影响。神经疾病中的分子遗传异常可能直接在受体位点或以其他方式（如转导、翻译或表达）影响神经传递及药物作用。对这些异常的进一步了解可能为药物治疗提供新靶点。迄今为止开发的大多数抗癫痫和抗肌阵挛药物旨在对症状进行广谱治疗，而非针对前脑或后脑等区域问题进行治疗。因此，目前可用的药物有广泛的副作用，如认知障碍、震颤、致畸性等。为了开发更具区域特异性和更有效的药物，我们需要更好地了解肌阵挛和癫痫中局部中枢神经系统问题。分子生物学技术的发展和应用极大地增加了我们对受体和转运体的认识。可以想象，在不久的将来，我们将能够确定小突变是否会影响这些分子的结构和功能。此外，对癫痫脑（或许还有肌阵挛脑）中剩余神经元的细胞死亡和发芽过程的了解，增加了设计出疗效更高、副作用更少的区域定向药物的可能性。目前对中枢神经元的认识进展应能在未来开发出令人兴奋的新药物疗法。
