Why are antiepileptic drugs used for nonepileptic conditions?
Why are antiepileptic drugs used for nonepileptic conditions?
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DOI：
10.1111/j.1528-1167.2012.03712.x
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发表时间：
2012-12-01
期刊：
影响因子：
5.6
通讯作者：
Bialer, Meir
中科院分区：
文献类型：
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作者：
Bialer, Meir
抗癫痫药物（AEDs）被用于治疗各种非癫痫性中枢神经系统（CNS）疾病，包括神经病学和精神病学。大多数AEDs具有多种作用机制（MOAs），包括调节γ -氨基丁酸（GABA）能和谷氨酸能神经传递，以及改变电压门控离子通道或细胞内信号通路。这些moa可以解释AEDs在治疗双相情感障碍和神经性疼痛方面的疗效。双相情感障碍和癫痫有一些共同的特征，如它们的发作性和相关的点燃现象，这导致监管部门批准并使用卡马西平（CBZ）、丙戊酸（VPA）和拉莫三嗪（LTG）治疗双相情感障碍。开发具有改善情绪稳定活性的药物的主要限制是缺乏对双相情感障碍治疗机制的了解。与癫痫相反，双相情感障碍没有被普遍接受的动物模型，也没有模型能够表现出典型的情绪波动。尽管大多数AEDs的情绪稳定作用已被研究，但只有三种（如VPA、CBZ和LTG）在患者中显示出临床疗效。这表明药物在情绪障碍和癫痫中的作用机制只有部分重叠。周围神经损伤导致神经系统的细胞和分子改变，导致异位，重复性放电，被认为是慢性疼痛。癫痫发作的另一个特征是大脑神经元的高度兴奋性。神经性疼痛的自发电发生与癫痫有相似之处。钠通道表达的改变提示癫痫性高兴奋性的机制可能与神经性疼痛的机制相似。AEDs加巴喷丁（GBP）和普瑞巴林（PGB）已成为治疗各种神经性疼痛综合征的主要药物，因为它们能够抑制疼痛通路上的神经元过度活跃。关于GBP和PGB如何缓解神经性疼痛的一种解释是，它们选择性地与肌肉组织和大脑中的Ca+2通道亚基α 2- δ结合。自1990年以来，已有16种新型抗癫痫药进入市场，抗癫痫药市场非常拥挤。因此，2012年，即使难治性癫痫的临床需求仍未得到满足，但仅癫痫对制药行业没有吸引力。由于这种情况，未来新型aed的设计还必须包括非癫痫性中枢神经系统疾病，如双相情感障碍和神经性疼痛的潜力。这两种适应症的全球市场规模与癫痫相似，但目前批准用于治疗的药物都少于癫痫。因此，具有双相情感障碍和神经性疼痛适应症的新型AED的潜在市场规模可能是癫痫单独适应症的三倍。
Antiepileptic drugs (AEDs) are used to treat various nonepileptic central nervous system (CNS) disorders, both in neurology and psychiatry. Most AEDs have multiple mechanisms of action (MOAs), which include modulation of gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission, and alteration of voltage-gated ion channels or intracellular signaling pathways. These MOAs may explain the efficacy of AEDs in the treatment of bipolar disorder and neuropathic pain. Bipolar disorder and epilepsy have some common features, such as their episodic nature and associated kindling phenomena, which led to the regulatory approval and use of the AEDs carbamazepine (CBZ), valproic acid (VPA), and lamotrigine (LTG) in the treatment of bipolar disorder. A major limitation for the development of drugs with improved mood-stabilizing activity is the lack of knowledge on the mechanism of treatment for bipolar disorder. In contrast to epilepsy, no animal models in bipolar disorder are universally accepted and no model is able to exhibit the characteristic mood swings. Although most AEDs have now been investigated for their mood-stabilizing effects, only three (e.g., VPA, CBZ, and LTG) demonstrated clinical efficacy in patients. This suggests that the mechanism of drug action in mood disorder and in epilepsy only partially overlaps. Peripheral nerve damage leads to the initiation of cellular and molecular changes in the nervous system resulting in ectopic, repetitive firing perceived as chronic pain. Epileptic seizures are also characterized by hyperexcitability of neurons in the brain. The spontaneous electrogenesis in neuropathic pain has similarities to that of epilepsy. Alteration in sodium channels expression suggests that the mechanism underlying epileptic hyperexcitability may be similar to those underlying neuropathic pain. The AEDs gabapentin (GBP) and pregabalin (PGB) have become the mainstay of treatment for various neuropathic pain syndromes, owing to their ability to inhibit neuronal hyperactivity along the pain pathways. One explanation for how GBP and PGB relieve neuropathic pain is that they bind selectively to the Ca+2-channel subunit alpha 2-delta in muscle tissue and brain. With 16 new AEDs having entered the market since 1990 the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2012 to the pharmaceutical industry, even though the clinical needs of refractory epilepsy remain unmet. Due to this situation, the future design of new AEDs must also include a potential in nonepileptic CNS disorders, such as bipolar disorder and neuropathic pain. The global market size of each of these two indications is similar to that of epilepsy, whereas they both currently have fewer approved drugs for treatment than epilepsy. Therefore, a new AED with additional approved indications in bipolar disorder and neuropathic pain might have a potential market size three times larger than that of epilepsy alone.