GABA (A)受体的生理及其关系的作用机制,5-benzodiazepine clobazam。

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Sankar R

GABA (A)受体的生理及其关系的作用机制,5-benzodiazepine clobazam。

中枢神经系统药物。2012年3月1;26 (3):229 - 44。doi: 10.2165 / 11599020-000000000-00000。

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22145708 (在PubMed
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文摘

Clobazam最初在1970年代早期开发nonsedative抗焦虑剂,和目前可用的辅助治疗癫痫和焦虑症在100多个国家。2011年10月,clobazam (Onfi;美国Lundbeck公司公司,它是一家迪尔菲尔德,IL)被美国FDA批准用于辅助治疗癫痫的治疗与Lennox-Gastaut综合症2岁以上的患者。长效1,5-benzodiazepine的结构区别与经典1,4-benzodiazepines,如安定、氯羟去甲安定、氯硝西泮。Clobazam好吸收,峰值浓度发生线性管理后1 - 4小时。N-desmethylclobazam clobazam及其活性代谢物,通过细胞色素P450在肝脏代谢途径。的平均半衰期N-desmethylclobazam(67.5小时)是近一倍的平均半衰期clobazam(37.5小时)。Clobazam合成与期待,其独特的化学结构提供更大的功效benzodiazepine-associated副作用较少。经常报道clobazam疗法的副作用包括头晕、镇静、嗜睡和共济失调。证据来自大约50癫痫成人和儿童临床试验表明,镇静的效果观察与clobazam治疗比报道的那么严重,4-benzodiazepines。 In several studies of healthy volunteers and patients with anxiety, clobazam appeared to enhance participants' performance in cognitive tests, further distinguishing it from the 1,4-benzodiazepines. The anxiolytic and anticonvulsant effects of clobazam are associated with allosteric activation of the ligand-gated GABA(A) receptor. GABA(A) receptors are found extensively throughout the CNS, occurring synaptically and extrasynaptically. GABA(A) receptors are composed of five protein subunits, two copies of a single type of alpha subunit, two copies of one type of beta subunit and a gamma subunit. This arrangement results in a diverse assortment of receptor subtypes. As benzodiazepine pharmacology is influenced by differences in affinity for particular GABA(A) subtypes, characterizing the selectivity of different benzodiazepines is a promising avenue for establishing appropriate use of these agents in neurological disorders. Molecular techniques have significantly advanced since the inception of clobazam as a clinical agent, adding to the understanding of the GABA(A) receptor, its subunits and benzodiazepine pharmacology. Transgenic mouse models have been particularly useful in this regard. Comparative studies between transgenic and wild-type mice have further defined relationships between GABA(A) receptor composition and drug effects. From such studies, we have learned that sedating and amnesic effects are mediated by the GABA(A) alpha(1) subunit, alpha(2) receptors mediate anxiolytic effects, alpha subunits are involved with anticonvulsant activity, alpha(5) may be implicated in learning and memory, and beta(3) subunit deficiency decreases GABA inhibition. Despite progress in determining the role of various subunits to specific benzodiazepine pharmacological actions, the precise mechanism of action of clobazam, and more importantly, how that mechanism of action translates into clinical consequences (i.e. efficacy, tolerability and safety) remain unknown. Testing clobazam and 1,4-benzodiazepines using a range of recombinant GABA(A) receptor subtypes would hopefully elucidate the subunits involved and strengthen our understanding of clobazam and its mechanism of action.

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