Isobolographic analysis of adjunct antiseizure activity of the FDA-approved cannabidiol with neurosteroids and benzodiazepines in adult refractory focal onset epilepsy.
Isobolographic analysis of adjunct antiseizure activity of the FDA-approved cannabidiol with neurosteroids and benzodiazepines in adult refractory focal onset epilepsy.
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FDA 批准的大麻二酚与神经类固醇和苯二氮卓类药物在成人难治性局灶性癫痫中的辅助抗癫痫活性的等辐射分析。
DOI：
10.1016/j.expneurol.2022.114294
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发表时间：
2023
影响因子：
5.3
通讯作者：
Reddy,DoodipalaSamba
中科院分区：
文献类型：
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作者：
Golub,Victoria;Ramakrishnan,Sreevidhya;Reddy,DoodipalaSamba
癫痫是一种严重的神经系统疾病，与反复发作和不可预测的癫痫发作以及广泛的神经精神共病相关。癫痫无法治愈，超过三分之一的癫痫患者被诊断患有药物难治性癫痫，这表明迫切需要新型抗癫痫药物（ASM）。大麻二酚（CBD）已被证明可以减少儿童癫痫发作，如Dravet和Lennox-Gastaut综合征;然而，它尚未被严格测试成人癫痫发作或难治性局灶性癫痫模型。虽然确切的机制尚不清楚，但它可能以某些GABA-A受体调节药物（如神经类固醇和苯二氮卓类）特有的方式发挥作用。在这项研究中，我们试图确定辅助抗癫痫活性的临床CBD产品在成人6 Hz模型的局灶性难治性癫痫。以剂量-反应和时程方式单独评估CBD，并与两种ASM加奈索酮（神经类固醇）和咪达唑仑（苯二氮卓类）联合治疗6 Hz诱导的难治性局灶性发作和全身性癫痫发作。在药理学研究中，CBD对癫痫发作产生剂量依赖性保护作用（ED 50，53 mg/kg，i. p.）没有任何副作用。CBD显着降低电图活动和行为发作反应，没有明显的性别差异。CBD与加奈索酮或咪达唑仑以三种标准比例（1：1，1：3，3：1）结合使用等效线图设计进行评估。等效辐射分析显示CBD +加奈索酮和CBD +咪达唑仑的组合方案产生0.313和0.164的组合指数，表明对癫痫发作保护的强协同作用，具有很少至没有毒性。总之，这些结果证明了CBD单药治疗的治疗潜力，以及作为成人局灶性难治性癫痫的辅助治疗与GABA能ASM的组合。
Epilepsy is a serious neurological disorder associated with recurrent and unpredictable seizures and extensive neuropsychiatric comorbidities. There is no cure for epilepsy, and over one third of epileptic patients have been diagnosed with drug-refractory epilepsy, indicating the critical need for novel antiseizure medications (ASMs). Cannabidiol (CBD) has been shown to decrease seizures in pediatric epilepsies, such as Dravet and Lennox-Gastaut syndromes; however, it has not been rigorously tested for adult seizures or in models of refractory focal epilepsy. Although the exact mechanism is unknown, it is likely to act in a way that is unique to certain GABA-A receptor-modulating drugs, such as neurosteroids and benzodiazepines. In this study, we sought to determine the adjunct antiseizure activity of a clinical CBD product in an adult 6-Hz model of focal refractory epilepsy. CBD was evaluated alone in both a dose-response and time-course manner and in an adjunct combination with two ASMs ganaxolone (neurosteroid) and midazolam (benzodiazepine) against 6-Hz-induced refractory focal onset, generalized seizures. In pharmacological studies, CBD produced dose-dependent protection against seizures (ED50, 53 mg/kg, i.p.) without any side effects. CBD significantly reduced both electrographic activity and behavioral ictal responses with no apparent sex differences. CBD was evaluated in an isobologram design in conjunction with ganaxolone or midazolam at three standard ratios (1:1, 1:3, 3:1). Isobolographic analysis shows the combination regimens of CBD + ganaxolone and CBD + midazolam exerted combination index of 0.313 and 0.164, indicating strong synergism for seizure protection, with little to no toxicity. Together, these results demonstrate the therapeutic potential of CBD monotherapy and as an adjunct therapy for adult focal refractory epilepsy in combination with GABAergic ASMs.