Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O.BOX 1982, Dammam, 31441 Saudi Arabia.
Department of Pharmaceutical Sciences, Faculty of Applied Sc. and Tech, University of Kashmir, Srinagar, India.
Eur J Pharm Sci. 2020 Apr 15;146:105261. doi: 10.1016/j.ejps.2020.105261. Epub 2020 Feb 13.
The evidence to guide clinicians regarding rationale polytherapy with current antiepileptic drugs (AEDs) is lacking, and current practice recommendations are largely empirical. The excessive drug loading with combinatorial therapies of existing AEDs are associated with escalated neurotoxicity, and that emergence of pharmacoresistant seizures couldn't be averted. In pursuit of judicious selection of novel AEDs in combinatorial therapies with mechanism based evidences, standardized dose of raloxifene, fluoxetine, bromocriptine and their low dose combinations, were experimentally tested for their impact on maximal electroshock (MES) induced tonic hind limb extension (THLE) in mice. Hippocampal neuropeptide Y (NPY) levels, oxidative stress and histopathological studies were undertaken. The results suggest the potentiating effect of 4 mg/kg raloxifene on 14 mg/kg fluoxetine against MES induced THLE, as otherwise monotherapy with 4 mg/kg raloxifene was unable to produce an effect. The results also depicted better efficacy than carbamazepine (20 mg/kg), standard AED. Most profoundly, MES-induced significant (P < 0.001) reduction in hippocampal NPY levels, that were escalated insignificantly with the duo-drug combination, suggesting some other mechanism in mitigation of electroshock induced seizures. These results were later corroborated with assays to assess oxidative stress and neuronal damage. In conclusion, the results demonstrated the propitious therapeutic benefit of duo-drug low dose combination of drugs; raloxifene and fluoxetine, with diverse mode of actions fetching greater effectiveness in the management of generalized tonic clonic seizures (GTCS).
缺乏指导临床医生合理使用现有抗癫痫药物（AEDs）进行多药治疗的证据，目前的实践建议主要是经验性的。现有 AED 联合治疗的过度药物负荷与神经毒性的增加有关，而且无法避免出现药物抵抗性发作。为了根据基于机制的证据明智地选择新型 AED 进行联合治疗，我们对标准剂量的雷洛昔芬、氟西汀、溴隐亭及其低剂量组合进行了实验测试，以研究它们对小鼠最大电休克（MES）诱导的强直后肢伸展（THLE）的影响。进行了海马神经肽 Y（NPY）水平、氧化应激和组织病理学研究。结果表明，4mg/kg 雷洛昔芬对 14mg/kg 氟西汀对 MES 诱导的 THLE 具有增强作用，否则单独使用 4mg/kg 雷洛昔芬无法产生作用。结果还显示出比卡马西平（20mg/kg）更好的疗效，即标准 AED。最重要的是，MES 诱导的海马 NPY 水平显著降低（P<0.001），而与双药联合治疗相比，NPY 水平升高不显著，这表明在减轻电休克诱导的癫痫发作方面存在其他机制。这些结果后来通过评估氧化应激和神经元损伤的测定得到了证实。总之，结果表明，雷洛昔芬和氟西汀这两种具有不同作用机制的药物低剂量联合使用具有良好的治疗益处，在治疗全面强直阵挛发作（GTCS）方面更有效。
