New application of an old drug proparacaine in treating epilepsy via liposomal hydrogel formulation
New application of an old drug proparacaine in treating epilepsy via liposomal hydrogel formulation
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老药丙美卡因脂质体水凝胶制剂治疗癫痫的新应用。
DOI：
10.1016/j.phrs.2021.105636
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发表时间：
2021-05-12
影响因子：
9.3
通讯作者：
Han, Feng
中科院分区：
文献类型：
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作者：
Taleb, Abdoh;Zhou, Ya-Ping;Han, Feng
丙美卡因（PPC）是先前发现的通过阻断中央Nav1.3用于眼科验光和手术的局部麻醉剂。本研究发现，盐酸丙美卡因（PPC-HCl）对匹罗卡品致痫小鼠有明显的抗痫作用。更重要的是，PPCHCl长期治疗完全终止了自发性复发性癫痫发作的发生，而没有显著的毒性。通过全基因组水平的转录组学分析，PPC-HCl的慢性治疗没有引起明显的细胞毒性、神经精神不良反应、肝毒性、心脏毒性，甚至遗传毒性。仅在高剂量（50 mg/kg）时，通过心电图测量的QRS间期略有延长，这与左乙拉西坦的影响相似。然而，为了克服这个潜在的问题，我们采用了脂质体包封策略，可以减轻心脏毒性，并制备了一种类型的水凝胶含有PPC盐酸缓释。将含有脂质体PPC-HCl的温敏性壳聚糖基水凝胶植入皮下组织中可立即和持久地缓解癫痫小鼠自发性复发性癫痫发作，而不影响QRS间期。因此，这种新的丙美卡因脂质体水凝胶制剂可以开发为用于治疗癫痫的透皮贴剂，避免了目前临床上抗癫痫药物长期治疗后的严重毒性。
Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPCHCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic.