Löscher W, Hönack D
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Epilepsia. 1997 Jan;38(1):106-13. doi: 10.1111/j.1528-1157.1997.tb01084.x.
A drawback of carbamazepine (CBZ), a major antiepileptic drug (AED) with clinical efficacy against partial and generalized convulsive seizures, is its isolubility in aqueous vehicles, which is generally considered a contraindication to parenteral administration in epileptic patients. However, CBZ can be dissolved in glycofurol, a solvent used clinically as a vehicle for parenteral preparations of drugs such as diazepam (DZP) and phenytoin (PHT). Furthermore, aqueous CBZ solutions can be prepared by complexing CBZ with 2-hydroxypropyl-beta-cyclodextrin (HP beta CD), an inert beta-cyclodextrin derivative believed to have acceptable tolerability for human use. Such solutions of CBZ have been proposed to be suitable for intravenous administration in treatment of convulsive (grand mal) status epilepticus (CSE).
A series of five generalized tonic-clonic seizures (GTCS) in 30 min was induced by repeated transauricular electrical stimulation in mice. In this model of convulsive (grand mal) SE, the anticonvulsant potency of intravenous CBZ dissolved in aqueous dilutions of either HP beta CD or glycofurol was evaluated.
In both solutions, CBZ rapidly suppressed seizures after intravenous bolus injection. Potent anticonvulsant activity was obtained as early as 30 s after injection, and peak effects were observed at approximately 3 min. ED50 for blockade of GTCS throughout the 30-min period of repeated electrical stimulation was approximately 7 mg/kg, similar to the potency of DZP in this model. Whereas the HP beta CD/CBZ solutions were tolerated by the animals, with no pronounced behavioral or motor adverse effects, the glycofurol/CBZ solutions induced marked sedation and motor impairment, indicating interactions between drug and solvent. Determination of CBZ in plasma and brain demonstrated that the rapid onset of anticonvulsant action after intravenous bolus injection was related to rapid drug penetration into brain tissue.
An intravenous formulation of CBZ achieved through complexing with HP beta CD might be suitable for parenteral use in acute clinical conditions such as SE, particularly because CBZ has the advantage of being almost free of respiratory or cardiovascular adverse effects.
卡马西平（CBZ）是一种主要的抗癫痫药物（AED），对部分性和全身性惊厥发作具有临床疗效，但其在水性载体中的溶解度较低，这通常被认为是癫痫患者胃肠外给药的禁忌证。然而，CBZ可溶于聚乙二醇400蓖麻油，该溶剂在临床上用作地西泮（DZP）和苯妥英（PHT）等药物胃肠外制剂的载体。此外，CBZ水溶液可通过将CBZ与2-羟丙基-β-环糊精（HPβCD）络合来制备，HPβCD是一种惰性β-环糊精衍生物，据信对人体具有可接受的耐受性。已有人提出这种CBZ溶液适用于静脉给药治疗惊厥性（大发作）癫痫持续状态（CSE）。
通过重复经耳电刺激在小鼠中诱导30分钟内发生一系列五次全身性强直阵挛发作（GTCS）。在这种惊厥性（大发作）癫痫持续状态模型中，评估了溶解于HPβCD或聚乙二醇400蓖麻油水性稀释液中的静脉注射CBZ的抗惊厥效力。
在两种溶液中，静脉推注后CBZ均能迅速抑制癫痫发作。注射后早在30秒就获得了强效抗惊厥活性，在约3分钟时观察到峰值效应。在整个30分钟的重复电刺激期间，阻断GTCS的半数有效剂量（ED50）约为7mg/kg，与该模型中DZP的效力相似。虽然动物对HPβCD/CBZ溶液耐受，没有明显的行为或运动不良反应，但聚乙二醇400蓖麻油/CBZ溶液引起明显的镇静和运动障碍，表明药物与溶剂之间存在相互作用。血浆和脑中CBZ的测定表明，静脉推注后抗惊厥作用的快速起效与药物快速渗透到脑组织有关。
通过与HPβCD络合实现的CBZ静脉制剂可能适用于癫痫持续状态等急性临床情况的胃肠外使用，特别是因为CBZ具有几乎无呼吸或心血管不良反应的优点。
