Intravenous carbamazepine: Comparison of different parenteral formulations in a mouse model of convulsive status epilepticus

Abstract

Purpose: A drawback of carbamazepine (CBZ), a major antiepileptic drug (AED) with clinical efficacy against partial and generalized convulsive seizures, is its insolubility 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-β-cyclodextrin (HPβCD), an inert β- 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). Methods: 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 HPβCD or glycofurol was evaluated. Results: 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 ~3 min. ED50 for blockade of GTCS throughout the 30-min period of repeated electrical stimulation was ~7 mg/kg, similar to the potency of DZP in this model. Whereas the HPβCD/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. Conclusions: An intravenous formulation of CBZ achieved through complexing with HPβCD 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.