Intravenous carbamazepine: comparison of different parenteral formulations in a mouse model of convulsive status epilepticus.
OBJECTIVE
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).


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 HP beta CD 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 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.


CONCLUSIONS
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.
Löscher
W
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Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Hönack
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D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D002220:Carbamazepine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003505:Cyclodextrins / Q000008:administration & dosage; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004597:Electroshock; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage; D011092:Polyethylene Glycols / Q000008:administration & dosage; D051381:Rats; D012996:Solutions; D012997:Solvents / Q000008:administration & dosage; D013226:Status Epilepticus / Q000209:etiology / Q000517:prevention & control*; D047392:beta-Cyclodextrins
D003505:Cyclodextrins; D014677:Pharmaceutical Vehicles; D012996:Solutions; D012997:Solvents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002220:Carbamazepine; D011092:Polyethylene Glycols; C018557:glycofurol