Effects of pretreatment with etomidate, ketamine, phenytoin, and phenytoin/ midazolam on acute, lethal cocaine toxicity Bulent Erdur 1 , Eylem Degirmenci 1 , Selim Kortunay 1 , Aykut Yuksel 2 , Murat Seyit 1 , Ahmet Ergin 1 1 Department of Emergency Medicine, Medical Faculty, Pamukkale University, Denizli, Turkey, 2 Department of Emergency Medicine, Goztepe Training and Research Hospital, Istanbul, Turkey Objective: To evaluate the effects of etomidate, ketamine, phenytoin, and phenytoin/midazolam in a mouse model of acute cocaine toxicity. Methods: We performed a randomized controlled study consisting of five groups (n525 each) of rats that received intraperitoneal injections of normal saline solution, 5 mg/kg ketamine, 7.5 mg/kg etomidate, 40 mg/kg phenytoin, and 40 mg/kg phenytoin and 2 mg/kg midazolam 10 minutes before cocaine hydrochloride (105 mg/kg). Following cocaine administration, a blinded observer watched the animals for 30 minutes to assess seizures (popcorn jumping, tonic-clonic activity, or loss of righting reflex), and lethality for 30 minutes. Results: The number of animals with seizures was lower in the etomidate (60%), phenytoin (40%), and phenytoin/midazolam (40%) groups (P,0.001). The etomidate (24%) and phenytoin/midazolam (16%) treatments were most effective in preventing lethality (P,0.001). Conversely, compared to the vehicle group (72%), cocaine-induced lethality was higher in the ketamine (84%) and phenytoin (92%) groups. All treatments prolonged the time to seizure, but this effect was most pronounced in the etomidate and phenytoin/midazolam groups, which also had the longest average time to lethality. Discussion: The present study provides the first experimental evidence supporting the use of etomidate to treat cocaine-induced seizures. Notably, ketamine and phenytoin were ineffective. Our findings suggest that premedication with etomidate, phenytoin, and phenytoin/midazolam reduced seizure activity in an acute cocaine toxicity mouse model. Keywords: Benzodiazepine, Cocaine intoxication, Etomidate, Ketamine, Phenytoin Introduction The use of cocaine can cause acute or chronic toxicity, and approximately 5–10% of emergency department visits in the United States are believed to be secondary to cocaine usage. 1 Cocaine is asso- ciated with many health complications that affect the neurological, cardiovascular, and gastrointesti- nal systems. 1–4 Cocaine increases the activity of monoamine neu- rotransmitters in the central and peripheral nervous system by blocking reuptake transporters for dopa- mine, norepinephrine, and serotonin. In addition, cocaine modulates preprodynorphin and the endo- genous opiate system. It is well known that the potent anaesthetic effects of cocaine are primarily mediated through its interactions with neuronal sodium channels. 5 Acute cocaine poisoning causes neuronal hyper- excitability and can be fatal. 3 One of the most im- portant and obvious manifestations of cocaine toxicity is the occurrence of seizures and/or status epilepticus. 6 Preclinical models have demonstrated that cocaine-induced convulsions are relatively insen- sitive to standard anticonvulsant therapies, but the mechanism has not been fully elucidated. Pharma- cological studies have demonstrated the involvement of gamma-aminobutyric-acid (GABA)-A receptors; diazepam, phenobarbital, and SKF-1000330A, an inhibitor of GABA uptake, protect against cocaine- induced seizures. N-methyl-D-aspartate (NMDA) receptor antagonists have also been reported to be effective. 7 While there are no specific treatments to eliminate the toxic effects of cocaine, they can be attenuated by serotonin, muscarinic, cholinergic, and Neurological Research ner2897.3d 7/9/12 13:14:58 The Charlesworth Group, Wakefield +44(0)1924 369598 - Rev 7.51n/W (Jan 20 2003) Correspondence to: Eylem Degirmenci, Pamukkale Universitesi Tip Fakultesi, Noroloji AD, 20070, Kinikli-Denizli, Turkey. Email: eylemteke@ yahoo.com ß W. S. Maney & Son Ltd 2012 DOI 10.1179/1743132812Y.0000000097 Neurological Research 2012 VOL. 000 NO. 000 1