Flumazenil induces seizures and death in mixed cocaine-diazepam intoxications.
OBJECTIVE
Administration of the benzodiazepine antagonist flumazenil may unmask seizures in mixed cocaine-benzodiazepine intoxication.


METHODS
Male Sprague-Dawley rats received 100 mg/kg cocaine IP alone, 5 mg/kg diazepam alone, or a combination of diazepam and cocaine. Three minutes later, groups were challenged with vehicle or flumazenil 5 or 10 mg/kg IP. Animal behavior, seizures (time to and incidence), death (time to and incidence), and cortical EEG tracings were recorded.


METHODS
Administration of flumazenil to animals after they had received a combination dose of cocaine and diazepam.


RESULTS
In group 1, animals received cocaine followed by vehicle. This resulted in 100% developing seizures and death. Group 2 received diazepam alone followed by vehicle. Animals became somnolent and none died. Group 3 received diazepam followed by 5 mg/kg flumazenil. Animals became somnolent after diazepam and then active after flumazenil administration. In group 4, a combination of cocaine and diazepam was administered simultaneously. This resulted in no overt or EEG-detectable seizures and a 50% incidence of death. Group 5 received a similar combination of cocaine and diazepam, followed later by 5 mg/kg flumazenil. This resulted in an increased incidence of seizures, 90% (P < .01), and death, 100% (P < or = .01), compared with group 4. Group 6 received cocaine and diazepam followed by 10 mg/kg flumazenil. This also resulted in an increased incidence of seizures, 90% (P < or = .01), and death, 90% (P < or = .05), compared with group 4.


CONCLUSIONS
Flumazenil can unmask seizures and increase the incidence of death in a model of combined cocaine-diazepam intoxications.
Derlet
R W
RW
Division of Emergency Medicine and Clinical Toxicology, School of Medicine, University of California, Davis, Sacramento.
Albertson
T E
TE
D000818:Animals; D003042:Cocaine / Q000506:poisoning*; D003975:Diazepam / Q000506:poisoning*; D004569:Electroencephalography / Q000187:drug effects; D005442:Flumazenil / Q000009:adverse effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced*
D005442:Flumazenil; D003042:Cocaine; D003975:Diazepam