A bacterial cocaine esterase protects against cocaine-induced epileptogenic activity and lethality.
OBJECTIVE
Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality.


METHODS
Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine.


RESULTS
The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (-)-2beta-carbomethoxy-3beta-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine.


CONCLUSIONS
The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted.
Jutkiewicz
Emily M
EM
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA. ejutkiew@umich.edu
Baladi
Michelle G
MG
Cooper
Ziva D
ZD
Narasimhan
Diwahar
D
Sunahara
Roger K
RK
Woods
James H
JH
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001419:Bacteria / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000627:therapeutic use*; D003042:Cocaine / Q000031:analogs & derivatives / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000401:mortality; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000627:therapeutic use; D008297:Male; D008874:Midazolam / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control*; D016896:Treatment Outcome
D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; C021278:troparil; D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine; D008874:Midazolam