Ecgonine methyl ester protects against cocaine lethality in mice.
BACKGROUND
Plasma cholinesterase (PChE) metabolizes cocaine to ecgonine methyl ester (EME). Limited data demonstrate that EME is a mild vasodilator. Exogenous PChE protects against cocaine-induced seizures and lethality. It is unclear whether this protective effect results from enhanced degradation of cocaine, the loss of active metabolites (benzoylecgonine, norcocaine), or the production of a beneficial metabolite (EME). This study was designed to further investigate the pharmacologic effects of EME.


METHODS
All experiments used female ICR Swiss albino mice weighing 20-30 grams. Mice were acclimated to 12 h alternating light-dark cycles and given food and water ad libitum. Using a randomized, blinded protocol, 80 mice were then pretreated with either IP EME (50 mg/kg) in a 0.9% sodium chloride solution or an equal volume of 0.9% sodium chloride solution as control. Five minutes later, all animals received 126 mg/kg of cocaine IP and were observed for seizures and death. Fatality was compared using a Fisher's exact test, and the time to seizures and death were compared using a Mann-Whitney U statistic.


RESULTS
Pretreatment with EME increased survival following cocaine (9/40 vs. 2/40, for EME vs. control, respectively, p<0.05). The median times to seizure and death for both groups were 2.0 vs. 1.5 min (p>0.05), and 4.5 vs. 4.6 min (p>0.05) (EME vs. control for seizures and death, respectively).


CONCLUSIONS
In this animal model, EME is protective against cocaine lethality. This effect is consistent with the previously described vasodilatory effects of EME. Further studies are indicated to determine whether the increase in EME produced by exogenous PChE administration contributes to the benefits that occur when PChE is given to cocaine-poisoned animals.
Hoffman
Robert S
RS
New York City Department of Health and Mental Hygiene Poison Control Center, New York University School of Medicine, New York, New York 10016, USA. bobhoff@POL.net
Kaplan
Joseph L
JL
Hung
Oliver L
OL
Goldfrank
Lewis R
LR
D000818:Animals; D002802:Cholinesterases / Q000097:blood; D003042:Cocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000506:poisoning* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011041:Poisoning / Q000517:prevention & control
D009294:Narcotics; D002802:Cholinesterases; D003042:Cocaine; C034524:ecgonine methyl ester