Effects of cocaine esterase following its repeated administration with cocaine in mice.
BACKGROUND
A bacterial cocaine esterase (CocE) produces robust protection and reversal of cocaine toxicity. The aim of this study was to investigate how effectiveness of CocE was changed following its repeated administration together with cocaine.


METHODS
Cocaine toxicity was quantified by measuring the occurrence of convulsions and lethality in mice. Immunologic responses of CocE were determined using ELISA. In the protection experiment, i.v. CocE 0.3mg was given 1min before a lethal dose of i.p. cocaine 180mg/kg. In the rescue experiment, i.v. CocE 0.3mg was given 1min after the occurrence of convulsions elicited by i.p. cocaine 100mg/kg. In both treatment paradigms, four trials were conducted in the same animals with a 2-week interval.


RESULTS
CocE retained its effectiveness to protect or rescue mice during the first two trials and these mice did not show an immune response. In contrast, CocE's effectiveness was gradually reduced in the last two trials, accompanied by 10- and 100-fold increases in anti-CocE antibody titers. Nevertheless, effectiveness of CocE could be partially recovered by increasing the dose of CocE. In addition, escalating the dose of CocE from the minimum effective dose for repeated administration could also retain CocE's effectiveness longer and slow the production of anti-CocE antibodies.


CONCLUSIONS
These results indicate that CocE is a weak antigen and it can maintain its protective and rescuing ability initially against cocaine-induced toxicity. Decreased effectiveness of CocE following repeated use can be partially improved by adjusting the dose and frequency of CocE treatment.
Ko
Mei-Chuan
MC
Department of Pharmacology, University of Michigan, Medical School, Ann Arbor, MI 48109, USA. mko@umich.edu
Narasimhan
Diwahar
D
Berlin
Aaron A
AA
Lukacs
Nicholas W
NW
Sunahara
Roger K
RK
Woods
James H
JH
D000818:Animals; D000906:Antibodies / Q000097:blood; D000918:Antibody Specificity; D002265:Carboxylic Ester Hydrolases / Q000494:pharmacology* / Q000627:therapeutic use; D003042:Cocaine / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism* / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008297:Male; D051379:Mice; D011187:Posture; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
D000906:Antibodies; D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine