title: Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats.
abstract: BACKGROUND
  A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DM CocE) has been shown to protect mice from cocaine-induced lethality, inhibit the reinforcing effects of cocaine in rats, and reverse cocaine's cardiovascular effects in rhesus monkeys. The current studies evaluated the effectiveness of DM CocE to protect against, and reverse cocaine's cardiovascular, convulsant, and lethal effects in male and female rats.
  
  
  METHODS
  Pretreatment studies were used to determine the effectiveness and in vivo duration of action for DM CocE to protect rats against the occurrence of cardiovascular changes, convulsion and lethality associated with acute cocaine toxicity. Posttreatment studies were used to evaluate the capacity of DM CocE to rescue rats from the cardiovascular and lethal effects of large doses of cocaine. In addition, male and female rats were studied to determine if there were any potential effects of sex on the capacity of DM CocE to protect against, or reverse acute cocaine toxicity in rats.
  
  
  RESULTS
  Pretreatment with DM CocE dose-dependently protected rats against cocaine-induced cardiovascular changes, convulsion and lethality, with higher doses active for up to 4h, and shifting cocaine-induced lethality at least 10-fold to the right. In addition to dose-dependently recovering rats from an otherwise lethal dose of cocaine, post-treatment with DM CocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DM CocE to protect against, or reverse acute cocaine toxicity.
  
  
  CONCLUSIONS
  Together, these results support the development of DM CocE for the treatment of acute cocaine toxicity.
authors.affiliation: Department of Pharmacology, 1301 MSRB III, 1150 W. Medical Center Drive, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA. collinsg@umich.edu
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Collins
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Zaks
authors.forename: Alyssa R
authors.initials: AR
authors.lastname: Cunningham
authors.forename: Carley
authors.initials: C
authors.lastname: St Clair
authors.forename: Joseph
authors.initials: J
authors.lastname: Nichols
authors.forename: Diwahar
authors.initials: D
authors.lastname: Narasimhan
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Ko
authors.forename: Roger K
authors.initials: RK
authors.lastname: Sunahara
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D003042:Cocaine / Q000506:poisoning*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine