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.
BACKGROUND: A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DMCocE) 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 DMCocE 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 DMCocE 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 DMCocE 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 DMCocE to protect against, or reverse acute cocaine toxicity in rats. RESULTS: Pretreatment with DMCocE 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 DMCocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DMCocE to protect against, or reverse acute cocaine toxicity. CONCLUSIONS: Together, these results support the development of DMCocE for the treatment of acute cocaine toxicity.
Authors: Mei-Chuan Ko; Luvina D Bowen; Diwahar Narasimhan; Aaron A Berlin; Nicholas W Lukacs; Roger K Sunahara; Ziva D Cooper; James H Woods Journal: J Pharmacol Exp Ther Date: 2006-11-17 Impact factor: 4.030
Authors: James McCord; Hani Jneid; Judd E Hollander; James A de Lemos; Bojan Cercek; Priscilla Hsue; W Brian Gibler; E Magnus Ohman; Barbara Drew; George Philippides; L Kristin Newby Journal: Circulation Date: 2008-03-17 Impact factor: 29.690
Authors: Mei-Chuan Ko; Diwahar Narasimhan; Aaron A Berlin; Nicholas W Lukacs; Roger K Sunahara; James H Woods Journal: Drug Alcohol Depend Date: 2009-02-13 Impact factor: 4.492
Authors: Gregory T Collins; Remy L Brim; Diwahar Narasimhan; Mei-Chuan Ko; Roger K Sunahara; Chang-Guo Zhan; James H Woods Journal: J Pharmacol Exp Ther Date: 2009-08-26 Impact factor: 4.030
Authors: Daquan Gao; Diwahar L Narasimhan; Joanne Macdonald; Remy Brim; Mei-Chuan Ko; Donald W Landry; James H Woods; Roger K Sunahara; Chang-Guo Zhan Journal: Mol Pharmacol Date: 2008-11-05 Impact factor: 4.436
Authors: Margaret Haney; Erik W Gunderson; Huiping Jiang; Eric D Collins; Richard W Foltin Journal: Biol Psychiatry Date: 2010-01-01 Impact factor: 13.382
Authors: Stephen Brimijoin; Yang Gao; Justin J Anker; Luke A Gliddon; David Lafleur; R Shah; Qinghai Zhao; M Singh; Marilyn E Carroll Journal: Neuropsychopharmacology Date: 2008-01-16 Impact factor: 7.853
Authors: Emily M Jutkiewicz; Michelle G Baladi; Ziva D Cooper; Diwahar Narasimhan; Roger K Sunahara; James H Woods Journal: Ann Emerg Med Date: 2008-11-14 Impact factor: 5.721
Authors: Gregory T Collins; Remy L Brim; Kathleen R Noon; Diwahar Narasimhan; Nicholas W Lukacs; Roger K Sunahara; James H Woods; Mei-Chuan Ko Journal: J Pharmacol Exp Ther Date: 2012-04-19 Impact factor: 4.030
Authors: Remy L Brim; Kathleen R Noon; Joseph Nichols; Diwahar Narasimhan; James H Woods; Roger K Sunahara Journal: Drug Alcohol Depend Date: 2011-07-19 Impact factor: 4.492
Authors: Remy L Brim; Kathleen R Noon; Gregory T Collins; Aron Stein; Joseph Nichols; Diwa Narasimhan; Mei-Chuan Ko; James H Woods; Roger K Sunahara Journal: J Pharmacol Exp Ther Date: 2011-10-11 Impact factor: 4.030
Authors: Gregory T Collins; Diwahar Narasimhan; Alyssa R Cunningham; Matthew E Zaks; Joseph Nichols; Mei-Chuan Ko; Roger K Sunahara; James H Woods Journal: Neuropsychopharmacology Date: 2011-10-12 Impact factor: 7.853
Authors: Lei Fang; K Martin Chow; Shurong Hou; Liu Xue; Xiabin Chen; David W Rodgers; Fang Zheng; Chang-Guo Zhan Journal: ACS Chem Biol Date: 2014-06-11 Impact factor: 5.100