Cocaine Esterase: Interactions with Cocaine and Immune Responses in Mice

Ko, Mei‐Chuan; Bowen, Luvina D.; Narasimhan, Diwahar; Berlin, Aaron A.; Lukacs, Nicholas W.; Sunahara, Roger K.; Cooper, Ziva D.; Woods, James H.

doi:10.1124/jpet.106.114223

Cited by 41 publications

(77 citation statements)

References 30 publications

(43 reference statements)

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“…Furthermore, as a foreign protein, cocaine esterase can be expected to evoke immune responses in humans. In mice, anti-esterase antibodies appeared after three injections (Ko et al, 2007) and reduced the protective activity of further administrations. Chronic interventions with bacterial enzymes, therefore, are unrealistic.…”

Section: Discussion Previous Development Of Cocaine Hydrolases and Bimentioning

confidence: 99%

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

Brimijoin

Gao

Anker

et al. 2008

Neuropsychopharmacol

125

167

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Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans.

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Section: Discussion Previous Development Of Cocaine Hydrolases and Bimentioning

confidence: 99%

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

Brimijoin

Gao

Anker

et al. 2008

Neuropsychopharmacol

125

167

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“…3b). We have previously demonstrated that wt CocE is rendered ineffective at preventing lethality from a challenge dose of cocaine after a 30-min pretreatment (Ko et al, 2007). CocE-T172R/G173Q (1 mg) protected 50% of animals from a LD 100 dose (180 mg/kg) of cocaine up to 4 h after CocE administration (Gao et al, 2009).…”

Section: Thermostability Of Mutantsmentioning

confidence: 99%

“…found in the Rhizosphere soil surrounding the coca plant, CocE has a high V max toward cocaine (V max ϭ 2300 min Ϫ1 ) (Gao et al, 2009) and produces the same products as BchE (Bresler et al, 2000). CocE has previously been shown to block cocaine-induced cardiac disturbance, neurological changes, and lethality in rodents when administered before or after cocaine (Cooper et al, 2006;Jutkiewicz et al, 2009;Ko et al, 2007;Wood et al, 2010).…”

mentioning

confidence: 99%

“…The wild-type (wt) CocE cannot be used as a pharmacotherapy for cocaine abuse because of its 13.7-min half-life at 37°C (Cooper et al, 2006;Ko et al, 2007;Gao et al, 2009). We have previously identified a mutant of CocE (T172R and G173Q) that extends the half-life of CocE to ϳ4.5 h, as assessed by in vitro kinetic assays (at 37°C) or in vivo by protection against cocaine-induced lethality in mice (Gao et al, 2009).…”

mentioning

confidence: 99%

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A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse

Brim¹,

Nance²,

Youngstrom³

et al. 2010

Mol Pharmacol

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Rhodococcal cocaine esterase (CocE) is an attractive potential treatment for both cocaine overdose and cocaine addiction. CocE directly degrades cocaine into inactive products, whereas traditional small-molecule approaches require blockade of the inhibitory action of cocaine on a diverse array of monoamine transporters and ion channels. The usefulness of wild-type (wt) cocaine esterase is hampered by its inactivation at 37°C. Herein, we characterize the most thermostable form of this enzyme to date, CocE-L169K/G173Q. In vitro kinetic analyses reveal that CocE-L169K/G173Q displays a half-life of 2.9 days at 37°C, which represents a 340-fold improvement over wt and is 15-fold greater than previously reported mutants.

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“…Although the wild-type (wt) form of CocE is capable of dose dependently protecting mice and rats against the cardiovascular, convulsant, and lethal effects of cocaine, it is rapidly inactivated at body temperature resulting in an in vivo half-life of B15 min (Cooper et al, 2006;Jutkiewicz et al, 2009;Ko et al, 2007Ko et al, , 2009Wood et al, 2010). Sitedirected mutagenesis studies aimed at improving the thermostability of CocE have identified an equally efficient mutant CocE (T172R/G173Q CocE, RQ CocE, DM CocE) with an in vivo half-life of B4.5 h in mice (Gao et al, 2009;Narasimhan et al, 2010), and a high degree of pharmacologic specificity (Brim et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

Collins

Narasimhan

Cunningham

et al. 2011

Neuropsychopharmacol

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Recent mutagenesis studies have identified a mutant G4C/S10C/T172R/G173Q cocaine esterase (CCRQ CocE) with an in vitro duration of action of 440 days. Although the in vivo duration of CCRQ CocE's action was o24 h, modification of this enzyme with polyethylene glycol (PEG) polymers resulted in a CocE (PEG-CCRQ CocE) capable of preventing cocaine-induced lethality for up to 72 h. The current studies were aimed at providing a detailed characterization of the effectiveness, selectivity, and duration of PEG-CCRQ CocE's actions in cocaine self-administration and discrimination assays in rats. Pretreatment with PEG-CCRQ CocE produced dose-dependent rightward shifts in the dose-response curves for cocaine self-administration and discrimination, with the highest dose of PEG-CCRQ CocE capable of producing an initial shift of cocaine's reinforcing and interoceptive effects of 430-fold to the right, with significant inhibition of these effects observed for up to 72 h. Although PEG-CCRQ CocE also produced slight reductions in the rates of methylphenidate-and foodreinforced responding, these effects were short-lived, lasting o24 h. Finally, when taken together with the finding that PEG-CCRQ CocE failed to alter the cocaine-like interoceptive effects of either methylphenidate or d-amphetamine, these results suggest that PEG-CCRQ CocE possesses a high degree of pharmacologic specificity for cocaine and a prolonged in vivo duration of action. In conclusion, these studies provide strong evidence to support the further development of long-lasting, highly efficient CocEs, such as PEG-CCRQ CocE, as a potential therapeutic option for the treatment of cocaine abuse in humans.

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Cocaine Esterase: Interactions with Cocaine and Immune Responses in Mice

Cited by 41 publications

References 30 publications

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

A Thermally Stable Form of Bacterial Cocaine Esterase: A Potential Therapeutic Agent for Treatment of Cocaine Abuse

Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

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