Effectiveness of a Cocaine Hydrolase for Cocaine Toxicity Treatment in Male and Female Rats
Development of a truly effective medication for treatment of cocaine abuse has been a grand challenge. There is no FDA-approved therapeutic agent specific for cocaine addiction or overdose. An enzyme therapy using an efficient cocaine-metabolizing enzyme could be a promising treatment strategy for cocaine overdose and addiction. One of our previously designed cocaine hydrolases (CocHs), known as CocH1, was fused with human serum albumin (HSA) to prolong the biological half-life. The fusion protein CocH1-HSA is an investigational new drug (IND) approved by the FDA for clinical trials in cocaine addiction treatment, but not in cocaine overdose/toxicity treatment. In the present study, we aimed to evaluate the pharmacokinetic profile of CocH1-HSA and its effectiveness for cocaine toxicity treatment in male and female rats and demonstrate the clinical potential. The data demonstrate that enzyme CocH1-HSA has very similar pharmacokinetic profile in male and female rats. For both male and female rats, the enzyme can rapidly eliminate cocaine even if the cocaine dose is as high as 180 mg/kg (LD100). Based on the animal data, whenever the enzyme is given to a living subject, the remaining cocaine in the body will be converted rapidly to physiologically inactive metabolites and, thus, reverse the cocaine toxicity and help the subject to recover. So, an enzyme therapy using CocH1-HSA can effectively treat cocaine toxicity and prevent the subject from further damage by cocaine. The data obtained clearly demonstrate the promising clinical potential of CocH1-HSA in cocaine overdose treatment for both genders.
KEY WORDSDrug abuse Drug overdose Cocaine toxicity Enzyme therapy Drug metabolism
X.Z. and Z.Z. performed in vivo studies and analyzed the data. T.Z. and J.D. contributed to the in vivo studies. X.C. analyzed the blood samples. Z.J. prepared the experimental materials. C.-G.Z. and F.Z. designed the study, analyzed the data, and finalized the manuscript. All authors reviewed the manuscript.
This work was supported in part by the National Institutes of Health (NIH grants UH2/UH3 DA041115, R01 DA035552, R01 DA032910, R01 DA013930, and R01 DA025100) and the National Science Foundation (NSF grant CHE-1111761).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
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