The long-term objectives of this project are to develop immunotherapeutic methods for the treatment of drug abuse.
The specific aims are designed to test the hypothesis that high affinity anti-drug monoclonal antibodies can be used to block and reverse the acute behavioral toxicity of drugs of abuse. For these studies, Fab fragments of anti-phencyclidine (PCP) monoclonal antibodies will be used as a prototype to study the ability of the antibodies fragments to significantly alter the pharmacokinetics of high volume of distribution drugs, and to antagonize the acute behavioral toxicity of drugs of abuse. The experiments in this proposal will proceed in a systematic manner, similar to the pharmacokinetic and behavioral testing of any new drug. First, gram (6-13.5 grams) quantities of monoclonal anti-PCP Fab will be generated and purified. Then, the in vivo effect of these monoclonal antibody fragments on the pharmacokinetics of PCP and metabolites will be extensively characterized in the rat. These pharmacokinetic studies will include pretreatment of rats with the antibody antagonist to block distribution of PCP and treatment with antibody antagonist after the administration of PCP to remove PCP from central nervous system sites of action. Finally, with the knowledge gained in the pharmacokinetic studies, anti-PCP Fab will be used to block and reverse the effects of pharmacologically active doses of PCP and two other potent arylcyclohexylamines. These studies could lead to an important method for preventing and reversing the adverse effects of drugs of abuse and in particular, it could provide an important new method for treating the violent, frightening and sometimes irreversible psychotic effects of PCP.
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