Abstract
The development of treatment strategies for drug intoxication has been hindered in part by the lack of clinically useful antagonists. Consequently, the major goal of these studies was to determine whether a monoclonal antibody Fab fragment (of IgG) could be used as an effective drug class-selective antagonist and to understand better the dose-response relationships for reversing CNS drug toxicity. Changes in drug-induced locomotor effects in a rat model were used to assess the ability of the antiphencyclidine (anti-PCP) Fab to reverse the behavioral effects of PCP and other potent arylcyclohexylamines. In experiments to determine the pharmacodynamics of Fabinduced antagonism of behavioral effects, the Fab completely reversed all PCP-induced locomotor effects in a Fab dose-dependent manner with a minimal effective dose of 0.18 mole-equivalents of Fab and an ED50 value of about one-third mole-equivalent. The anti-PCP Fab also completely reversed the locomotor effects induced by two other structurally related potent analogs of PCP: 1-[1-(2-thienyl)cyclohexyl]piperidine andN-ethyl-1-phenylcyclohexylamine. In addition, pharmacological and immunological selectivity was further tested by treatment of the behavioral effects induced by the structurally unrelated locomotor stimulant (+)methamphetamine. The antibody did not effectively reverse the effects of methamphetamine-induced locomotor activity. These results indicate that antibody-based medications can be developed to treat toxicity caused by classes of drugs as well as by individual drugs.
Footnotes
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Send reprint requests to: S. Michael Owens, Ph.D., Department of Pharmacology and Toxicology, Slot 611, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205.
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1 The work was supported by the National Institute on Drug Abuse [R01 DA07610, K02 DA00110 (S.M.O.), T32 DA07260 (J.S.H.), and F31 DA05795 (J.W.P.)]. Preliminary reports of these studies were presented at the 1997 annual meetings of the College on Problems of Drug Dependence (Nashville, TN) and the Society for Neuroscience (New Orleans, LA).
- Abbreviations:
- AUC
- area under the behavioral responsevs. time curve
- Fab
- the antigen binding fragment of IgG
- mAb
- monoclonal antibody
- Mes
- 2-[N-morpholino]ethanesulfonic acid
- mol-eq
- mole-equivalents
- NMDA
- N-methyl-d-aspartate
- PCE
- N-ethyl-1-phenylcyclohexylamine
- PCP
- phencyclidine
- RIA
- radioimmunoassay
- TCP
- 1-[1-(2-thienyl)cyclohexyl]piperidine
- [3H]PCP
- (1-[1(phenyl-3,4-3H(n))cyclohexyl]piperidine)
- Received November 28, 1997.
- Accepted February 20, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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