Pharmacodynamics of a monoclonal antiphencyclidine Fab with broad selectivity for phencyclidine-like drugs.
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 and N-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.
Hardin
J S
JS
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Wessinger
W D
WD
Proksch
J W
JW
Owens
S M
SM
D018663:Adrenergic Agents / Q000276:immunology; D000818:Animals; D003514:Cyclohexylamines / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000276:immunology* / Q000494:pharmacology; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000494:pharmacology*; D008297:Male; D008694:Methamphetamine / Q000276:immunology; D009043:Motor Activity / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000276:immunology; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000276:immunology* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D018663:Adrenergic Agents; D003514:Cyclohexylamines; D018691:Excitatory Amino Acid Antagonists; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D018696:Neuroprotective Agents; D008694:Methamphetamine; C012058:tenocyclidine; D010622:Phencyclidine; C023851:N-ethyl-1-phenylcyclohexylamine