Antiphencyclidine monoclonal Fab fragments reverse phencyclidine- induced behavioral effects and ataxia in rats

JL Valentine, M Mayersohn, WD Wessinger, LW Arnold and SM Owens

Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.

Antiphencyclidine monoclonal antibody binding fragments (anti-PCP Fab) were studied in rats as a possible treatment for phencyclidine (PCP) overdose. Each male Sprague-Dawley rat (n = 4 per group) received an i.v. dose of 1 mg/kg of PCP followed 5 min later (as toxicity maximized) by one of three treatments in a random cross-over design. The treatments were 1 ml of saline, a nonspecific polyclonal human Fab, or a high affinity (Kd = 1.8 nM) anti-PCP monoclonal Fab. The doses of the nonspecific and anti-PCP Fab were 0.3, 1.0 and 3.0 times the mole equivalent (mol-eq) dose of PCP. Changes in locomotor activity and ataxia were the best indicators of PCP-induced behaviors among several time-dependent behavioral changes that were evaluated. PCP administration followed by saline treatment resulted in increases in locomotor activity and ataxia that declined to base line after 35 to 40 min. Anti-PCP Fab at 1.0 and 3.0 times the mol-eq dose of PCP significantly (P < .05) and rapidly reversed PCP-induced behaviors to base-line values. Although the 0.3 mol-eq dose of Fab appeared to slightly decrease the behavioral toxicity, the effects were not statistically different from controls in most cases. No significant effects on PCP-induced behaviors were observed after any dose of the nonspecific Fab. In addition, pharmacological and immunological specificity were tested further by treatment of MK-801 (+)-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine--induced behavioral effects. MK-801 is a PCP-like, noncompetitive N-methyl-D-aspartate receptor antagonist which is structurally unrelated to PCP. The anti- PCP Fab treatment had no effect on MK-801-induced locomotor activity. These data clearly show that anti-PCP Fab is a specific PCP antagonist that can rapidly reverse PCP-induced behavioral toxicity in the rat.

Volume 278, Issue 2, pp. 709-716, 08/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				E. C. Peterson, M. Gunnell, Y. Che, R. L. Goforth, F. I. Carroll, R. Henry, H. Liu, and S. M. Owens Using Hapten Design to Discover Therapeutic Monoclonal Antibodies for Treating Methamphetamine Abuse J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 30 - 39. [Abstract] [Full Text] [PDF]

				A. B. Norman, M. R. Tabet, M. K. Norman, W. R. Buesing, A. J. Pesce, and W. J. Ball A Chimeric Human/Murine Anticocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in Mice J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 145 - 153. [Abstract] [Full Text] [PDF]

				G. Pitas, E. M. Laurenzana, D. K. Williams, S. M. Owens, and W. B. Gentry ANTI-PHENCYCLIDINE MONOCLONAL ANTIBODY BINDING CAPACITY IS NOT THE ONLY DETERMINANT OF EFFECTIVENESS, DISPROVING THE CONCEPT THAT ANTIBODY CAPACITY IS EASILY SURMOUNTED Drug Metab. Dispos., June 1, 2006; 34(6): 906 - 912. [Abstract] [Full Text] [PDF]

				E. M. Laurenzana, K. A. Byrnes-Blake, A. Milesi-Halle, W. B. Gentry, D. K. Williams, and S. M. Owens USE OF ANTI-(+)-METHAMPHETAMINE MONOCLONAL ANTIBODY TO SIGNIFICANTLY ALTER (+)-METHAMPHETAMINE AND (+)-AMPHETAMINE DISPOSITION IN RATS Drug Metab. Dispos., November 1, 2003; 31(11): 1320 - 1326. [Abstract] [Full Text] [PDF]

				E. M. Laurenzana, M. G. Gunnell, W. B. Gentry, and S. M. Owens Treatment of Adverse Effects of Excessive Phencyclidine Exposure in Rats with a Minimal Dose of Monoclonal Antibody J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1092 - 1098. [Abstract] [Full Text] [PDF]

				J. S. Hardin, W. D. Wessinger, G. R. Wenger, J. W. Proksch, E. M. Laurenzana, and S. M. Owens A Single Dose of Monoclonal Anti-Phencyclidine IgG Offers Long-Term Reductions in Phencyclidine Behavioral Effects in Rats J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 119 - 126. [Abstract] [Full Text] [PDF]

				J. W. Proksch, W. B. Gentry, and S. M. Owens The Effect of Rate of Drug Administration on the Extent and Time Course of Phencyclidine Distribution in Rat Brain, Testis, and Serum Drug Metab. Dispos., July 1, 2000; 28(7): 742 - 747. [Abstract] [Full Text]

				J. R. Cashman, C. E. Berkman, and G. E. Underiner Catalytic Antibodies that Hydrolyze (-)-Cocaine Obtained by a High-Throughput Procedure J. Pharmacol. Exp. Ther., June 1, 2000; 293(3): 952 - 961. [Abstract] [Full Text]

				J. W. Proksch, W. B. Gentry, and S. M. Owens Anti-Phencyclidine Monoclonal Antibodies Provide Long-Term Reductions in Brain Phencyclidine Concentrations during Chronic Phencyclidine Administration in Rats J. Pharmacol. Exp. Ther., March 1, 2000; 292(3): 831 - 837. [Abstract] [Full Text]

				J. W. Proksch, W. B. Gentry, and S. M. Owens Pharmacokinetic Mechanisms for Obtaining High Renal Coelimination of Phencyclidine and a Monoclonal Antiphencyclidine Antigen-Binding Fragment of Immunoglobulin G in the Rat J. Pharmacol. Exp. Ther., November 1, 1998; 287(2): 616 - 624. [Abstract] [Full Text]

				K. Lim, S. M. Owens, L. Arnold, J. C. Sacchettini, and D. S. Linthicum Crystal Structure of Monoclonal 6B5 Fab Complexed with Phencyclidine J. Biol. Chem., October 30, 1998; 273(44): 28576 - 28582. [Abstract] [Full Text] [PDF]

				J. S. Hardin, W. D. Wessinger, J. W. Proksch, and S. M. Owens Pharmacodynamics of a Monoclonal Antiphencyclidine Fab with Broad Selectivity for Phencyclidine-Like Drugs1 J. Pharmacol. Exp. Ther., June 1, 1998; 285(3): 1113 - 1122. [Abstract] [Full Text]

				Y. Hieda, D. E. Keyler, J. T. Vandevoort, J. K. Kane, C. A. Ross, D. E. Raphael, R. S. Niedbalas, and P. R. Pentel Active Immunization Alters the Plasma Nicotine Concentration in Rats J. Pharmacol. Exp. Ther., December 1, 1997; 283(3): 1076 - 1081. [Abstract] [Full Text]