Abstract
These studies tested the hypothesis that a single dose of high-affinity anti-phencyclidine monoclonal antibody (anti-PCP mAb) provides long-term protection against behavioral effects of repeated PCP administration in rats. Rats were treated with saline, nonspecific bovine IgG (NS-IgG), or anti-PCP mAb (1.0 g/kg). The next morning, the rats were challenged with escalating i.v. doses of PCP (0.32, 0.56, and 1.0 mg/kg) at 90-min intervals. This regimen was repeated every 3 days for 2 weeks. In the saline and NS-IgG control groups, PCP yielded reproducible and linear dose-dependent effects that remained constant during the experiment. In contrast, the anti-PCP mAb treatment blocked PCP effects on day 1, and sustained significant (P< 0.05) reductions in drug effects for the entire 2-week experiment. Brain PCP concentrations (determined at study termination) were reduced by ∼55%, whereas serum concentrations were increased over 4000% compared with controls. Thus, a single dose of antibody medication provided long-term reductions in drug effects and brain concentrations, beyond the expected capacity of the drug-antibody interaction. These data challenge current concepts about in vivo dose dependence and unimolecular interaction between antibody binding sites and small molecules and establish that neuroprotection by mAbs may have an unique mechanism of action.
Footnotes
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↵1 Current address: Department of Emergency Medicine, Pitt County Memorial Hospital, Greenville, NC 27835.
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↵2 Current address: Molecumetics, 2023 120th Avenue NE, Bellevue, WA 98005.
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This work was supported by National Institute on Drug Abuse Grants DA 07610 (to S.M.O.), F30 DA 05863 (to J.S.H.), and F31 DA 05795 (to J.W.P.). A preliminary report of these data was previously presented at a meeting of the American Society for Clinical Pharmacology and Therapeutics (1999) 100:PII-25.
- Abbreviations:
- mAb
- monoclonal antibody
- PCP
- phencyclidine
- NS-IgG
- nonspecific bovine IgG
- CNS
- central nervous system
- Received February 5, 2002.
- Accepted March 11, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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