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ToxSci Advance Access originally published online on July 11, 2003
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Toxicological Sciences 77, 258-262 (2004)
Copyright © 2004 by the Society of Toxicology

ENVIRONMENTAL TOXICOLOGY

Comparing Therapeutic and Prophylactic Protection against the Lethal Effect of Paraoxon

I. Petrikovics*, D. Papahadjopoulos{dagger}, K. Hong{dagger}, T.-C. Cheng*, S. I. Baskin*,1, J. Jiang§, J. C. Jaszberenyi{ddagger}, B. A. Logue*, M. Szilasi, W. D. McGuinn§ and J. L. Way§

* U.S.A. Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010; {dagger} Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143; {ddagger} Technical University of Budapest, Hungary, H-1010, Debrecen, Hungary H-4031; § Department of Medical Pharmacology and Toxicology, Texas A&M University, College of Medicine, College Station, Texas 77843; and University Medical School, Department of Pulmonology, Debrecen, Hungary H-4031

Prophylactic and therapeutic efficacy against organophosphorus (OP) intoxication by pralidoxime (2-PAM) and atropine were studied and compared with sterically stabilized long-circulating liposomes encapsulating recombinant organophosphorus hydrolase (OPH), either alone or in various specific combinations, in paraoxon poisoning. Prophylactic and therapeutic properties of atropine and 2-PAM are diminished when they are used alone. However, their prophylactic effects are enhanced when they are used in combination. Present studies indicate that sterically stabilized liposomes (SL) encapsulating recombinant OPH (SL-OPH) alone can provide much better therapeutic and prophylactic protection than the classic 2-PAM + atropine combination. This protection was even more dramatic when SL-OPH was employed in combination with 2-PAM and/or atropine: the magnitude of prophylactic antidotal protection was an astounding 1022 LD50 [920 mg/kg (LD50 of paraoxon with antagonists)/ 0.95 mg/kg (LD50 of control paraoxon)], and the therapeutic antidotal protection was 156 LD50 [140 mg/kg (LD50 of paraoxon with antagonists)/0.9 mg/kg (LD50 of control paraoxon)]. The current study firmly establishes the value of using liposome encapsulating OPH.

Key Words: organophosphorus hydrolase (OPH); OPA anhydrase; paraoxonase; paraoxon antagonism; sterically stabilized liposomes; stealth liposomes; long circulating liposomes; organophorus antagonism; prophylactic; therapeutic.


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