Comparing therapeutic and prophylactic protection against the lethal effect of paraoxon.
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 LD(50) [920 mg/kg (LD(50) of paraoxon with antagonists)/ 0.95 mg/kg (LD(50) of control paraoxon)], and the therapeutic antidotal protection was 156 LD(50) [140 mg/kg (LD(50) of paraoxon with antagonists)/0.9 mg/kg (LD(50) of control paraoxon)]. The current study firmly establishes the value of using liposome encapsulating OPH.
Petrikovics
I
I
U.S.A. Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA.
Papahadjopoulos
D
D
Hong
K
K
Cheng
T-C
TC
Baskin
S I
SI
Jiang
J
J
Jaszberenyi
J C
JC
Logue
B A
BA
Szilasi
M
M
McGuinn
W D
WD
Way
J L
JL
D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D043303:Aryldialkylphosphatase / Q000008:administration & dosage*; D001285:Atropine / Q000494:pharmacology* / Q000627:therapeutic use*; D002801:Cholinesterase Reactivators / Q000494:pharmacology / Q000627:therapeutic use; D004338:Drug Combinations; D007306:Insecticides / Q000506:poisoning*; D007928:Lethal Dose 50; D008081:Liposomes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000517:prevention & control*; D010261:Paraoxon / Q000506:poisoning*; D011220:Pralidoxime Compounds / Q000494:pharmacology* / Q000627:therapeutic use*
D000931:Antidotes; D002801:Cholinesterase Reactivators; D004338:Drug Combinations; D007306:Insecticides; D008081:Liposomes; D018727:Muscarinic Antagonists; D011220:Pralidoxime Compounds; D001285:Atropine; D043303:Aryldialkylphosphatase; C028797:pralidoxime; D010261:Paraoxon