Protection against diisopropylfluorophosphate intoxication by meptazinol.
The protective action of meptazinol against diisopropylfluorophosphate (DFP) was evaluated in mice which were not receiving any other therapy and in preparations of electric eel AChE and horse serum BuChE. Meptazinol injected subcutaneously in mice produced a dose-dependent reduction in the mortality resulting from a LD99.1 (8 mg/kg sc) of DFP administered later. The effectiveness of protection was inversely correlated to the time between meptazinol and DFP administrations. Under these conditions, the ED50s (95% confidence limits) of meptazinol given 15, 30, and 60 min before poisoning were 7.2 (6.4-8.1), 15.8 (13.7-18.2), and 28 (23.5-33.3) mg/kg, respectively, while full protection (100% of survivors) was obtained with 15, 30, and 60 mg/kg drug doses, respectively. Meptazinol was completely ineffective against DFP-induced lethality when administered 3 min after the poison. The protective ratio of 30 mg/kg meptazinol injected 15 min before DFP was 5.0. Pretreatment of mice with 15, 30, and 60 mg/kg meptazinol 15 min before DFP (8 mg/kg) increased brain AChE activity in DFP-treated mice from 5 +/- 0.5% to 16.2 +/- 2.5%, 42.5 +/- 4%, and 81.2 +/- 4% of control values, respectively, while it failed to increase plasma BuChE activity. Finally, concentrations of meptazinol ranging between 0.1 and 10 microM were found to afford complete protection of eel AChE against irreversible inhibition by 40 microM DFP. By contrast, horse serum BuChE was not protected against the same inhibitor by concentrations of meptazinol up to 1 mM. It is concluded that protection against DFP intoxication by meptazinol is most probably due to its protective action toward AChE.
Galli
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Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
Mazri
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D000110:Acetylcholinesterase / Q000032:analysis; D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000097:blood; D007531:Isoflurophate / Q000506:poisoning*; D008297:Male; D008621:Meptazinol / Q000494:pharmacology*; D051379:Mice
D001381:Azepines; D007531:Isoflurophate; D008621:Meptazinol; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase