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Determination of therapeutic doses of bisquaternary oximes in large animals
Author(s) -
Chen R.,
Raveh L.,
Zomber G.,
Rabinovitz I.,
Cohen G.,
Adani R.,
Amitai G.
Publication year - 2001
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.756
Subject(s) - tabun , chemistry , oxime , pharmacology , therapeutic index , beagle , toxicity , nerve agent , toxicology , stereochemistry , drug , medicinal chemistry , biochemistry , organic chemistry , medicine , biology , enzyme , acetylcholinesterase
This report presents a non‐lethal method for estimating a range of therapeutic doses of bisquaternary oximes that serve as antidotes against organophosphorus poisoning. We have estimated therapeutic oxime doses that are equivalent in their relative toxicity rather than selecting arbitrary fractions of their LD 50 . Thus, toxic signs of the oximes HI‐6, HLö‐7, Toxogonin, AB‐8 and AB‐13 were monitored quantitatively in baboon monkeys and beagle dogs. Using Toxogonin as a reference oxime, a calculated unit of equivalent dose (CED) was defined as the oxime dose equal to the ratio between its minimal toxic dose (MTD) and the therapeutic ratio (TR) of Toxogonin i.e. CED = MTD/TR. Assuming that the tails of dose–response curves of toxicity for bisquaternary oximes are shallow and similar to one another, one could substitute the ED 10 for the MTD. The ED 10 values for bisquaternary oximes were estimated using the log‐log model following experimental observations and quantitative scoring of toxic signs in dogs and monkeys. The MTD values then were calculated using the ED 10 values and the experimental therapeutic dose of the reference oxime Toxogonin. The following CED values were obtained for AB‐8, AB‐13, Toxogonin, HI‐6 and HLö‐7 in dogs (d) and monkeys (m): 98.7, 74.2, 30.0, 14.5 and 12.1 (d) and 281.9, 232.1, 41.7, 192.9 and 92.9 (m) µmol kg −1 , respectively. The antidotal efficacy of these oximes against poisoning by the nerve agent tabun was determined in dogs and monkeys. These dose‐dependent efficacy data were obtained at 0.3 × CED, 1 × CED and 3 × CED of oximes in combination with atropine. These data provide comparative therapeutic values using oxime doses based on their relative toxicity. The highest antidotal efficacy against tabun in dogs was obtained for toxogonin, whereas HLö‐7 and AB‐13 were most efficacious in monkeys. Copyright © 2001 John Wiley & Sons, Ltd.