Determination of therapeutic doses of bisquaternary oximes in large animals

This report presents a non-lethal method for estimating a range of therapeu tic doses of bisquaternary oximes that serve as antidotes against organopho sphorus poisoning. We have estimated therapeutic oxime doses that are equiv alent in their relative toxicity rather than selecting arbitrary fractions of their LD50. Thus, toxic signs of the oximes HI-6, HLo-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 = MT D/TR. Assuming that the tails of dose-response curves of toxicity for bisqu aternary oximes are shallow and similar to one another, one could substitut e the ED10 for the MTD. The EDI, values for bisquaternary oximes were estim ated using the log-log model following experimental observations and quanti tative scoring of toxic signs in dogs and monkeys. The MTD values then were calculated using the ED10 values and the experimental therapeutic dose of the reference oxime Toxogonin. The following CED values were obtained for A B-8, AB-13, Toxogonin, HI-6 and HL6-7 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) mu m ol kg(-1), respectively. The antidotal efficacy of these oximes against poi soning by the nerve agent tabun was determined in dogs and monkeys. These d ose-dependent efficacy data were obtained at 0.3 x CED, 1 x CED and 3 x CED of oximes in combination with atropine. These data provide comparative the rapeutic values using oxime doses based on their relative toxicity. The hig hest antidotal efficacy against tabun in dogs was obtained for toxogonin, w hereas HLo-7 and AB-13 were most efficacious in monkeys. Copyright (C) 2001 John Wiley & Sons, Ltd.