REACTIVATING POTENCY OF OBIDOXIME, PRALIDOXIME, HI-6 AND HLO-7 IN HUMAN ERYTHROCYTE ACETYLCHOLINESTERASE INHIBITED BY HIGHLY TOXIC ORGANOPHOSPHORUS COMPOUNDS

The treatment of poisoning by highly toxic organophosphorus compounds (nerve agents) is unsatisfactory. Until now, the efficacy of new poten tial antidotes has primarily been evaluated in animals. However, the e xtrapolation of these results to humans is hampered by species differe nces. Since oximes are believed to act primarily through reactivation of inhibited acetylcholinesterase (AChE) and erythrocyte AChE is regar ded to be a good marker for the synaptic enzyme, the reactivating pote ncy can be investigated with human erythrocyte AChE in vitro. The pres ent study was undertaken to evaluate the ability of various oximes at concentrations therapeutically relevant in humans to reactivate human erythrocyte AChE inhibited by different nerve agents. Isolated human e rythrocyte AChE was inhibited with soman, sarin, cyclosarin, tabun or VX for 30 min and reactivated in the absence of inhibitory activity ov er 5-60 min by obidoxime, pralidoxime, HI 6 or HLo 7 (10 and 30 mu M). The AChE activity was determined photometrically. The reactivation of human AChE by oximes was dependent on the organophosphate used. After soman, sarin, cyclosarin, or VX the reactivating potency decreased in the order HLo 7 > HI 6 > obidoxime > pralidoxime. Obidoxime and prali doxime were weak reactivators of cyclosarin-inhibited AChE. Only obido xime and HLo 7 reactivated tabun-inhibited AChE partially (20%), while pralidoxime and HI 6 were almost ineffective (5%). Therefore, HLo 7 m ay serve as a broad-spectrum reactivator in nerve agent poisoning at d oses therapeutically relevant in humans.