PHARMACOKINETICS AND EFFECTS OF HI-6 IN BLOOD AND BRAIN OF SOMAN-INTOXICATED RATS - A MICRODIALYSIS STUDY

The bispyridinium oxime HI 6 (1-(((4-amino-carbonyl)pyridino)methoxy) dichloride monohydrate), combined with atropine, is effective for trea ting poisoning with organophosphate nerve agents. The protective actio n of HI 6 in soman poisoning has been attributed mainly to its periphe ral reactivation of inhibited acetylcholinesterase. In the present stu dy we investigated whether high intramuscular doses of HT 6 can reach the brain in a sufficient amount to reactivate inhibited brain acetylc holinesterase. Microdialysis probes were implanted in the jugular vein and striatum and dialysis samples were collected simultaneously from the two sites in awake, freely moving rats. Pharmacokinetic parameters of unbound HI 6 in blood and brain were calculated after administrati on of HI 6 (50, 75 or 100 mg/kg i.m.) in control rats and rats injecte d with soman (90 mu g/kg s.c., 0.9 LD50) 1 min before HI 6 treatment. We found that signs of soman poisoning correlated positively to acetyl cholinesterase inhibition and negatively to the concentration of unbou nd HI 6 in the brain and that soman intoxication significantly decreas ed uptake of HI 6 into the brain. (C) 1997 Elsevier Science B.V.