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)methyl)-2-(hydroxyimino )methyl)-pyridinium dichloride monohydrate), combined with atropine, is effective for treating poisoning with organophosphate nerve agents. The protective action of HI 6 in soman poisoning has been attributed mainly to its peripheral reactivation of inhibited acetylcholinesterase. In the present study we investigated whether high intramuscular doses of HI 6 can reach the brain in a sufficient amount to reactivate inhibited brain acetylcholinesterase. 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 administration of HI 6 (50, 75 or 100 mg/kg i.m.) in control rats and rats injected with soman (90 microg/kg s.c., 0.9 LD50) 1 min before HI 6 treatment. We found that signs of soman poisoning correlated positively to acetylcholinesterase inhibition and negatively to the concentration of unbound HI 6 in the brain and that soman intoxication significantly decreased uptake of HI 6 into the brain.
Cassel
G
G
Department of Biomedicine, Defence Research Establishment, Umea, Sweden. cassel@ume.foa.se
Karlsson
L
L
Waara
L
L
Ang
K W
KW
Göransson-Nyberg
A
A
D000110:Acetylcholinesterase / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D000931:Antidotes / Q000493:pharmacokinetics* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000506:poisoning; D002801:Cholinesterase Reactivators / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation; D008297:Male; D017551:Microdialysis; D010091:Oximes; D011726:Pyridinium Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012999:Soman / Q000494:pharmacology / Q000506:poisoning*
D000931:Antidotes; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride; D004298:Dopamine