THE ACETYLCHOLINESTERASE OXIME REACTIVATOR HI-6 IN MAN - PHARMACOKINETICS AND TOLERABILITY IN COMBINATION WITH ATROPINE

In a double-blind, placebo-controlled, single-dose ascending pharmacok inetics and tolerance study, we evaluated the bispyridinium oxime HI-6 dichloride monohydrate (62.5, 125, 250, and 500 mg), administered int ramuscularly with atropine sulphate, 2 mg, in 24 healthy male voluntee rs. The plasma HI-6 peak concentration (C-max) and area under the conc entration-time curve (AUC) demonstrated linear pharmacokinetics with l ow intradose variability, suggestive of uniformity of effect among sub jects. HI-6 (500 mg) attained plasma drug concentrations that appeared adequate for practical use as an antidote. The mean+/-SD time to maxi mum plasma HI-6 concentration (t(max)=0.69+/-0.21 h, n=16), and absorp tion half-life (t/2(a)=0.17+/-0.05 h) indicated rapid onset of effect. The volume of distribution (V-d=0.25+/-0.04 L kg(-1) TBW) approximate d the extracellular fluid volume. A high total body clearance (CL = 25 2+/-52 mL min(-1)) and short apparent elimination half-life (t/2(e)=1. 15+/-0.19 h) were expected for this polar quaternary ammonium drug. Th e renal clearance CL(r)=137+/-33 mL min(-1)), which approximated the e xpected glomerular filtration rate, and 24h urinary excretion of uncha nged drug (55+/-10%) indicated substantial non-renal elimination. Bloo d pressure, heart rate, respiratory rate, electrocardiographic paramet ers, mental acuity, and vision were not altered. Adverse events and ch anges in serum, urine, and semen laboratory tests were mild. The pharm acokinetics, safety, and apparent efficacy of HI-6 suggest it may be a superior oxime antidote against nerve agent poisoning.