In a double-blind, placebo-controlled, single-dose ascending pharmacokinetics and tolerance study, we evaluated the bispyridinium oxime HI-6 dichloride monohydrate (62.5, 125, 250, and 500 mg), administered intramuscularly with atropine sulphate, 2 mg, in 24 healthy male volunteers. The plasma HI-6 peak concentration (Cmax) and area under the concentration-time curve (AUC) demonstrated linear pharmacokinetics with low intradose variability, suggestive of uniformity of effect among subjects. HI-6 (500 mg) attained plasma drug concentrations that appeared adequate for practical use as an antidote. The mean +/- SD time to maximum plasma HI-6 concentration (tmax = 0.69 +/- 0.21 h, n = 16), and absorption half-life (t/2a = 0.17 +/- 0.05 h) indicated rapid onset of effect. The volume of distribution (Vd = 0.25 +/- 0.04 L kg-1 TBW) approximated the extracellular fluid volume. A high total body clearance (CL = 252 +/- 52 mL min-1) and short apparent elimination half-life (t/2e = 1.15 +/- 0.19 h) were expected for this polar quaternary ammonium drug. The renal clearance CLr = 137 +/- 33 mL min-1), which approximated the expected glomerular filtration rate, and 24 h urinary excretion of unchanged drug (55 +/- 10%) indicated substantial non-renal elimination. Blood pressure, heart rate, respiratory rate, electrocardiographic parameters, mental acuity, and vision were not altered. Adverse events and changes in serum, urine, and semen laboratory tests were mild. The pharmacokinetics, safety, and apparent efficacy of HI-6 suggest it may be a superior oxime antidote against nerve agent poisoning.
MADILL, H. U., STLWART, V(i. C., AND SAVOYE, M. L. 4948. Central and peripheral antichoIinergic potency of some drugs antagonistic to anticholinesterase poisoning. Can. J. Physiol. Pharmcol. 46, 559-565.The central and peripheral anticholinergic potency of nine drugs together with their therapeutic effectiveness in treating satin poisoning was measured and compared with atropine. There was a direct relationship between the anticholinergic poteilcies of these drugs as measured by tests indicative of activity in the central nervous system and their therapeutic effectiveness in treating sarin poisoning. One exception to this was shown by the drug cararniphen, which s h o~e d significantly higher therapeutic protection than the drug atropine at equinlolar dosages, yet was less active as a peripheral or central anticholinergic drug. High levels of therapeutic protection were directly rclatcd to high levels of central anticholinergic potency.
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