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The acetylcholinesterase oxime reactivator HI‐6 in man: Pharmacokinetics and tolerability in combination with atropine
Author(s) -
Clement John G.,
Bailey David G.,
Madill Herbert D.,
Tran Lan T.,
Spence J. David
Publication year - 1995
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510160506
Subject(s) - pharmacokinetics , volume of distribution , cmax , antidote , chemistry , pharmacology , renal function , atropine , renal physiology , medicine , anesthesia , toxicity , biochemistry , organic chemistry
Abstract 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 ( C max ) 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 ( t max = 0.69 ± 0.21 h, n = 16), and absorption 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) approximated the extracellular fluid volume. A high total body clearance (CL = 252 ± 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. The renal clearance (CL r = 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.