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 (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.
journal_name
Biopharm Drug Disposjournal_title
Biopharmaceutics & drug dispositionauthors
Clement JG,Bailey DG,Madill HD,Tran LT,Spence JDdoi
10.1002/bdd.2510160506subject
Has Abstractpub_date
1995-07-01 00:00:00pages
415-25issue
5eissn
0142-2782issn
1099-081Xjournal_volume
16pub_type
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