The acetylcholinesterase oxime reactivator HI‐6 in man: Pharmacokinetics and tolerability in combination with atropine

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.

Reactivation of organophosphate‐inhibited human AChE by combinations of obidoxime and HI 6 in vitro

“…An initial oxime concentration of 30 μM was selected since pharmacokinetic data in humans indicate a peak plasma concentration of i.m. HI 6 (500 mg) and obidoxime (220 mg) in the range 30-40 μM (Clement et al, 1995;Sidell and Groff, 1970). Such oxime doses are presently used in autoinjectors (Szinicz and Kullmann, 1990;Clement et al, 1995).…”

“…HI 6 (500 mg) and obidoxime (220 mg) in the range 30-40 μM (Clement et al, 1995;Sidell and Groff, 1970). Such oxime doses are presently used in autoinjectors (Szinicz and Kullmann, 1990;Clement et al, 1995). Additional experiments were performed with lower (10 μM) obidoxime and HI 6 concentrations in order to estimate the ability to use these oximes at different doses.…”

Pseudocatalytic scavenging of the nerve agent VX with human blood components and the oximes obidoxime and HI-6

“…We added the oximes obidoxime and HI-6 in concentrations of 50 µM to our model-a concentration comparable to the C max after intramuscular injection of 250 mg obidoxime and 500 mg HI-6 in humans (Sidell and Groff 1970;Clement et al 1995). Both oximes are supposed to turn ChE into a pseudocatalytic scavenger thus elevating the endogenous scavenging capacity to steadily decrease the VX load in the body.…”

Development and validation of a sensitive HPLC method for the quantification of HI-6 in guinea pig plasma and evaluated in domestic swine

“…Previous methods have been used to determine HI-6 plasma concentrations in mice [11], guinea pigs [17], rats [5,6,9], rabbits [10], canines [8,9], swine [7,16,18], non-human primates [17][18][19] and man [4].…”

“…To identify and quantify HI-6 in plasma samples, a rapid high performance liquid chromatography (HPLC) method was required. HPLC techniques for the quantitative analysis of HI-6 have been reported that generally require relatively tedious extractions [4], lengthy chromatographic separations [4][5][6][7] and large sample volumes [5]. The method reported here was designed to improve on previous methods and also be in compliance with Good Laboratory Practices, so as to enable the data to be used for regulatory submission.…”