Hormone- and dose schedule-dependent protection by HI-6 against soman and tabun poisoning

Lundy, Paul M.; Goulet, Jean Christophe; Hand, Brian T.

doi:10.1016/0272-0590(89)90032-8

Cited by 25 publications

(16 citation statements)

References 17 publications

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“…However, whatever difference may have existed was abolished following soman. It appears unlikely that there were any differences in the distribution which could account for the rather large difference in protective effects of HI-6 in the two sexes (Lundy et al 1989).…”

Section: Measurement Of [14c] H1-6 In Individual Organsmentioning

confidence: 94%

“…following the procedure reported in previous protection studies with non-radioactive HI-6 alone (Lundy et al 1989). The rats all received a calculated dose of [~4C] HI-6 10.2 laCi/100 g.…”

Section: Synthesis Of[i4c] Hi-6mentioning

confidence: 96%

“…Female rats which were pretreated with atropine and HI-6 were protected much more efficiently than were similarly treated males (Lundy et al 1989). Chronic administration of a male or female sex hormone to the opposite gender reversed the sex-related response.…”

Section: Introductionmentioning

confidence: 91%

“…The LDs0 value of soman used in this study was 110/.tg/kg s. c. (Lundy et al 1989). Forty-five minutes after either [14C] HI-6 alone or soman plus [14C] HI-6, the animals were prepared for autoradiography.…”

Section: Synthesis Of[i4c] Hi-6mentioning

confidence: 99%

“…The amount of radioactivity present was used to calculate the tissue concentration (I.tg/g wet wt) of HI-6. Soman was prepared by fractional distillation and analyzed for purity (>98%) as outlined previously (Lundy et al 1989).…”

Section: Measurement Of [14c] H1-6 In Individual Organsmentioning

confidence: 99%

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Distribution of the bispyridinium oxime [14C] HI-6 in male and female rats

Lundy¹,

Hand²,

Broxup³

et al. 1990

Arch Toxicol

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Female rats poisoned with multiple LD50s of soman or tabun have been shown previously to respond to the protective effects of HI-6 more positively than male rats. This present study was designed first to determine the distribution pattern and concentration of [14C] HI-6 in rats, and secondly, to determine the possibility that HI-6 might be located in high concentrations in critical tissues in the female as opposed to the male. To these ends, [14C] HI-6 was administered to groups of male and female rats and its radiolabelled distribution determined by whole body autoradiography and/or by measurement of its actual concentration, by scintillation spectrometry. The experiments were repeated in the presence of 2 x LD50 soman and supporting therapy with atropine. In both sexes, HI-6 levels were highest in the kidney, followed in order by cartilage greater than plasma greater than liver greater than heart greater than or equal to lung greater than or equal to diaphragm greater than brain and spinal cord. The relative distribution in the two sexes was confirmed by both methods and was not significantly altered in the presence of soman and atropine. The lack of a measurable difference in tissue distribution of [14C] HI-6 derived radioactivity between males and females suggested that the hormone-dependent difference in the protective effects previously observed was not due to selective accumulation of [14C] HI-6 in organs believed to be important in its therapeutic activity, such as brain or diaphragm.

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Section: Measurement Of [14c] H1-6 In Individual Organsmentioning

confidence: 94%

“…following the procedure reported in previous protection studies with non-radioactive HI-6 alone (Lundy et al 1989). The rats all received a calculated dose of [~4C] HI-6 10.2 laCi/100 g.…”

Section: Synthesis Of[i4c] Hi-6mentioning

confidence: 96%

Section: Introductionmentioning

confidence: 91%

Section: Synthesis Of[i4c] Hi-6mentioning

confidence: 99%

Section: Measurement Of [14c] H1-6 In Individual Organsmentioning

confidence: 99%

See 3 more Smart Citations

Distribution of the bispyridinium oxime [14C] HI-6 in male and female rats

Lundy¹,

Hand²,

Broxup³

et al. 1990

Arch Toxicol

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Bioavailability and disposition kinetics of HI‐6 in Beagle dogs

Baggot

Buckpitt

Johnson³

et al. 1993

Biopharm & Drug Disp

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The absorption and disposition kinetics of HI-6 were determined in Beagle dogs given single doses (25 mg kg-1) of the drug by the intravenous, intramuscular, and oral routes. Concentrations of the oxime in plasma and urine were measured by HPLC. A two-compartment open model was used to describe the disposition curve following intravenous drug administration while a one-compartment open model with first-order absorption adequately described the data following intramuscular or oral administration of the dose. Extravascular distribution of HI-6 was limited (Vss 203 ml kg-1) and the drug was eliminated rapidly after intravenous administration (t1/2 46.5 min, MAT 55.4 min). Systemic clearance was 3.68 ml min-1 x kg. A major fraction of the dose (63.7 per cent) was excreted in urine over a 24-h collection period. Following intramuscular drug administration, the absorption half-life (t1/2(a), 5.3 min), MAT (17.1 min), Cmax (70.37 micrograms ml-1) and tmax (15.9 min) indicate that the drug was rapidly absorbed. Systemic availability was 83.43 per cent after oral drug administration, absorption was preceded by a lag time (23.2 min). The t1/2(a) (41.5 min), MAT (81.6 min), Cmax (4.30 micrograms ml-1) and Tmax (90.6 min) indicate somewhat delayed absorption. Systemic availability (11.38 per cent) and the fraction of dose excreted unchanged in the urine (9.3 per cent) show that the drug was poorly absorbed. The apparent half-life (58.0 min) and MRT (137.6 min) following oral administration were significantly longer (p < 0.05) than following intravenous or intramuscular administration suggesting that the rate of absorption from the gastrointestinal tract decreases the elimination rate of the drug. In conclusion, HI-6 has limited distribution within the body, is rapidly eliminated mainly by renal excretion unchanged in the urine, and the bioavailability (i.e. rate and extent of absorption) of the drug varies with the route of administration.

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Review of oximes available for treatment of nerve agent poisoning

Dawson

1994

J of Applied Toxicology

301

171

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A review was conducted of papers describing the use of N-methyl-2-pyridinealdoxime (PAM), toxogonin or HI-6 as antidotes to the nerve agents tabun, sarin, soman and VX. The review included use of the oxime alone, oxime plus atropine and oxime plus atropine plus diazepam, given therapeutically, i.e. after nerve agent, in all cases. Experiments with any of these compounds given prophylactically were not considered. The review also included protocols of pyridostigmine prophylaxis and oxime-atropine therapy (with or without diazepam). It was difficult to draw conclusions as to the best oxime to use, because of lack of data in many cases. The identity of the oxime did not appear to be important when pyridostigmine prophylaxis was combined with atropine-oxime-diazepam therapy; in these cases, very good protection was observed in guinea pigs against all four nerve agents. The choice of oxime based on the data presently available may well depend on factors other than protection against lethality, such as cost and availability of the oxime and human toxicity of the oxime. This last factor was also reviewed, and the results showed that toxogonin is likely to cause more side-effects than PAM or HI-6. The efficacy of the oximes against the emerging threat agent GF was also reviewed.

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Hormone- and dose schedule-dependent protection by HI-6 against soman and tabun poisoning

Cited by 25 publications

References 17 publications

Distribution of the bispyridinium oxime [14C] HI-6 in male and female rats

Distribution of the bispyridinium oxime [14C] HI-6 in male and female rats

Bioavailability and disposition kinetics of HI‐6 in Beagle dogs

Review of oximes available for treatment of nerve agent poisoning

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