The pharmacokinetics of HI‐6 in beagle dogs

Simons, Keith J.; Briggs, Colin J.

doi:10.1002/bdd.2510040409

Cited by 27 publications

(12 citation statements)

References 7 publications

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“…The apparent volume of distribution is 0.25 1/kg and corresponds to the volume of other bispyridinium compounds (Sidell et al 1972;Simons and Briggs 1983;Kusic et al 1985;Klimmek and Eyer 1985;1986). The apparent volume of distribution is 0.25 1/kg and corresponds to the volume of other bispyridinium compounds (Sidell et al 1972;Simons and Briggs 1983;Kusic et al 1985;Klimmek and Eyer 1985;1986).…”

Section: Discussionmentioning

confidence: 99%

HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

Eyer

Hagedorn²,

Klimmek

et al. 1992

Arch Toxicol

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HLö 7 dimethanesulfonate (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2,4-bis [(hydroxyimino)methyl]pyridinium dimethanesulfonate) is a broad-spectrum reactivator against highly toxic organophosphorus compounds. The compound was synthesized by a new route with the carcinogenic bis(chloromethyl)ether being substituted by the non-mutagenic bis(methylsulfonoxymethyl)ether. The very soluble dimethanesulfonate of obidoxime was also prepared by this way. HLö 7 dimethanesulfonate is the first water-soluble salt of HLö 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HLö 7 are not very stable (calculated shelf-life 0.2 years when stored at 8 degrees C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of the syn/syn-isomer, less than 2% of the syn/anti-isomer and some minor identified by-products. HLö 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HLö 7 was superior to HI 6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2- [(hydroxyimino)methyl]pyridinium dichloride) in reactivating soman and sarin-inhibited AChE from erythrocytes, and literature data indicate that HLö 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HLö 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HLö 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HLö 7 was less effective than HI 6 (protective ratio: 2.3 versus 5.2 for soman; 5.2 versus 6.8 for sarin; 4.3 versus 3.8 for tabun). The mean survival time of anaesthetized guinea-pigs exposed to 5 LD50 soman (6.3 min) was increased by atropine (27 min) and atropine + HLö (57 min). HLö 7 alone did not prolong the survival. The most impressive effect of HLö 7 was on respiration: 3 min after i.v. injection of HLö 7 and atropine, the depressed respiration increased rapidly to 60% of control and remained at that level during the observation period (60 min). With atropine alone, respiration recovered only slowly. Behavioural and physiologic parameters were determined in atropine-protected mice exposed to a sublethal soman dose. The running performance was significantly improved by HLö 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HLö 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HLö 7 in male beagle dogs are similar to those of HI 6.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussionmentioning

confidence: 99%

HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

Eyer

Hagedorn²,

Klimmek

et al. 1992

Arch Toxicol

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“…where C = plasma concentration (ng mL-I), t = time (min), klz=rate constant of distribution (min-I), and klo= rate constant of elimination (min-I), and where A and B are coefficient constants for the elimination and distribution phase, respectively. This model was also employed to describe the pharmacokinetics of HI-6 intravenously administered to dogs (Simons & Briggs 1983) and rats (Simons & Briggs 1985). The t i of the distribution phase for rabbits (5.0 f 2.6 min) was short and in agreement with the 4.1 rnin value for rats (Simons & Briggs 1985) and 6.3 rnin value for dogs (Simons & Briggs 1983).…”

Section: Resultsmentioning

confidence: 65%

“…Only a few studies have investigated HI-6 pharmacokinetics in any ,pies. These species include rat (Maksimovic 1979;Simons & B &~S 1985), dog (Simons & Briggs 1983), and man (Kusic et al 1985). The pharmacokinetics in a variety of species provide a p o d means to correlate interspecies efficacy.…”

Section: Hi-6 Pharmacokinetics In Rabbits After Intravenous and Intramentioning

confidence: 99%

HI-6 pharmacokinetics in rabbits after intravenous and intramuscular administration

Lukey

Woodard

Clark

et al. 1992

Journal of Pharmacy and Pharmacology

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The pharmacokinetics of HI-6 ((4-carboxamidopyridinium (1) methyl)-(2'-hydroxyiminomethyl-pyridinium (1') methyl) ether dichloride) have been studied in rabbits receiving an intramuscular (50 micrograms kg-1) or intravenous (12.5 micrograms kg-1) dose. The plasma concentration-time profile for the intramuscular dose (n = 8) fits a one-compartment open model with first-order absorption and elimination. The absorption half-life was 2 min and maximum concentration (51 micrograms mL-1) was reached in 9 min. The pharmacokinetics for the intravenous dose (n = 8) was described by a two-compartment open model with first-order distribution and elimination. The apparent volume of distribution was 0.1 L kg-1. Half-lives of distribution and elimination were 5 and 38 min, respectively. The results indicate HI-6 is rapidly absorbed, distributed and eliminated in rabbits receiving an intramuscular dose.

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“…Blood samples (5 ml) were drawn at 0, 1, 2,4,8,12,16,20,40,60,80,120,240, and 300 min post-injection. Plasma oxime levels were determined by high performance liquid chromatography with ultraviolet d e t e c t i~n .~…”

Section: Methodsmentioning

confidence: 99%

HI‐6 and 2‐pam in sheep: Pharmacokinetics and effects on muscle tissue following intramuscular injection

Moore

Hayward

et al. 1991

Biopharm & Drug Disp

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The pharmacokinetics of 2-PAM, a component of the current nerve agent antidote therapy for U.S. military forces was compared to the pharmacokinetics of another acetylcholinesterase reactivator HI-6. Additionally, the effects of these compounds on muscle tissue following intramuscular injection was examined. Plasma concentrations of the oximes were determined by HPLC. Plasma concentration-time profiles for both oximes fit a one-compartment open model with first-order absorption and elimination. The results demonstrate that the half-time of absorption of HI-6 was significantly higher than that for 2-PAM. Musculoirritancy was assessed on the basis of quantitative histological examinations of the injection sites and by the measurement of serum creatinine phosphokinase. Comparison of the scores from the histological sections demonstrate no difference between the two oximes. Serum creatinine phosphokinase values were elevated following injections of HI-6, but were not consistently elevated following the 2-PAM injections.

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The pharmacokinetics of HI‐6 in beagle dogs

Cited by 27 publications

References 7 publications

HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

HI-6 pharmacokinetics in rabbits after intravenous and intramuscular administration

HI‐6 and 2‐pam in sheep: Pharmacokinetics and effects on muscle tissue following intramuscular injection

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