Oximes and Hydroxamic Acids as Antidotes in Anticholinesterase Poisoning

Abstract

It has recently been shown in vitro that oximes i(I) and hydroxamic acids (II) will both react with :and reactivate cholinesterase (ChE) (Hackley, Plapinger, Stolberg, and WagnerJauregg, 1955;Wilson, Ginsburg, and Meislich, 1955;Childs, Davies, Green, and Rutland, 1955 Those oximes which appeared from the screening tests to give the greatest degree of protection against sarin poisoning have been studied in greater detail, both in other species against sarin and also in the rat against tetraethylpyrophosphate (TEPP) and diisopropyl phosphorofluoridate (dyflos). METHODSIn the preliminary examination of oximes and hydroxamic acids all the tests were carried out on female albino rats of 180-200 g. In the more detailed experiments mice (18-22 g.), guinea-pigs (230-380 g.), rabbits (1.3-1.7 kg.) and monkeys (2.7-5.0 kg.) were also employed. Except with monkeys, where both sexes were used, the animals were all female.The oximes and hydroxamic acids were dissolved in water and given by intraperitoneal injection, the antiChE compounds being diluted with saline and given by subcutaneous injection.Toxicity Screening in Rats.-Because the object of this investigation was to search for potential therapeutic agents for antiChE poisoning, an arbitrary upper limit of test dose was set at 150 mg. /kg. Since at this dose many oximes proved toxic, a range of doses was used down to a lower limit of 13 mg./kg., the ratio between successive doses being 1.5. Two rats were tested at each dose level. By this screening procedure the maximum dose (up to the limit of 150 mg./kg.) which produced no obvious effects was determined. The compounds were given by intraperitoneal injection, the volume of injection varying according to the solubility of the substance. It was never greater than 5 ml., which appeared to be well tolerated.Screening of Compounds against Sarin in Rats.-Two types of experiment were carried out in which the oximes and hydroxamic acids were tested against twice the LD50 of sarin (0.24 mg./kg.). In the first the compound was given 15 min. before the sari, and this test has been termed " prophylactic." The second test, in which the compound was given 30 sec. after the inhibitor, has been called "therapeutic." (The designation of these tests as " prophylactic" and " therapeutic " is made for convenience and does not in any way imply the mechanism of action of the compound.) In both tests groups of 5 rats were used. The oximes and hydroxamic acids were given intraperitoneally at the previously determined maximum dose which produced no signs. The sarin was given by subcutaneous injection at a standard volume of 1 ml./kg. The number of dead up to 48 hr. and the time interval to death were used in the estimation of the effectiveness of the compounds tested.Further Experiments on Oximes.-In order to investigate more fully the effect in antiChE poisoning of those oximes which proved the most promising against sarin in the screening tests, experiments were

Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats

“…The effectiveness of oxime therapy depends on the OP compounds, the animal species and the time lapse between poisoning and therapy (Askew 1956;Talbot et al 1988). In the case of the OP nerve agent soman, it is extremely difficult to demonstrate, in animal studies, any efficacy or reactivation of inhibited ChE with the use of conventional oximes, such as 2-PAM or obidoxime (Heilbronn and Tolagen 1965;Clement 1979b;Shih et al 1991).…”

“…Since the antidotal effects of oximes are generally thought to be due to their ability to reactivate the inhibited ChE enzyme (De Jong and Wolfing 1980;Harris et al 1981;Harris and Stitcher 1983), and there are reported species differences in response to each oxime (Frawley et al 1952;Askew 1956), the present study was undertaken to investigate and compare the effects of these oximes on soman-inhibited ChE in vivo in another species, the rat. It was concluded in our earlier intensive studies in rats (Shih et al 1991) that 2-PAM does not reactivate soman-inhibited ChE in any tissues studied; 2-PAM was not used in the present study.…”

Multiple Effects of 2,3‐Butanedione Monoxime

“…1955). In contrast, pretreatment of rats with 2Jbutanedione monoxime prior to sarin increased survival rate t o 80% (Askew 1956). The drug also had a beneficial effect when administered after intoxication with sarin.…”

On the role of G protein activation and phosphorylation in desensitization to acetylcholine in guinea‐pig atrial cells.

“…a phosphatase-like activity for which it was synthesized (Wilson & Ginsburg, 1955). In neuromuscular poisoning it reactivates acetyleholinesterase by dephosphorylation (Askew, 1956) and it inhibits cardiac and neuronal L-type Ca2+ currents with ID50s (the dose required to inhibit by 50%) of 5-8 and 20 mm respectively, an effect again attributed to dephosphorylation (Chapman, 1992;Huang & McArdle, 1992). Figure IIA Fig.…”