A rise of body temperature into a range lethal to mice preceded death in groups of mice injected with amphetamine sulphate. At dose levels from 8.8 to 66.7 mg/kg, mortality was associated with the extent of rise in body temperature of the mice, irrespective of the actual dose administered. Isolated mice given comparable doses of amphetamine also showed a marked increase in body temperature. However, except in a very few cases, it did not rise into the range found to be lethal. Amphetamine was more toxic to isolated mice subjected to foot-shock than to isolated mice housed under normal conditions. This has also been shown to be related to the extent of rise in body temperature of the mice. The effect of a number of substances on grouped amphetamine toxicity was investigated. Chlorpromazine and phenoxybenzamine partially antagonized the sharp rise in temperature following the administration of amphetamine, and also significantly reduced mortality. Calcium acetylsalicylate was without effect on the rise of body temperature or on mortality.Both the hypothermic compound 4-methyl-5-(,8-chlorethyl)-thiazole (S.C.T.Z.) and L-thyroxine sodium potentiated the rise in temperature and caused a significant increase in mortality.
Three oximes, monoisonitrosoacetone (MINA), pyridine-2-aldoxime methiodide (PAM) and diacetylmonoxime (DAM), have been examined in combination with atropine as antidotes in sarin poisoning. When treatment was administered 15 min. before sarin, atropine enhanced the protective effect of MINA and DAM 2 to 3 times and of PAM 9 to 10 times in mice and rats. In mice, rats, and guinea-pigs, atropine increased by no more than 2 times the protective effect of all three oximes when given 30 sec. after sarin. Atropine given to monkeys 1 min. after sarin raised the LD50 approximately 3 times. When given in conjunction with MINA or DAM, the LD50 of sarin was raised 7 to 14 times.It has been shown previously that two oximes, monoisonitrosoacetone (MINA) and diacetylmonoxime (DAM), exert a marked protective effect in rats poisoned with isopropyl methylphosphonofluoridate (sarin) (Askew, 1956). Although less active in other species, they still appeared sufficiently promising to justify a further examination in conjunction with atropine. A third oxime, pyridine-2-aldoxime methiodide (PAM), the fastest known reactivator in vitro of cholinesterase (ChE) inhibited by sarin , was found ineffective against sarin poisoning in rats (Askew, 1956), although active in mice poisoned with diisopropyl phosphorofluoridate (dyflos, DFP) or diethyl p-nitrophenyl phosphate (paraoxon) (Kewitz, Wilson, and Nachmansohn, 1956). These three oximes have now been examined as adjuvants to atropine in sarin poisoning. METHODSThe animals used were female mice (18 to 22 g.), rats (180 to 200 g.) and guinea-pigs (320 to 380 g.), and male and female monkeys (2.5 to 4.0 kg.).The oximes and atropine were given intraperitoneally in aqueous solution, except where otherwise stated. When atropine was given in conjunction with an oxime, the required amount of atropine was dissolved in the oxime solution immediately before use. Sarin was diluted with 0.85% saline and injected subcutaneously in a standard volume for each species. This was 10 ml./kg. for mice, 1 ml./kg. for rats and guinea-pigs, and 0.2 ml./kg. for monkeys.LD50 values, based on a 24 hr. mortality, were determined both for sarin alone and sarin in the presence of oximes or atropine or both. For each test, the same number of animals was used at each dose, but this number varied in different experiments between four and six animals/ group. The ratio between successive doses was 1.26. Since the supply of monkeys was limited, the number used varied at different dose levels, but it was never less than two; here the ratio between doses was 1.3. LD50 values were normally calculated by the method of moving averages (Thompson, 1947), using the tables constructed by Weil (1952). Where this was not possible the technique of probit analysis (Finney, 1947) was employed. The " relative potency " of an oxime has been expressed as the ratio of the LD50 of sarin in the presence of an oxime to the LD50 of sarin alone. The limits were obtained from the sum of the variances (V) of the individual estimates of the log. LD...
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
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