Some of the pharmacological properties of a new filaricide shown by Hewitt and coworkers1* to be highly active against naturally acquired infections have been studied in seven species of laboratory animals. The compound, 1-diethylcarbamyl-4-methylpiperazine hydrochloride, also referred to as Hetrazan and 84L, has a molecular weight of 234.ti3 and possesses the following structural formula :It is a colorless crystalline solid highly soluble in water. The pH of a 1.0 per cent solution is 4.l. In these experiments, however, the solutions were always adjusted to pH 7.4. RESULTS Acute ToxicitySINGLE DOSES. Mice and Rats. The dose-effect relations have been determined in albino mice and rats after oral, intraperitoneal, and intravenous administrations, TABLE 1 summarizes the data from 238 mice and 260 rats. Values for the L.D.50 in mg. per kg. were : orally, mice 660, rats 1380; intraperitoneally, mice 248, rats 465 ; intravenously, mice 82, rats 150. The 19/20 fiducial limits are narrow and the slopes of the mortality curves are steep. Toxic doses produced convulsions which were predominantly tonic. The convulsant dose, however, was considerably below the fatal dose. Guinea Pigs, Rabbits, and Cats. The upper limits of tolerance were determined only in mice and rats; nevertheless, in other species, rather large doses failed to produce serious reactions. Ten guinea pigs given 50 mg. per kg. intraperitoneally showed no symptoms. No objectionable reactions were observed in 15 rabbits given 100 mg. per kg. by the same (141) I 150 L.D., b 19/20 Fiducial $ limits k i , 611-713 1182-1620 2 Y 0 $ 169-362 2 451-479 % 2 b b trl T h 2 75-90 139-162 2 Weight range in grams: mice. 18-25: rats, 100-250. 79 74 76 77 75 68 88 91 72 67 74 77 75 79 73 67 Rats were fasted sixteen to seventeen hours. Muscular tremors were observed.
UOMYCIN,* aureomycin A-377, is a yellow crystalline antibiotic [ 182 1 * Trade mark Harned et al.: Pharmacology 183 per kg.;(d) at one hour and at two hours, the dogs were catheterized and the bladders washed with 0.9 per cent sodium chloride; (e) the specimens were alkalinized and the amount of dye determined with a photoelectric colorimeter (filter No. 540). Normal dogs excreted from 60 to 85 per cent during the first hour.Liver function was estimated by injecting intravenously 5 mg. per kg. of bromsulphalein. Blood w&s drawn at 5 and 30 minutes subsequent to the dose and the amount of the dye retained in the serum was estimated with a photoelectric colorimeter (filter No. 560). Normal retention at thirty minutes was from 0 to 15 per cent.Tests for histaminic action were made on isolated guinea pig gut and also by following the changes in blood pressure in anesthetized cats. Antihistaminic action was tested on the isolated guinea pig gut and on guinea pigs in 8. spray chamber.Tests for antipyretic action were made by following the rectal temperatures of rabbits injected intravenously with 0.25 cc. per kg. of typhoid vaccine, and of rats injected subcutaneously with 10 cc. per kg. of a 15 per cent suspension of yeasks Tests for irritation were made by the intracutaneous injection into the guinea pig skin and by local application to the conjunctival sac of the rabbit eye. In the eye, three or six drops at five minute intervals were used. Blood, urine and cerebrospinal fluid levels of duomycin were estimated biologically against Bacillus subtilis using a four hour period.6Duomycin is soluble in acid and in alkaline solutions, but is almost insoluble at pH 7. Four per cent solutions may be easily prepared as the hydrochloride pH 2.5 or as a sodium salt in a carbonate buffer pH 8.5.At pH 2.5, the salt is stable but at pH 8.5,25" C., it loses 12 per cent of its activity in 30 minutes, 20 per cent in 1 hour, and 40 per cent in 2 hours. Duomycin was administered parenterally usually as a 1 or 2 per cent solution pH 2.5 or pH 8.5. The hydrochloride was always used for the oral doses unless a different form was specified.Acute Toxicity Single Doses, Unanesthetized Animals. Orally, the toxicity is of a lorn order. Mice tolerated 1500 mg. per kg. and rats, 3000 mg. per kg. At 2500 mg. per kg., the mouse-mortality was 5 per cent (TABLE 1). No attempt was made to determine the maximal tolerated dose in larger animals. Intravenously, the L.D.50 for the hydrochloride was 134 mg. per kg. for mice and 118 mg. per kg. for rats (FIGURE 1). The alFline form appeared to be a little more toxic in mice but less toxic in rats (TABLE 1). These differences, however, are not significant. Three unanesthetized dogs readily tolerated intravenously, doses of 50 mg. per kg., pH 2.5,* given at a rate of 10 mg. per kg. per minute. Some days later, this dose in Doaes larger than SO m . per kg. of duomycin hydrochloride pH 4.5 produce hemoglobinuria. An e urvalrnt quantity of hykochloric acid will produce the same result. Hemoglohinuria has nevce ...
A a result of an investigation of the effects of drugs on the carbohydrate metabolism of rats, control glucose tolerance tests revealed that pedigreed, sexually mature, male rats of the Yale strain 2 exhibited a significantly lower glucose tolerance than rats of the Wistar strain of corresponding age and sex, grown under the same conditions and maintained on the same diet. In view of the extensive use of rats in carbohydrate studies, considerable importance is attached to the questions, a), Which strain has a 'normal' carbohydrate tolerance? b), What criteria justify the designation 'normal' carbohydrate tolerance in the rat?Relative to these questions, the data here reported cover a period of 22 months and consist of 425 glucose tolerance tests on 240 rats, normal with respect to weight gains and general physical appearance.
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