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.
Two S-ethylene substituted phosphoramides were reported by Buckley et al. ( l ) , Burchenal et a L ( 2 ) and Lewis et d ( 3 ) to be as effectii-e as Triethylene melamine in retarding the qrowth of a number of experimental tumors. The inhibitory effect of a large series of ethylenimine derivatives against a wide tumor spectrum has been reported independently by this laboratory(4,S).The purpose of the studies reported here was to select ethylenimine derivatives* which markedlj-.inhibit the metastasizing tendency of the mammary adenocarcinoma of the Hooded Brown Rat.Jlatrrials nrtd methods. Approximately 2 x 2 in111 iragments of mammary adenocarcinoma. R2126, were implanted aseptically by trocar into the subcutaneous tissue of the right side oi inbred Hooded rats weighing 100-120 g. The rats were weighed, housed individually and arranged ' 7 feiiiales and 8 males per group. Treatnients were started 48 hours after implantat ion. Included in each experiment were one saline-treated group that served as a negative control, and one Triethylene-melamine-treated group that served as a positive control. -\ synthetic diet(3) and water were * Supplied by Calco Chemical Division. -4merican Cyanamid Co., Bound Brook, S. J .given ad libitum. The compounds were prepared in buffered saline and the concentrations used as indicated in Table I. Injections were administered intraperitoneally daily or every other day in a volume of 0.5-1.0 ml. The period of treatment was approximately 42 days. At the end of this time all animals were sacrificed and the lungs excised. Observations were made on the gross metastatic lesions of the lungs and a section+ was fixed for histological study. The inhibitory effects on the primary tumor have been reported previously ( 5 ) .Results. The pooled results of several experiments in Table I indicate that the 5 compounds at the levels tested markedly reduce the incidence of metastases to the lungs. Fig. 1 illustrates the effect of these compounds on the gross metastatic tumors of the lung. The control lungs on the left show the typical metastatic growths. On the right is shown typical treated lungs with no visible metastatic lesions. Histologically the control lungs show tumor masses so extensive that the normal architecture of the lungs has been nearly destroyed. The lungs of the treated animals t The authors are indebted to Mrs. Hester S. Sch,urr for the preparation of the tissues for hktological study.
A myeloid chloroleukemia in the rat has been studied and developed into an assay for the screening of antileukemic compounds. A series of phosphoramide derivatives have been found to be effective against this leukemia, and comparative studies on their activity have been made. These compounds appear to be as effective as TEM and can be administered at higher dosage levels. All of the compounds produced a prompt remission of the disease.
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