This paper describes an investigation of the antifilarial action of hetrazan in experimental animals, with special reference to the mechanism underlying its action. A preliminary communication on the work was given by Hawking, Sewell, and Thurston (1948).Hetrazan is-I -diethylcarbamyl-4-methylpiperazineThe antifilarial action of hetrazan was discovered and described by Hewitt, Kushner, Stewart, White, Wallace, and SubbaRow (1947) working with cotton rats infected with Litomosaides carinii, and its action on human filariasis due to W. bancrofti was shown by Santiago-Stevenson,-Oliver-Gonzalez, and Hewitt (1947). The present experiments were carried out on cotton rats bred at this Institute and infected with Litomosoides by the methods described by Hawking and Sewell (1948). The hetrazan used was the dihydrogen citrate, kindly supplied by American Cyanamid Co., and all doses refer to this salt. Microfilaria counts were made by spreading 5 to 20 cu.mm. of blood on a slide to form a thick film, dehaemoglobinizing in water, fixing in alcohol, and staining with hot haemalum or with Giemsa's stain; the microfilariae were then counted under the microscope.Preliminary experiments in vivo Infected cotton rats were given hetrazan by intraperitoneal injection according to the schedules shown in Table I and daily counts were made of the microfilariae in the blood taken from the tail. The rats were treated about seventy days after infection; during the next month untreated rats usually show a gradual increase in the microfilaria count. According to Harned et al. (1948) the LD50 of hetrazan hydrochloride when given intraperitoneally to rats is 465 mg./kg. In our experiments single intraperitoneal doses of 500 mg. of the citrate per kg. or hourly doses 100 mg./kg. usually caused prostration for 1-1 hour after each injection; repetition of the 500 mg./kg. dose after one day sometimes caused death, but 250 mg./kg. twice daily was well tolerated. The effect on the number of microfilariae in the blood varied considerably in different animals so that precise quantitative results

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This paper describes an investigation of compounds for their chemotherapeutic action on experimental filariasis due to Litomosoides carinii in the cotton rat, Sigmodon hispidus. Attention was drawn by Culbertson and Rose (1944) to the value of rats naturally infected with Litomosoides for experiments on filariasis, and the transmission by the tropical rat mite, Liponyssus bacoti, was demonstrated by Williams andBrown (1945) and by-Scott (1946). The method used in the Lederle Laboratories for testing drugs against naturally acquired filarial infections in cotton rats have been described by Hewitt, Wallace, White, and SubbaRow (1947). Early in 1946, a colony of rats infected with Litomosoides was established in this Institute, and this has supplied the animals for the present work, which is believed to be the first large scale search for antifilarial remedies which has been made with cotton rats infected in the laboratory. METHODSInfection and maintenance of rats.-The procedures for propagating the L. carinii infection in cotton rats have already been described in a previous paper (Hawking and Sewell, 1948). Briefly, tanks were set up with entomologically pure colonies of Liponyssus bacoti, on a sub-stratum of plaster-of-Paris and sawdust. The mites were infected with the larval stages of Litomosoides carinii by allowing them to feed on several cotton rats which had numerous microfilariae in their peripheral blood. The infected rats were then removed and recently weaned rats were placed in the tanks for a period of 14 days. The rats were then freed of mites and removed to a storage room for the incubation period of about fifty days. Smears of tail blood were made weekly during the sixth to ninth weeks of storage. Those rats which failed to show microfilariae in their blood at the fourth examination were exposed to infection a second time. The following notes describe our further experience since the publication of the previous paper.In the last two and a half years approximately 2,500 cotton rats have been exposed in infection tanks, and of these roughly 80 per cent have been found to have microfilariae in their peripheral blood after the first exposure. A more detailed analysis can be made for the period between January, 1948, and March, 1949, during which time 781 rats were exposed: of these, 121 (15 per cent) died before the termination of the incubation period; 576 (74 per cent) were subsequently found to be infected, while 84 (11 per cent) did not show microfilariae for three months after removal from the tanks. If the number of deaths be subtracted from the number exposed, the net percentage infected was 87. Excluding deaths, the percentage of rats infected was not related to the season of the year. Neither the percentage of rats infected nor the average wormload per rat in each batch was related to the number of rats in that batch, but this