The Mode of Action of Hetrazan on Filarial Worms

Abstract

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

ACTION OF DIETHYLCARBAMAZINE IN VITRO ON INFECTIVE LARVAE OF WUCHERERIA BANCROFTI

“…In very few cases has this drug shown any in vitro effect on the different stage of filarial worms (Hawking et al, 1950), and it may well be that in vivo the drug acts indirectly by rendering the larvae more susceptible to phagocytosis.…”

“…Hawking, Sewell and Thurston (1950) found evidence of a lethal effect in vivo against infective larvae of Litomosoidew carinti when the drug was given to cotton rats before and during the period of exposure to infected mites (Liponyssus bacoti). When given after infection, it appeared that developing males may be affected.…”

Chemotherapeutic reactions of Chandlerella hawkingi, the filarial parasite of the Indian jungle crow, Corvus macrorhynchos (Wagler)

“…No record is available of the effects of this drug on other bird filariae. The mode of action of diethylcarbamazine on mammalian microfilariae is peculiar in that it exerts no direct lethal action on the larvae but sensitizes them so that they become susceptible to phagocytosis by fixed macrophages of the reticuloendothelial system in the liver (Hawking, Sewell & Thurston, 1950). The microfilariae of Ch.…”

Investigating development of infective stage larvae of filarial nematodes

“…Although the precise step at which DEC is operating in this pathway is not completely agreed upon, micromolar concentrations of the drug cause an increase in 5-HETE and block production of leukotrienes B 4 (LTB 4 ) and C 4 (LTC 4 ), suggesting the synthesis of leukotriene A 4 (the precursor of both LTB 4 and LTC 4 ) has been inhibited (36). Hawking et al (37) performed perhaps the most extensive studies on the anti-filarial activities of DEC soon after the drug's discovery. They found that cotton rats infected with L. carinii remained capable of developing patent infections if DEC treatment was delayed 1-2 weeks following infection, while those treated with DEC from the start of infection failed to develop patent infections.…”