Inhibition of Egg Production of Schistosoma mansoni in Mice Treated with Nicarbazin

Abstract

The reproduction of Schistosoma mansoni, in experimentally infected mice, was suppressed by treatment with nicarbazin (complex of 4,4'-dinitrocarbanilide and 2-hydroxy-4,6-dimethylpyrimidine). When fed to mice at 0.2% in the diet, nicarbazin completely suppressed the deposition of schistosome eggs, but did not kill the worms. The worms were not killed even when the drug was fed at 0.3% for 18 weeks, or at 1.0% for 2 weeks (the highest dosage tested). Inhibition of egg production was observed as early as 2 days after the onset of nicarbazin treatment. The inhibitory effect was reversible, and clinical relapse occurred when the drug was withdrawn. No effect was observed when nicarbazin was administered by gavage as a series of 10 doses at 250 mg/kg. Nicarbazin (an equimolecular complex of 4,4'dinitrocarbanilide and 2-hydroxy-4,6-dimethylpyrimidine) was reported to have slight antischistosomal activity (Cuckler et al., 1956). Subsequent investigation revealed that, at well-tolerated dosages, nicarbazin is extremely efficacious in preventing the pathological effects of schistosomiasis. The action of nicarbazin is unusual in that it seems to be directed chiefly against the maturation and the reproductive function of the worms. The experiments reported below illustrate this unusual activity. METHODS AND MATERIALS The mice used were albino males of approximately 20 g body weight. They were exposed percutaneously to cercariae whose number (100 to 200 per mouse unless otherwise specified) had been established by a sampling method. In those experiments concerned with the speed of action of nicarbazin, treatment was started 7 to 8 weeks after exposure to infection. In all other therapeutic experiments, treatment was begun 4 weeks after exposure, i.e., at a time when mating would be occurring, but eggs would not have been laid (Standen, 1953). Drugs were either incorporated in the mouse feed (Purina Laboratory Chow) and fed to the mice, or were administered by stomach tube as a suspension in 2% methylcellulose. Unless otherwise specified the mice were necropsied 11 to 18 days after the completion of treatment. Because pilot studies had shown that nicarbazin did not kill schistosomes, no attempt was made to count the schistosomes at necropsy. Instead the presence of live worms was noted, and the severity of the macroscopic hepatic lesions was estimated and recorded according to an arbitrary scoring system. To minimize error due to subjectivity, these lesion scores have herein been assigned to two categories of mice: (1) Those with essentially no Received for publication 24 May 1967. lesions; this usually meant complete absence of lesions, but the existence of a few scattered lesions did not prevent an occasional mouse from being included in this category. (2) Mice whose livers were mottled with lesions; this mottling was usually dense, giving the livers a grayish-white appearance, but in a few instances it might have been termed moderate or even slight. Undoubtedly the slightto-moderate mottling in some instances reflected a partial suppression due to medication, but in order to reach a conservative and unequivocal estimate of efficacy, such mottling was grouped with the most intense mottling. The distribution of eggshell material and vitelline cells was studied by means of the diazo method of Johri and Smyth (1956).