Therapeutic Effect of Thiabendazole on Angiostrongylus cantonensis Infections in Rats

Abstract

Thiabendazole was highly effective in controlling the early invasive stages of the rat lungworm, Angiostrongylus cantonensis. The feeding of diets containing 0.1% thiabendazole to lungwormexposed rats for 7, 14, or 21 days, beginning on the day of exposure to infection, almost completely inhibited the development of lungworms. The worms appeared least susceptible to thiabendazole during the 3rd week of their development in the rat. When the parasites were 4 to 6 weeks of age, they were again vulnerable to the anthelmintic action of thiabendazole. Dose-response relationships were observed when oral dosages of thiabendazole were administered to lungworm-infected rats. Depending upon the dosage, time, and duration of medication, the worms were killed, their migration to the lungs was delayed, or their oviposition was prevented. Since these worms appear particularly susceptible while migrating to and in the brain of rats, thiabendazole should be considered for possible therapy of parasitic meningoencephalitis in man. Recent reports by Horio and Alicata (1961), Alicata (1962), and Rosen et al. (1962) indicate that Angiostrongylus cantonensis (Chen) Dougherty, a metastrongylid lungworm of rats, is the cause of a previously unexplained meningoencephalitis in man in Hawaii, Tahiti, and possibly other Pacific islands and areas. This parasite has been reported in rats from eastern Asia (China, Malaya, Thailand), Australia, and various Pacific islands including Cook Islands, Formosa, Guam, Hawaii, Loyalty Islands, Ponape, Marshall Islands, New Caledonia, New Hebrides, Saipan, Tahiti, and Truk Islands (Alicata and McCarthy, 1964). In Australia, MacKerras and Sandars (1955) studied its life history and reported that the slug, Agriolimax laevis, serves as an intermediate host. Since that time, numerous other mollusks and land planarians have been found to serve as natural or experimental intermediate hosts (Alicata, 1962, 1963; Weinstein et al., 1963). Because of the recognition of this new disease in man and its wide distribution in the Pacific and Southeast Asia (Smit, 1963), studies were conducted to determine whether thiabendazole, a potent and broad-spectrum anthelReceived for publication 7 December 1964. * This investigation supported in part by Grant NB-04965 of the National Institutes of Health, USPHS. t Merck Institute for Therapeutic Research, Rahway, New Jersey. t University of Hawaii, Honolulu. mintic (Brown et al., 1961), would affect this lungworm. The results show that thiabendazole affects the development of A. cantonensis in rats. MATERIALS AND METHODS Infective larvae of A. cantonensis were obtained either from naturally infected land snails (Achatina fulica) of Hawaiian origin or from laboratoryreared experimentally infected snails, Australorbis glabratus. The larvae were freed by maceration and artificial digestion of snail tissue or, in the case of A. glabratus, by maceration and sedimentation in Ringer's solution. Larvae freed by digestion were washed in Ringer's solution, strained through gauze, and concentrated by sedimentation. Young rats (70 to 80 g) were inoculated orally with 25, 50, 100, or 150 larvae suspended in 1 or 2 ml Ringer's solution. Rats were randomly assigned to treatment groups; in two experiments each group consisted of five males and five females initially. In the third experiment, the groups consisted of five rats each. Groups of uninfected controls were maintained in each experiment. Thiabendazole was administered either by gavage or by feeding finely ground laboratory chow to which thiabendazole was added and carefully mixed in concentrations of 0.025 to 0.4%. At necropsy the brain, heart, and lungs of each animal were examined for Angiostrongylus. The brain was removed from the cranium, and all surfaces were scrutinized for worms and evidence of lesions. The heart and lungs were separated by pulling them apart, breaking the pulmonary vessels without injury to the worms. Left and right auricles and ventricles were teased open and their cavities and contents examined although no worms were recovered from the left side of the heart. Worms protruding from the larger pulmonary ves-