Anthelmintic Studies with Pyrantel. II. Prophylactic Activity in a Mouse-Ascaris suum Test Model

Abstract

Mouse lung lesions were graded (0 to 5 according to severity) and the numbers of larvae per lung were determined at various time intervals after inoculation of 5,000 embryonated A. suum ova. It was concluded that 8 days post-infection (p.i.) is the optimal time for measuring the effect of drug treatment on the severity of pathology. The straight line obtained from a semilog plot of 8-day p.i. lesion scores and inoculum size (500 to 5,000 ova) was used as a standard curve. The effectiveness of a given treatment on the average lesion score of a treated group was expressed as a percent reduction in inoculum effectiveness. Using a multiple dose regimen pyrantel HC1 was shown to be very active (minimum effective dose = 0.5 mg/kg) against the larvae present in the intestinal lumen (hatching larvae). Subsequent studies revealed that when administered within 1 hr after ova inoculation a single dose at a given mg/kg level is virtually equal in effectiveness to multiple doses given at hourly intervals. Studies in which mice were killed at various time intervals, 15 to 120 min p.i., showed that after 60 min many embryonated ova and hatched larvae are below the ileocecal junction. Thus a dose administered within the first 60 min affords soluble compounds such as pyrantel HC1 the maximum pharmacokinetic opportunity to exert an anthelmintic effect. With either the single or multiple dose regimen pyrantel HC1 was found to posssess a unique degree of activity when compared to piperazine, tetramisole, and thiabendazole. When administered in the feed for 7 hr, commencing 2 hr before ova inoculation, its minimum effective concentration was 0.005%. The reference compounds were only effective at concentrations in excess of 0.1%. The life cycle and pathogenicity of Ascaris suum Goeze (1782) have been studied by innumerable scientists for over a century and a half. When Stewart (1917) found the mouse to be a satisfactory host for the immature stages of A. suum and A. lumbricoides, it afforded investigators an easily manipulated test model with which to work. However, it was 38 years later before the A. suum-mouse test model was used to evaluate an anthelmintic (Brown and Chan, 1955). At that time high doses of piperazine HC1 were shown to have an effect against A. suum larvae in the small intestine of mice using as the basis of activity a reduction in the severity of lung lesions, the same basis more recently used by other workers (Howes and Lynch, 1967; Boisvenue et al., 1968). The utilization of the A. suum-mouse test model in the evaluation of the hydrochloride salt of pyrantel (trans-l-methyl-1,4,5,6-tetra-hydro-2[2-(2-thienyl)vinyl]pyrimidine), a new broad spectrum anthelmintic (Austin et al., 1966; Comwell, 1966; Howes and Lynch, 1967) is the subject of this paper. MATERIALS AND METHODS