1. Studies on the quantitative significance of protozoa on carbon and nitrogen digestion and metabolism in the rumen were carried out in sheep given a diet of pelleted concentrate (500 g/d) and chopped hay (500 g/d).2. Measurements were made of apparent digestibility; flows of organic matter and dietary and microbial non-ammonia N (NAN) (using 16NH:) to the duodenum; and rates of production, interconversion and metabolism of the major C fermentation end-products (from mathematical modelling of 14C isotope values).3. The population density of bacteria in the rumen increased as a result of defamation (28.6 compared with 8.2 x lo0 organisms/ml). This high density was associated with greater utilization of volatile fatty acids (VFA) within the rumen.4. The rate of irreversible loss (IL) of bicarbonatefcarbon dioxide from the rumen was greater in the defaunated animals (98.5 v. 57.2 g C/d) but the IL from the blood was greater in the faunated group (138.6 v. g C/d). This is consistent with the hypothesis that the high population density of bacteria found in the rumen fluid of defaunated animals may result in increased fermentation of rumen VFA and digestible dietary carbohydrate, thereby increasing the output of CO, from the rumen and reducing the quantity of VFA (hence energy) available to the host.5. There was no difference in the flow of organic matter (OM) to the duodenum but there was a higher faecal excretion of OM in defaunated animals (apparent OM digestibility: 0.72 in faunated, 0.67 in defaunated).6. Defamation did not significantly increase the flow of NAN to the duodenum, the percentage of duodenal NAN of bacterial origin or the quantity of microbial NAN synthesized/g organic matter fermented. Faecal excretion of NAN was higher in defaunated animals (5.3 v. 3.6 g N/d).

Methyridine [2-(,8-methoxyethyl)pyridine] reached the blood and all regions of the alimentary canal following oral or subcutaneous administration of therapeutic doses of the drug. Concentrations in the lower gut were highest following subcutaneous administration, and there was a close association between blood and intestinal levelssuggesting that the drug is excreted into the alimentary canal along its whole length. In vitro experiments with intact nematodes (Ostertagia spp. from sheep; Nematospiroides dubius and Heterakis spumosa from mice; and Nippostrongylus muris from rats) and with preparations of Ascaris sp. have demonstrated that methyridine passes through the cuticle and exerts an "irreversible " paralysing effect on the worms. This action is obtained within 1 hr at concentrations similar to peak levels shown to be present in the alimentary canal following the administration of therapeutic doses. Concentrations of the drug were found to be higher in the abomasum than in the intestine of sheep and yet the anthelmintic activity of methyridine is greatest against intestinal nematodes. No significant differences in the resistance of various nematode species to the drug were demonstrated, but the amount of methyridine entering ascarids was significantly greater at pH 8 than at pH 5 or 3. In addition, the in vitro anthelmintic activity of the compound was greatest in alkaline solutions, which probably accounts for the differences in anthelmintic activity noted in various parts of the alimentary canal. The paralysing effect of methyridine on nematodes isprobably due to a neuromuscular block of the decamethonium type, and this can also be produced in the host by over-dosage. It is suggested that nematode tissues are more sensitive to this action than vertebrate tissues.Experiments in laboratory animals (Broome & Greenhalgh, 1961a and b) and farm animals (Walley, 1961) have demonstrated considerable anthelmintic activity against nematode infections of the gastro-intestinal tract following treatment with the compound methyridine [2-(fi-methoxyethyl)pyridine; "Promintic "]. The same reports indicate a number of features which make the drug unique among known anthelmintics. In particular, it is a liquid which is extremely water-soluble and which is most effective when administered subcutaneously. These peculiarities clearly merited this study of its mode of action. In the work described below estimations have been made of the drug concentration in various parts of the body and of the effect of the drug in vitro against various nematodes. The results are then correlated in an attempt to show how the in vivo anthelmintic activity is achieved.M

Critical studies using mice infected experimentally with nematodes (Nematospiroides dubius, Nippostrongylus muris and Heterakis spumosa) have shown methyridine to be an extremely effective anthelmintic when administered orally or subcutaneously. Comparisons of the two treatment regimes show subcutaneous administration to be the more efficient in terms of absolute dose, but neither treatment has a significant advantage in therapeutic safety margin. Methyridine has a more uniform anthelmintic action than either phenothiazine or bephenium against adult forms of the three test nematodes. In addition the drug possesses activity against all stages of certain immature nematode infections.

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