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The mode of action of sulphonamides, proguanil and pyrimethamine on Plasmodium gallinaceum.

British journal of pharmacology and chemotherapy 07/1955; 10(2):208-14. DOI: 10.1111/j.1476-5381.1955.tb00084.x
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  • Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie 02/1957; 49:425-61.
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    ABSTRACT: Trimethoprim, a 2,4-diaminopyrimidine derivative which inhibits the growth of some bacteria by interfering with folic acid synthesis, inhibited the growth of several strains of the trachoma agent. Inhibition was most clearly demonstrated by measuring prolongation of mean death time of groups of chick embryos inoculated with a single lethal dose of agent. Over a certain range, prolongation was proportional to the logarithm of concentration of inhibitor; higher concentrations were toxic for the embryo. On a weight basis, trimethoprim was not as active as sulphafurazole. Inoculation in conjunction with sulphafurazole resulted in slight potentiation of activity. A related pyrimidine derivative, the antimalarial drug pyrimethamine, also significantly inhibited the growth of one strain of trachoma.In cell culture, trimethoprim decreased the number of inclusions formed by a suspension of the trachoma agent and induced morphological changes in the inclusions similar to those caused by sulphafurazole.Inhibition of the growth of the trachoma agent in the chick embryo was reversed by leucovorin calcium. It is concluded that, as with bacteria, the drug acts by blocking the folio acid cycle and that the trachoma agent most probably contains a dihydrofolate reductase.
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    ABSTRACT: Treatment with sulfadiazine prevented most of the increase in folic and folinic acid which otherwise occurred in the red blood cells of ducks infected with Plasmodium lophurae. The same effect was observed when a sulfadiazine-resistant strain of P. lophurae was treated with sulfadiazine at doses having no effect on the infection: the increase in folic and folinic acids was markedly less than that in untreated infections with the same strain. When the sulfadiazine-resistant strain was treated with pyrimethamine, to which it was also resistant, the increase in folinic acid was inhibited, but not that in folic acid. Each drug exerted its characteristic inhibitory effect on the folinic acid-synthesizing mechanism, yet the parasites of the resistant strain continued to multiply. This synthetic mechanism may reside in the infected red cells rather than in the parasites. The resistance to sulfadiazine and pyrimethamine appears to depend on a decreased requirement for the products of the reactions inhibited by these drugs.
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