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

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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    • "minimum effective therapeutic dose to the toxic dose suggests that the difference between the binding of trimethoprim to reductases of these agents and to the reductases of the chick embryo was less than the differences between the binding of the enzymes of susceptible bacteria and mammalian tissues. Although the pyrimidine somewhat enhanced the activity of a sulphonamide its effect was slight compared with potentiation against bacteria and susceptible protozoa (Clarke, 1962; Eyles & Coleman, 1953; Rollo, 1955). The low degree of potentiation may be due to poor and incomplete binding of the reductases of the trachoma agent, so that some enzyme is free to deal with folate that has escaped the blocking effects of the sulphonamide. "
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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.
    Journal of general microbiology 04/1968; 50(3):Suppl:8. DOI:10.1017/S0022172400041152
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    Proceedings of the Royal Society of Medicine 12/1956; 49(11):871-3.
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    British journal of pharmacology and chemotherapy 01/1957; 11(4):454-7. DOI:10.1111/j.1476-5381.1956.tb00016.x
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