THE MODE OF ACTION OF SULPHONAMIDES, PROGUANIL AND PYRIMETHAMINE ON PLASMODIUM GALLINACEUM

Abstract

Despite the mass of information on the antimalarial action of sulphonamides, proguanil, and pyrimethamine (see Goodwin and Rollo, 1955), there is as yet no complete picture of the relationship between them, although they all probably act upon the same metabolic pathway in the synthesis of nucleoprotein. Hawking (1953a) in his review of protozoal chemotherapy pointed out: " Many different lines of work appear to be converging here towards a general explanation, but it will be necessary to achieve further elucidation of the metabolism of p-aminobenzoic acid (PAB) and of folic acid by the malarial parasite before all the different facts in the jigsaw puzzle can be fitted into place." In this paper an attempt is made to fill some of the gaps in our knowledge of crossresistance, potentiation, and antagonism between antimalarial drugs, by reviewing and analysing the known facts, in the light of new data. METHODSThe parent strain of Plasmodium gallinaceum was that maintained in these laboratories for many years by blood and occasional mosquito passage in young chicks. This and the other drug-treated strains have, during the course of the experiments, been passaged solely by blood inoculation. Five-or twelve-day-old chicks (Rhode Island Red-Light Sussex cross) were inoculated intravenously with approximately 50 million parasitized red blood cells. The antimalarial drugs were given orally either in solution or, if insoluble in water, in gum tragacanth suspension. Starting a few hours after inoculation, a total of seven doses was given over 3-} days. Infection was assessed from stained blood films on the fourth day after inoculation, when in untreated controls about 70-90% of the red blood cells were infected. The infected red cells in the test animals were counted and the results were expressed as percentages of the controls. That dose which reduces parasitaemia to 50% of the mean parasitaemia of untreated controls (ED5O) was obtained from a 3-or 4-dose assay (Rollo, 1952). A group of five chicks was normally used at each dose level.Cross-resistance.-A strain of P. galinaceum (P.36), which was highly resistant to proguanil and to pyrimethamine, was obtained from Dr. D. G. Davey, of Imperial Chemical Industries. The sensitivity of this strain to sulphadiazine was tested in order to complete the picture of cross-resistance relationships reviewed by Thurston (1953). Two further strains were prepared by treating successive passages with subcurative doses of proguanil and pyrimethamine respectively. During each passage the chicks received a total of seven doses of the drug as described above. Both strains were passaged and treated in parallel and were tested periodically for cross-resistance during the early stages of the development of drug resistance.Potentiation.-The potentiating effect of pyrimethamine upon the activity of proguanil was investigated by giving the drugs both singly, and together in various proportions, to groups of infected chicks. ED50's were determined from the dose-response curves and were plotted on a ...

Potentiating effect of pyrimethamine and sulfadoxine against dihydrofolate reductase from pyrimethamine-sensitive and pyrimethamine-resistant Plasmodium chabaudi

“…When sulfonamides, which are inhibitors of dihydropteroate synthetase (EC 2.5.1.15), were used in combination with pyrimethamine or other inhibitors of dihydrofolate reductase, the antimalarial action of the combined drugs was greatly enhanced (3,17,22,38). This result is of great advantage, since the dosage of individual components required for antimalarial activity is reduced (39,42).…”

In vitro activities of and mechanisms of resistance to antifol antimalarial drugs

“…Reversal of the activity of sulfonamides and DHFR inhibitors by FA has been reported with P. gallinaceum in vivo (17) and P. knowlesi in vitro (15). It has been attributed possibly to breakdown of the intact molecule and utilization of the (p-aminobenzoyl)glutamate (PABG) or to contamination of the FA used in those studies (7).…”

Synergy between verapamil and other multidrug-resistance modulators in model membranes

“…In addition, combinations of antimalarial drugs such as quinine are highly synergistic, with dose factors in the range of 15-36 (Rollo 1955). However, such high potentiation levels, leading to dose factors as high as 15-600, usually result from sequential blockade of steps along the same biochemical pathway (Pöch and Holzmann 1980;Rollo 1955).…”