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Title: Sulphonamides in malaria
Author: Laing, A. B. G.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1969
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Abstract:
This thesis is based on observations made by the writer during the years 1964 to 1967 on the antimalarial effects of sulphormethoxine, dapsone and various combinations of these drugs with pyrimethamine against human malaria. The various trials wore carried out in Tanzania and to a lesser extant in West Malaysia; reprints of publications by the writer on various aspects of these trials including two papers extracted from this thesis are attached as a supplement. Sulphonamides have been known to have antimalarial properties almost since the time of their discovery as chemotherapeutic agents in 1935 but the potent, synthetic antimalarial drugs discovered as a result of intensive research during and after the second world war have made them more or less obsolete in terms of malaria chemotherapy; moreover the possibility of serious toxic effects at the high dosage required with the early sulphonamides was a further objection to their use in this field. However, since the finding soon after the war that human malaria parasites would become resistant to the synthetic antimalarials, culminating in the emergence of Plasmodium falciparum not only resistant to the 4-amino-quinolines but also to pyrimethamine, proguanil and mepacrine, the situation was indeed serious - particularly as some of these multiple drug-resistant strains showed a partial resistance to quinine also. It was against this sad background of the increasing impotence of the 'wonder drugs' of malaria chemotherapy that the sulphonamides, which in spite of antibiotics still retained a considerable degree of popularity, especially in their new form as long-acting sulphonamides, were re-examined by various workers for their antimalarial properties, A further cause of this renewed interest in these compounds was their potentiation effect with proguanil and pyrimethamine by which comparatively small doses of two drugs in combination were as effective as large doses of either separately. The writer had the opportunity of entering this field of research in Tanzania with clinical trials of the antimalarial effects of the new ' week-long-acting' sulphonamide, sulphomethoxine (Fanasil), in an area of the country where pyrimethamine-resistant strains of P. falciparum were known to exist. Preliminary trials in 1964 among asymptomatic schoolchildren showed that sulphormethoxine in weekly doses of 500 mg. suppressed both pyrimetnamine-sensitive and pyrimethamine-resiatant strains of P. falciparum but further trials showed that this level of dosage was unnecessarily high, suppression being achieved with 125 mg. and in combination with pyrimethamine with as little as 75 mg In trials of the drug as a therapeutic schizontocide in single doses of 1.0 gramme for an adult and proportionately less for children, its action was rather slow; however, in doses of 500 mg. given in combination with pyrimethamine 12.5 mg, the schizontocidal effect was as potent as that of chloroquine. Likewise dapsone which was known to have similar antimalarial properties to the sulphonamides was tried and found also to exert a slow schizontocidal effect in doses of 200 mg. but in doses of 100 mg. in combination with pyrimethamine 12.5 mg., the schizontocidal effect was as effective as chloroquine. In addition, investigations into the sporontocidal effects of these drugs showed that neither prevented sporogony in Anopheles gambiae but that in combination with pyrimethamine doses as low as 6.25 mg. of the latter apparently exerted a sporontocidal effect. In West Malaysia where the writer had the opportunity of carrying out clinical trials for a six month period in early 1966, sulphormethoxine was again an effective but slow schizontocide against P. falciparum; it was much less effective against P. vivax but in combination with pyrimethamine, a potent schizontocidal action was achieved against both species although this was not as great as against P. falciparum experienced in East Africa. Against chloroquine-resistant falciparum malaria in the northwest of the country (about one third of patients whom the writer treated with chloroquine in Perlis were infected with chloroquine-resistant parasites) the combination of sulphormethoxine 1.0 gramme with pyrimethamine 50 mg. quickly and effectively cleared asexual parasitaemia in three patients in which this combination was tried. In field trials in Perlis, combined sulphormethoxine 500 mg. with pyrimethamine 12.5 mg, was effective in suppressing asexual parasitaemias previously found to be resistant to chloroquine in doses of 10 mg. per kg. body weight. No side effects or toxic effects were encountered in any of the trial subjects or patients treated. In three Malay patients deficient in the enzyme glucose-6-phosphate dehydrogenase no haemolytic crises occurred after treatment with sulphormethoxine. Other trials confirming the effectiveness of single dose treatment with sulphormethoxine and pyrimethamine in multiple drug-resistant malaria are reviewed including the several variations on a similar theme tried out by the Americans in Vietnam and elsewhere. It is concluded that this form of treatment is an important advance in the chemotherapy of malaria resistant to other drugs but cannot yet be recommended for chemoprophylaxis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.777457  DOI: Not available
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