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.
