New Concepts in the Treatment of Relapsing Malaria

The Charles Franklin Craig Lecture, 1946

James J. Sapero
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Summary and Concluding Remarks

It has been pointed out that despite the magnificent contributions of wartime research towards the producing of new and more efficacious antimalarial drugs, the ideal drug capable of radical cure remains to be discovered. This means that the practicing physician must continue to deal with antimalarial agents known to be of sub-optimal efficacy—that ways and means must be devised of attaining the best possible effects from drugs only partially effective in overcoming the notorious relapsing tendency of malarial infections.

Attempts to discover the most efficacious scheme of treatment however have in the past led to much confusion and controversy. This is to be expected for frequently, identical therapeutic schemes, when repeated on different groups, have produced amazingly different results.

The objective in this lecture, then, has been to examine the probable underlying causes which have led to discrepancies and confusion in therapeutic evaluation.

To emphasize the major factors which seem to be concerned, a formula of radical cure has been devised. The formula states that the probability of radical cure in an individual, or of cures in a group is determined by the effectiveness attained by the factor of drug efficacy plus that attained by the factor of host immunity. The net effect of these in turn is reduced or augmented by a third factor, the inherent characteristics of the species or strains of malaria concerned.

The formula is not intended as a precise statistical method which will determine the likelihood of cure. Rather it purports to express the broad and general principles which are concerned in the mechanism of cure. Its workings for illustrative purposes, however may be demonstrated arithmetically. For example if inadequate treatment, roughly of 25 per cent efficaciousness is given, and if immune response similarly is about 25 per cent, the net result of these two factors alone would give about 50 per cent cures. This percentage, however, when multiplied by the third factor, might be either doubled or halved. Thus 100 per cent cures might still follow if the strain concerned were drug susceptible, or there might be only 25 per cent cures, if the strain were inherently drug resistant. This suggests how variably the mechanism of cure may operate to produce almost any given curative result.

The formula emphasizes: (a) That results achieved by any given system of treatment may be dominated by factors quite independent of the treatment itself; (b) if identical regimens of treatment are employed in different groups, variable results are inevitable, for only by coincidence could either of the other two factors operate in an identical manner; (c) that as a result, divergent results which follow in trials evaluating treatment, actually should not be confusing, but are to be expected; and finally, (d) that the common recourse which is so often taken when a plan of treatment fails, such as doubling or prolonging dosage or otherwise revising standard forms of treatment, should be undertaken only when one is convinced that the true explanation of failure does not rest in the operation of other equally influential factors.

Finally, a full consideration of the problem of preventing reactivation seems to demand not only the broader concepts which the formula suggest, but in addition, an understanding of many newer concepts by which each of the various factors in the formula tend to express themselves. Among the most important of these is the postulate that an exo-erythrocytic cycle exists in man; and the corollary, that two types of reactivation occur: exo-erythrocytic (relapses) as well as erythrocytic (recrudescences). In regard to therapy which aims at radical cure, the use of drugs capable of both exo-erythrocytic and erythrocytic activity appears to be essential. In regard to immunity sporozoite dosage looms as of new interest and of great importance is the pattern of clinical activity in the human host. Drug susceptibility and the pattern of relapse appear to be the essential elements peculiar to species or strains of species which are important in determining whether cure or clinical reactivity will follow.

These are matters, then, that constitute new concepts which, in turn, promise to provide a more rational and better understanding of the many difficult problems involved in the treatment of relapsing malaria.

Author Notes

Captain, Medical Corps, U. S. N. Malaria and Epidemic Disease Control Officer, South Pacific Areas and South Pacific Forces (1942–44), and of the Pacific Ocean Areas (1945–46).