In view of the problems caused by the chloroquine-resistance of some strains of Plasmodium falciparum, the authors have investigated the effectiveness of diaphenylsulfone against two such resistant strains, from Malaya and Viet-Nam. They found that diaphenylsulfone given during acute attacks of malaria had a blood schizontocidal activity against the Malayan resistant strain but was not rapidly effective in terminating acute attacks in non-immune persons, and that, when the drug was given prophylactically in relatively small doses, it was substantially effective in preventing patency of mosquito-induced infection with the same strain. The protective effect of diaphenylsulfone is that of a clinical prophylactic or suppressive drug; it does not appear to be a true causal prophylactic. It was also found that the protective effect is vitiated by the concurrent administration of paraaminobenzoic acid.These studies indicate a need for further assessment of the antimalarial value of sulfones and sulfonamides, both alone and in combination with other drugs, for prevention and cure.
From an extensive search of one of the largest inpatient leprosaria in the world, at Sungei Buloh, Malaysia, nine patients with lepromatous leprosy were discovered who gave prima facie evidence of sulfone resistance. The evidence was based on a failure to show clinical improvement over at least five years despite treatment with sulfones and an absence of a satisfactory fall in the bacteriologic (BI) or the morphologic (MI) index. The selected patients were admitted to our Research Unit for (a) a further six month, rigorously controlled, trial period on DDS (as injectable sulfone, 300 mgm. twice weekly) and (b) DDS sensitivity tests, based on use of the foot pad infection in mice with bacilli obtained from skin biopsies. The response of the nine patients to the six month trial period on DDS was assessed clinically, bacteriologically and histologically, and revealed that only four of the patients failed to respond satisfactorily. Furthermore, the sensitivity tests in the mouse foot pad infection showed that only the strains of M. leprae from the four patients who failed to improve were insensitive to DDS. Thus there was a good correlation between the results of the clinical and experimental studies and for the first time direct proof for the existence of DDS resistant strain s of M. leprae. The MI proved to be the most sensitive of the assessments used to determine the response of the selected patients to a trial period on DDS. The histology of patients with drug resistance is essentially that of relapsing or very acute leprosy. Its features have much in common with those of "histoid" lesions, the latter being distinguished mainly by the absence of cytologic maturation. Classification is complicated by the presence of borderline features in otherwise lepromatous lesions.
The first three patients with proven DDS-resistant leprosy infections were treated for one year with the riminophenazine
derivative B.663 (300 mgm. daily for six days a week). All of them showed satisfactory clinical, bacteriologic and histologic
improvement, which at the time of writing has been maintained for a total period of 28 months. The results show that
active leprosy resulting from resistance to one drug can still respond satisfactorily to a different type of drug, as is the case with drug resistance in other bacterial infections. In this limited study B.663 showed no toxicity, but the degree of skin discoloration was disconcerting to Chinese patients.
Proof that a patient is suffering from sulfone-resistant leprosy depends on demonstrating that his bacilli can multiply in the mouse foot pad even when the mice are fed sulfone in the diet. Hitherto the maximal dose of DDS tolerated by the mouse has been used in such tests. This paper concerns a patient whose bacilli multiplied in mice fed lower doses of DDS, but were inhibited when the maximal dose was used . His clinical features are distinctive and probably characteristic of this type of "partial" resistance. It is likely that more cases of this type will be found . Recommendations are made concerning the investigation of possible DDS-resistant leprosy patients and their treatment.