As a part of the programme of the Therapy of Leprosy (THELEP) Scientific Working Group, a number of compounds with potential activity against My cobacterium leprae were prepared in other laboratories. We report here the results of studies of their activity against M. leprae with the use of the kinetic method in mice. A modified protocol is described that facilitates comparison of drugs in the same experiment. Two analogues of cycloserine, glycylhydroxamic acid and beta-analylhydroxamic acid were inactive in a dosage of 0• 1 % in the diet. Isoetam, (D-2,2'-(ethylendiimino)-di-I-butanol)di-isoniazid methane sul phonate was also inactive at this dosage. Three compounds related to dapsone, 4-nitro-N'-phenylsulphonamide, 4-amino-N'-phenylsulphonamide, and 4,4'-dia minobenzene sulphonic acid phenyl ester, had little or no activity at dosages of 0'01% in the diet in experiments with strains shown to have normal susceptibility to dapsone. Two thiosemicarbazones, pyridinal-4-thiosemicarbazone and pyri dinal-2-thiosemicarbazone, were inactive in dosages of 0•0 I %; the latter was inactive at 0'01% in an experiment where thiacetazone was shown to have bactericidal-type activity at a dosage of 0' 1% and marginal activity at 0'01%. Brodimoprim, a dihydrofolate reductase inhibitor, which is related to trimetho prim but has a longer half-life, was inactive in a dosage of 0• 1 %; it had no synergistic effect with 0•0 I % dapsone against a dapsone-susceptible strain. It was also inactive against a dapsone-resistant strain, alone or in combination with dapsone. The cyanimino analogs of ethionamide and prothionamide were inactive in a dosage of 0• 1 % against an ethionamide-susceptible strain. Experi ments with a series of compounds related to chaulmoogric acid were unsuccessful because the compounds were too toxic. Experiments with a series of compounds related to clofazimine were unsuccessful because their pharmacokinetics were unfavourable for study at dosages where clofazimine itself was active. The limitations imposed by the mouse-foot-pad system are discussed and related to those in other experimental systems.

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Summary In an attempt to explain wide patient-to-patient variation of the rate at which patients respond to chemotherapy with acedapsone, the relationship between the logarithm l O of the number of Mycobacterium /eprae in the patient's pretreatment skin-biopsy specimen, and the rapidity with which the organisms became non-infective for mice, was examined for a number of patients with previously untreated lepromatous leprosy, treated in the course of a clinical trial in Cebu, Philippines. Analysis of the data failed to reveal such a relationship.Acedapsone [4,4' -diacetamidodiphenylsulphone (DADDS)], which produces a prolonged, low plasma level of dapsone after intramuscular administration, 1 has been shown to be an effective chemotherapeutic agent in clinical trials among patients with lepromatous leprosy. 2, 3 In the course of these trials, some patients responded as rapidly as patients treated with dapsone in full dosage, as measured by inoculation of mice with organisms recovered from skin-biopsy specimens obtained at intervals during treatment, whereas others responded much more slowly. Work was subsequently undertaken to identify the factors that determine the rate of response to treatment with acedapsone. To date, studies have shown that neither the susceptibility of the individual patient-strains of My cobacterium leprae, all susceptible to dapsone administered to mice in a concentration of 0·0001 g/lOO g diet or less,4 nor the ratio of mono acetyl dapsone to dapsone in the plasma of the patientS determines the rate at which the patients respond to t Deceased.