Biomedical subjects
Publications and source records attributed to L Levy.
Of 25 dapsone derivatives and analogs screened for activity against Mycobacterium leprae in the mouse footpad system, only 7 were active. All seven were metabolized to or contaminated with dapsone.
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Contrary to the results of an earlier study in which polyinosinic-polycytidylic acid [poly(I:C)] administered intraperitoneally to mice had no effect on multiplication of Mycobacterium leprae in the mouse footpad, the local administration of poly(I:C) every 12 h for 15 doses during logarithmic multiplication was found both to inhibit bacterial multiplication and to produce high tissue levels of interferon (IF). Local administration of poly(I) alone inhibited multiplication of M. leprae to almost as great a degree without at the same time producing a measurable IF titer in the footpad tissues. Mouse IF and "mock" IF both inhibited bacterial multiplication to the same degree, but administration of only the former resulted in a measurable IF titer. Polyadenylic-polyuridylic acid administered locally neither inhibited multiplication nor induced IF; fetal calf serum, administered in the same concentration as found in the preparations of IF and mock IF, was modestly inhibitory, without inducing IF. Thus, the local administration of poly(I:C) appears to have inhibited multiplication of M. leprae independently of IF induction.
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In 22 lepromatous Filipino patients receiving their first injection of 225 mg acedapsone (DADDS), dapsone (DDS), and monoacetyl DDS (MADDS) were present in plasma in approximately equal quantities. Peak levels of parent drug, DDS, and MADDS occurred between 22 and 35 days. The half-times of disappearance (T1/2) from plasma were 43 days for DDS and MADDS and 46 days for DADDS. Acetylator phenotyping with sulfamethazine (SMZ) and DDS showed that 17 patients were rapid and 5 patients were slow acetylators. Correlations between acetylation of SMZ and DDS after DDS and of acetylation of DDS after DDS and DADDS were highly significant. However, acetylation of DDS after DADDS did not differentiate the patients into acetylator phenotypes. The T1/2 of DDS after DDS in the patients was directly related to the minimum levels of DDS at 77 days after DADDS treatment. These minimum levels were 8-fold higher than the minimum inhibitory concentration (MIC) of DDS for Mycobacterium leprae in mice and rats, but not all patients responded satisfactorily. No relationship could be demonstrated between the bacteriologic response and any of the pharmacologic parameters examined in these Filipino patients. In a companion study, minimum levels of DADDS, MADDS, and DDS were determined in 447 leprosy patients of all disease types from the Karimui District of Papua New Guinea who had been receiving 225 mg DADDS every 70 to 80 days for the past 5 years. All patients exhibited DDS levels above the MIC of DDS for M. leprae, no significant differences in plasma sulfone levels were found among disease types, no relationship between rate of healing in paucibacillary patients and sulfone levels were found, and type of response in multibacillary patients and sulfone levels were unrelated. No substantial accumulation of the sulfones in the Karimui patients receiving continuous therapy with DADDS for 5 years was indicated from a comparison with the levels in the Filipino patients following a single injection of DADDS.
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Metabolism of ss-DNA in Swiss Webster mice and NZB/W mice was studied. The delay in intra-hepatic catabolism of ssDNA in old NZB/W female mice seems to correlate with the presence of increased anti-DNA antibodies; similar to effects produced in Swiss Webster mice that have been pretreated with a small dose of carbon black. Neither impairment in the phagocytic ability nor a decrease in DNase activity are found in the mice who are relatively unable to metabolize ssDNA. These observations are discussed in relation to possible pathogenesis in NZB/W mice.
In the course of a clinical trial of acedapsone therapy in 17 patients with lepromatous leprosy, the rate of response to therapy was measured by inoculation of mice with Mycobacterium leprae recovered from biopsy specimens of skin lesions obtained before treatment and at intervals of 4, 12, and 24 weeks after institution of treatment. The susceptibility of each isolate of M. leprae to dapsone (4,4'-diaminodiphenylsulfone [DDS]) was measured by passaging organisms that had multiplied in mice to new groups of untreated mice and to mice treated with DDS incorporated in the mouse chow in concentrations of 10(-5), 3 x 10(-5), and 10(-4) g/100 ml. The rate of response to acedapsone therapy and the susceptibility of patient strains of M. leprae to DDS varied widely among patients. All isolates were inhibited from multiplication by treatment of mice with 10(-4) g of DDS per 100 ml; all but two isolates were susceptible to 3 x 10(-5) g of DDS per 100 ml; and 17 of 36 isolates, representing nine patient strains, were susceptible to 10(-5) g of DDS per 100 ml. Plasma levels of DDS measured in the mice administered these diets show that the minimal inhibitory concentration of DDS for M. leprae isolated from untreated patients is about 3 ng/ml. No relationship could be demonstrated between DDS susceptibility of pretreatment isolates of M. leprae and the rate at which patients responded to acedapsone therapy. Neither acedapsone treatment of patients nor DDS treatment of mice appeared to select genotypically more resistant M. leprae.
Dapsone (4,4'-diaminodiphenylsulfone), incorporated into the mouse chow in a concentration of 0.1 g/100 g of diet, was administered for 1 week to mice in which Mycobacterium leprae had multiplied to the level of 10(6) organisms/footpad. M. leprae were harvested from these and also from control mice, diluted serially, and inoculated into additional mice. The organisms recovered from untreated mice multiplied in passage with a mean doubling time of 12.2 days, and 35% or more of the inoculated organisms were viable, i.e., capable of infecting mice. Growth curves of M. leprae recovered from dapsone-treated animals lagged behind those of organisms from control animals by an average of 78 days, equivalent to 98.8% killing. Foot-by-foot harvests showed that only 0.2% of the M. leprae recovered from treated mice were viable, suggesting that treatment of mice with dapsone had been accompanied by killing of 99.4% of the viable M. leprae.
Several experiments were carried out to measure the ability of neonatally thymectomized Lewis rats (NTLR) to limit multiplication of Mycobacterium leprae. NTLR inoculated in one hind footpad with 10(7) viable M. leprae and challenged in the other hind footpad with 5 x 10(3) organisms simultaneously or 120 or 180 days later permitted multiplication in both sites. By contrast, immunologically intact rats similarly inoculated did not permit multiplication from either inoculum. NTLR and immunologically normal BALB/c mice were equally susceptible to infection with M. leprae, in that multiplication occurred regularly in the footpads of both species when inoculated with a bacterial suspension diluted to provide five organisms per footpad. Finally, multiplication occurred when five viable M. leprae diluted with 10(7) heat-killed organisms were inoculated into the footpads of NTLR. Although there was some evidence that NTLR are not completely immunosuppressed, NTLR appear to be capable of detecting much smaller proportions of viable M. leprae than can be detected by immunologically normal mice.
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