title: Antimycobacterial activities of two newer ansamycins, R-76-1 and DL 473.
abstract: The antimycobacterial activities of two newer ansamycins, isobutylpiperazinylrifamycin SV (R-76-1) and cyclopentylrifamycin SV (DL 473), were compared with those of rifampin (RMP) both in vitro and in vivo. In terms of minimal inhibitory concentrations against a number of cultivable mycobacteria, R-76-1 was about eight times more active in vitro than RMP; whereas DL 473 was only slightly more active than RMP. Therapeutic activities of R-76-1 versus RMP and DL 473 versus RMP were compared, respectively, in the experimental infection of mice with Mycobacterium lepraemurium by different treatment schedules (immediate and delayed) and dosage regimens. R-76-1 appeared to have been three times more effective than RMP; DL 473 was also more effective than RMP in that an equivalent therapeutic effect could be obtained by fewer doses of DL 473 than of RMP, and in that DL 473 exerted a more prolonged activity than RMP. With the kinetic method and a dosage of 0.001% in the diet, R-76-1 demonstrated a bactericidal-type effect against M. leprae whereas RMP did not; with the proportional bactericidal method, R-76-1 possessed about three times the bactericidal activity of RMP against M. leprae. When drugs were administered once in 4 weeks, the RMP dose required to prevent multiplication of M. leprae in the foot pads of half of the mice was in the range of 1.25 to 2.5 mg/kg; whereas that of DL 473 was less than 0.625 mg/kg. With the proportional bactericidal method, even a single dose of 1.25 mg DL 473 per kg was active against M. leprae; whereas the smallest single active dose of RMP was 10 mg/kg. DL 473 in single doses of 5 mg/kg and 10 mg/kg was significantly more effective than RMP in equal doses and, among the intermittent regimens administered four times, once every 4 weeks, no significant differences of bactericidal activity were observed between RMP at 20 mg/kg and DL 473 at 0.625 mg/kg. A preliminary clinical trial of R-76-1 in 20 patients with lepromatous leprosy showed that the compound, administered in a dosage of 150 mg daily, was very effective.
mesh_terms: D000818:Animals; D006801:Humans; D007917:Leprostatic Agents / Q000494:pharmacology*; D007918:Leprosy / Q000188:drug therapy*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009164:Mycobacterium Infections / Q000188:drug therapy* / Q000382:microbiology; D009166:Mycobacterium leprae / Q000187:drug effects*; D009167:Mycobacterium lepraemurium / Q000187:drug effects; D012293:Rifampin / Q000031:analogs & derivatives* / Q000494:pharmacology; D012294:Rifamycins / Q000494:pharmacology
chemical_list: D007917:Leprostatic Agents; D012294:Rifamycins; C038966:3-formylrifamycin SV; C035703:rifamdin; D012293:Rifampin; C018421:rifapentine