title: Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice.
abstract: The non-steroidal anti-inflammatory drug diclofenac (DCL) shows noteworthy in vitro and in vivo antimycobacterial activity. The aim of this study was to ascertain whether DCL used in combination with the first-line antitubercular antibiotic streptomycin (STM) synergistically augments its efficacy in vitro as well as in a murine tuberculosis infection model. In vitro minimum inhibitory concentrations (MICs) and synergistic activities of the drugs with respect to standard strains and clinical isolates of Mycobacterium tuberculosis were determined. Swiss albino male mice were intravenously infected with 2.3x10(7) M. tuberculosis H37Rv. Mice were treated with DCL or STM alone as well as in combination for 4 weeks to determine the survival rate, spleen weight and colony-forming unit (CFU) counts in the lungs and spleen. DCL was bactericidal at 40 microg/mL (4xMIC) against M. tuberculosis H37Rv and was synergistic with STM in vitro (fractional inhibitory concentration index 0.37). A dose of 10 microg/g/day DCL or 150 microg/g/day STM for 4 weeks, administered from 1 day post infection, significantly (P<0.05) lowered bacterial counts and reduced mean spleen weight of mice compared with untreated animals. Simultaneous administration of both agents further decreased CFU counts (P<0.05) in the lungs and spleen compared with mice receiving STM alone. Thus, the ability of extended antibiotic therapy may be improved with the help of this synergistic drug pair in murine tuberculosis, and further investigations may throw light on new directions to combat multidrug-resistant tuberculosis infections in humans.
authors.affiliation: Institute of Laboratory Animal Resources, Laboratory Animal Medicine, College of Veterinary Medicine, 85-Dong, 733-Ho, Seoul National University, San 56-1, Shillim 9 Dong, Gwanak-gu, Seoul, South Korea.
authors.forename: Noton Kumar
authors.initials: NK
authors.lastname: Dutta
authors.forename: Kaushiki
authors.initials: K
authors.lastname: Mazumdar
authors.forename: Sujata G
authors.initials: SG
authors.lastname: Dastidar
authors.forename: Jae-Hak
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004008:Diclofenac / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D013307:Streptomycin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D013307:Streptomycin