title: Canine visceral leishmaniasis: comparison of in vitro leishmanicidal activity of marbofloxacin, meglumine antimoniate and sodium stibogluconate.
abstract: The control of canine leishmaniasis largely depends on the success of treatment. Drugs currently available to treat this disease are toxic and partially effective. The curative effect of marbofloxacin, a third-generation fluoroquinolone developed for veterinarian individual treatment, was evaluated in vitro in the presence of Leishmania infantum promastigotes and dog-monocyte-derived macrophages; meglumine antimoniate and sodium stibogluconate were used as comparative treatments. We observed that the killing of Leishmania promastigotes and intracellular amastigotes by marbofloxacin was dose-dependent. We demonstrated that successful treatment of canine infected macrophages for 48 h was possible with 500 microg/ml of marbofloxacin. Leishmanicidal activity acted through a TNF-alpha and nitric oxide pathway and correlated with the generation of nitric oxide (NO(2)) production by monocytes derived macrophages from infected (23+/-5 microM) or healthy (21+/-6 microM) dogs, in comparison with NO(2) concentration in infected/non-treated macrophages (< 3 microM, P<0.01). This significant induced parasiticidal effect correlated with extensive elimination of amastigotes by macrophages derived from infected (11+/-5) and healthy dogs (6+/-2), when compared to infected/non-treated macrophages (530+/-105 and 472+/-86 amastigotes, respectively, P< 0.01). Marbofloxacin was shown to be non-toxic at 500 microg/ml in vitro and no cell apoptosis was observed. The molecule was able to induce a parasitic process after significant elimination of amastigotes in leishmania-infected dog macrophages. We propose that marbofloxacin, compared to standard chemotherapeutic agents (meglumine antimoniate and sodium stibogluconate), could be an effective and pragmatic oral route alternative to treat canine leishmaniasis.
authors.affiliation: INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Université Paris VI, CHU-Pitié Salpétrière, 75013 Paris, France. vouldouk@ext.jussieu.fr
authors.forename: Ioannis
authors.initials: I
authors.lastname: Vouldoukis
authors.forename: Sandrine
authors.initials: S
authors.lastname: Rougier
authors.forename: Bernard
authors.initials: B
authors.lastname: Dugas
authors.forename: Paco
authors.initials: P
authors.lastname: Pino
authors.forename: Dominique
authors.initials: D
authors.lastname: Mazier
authors.forename: Frédérique
authors.initials: F
authors.lastname: Woehrlé
mesh_terms: D000818:Animals; D000967:Antimony Sodium Gluconate / Q000494:pharmacology / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004283:Dog Diseases / Q000188:drug therapy* / Q000469:parasitology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005347:Fibroblasts / Q000166:cytology; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000032:analysis; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000662:veterinary*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D008536:Meglumine / Q000494:pharmacology / Q000627:therapeutic use; D000077485:Meglumine Antimoniate; D051379:Mice; D009569:Nitric Oxide / Q000032:analysis; D009942:Organometallic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D021261:Parasitic Sensitivity Tests / Q000662:veterinary; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D024841:Fluoroquinolones; D015850:Interleukin-6; D009942:Organometallic Compounds; D015363:Quinolones; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008536:Meglumine; D000077485:Meglumine Antimoniate; C080260:marbofloxacin; D000967:Antimony Sodium Gluconate