title: The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice.
abstract: Consecutive administration of ascofuranone without glycerol was found to have therapeutic efficacy against Trypanosoma brucei brucei infection in mice. A suspension of ascofuranone (25-100 mg/kg) was administrated intraperitoneally every 24 h for 1-4 consecutive days to trypanosome-infected mice and efficacy was compared with oral treatment. With intraperitoneal administration, all mice treated with 100 mg/kg ascofuranone for 4 consecutive days were cured. On contrary, with oral treatment a higher dose of ascofuranone (400 mg/kg) was needed for 8 consecutive days to cure the mice. With intraperitoneal treatment, parasitemia was strongly suppressed, with almost all long slender bloodstream forms of the parasite changed to short stumpy forms by day 3 and the parasites have been eliminated 4 days after the start of treatment. These ascofuranone-induced short stumpy forms were morphologically analogous to the stumpy forms 2 days after peak parasitemia of pleomorphic clone of T. b. brucei GUTat 3.1. However, the properties of ubiquinol oxidase activity, which is the target of ascofuranone, in mitochondria isolated from before and after treatment, were almost same. The enzymatic activities of ubiquinol oxidase were only decreased to approximately 30% within a day after treatment, and then kept at nearly the same level. In the present study, we have improved regimen for administration of ascofuranone without glycerol, and demonstrated that consecutively administrated ascofuranone showed trypanocidal effects in T. b. brucei infected mice. Our present results strongly suggest that consecutive administration of ascofuranone may be an effective chemotherapy for African trypanosomiasis.
authors.affiliation: Department of Molecular Parasitology, Nagoya City University, Graduate School of Medical Sciences, Nagoya 467-8601, Japan. yabu@med.nagoya-u.ac.jp
authors.forename: Yoshisada
authors.initials: Y
authors.lastname: Yabu
authors.forename: Ayako
authors.initials: A
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Coh-ichi
authors.initials: C
authors.lastname: Nihei
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kawai
authors.forename: Nobuko
authors.initials: N
authors.lastname: Minagawa
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Hosokawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagai
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ohta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D007274:Injections, Intraperitoneal / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010088:Oxidoreductases / Q000032:analysis / Q000378:metabolism; D012717:Sesquiterpenes / Q000008:administration & dosage* / Q000097:blood / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D012717:Sesquiterpenes; D010088:Oxidoreductases; C020094:duroquinol oxidase; C006640:ascofuranone