title: In Vitro,Ex Vivo, andIn VivoActivities of Diamidines against Trypanosoma congolense and Trypanosoma vivax.
abstract: African animal trypanosomosis (AAT) is caused by the tsetse fly-transmitted protozoansTrypanosoma congolenseandT. vivaxand leads to huge agricultural losses throughout sub-Saharan Africa. Three drugs are available to treat nagana in cattle (diminazene diaceturate, homidium chloride, and isometamidium chloride). With increasing reports of drug-resistant populations, new molecules should be investigated as potential candidates to combat nagana. Dicationic compounds have been demonstrated to have excellent efficacy against different kinetoplastid parasites. This study therefore evaluated the activities of 37 diamidines, usingin vitroandex vivodrug sensitivity assays. The 50% inhibitory concentrations obtained ranged from 0.007 to 0.562 μg/ml forT. congolenseand from 0.019 to 0.607 μg/ml forT. vivaxOn the basis of these promising results, 33 of these diamidines were further examined usingin vivomouse models of infection. Minimal curative doses of 1.25 mg/kg of body weight for bothT. congolense- andT. vivax-infected mice were seen when the diamidines were administered intraperitoneally (i.p.) over 4 consecutive days. From these observations, 15 of these 33 diamidines were then further testedin vivo, using a single bolus dose for administration. The total cure of mice infected withT. congolenseandT. vivaxwas seen with single i.p. doses of 5 and 2.5 mg/kg, respectively. This study identified a selection of diamidines which could be considered lead compounds for the treatment of nagana.
authors.affiliation: Parasite Chemotherapy, Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland Kirsten.Gillingwater@unibas.ch.|University of Basel, Basel, Switzerland.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Gillingwater
authors.affiliation: Parasite Chemotherapy, Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Christina
authors.initials: C
authors.lastname: Kunz
authors.affiliation: Parasite Chemotherapy, Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Christiane
authors.initials: C
authors.lastname: Braghiroli
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Boykin
authors.affiliation: Department of Pathology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.affiliation: Parasite Chemotherapy, Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
mesh_terms: D017954:Africa South of the Sahara; D000818:Animals; D002417:Cattle; D002418:Cattle Diseases / Q000188:drug therapy* / Q000469:parasitology; D004351:Drug Resistance; D005260:Female; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000494:pharmacology*; D014348:Trypanosoma congolense / Q000187:drug effects*; D016689:Trypanosoma vivax / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology / Q000662:veterinary*; D014370:Tsetse Flies / Q000469:parasitology
chemical_list: D010419:Pentamidine
keywords: Trypanosoma; chemotherapy; diamidines; in vitro drug sensitivity assays; in vivo animal models; nagana