The susceptibility of Trypanosoma congolense and Trypanosoma brucei to isometamidium chloride and its synthetic impurities.
Since the 1950s, the chemotherapy of animal African trypanosomosis in cattle has essentially relied on only two compounds: isometamidium chloride (ISM), a phenanthridine, and diminazene aceturate, an aromatic diamidine. The commercial formulations of ISM, including Veridium(®) and Samorin(®), are a mixture of different compounds: ISM is the major component, mixed with the red isomer, blue isomer and disubstituted compound. To investigate the pharmacological effects of these individual compounds ISM, the blue and red isomers and the disubstituted compound were synthesised and purified by HPLC. The activity of each compound was analysed both in vitro, and in mice in vivo. For the in vitro analysis, a drug sensitivity assay was developed in 96-well tissue culture plates to determine the effective concentration which killed 50% of trypanosome population within 48 h of drug exposure (IC50). All compounds tested in vitro possessed trypanocidal activity, and purified ISM was the most active. Veridium(®) and Samorin(®) had similar IC50 values to purified ISM for both Trypanosoma congolense and Trypanosoma brucei brucei. The disubstituted compound had the highest IC50 values whereas intermediate IC50 values were obtained for the blue and red isomers. In vivo, single-dose tests were used to evaluate the trypanocidal and prophylactic activity against T. congolense. Interestingly, the prophylactic effect two months post treatment was as efficient with ISM, Veridium(®), Samorin(®) and the disubstituted compound at the highest dose of 1mg/kg whereas the red and blue isomers both showed much lower prophylactic activity. This study on T. congolense implies that it is necessary to limit the quantity of the blue and red isomers in the commercial mixture. Finally, the in vitro sensitivity assay may be useful for screening new trypanocides but also for the testing and detection of resistant trypanosome isolates.
CNRS, Université Bordeaux Segalen, Microbiologie fondamentale et Pathogénicité, UMR 5234, F-33000 Bordeaux, France.
Annelise
A
Sahin
CNRS, Université Bordeaux Segalen, Microbiologie fondamentale et Pathogénicité, UMR 5234, F-33000 Bordeaux, France.
Corinne
C
Asencio
CNRS, Université Bordeaux Segalen, Microbiologie fondamentale et Pathogénicité, UMR 5234, F-33000 Bordeaux, France.
Julien
J
Izotte
CNRS, Université Bordeaux Segalen, Microbiologie fondamentale et Pathogénicité, UMR 5234, F-33000 Bordeaux, France.
Davita
D
Pillay
CNRS, Université Bordeaux Segalen, Microbiologie fondamentale et Pathogénicité, UMR 5234, F-33000 Bordeaux, France.
Virginie
V
Coustou
Ceva Santé Animale, 10 avenue de la Ballastière, 33500 Libourne, France.
Hamadi
H
Karembe
CNRS, Université Bordeaux Segalen, Microbiologie fondamentale et Pathogénicité, UMR 5234, F-33000 Bordeaux, France. Electronic address: theo.baltz@u-bordeaux2.fr.
Théo
T
Baltz
D000818:Animals; D005260:Female; D007928:Lethal Dose 50; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010617:Phenanthridines / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014348:Trypanosoma congolense / Q000187:drug effects*; D014352:Trypanosomiasis / Q000188:drug therapy
D010617:Phenanthridines; D014344:Trypanocidal Agents; C000702:isometamidium chloride
Drug sensitivity; Isomers; Isometamidium; Trypanosoma