Pharmacokinetics and efficacy of isometamidium chloride against Trypanosoma vivax in cattle

Abstract

We evaluated the pharmacokinetics (pk), preventive efficacy (PE) and therapeutic efficacy (TE) of isometamidium chloride (ISM) against T. vivax. For the pk study, the animals received ISM 1 mg/kg (1 mL/40 kg) on day 0 and plasma samples were collected at day 0 (immediately before treatment), 1 h, 3 h 6 h, 9 h and 12 h after treatment, D + 1 (24 h and 36 h), D + 2 (48 h), D + 7, D + 14, D + 21, D + 28, D + 42, D + 56 and D + 68 post treatment. Plasma samples were analyzed using mass spectrometry coupled to ultra-performance liquid chromatography (UPLC). As result for pk study, the ISM 1 mg/kg reached the highest plasma concentrations 1 h after administration (488.57 ± 208.59 μg/L) and was found in plasma until 24 h. No further detection of ISM in plasma happened beyond 36 h after treatment. For the PE study, twenty-four bovines divided in four groups of six animals each. All groups received ISM 1 mg/kg (1 mL/40 kg) on different days. The T01 group received ISM on day -120, while the T02 animals were treated with ISM on day -90, T03 was treated with ISM on day -60, and the control group (T04) consisted of two animals that received saline solution on day -120, two other animals that received the solution on day -90, and the last two animals that received saline on day -60. In the PE study, the experimental infection with 1 × 106 trypomastigotes of T. vivax of the 24 animals occurred on day 0. Until day 30 after infection, the analysis of T. vivax was performed by the Woo, Brener and cPCR methods, to determine the PE of ISM after 60, 90 and 120 days. As result for the PE study, the PE of ISM against T. vivax was 100 % up to 90 days. For the TE study, 16 animals were experimentally infected with T. vivax trypomastigotes on day -5. On Day 0, the animals were divided into two groups or eight animals each: T01 treated with ISM 0.5 mg/kg (1 mL/80 kg), and T02 treated with saline solution (control). Blood samples after treatment were again analyzed by the Woo, Brener and cPCR methods to determine TE of ISM. Furthermore, in the TE study, to prove that the animals in the treated group were not infected with T. vivax, a biological test was performed on young goats on day +45. As result for the TE study, the TE of ISM 0.5 mg/kg was 100 %, and no young goats were infected. In conclusion, the commercial ISM-based product tested here can be used both preventively and therapeutically against T. vivax. We evaluated the pharmacokinetics (pk), preventive efficacy (PE) and therapeutic efficacy (TE) of isometamidium chloride (ISM) against T. vivax. For the pk study, the animals received ISM 1 mg/kg (1 mL/40 kg) on day 0 and plasma samples were collected at day 0 (immediately before treatment), 1 h, 3 h 6 h, 9 h and 12 h after treatment, D + 1 (24 h and 36 h), D + 2 (48 h), D + 7, D + 14, D + 21, D + 28, D + 42, D + 56 and D + 68 post treatment. Plasma samples were analyzed using mass spectrometry coupled to ultra-performance liquid chromatography (UPLC). As result for pk study, the ISM 1 mg/kg reached the highest plasma concentrations 1 h after administration (488.57 ± 208.59 μg/L) and was found in plasma until 24 h. No further detection of ISM in plasma happened beyond 36 h after treatment. For the PE study, twenty-four bovines divided in four groups of six animals each. All groups received ISM 1 mg/kg (1 mL/40 kg) on different days. The T01 group received ISM on day -120, while the T02 animals were treated with ISM on day -90, T03 was treated with ISM on day -60, and the control group (T04) consisted of two animals that received saline solution on day -120, two other animals that received the solution on day -90, and the last two animals that received saline on day -60. In the PE study, the experimental infection with 1 × 106 trypomastigotes of T. vivax of the 24 animals occurred on day 0. Until day 30 after infection, the analysis of T. vivax was performed by the Woo, Brener and cPCR methods, to determine the PE of ISM after 60, 90 and 120 days. As result for the PE study, the PE of ISM against T. vivax was 100 % up to 90 days. For the TE study, 16 animals were experimentally infected with T. vivax trypomastigotes on day -5. On Day 0, the animals were divided into two groups or eight animals each: T01 treated with ISM 0.5 mg/kg (1 mL/80 kg), and T02 treated with saline solution (control). Blood samples after treatment were again analyzed by the Woo, Brener and cPCR methods to determine TE of ISM. Furthermore, in the TE study, to prove that the animals in the treated group were not infected with T. vivax, a biological test was performed on young goats on day +45. As result for the TE study, the TE of ISM 0.5 mg/kg was 100 %, and no young goats were infected. In conclusion, the commercial ISM-based product tested here can be used both preventively and therapeutically against T. vivax.