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Título: | Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy |
Autor: | Sánchez Sánchez, R.; Ferre, Ignacio; Re, M.; Ramos, J. J.; Regidor-Cerrillo, Javier; Díaz, M. P.; González-Huecas, M.; Tabanera, E.; Benavides, Julio CSIC ORCID ; Hemphill, A.; Hulverson, M. A.; Barrett, L. K.; Choi, R.; Whitman, G. R.; Ojo, K. K.; Van Voorhis, W. C.; Ortega Mora, Luis M. | Palabras clave: | BKI-1294 Toxoplasma gondii Abortion Protein kinase inhibitor Safety Sheep Treatment Vertical transmission |
Fecha de publicación: | 2019 | Editor: | American Society for Microbiology | Citación: | Antimicrobial Agents and Chemotherapy 63 (2019) | Resumen: | Previous studies on drug efficacy showed low protection against abortion and vertical transmission of Toxoplasma gondii in pregnant sheep. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. Here, we present the safety and efficacy of BKI-1294 treatment (dosed orally at 100 mg/kg of body weight 5 times every 48 h) initiated 48 h after oral infection of sheep at midpregnancy with 1,000 TgShSp1 oocysts. BKI-1294 demonstrated systemic exposure in pregnant ewes, with maximum plasma concentrations of 2 to 3 M and trough concentrations of 0.4 M at 48 h after each dose. Oral administration of BKI-1294 in uninfected sheep at midpregnancy was deemed safe, since there were no changes in behavior, fecal consistency, rectal temperatures, hematological and biochemical parameters, or fetal mortality/morbidity. In ewes infected with a T. gondii oocyst dose lethal for fetuses, BKI-1294 treatment led to a minor rectal temperature increase after infection and a decrease in fetal/lamb mortality of 71%. None of the lambs born alive in the treated group exhibited congenital encephalitis lesions, and vertical transmission was prevented in 53% of them. BKI-1294 treatment during infection led to strong interferon gamma production after cell stimulation in vitro and a low humoral immune response to soluble tachyzoite antigens but high levels of anti-SAG1 antibodies. The results demonstrate a proof of concept for the therapeutic use of BKI-1294 to protect ovine fetuses from T. gondii infection during pregnancy. | Descripción: | 16 páginas, 3 tablas, 6 figuras. | Versión del editor: | http://dx.doi.org/10.1128/AAC.02527-18 | URI: | http://hdl.handle.net/10261/212859 | DOI: | 10.1128/AAC.02527-18 | Identificadores: | doi: 10.1128/AAC.02527-18 issn: 1098-6596 |
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