RT Journal Article
T1 Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
A1 Sánchez Sánchez, Roberto
A1 Ferré Pérez, Ignacio
A1 Re, Michela Tatiana
A1 Vázquez Arbáizar, María Patricia
A1 Ferrer, Luis Miguel
A1 Blanco Murcia, Francisco Javier
A1 Regidor Cerrillo, Javier
A1 Pizarro Díaz, Manuel
A1 González Huecas, Marta
A1 Tabanera De Lucio, Enrique
A1 García Lunar, Paula
A1 Benavides, Julio
A1 Castaño, Pablo
A1 Hemphill, Andrew
A1 Hulverson, Matthew A.
A1 Whitman, Grant R.
A1 Rivas, Kasey L.
A1 Choi, Ryan
A1 Ojo, Kayode K.
A1 Barrett, Lynn K.
A1 Van Voorhis, Wesley C.
A1 Ortega Mora, Luis Miguel
AB Neospora caninum is one of the main causes of abortion in cattle, and recent studies have highlighted its relevance as an abortifacient in small ruminants. Vaccines or drugs for the control of neosporosis are lacking. 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. We here present the pharmacokinetics, safety and efficacy of BKI-1553 in pregnant ewes and foetuses using a pregnant sheep model of N. caninum infection. BKI-1553 showed exposure in pregnant ewes with trough concentrations of approximately 4 μM, and of 1  μM in foetuses. Subcutaneous BKI-1553 administration increased rectal temperatures shortly after treatment, and resulted in dermal nodules triggering a slight monocytosis after repeated doses at short intervals. BKI-1553 treatment decreased fever in infected pregnant ewes already after two applications, resulted in a 37–50% reduction in foetal mortality, and modulated immune responses; IFNγ levels were increased early after infection and IgG levels were reduced subsequently. N. caninum was abundantly found in placental tissues; however, parasite detection in foetal brain tissue decreased from 94% in the infected/untreated group to 69–71% in the treated groups. In summary, BKI-1553 confers partial protection against abortion in a ruminant experimental model of N. caninum infection during pregnancy. In addition, reduced parasite detection, parasite load and lesions in foetal brains were observed.
PB Elsevier
YR 2018
FD 2018
LK https://hdl.handle.net/20.500.14352/111891
UL https://hdl.handle.net/20.500.14352/111891
LA eng
NO Sánchez-Sánchez, R., Ferre, I., Re, M., Vázquez, P., Ferrer, L. M., Blanco-Murcia, J., Regidor-Cerrillo, J., Pizarro Díaz, M., González-Huecas, M., Tabanera, E., García-Lunar, P., Benavides, J., Castaño, P., Hemphill, A., Hulverson, M. A., Whitman, G. R., Rivas, K. L., Choi, R., Ojo, K. K., Barrett, L. K., … Ortega-Mora, L. M. (2018). Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites. International journal for parasitology. Drugs and drug resistance, 8(1), 112–124. https://doi.org/10.1016/j.ijpddr.2018.02.003
NO JUSTIFICACIÓN DE AUTORES:IF, AH, KO, WVV and LMO conceived the study and participated in its design. RSS wrote the manuscript, with results interpretation and discussion inputs from IF, JRC, AH, MH, KR, LB, WVV and LMO. LMF selected the animals and executed the reproductive programme. PGL and JRC prepared the inocula and performed the infections. RSS, PGL, MR, JBM, MPD, MGH, ET, PC and JB participated in inoculation and clinical examination of animals, performed necropsies and sampling of the animals and performed haematological, biochemical and histopathological analyses. MH, GR, KR, RC, LB, KO and WVV determined the pharmacokinetics of the compound. RSS and PV performed PCR and qPCR analyses, serological assays, statistical analysis and interpreted the results. All authors read and approved the final manuscript.
NO Ministerio de Educación, Cultura y Deporte (España)
NO Ministerio de Economía, Comercio y Empresa (España)
NO Swiss National Science Foundation
NO National Institutes of Health (Estados Unidos)
NO Department of Agriculture (Estados Unidos)
NO Comunidad de Madrid
DS Docta Complutense
RD 2 may 2025