000070044 001__ 70044
000070044 005__ 20180421140630.0
000070044 0247_ $$2doi$$a10.1016/j.ijpddr.2018.02.003
000070044 0248_ $$2sideral$$a105424
000070044 037__ $$aART-2018-105424
000070044 041__ $$aeng
000070044 100__ $$aSánchez-Sánchez, R.
000070044 245__ $$aSafety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites
000070044 260__ $$c2018
000070044 5060_ $$aAccess copy available to the general public$$fUnrestricted
000070044 5203_ $$aNeospora 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; IFN¿ 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.
000070044 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000070044 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000070044 700__ $$aFerre, I.
000070044 700__ $$aRe, M.
000070044 700__ $$aVázquez, P.
000070044 700__ $$0(orcid)0000-0003-0042-8800$$aFerrer, L.M.$$uUniversidad de Zaragoza
000070044 700__ $$aBlanco-Murcia, J.
000070044 700__ $$aRegidor-Cerrillo, J.
000070044 700__ $$aPizarro Díaz, M.
000070044 700__ $$aGonzález-Huecas, M.
000070044 700__ $$aTabanera, E.
000070044 700__ $$aGarcía-Lunar, P.
000070044 700__ $$aBenavides, J.
000070044 700__ $$aCastaño, P.
000070044 700__ $$aHemphill, A.
000070044 700__ $$aHulverson, M.A.
000070044 700__ $$aWhitman, G.R.
000070044 700__ $$aRivas, K.L.
000070044 700__ $$aChoi, R.
000070044 700__ $$aOjo, K.K.
000070044 700__ $$aBarrett, L.K.
000070044 700__ $$aVan Voorhis, W.C.
000070044 700__ $$aOrtega-Mora, L.M.
000070044 7102_ $$11009$$2617$$aUniversidad de Zaragoza$$bDepartamento de Patología Animal$$cMedicina y Cirugía Animal
000070044 773__ $$g8, 1 (2018), 112-124$$tInternational journal for parasitology, drugs and drug resistance$$x2211-3207
000070044 8564_ $$s433776$$uhttp://zaguan.unizar.es/record/70044/files/texto_completo.pdf$$yVersión publicada
000070044 8564_ $$s93499$$uhttp://zaguan.unizar.es/record/70044/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000070044 909CO $$ooai:zaguan.unizar.es:70044$$particulos$$pdriver
000070044 951__ $$a2018-04-20-14:38:39
000070044 980__ $$aARTICLE