Safety and efficacy of the bumped kinase inhibitor BKI-1553 in pregnant sheep experimentally infected with Neospora caninum tachyzoites

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; 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

Fit for what?: towards explaining Battlegroup inaction

The thrust of this paper concerns the case of the European Battlegroup (BG) non-deployment in late 2008, when the United Nations requested European military support for the United Nations Organisation Mission peacekeeping force in the Democratic Republic of the Congo (DRC). The argument is built on the fact that when, in official documents, the EU approaches the European security and ESDP/CSDP's military crisis management policy and interventions, it makes strong references to the United Nations and the UN Charter Chapter VII's mandate of restoring international peace and security. Such references make it seem that supporting the UN when it deals with threats and crises is a primary concern of the EU and the member states. These allusions lead to the main contention of this paper, that there is much ambivalence in these indications. The paper develops its argument from one key hypothesis; namely, that the non-deployment of a European BG in the DRC, at the end of 2008, constitutes a useful case study for detecting a number of ambiguities of the EU in respect of its declarations in the official documents establishing the European military crisis management intervention structure

Atrial fibrillation: Prevalence after minimally invasive direct and standard coronary artery bypass

Background. This study identified and compared the prevalence of new-onset atrial fibrillation (AFIB) following standard coronary artery bypass grafting (SCABG) with cardiopulmonary bypass (CPB) and minimally invasive direct vision coronary artery bypass grafting (MIDCAB) without CPB. A further comparison was made between AFIB prevalence in SCABG and MIDCAB subjects with two or fewer bypasses. Methods. This is a retrospective, comparative survey. Patients with new-onset AFIB who underwent SCABG or MIDCAB alone were identified electronically using a triangulated method (International Classification of Diseases, 9th revision, Clinical Modification [ICD-9 CM] code; clinical database word search; and pharmacy database drug search). Results. The total sample (n = 814; 94 MIDCAB, 720 SCABG) exhibited a trend toward lower AFIB prevalence in MIDCAB (23.4%) versus SCABG (33.1%) subjects (p = 0.059). AFIB prevalence in the SCABG subset with two or less vessel bypasses (n = 98; n = 18 single vessel, n = 80 double vessels) and MIDCAB subjects (n = 94; n = 90 single vessels, n = 4 double vessels) was almost identical (SCABG subset 24.5% versus MIDCAB 23.4%, p = 0.860). Slightly more than half (56.9%) of new-onset AFIB subjects were identified by ICD-9 CM codes, with the remainder by word search (37.7%) or procainamide query (5.4%). Conclusions. In this sample, the number of vessels bypassed seemed to have a greater influence on AFIB prevalence than the application of CPB or the surgical approach. Retrospective identification of AFIB cases by ICD-9 CM code grossly underestimated AFIB prevalence. © 2001 by The Society of Thoracic Surgeons

Comparison of Toxicities among Different Bumped Kinase Inhibitor Analogs for Treatment of Cryptosporidiosis

Recent advances on the development of bumped kinase inhibitors for treatment of cryptosporidiosis have focused on the 5-aminopyrazole-4-carboxamide scaffold, due to analogs that have less hERG inhibition, superior efficacy, and strong in vitro safety profiles. Three compounds, BKI-1770, -1841, and -1708, showed strong efficacy in C. parvum infected mice. Both BKI-1770 and BKI-1841 had efficacy in the C. parvum newborn calf model, reducing diarrhea and oocyst excretion. However, both compounds caused hyperflexion of the limbs seen as dropped pasterns. Toxicity experiments in rats and calves dosed with BKI-1770 showed enlargement of the epiphyseal growth plate at doses only slightly higher than the efficacious dose. Mice were used as a screen to check for bone toxicity, by changes to the tibia epiphyseal growth plate, or neurological causes, by use of a locomotor activity box. These results showed neurological effects from both BKI-1770 and BKI-1841 and bone toxicity in mice from BKI-1770, indicating one or both effects may be contributing to toxicity. However, BKI-1708 remains a viable treatment candidate for further evaluation as it showed no signs of bone toxicity or neurological effects in mice. Copyright © 2023 Hulverson et al.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]