Repurposing strategies for Chagas disease therapy: the effect of imatinib and derivatives against Trypanosoma cruzi.

Chagas disease (CD) is a neglected parasitic condition endemic in the Americas caused by Trypanosoma cruzi. Patients present an acute phase that may or not be symptomatic, followed by lifelong chronic stage, mostly indeterminate, or with cardiac and/or digestive progressive lesions. Benznidazole (BZ) and nifurtimox are the only drugs approved for treatment but not effective in the late chronic phase and many strains of the parasite are naturally resistant. New alternative therapy is required to address this serious public health issue. Repositioning and combination represent faster, and cheaper trial strategies encouraged for neglected diseases. The effect of imatinib (IMB), a tyrosine kinase inhibitor designed for use in neoplasias, was assessed in vitro on T. cruzi and mammalian host cells. In comparison with BZ, IMB was moderately active against different strains and forms of the parasite. The combination IMB + BZ in fixed-ratio proportions was additive. Novel 14 derivatives of IMB were screened and a 3,2-difluoro-2-phenylacetamide (3e) was as potent as BZ on T. cruzi but had low selectivity index. The results demonstrate the importance of phenotypic assays, encourage the improvement of IMB derivatives to reach selectivity and testify to the use of repurposing and combination in drug screening for CD.

Variables associated with the risk of early death after liver transplantation at a liver transplant unit in a university hospital.

BACKGROUND: Graft dysfunction after liver transplantation is a serious complication that can lead to graft loss and patient death. This was a study to identify risk factors for early death (up to 30 days after transplantation). METHODS: It was an observational and retrospective analysis at the Liver Transplantation Unit, Hospital de Clinicas, State University of Campinas, Brazil. From July 1994 to December 2012, 302 patients were included (>18 years old, piggyback technique). Of these cases, 26% died within 30 days. For analysis, Student t tests and chi-square were used to analyze receptor-related (age, body mass index, serum sodium, graft dysfunction, Model for End-Stage Liver Disease score, renal function, and early graft dysfunction [EGD type 1, 2, or 3]), surgery (hot and cold ischemia, surgical time, and units of packed erythrocytes [pRBC]), and donor (age, hypotension, and brain death cause) factors. Risk factors were identified by means of logistic regression model adjusted by the Hosmer-Lemeshow test with significance set at P < .05. RESULTS: We found that hyponatremic recipients had a 6.26-fold higher risk for early death. There was a 9% reduced chance of death when the recipient serum sodium increased 1 unit. The chance of EGD3 to have early death was 18-fold higher than for EGD1 and there was a 13% increased risk for death for each unit of pRBC transfused. CONCLUSIONS: Donor total bilirubin, hyponatremia, massive transfusion, and EGD3 in the allocation graft should be observed for better results in the postoperative period.

Assessment of causes of early death after twenty years of liver transplantation.

BACKGROUND: Postoperative poor graft function is a serious complication that can lead to graft loss requiring retransplantation or even death. The postoperative complications of primary nonfunction (PNF), early graft dysfunction (EGD), bleeding due to coagulopathy, and hepatic artery thrombosis (HAT) can lead to graft loss requiring retransplantation or even death. We determined the causes of death after liver transplantation. METHODS: This was an observational descriptive study on adult liver transplant recipients from September 1991 to December 2011. The cutoff for the definition of death was 30 days after surgery. We included patients older than 18 years of age who underwent liver grafts using the piggyback technique, excluding those who had retransplantations or liver-kidney transplantations. RESULTS: We analyzed 561 liver transplantations through chart review. After application of exclusion criteria we had 81 patients for analysis. Overall mortality was classified into 3 main causes: PNF (34/81; 42%), EGD (10/81; 12%), and abdominal bleeding due to coagulopathy (9/81; 11%). CONCLUSION: Despite advances, mortality in the first 30 days after surgery is still high, mainly related to the occurrence of PNF and EGD, whose causality was associated with red blood cell transfusion (>5 U).