Determinants of Accelerated Small Intestinal Transit in Alcohol-Related Chronic Pancreatitis

Patients with chronic pancreatitis may have abnormal gastrointestinal transit, but the factors underlying these abnormalities are poorly understood. Gastrointestinal transit was assessed, in 40 male outpatients with alcohol-related chronic pancreatitis and 18 controls, by scintigraphy after a liquid meal labeled with (99m)technetium-phytate. Blood and urinary glucose, fecal fat excretion, nutritional status, and cardiovascular autonomic function were determined in all patients. The influence of diabetes mellitus, malabsorption, malnutrition, and autonomic neuropathy on abnormal gastrointestinal transit was assessed by univariate analysis and Bayesian multiple regression analysis. Accelerated gastrointestinal transit was found in 11 patients who showed abnormally rapid arrival of the meal marker to the cecum. Univariate and Bayesian analysis showed that diabetes mellitus and autonomic neuropathy had significant influences on rapid transit, which was not associated with either malabsorption or malnutrition. In conclusion, rapid gastrointestinal transit in patients with alcohol-related chronic pancreatitis is related to diabetes mellitus and autonomic neuropathy.

Kinetic and Crystallographic Studies on Glyceraldehyde-3-Phosphate Dehydrogenase from Trypanosoma cruzi in Complex with Iodoacetate

Kinetic and crystallographic studies on the formation of the complex between iodoacetate and the enzyme glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi were conducted in order to investigate the mechanistic and structural basis underlying enzyme inactivation. The crystallographic complex reveal important structural features useful for the design of novel inhibitors.

Discovery of novel Trypanosoma cruzi glyceraldehyde-3-phosphate dehydrogenase inhibitors

Based on its essential role in the life cycle of Trypanosoma cruzi, the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been considered a promising target for the development of novel chemotherapeutic agents for the treatment of Chagas` disease. In the course of our research program to discover novel inhibitors of this trypanosomatid enzyme, we have explored a combination of structure and ligand-based virtual screening techniques as a complementary approach to a biochemical screening of natural products using a standard biochemical assay. Seven natural products, including anacardic acids,. avonoid derivatives, and one glucosylxanthone were identified as novel inhibitors of T. cruzi GAPDH. Promiscuous inhibition induced by nonspecific aggregation has been discarded as specific inhibition was not reversed or affected in all cases in the presence of Triton X-100, demonstrating the ability of the assay to find authentic inhibitors of the enzyme. The structural diversity of this series of promising natural products is of special interest in drug design, and should therefore be useful in future medicinal chemistry efforts aimed at the development of new GAPDH inhibitors having increased potency. (C) 2009 Elsevier Ltd. All rights reserved.