Structural Basis for Inhibition Promiscuity of Dual Specific Thrombin and Factor Xa Blood Coagulation Inhibitors

AbstractBackground: A major current focus of pharmaceutical research is the development of selective inhibitors of the blood coagulation enzymes thrombin or factor Xa to be used as orally bioavailable anticoagulant drugs in thromboembolic disorders and in the prevention of venous and arterial thrombosis. Simultaneous direct inhibition of thrombin and factor Xa by synthetic proteinase inhibitors as a novel approach to antithrombotic therapy could result in potent anticoagulants with improved pharmacological properties.Results: The binding mode of such dual specific inhibitors of thrombin and factor Xa was determined for the first time by comparative crystallography using human α-thrombin, human des-Gla (1–44) factor Xa and bovine trypsin as the ligand receptors. The benzamidine-based inhibitors utilize two different conformations for the interaction with thrombin and factor Xa/trypsin, which are evoked by the steric requirements of the topologically different S2 subsites of the enzymes. Compared to the unliganded forms of the proteinases, ligand binding induces conformational adjustments of thrombin and factor Xa active site residues indicative of a pronounced induced fit mechanism.Conclusion: The structural data reveal the molecular basis for a desired unselective inhibition of the two key components of the blood coagulation cascade. The 4-(1-methyl-benzimidazole-2-yl)-methylamino-benzamidine moieties of the inhibitors are able to fill both the small solvent accessible as well as the larger hydrophobic S2 pockets of factor Xa and thrombin, respectively. Distal fragments of the inhibitors are identified which fit into both the cation hole/aromatic box of factor Xa and the hydrophobic aryl binding site of thrombin. Thus, binding constants in the medium-to-low nanomolar range are obtained against both enzymes

Lebensmittelpräferenzen bei Patienten mit gastrointestinalen Tumoren

Inappetenz und Gewichtsverlust sind bei Patienten, die an gastrointestinalen Tumoren erkrankt sind, häufige Symptome. Kenntnisse über Lebensmittelpräferenzen und Ernährungsgewohnheiten bei diesen Patienten sind wichtig für die Betreuung und diätetische Therapie dieser Tumorpatienten. Bei 100 Patienten, die an gastrointestinalen Tumoren (TP) erkrankt waren, untersuchten wir Ernährungsgewohnheiten, Verzehrhäufigkeiten und Lebensmittelpräferenzen mit Hilfe eines Fragebogens. Zusätzlich wurde zur Bestimmung der Körperzusammensetzung Größe, Gewicht, Body Maß Index (BMI), per Anthropometrie Armmuskelmasse (AMA) und Armfettmasse (AFA) und per Bioeletrischer Impedanzanalyse Impedanz Z, Resistanz R, Reaktanz Xc, Phasenwinkel phi und Körperzellmasse (BCM) ermittelt. Die erhobenen Daten wurden mit den Angaben einer gesunden Kontrollgruppe (KG) verglichen. Im Vergleich zur KG wurden Veränderungen zu Gunsten einer leicht verdaulichen Kost, z.B. häufiger Verzehr von Kartoffelpüree, Grießbrei und Tee bzw. Ablehnung von Schmalz, Hülsenfrüchten, Vollkornprodukten, alkoholische oder kohlensäurehaltige Getränke, angegeben. Eine Präferenz eines Lebensmittels durch TP konnte nicht ermittelt werden. TP, die eine Chemotherapie zum Zeitpunkt der Datenerhebung erhielten, bevorzugten kalorienreiche und geschmacksintensive Lebensmittel wie Sahne, Brühe, Salzgebäck und Schokolade. AFA und BCM waren in der TP Gruppe deutlich reduziert, obwohl Gewicht und BMI in TP und KG ähnlich waren. In der Betreuung von TP sollte auf Geschmacksveränderungen geachtet werden, um rechtzeitig eine reduzierte Nahrungsaufnahme zu erkennen. Untersuchungen, inwieweit Veränderungen des Geschmackssinns durch Tumorerkrankung oder Chemotherapie beeinflußt werden, stehen noch aus.Low appetite and weight loss are frequent symptoms in patients with gastrointestinal malignancies (TP). Knowledge about food preferences and nutritional habits of TP are important for the care and treatment of these patients. Nutritional habits, food frequencies and food preferences of 100 patients with gastrointestinal malignancies were analyzed using a questionnaire. To characterize patient’s body composition body size, body weight, body mass index (BMI), arm-muscle-mass (AMA) and arm-fat-mass (AFA) was measured anthropometrically and impedance Z, resistance R, reactance Xc, phase angel phi and body cell mass (BCM) by bioelectrical impedance analysis was determined. All these data were compared to a healthy controlgroup in the same age. Compared to the controlgroup TP ate an easy digestive diet like smashed potatoes, semolina pudding and tea more frequent and avoided lard, legumes, whole-mead products, alcoholic and carbonated drinks. No food preference could be found. TP undergoing cytostatical treatment during the study preferred high caloric and intensive tasting food like cream, broth, salty pastry and chocolate. In TP AFA and BCM were clearly reduced, but no difference in body weight and BMI was detected. Tumorpatients should care for changes in their taste, to detect early symptoms of reduced food intake. Investigations of the influence of cytostatical treatments on taste sensitivity are still needed. Early symptoms of malnutrition can be found using anthropometry and bioelectrical impedance analysis

Suspension Stability of Illinois Soybean Beverage

121 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1977.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD