Effect of insulin on small intestinal transit in normal mice is independent of blood glucose level

BACKGROUND: Insulin is the drug of choice in the management of diabetes mellitus (DM). About 76 % of diabetic patients suffer from gastrointestinal (GI) disorders. Therapy of DM with insulin primarily involves lowering of elevated blood glucose levels. Hence, on any organ in addition to insulin's effect, hypoglycaemic effect also prevails. A systematic study exploring the effect of insulin on small intestinal transit in normal laboratory animals is lacking. Hence, in the present study, the possible effect of insulin with or without associated hypoglycaemia on small intestinal transit in normal mice was examined. RESULTS: Insulin in all the doses tested (2 μ, 2 m and 2 U/kg) elicited a significant acceleration of SIT. The lower doses of insulin (2 μ and 2 m U/kg) produced significant acceleration of SIT and were associated with normal blood glucose levels. However, the highest dose of insulin (2 U/kg) produced an acceleration of SIT that was associated with significant fall in blood glucose levels. Further, the 2 m and 2 U doses of insulin significantly elevated serum insulin and C-peptide levels. CONCLUSION: Insulin at the lowest dose produced an acceleratory effect on SIT that was independent of blood glucose and serum insulin levels in normal mice

Translational potential of a mouse in vitro bioassay in predicting gastrointestinal adverse drug reactions in Phase I clinical trials.

Motility-related gastrointestinal (GI) adverse drug reactions (GADRs) such as diarrhea and constipation are a common and deleterious feature associated with drug development. Novel biomarkers of GI function are therefore required to aid decision making on the GI liability of compounds in development

The Relationship among Glycemic, Small Intestinal Transit and Insulinemic States in Normal Mice

in levels and SIT was observed in 36 group. At a lower doses of dextrose administration (0.4 and 1 g/kg) no association of BG with SIT was seen, but, when the dose was increased by 4 g/kg an inverse relationship observed with SIT. Similarly with the lower doses of dextrose no association between insulinemic state and SIT was observed. But, when the dose of dextrose increased to 4 g/kg an inverse relationship between serum insulin levels and SIT was observed. It can be concluded from this study that a fall in BG levels or serum insulin levels favours attenuation of SIT from 6-30 h of food deprivation. Normal to moderate glycemic or insulinemic states have no influence on SIT

Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: Results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE

Background: Semuloparin is a novel ultra-low-molecular-weight heparin under development for venous thromboembolism (VTE) prevention in patients at increased risk, such as surgical and cancer patients. Objectives: Three Phase III studies compared semuloparin and enoxaparin after major orthopedic surgery: elective knee replacement (SAVE-KNEE), elective hip replacement (SAVE-HIP1) and hip fracture surgery (SAVE-HIP2). Patients/Methods: All studies were multinational, randomized and double-blind. Semuloparin and enoxaparin were administered for 7-10days after surgery. Mandatory bilateral venography was to be performed between days 7 and 11. The primary efficacy endpoint was a composite of any deep vein thrombosis, non-fatal pulmonary embolism or all-cause death. Safety outcomes included major bleeding, clinically relevant non-major (CRNM) bleeding, and any clinically relevant bleeding (major bleeding plus CRNM). Results: In total, 1150, 2326 and 1003 patients were randomized in SAVE-KNEE, SAVE-HIP1 and SAVE-HIP2, respectively. In all studies, the incidences of the primary efficacy endpoint were numerically lower in the semuloparin group vs. the enoxaparin group, but the difference was statistically significant only in SAVE-HIP1. In SAVE-HIP1, clinically relevant bleeding and major bleeding were significantly lower in the semuloparin vs. the enoxaparin group. In SAVE-KNEE and SAVE-HIP2, clinically relevant bleeding tended to be higher in the semuloparin group, but rates of major bleeding were similar in the two groups. Other safety parameters were generally similar between treatment groups. Conclusions: Semuloparin was superior to enoxaparin for VTE prevention after hip replacement surgery, but failed to demonstrate superiority after knee replacement surgery and hip fracture surgery. Semuloparin and enoxaparin exhibited generally similar safety profiles. \ua9 2012 International Society on Thrombosis and Haemostasis