Drugs for Treating Opioid-Induced Constipation: A Mixed Treatment Comparison Network Meta-analysis of Randomized Controlled Clinical Trials

Context

Opioid-induced constipation is a common problem associated with chronic use of opioid analgesics.

Study of the pituitary-thyroid functions at high altitude in man.

The alterations in serum levels of T3, T4, TSH and TBG, TSH response to 100 mug iv TRH, and urinary excretion of T3 and T4 were studied in 8 healthy men at sea level (SL), on days 1, 2, 4, 8 and 16 after arrival by air at high altitude (3,700 m, HA), and during days 5 to 7 after their return to SL. No significant alterations in serum levels of TSH and TBG or TSH response to TRH were observed during exposure to HA or on return to SL. There was, however, an acute elevation in both serum total T3 and T4. Serum total T3 from a mean basal+/-SE value of 128+/-13 ng/dl increased to 320+/-18 on day 1 and remained significantly elevated at 225+/-48 up to day 8 after arrival at high altitude. Similarly serum total T4 increased from basal level of 9+/-0.92 mug/dl to 15.2+/-1.2 and remained elevated till day 16 and it was 11+/-1.19 mug/dl during days 5 to 7 after return to SL. The urinary excretion of both T3 and T4 was decreased. These changes perhaps were the result of complex physiologic adjustments on acute exposure to high altitude, like shrinkage of the T3 and T4 distribution pools, altered binding capacities of thyroid hormones binding proteins, and a reduction in clearance of thyroid hormones from the plasma compartment; and were probably not suggestive of an enhanced thyroid activity. Their actual significance in high altitude adaptation in man is not clearly understood.     

Prostacyclin analogs stimulate receptor-mediated cAMP synthesis and ATP release from rabbit and human erythrocytes

Objectives: The purpose of this study was to establish that the prostacyclin (PGI₂) receptor (IP receptor) is present on rabbit and human erythrocytes and that its activation stimulates cyclic adenosine monophosphate (cAMP) synthesis and adenosine triphosphate (ATP) release. Methods: The effect of incubation of erythrocytes with the active PGI₂ analogs, iloprost or UT‐15C, on cAMP levels and ATP release was determined in the absence and presence of the IP receptor antagonist, CAY10441. Western analysis was used to determine the presence of the IP receptor on isolated membranes. To establish that effects of PGI₂ analogs were not due to prostaglandin E₂(PGE₂) receptor activation, the effect of PGE₂ on cAMP levels and ATP release was determined. Results: Rabbit and human erythrocytes possess IP receptors. Iloprost and UT‐15C stimulated increases in cAMP and ATP release that were prevented by the IP receptor antagonist, CAY10441. PGE₂ did not stimulate cAMP accumulation or ATP release and did not inhibit iloprost‐induced increases in cAMP. Conclusions: This study establishes that the IP receptor is present on rabbit and human erythrocytes and that its activation results in increases in cAMP and ATP release. These results suggest a novel mechanism by which PGI₂ and its active analogs, when administered pharmacologically, could produce vasodilation.     

Effect of various regimens of chronic and acute nicotine exposure on myocardial infarct size in the dog

Smoking is a risk factor for atherosclerotic coronary heart disease, and the risk increases with increasing numbers of cigarettes smoked. The effect of cigarette smoking on the size of acute myocardial infarction (AMI) has not been evaluated. This study describes the effect of 1 component of tobacco smoke, nicotine, on the size of experimentally induced AMI in closed-chest dogs. Daily exposure to nicotine before AMI increased the volume of infarcted tissue (p less than 0.0001). Acute exposure to nicotine (with prior chronic exposure) resulted in a larger volume of infarcted tissue (p less than 0.0001). Thus, chronic, acute and post-AMI exposure to nicotine has an adverse effect on the volume of subsequent infarcted tissue, and continued exposure after AMI further enlarges infarct size.     

TLR2- and Dectin 1–Associated Innate Immune Response Modulates T-Cell Response to Pancreatic β-Cell Antigen and Prevents Type 1 Diabetes

The progression of autoimmune diseases is dictated by deviations in the fine balance between proinflammatory versus regulatory responses, and pathogen recognition receptors (PRRs) play a key role in maintaining this balance. Previously, we have reported that ligation of Toll-like receptor 2 (TLR2) and Dectin 1 on antigen-presenting cells by zymosan results in a regulatory immune response that prevents type 1 diabetes (T1D). Here, we show that TLR2 and Dectin 1 engagement by zymosan promotes regulatory T-cell (Treg) responses against the pancreatic β-cell–specific antigen (Ag). Unlike the TLR4 ligand, bacterial lipopolysaccharide, which induced proinflammatory cytokines and pathogenic T cells, zymosan induced a mixture of pro- and anti-inflammatory factors and Tregs, both in vitro and in vivo. Ag-specific T cells that are activated using zymosan-exposed dendritic cells (DCs) expressed Foxp3 and produced large amounts of IL-10, TGF-β1, and IL-17. NOD mice that received β-cell-Ag–loaded, zymosan-exposed DCs showed delayed hyperglycemia. Injection of NOD mice at the prediabetic age and early hyperglycemic stage with β-cell-Ag, along with zymosan, results in a superior protection of the NOD mice from diabetes as compared with mice that received zymosan alone. This therapeutic effect was associated with increased frequencies of IL-10–, IL-17–, IL-4–, and Foxp3-positive T cells, especially in the pancreatic lymph nodes. These results show that zymosan can be used as an immune regulatory adjuvant for modulating the T-cell response to pancreatic β-cell-Ag and reversing early-stage hyperglycemia in T1D.