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Sample records for once-daily human glucagon-like

  1. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial

    DEFF Research Database (Denmark)

    Madsbad, Sten; Schmitz, Ole; Ranstam, Jonas;

    2004-01-01

    OBJECTIVE: Liraglutide is a long-acting glucagon-like peptide 1 analog designed for once daily injection. This study assessed the efficacy and safety of liraglutide after 12 weeks of treatment in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind, randomized, parallel...

  2. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial

    DEFF Research Database (Denmark)

    Madsbad, Sten; Schmitz, Ole; Ranstam, Jonas

    2004-01-01

    OBJECTIVE: Liraglutide is a long-acting glucagon-like peptide 1 analog designed for once daily injection. This study assessed the efficacy and safety of liraglutide after 12 weeks of treatment in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A double-blind, randomized, parallel...

  3. Bioactivity of a modified human Glucagon-like peptide-1

    Science.gov (United States)

    Xu, Fangfang; Wang, Kevin Yueju; Wang, Nan; Li, Gangqiang; Liu, Dehu

    2017-01-01

    Diabetes has become the third largest cause of death in humans worldwide. Therefore, effective treatment for this disease remains a critical issue. Glucagon-like peptide-1 (GLP-1) plays an important role in glucose homeostasis, and therefore represents a promising candidate to use for the treatment of diabetes. Native GLP-1, however, is quickly degraded in in the circulatory system; which limits its clinical application. In the present study, a chemically-synthesized, modified analogue of human GLP-1 (mGLP-1) was designed. Our analyses indicated that, relative to native GLP-1, mGLP-1 is more resistant to trypsin and pancreatin degradation. mGLP-1 promotes mouse pancreatic β-cell proliferation by up-regulating the expression level of cyclin E, CDK2, Bcl-2 and down-regulating Bax, p21, and stimulates insulin secretion. An oral glucose tolerance test indicated that mGLP-1 significantly improved glucose tolerance in mice. Intraperitoneal injections of mGLP-1 into streptozotocin (STZ)-induced type 2 diabetic mice significantly reduced blood sugar levels and stimulated insulin secretion. Oral gavages of mGLP-1 in diabetic mice did not result in significant hypoglycemic activity. PMID:28152036

  4. Stability of glucagon-like peptide-1 and glucagon in human plasma

    DEFF Research Database (Denmark)

    Albrechtsen, Nicolai Jacob Wewer; Bak, Monika Judyta; Hartmann, Bolette;

    2015-01-01

    To investigate the stability of glucagon-like peptide-1(GLP-1) and glucagon in plasma under short- and long-term storage conditions. Methods: Pooled human plasma (n=20), to which a dipeptidyl peptidase 4 (DPP-4) inhibitor and aprotinin were added, was spiked with synthetic GLP-1 (intact, 7-36NH2 ...

  5. Amyloidogenicity and aggregate cytotoxicity of human glucagon-like peptide-1 (hGLP-1).

    Science.gov (United States)

    Poon, S; Birkett, N R; Fowler, S B; Luisi, B F; Dobson, C M; Zurdo, J

    2009-01-01

    The potential of human glucagon-like peptide-1 (hGLP-1) as a therapeutic agent is limited by its high aggregation propensity. We show that hGLP-1 forms amyloid-like structures that are preceded by cytotoxic aggregates, suggesting that aggregation of biopharmaceuticals could present a cytotoxic risk to patients besides the reported increased risk in immunogenicity.

  6. Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children.

    NARCIS (Netherlands)

    LePrevost, M.; Green, H.; Flynn, J.; Head, S.; Clapson, M.; Lyall, H.; Novelli, V.; Farrelly, L.; Walker, A.S.; Burger, D.M.; Gibb, D.

    2006-01-01

    BACKGROUND: Data on adherence to and acceptability of once daily lamivudine and abacavir are few. METHODS: Twenty-four U.K. human immunodeficiency virus type-1 infected children 2-13 years of age participated in the Pediatric European Network for the Treatment of AIDS (PENTA) 13 single arm, open lab

  7. Overnight hypoxic exposure and glucagon-like peptide-1 and leptin levels in humans

    DEFF Research Database (Denmark)

    Snyder, Eric M; Carr, Richard D; Deacon, Carolyn F

    2008-01-01

    Altitude exposure has been associated with loss of appetite and weight loss in healthy humans; however, the endocrine factors that contribute to these changes remain unclear. Leptin and glucagon-like peptide-1 (GLP-1) are peptide hormones that contribute to the regulation of appetite. Leptin...... increases with hypoxia; however, the influence of hypoxia on GLP-1 has not been studied in animals or humans to date. We sought to determine the influence of normobaric hypoxia on plasma leptin and GLP-1 levels in 25 healthy humans. Subjects ingested a control meal during normoxia and after 17 h of exposure...... to normobaric hypoxia (fraction of inspired oxygen of 12.5%, simulating approximately 4100 m). Plasma leptin was assessed before the meal, and GLP-1 was assessed premeal, at 20 min postmeal, and at 40 min postmeal. We found that hypoxia caused a significant elevation in plasma leptin levels (normoxia, 4.9 +/- 0...

  8. Glucagon-like peptide-1 activates endothelial nitric oxide synthase in human umbilical vein endothelial cells

    Institute of Scientific and Technical Information of China (English)

    Li DING; Jin ZHANG

    2012-01-01

    To investigate the effects of glucagon-like peptide-1 (GLP-1) on endothelial NO synthase (eNOS) in human umbilical vein endothelial cells (HUVECs),and elucidate whether GLP-1 receptor (GLP-1R) and GLP-1(9-36) are involved in these effects.Methods:HUVECs were used.The activity of eNOS was measured with NOS assay kit.Phosphorylated and total eNOS proteins were detected using Western blot analysis.The level of eNOS mRNA was quantified with real-time RT-PCR.Results:Incubation of HUVECs with GLP-1 (50-5000 pmol/L) for 30 min significantly increased the activity of eNOS.Incubation of HUVECs with GLP-1 (500-5000 pmol/L) for 5 or 10 min increased eNOS phosphorylated at ser-1177.Incubation with GLP-1 (5000 pmol/L) for 48 h elevated the level of eNOS protein,did not affect the level of eNOS mRNA.GLP-1R agonists exenatide and GLP-1(9-36) at the concentration of 5000 pmol/L increased the activity,phosphorylation and protein level of eNOS.GLP-1R antagonist exendin(9-39) or DPP-4 inhibitor sitagliptin,which abolished GLP-1(9-36) formation,at the concentration of 5000 pmol/L partially blocked the effects of GLP-1 on eNOS.Conclusion:GLP-1 upregulated the activity and protein expression of eNOS in HUVECs through the GLP-1R-dependent and GLP-1(9-36)-related pathways.GLP-1 may prevent or delay the formation of atherosclerosis in diabetes mellitus by improving the function of eNOS.

  9. Stability of glucagon-like peptide 1 and glucagon in human plasma

    Science.gov (United States)

    Wewer Albrechtsen, Nicolai J; Bak, Monika J; Hartmann, Bolette; Christensen, Louise Wulff; Kuhre, Rune E; Deacon, Carolyn F; Holst, Jens J

    2015-01-01

    To investigate the stability of glucagon-like peptide 1 (GLP-1) and glucagon in plasma under short- and long-term storage conditions. Pooled human plasma (n=20), to which a dipeptidyl peptidase 4 (DPP4) inhibitor and aprotinin were added, was spiked with synthetic GLP-1 (intact, 7–36NH2 as well as the primary metabolite, GLP-1 9–36NH2) or glucagon. Peptide recoveries were measured in samples kept for 1 and 3 h at room temperature or on ice, treated with various enzyme inhibitors, after up to three thawing–refreezing cycles, and after storage at −20 and −80 °C for up to 1 year. Recoveries were unaffected by freezing cycles or if plasma was stored on ice for up to 3 h, but were impaired when samples stood at RT for more than 1 h. Recovery of intact GLP-1 increased by addition of a DPP4 inhibitor (no ice), but was not further improved by neutral endopeptidase 24.11 inhibitor or an inhibitor cocktail. GLP-1, but not glucagon, was stable for at least 1 year. Surprisingly, the recovery of glucagon was reduced by almost 50% by freezing compared with immediate analysis, regardless of storage time. Plasma handling procedures can significantly influence results of subsequent hormone analysis. Our data support addition of DPP4 inhibitor for GLP-1 measurement as well as cooling on ice of both GLP-1 and glucagon. Freeze–thaw cycles did not significantly affect stability of GLP-1 or glucagon. Long-term storage may affect glucagon levels regardless of storage temperature and results should be interpreted with caution. PMID:25596009

  10. Glucagon-like peptide-2 increases mesenteric blood flow in humans

    DEFF Research Database (Denmark)

    Bremholm, Lasse; Hornum, Mads; Henriksen, Birthe Merete;

    2008-01-01

    OBJECTIVE: Mesenteric blood flow is believed to be influenced by digestion and absorption of ingested macronutrients. We hypothesized that the intestinotrophic hormone, GLP-2 (glucagons-like peptide 2), may be involved in the regulation of mesenteric blood flow. Changes in mesenteric blood flow...... were measured by Doppler ultrasound scanning of the superior mesenteric artery (SMA). The aim of the study was to demonstrate the influence of GLP-2 on this flow, expressed as changes in resistance index (RI). MATERIAL AND METHODS: A homogeneous group of 10 fasting healthy volunteers completed a 2-day...... support the hypothesis that GLP-2 is an important regulator of mesenteric blood flow....

  11. Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects

    DEFF Research Database (Denmark)

    Näslund, Erik; King, N; Mansten, S

    2004-01-01

    Recombinant glucagon-like peptide-1 (7-36)amide (rGLP-1) was recently shown to cause significant weight loss in type 2 diabetics when administered for 6 weeks as a continuous subcutaneous infusion. The mechanisms responsible for the weight loss are not clarified. In the present study, rGLP-1.......05) was registered after 5 d with PSI of rGLP-1. Gastric emptying rate was reduced during both PSI (Pmore rapidly and to a greater extent with PSI of rGLP-1. To conclude, a 5 d treatment of rGLP-1 at high doses by PSI, but not CSI, promptly slowed gastric emptying...... as a probable mechanism of action of increased satiety, decreased hunger and, hence, reduced food intake with an ensuing weight loss....

  12. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial

    DEFF Research Database (Denmark)

    Madsbad, Sten; Schmitz, Ole; Ranstam, Jonas

    2004-01-01

    -group, placebo-controlled trial with an open-label comparator arm was conducted among 193 outpatients with type 2 diabetes. The mean age was 56.6 years and the mean HbA(1c) was 7.6% across the treatment groups. Patients were randomly assigned to one of five fixed-dosage groups of liraglutide (0.045, 0.225, 0....... Patients treated with glimepiride had decreased HbA(1c) and fasting glucose, but slightly increased body weight. No safety issues were raised for liraglutide; observed adverse events were mild and transient. CONCLUSIONS: A once-daily dose of liraglutide provides efficacious glycemic control...

  13. Carboxypeptidase-B-like processing of the C-terminus of glucagon-like peptide-2 in pig and human small intestine

    DEFF Research Database (Denmark)

    Orskov, C; Buhl, T; Rabenhøj, L

    1989-01-01

    no mutual cross-reactivity. By gel filtration of extracts of pig and human small intestine, the immunoreactivity eluting at the position of GLP-2 was identified by the radioimmunoassays for glucagon-like peptide-2 (PG 126-159) and for PG 151-158, whereas the assay for PG 151-160 was completely negative. We...

  14. The glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans

    DEFF Research Database (Denmark)

    Meier, Juris J; Gethmann, Arnica; Nauck, Michael A;

    2006-01-01

    Glucagon-like peptide 1 (GLP-1) lowers glycemia by modulating gastric emptying and endocrine pancreatic secretion. Rapidly after its secretion, GLP-1-(7-36) amide is degraded to the metabolite GLP-1-(9-36) amide. The effects of GLP-1-(9-36) amide in humans are less well characterized. Fourteen he...

  15. Differentiating effects of the glucagon-like peptide-1 analogue exendin-4 in a human neuronal cell model.

    Science.gov (United States)

    Luciani, Paola; Deledda, Cristiana; Benvenuti, Susanna; Cellai, Ilaria; Squecco, Roberta; Monici, Monica; Cialdai, Francesca; Luciani, Giorgia; Danza, Giovanna; Di Stefano, Chiara; Francini, Fabio; Peri, Alessandro

    2010-11-01

    Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptide with neurotrophic properties, as assessed in animal cell models. Exendin-4, a GLP-1 analogue, has been recently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to morphologically, structurally, and functionally characterize the differentiating actions of exendin-4 using a human neuronal cell model (i.e., SH-SY5Y cells). We found that exendin-4 increased the number of neurites paralleled by dramatic changes in intracellular actin and tubulin distribution. Electrophysiological analyses showed an increase in cell membrane surface and in stretch-activated-channels sensitivity, an increased conductance of Na(+) channels and amplitude of Ca(++) currents (T- and L-type), typical of a more mature neuronal phenotype. To our knowledge, this is the first demonstration that exendin-4 promotes neuronal differentiation in human cells. Noteworthy, our data support the claimed favorable role of exendin-4 against diabetic neuropathy as well as against different neurodegenerative diseases.

  16. Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation.

    Science.gov (United States)

    Shiraishi, Daisuke; Fujiwara, Yukio; Komohara, Yoshihiro; Mizuta, Hiroshi; Takeya, Motohiro

    2012-08-24

    It is known that glucagon-like peptide-1 (GLP-1) is a hormone secreted postprandially from the L-cells of the small intestine and regulates glucose homeostasis. GLP-1 is now used for the treatment of diabetes because of its beneficial role against insulin resistance. The GLP-1 receptor (GLP-1R) is expressed on many cell types, including macrophages, and GLP-1 suppresses the development of atherosclerosis by inhibiting macrophage function. However, there have so far been few studies that have investigated the significance of GLP-1/GLP-1R signaling in macrophage activation. In the present study, we examined the effect of GLP-1 and exenatide, a GLP-1R agonist, on human monocyte-derived macrophage (HMDM) activation. We found that GLP-1 induced signal transducer and activator of transcription 3 (STAT3) activation. Silencing of GLP-1R suppressed the GLP-1-induced STAT3 activation. In addition, alternatively activated (M2) macrophage-related molecules, such as IL-10, CD163, and CD204 in HMDM, were significantly upregulated by GLP-1. Furthermore, the co-culture of 3T3-L1 adipocytes with GLP-1-treated RAW 264.7 macrophages increased the secretion of adiponectin compared to co-culture of the 3T3-L1 adipocytes with untreated RAW 264.7 macrophages. Our results demonstrate that GLP-1 induces macrophage polarization toward the M2 phenotype, which may contribute to the protective effects of GLP-1 against diabetes and cardiovascular diseases.

  17. Hyperglycemia acutely lowers the postprandial excursions of glucagon-like Peptide-1 and gastric inhibitory polypeptide in humans

    DEFF Research Database (Denmark)

    Vollmer, Kirsten; Gardiwal, Husai; Menge, Bjoern A;

    2009-01-01

    INTRODUCTION: Impaired secretion of glucagon-like peptide 1 (GLP-1) has been suggested to contribute to the deficient incretin effect in patients with type 2 diabetes. It is unclear whether this is a primary defect or a consequence of the hyperglycemia in type 2 diabetes. We examined whether acut...

  18. Exenatide, a Glucagon-like Peptide-1 Receptor Agonist, Acutely Inhibits Intestinal Lipoprotein Production in Healthy Humans

    NARCIS (Netherlands)

    Xiao, Changting; Bandsma, Robert H. J.; Dash, Satya; Szeto, Linda; Lewis, Gary F.

    Objective-Incretin-based therapies for the treatment of type 2 diabetes mellitus improve plasma lipid profiles and postprandial lipemia, but their exact mechanism of action remains unclear. Here, we examined the acute effect of the glucagon-like peptide-1 receptor agonist, exenatide, on intestinal

  19. Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia

    DEFF Research Database (Denmark)

    Green, Charlotte J; Henriksen, Tora I; Pedersen, Bente K;

    2012-01-01

    Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent......, the glucose-dependency of its extra-pancreatic effects has not been examined....

  20. Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist Stimulates Insulin Secretion in Rodents and From Human Islets

    Science.gov (United States)

    Sloop, Kyle W.; Willard, Francis S.; Brenner, Martin B.; Ficorilli, James; Valasek, Kathleen; Showalter, Aaron D.; Farb, Thomas B.; Cao, Julia X.C.; Cox, Amy L.; Michael, M. Dodson; Gutierrez Sanfeliciano, Sonia Maria; Tebbe, Mark J.; Coghlan, Michael J.

    2010-01-01

    OBJECTIVE The clinical effectiveness of parenterally-administered glucagon-like peptide-1 (GLP-1) mimetics to improve glucose control in patients suffering from type 2 diabetes strongly supports discovery pursuits aimed at identifying and developing orally active, small molecule GLP-1 receptor agonists. The purpose of these studies was to identify and characterize novel nonpeptide agonists of the GLP-1 receptor. RESEARCH DESIGN AND METHODS Screening using cells expressing the GLP-1 receptor and insulin secretion assays with rodent and human islets were used to identify novel molecules. The intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp characterized the insulinotropic effects of compounds in vivo. RESULTS Novel low molecular weight pyrimidine-based compounds that activate the GLP-1 receptor and stimulate glucose-dependent insulin secretion are described. These molecules induce GLP-1 receptor-mediated cAMP signaling in HEK293 cells expressing the GLP-1 receptor and increase insulin secretion from rodent islets in a dose-dependent manner. The compounds activate GLP-1 receptor signaling, both alone or in an additive fashion when combined with the endogenous GLP-1 peptide; however, these agonists do not compete with radiolabeled GLP-1 in receptor-binding assays. In vivo studies using the IVGTT and the hyperglycemic clamp in Sprague Dawley rats demonstrate increased insulin secretion in compound-treated animals. Further, perifusion assays with human islets isolated from a donor with type 2 diabetes show near-normalization of insulin secretion upon compound treatment. CONCLUSIONS These studies characterize the insulinotropic effects of an early-stage, small molecule GLP-1 receptor agonist and provide compelling evidence to support pharmaceutical optimization. PMID:20823098

  1. The role of glucagon-like peptide 1 in glucose homeostasis and in other aspects of human physiology.

    Science.gov (United States)

    Franek, Edward; Gajos, Grzegorz; Gumprecht, Janusz; Kretowski, Adam; Zahorska-Markiewicz, Barbara; Małecki, Maciej T

    2009-11-01

    This paper reviews the structure, function, and pathophysiology of glucagon-like peptide 1 (GLP-1). It describes the physiology and pathophysiology of the incretin axis, of which GLP-1 is a component, as well as the biosynthesis, secretion, activity, and degradation of this intestinal hormone. Effects of GLP-1 on the endocrine function of the pancreas, cardiovascular system, central nervous system, and on water-electrolyte balance have been also presented.

  2. Glucagon like peptide-1-induced glucose metabolism in differentiated human muscle satellite cells is attenuated by hyperglycemia.

    Directory of Open Access Journals (Sweden)

    Charlotte J Green

    Full Text Available BACKGROUND: Glucagon like peptide-1 (GLP-1 stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined. METHODS: Skeletal muscle satellite cells isolated from young (22.5 ± 0.97 yr, lean (BMI 22.5 ± 0.6 kg/m(2, healthy males were differentiated in media containing either 22.5 mM (high or 5 mM (normal glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis. RESULTS: We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes. Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia. CONCLUSIONS: GLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation

  3. Glucagon-like peptide-1

    DEFF Research Database (Denmark)

    Deacon, C F; Holst, Jens Juul; Carr, R D

    1999-01-01

    Type 2 diabetes mellitus is a metabolic disease resulting in raised blood sugar which, if not satisfactorily controlled, can cause severe and often debilitating complications. Unfortunately, for many patients, the existing therapies do not give adequate control. Glucagon-like peptide-1 (GLP-1) is...

  4. Glucagon-like peptide-1

    DEFF Research Database (Denmark)

    Holst, Jens Juul

    2006-01-01

    The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal...

  5. Assessment of analgesia in human chronic pain. Randomized double-blind crossover study of once daily repro-dose morphine versus MST continus.

    Science.gov (United States)

    Peat, S; Sweet, P; Miah, Y; Barklamb, M; Larsen, U

    1999-10-01

    This study evaluated Repro-Dose morphine (RDM; Reliadol from Nycomed Pharma), a new once daily controlled-release morphine formulation, against twice daily MST Continuous (MST) at steady state in patients with chronic opioid responsive pain. A randomized double-blind two-way crossover design was used to evaluate the efficacy and adverse effects of RDM once daily or MST twice daily, at the same total daily doses, in patients with chronic stable pain (dose range 20-120 mg per day). During the RDM limb of the study active drug was administered in the evening and placebo in the morning. Dextromoramide was provided as escape analgesia throughout the study. Following a 5-day screening period, during which stability of oral opioid dose was verified, patients underwent two 5-day treatment periods, (one MST, one RDM) in random sequence. Pain scores, escape analgesia requirements and side-effects were compared using data from days 3, 4 and 5 of each treatment period. Any events or medication changes occurring during the study period thought liable to influence analgesia were regarded as protocol violations. Overall assessment and period preference was assessed by direct questioning. RDM treatment was regarded as successful if the amount of escape medication required during the RDM period was equal to or less than that required during the MST period. Forty-seven patients were included in the study, of whom 40 completed both periods [the intention to treat (ITT) population], 31 in strict accordance with the protocol [the per protocol (PP) population]. Results were similar for both populations. There was no significant difference in pain scores or incidence of adverse events occurring during the MST and RDM periods. For the ITT population, requirements for escape medication during the RDM period were less than, equal to or greater than those recorded during the MST period for 14, 15, and 11 patients, respectively. Twenty-nine of 40 patients (72.5%) were therefore RDM treatment

  6. PGC-1beta is downregulated by training in human skeletal muscle: no effect of training twice every second day vs. once daily on expression of the PGC-1 family

    DEFF Research Database (Denmark)

    Mortensen, Ole Hartvig; Plomgaard, Peter; Fischer, Christian P;

    2007-01-01

    be observed in the acute response to endurance exercise. Furthermore, we hypothesized that expression levels of the PGC-1 family differ with muscular fiber-type composition. Thus, before and after 10 wk of knee extensor endurance training, training one leg once daily and the other leg twice daily every second...... endurance training, whereas PGC-1beta did not change. The mRNA levels of the PGC-1 family were examined in different types of human skeletal muscle (triceps, soleus, and vastus lateralis; n = 7). Only the expression level of PGC-1beta differed and correlated inversely with percentage of type I fibers......We hypothesized that the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) family of transcriptional coactivators (PGC-1alpha, PGC-1beta, and PRC) is differentially regulated by training once daily vs. training twice daily every second day and that this difference might...

  7. Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina

    2007-01-01

    The incretin hormones are intestinal peptides that enhance insulin secretion following ingestion of nutrients. Liraglutide is a glucagon-like peptide-1 receptor analogue, which is obtained by derivatising glucagon-like peptide-1 with a fatty acid, providing a compound with pharmacokinetic propert...... transient nausea and diarrhoea. This article reviews the mechanisms of action and efficacy of liraglutide for the treatment of Type 2 diabetes mellitus. This agent is presently in Phase III clinical development....... properties that are suitable for once-daily dosing. Liraglutide has demonstrated lasting improvement of HbA(1c )levels, weight reduction and improved beta-cell function in patients with Type 2 diabetes mellitus. Liraglutide is well tolerated; the adverse events that are most frequently reported being...

  8. Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans

    DEFF Research Database (Denmark)

    Orskov, C; Rabenhøj, L; Wettergren, A

    1994-01-01

    plasma were 7 +/- 1 and 6 +/- 1 pM, respectively (n = 6). In response to a breakfast meal, the concentration of amidated GLP-I rose significantly amounting to 41 +/- 5 pM 90 min after the meal ingestion, whereas the concentration of glycine-extended GLP-I only rose slightly to a maximum of 10 +/- 1 p......M. Thus, both amidated and glycine-extended GLP-I molecules are produced in the small intestine and in the pancreas in humans. Both amidated and glycine-extended GLP-I are measurable in fasting plasma.(ABSTRACT TRUNCATED AT 250 WORDS)...

  9. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans

    NARCIS (Netherlands)

    van Bloemendaal, L.; Veltman, D. J.; ten Kulve, J. S.; Groot, P. F. C.; Ruhe, H. G.; Barkhof, F.; Sloan, J. H.; Diamant, M.; Ijzerman, R. G.

    2015-01-01

    AimTo test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. MethodsAs part of a larger study, we determined the effects of GLP-1 receptor activation on brain respo

  10. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans

    NARCIS (Netherlands)

    van Bloemendaal, L.; Veltman, D. J.; ten Kulve, J. S.; Groot, P. F. C.; Ruhe, H. G.; Barkhof, F.; Sloan, J. H.; Diamant, M.; Ijzerman, R. G.

    2015-01-01

    AimTo test the hypothesis that food intake reduction after glucagon-like peptide-1 (GLP-1) receptor activation is mediated through brain areas regulating anticipatory and consummatory food reward. MethodsAs part of a larger study, we determined the effects of GLP-1 receptor activation on brain respo

  11. Expression of cholecystokinin2-receptor in rat and human L cells and the stimulation of glucagon-like peptide-1 secretion by gastrin treatment.

    Science.gov (United States)

    Cao, Yang; Cao, Xun; Liu, Xiao-Min

    2015-03-01

    Gastrin is a gastrointestinal hormone secreted by G cells. Hypergastrinemia can improve blood glucose and glycosylated hemoglobin levels. These positive effects are primarily due to the trophic effects of gastrin on β-cells. In recent years, many receptors that regulate secretion of glucagon-like peptide 1 (GLP-1) have been identified in enteroendocrine L cell lines. This led us to hypothesize that, in addition to the trophic effects of gastrin on β-cells, L cells also express cholecystokinin2-receptor (CCK2R), which may regulate GLP-1 secretion and have synergistic effects on glucose homeostasis. Our research provides a preliminary analysis of CCK2R expression and the stimulating effect of gastrin treatment on GLP-1 secretion in a human endocrine L cell line, using RT-PCR, Western blot, immunocytochemistry, and ELISA analyses. The expression of proglucagon and prohormone convertase 3, which regulate GLP-1 biosynthesis, were also analyzed by real-time PCR. Double immunofluorescence labeling was utilized to assess the intracellular localization of CCK2R and GLP-1 in L cells harvested from rat colon tissue. Our results showed that CCK2R was expressed in both the human L cell line and the rat L cells. We also showed that treatment with gastrin, a CCK2R agonist, stimulated the secretion of GLP-1, and that this effect was likely due to increased expression of proglucagon and PCSK1 (also known as prohormone convertase 3 (PC3 gene)). These results not only provide a basis for the role gastrin may play in intestinal L cells, and may also provide the basis for the development of a method of gastrin-mediated glycemic regulation.

  12. PGC-1beta is downregulated by training in human skeletal muscle: no effect of training twice every second day vs. once daily on expression of the PGC-1 family.

    Science.gov (United States)

    Mortensen, Ole Hartvig; Plomgaard, Peter; Fischer, Christian P; Hansen, Anne K; Pilegaard, Henriette; Pedersen, Bente Klarlund

    2007-11-01

    We hypothesized that the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) family of transcriptional coactivators (PGC-1alpha, PGC-1beta, and PRC) is differentially regulated by training once daily vs. training twice daily every second day and that this difference might be observed in the acute response to endurance exercise. Furthermore, we hypothesized that expression levels of the PGC-1 family differ with muscular fiber-type composition. Thus, before and after 10 wk of knee extensor endurance training, training one leg once daily and the other leg twice daily every second day, keeping the total amount of training for the legs equal, skeletal muscle mRNA expression levels of PGC-1alpha, PGC-1beta, and PRC were determined in young healthy men (n = 7) in response to 3 h of acute exercise. No significant difference was found between the two legs, suggesting that regulation of the PGC-1 family is independent of training protocol. Training decreased PGC-1beta in both legs, whereas PGC-1alpha was increased, but not significantly, in the leg training once daily. PRC did not change with training. Both PGC-1alpha and PRC were increased by acute exercise both before and after endurance training, whereas PGC-1beta did not change. The mRNA levels of the PGC-1 family were examined in different types of human skeletal muscle (triceps, soleus, and vastus lateralis; n = 7). Only the expression level of PGC-1beta differed and correlated inversely with percentage of type I fibers. In conclusion, there was no difference between training protocols on the acute exercise and training response of the PGC-1 family. However, training caused a decrease in PGC-1beta mRNA levels.

  13. Treatment with the human once-weekly glucagon-like peptide-1 analog taspoglutide in combination with metformin improves glycemic control and lowers body weight in patients with type 2 diabetes inadequately controlled with metformin alone: a double-blind placebo-controlled study

    National Research Council Canada - National Science Library

    Nauck, Michael A; Ratner, Robert E; Kapitza, Christoph; Berria, Rachele; Boldrin, Mark; Balena, Raffaella

    2009-01-01

    To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inadequately controlled with metformin. Type 2 diabetic (n = 306...

  14. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis.

    LENUS (Irish Health Repository)

    Hogan, A E

    2011-11-01

    The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells.

  15. Glucagon-Like Peptide-1 Gene Therapy

    Directory of Open Access Journals (Sweden)

    Anne M. Rowzee

    2011-01-01

    Full Text Available Glucagon-like peptide 1 (GLP-1 is a small peptide component of the prohormone, proglucagon, that is produced in the gut. Exendin-4, a GLP-1 receptor agonist originally isolated from the saliva of H. suspectum or Gila monster, is a peptide that shares sequence and functional homology with GLP-1. Both peptides have been demonstrated to stimulate insulin secretion, inhibit glucagon secretion, promote satiety and slow gastric emptying. As such, GLP-1 and Exendin-4 have become attractive pharmaceutical targets as an adjunctive therapy for individuals with type II diabetes mellitus, with several products currently available clinically. Herein we summarize the cell biology leading to GLP-1 production and secretion from intestinal L-cells and the endocrine functions of this peptide and Exendin-4 in humans. Additionally, gene therapeutic applications of GLP-1 and Exendin-4 are discussed with a focus on recent work using the salivary gland as a gene therapy target organ for the treatment of diabetes mellitus.

  16. Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients▿

    Science.gov (United States)

    Marin-Niebla, Ana; Lopez-Cortes, Luis Fernando; Ruiz-Valderas, Rosa; Viciana, Pompeyo; Mata, Rosario; Gutierrez, Alicia; Pascual, Rosario; Rodriguez, Magdalena

    2007-01-01

    We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/μl, and the median VL was 4.8 log10 copies/ml. Median Cmax, area under the concentration-time curve from 0 to 24 h, and Cmin plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng·h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate Cmin levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI

  17. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide.

    Science.gov (United States)

    Lau, Jesper; Bloch, Paw; Schäffer, Lauge; Pettersson, Ingrid; Spetzler, Jane; Kofoed, Jacob; Madsen, Kjeld; Knudsen, Lotte Bjerre; McGuire, James; Steensgaard, Dorte Bjerre; Strauss, Holger Martin; Gram, Dorte X; Knudsen, Sanne Møller; Nielsen, Flemming Seier; Thygesen, Peter; Reedtz-Runge, Steffen; Kruse, Thomas

    2015-09-24

    Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue that binds to serum albumin in vivo and is approved for once-daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once weekly GLP-1 analogue by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analogue. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib(8), Arg(34)) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 ± 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clinical testing.

  18. Second extracellular loop of human glucagon-like peptide-1 receptor (GLP-1R) has a critical role in GLP-1 peptide binding and receptor activation.

    Science.gov (United States)

    Koole, Cassandra; Wootten, Denise; Simms, John; Miller, Laurence J; Christopoulos, Arthur; Sexton, Patrick M

    2012-02-03

    The glucagon-like peptide-1 receptor (GLP-1R) is a therapeutically important family B G protein-coupled receptor (GPCR) that is pleiotropically coupled to multiple signaling effectors and, with actions including regulation of insulin biosynthesis and secretion, is one of the key targets in the management of type II diabetes mellitus. However, there is limited understanding of the role of the receptor core in orthosteric ligand binding and biological activity. To assess involvement of the extracellular loop (ECL) 2 in ligand-receptor interactions and receptor activation, we performed alanine scanning mutagenesis of loop residues and assessed the impact on receptor expression and GLP-1(1-36)-NH(2) or GLP-1(7-36)-NH(2) binding and activation of three physiologically relevant signaling pathways as follows: cAMP formation, intracellular Ca(2+) (Ca(2+)(i)) mobilization, and phosphorylation of extracellular signal-regulated kinases 1 and 2 (pERK1/2). Although antagonist peptide binding was unaltered, almost all mutations affected GLP-1 peptide agonist binding and/or coupling efficacy, indicating an important role in receptor activation. However, mutation of several residues displayed distinct pathway responses with respect to wild type receptor, including Arg-299 and Tyr-305, where mutation significantly enhanced both GLP-1(1-36)-NH(2)- and GLP-1(7-36)-NH(2)-mediated signaling bias for pERK1/2. In addition, mutation of Cys-296, Trp-297, Asn-300, Asn-302, and Leu-307 significantly increased GLP-1(7-36)-NH(2)-mediated signaling bias toward pERK1/2. Of all mutants studied, only mutation of Trp-306 to alanine abolished all biological activity. These data suggest a critical role of ECL2 of the GLP-1R in the activation transition(s) of the receptor and the importance of this region in the determination of both GLP-1 peptide- and pathway-specific effects.

  19. Intracerebroventricular injection of encapsulated human mesenchymal cells producing glucagon-like peptide 1 prolongs survival in a mouse model of ALS.

    Directory of Open Access Journals (Sweden)

    Sarah Knippenberg

    Full Text Available BACKGROUND: As pharmacological therapies have largely failed so far, stem cell therapy has recently come into the focus of ALS research. Neuroprotective potential was shown for several types of stem and progenitor cells, mainly due to release of trophic factors. In the present study, we assessed the effects of intracerebroventricular injection of glucagon-like peptide 1 (GLP-1 releasing mesenchymal stromal cells (MSC in mutant SOD1 (G93A transgenic mice. METHODOLOGY/PRINCIPAL FINDINGS: To improve the neuroprotective effects of native MSC, they had been transfected with a plasmid vector encoding a GLP-1 fusion gene prior to the injection, as GLP-1 was shown to exhibit neuroprotective properties before. Cells were encapsulated and therefore protected against rejection. After intracerebroventricular injection of these GLP-1 MSC capsules in presymptomatic SOD1 (G93A mice, we assessed possible protective effects by survival analysis, measurement of body weight, daily monitoring and evaluation of motor performance by rotarod and footprint analyses. Motor neuron numbers in the spinal cord as well as the amount of astrocytosis, microglial activation, heat shock response and neuronal nitric oxide synthase (nNOS expression were analyzed by immunohistological methods. Treatment with GLP-1 producing MSC capsules significantly prolonged survival by 13 days, delayed symptom onset by 15 days and weight loss by 14 days and led to significant improvements in motor performance tests compared to vehicle treated controls. Histological data are mainly in favour of anti-inflammatory effects of GLP-1 producing MSC capsules with reduced detection of inflammatory markers and a significant heat shock protein increase. CONCLUSION/SIGNIFICANCE: Intracerebroventricular injection of GLP-1 MSC capsules shows neuroprotective potential in the SOD1 (G93A mouse model.

  20. Pharmacokinetics and pharmacodynamics of boosted once-daily darunavir.

    Science.gov (United States)

    Kakuda, Thomas N; Brochot, Anne; Tomaka, Frank L; Vangeneugden, Tony; Van De Casteele, Tom; Hoetelmans, Richard M W

    2014-10-01

    The ability to dose antiretroviral agents once daily simplifies the often complex therapeutic regimens required for the successful treatment of HIV infection. Thus, once-daily dosing can lead to improved patient adherence to medication and, consequently, sustained virological suppression and reduction in the risk of emergence of drug resistance. Several trials have evaluated once-daily darunavir/ritonavir in combination with other antiretrovirals (ARTEMIS and ODIN trials) or as monotherapy (MONET, MONOI and PROTEA trials) in HIV-1-infected adults. Data from ARTEMIS and ODIN demonstrate non-inferiority of once-daily darunavir/ritonavir against a comparator and, together with pharmacokinetic data, have established the suitability of once-daily darunavir/ritonavir for treatment-naive and treatment-experienced patients with no darunavir resistance-associated mutations. The findings of ARTEMIS and ODIN have led to recent updates to treatment guidelines, whereby once-daily darunavir/ritonavir, given with other antiretrovirals, is now a preferred treatment option for antiretroviral-naive adult patients and a simplified treatment option for antiretroviral-experienced adults who have no darunavir resistance-associated mutations. Once-daily dosing with darunavir/ritonavir is an option for treatment-naive and for treatment-experienced paediatric patients with no darunavir resistance-associated mutations based on the findings of the DIONE trial and ARIEL substudy. This article reviews the pharmacokinetics, efficacy, safety and tolerability of once-daily boosted darunavir. The feasibility of darunavir/ritonavir monotherapy as a treatment approach for some patients is also discussed. Finally, data on a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily are presented, showing comparable darunavir bioavailability to that obtained with 800/100 mg of darunavir/ritonavir once daily. © The Author 2014. Published by Oxford University Press on behalf of the British

  1. Liraglutide: A review of its therapeutic use as a once daily GLP-1 analog for the management of type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Mala Dharmalingam

    2011-01-01

    Full Text Available Type 2 diabetes mellitus (T2DM is a progressive disease associated with significant morbidity and mortality. Even though progress have been accomplished in the management of type 2 diabetes, current treatment preferences for patients with this disease still fall short to address disease progression. With the present therapy, glycaemic control remains suboptimal and are often associated with weight gain and hypoglycaemia. Glucagon like peptide-1 (GLP-1 is an incretin hormone secreted from the small intestine that lowers fasting and postprandial glucose through multiple mechanisms including glucose-dependent insulin secretion, reduction of glucagon secretion, delaying gastric emptying and increased satiety. Liraglutide, a human glucagon-like peptide 1 (GLP-1 analogue is a treatment for T2DM that is administered as a once-daily subcutaneous injection. The efficacy and tolerability of liraglutide at doses of 0.6, 1.2, and 1.8 mg for T2DM, in combination with, and compared with, other T2DM treatments were investigated in the Liraglutide Effect and Action in Diabetes (LEAD Phase III clinical trial program. In the LEAD trial, treatment with liraglutide was associated with substantial improvements in glycaemic control and low risk of hypoglycaemia. In addition liraglutide significantly improved β-cell function, reduced systolic blood pressure (BP and induced weight loss. Overall, liraglutide was well tolerated. Recent data on safety and efficacy of liraglutide from real-life clinical practice settings also reiterate the better therapeutic profile of this molecule. Based on results from the LEAD programme, and real-life clinical experience, liraglutide has been demonstrated as an effective therapeutic intervention even at the early stage of diabetes regardless of with what, it has been used.

  2. Glucagon-like peptides 1 and 2

    DEFF Research Database (Denmark)

    Kissow, Hannelouise

    2015-01-01

    PURPOSE OF REVIEW: Chemotherapy often causes adverse effects, including pain, bloating, diarrhea, and inflammation and ulceration of the mucous membranes lining the digestive tract, which are collectively referred to as mucositis. Unfortunately, no remedy has been found yet to manage these side......-effects. RECENT FINDINGS: The intestinal glucagon-like peptide-2 (GLP-2) is secreted from the intestinal endocrine L cells after nutrient intake, but recent findings show that the peptide concentration in the plasma also rises after intestinal injury and that GLP-2 receptor activation is crucial for intestinal...... for therapeutic use. In type 2 diabetic and obese patients, GLP secretion is impaired. Elucidating the role of these endogenous hormones could lead to the identification of mucositis risk factors and an alternative preventive therapy for these patients....

  3. Glucagon-like peptide 1 (7-36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling

    DEFF Research Database (Denmark)

    Gromada, J; Bokvist, K; Ding, W G;

    1998-01-01

    The effect of glucagon-like peptide 1(7-36) amide [GLP-1(7-36) amide] on membrane potential, whole-cell ATP-sensitive potassium channel (K[ATP]) and Ca2+ currents, cytoplasmic Ca2+ concentration, and exocytosis was explored in single human beta-cells. GLP-1(7-36) amide induced membrane...... depolarization that was associated with inhibition of whole-cell K(ATP) current. In addition, GLP-1(7-36) amide (and forskolin) produced greater than fourfold potentiation of Ca2+-dependent exocytosis. The latter effect resulted in part (40%) from acceleration of Ca2+ influx through voltage-dependent (L-type) Ca......2+ channels. More importantly, GLP-1(7-36) amide (via generation of cyclic AMP and activation of protein kinase A) potentiated exocytosis at a site distal to a rise in the cytoplasmic Ca2+ concentration. Photorelease of caged cAMP produced a two- to threefold potentiation of exocytosis when...

  4. Enteral nutrients potentiate glucagon-like peptide-2 action and reduce dependence on parenteral nutrition in a rat model of human intestinal failure

    DEFF Research Database (Denmark)

    Brinkman, Adam S; Murali, Sangita G; Hitt, Stacy

    2012-01-01

    human SBS and requires parenteral nutrition (PN). Male Sprague-Dawley rats were assigned to one of five groups and maintained with PN for 18 days: total parenteral nutrition (TPN) alone, TPN + GLP-2 (100 μg·kg(-1)·day(-1)), PN + EN + GLP-2(7 days), PN + EN + GLP-2(18 days), and a nonsurgical oral...

  5. The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.

    Science.gov (United States)

    Suchankova, P; Yan, J; Schwandt, M L; Stangl, B L; Caparelli, E C; Momenan, R; Jerlhag, E; Engel, J A; Hodgkinson, C A; Egli, M; Lopez, M F; Becker, H C; Goldman, D; Heilig, M; Ramchandani, V A; Leggio, L

    2015-06-16

    The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

  6. Genetically-Encoded Photocrosslinkers Determine the Biological Binding Site of Exendin-4 in the N-Terminal Domain of the Intact Human Glucagon-Like Peptide-1 Receptor (GLP-1R).

    Science.gov (United States)

    Koole, Cassandra; Reynolds, Christopher A; Mobarec, Juan C; Hick, Caroline; Sexton, Patrick M; Sakmar, Thomas P

    2017-03-10

    The glucagon-like peptide-1 receptor (GLP-1R) is a key therapeutic target in the management of type II diabetes mellitus, with actions including regulation of insulin biosynthesis and secretion, promotion of satiety and preservation of β-cell mass. Like most class B G protein-coupled receptors (GPCRs), there is limited knowledge linking biological activity of the GLP-1R with the molecular structure of an intact, full-length, functional receptor-ligand complex. In this study, we have utilized genetic code expansion to site-specifically incorporate the photoactive amino acid p-azido-L-phenylalanine (azF) into N-terminal residues of a full-length, functional human GLP-1R in mammalian cells. UV-mediated photolysis of azF was then carried out to induce targeted photocrosslinking to determine the proximity of the azido group in the mutant receptor with the peptide exendin-4. Crosslinking data were compared directly to the crystal structure of the isolated N-terminal extracellular domain (ECD) of the GLP-1R in complex with exendin(9-39), revealing both similarities as well as distinct differences in the mode of interaction. Generation of a molecular model to accommodate the photocrosslinking constraints highlights the potential influence of environmental conditions on the conformation of the receptor-peptide complex, including folding dynamics of the peptide and formation of dimeric and higher order oligomeric receptor multimers. These data demonstrate that crystal structures of isolated receptor regions may not give a complete reflection of peptide-receptor interactions, and should be combined with additional experimental constraints to reveal peptide-receptor interactions occurring in the dynamic, native, full-length receptor state.

  7. Once-daily mesalamine granules for ulcerative colitis.

    Science.gov (United States)

    Lawlor, Garrett; Ahmed, Awais; Moss, Alan C

    2010-07-01

    Mesalamine extended-release capsules (Apriso [Salix Pharmaceuticals, Raleigh, NC, USA]) are the first once-daily mesalamine preparation approved by the US FDA for the maintenance of remission of ulcerative colitis (UC). Each mesalamine extended-release capsule contains granules of a mesalamine-polymer matrix that are coated with a pH-sensitive resin. This design begins releasing mesalamine (0.375 g) once the pH is more than 6 in the ileum and colon. Two clinical trials have reported that mesalamine extended-release capsules (1.5 g/day) maintained remission in 79% of patients with UC who were in clinical remission. Reported adherence with mesalamine extended-release capsules once daily was high (>90%) in these studies. This article examines the efficacy and safety of mesalamine extended-release capsules in the maintenance of remission in patients with UC.

  8. Pharmacokinetic profile of once-daily cyclobenzaprine extended-release.

    Science.gov (United States)

    Darwish, Mona; Hellriegel, Edward T

    2010-11-01

    Cyclobenzaprine immediate-release (CIR) is a widely prescribed skeletal muscle relaxant with an established efficacy and safety profile in patients with muscle spasm associated with acute, painful conditions, although it is commonly associated with sedation. CIR is typically prescribed at a dosage of 10 mg three-times-daily. This review focuses on the pharmacokinetic profile of a new formulation, cyclobenzaprine extended-release (CER), which delivers a sustained plasma cyclobenzaprine concentration over 24 h, allowing once-daily dosing. Results from CER pharmacokinetic studies conducted through August 2010 are summarized. This review provides information on the first four studies assessing the single-dose and steady-state pharmacokinetic profile of CER. Once-daily CER 30 mg and three-times-daily CIR 10 mg produced comparable systemic exposures to cyclobenzaprine, but pharmacokinetic profiles were qualitatively different. CER was characterized by a single daily peak in cyclobenzaprine concentration versus three peaks/day for CIR. With once-daily dosing of CER, cyclobenzaprine concentration is sustained over 24 h. CER 30 mg provides approximately twice the exposure as CER 15 mg. Systemic exposure to CER is increased in the presence of food and in elderly subjects. Steady-state is achieved by day 7 of dosing.

  9. Pharmacokinetics and pharmacodynamics of the glucagon-like peptide-1 analog liraglutide in healthy cats.

    Science.gov (United States)

    Hall, M J; Adin, C A; Borin-Crivellenti, S; Rudinsky, A J; Rajala-Schultz, P; Lakritz, J; Gilor, C

    2015-04-01

    Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that induces glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Glucagon-like peptide-1 also increases beta cell mass and satiation while decelerating gastric emptying. Liraglutide is a fatty-acid derivative of GLP-1 with a protracted pharmacokinetic profile that is used in people for treatment of type II diabetes mellitus and obesity. The aim of this study was to determine the pharmacokinetics and pharmacodynamics of liraglutide in healthy cats. Hyperglycemic clamps were performed on days 0 (HGC) and 14 (LgHGC) in 7 healthy cats. Liraglutide was administered subcutaneously (0.6 mg/cat) once daily on days 8 through 14. Compared with the HGC (mean ± standard deviation; 455.5 ± 115.8 ng/L), insulin concentrations during LgHGC were increased (760.8 ± 350.7 ng/L; P = 0.0022), glucagon concentrations decreased (0.66 ± 0.4 pmol/L during HGC vs 0.5 ± 0.4 pmol/L during LgHGC; P = 0.0089), and there was a trend toward an increased total glucose infused (median [range] = 1.61 (1.11-2.54) g/kg and 2.25 (1.64-3.10) g/kg, respectively; P = 0.087). Appetite reduction and decreased body weight (9% ± 3%; P = 0.006) were observed in all cats. Liraglutide has similar effects and pharmacokinetics profile in cats to those reported in people. With a half-life of approximately 12 h, once daily dosing might be feasible; however, significant effects on appetite and weight loss may necessitate dosage or dosing frequency reductions. Further investigation of liraglutide in diabetic cats and overweight cats is warranted.

  10. Once-Daily Radiation Therapy for Inflammatory Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Lindsay [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Harmsen, William [Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota (United States); Blanchard, Miran [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Goetz, Matthew [Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota (United States); Jakub, James [Department of Surgery, Mayo Clinic, Rochester, Minnesota (United States); Mutter, Robert; Petersen, Ivy; Rooney, Jessica [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Stauder, Michael [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Yan, Elizabeth [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Laack, Nadia, E-mail: laack.nadia@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2014-08-01

    Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive breast cancer variant treated with multimodality therapy. A variety of approaches intended to escalate the intensity and efficacy of radiation therapy have been reported, including twice-daily radiation therapy, dose escalation, and aggressive use of bolus. Herein, we examine our outcomes for patients treated with once-daily radiation therapy with aggressive bolus utilization, focusing on treatment technique. Methods and Materials: A retrospective review of patients with nonmetastatic IBC treated from January 1, 2000, through December 31, 2010, was performed. Locoregional control (LRC), disease-free survival (DFS), overall survival (OS) and predictors thereof were assessed. Results: Fifty-two women with IBC were identified, 49 (94%) of whom were treated with neoadjuvant chemotherapy. All underwent mastectomy followed by adjuvant radiation therapy. Radiation was delivered in once-daily fractions of 1.8 to 2.25 Gy (median, 2 Gy). Patients were typically treated with daily 1-cm bolus throughout treatment, and 33 (63%) received a subsequent boost to the mastectomy scar. Five-year Kaplan Meier survival estimates for LRC, DFS, and OS were 81%, 56%, and 64%, respectively. Locoregional recurrence was associated with poorer OS (P<.001; hazard ratio [HR], 4.1). Extracapsular extension was associated with worse LRC (P=.02), DFS (P=.007), and OS (P=.002). Age greater than 50 years was associated with better DFS (P=.03). Pathologic complete response was associated with a trend toward improved LRC (P=.06). Conclusions: Once-daily radiation therapy with aggressive use of bolus for IBC results in outcomes consistent with previous reports using various intensified radiation therapy regimens. LRC remains a challenge despite modern systemic therapy. Extracapsular extension, age ≤50 years, and lack of complete response to chemotherapy appear to be associated with worse outcomes. Novel strategies are needed in IBC

  11. GLP-1对人脐静脉内皮细胞释放NO的影响及机制的研究%Effects and Mechanism of Glucagon like Peptide-1 on Nitric Oxide Release in Human Umbilical Vein Endothelial Cells

    Institute of Scientific and Technical Information of China (English)

    丁丽; 张绍维; 赵文洲; 罗晶; 王巍; 张锦

    2015-01-01

    Objective:To investigate the effects of glucagon-like peptide-1 (GLP-1) on nitric oxide (NO) release in human umbilical vein endothelial cells (HUVECs) and whether GLP-1 receptor (GLP-1R) and GLP-1 (9-36) are involved in mediating the effects.Methods:HUVECs were incubated in the presence or absence of GLP-1,exenatide (a GLP-1R agonist) or GLP-1 (9-36),or incubated in the presence of GLP-1 with or without exendin (9-39) (a GLP-1R antagonist) and/or sitagliptin (inhibitting formation of GLP-1 [9-36]).NO content in the cell culture medium was measured by adopting nitrate reductase method.Results:GLP-1 dose-dependently promoted NO release in HUVECs.Exenatide and GLP-1 (9-36) both increased NO release.Exendin (9-39) and sitagliptin both partly blocked the effects of GLP-1.Conclusion:GLP-1 may have directly protective effect on endothelium by increasing NO release in HUVECs through GLP-1 R-dependent and GLP-1 (9-36)-related pathways.%目的:观察胰高糖素样肽-1(GLP-1)对脐静脉内皮细胞(HUVECs)释放一氧化氮(NO)的影响,并探讨GLP-1受体及GLP-1(9-36)在其中的作用.方法:分别以GLP-1、艾塞那肽、GLP-1 (9-36)、GLP-1+exendin(9-39)、GLP-1+西格列汀、GLP-1+西格列汀+exendin(9-39)孵育HUVECs,取培养上清以硝酸还原酶法检测NO浓度.结果:GLP-1剂量依赖性的增加HUVECs中NO释放,艾塞那肽和GLP-1 (9-36)均可刺激NO释放,exendin(9-39)和西格列汀均可部分阻断GLP-1引起的NO释放.结论:GLP-1可能通过GLP-1受体及GLP-1 (9-36)相关的途径刺激HUVECs NO释放,发挥直接的血管保护作用.

  12. Porcine glucagon-like peptide-2: structure, signaling, metabolism and effects

    DEFF Research Database (Denmark)

    Pedersen, Nis Borbye; Hjøllund, Karina Rahr; Johnsen, Anders H

    2007-01-01

    Mass spectrometry of HPLC-purified porcine glucagon-like peptide-2 (pGLP-2)(1) revealed a 35 amino acid sequence with C-terminal Ser and Leu, in contrast to the 33 amino acids of human, cow, rat and mouse GLP-2. Synthetic pGLP-2 stimulated cAMP-production in COS-7 cells expressing human GLP-2 (h...

  13. The effect of glucagon-like peptide-1 and glucagon-like peptide-2 on microcirculation: a systematic review.

    Science.gov (United States)

    Nerup, Nikolaj; Ambrus, Rikard; Lindhe, Joanna; Achiam, Michael P; Jeppesen, Palle B; Svendsen, Lars B

    2017-03-07

    Glucagon-like peptide-1 (GLP-1) and -2 (GLP-2) are gut-derived hormones used in the treatment of diabetes type-2 and short bowel syndrome, respectively. GLP-1 attenuates insulin resistance and GLP-2 reduces enterocyte apoptosis and enhances crypt cell proliferation in the small intestine. In addition, both hormones have vasoactive effects and may be useful in situations with impaired microcirculation. The aim of this systematic review was to provide an overview of the potential effects of GLP-1 and GLP-2 on microcirculation. A systematic search was performed independently by two authors in the following databases: PubMed, Embase, Cochrane library, Scopus, and Web of Science. Of 1111 screened papers, 20 studies were included in this review: 16 studies in animals, three in humans, and one in humans and rats. The studies were few and heterogeneous and had a high risk of bias. However, it seems that GLP-1 regulates the pancreatic, skeletal, and cardiac muscle flow, indicating a role in the glucose homeostasis, while GLP-2 acts primarily in the regulation of the microcirculation of the mid-intestine. These findings may be useful in gastrointestinal surgery and in situations with impaired microcirculation of the gut. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  14. Once daily dose gentamicin in neonates - is our dosing correct?

    Science.gov (United States)

    Serane, Tiroumourougane V; Zengeya, Stanley; Penford, Gemma; Cooke, Jane; Khanna, Gitika; McGregor-Colman, Elle

    2009-07-01

    The aim of this paper is to study the safety and efficacy (measured by therapeutic level) of once daily gentamicin in neonates >or=32 weeks of gestation and or=32 weeks of gestation and 2 mg/L. Only 39 (60%) had peak and trough levels within the therapeutic range. All babies who had audiometric evaluation (62 out of 65) had normal hearing. Out of the 65 babies, 60 had paired serum creatinine levels estimated and none had evidence of renal dysfunction. Among term neonates, only 2 out of 50 had the trough serum concentration of >2 mg/L. In 38 (76%) of the 50 neonates, the trough serum gentamicin concentration was <2.0 mg/L and the peak level was <10 mg/L. Forty-eight babies had audiometric evaluation which was normal. A dose of 4 mg/kg/day produces serum gentamicin levels outside the therapeutic range in two-fifths of neonates between 32 and 36 +/- 6 weeks. A single dose of 4 mg/kg/day of gentamicin is appropriate for term babies and probably excessive for 32-36 weeks' neonates.

  15. Synthesis and Evaluation of a Series of Long-Acting Glucagon-Like Peptide-1 (GLP-1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes.

    Science.gov (United States)

    Irwin, Nigel; Patterson, Steven; de Kort, Martin; Moffett, R Charlotte; Wisse, Jeffry A J; Dokter, Wim H A; Bos, Ebo S; Miltenburg, André M M; Flatt, Peter R

    2015-08-01

    The present study details the development of a family of novel D-Ala(8) glucagon-like peptide-1 (GLP-1) peptide conjugates by site specific conjugation to an antithrombin III (ATIII) binding carrier pentasaccharide through tetraethylene glycol linkers. All conjugates were found to possess potent insulin-releasing activity. Peptides with short linkers (GLP-1 receptor (GLP-1-R) binding affinity. All D-Ala(8) GLP-1 conjugates exhibited prominent glucose-lowering action. Biological activity of the Lys(37) short-linker peptide was evident up to 72 h post-injection. In agreement, the pharmacokinetic profile of this conjugate (t1/2 , 11 h) was superior to that of the GLP-1-R agonist, exenatide. Once-daily injection of the Lys(37) short-linker peptide in ob/ob mice for 21 days significantly decreased food intake and improved HbA1c and glucose tolerance. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys(37) short-linker peptide were similar to or better than either exenatide or liraglutide, another GLP-1-R agonist. In conclusion, GLP-1 peptides conjugated to an ATIII binding carrier pentasaccharide have a substantially prolonged bioactive profile compatible for possible once-weekly treatment of type 2 diabetes in humans.

  16. Adherence to GLP-1 receptor agonist therapy administered by once-daily or once-weekly injection in patients with type 2 diabetes in Germany

    Directory of Open Access Journals (Sweden)

    Qiao Q

    2016-06-01

    Full Text Available Qing Qiao,1 Mario JNM Ouwens,1 Susan Grandy,2 Kristina Johnsson,1 Karel Kostev3 1Global Medicines Development, AstraZeneca, Gothenburg, Sweden; 2Global Medicines Development, AstraZeneca, Gaithersburg, MD, USA; 3Epidemiology and Evidence-Based Medicine, Real-World Evidence Solutions, IMS Health, Frankfurt am Main, Germany Aim: This study aimed to compare 6-month adherence to therapy with exenatide once weekly (Bydureon® vs liraglutide once daily (Victoza® in patients with type 2 diabetes under primary care in Germany.Methods: A nationwide longitudinal prescription database (LRx, (between January 2011 and September 2014 was used to analyze adherence to therapy. The proportion of days covered (PDC by prescription was used as a measure of adherence in the 6-month postindex period. Logistic regression analyses were performed to investigate the associations between glucagon-like peptide-1 receptor agonist therapy adjusting for age, sex, and cotherapy.Results: Therapy was initiated in 5,449 patients with exenatide once weekly (age: 59.7±11.8 years; 51.4% were male and in 24,648 patients with liraglutide once daily (age: 59.4±11.4 years; 49.7% were male. The median PDC was 0.88 for exenatide once weekly and 0.77 for liraglutide once daily (P<0.05. Once-weekly exenatide was associated with significantly higher adherence. Odds ratio (95% confidence interval for having a PDC of ≥0.80 was 1.78 (1.62–1.96 for exenatide once weekly compared with liraglutide once daily after adjusting for age, sex, and cotherapy.Conclusion: Adherence to treatment with exenatide once weekly was significantly increased compared to that with liraglutide once daily over 6 months in patients with type 2 diabetes. Keywords: type 2 diabetes, GLP-1 receptor agonists, adherence

  17. Therapeutic strategies based on glucagon-like peptide 1

    DEFF Research Database (Denmark)

    Deacon, Carolyn F

    2004-01-01

    Glucagon-like peptide (GLP)-1 is an incretin hormone with potent glucose-dependent insulinotropic and glucagonostatic actions, trophic effects on the pancreatic beta-cells, and inhibitory effects on gastrointestinal secretion and motility, which combine to lower plasma glucose and reduce glycemic...... of the peptide....

  18. Glucagon-like peptide 1--a cardiologic dimension

    DEFF Research Database (Denmark)

    Treiman, Marek; Elvekjaer, Mikkel; Engstrøm, Thomas

    2010-01-01

    Recent experimental data suggest glucagon-like peptide 1 (GLP-1) and its analogs to have direct effects on the cardiovascular system, in addition to their classic glucoregulatory actions. These direct effects may be cardioprotective, contractility augmenting, and vasorelaxant. A few preliminary c...

  19. Clinical potential of lixisenatide once daily treatment for type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Petersen AB

    2013-06-01

    Full Text Available Andreas B Petersen,1 Mikkel Christensen1,21Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark; 2Diabetes Research Division, Department of Internal Medicine, Gentofte Hospital, Copenhagen, DenmarkAbstract: The glucagon-like peptide (GLP-1 receptor agonist lixisenatide (Lyxumia® was approved for marketing by the European Medicines Agency in February 2013 and has been evaluated in a clinical study program called GetGoal. Lixisenatide activates the GLP-1 receptor and thereby exercises the range of physiological effects generated by GLP-1, which consist of increased insulin secretion, inhibition of glucagon secretion, and decreased gastrointestinal motility alongside the promotion of satiety. In the GetGoal study program, lixisenatide demonstrated significant reductions in glycated hemoglobin (HbA1c, and fasting and postprandial plasma glucose compared with placebo. The effect on glycemia was evident, with both monotherapy and in combination with insulin and various oral antidiabetic agents. Furthermore, a general trend towards reduced bodyweight was reported. In head-to-head trials with the other GLP-1 receptor agonists (exenatide and liraglutide on the market, lixisenatide demonstrated a superior effect with respect to reduction in postprandial plasma glucose and had a tendency towards fewer adverse events. However, lixisenatide seemed to be less efficient or at best, equivalent to exenatide and liraglutide in reducing HbA1c, fasting plasma glucose, and bodyweight. The combination of a substantial effect on postprandial plasma glucose and a labeling with once daily administration separates lixisenatide from the other GLP-1 receptor agonists. The combination of basal insulin, having a lowering effect on fasting plasma glucose, and lixisenatide, curtailing the postprandial glucose excursions, makes sense from a clinical point of view. Not surprisingly, lixisenatide is undergoing clinical development as a combination

  20. Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Lars Bo; Ploug, K.B.; Swift, P.

    2007-01-01

    The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent......The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose......-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the K(ATP) channel subunits, Kir6.2 and SUR1, in human L- and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu23Lys, exerts a functional impact...... on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes....

  1. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury.

    Science.gov (United States)

    Goto, Hiromasa; Nomiyama, Takashi; Mita, Tomoya; Yasunari, Eisuke; Azuma, Kosuke; Komiya, Koji; Arakawa, Masayuki; Jin, Wen Long; Kanazawa, Akio; Kawamori, Ryuzo; Fujitani, Yoshio; Hirose, Takahisa; Watada, Hirotaka

    2011-02-04

    Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. Glucagon-Like Peptide 1 Receptor Agonists for Type 2 Diabetes.

    Science.gov (United States)

    Hinnen, Deborah

    2017-08-01

    The incretin system has become an important target in the treatment of type 2 diabetes in recent years, and glucagon-like peptide 1 (GLP-1) is of particular interest for its glucose-lowering effects. The physiological response to oral ingestion of nutrients, involving the incretin system, is reduced in some patients with type 2 diabetes but may be augmented by administration of GLP-1 receptor agonists. The GLP-1 receptor agonists currently approved in the United States for the treatment of type 2 diabetes include exenatide (administered twice daily), liraglutide and lixisenatide (administered once daily), and the once-weekly agents exenatide extended-release, albiglutide, and dulaglutide. These agents have been shown to reduce A1C (by ∼0.8-1.6%), body weight (by ∼1-3 kg), blood pressure, and lipids. GLP-1 receptor agonists are associated with a low risk of hypoglycemia, and the most common adverse effects are gastrointestinal. Proper patient selection and education can assist in achieving positive treatment outcomes.

  3. Glucagon-like peptide-1, glucose homeostasis and diabetes

    DEFF Research Database (Denmark)

    Holst, Jens Juul; Deacon, Carolyn F; Vilsbøll, Tina

    2008-01-01

    Incretins, enhancers of insulin secretion, are essential for glucose tolerance, and a reduction in their function might contribute to poor beta-cell function in patients with type-2 diabetes mellitus. However, at supraphysiological doses, the incretin glucagon-like peptide-1 (GLP-1) protects...... as therapies for type-2 diabetes and have recently reached the market. The pathophysiological basis the clinical use of these therapeutics is reviewed here....

  4. Ileal tight junction gene expression in glucagon-like peptide 2-treated dairy bull calves with and without coccidiosis

    Science.gov (United States)

    Intestinal gut permeability is partially regulated by the intestinotrophic hormone glucagon-like peptide 2 (GLP-2). Specifically, disease models in mice and human cell lines have implicated GLP-2 in the regulation of the tight junction milieu within the intestinal tract. Therapeutic administration o...

  5. Once-daily antiretroviral therapy in a cohort of HIV-infected children and adolescents.

    Science.gov (United States)

    Jiménez-Montero, Beatriz; Beceiro, José; de José-Gómez, M Isabel; González-Tomé, M Isabel; Gurbindo-Gutierrez, Dolores; Martínez-Pérez, Jorge; Mellado-Peña, M José; Navarro-Gómez, M Luisa; Roa-Francia, Miguel A; Rojo-Conejo, Pablo; Saavedra-Lozano, Jesús; Jiménez de Ory, Santiago; Ramos-Amador, José T

    2014-10-01

    We evaluated the evolution over time of once-daily antiretroviral therapy in HIV-infected children and its relationship with adherence. An increase on the prevalence of once-daily antiretroviral therapy was observed over time (from 0.9% in 2002 to 44.2% in 2011). There was no difference in adherence regarding once-daily or BID regimens in 2011. Adherence was related to age and pill burden.

  6. Chronopharmacokinetics of once daily dosed aminoglycosides in hospitalized infectious patients

    NARCIS (Netherlands)

    van Maarseveen, Erik; Man, Wai Hong; Proost, Johannes; Neef, Cees; Touw, Daniël

    2015-01-01

    BACKGROUND: hospitalized patients with serious infections treated with aminoglycosides are at risk of developing nephrotoxicity. Previous clinical studies have shown that the pharmacokinetics of aminoglycosides in humans follow a circadian rhythm. Therefore, the time of administration could have imp

  7. Chronopharmacokinetics of once daily dosed aminoglycosides in hospitalized infectious patients

    NARCIS (Netherlands)

    van Maarseveen, Erik; Man, Wai Hong; Proost, Johannes; Neef, Cees; Touw, Daniel

    2015-01-01

    Background hospitalized patients with serious infections treated with aminoglycosides are at risk of developing nephrotoxicity. Previous clinical studies have shown that the pharmacokinetics of aminoglycosides in humans follow a circadian rhythm. Therefore, the time of administration could have impo

  8. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Body Weight: A Meta-Analysis

    OpenAIRE

    Matteo Monami; Ilaria Dicembrini; Niccolò Marchionni; Rotella, Carlo M.; Edoardo Mannucci

    2012-01-01

    Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for “exenatide,” “liraglutide,” “albiglutide,” “semaglutide,” and “lixisenatide” was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or...

  9. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System

    DEFF Research Database (Denmark)

    Muscogiuri, Giovanna; DeFronzo, Ralph A; Gastaldelli, Amalia

    2017-01-01

    Glucagon-like peptide-1 (GLP-1) is released in response to meals and exerts important roles in the maintenance of normal glucose homeostasis. GLP-1 is also important in the regulation of neurologic and cognitive functions. These actions are mediated via neurons in the nucleus of the solitary trac...... human trials report a neuroprotective effect of GLP-1-RAs in Alzheimer's and Parkinson's disease. In this review, we discuss the role of GLP-1 and GLP-1-RAs in the nervous system with focus on GLP-1 actions on appetite regulation, glucose homeostasis, and neuroprotection....

  10. Real-world glycemic outcomes in patients with type 2 diabetes initiating exenatide once weekly and liraglutide once daily: a retrospective cohort study

    Directory of Open Access Journals (Sweden)

    Saunders WB

    2016-07-01

    Full Text Available William B Saunders,1 Hiep Nguyen,2 Iftekhar Kalsekar2 1Department of Public Health Sciences, College of Health and Human Services, The University of North Carolina at Charlotte, Charlotte, NC, 2AstraZeneca, Fort Washington, PA, USA Aim: The glucagon-like peptide-1 receptor agonists exenatide once weekly (QW and liraglutide once daily (QD have demonstrated improvements in glycemic outcomes in patients with type 2 diabetes mellitus in randomized clinical trials. However, little is known about their real-world comparative effectiveness. This retrospective cohort study used the Quintiles Electronic Medical Record database to evaluate the 6-month change in glycated hemoglobin (A1C for patients initiating exenatide QW or liraglutide QD.Methods: Patients with type 2 diabetes mellitus prescribed exenatide QW (n=664 or liraglutide QD (n=3,283 between February 1, 2012 and May 31, 2013 were identified. Baseline A1C measures were from 75 days before to 15 days after initiating exenatide QW or liraglutide QD, with follow-up measures documented at 6 months (±45 days. Adjusted linear regression models compared the difference in mean A1C change. A priori defined sensitivity analysis was performed in the subgroup of patients with baseline A1C ≥7.0% and no prescription for insulin during the 12-month pre-index period.Results: For exenatide QW and liraglutide QD, respectively, mean (SD age of the main study cohort was 58.01 (10.97 and 58.12 (11.05 years, mean (SD baseline A1C was 8.4% (1.6 and 8.4% (1.6, and 48.2% and 54.2% of patients were women. In adjusted models, change in A1C did not differ between exenatide QW and liraglutide QD during 6 months of follow-up. Results were consistent in the subgroup analyses.Conclusion: In a real-world setting, A1C similarly improves in patients initiating exenatide QW or liraglutide QD. Keywords: diabetes, exenatide, outcomes

  11. Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury

    Energy Technology Data Exchange (ETDEWEB)

    Goto, Hiromasa [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Nomiyama, Takashi, E-mail: tnomiyama@fukuoka-u.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Mita, Tomoya; Yasunari, Eisuke; Azuma, Kosuke; Komiya, Koji; Arakawa, Masayuki; Jin, Wen Long; Kanazawa, Akio [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Sportology Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Fujitani, Yoshio; Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan); Sportology Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421 (Japan)

    2011-02-04

    Research highlights: {yields} Exendin-4 reduces neointimal formation after vascular injury in a mouse model. {yields} Exendin-4 dose not alter metabolic parameters in non-diabetic, non-obese mouse model. {yields} Exendin-4 reduces PDGF-induced cell proliferation in cultured SMCs. {yields} Exendin-4 may reduces neointimal formation after vascular injury at least in part through its direct action on SMCs. -- Abstract: Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4 weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10 nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

  12. The discovery of glucagon-like peptide 1.

    Science.gov (United States)

    Lund, P Kay

    2005-06-15

    The discovery of glucagon-like peptide 1 (GLP-1) began more than two decades ago with the observations that anglerfish islet proglucagon messenger RNAs (mRNAs) contained coding sequences for two glucagon-related peptides arranged in tandem. Subsequent analyses revealed that mammalian proglucagon mRNAs encoded a precursor containing the sequence of pancreatic glucagon, intestinal glicentin and two glucagon-related peptides termed GLP-1 and GLP-2. Multidisciplinary approaches were then required to define the structure of biologically active GLP-1 7-36 amide and its role as an incretin, satiety hormone and, most recently, a neuroprotective peptide. This historial perspective outlines the use of traditional recombinant DNA approaches to derive the GLP-1 sequence and highlights the challenges and combination of clinical and basic science approaches required to define the physiology and pathophysiology of bioactive peptides discovered through genomics.

  13. Clinical potential of lixisenatide once daily treatment for type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Petersen, Andreas Brønden; Christensen, Mikkel

    2013-01-01

    The glucagon-like peptide (GLP)-1 receptor agonist lixisenatide (Lyxumia(®)) was approved for marketing by the European Medicines Agency in February 2013 and has been evaluated in a clinical study program called GetGoal. Lixisenatide activates the GLP-1 receptor and thereby exercises the range of...... of lixisenatide seems to be in combination with basal insulin. A large multicenter study will determine the future potential of lixisenatide in preventing cardiovascular events and mortality, in patients with type 2 diabetes and recent acute coronary syndrome.......The glucagon-like peptide (GLP)-1 receptor agonist lixisenatide (Lyxumia(®)) was approved for marketing by the European Medicines Agency in February 2013 and has been evaluated in a clinical study program called GetGoal. Lixisenatide activates the GLP-1 receptor and thereby exercises the range...

  14. Co-localisation of the Kir6.2/SUR1 channel complex with glucagon-like peptide-1 and glucose-dependent insulinotrophic polypeptide expression in human ileal cells and implications for glycaemic control in new onset type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Lotte B; Ploug, Kenneth B; Swift, Peter

    2007-01-01

    OBJECTIVE: The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose......-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate the expression and co-localisation of the K(ATP) channel subunits, Kir6.2 and SUR1, in human L- and K-cells and 2) investigate if a common hyperactive variant of the Kir6.2 subunit, Glu23Lys, exerts a functional impact...... on glucose-sensing tissues in vivo that may affect the overall glycaemic control in children with new-onset type 1 diabetes. DESIGN AND METHODS: Western blot and immunohistochemical analyses were performed for expression and co-localisation studies. Meal-stimulated C-peptide test was carried out in 257...

  15. Once-daily medications for the pharmacological management of ADHD in adults

    Directory of Open Access Journals (Sweden)

    Oleg v Tcheremissine

    2009-05-01

    Full Text Available Oleg v Tcheremissine1, Lori M Lieving21Department of Psychiatry, Behavioral Health Center – Carolinas Medical Center, Charlotte, NC, USA; 2Carolinas College of Health Sciences, Charlotte, NC, USAAbstract: Attention-deficit/hyperactivity disorder (ADHD is the most commonly diagnosed psychiatric disorder in children and adolescents. Symptoms of ADHD often persist beyond childhood and present significant challenges to adults. Pharmacotherapy is a first-line treatment option for ADHD across all age groups. The current review’s goals are (a to critically examine the current state of knowledge regarding once-daily formulations of pharmacotherapies for treatment of adults with ADHD and (b to provide clinicians with evidence-based information regarding the safety, efficacy and tolerability of once-daily medications for adult ADHD. The reviewed body of evidence strongly supports the use of pharmacotherapy as a first-line therapeutic option for the treatment of adults with ADHD. The once-daily pharmacological agents are effective therapeutic options for the treatment of adults with ADHD. In the US, based on the available evidence, once-daily medications are currently underutilized in adults with ADHD compared to pediatric population.Keywords: adults, attention deficit/hyperactivity disorder, once-daily pharmacotherapies

  16. The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liraglutide, a glucagon-like peptide 1 receptor agonist, in mice.

    Science.gov (United States)

    Nonogaki, Katsunori; Suzuki, Marina; Sanuki, Marin; Wakameda, Mamoru; Tamari, Tomohiro

    2011-07-29

    Glucagon-like peptide 1 (GLP-1), an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, induce satiety. The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake. Here we show that systemic administration of GLP-1 (50 and 200μg/kg)-induced anorexia was blunted in mice with a 5HT2CR null mutation, and was attenuated in mice with a heterozygous MC4R mutation. On the other hand, systemic administration of liraglutide (50 and 100μg/kg) suppressed food intake in mice lacking 5-HT2CR, mice with a heterozygous mutation of MC4R and wild-type mice matched for age. Moreover, once-daily consecutive intraperitoneal administration of liraglutide (100μg/kg) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of MC4R as well as wild-type mice. These findings suggest that GLP-1 and liraglutide induce anorexia via different central pathways.

  17. A Safety and Dosing Study of Glucagon-Like Peptide 2 in Children With Intestinal Failure

    DEFF Research Database (Denmark)

    Sigalet, David L; Brindle, Mary; Boctor, Dana

    2016-01-01

    BACKGROUND AND AIMS: A glucagon-like peptide 2 (GLP-2) analogue is approved for adults with intestinal failure, but no studies of GLP-2 have included children. This study examined the pharmacokinetics, safety, and nutritional effects of GLP-2 in children with intestinal failure. METHODS: Native...... human GLP-2(1-33) was synthesized following good manufacturing practices. In an open-label trial, with parental consent, 7 parenteral nutrition-dependent pediatric patients were treated with subcutaneous GLP-2 (20 µg/kg/d) for 3 days (phase 1) and, if tolerated, continued for 42 days (phase 2......). Nutritional treatment was directed by the primary caregivers. Patients were followed to 1 year. RESULTS: Seven patients were enrolled (age: 4.0 ± 0.8 years; bowel length, mean ± SEM: 24% ± 4% of predicted). All were parenteral nutrition dependent since birth, receiving 44% ± 5% of calories by parenteral...

  18. Cell-based delivery of glucagon-like peptide-1 using encapsulated mesenchymal stem cells

    DEFF Research Database (Denmark)

    Wallrapp, Christine; Thoenes, Eric; Thürmer, Frank

    2013-01-01

    Glucagon-like peptide-1 (GLP-1) CellBeads are cell-based implants for the sustained local delivery of bioactive factors. They consist of GLP-1 secreting mesenchymal stem cells encapsulated in a spherically shaped immuno-isolating alginate matrix. A highly standardized and reproducible encapsulation...... and quality control is performed in compliance with good manufacturing practice and fulfils all regulatory requirements for human clinical use. GLP-1 CellBeads combine the neuro- and cardioprotective properties of both GLP-1 and mesenchymal stem cells. First promising results were obtained from preclinical...... method is described for the manufacturing of homogeneous CellBeads. Viability and sustained secretion was shown for the recombinant GLP-1 and the cell endogenous bioactive factors like vascular endothelial growth factor, neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor. Manufacturing...

  19. Twice-Daily versus Once-Daily Pramipexole Extended Release Dosage Regimens in Parkinson's Disease.

    Science.gov (United States)

    Yun, Ji Young; Kim, Young Eun; Yang, Hui-Jun; Kim, Han-Joon; Jeon, Beomseok

    2017-01-01

    This open-label study aimed to compare once-daily and twice-daily pramipexole extended release (PER) treatment in Parkinson's disease (PD). PD patients on dopamine agonist therapy, but with unsatisfactory control, were enrolled. Existing agonist doses were switched into equivalent PER doses. Subjects were consecutively enrolled into either once-daily-first or twice-daily-first groups and received the prescribed amount in one or two, respectively, daily doses for 8 weeks. For the second period, subjects switched regimens in a crossover manner. The forty-four patients completed a questionnaire requesting preference during their last visit. We measured the UPDRS-III, Hoehn and Yahr stages (H&Y) in medication-on state, Parkinson's disease sleep scale (PDSS), and Epworth Sleepiness Scale. Eighteen patients preferred a twice-daily regimen, 12 preferred a once-daily regimen, and 14 had no preference. After the trial, 14 subjects wanted to be on a once-daily regimen, 25 chose a twice-daily regimen, and 5 wanted to maintain the prestudy regimen. Main reasons for choosing the twice-daily regimen were decreased off-duration, more tolerable off-symptoms, and psychological stability. The mean UPDRS-III, H&Y, and PDSS were not different. Daytime sleepiness was significantly high in the once-daily regimen, whereas nocturnal hallucinations were more common in the twice-daily. Multiple dosing should be considered if once-daily dosing is unsatisfactory. This study is registered as NCT01515774 at ClinicalTrials.gov.

  20. Efficacy and safety of once daily low molecular weight heparin (tinzaparin sodium) in high risk pregnancy.

    LENUS (Irish Health Repository)

    Ní Ainle, Fionnuala

    2008-10-01

    Low molecular weight heparin (LMWH) is widely regarded as the anticoagulant treatment of choice for the prevention and treatment of venous thromboembolism during pregnancy. However, previous studies have demonstrated that the pharmacokinetic profiles of LMWH vary significantly with increasing gestation. Consequently, it remains unclear whether LMWH regimens recommended for use in nonpregnant individuals can be safely extrapolated to pregnant women. The aims of this study were to assess the safety and the efficacy of tinzaparin sodium (Innohep) administered only once daily during pregnancy. A systematic retrospective review identified a cohort of 37 high-risk pregnancies which had been managed using tinzaparin 175 IU\\/kg once daily. In 26 cases, the index pregnancy had been complicated by development of an acute venous thromboembolism (17 deep vein thrombosis and nine pulmonary embolism). For each individual, case notes were examined and data extracted using a predetermined questionnaire. No episodes of recurrent venous thromboembolism were identified amongst this cohort of pregnancies managed using once daily LMWH administration. However, two unusual thrombotic complications were observed, including a parietal infarct in one patient, and a postpartum cerebral venous thrombosis in another. Once daily tinzaparin was well tolerated, with no cases of heparin-induced thrombocytopaenia, symptomatic osteoporosis, or foetal malformations. Tinzaparin dose modification based upon peak anti-Xa levels occurred in 45% of the cases examined. The present study is the largest study to have examined the clinical efficacy of once daily LMWH for use in pregnant women at high risk of venous thromboembolism. Our data support the safety and efficacy of antenatal tinzaparin at a dose of 175 IU\\/kg. In order to determine whether this once daily regimen provides equivalent (or indeed greater) thromboprophylaxis to twice daily LMWH regimens during pregnancy will require highly powered

  1. Twice-Daily versus Once-Daily Pramipexole Extended Release Dosage Regimens in Parkinson's Disease

    Science.gov (United States)

    Kim, Young Eun; Yang, Hui-Jun; Kim, Han-Joon

    2017-01-01

    This open-label study aimed to compare once-daily and twice-daily pramipexole extended release (PER) treatment in Parkinson's disease (PD). PD patients on dopamine agonist therapy, but with unsatisfactory control, were enrolled. Existing agonist doses were switched into equivalent PER doses. Subjects were consecutively enrolled into either once-daily-first or twice-daily-first groups and received the prescribed amount in one or two, respectively, daily doses for 8 weeks. For the second period, subjects switched regimens in a crossover manner. The forty-four patients completed a questionnaire requesting preference during their last visit. We measured the UPDRS-III, Hoehn and Yahr stages (H&Y) in medication-on state, Parkinson's disease sleep scale (PDSS), and Epworth Sleepiness Scale. Eighteen patients preferred a twice-daily regimen, 12 preferred a once-daily regimen, and 14 had no preference. After the trial, 14 subjects wanted to be on a once-daily regimen, 25 chose a twice-daily regimen, and 5 wanted to maintain the prestudy regimen. Main reasons for choosing the twice-daily regimen were decreased off-duration, more tolerable off-symptoms, and psychological stability. The mean UPDRS-III, H&Y, and PDSS were not different. Daytime sleepiness was significantly high in the once-daily regimen, whereas nocturnal hallucinations were more common in the twice-daily. Multiple dosing should be considered if once-daily dosing is unsatisfactory. This study is registered as NCT01515774 at ClinicalTrials.gov. PMID:28265478

  2. [Dulaglutide (Trulicity®), a new once-weekly agonist of glucagon-like peptide-1 receptors for type 2 diabetes].

    Science.gov (United States)

    Scheen, A J

    2016-03-01

    Dulaglutide (Trulicity®) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors indicated in the treatment of type 2 diabetes. Phase III clinical trials in AWARD programme demonstrated the efficacy and safety of dulaglutide in patients with type 2 diabetes treated by diet and exercise, metformin, a combination of metformin and a sulfonylurea or metformin and pioglitazone or even by supplements of prandial insulin. In the AWARD programme, dulaglutide (subcutaneous 0.75 or 1.5 mg once weekly) exerted a greater glucose-lowering activity than metformin, sitagliptin, exenatide or insulin glargine, and was non-inferior to liraglutide 1.8 mg once daily. Dulaglutide is currently reimbursed in Belgium after failure of and in combination with a dual oral therapy with metformin and a sulfonylurea or metformin and pioglitazone.

  3. Intestinal growth adaptation and glucagon-like peptide 2 in rats with ileal-jejunal transposition or small bowel resection

    DEFF Research Database (Denmark)

    Thulesen, Jesper; Hartmann, B.; Kissow, H.;

    2001-01-01

    Anatomy, glucagon-like peptide 2, small intestine, short bowel, intestinal adaptation, growth factors, rat......Anatomy, glucagon-like peptide 2, small intestine, short bowel, intestinal adaptation, growth factors, rat...

  4. The pharmacokinetics of abacavir 600 mg once daily in HIV-1-positive pregnant women

    NARCIS (Netherlands)

    Schalkwijk, S.J.; Colbers, A.; Konopnicki, D.; Weizsacker, K.; Molto, J.; Tenorio, C.H.; Hawkins, D.; Taylor, G.; Wood, C.; Ende, M. van der; Burger, D.M.

    2016-01-01

    OBJECTIVE: To describe the pharmacokinetics of abacavir 600 mg once daily (q.d.) in HIV-1-positive women during pregnancy and postpartum. DESIGN: A nonrandomized, open-label, multicentre, phase-IV study. METHODS: HIV-positive pregnant women receiving abacavir 600 mg q.d. as part of clinical care wer

  5. The pharmacokinetics of abacavir 600 mg once daily in HIV-1-positive pregnant women

    NARCIS (Netherlands)

    Schalkwijk, S.J.; Colbers, A.; Konopnicki, D.; Weizsacker, K.; Molto, J.; Tenorio, C.H.; Hawkins, D.; Taylor, G.; Wood, C.; Ende, M. van der; Burger, D.M.

    2016-01-01

    OBJECTIVE: To describe the pharmacokinetics of abacavir 600 mg once daily (q.d.) in HIV-1-positive women during pregnancy and postpartum. DESIGN: A nonrandomized, open-label, multicentre, phase-IV study. METHODS: HIV-positive pregnant women receiving abacavir 600 mg q.d. as part of clinical care wer

  6. Benefits of once-daily therapies in the treatment of hypertension

    Science.gov (United States)

    Flack, John M; Nasser, Samar A

    2011-01-01

    In patients with hypertension, 24-hour blood pressure control is the major therapeutic goal. The number of daily doses is one characteristic of an antihypertensive agent that may affect the adequacy of 24-hour control. One measure of therapeutic coverage is the 24-hour trough-to-peak ratio, which determines the suitability of an agent for once-daily administration. The closer an agent is to a 100% trough-to-peak ratio, the more uniform the 24-hour coverage and therefore blood pressure control. High trough-to-peak ratio, long-acting antihypertensive medications lower blood pressure more gradually, which reduces the likelihood of adverse events attributable to abrupt drug action that occurs with shorter-acting agents. In hypertension, the natural diurnal variation of blood pressure may be altered, including elevated nighttime pressures. An optimal once-daily hypertension therapy would not only lower blood pressure but also normalize any blunted circadian variations in blood pressure. The benefits of once-daily agents with sustained therapeutic coverage may also be explained, in part, by increased patient adherence to simpler regimens as well as lower loss of blood pressure control during virtually inevitable intermittent noncompliance. Studies have demonstrated that once-daily antihypertensive agents have the highest adherence compared with twice-daily or multiple daily doses, including greater adherence to the prescribed timing of doses. PMID:22241952

  7. Effects of Once-Daily Oral and Transdermal Methylphenidate on Sleep Behavior of Children with ADHD

    Science.gov (United States)

    Faraone, Stephen V.; Glatt, Stephen J.; Bukstein, Oscar G.; Lopez, Frank A.; Arnold, L. Eugene; Findling, Robert L.

    2009-01-01

    Objective: Methylphenidate is a leading first-line treatment for ADHD (AD/HD). This stimulant has long been suspected to adversely affect sleeping patterns of treated individuals, especially children. There are few studies on the effects of recently developed longer-acting methylphenidate treatments, such as once-daily oral or transdermal…

  8. Glucagon-like peptide-2 stimulates mucosal microcirculation measured by laser Doppler flowmetry in end-jejunostomy short bowel syndrome patients

    DEFF Research Database (Denmark)

    Høyerup, P; Hellström, P M; Schmidt, P T;

    2013-01-01

    In animal and human studies glucagon-like peptide-2 (GLP-2) has been shown to increase blood flow in the superior mesenteric artery and the portal vein. This study describes the effect of GLP-2 measured directly on the intestinal mucosal blood flow by laser Doppler flowmetry (LDF) in end-jejunost...

  9. [Lys40(Ahx-DTPA-111In)NH2]exendin-4, a very promising ligand for glucagon-like peptide-1 (GLP-1) receptor targeting.

    NARCIS (Netherlands)

    Wild, D.; Behe, M.; Wicki, A.; Storch, D.; Waser, B.; Gotthardt, M.; Keil, B.; Christofori, G.; Reubi, J.C.; Macke, H.R.

    2006-01-01

    High levels of glucagon-like peptide-1 (GLP-1) receptor expression in human insulinomas and gastrinomas provide an attractive target for imaging, therapy, and intraoperative tumor localization, using receptor-avid radioligands. The goal of this study was to establish a tumor model for GLP-1 receptor

  10. Glucagon-like peptide 2 inhibits ghrelin secretion in humans

    DEFF Research Database (Denmark)

    Banasch, Matthias; Bulut, Kerem; Hagemann, Dirk;

    2006-01-01

    INTRODUCTION: The growth hormone secretagogue receptor ligand ghrelin is known to play a pivotal role in the central nervous control of energy homeostasis. Circulating ghrelin levels are high under fasting conditions and decline after meal ingestion, but the mechanisms underlying the postprandial...... drop in ghrelin levels are poorly understood. In the present study we addressed, whether (1) exogenous GLP-2 administration decreases ghrelin levels and (2) what other endogenous factors are related to ghrelin secretion under fasting conditions. PATIENTS AND METHODS: Fifteen healthy male volunteers...... were studied with the intravenous infusion of GLP-2 (2 pmol l(-1) min(-1)) or placebo over 120 min in the fasting state. Plasma concentrations of glucose, insulin, C-peptide, glucagon, intact GLP-2 and ghrelin were determined. RESULTS: During the infusion of GLP-2, plasma concentrations of intact GLP-2...

  11. Liraglutide, a human glucagon-like peptide-1 analogue, plays a role in reducing body weight in the patients with type 2 diabetes%人胰升糖素样肽1类似物利拉鲁肽减轻2型糖尿病患者体重的作用

    Institute of Scientific and Technical Information of China (English)

    邹大进

    2011-01-01

    肥胖与多种代谢异常相关,包括胰岛素抵抗和2型糖尿病.减轻体重能有效改善胰岛素敏感性,并由此降低肥胖相关的2型糖尿病和心血管疾病风险.研究证实,人胰升糖素样肽1(GLP-1)类似物利拉鲁肽不论单用还是与其他降糖药物联用,都可更好地控制血糖,保护胰岛β细胞功能,并通过抑制摄食和延缓胃肠蠕动减轻体重,这为2型糖尿病患者的治疗提供了新的选择.%Obesity is associated with numerous metabolic abnormalities, including insulin resistance and type 2 diabetes. Losing weight is an effective way of improving insulin sensitivity, thus decreasing the risk of obesityassociated diabetes and chronic cardiovascular disease. There is evidence that Liraglutide, as a human glucagon-like peptide-1 ( GLP-1 ) analogue, either using alone or combining with other glucose-lowering drugs, has effect on improving glycemic control, protecting β-cell function, and reducing body weight via inhibiting feeding behavior and delaying gastrointestinal motility. Therefore, liraglutide is a new option for treating type 2 diabetes patients.

  12. Once-daily dolutegravir is superior to once-daily darunavir/ritonavir in treatment-naïve HIV-1-positive individuals: 96 week results from FLAMINGO

    Directory of Open Access Journals (Sweden)

    Jean-Michel Molina

    2014-11-01

    Full Text Available Introduction: Dolutegravir (DTG 50 mg once daily was superior to darunavir/ritonavir (DRV/r 800 mg/100 mg once daily through Week 48, with 90% vs. 83% of participants achieving HIV RNA 50 c/mL (p=0.025 [1]. We present data through Week 96. Material and Methods: FLAMINGO is a multicentre, randomized, open-label, Phase IIIb non-inferiority study, in which HIV-1-positive ART-naïve adults with HIV-1 RNA≥1000 c/mL and no evidence of viral resistance were randomized 1:1 to receive DTG or DRV/r, with investigator-selected backbone NRTIs (TDF/FTC or ABC/3TC. Participants were stratified by screening HIV-1 RNA (≤100K c/mL and NRTI backbone. Results: A total of 484 adults were randomized and treated; 25% had baseline HIV RNA 100K c/mL. At Week 96, the proportion of participants with HIV RNA 50 c/mL was 80% in the DTG arm vs. 68% in the DRV/r arm (adjusted difference 12.4%; 95% CI 4.7, 20.2%; p=0.002. Secondary analyses supported primary results: per-protocol [(DTG 83% vs. DRV/r 70%, 95% CI 12.9 (5.3, 20.6] and treatment-related discontinuation = failure [(98% vs. 95%, 95% CI 3.2 (−0.3, 6.7]. Overall virologic non-response (DTG 8%; DRV/r 12% and non-response due to other reasons (DTG 12%; DRV/r 21% occurred less frequently on DTG. As at Week 48, the difference between arms was most pronounced in participants with high baseline viral load (82% vs. 52% response through Week 96 and in the TDF/FTC stratum (79% vs. 64%; consistent responses were seen in the ABC/3TC stratum (82% vs. 75%. Six participants (DTG 2, none post-Week 48; DRV/r 4, two post-Week 48 experienced protocol-defined virologic failure (PDVF; confirmed viral load 200 c/mL on or after Week 24; none had treatment-emergent resistance to study drugs. Most frequent drug-related adverse events (AEs were diarrhoea, nausea and headache, with diarrhoea significantly more common on DRV/r (24% than DTG (10%. Significantly more participants had Grade 2 fasting LDL toxicities on DRV/r (22% vs. DTG (7

  13. Plasma levels of glucagon like peptide-1 associate with diastolic function in elderly men

    DEFF Research Database (Denmark)

    Nathanson, D; Zethelius, B; Berne, C;

    2011-01-01

    Congestive heart failure is a major cause of morbidity and mortality in diabetes. Besides the glycaemic effects of glucagon-like peptide 1 (GLP-1) mimetics, their effects on the heart are of interest....

  14. Glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: new advances

    DEFF Research Database (Denmark)

    Asmar, Meena; Holst, Jens Juul

    2010-01-01

    This article highlights recent advances in our understanding of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) physiology and their various sites of action beyond the incretin effect.......This article highlights recent advances in our understanding of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) physiology and their various sites of action beyond the incretin effect....

  15. Evaluation of beta-cell secretory capacity using glucagon-like peptide 1

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Nielsen, Mette Toft; Krarup, T

    2000-01-01

    Beta-cell secretory capacity is often evaluated with a glucagon test or a meal test. However, glucagon-like peptide 1 (GLP-1) is the most insulinotropic hormone known, and the effect is preserved in type 2 diabetic patients.......Beta-cell secretory capacity is often evaluated with a glucagon test or a meal test. However, glucagon-like peptide 1 (GLP-1) is the most insulinotropic hormone known, and the effect is preserved in type 2 diabetic patients....

  16. Enteral supplementation with glutamine, fiber, and oligosaccharide modulates incretin and glucagon-like peptide-2 secretion

    OpenAIRE

    2014-01-01

    Aims/Introduction: A dietary supplementation product enriched with glutamine, dietary fiber and oligosaccharide (GFO) is widely applied for enteral nutrition support in Japan. The aim of the present study was to evaluate the effects of GFO ingestion on secretion of incretins, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 (GLP-2). Materials and Methods: We carried out a cross-over study involving 20 healthy Japanese volunteers. The partic...

  17. The antianginal efficacy and tolerability of controlled-release metoprolol once daily

    DEFF Research Database (Denmark)

    Egstrup, K; Gundersen, T; Härkönen, R;

    1988-01-01

    In a randomized, double-blind, cross-over study treatment with a new controlled-release (CR) preparation of metoprolol, given once daily, was compared with treatment with conventional metoprolol tablets, given twice daily, in 115 patients with stable effort angina pectoris. The patients were...... questionnaire. When all patients were analysed together there were no differences in antianginal efficacy between the two treatment regimens. However, when the group taking 200 mg daily was analysed separately better exercise tolerance was found during metoprolol CR therapy, as measured by onset of chest pain...... and ST-segment change, compared with conventional metoprolol therapy. The two formulations were well tolerated. When given once daily in a total daily dose of 100 mg, the CR preparation induced less adverse effects than the conventional tablets, 50 mg twice daily. It was concluded that the new metoprolol...

  18. Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I

    DEFF Research Database (Denmark)

    Orskov, C; Poulsen, Steen Seier; Møller, M

    1996-01-01

    The intestinal incretin hormone glucagon-like peptide I (GLP-I) inhibits gastric motility and secretion in normal, but not in vagotomized subjects, pointing to a centrally mediated effect. Therefore, our aim was to study the availability of rat brain GLP-I receptors to peripherally injected 125I-...

  19. Profile of glycopyrronium for once-daily treatment of moderate-to-severe COPD

    Directory of Open Access Journals (Sweden)

    Buhl R

    2012-10-01

    Full Text Available Roland Buhl,1 Donald Banerji21Pulmonary Department, Mainz University Hospital, Mainz, Germany; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, USAAbstract: Bronchodilators are central in the symptomatic management of chronic obstructive pulmonary disease (COPD. Long-acting muscarinic antagonists (LAMAs and long-acting β2-agonists (LABAs are the main classes of long-acting bronchodilators. To date, tiotropium is the only once-daily LAMA available for the treatment of COPD. Glycopyrronium is a novel LAMA, currently in development for COPD. Phase II studies have shown that glycopyrronium 50 µg once daily provides clinically significant 24-hour bronchodilation with a rapid onset of action, which is faster than that of tiotropium, and a favorable safety and tolerability profile. The Phase III GLycopyrronium bromide in COPD airWays (GLOW program has now confirmed the long-term efficacy and tolerability of glycopyrronium 50 µg once daily. The three studies included in this program have further shown that the effect of glycopyrronium versus placebo is similar to that of tiotropium in reducing dyspnea and the risk of exacerbations, as well as improving lung function, exercise tolerance, and health status in patients with COPD. The safety profile of glycopyrronium is also similar to that of tiotropium in terms of overall incidence of adverse events and muscarinic side effects. Glycopyrronium could be an alternative choice to tiotropium, and like tiotropium, has the potential to be used as a monotherapy or combination therapy. Phase II studies have shown that a fixed-dose combination of glycopyrronium and the 24-hour LABA indacaterol, produces rapid and sustained bronchodilation compared with indacaterol monotherapy in patients with COPD. Phase III studies are currently ongoing to assess the long-term efficacy and safety of this combination.Keywords: NVA237, glycopyrronium, chronic obstructive pulmonary disease, once daily, muscarinic

  20. Liraglutide: a once-daily GLP-1 analogue for the treatment of type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina

    2007-01-01

    properties that are suitable for once-daily dosing. Liraglutide has demonstrated lasting improvement of HbA(1c )levels, weight reduction and improved beta-cell function in patients with Type 2 diabetes mellitus. Liraglutide is well tolerated; the adverse events that are most frequently reported being...... transient nausea and diarrhoea. This article reviews the mechanisms of action and efficacy of liraglutide for the treatment of Type 2 diabetes mellitus. This agent is presently in Phase III clinical development....

  1. Update on the clinical utility of once-daily tacrolimus in the management of transplantation

    Directory of Open Access Journals (Sweden)

    Revollo J

    2015-05-01

    Full Text Available Jane Revollo Department of Pharmacy, Jackson Memorial Hospital, University of Miami Leonard M Miller School of Medicine Miami, FL, USAThe review by Posadas Salas and Srinivas of the clinical utility of once-daily tacrolimus formulations in the management of transplant patients1 was timely and relevant. It is worth noting, however, the data were presented in a way that overlooked several key differences between two distinct once-daily tacrolimus formulations. These formulations differ in bioavailability, Cmax, Tmax, dose required to achieve target trough levels, and time to reach target trough. The specific formulation and dosing information of one product was detailed in this review (described as modified release 4 [MR-4]; Astagraf®, Astellas Pharma Inc., Tokyo, Japan, but no formulation or dosing details were provided for a very different once-daily tacrolimus formulation (LCP-Tacro™; Veloxis Pharmaceuticals A/S, Hørsholm, Denmark for which a thorough review was recently published.2 The latter product is currently approved in Europe and under review by the US Food and Drug Administration in the US. In presenting data in this review, the authors did not identify which product was investigated in each of the studies discussed. This could easily lead to misinterpretation of results or erroneous conclusions, ie, that both once-daily formulations are the same. In fact, a careful parsing of the data clearly demonstrates that they are not equivalent. Misunderstanding of this point could have a potentially serious impact on appropriate dosing, safety, and patient management in the post-transplant setting. Differentiation between the two products is needed to clarify what appear to be conflicting results of the studies presented in this review.View original paper by Posadas Salas and Srinivas

  2. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison.

    Science.gov (United States)

    Kornmann, O; Dahl, R; Centanni, S; Dogra, A; Owen, R; Lassen, C; Kramer, B

    2011-02-01

    Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β(2)-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily β(2)-agonist, salmeterol, as an active control. Patients with moderate-to-severe COPD were randomised to 6 months double-blind treatment with indacaterol (150 μg once daily), salmeterol (50 μg twice daily) or placebo. The primary efficacy end-point was trough (24 h post-dose) forced expiratory volume in 1 s (FEV(1)) after 12 weeks. 1,002 patients were randomised and 838 (84%) completed the study. Indacaterol increased trough FEV(1) at week 12 by 170 mL over placebo (pindacaterol. Safety profiles were similar across the treatment groups, and both indacaterol and salmeterol were well tolerated. Once-daily treatment with 150 μg indacaterol had a significant and clinically relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 μg salmeterol. Indacaterol should prove a useful additional treatment for patients with COPD.

  3. Once-daily dosing of amikacin for treatment of Mycobacterium abscessus lung disease.

    Science.gov (United States)

    Lee, H; Sohn, Y M; Ko, J Y; Lee, S-Y; Jhun, B W; Park, H Y; Jeon, K; Kim, D H; Kim, S-Y; Choi, J E; Moon, I J; Shin, S J; Park, H J; Koh, W-J

    2017-07-01

    Tertiary referral centre, Samsung Medical Center, South Korea. To evaluate the pharmacokinetic parameters and toxicities of once-daily amikacin (AMK) dosing for lung disease due to Mycobacterium abscessus. A retrospective review of 48 patients with M. abscessus lung disease who received once-daily AMK for 4 weeks between January 2012 and June 2015. With a starting dose of 15 mg/kg/day and adjustment of AMK dose according to the peak serum level (Cmax), the Cmax target of 55-65 μg/ml was achieved in 31.3% (15/48) of patients in the first week, 68.8% (33/48) in week 2, 91.7% (44/48) in week 3 and 95.8% (46/48) in week 4. Transient nephrotoxicity developed in 6.3% (3/48) of patients and ototoxicity in 25.0% (6/24), which was determined by audiogram as hearing loss, asymptomatic in five patients and tinnitus in one. Multivariate analysis revealed that the highest drug concentration 12 h after administration was significantly associated with the development of toxicities (adjusted odds ratio 1.862, P = 0.047). Our results suggest that once-daily AMK for 4 weeks with a target Cmax of 55-65 μg/ml can be used in patients with M. abscessus lung disease, with careful monitoring of toxicity.

  4. Tadalafil once daily in the management of erectile dysfunction: patient and partner perspectives

    Directory of Open Access Journals (Sweden)

    Pierre Costa

    2009-04-01

    Full Text Available Pierre Costa1, Thierry Grivel2, Naji Gehchan31Service d’Urologie–Andrologie, Hôpital Caremeau, Nîmes, France; 2159, Avenue Sainte-Marguerite, Nice, France; 3Eli Lilly and Company, Lilly France – Medical Division, Suresnes, FranceAbstract: Erectile dysfunction (ED is a prevalent condition that affects men and their partners. Significant improvements in the sexual lives of these couples have been achieved with the introduction of phosphodiesterase 5 (PDE5 inhibitors. A PDE5 inhibitor is now widely recognized as the first-line therapy for the majority of men with ED. Currently, three PDE5 inhibitors – sildenafil, tadalafil and vardenafil – are approved to be taken as needed in anticipation of sexual activity, but only one of these, tadalafil, has been approved to be taken once daily. The primary aims of this review are to summarize the patients’ and partners’ viewpoints of ED management with PDE5 inhibitors, and to determine whether once-daily tadalafil can contribute to improving some psychological aspects of ED (such as sexual self-confidence, spontaneity and time concerns compared with on-demand tadalafil or other PDE5 inhibitors taken by patients with ED.Keywords: erectile dysfunction, once-daily treatment, patient and partner perspectives, phosphodiesterase 5 (PDE5 inhibitor

  5. Short Communication: Maraviroc Once-Daily: Experience in Routine Clinical Practice.

    Science.gov (United States)

    Saumoy, Maria; Llibre, Josep M; Terrón, Alberto; Knobel, Hernando; Arribas, José Ramón; Domingo, Pere; Arroyo-Manzano, David; Rivero, Antonio; Moreno, Santiago; Podzamczer, Daniel

    2017-01-01

    To assess the efficacy and safety of maraviroc (MVC) administered once-daily in routine clinical practice. A retrospective multicenter study (27 centers in Spain) was conducted. Data were collected from the records of patients starting a regimen with MVC. Laboratory and clinical data were recorded every 3 months the first year and every 6 months thereafter. Data are presented as median and interquartile range. Among 667 patients treated with MVC, 142 (21.3%) received MVC once-daily: 108 (76.1%), 150 mg and 34 (23.9%), and 300 mg. Age was 47 (42-45) years, there were 76.1% men, and 81 (57%) patients had baseline HIV-RNA MVC: salvage therapy (36.6%), drug toxicity (31.2%), simplification (16.9%), and immunodiscordant response (7.1%). Median follow-up was 13 (9-16) months. In 95.8%, a PI/r was part of the regimen (67% on dual therapy). At months 12 and 24, 73.3% and 68.2% of patients had HIV-RNA MVC: virologic failure (6), medical decision (5), and other reasons (14). Two patients presented grade 3 adverse events (hypertransaminasemia, hypertriglyceridemia) without the need for MVC withdrawal, whereas MVC was discontinued in two patients due to gastrointestinal toxicity. In routine clinical practice, MVC once-daily combined with at least PI/r was virologically effective and well tolerated in a high percentage of pretreated patients.

  6. Zaditen SRO permits once-daily dosing with superior efficacy in the prophylaxis of asthma.

    Science.gov (United States)

    Radielovic, P; Morley, J; Hansel, T T; Medici, T C

    1995-01-01

    This international, multicenter clinical trial was designed to compare the efficacy and safety of two different formulations of ketotifen: Zaditen SRO and Zaditen Standard Form. In a randomized double-blind study over a 12-week treatment period, 3 parallel groups of asthmatic subjects received Zaditen SRO (2 mg once daily), Zaditen SRO (4 mg once daily), or Zaditen Standard Form (1 mg twice daily). Asthmatic subjects (362 evaluable cases, aged 6-29 years) kept daily records of clinical symptoms, use of concomitant medication, and peak flow recordings and were examined at 2-week intervals up to the end of the study. Zaditen SRO 4 mg administered once a day at night showed a statistically significant faster onset of action and was more clinically effective than Zaditen Standard Form. The Zaditen SRO 4-mg and 2-mg formulations were at least as well tolerated as the standard form, with somnolence occurring equally after both formulations. In conclusion, Zaditen SRO (4 mg once daily) was found to be equally safe and more effective in the prophylactic treatment of mild and moderate bronchial asthma than Zaditen Standard Form (1 mg twice daily).

  7. A Review on the Association between Glucagon-Like Peptide-1 Receptor Agonists and Thyroid Cancer

    Directory of Open Access Journals (Sweden)

    Wei-Yih Chiu

    2012-01-01

    Full Text Available There is a concern on the risk of thyroid cancer associated with glucagon-like peptide-1 (GLP-1 analogs including liraglutide and exenatide. In this article, we review related experimental studies, clinical trials and observational human studies currently available. In rodents, liraglutide activated the GLP-1 receptors on C-cells, causing an increased incidence of C-cell neoplasia. Animal experiments with monkeys demonstrated no increase in calcitonin release and no C-cell proliferation after long-term liraglutide administration. Longitudinal 2-year data from clinical trials do not support any significant risk for the activation or growth of C-cell cancer in humans in response to liraglutide. However, an analysis of the FDA adverse event reporting system database suggested an increased risk for thyroid cancer associated with exenatide after its marketing. Noticeably, a recent study discovered that GLP-1 receptor could also be expressed in human papillary thyroid carcinomas (PTC, but the impact of GLP-1 analogs on PTC is not known. Therefore, GLP-1 analogs might increase the risk of thyroid C-cell pathology in rodents, but its risk in humans awaits confirmation. Since GLP-1 receptor is also expressed in PTC besides C-cells, it is important to investigate the actions of GLP-1 on different subtypes of thyroid cancer in the future.

  8. Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients.

    Science.gov (United States)

    Staatz, Christine E; Tett, Susan E

    2015-10-01

    Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf(®), a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf(®) and Envarsus(®) XR) and various generic versions of Prograf(®) are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid-organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf(®), Advagraf(®) and Envarsus(®) XR are not bioequivalent [in terms of the area under the concentration-time curve from 0 to 24 h (AUC0-24) or the minimum concentration (C min)]. Patients may require a daily dosage increase if converted from Prograf(®) to Advagraf(®), while a daily dosage reduction appears necessary for conversion from Prograf(®) to Envarsus(®) XR. Prograf(®) itself, or generic immediate-release tacrolimus, can be administered in a once-daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC0-24 and C min is variable and not strong for all three

  9. A once-daily HAART regimen containing indinavir + ritonavir plus one or two nucleoside reverse transcriptase inhibitors (PIPO study).

    NARCIS (Netherlands)

    Burger, D.M.; Aarnoutse, R.E.; Dieleman, J.P.; Gyssens, I.C.J.; Nouwen, J.; Marie, S. de; Koopmans, P.P.; Stek Jr, M.; Ende, M.E. van der

    2003-01-01

    INTRODUCTION: There is an increased interest in developing once-daily regimens for the treatment of HIV-infected patients. A Phase II study was conducted to investigate the pharmacokinetics, and short-term safety and efficacy of an indinavir/ritonavir combination as part of a once-daily regimen. MET

  10. Randomized, double-blind, multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease.

    Science.gov (United States)

    Hauser, Robert A; Schapira, Anthony H V; Rascol, Olivier; Barone, Paolo; Mizuno, Yoshikuni; Salin, Laurence; Haaksma, Monika; Juhel, Nolwenn; Poewe, Werner

    2010-11-15

    The objective of this study was to evaluate the efficacy and safety of pramipexole extended release (ER) administered once daily in early Parkinson's disease (PD). Pramipexole immediate release (IR) administered three times daily (TID) is an efficacious and generally well-tolerated treatment for PD. A pramipexole ER formulation is now available. We performed a randomized, double-blind, placebo and active comparator-controlled trial in subjects with early PD. The primary efficacy and safety evaluation of pramipexole ER compared with placebo took place at week 18. Two hundred fifty-nine subjects were randomized 2:2:1 to treatment with pramipexole ER once daily, pramipexole IR TID, or placebo. Levodopa rescue was required by 7 subjects in the placebo group (14%), 3 subjects in the pramipexole ER group (2.9%, P = 0.0160), and 1 subject in the pramipexole IR group (1.0%, P = 0.0017). Adjusted mean [standard error (SE)] change in Unified Parkinson Disease Rating Scale (UPDRS) II [activities of daily living (ADL)] + III (motor) scores from baseline to week 18, including post-levodopa rescue evaluations, was -5.1 (1.3) in the placebo group, -8.1 (1.1) in the pramipexole ER group (P = 0.0282), and -8.4 (1.1) in the pramipexole IR group (P = 0.0153). Adjusted mean (SE) change in UPDRS ADL + motor scores, censoring post-levodopa rescue data, was -2.7 (1.3) in the placebo group, -7.4 (1.1) in the pramipexole ER group (P = 0.0010), and -7.5 (1.1) in the pramipexole IR group (P = 0.0006). Adverse events more common with pramipexole ER than placebo included somnolence, nausea, constipation, and fatigue. Pramipexole ER administered once daily was demonstrated to be efficacious compared with placebo and provided similar efficacy and tolerability as pramipexole IR administered TID.

  11. A dynamic model of once-daily 5-aminosalicylic acid predicts clinical efficacy

    Institute of Scientific and Technical Information of China (English)

    Deepak; Parakkal; Eli; D; Ehrenpreis; Matthew; P; Thorpe; Karson; S; Putt; Bruce; Hannon

    2010-01-01

    New once daily mesalamine formulations may improve adherence to medication usage.Response to Asacol and other forms of 5-aminosalicyclic acid(5-ASA)is better correlated with tissue concentrations and best predicted by concentrations of the drug within the lumen of the colon.Our group used computer simulation to predict colonic 5-ASA levels after Asacol administration.In our study,the model simulated Asacol distribution in the healthy colon,and during quiescent and active ulcerative colitis.An Asacol dosage ...

  12. Maintaining remission in ulcerative colitis--role of once daily extended-release mesalamine.

    Science.gov (United States)

    Oliveira, Lilliana; Cohen, Russell D

    2011-02-27

    The aminosalicylates (5-ASA; also referred to as mesalamine-based agents) are considered as first-line in the maintenance of remission of mild to moderate ulcerative colitis (UC). Traditionally these agents have required a large pill burden and multiple daily dosing regimens which may account for the low adherence rates, especially in patients in remission. Extended-release mesalamine is the first once daily mesalamine product approved by the Food and Drug Administration for the maintenance of UC remission. This review will examine the pharmacokinetics, dosing, efficacy, and safety data of extended-release mesalamine, and discuss the potential role of improving medication compliance and decreasing costs in UC maintenance.

  13. Efficacy and safety of ciclesonide once daily and fluticasone propionate twice daily in children with asthma

    DEFF Research Database (Denmark)

    Pedersen, Søren; Engelstätter, Renate; Weber, Hans-Jochen

    2009-01-01

    the efficacy and safety of ciclesonide with fluticasone propionate in children with mainly moderate and severe persistent asthma. METHODS: Seven hundred and forty-four patients (aged 6-11years) were randomized to ciclesonide (80 or 160mug once daily) or fluticasone propionate (88mug twice daily), following a 2...... excretion, in children with moderate and severe asthma.......BACKGROUND: Ciclesonide is a new inhaled corticosteroid (ICS). Information about its clinical efficacy and safety in relation to other ICS in children is needed for clinical positioning. OBJECTIVE: This 12-week, randomized, double-blind, double-dummy, three-arm, parallel-group study compared...

  14. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain-Adipocyte Axis.

    Science.gov (United States)

    Geloneze, Bruno; de Lima-Júnior, José Carlos; Velloso, Lício A

    2017-02-23

    The complexity of neural circuits that control food intake and energy balance in the hypothalamic nuclei explains some of the constraints involved in the prevention and treatment of obesity. Two major neuronal populations present in the arcuate nucleus control caloric intake and energy expenditure: one population co-expresses orexigenic agouti-related peptide (AgRP) and neuropeptide Y and the other expresses the anorexigenic anorectic neuropeptides proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART). In addition to integrating signals from neurotransmitters and hormones, the hypothalamic systems that regulate energy homeostasis are affected by nutrients. Fat-rich diets, for instance, elicit hypothalamic inflammation (reactive activation and proliferation of microglia, a condition named gliosis). This process generates resistance to the anorexigenic hormones leptin and insulin, contributing to the genesis of obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have increasingly been used to treat type 2 diabetes mellitus. One compound (liraglutide) was recently approved for the treatment of obesity. Although most studies suggest that GLP-1RAs promote weight loss mainly due to their inhibitory effect on food intake, other central effects that have been described for native GLP-1 and some GLP-1RAs in rodents and humans encourage future clinical trials to explore additional mechanisms that potentially underlie the beneficial effects observed with this drug class. In this article we review the most relevant data exploring the mechanisms involved in the effects of GLP-1RAs in the brain-adipocyte axis.

  15. Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis.

    Science.gov (United States)

    Monami, Matteo; Dicembrini, Ilaria; Marchionni, Niccolò; Rotella, Carlo M; Mannucci, Edoardo

    2012-01-01

    Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs), approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for "exenatide," "liraglutide," "albiglutide," "semaglutide," and "lixisenatide" was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or active drugs. Twenty two (7,859 patients) and 7 (2,416 patients) trials with available results on body weight at 6 and 12 months, respectively, were included. When compared with placebo, GLP-1RAs determine a reduction of BMI at 6 months of -1.0 [-1.3; -0.6] kg/m(2). Considering the average BMI at baseline (32.4 kg/m(2)) these data means a weight reduction of about 3% at 6 months. This result could seem modest from a clinical standpoint; however, it could be affected by many factors contributing to an underestimation of the effect of GLP-1RA on body weight, such as non adequate doses, inclusion criteria, efficacy of GLP-1RA on reducing glycosuria, and association to non-pharmacological interventions not specifically aimed to weight reduction.

  16. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Body Weight: A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Matteo Monami

    2012-01-01

    Full Text Available Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs, approved as glucose-lowering drugs for the treatment of type 2 diabetes, have also been shown to reduce body weight. An extensive Medline, Cochrane database, and Embase search for “exenatide,” “liraglutide,” “albiglutide,” “semaglutide,” and “lixisenatide” was performed, collecting all randomized clinical trials on humans up to December 15, 2011, with a duration of at least 24 weeks, comparing GLP-1 receptor agonists with either placebo or active drugs. Twenty two (7,859 patients and 7 (2,416 patients trials with available results on body weight at 6 and 12 months, respectively, were included. When compared with placebo, GLP-1RAs determine a reduction of BMI at 6 months of −1.0 [−1.3; −0.6] kg/m2. Considering the average BMI at baseline (32.4 kg/m2 these data means a weight reduction of about 3% at 6 months. This result could seem modest from a clinical standpoint; however, it could be affected by many factors contributing to an underestimation of the effect of GLP-1RA on body weight, such as non adequate doses, inclusion criteria, efficacy of GLP-1RA on reducing glycosuria, and association to non-pharmacological interventions not specifically aimed to weight reduction.

  17. Real-world glycemic outcomes in patients with type 2 diabetes initiating exenatide once weekly and liraglutide once daily: a retrospective cohort study

    Science.gov (United States)

    Saunders, William B; Nguyen, Hiep; Kalsekar, Iftekhar

    2016-01-01

    Aim The glucagon-like peptide-1 receptor agonists exenatide once weekly (QW) and liraglutide once daily (QD) have demonstrated improvements in glycemic outcomes in patients with type 2 diabetes mellitus in randomized clinical trials. However, little is known about their real-world comparative effectiveness. This retrospective cohort study used the Quintiles Electronic Medical Record database to evaluate the 6-month change in glycated hemoglobin (A1C) for patients initiating exenatide QW or liraglutide QD. Methods Patients with type 2 diabetes mellitus prescribed exenatide QW (n=664) or liraglutide QD (n=3,283) between February 1, 2012 and May 31, 2013 were identified. Baseline A1C measures were from 75 days before to 15 days after initiating exenatide QW or liraglutide QD, with follow-up measures documented at 6 months (±45 days). Adjusted linear regression models compared the difference in mean A1C change. A priori defined sensitivity analysis was performed in the subgroup of patients with baseline A1C ≥7.0% and no prescription for insulin during the 12-month pre-index period. Results For exenatide QW and liraglutide QD, respectively, mean (SD) age of the main study cohort was 58.01 (10.97) and 58.12 (11.05) years, mean (SD) baseline A1C was 8.4% (1.6) and 8.4% (1.6), and 48.2% and 54.2% of patients were women. In adjusted models, change in A1C did not differ between exenatide QW and liraglutide QD during 6 months of follow-up. Results were consistent in the subgroup analyses. Conclusion In a real-world setting, A1C similarly improves in patients initiating exenatide QW or liraglutide QD. PMID:27486339

  18. Patient considerations in the management of ulcerative colitis: role of once-daily MMX mesalamine

    Directory of Open Access Journals (Sweden)

    Daniel B Zandman

    2009-03-01

    Full Text Available Daniel B Zandman, Mark A PeppercornHarvard Medical School, Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USAAbstract: Mesalamine and its derivatives are effective and well-tolerated therapies for ulcerative colitis. However, patient adherence to traditional mesalamine-based therapy is poor, and is often limited by heavy pill burdens and frequent dosing intervals. This can lead to ineffective disease control, impaired quality of life, and preventable morbidity and mortality. Previous studies have suggested that a once-daily mesalamine regimen would be strongly adhered to in the outpatient setting, but at that time no such formulation of mesalamine existed. In 2007, clinical trial data showed a novel, once-daily, multi-matrix (MMX formulation of mesalamine to be effective in both remission induction and remission maintenance. This breakthrough in drug delivery allowed the unification of an effective therapeutic with a formulation that enables outpatients to be increasingly adherent to their medication. In theory, this might result in improved outpatient disease control and a decreased number of flares. As the use of MMX mesalamine increases, studies examining the outpatient community adherence rate need to be performed.Keywords: mesalamine, MMX, Lialda™, ulcerative colitis, inflammatory bowel disease, adherence

  19. [Effectiveness of new, once-daily 5-aminosalicylic acid in the treatment of ulcerative colitis].

    Science.gov (United States)

    Lakatos, Péter László; Lakatos, László

    2009-03-01

    5-aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents is commercially available, including azo-bond pro-drugs such as sulfasalazine, olsalazine and balsalazide, and delayed- and controlled-release forms of mesalazine. In addition, the effectiveness of oral therapy relies on good compliance, which may be adversely affected by frequent daily dosing and a large number of tablets. Furthermore, poor adherence has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine including the unique multi-matrix delivery system and mesalazine granules were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of low pill burden and may contribute to increased long-term compliance and treatment success in clinical practice and might potentially further contribute to a decline in the risk for UC-associated colon cancers. In this systematic review, the authors summarize the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.

  20. Once daily 5-aminosalicylic acid for the treatment of ulcerative colitis; are we there yet?

    Science.gov (United States)

    Lakatos, Peter Laszlo; Lakatos, Laszlo

    2008-01-01

    5-Aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents are commercially available, including azo-bond pro-drugs such as sulfasalazine, olsalazine and balsalazide, and delayed- and controlled-release forms of mesalazine. In addition, the effectiveness of oral therapy relies on good compliance, which may be adversely affected by frequent daily dosing and a large number of tablets. Furthermore, poor adherence has been shown to be an important barrier to successful management of patients with UC. Recently, new, once daily formulations of mesalazine including the unique multi-matrix delivery system and mesalazine granules were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of low pill burden and may contribute to increased long-term compliance and treatment success in clinical practice and might potentially further contribute to a decline in the risk for UC-associated colon cancers. In this systematic review, the authors summarize the available literature on the short- and medium-term efficacy and safety of the new once daily mesalazine formulations.

  1. 利拉鲁肽对新诊断的糖化血红蛋白>9%的2型糖尿病患者的有效性及安全性%The efficacy and safety of human glucagon-like peptide-1 analogue liraglutide in newly diagnosed type 2 diabetes with glycosylated hemoglobin A1c > 9%

    Institute of Scientific and Technical Information of China (English)

    陈频; 陈晨; 邵珠林; 徐向进; 黄勤

    2015-01-01

    Objective To evaluate the efficacy and safety of human glucagon-like peptide-1 analogue liraglutide in newly diagnosed type 2 diabetes mellitus (T2DM) with glycosylated hemoglobin A1c (HbA1c) > 9%.Methods This was an open-labelled,randomized,parallel-group,treat-to-target trial.Newly diagnosed T2DM patients with HbA1c > 9% were enrolled.These patients were treated with metformin with repaglinide and randomized to receive once-daily liraglutide (LIRA,n =25) or the insulin glargine (IGla,n =24) at bedtime.Efficacy and safety were assessed and compared after 18-month treatment.Results (1) Compared with the baseline,patients with LIRA had significantly reduced mean body weight,BMI and waist circumference (P < 0.01),whereas,the above indexes were increased (P < 0.01) in patients treated with IGla.(2) After 18 months of treatment,fasting plasma glucose (FPG),2-hour plasma glucose after a 75g oral glucose load(2hPG) and HbA1c were significantly improved in all patients (P < 0.01),with 2hPG,mean blood glucose (MBG),the largest amplitude of glycemic excursions (LAGE),mean amplitude of glycemic excursions (MAGE) were significantly lower in LIRA group than in IGla group (all P < 0.05).(3) HOMA-IR decreased in both groups (P < 0.05).However,△I30/△G30,AUCCP180 and Matsuda index were only significantly increased in patients treated with LIRA (respectively,4.88 ± 1.55 vs 7.60 ± 1.91,9.23 ± 2.66 vs 13.18 ± 2.72,39.28 ± 20.35 vs 54.64 ± 23.34,all P < 0.01),while HOMA-IR reduced(4.41 ± 1.58 vs 3.52 ± 1.44,P <0.05).But in IGla group only HOMAIR was reduced (4.92 ± 1.84 vs 4.57 ± 1.80,P <0.05).The index of △I30/△G30,AUCCP180 and Matsuda index in LIRA group are higher than those of indexes in IGla group(respectively,7.60 ± 1.91 vs 4.18 ± 1.00,13.18 ± 2.72 vs 10.53 ± 2.68,54.64 ± 23.34 vs 41.65 ± 17.84,all P < 0.05),while HOMA-IR is lower (3.52 ± 1.44 vs 4.57 ± 1.80,P < 0.05).(4) The rate of HbA1 c ≤ 6.5 % and the dosages of oral

  2. Effects of Converting Tacrolimus Formulation from Twice-Daily to Once-Daily in Liver Transplantation Recipients

    Directory of Open Access Journals (Sweden)

    Ashok Thorat

    2014-01-01

    Full Text Available Typically, tacrolimus is administrated twice daily. Prolonged-release tacrolimus is the once-daily formulation and may be more convenient for patients. Experience with the administration of the once-daily formulation is still limited. This study enrolled 210 liver transplant recipients who had stable liver function and converted tacrolimus from a twice-daily to once-daily formulation on a 1 mg to 1 mg basis. Among 210 patients, seven patients (3.3% were withdrawn from the once-daily formulation due to allergy and fatigue. For the other patients, the trough concentration after converting to the once-daily formulation was lower than that of the twice-daily formulation. Liver enzymes were mildly elevated in 3 months after formulation conversion and serum creatinine and uric acid were mildly decreased. Seven patients (3.4% had clinical suspicion of acute rejection after the formulation conversion and three of them were caused by nonadherence. 155 patients (76.4% experienced a more convenient life with an increase of social activity. Forty-seven patients (23.2% experienced the convenience of once-daily formulation during overseas trips. In conclusion, tacrolimus can be safely converted from the twice-daily to the once-daily formulation for most stable liver recipients. Acute rejection may occur in a minority of patients during formulation conversion and should be carefully monitored.

  3. Randomised trial of once-daily vilanterol in children with asthma on inhaled corticosteroid therapy.

    Science.gov (United States)

    Oliver, Amanda J; Covar, Ronina A; Goldfrad, Caroline H; Klein, Ryan M; Pedersen, Søren E; Sorkness, Christine A; Tomkins, Susan A; Villarán, César; Grigg, Jonathan

    2016-04-05

    Inhaled corticosteroids (ICS) are effective maintenance treatments for childhood asthma; however, many children remain uncontrolled. Vilanterol (VI) is an inhaled long-acting beta-2 agonist which, in combination with the ICS fluticasone furoate, is being explored as a once-daily treatment for asthma in children. We evaluated the dose-response, efficacy, and safety of once-daily VI (6.25 μg, 12.5 μg and 25 μg) administered in the evening over 4 weeks, on background fluticasone propionate (FP) in children with asthma inadequately controlled on ICS. This was a Phase IIb, multicentre, randomised, double-blind, parallel-group, placebo-controlled study in children ages 5-11 years with persistent asthma on ICS and as-needed short-acting beta-agonist. The study comprised a 4-week run-in, 4-week treatment period, and 1-week follow-up. From study start, children replaced their current ICS with open-label FP 100 μg twice daily. Children were randomised to receive placebo, VI 6.25 μg, VI 12.5 μg or VI 25 μg once daily. Primary endpoint was treatment difference between VI 25 and placebo groups in mean change from baseline in evening peak expiratory flow averaged over the 4-week treatment. Secondary endpoints included change from baseline in trough forced expiratory volume in one second (FEV1) at Week 4 and change from baseline in percentage of rescue-free and symptom-free 24-h periods. Safety assessments included incidence of adverse events (AEs) and asthma exacerbations. In total, 456 children comprised the intention-to-treat population. The adjusted treatment difference between VI 25 and placebo groups for the primary endpoint was not statistically significant (p = 0.227) so no statistical inference was made for other VI dose comparisons or other endpoints. No difference in change from baseline in trough FEV1 was observed for any VI treatments versus placebo; however, VI 25 resulted in an additional 0.6 rescue-free days and 0.7 symptom-free days per week versus

  4. Maintaining remission in ulcerative colitis – role of once daily extended-release mesalamine

    Directory of Open Access Journals (Sweden)

    Lilliana Oliveira

    2011-02-01

    Full Text Available Lilliana Oliveira, Russell D CohenThe Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USAAbstract: The aminosalicylates (5-ASA; also referred to as mesalamine-based agents are considered as first-line in the maintenance of remission of mild to moderate ulcerative colitis (UC. Traditionally these agents have required a large pill burden and multiple daily dosing regimens which may account for the low adherence rates, especially in patients in remission. Extended-release mesalamine is the first once daily mesalamine product approved by the Food and Drug Administration for the maintenance of UC remission. This review will examine the pharmacokinetics, dosing, efficacy, and safety data of extended-release mesalamine, and discuss the potential role of improving medication compliance and decreasing costs in UC maintenance.Keywords: ulcerative colitis, 5-ASA, mesalamine, adherence, compliance, quality of life, costs

  5. Efficacy of Tadalafil once daily versus Fesoterodine in the treatment of overactive bladder in older patients.

    Science.gov (United States)

    Dell'Atti, L

    2015-01-01

    Several studies have suggested that phosphodiesterase type 5 inhibitors (5-PDEi) show a potential therapeutic use in the treatment of overactive bladder (OAB) and male lower urinary tract symptoms (LUTS). The aim of this study was to evaluating the efficacy on OAB symptoms, impact on quality of life and sexual function of tadalafil 5mg once daily in older patients versus fesoterodine 8 mg. 108 consecutive patients diagnosed with OAB were divided into 2 groups: Group A: 56 patients treated with tadalafil 5 mg once daily; Group B: 52 patients treated with fesoterodine 8 mg, both groups treated for a period of 12 weeks. Eligible patients were men aged ≥ 65 years with OAB symptoms, including urgency and increased frequency during a period of ≥ 1 year and urgency urinary incontinence during a period of ≥ 6 months before enrolment. Patients were asked to complete the 3-day voiding diary prior each scheduled visit at weeks 0, 4 and 12. During these visits, they were administered: Overactive Bladder Symptom Score (OABSS), International Prostate Symptoms Score (IPSS), International Index of Erectile Function (IIEF-5) and Quality of life (QoL). Not statistically significant differences emerged between the two groups at baseline, both patient groups had similar age and BMI; in each treatment group, the proportion of men ≥ 75 years was approximately 65%. From the results of our study, we can say that a treatment once a day with tadalafil improves not only significantly: micturition/24 hours (p fesoterodine treatment, but also the quality of life (p fesoterodine 8 mg is efficacious in the treatment of the symptoms of OAB in older adults, improving also the quality of life and sexual and social life.

  6. Multiple dose pharmacokinetics of a new once daily extended release tolterodine formulation versus immediate release tolterodine.

    Science.gov (United States)

    Olsson, B; Szamosi, J

    2001-01-01

    To determine the multiple dose pharmacokinetics of a new extended release (ER) capsule formulation of tolterodine, compared with the existing immediate release (IR) tablet, in healthy volunteers. Nonblind, randomised, 2-way crossover trial. 19 healthy volunteers (7 females, 12 males), mean age 33 years (range 18 to 55 years). Prior to the study, all volunteers were classified as either extensive or poor metabolisers by cytochrome P450 2D6 genotyping. Volunteers received tolterodine ER 4mg once daily or tolterodine IR 2mg twice daily for 6 days (all doses given as the L-tartrate salt). A washout period of 7 days separated the 2 treatments. Serum concentrations of tolterodine, its active 5-hydroxymethyl metabolite (5-HM) and the active moiety (extensive metabolisers: sum of unbound tolterodine + 5-HM; poor metabolisers: unbound tolterodine) were measured for up to 48 hours post-dose on day 6 (steady state). Tolerability was also determined. 17 volunteers (13 extensive metabolisers, 4 poor metabolisers) completed the study and were evaluable for both treatment periods. The 90% confidence interval for the geometric mean ratio of area under the serum concentration-time curve to 24 hours (AUC24) of the active moiety, for all volunteers combined, indicated equivalence for the 2 formulations. Pooled analysis also demonstrated that the peak serum concentration (Cmax) of the active moiety following administration of tolterodine ER was around 75% of that observed for the IR tablet, whereas the trough concentration was around 1.5-fold higher. Overall, the pharmacokinetics of tolterodine (irrespective of genotype) and 5-HM (extensive metabolisers only) were consistent with sustained drug release over 24 hours. Tolterodine ER was well tolerated. The new once daily ER formulation of tolterodine 4mg shows pharmacokinetic equivalence (AUC24) to the existing IR tablet given at a dose of 2mg twice daily. Findings of lower Cmax for tolterodine ER may explain the significantly lower

  7. Decreased Hypothalamic Glucagon-Like Peptide-1 Receptor Expression in Type 2 Diabetes Patients

    NARCIS (Netherlands)

    Ten Kulve, Jennifer S; van Bloemendaal, Liselotte; Balesar, Rawien; IJzerman, Richard G; Swaab, Dick F; Diamant, Michaela; la Fleur, Susanne E; Alkemade, Anneke

    2016-01-01

    CONTEXT: Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonist treatment in type 2 diabetes (T2DM) reduce blood glucose and food intake. It has been suggested that these effects are partly mediated through central GLP-1 receptors (GLP-1Rs). The rodent and nonhuman primate hypothalamus show clea

  8. Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates

    Science.gov (United States)

    Short bowel syndrome (SBS) is a frequent complication after intestinal resection in infants suffering from intestinal disease. We tested whether treatment with the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) increases intestinal volume and function in the period immediately following in...

  9. Impact of glucagon-like peptide-1 on myocardial glucose metabolism revisited

    DEFF Research Database (Denmark)

    Hansen, Jan; Brock, Birgitte; Bøtker, Hans Erik

    2014-01-01

    The gut hormone glucagon-like peptide-1 (GLP-1) is an insulinotropic incretin with significant cardiovascular impact. Two classes of medication, GLP-1 analogues and DPP-4 inhibitors, have been developed that circumvent the rapid degradation of GLP-1 by the enzyme dipeptidyl peptidase-4 (DPP-4), b...

  10. Determination of Glucagon-Like Peptide-1, Glucagon and Oxyntomodulin in Plasma

    DEFF Research Database (Denmark)

    Bak, Monika Judyta

    Glucagon-like peptide-1, glucagon and oxyntomodulin are three peptide hormones which play a significant role in diabetes, however there is a major controversy regarding their exact roles due to difficulties in measuring of these peptides because of molecular heterogeneity, low circulating concent...

  11. Diabetic intestinal growth adaptation and glucagon-like peptide 2 in the rat

    DEFF Research Database (Denmark)

    Thulesen, J; Hartmann, B; Nielsen, C;

    1999-01-01

    Dietary fibre influence growth and function of the upper gastrointestinal tract. This study investigates the importance of dietary fibre in intestinal growth in experimental diabetes, and correlates intestinal growth with plasma levels of the intestinotrophic factor, glucagon-like peptide 2 (GLP-2)....

  12. Intestinal Permeability and Glucagon-Like Peptide-2 in Children with Autism: A Controlled Pilot Study

    Science.gov (United States)

    Robertson, Marli A.; Sigalet, David L.; Holst, Jens J.; Meddings, Jon B.; Wood, Julie; Sharkey, Keith A.

    2008-01-01

    We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls…

  13. Intestinal permeability and glucagon-like peptide-2 in children with autism

    DEFF Research Database (Denmark)

    Robertson, Marli A; Sigalet, David L; Holst, Jens Juul

    2008-01-01

    We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response...

  14. Whey protein potentiates the intestinotrophic action of glucagon-like peptide-2 in parenterally fed rats

    DEFF Research Database (Denmark)

    Liu, Xiaowen; Murali, Sangita G; Holst, Jens J

    2009-01-01

    Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral...

  15. Glucagon-like peptide-2 in umbilical cord blood from mature infants

    DEFF Research Database (Denmark)

    Bodé, Susan; Hartmann, Bolette; Holst, Jens Juul

    2007-01-01

    BACKGROUND: Glucagon-like peptide-2 (GLP-2) seems to be a highly specific intestinotrophic mediator. From animal studies, GLP-2 is known to increase in the early neonatal period before it falls to adult level. No studies in newborn infants addressing this specific subject have been published so f...

  16. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice

    NARCIS (Netherlands)

    Ellenbroek, J.H.; Tons, H.A.; Westerouen van Meeteren, M.J.; de Graaf, N.; Hanegraaf, M.A.; Rabelink, T.J.; Carlotti, F.; de Koning, E.J.

    2013-01-01

    AIMS/HYPOTHESIS: Incretin-based therapies improve glycaemic control in patients with type 2 diabetes. In animal models of diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase beta cell mass. GLP-1RAs are also evaluated in non-diabetic individuals with obesity and cardiovascular di

  17. The effect of glucagon-like Peptide-2 receptor agonists on colonic anastomotic wound healing

    DEFF Research Database (Denmark)

    Redstone, Heather A; Buie, William D; Hart, David A;

    2010-01-01

    Background. Glucagon-like peptide 2 (GLP-2) is an intestinal specific trophic hormone, with therapeutic potential; the effects on intestinal healing are unknown. We used a rat model of colonic healing, under normoxic, and stress (hypoxic) conditions to examine the effect of GLP-2 on intestinal he...

  18. Glucagon-like peptide-1 analogue, liraglutide, in experimental cerebral malaria

    DEFF Research Database (Denmark)

    Della Valle, Brian William; Hempel, Casper; Staalsoe, Trine

    2016-01-01

    BACKGROUND: Cerebral malaria from Plasmodium falciparum infection is major cause of death in the tropics. The pathogenesis of the disease is complex and the contribution of reactive oxygen and nitrogen species (ROS/RNS) in the brain is incompletely understood. Insulinotropic glucagon-like peptide...

  19. Effects of chronic glucagon-like peptide-2 therapy during weaning in neonatal pigs

    DEFF Research Database (Denmark)

    Sigalet, David L; de Heuvel, Elaine; Wallace, Laurie;

    2014-01-01

    BACKGROUND: The enteroendocrine hormone glucagon like peptide-2 (GLP-2) and its ligands are under development as therapeutic agents for a variety of intestinal pathologies. A number of these conditions occur in neonates and infants, and thus a detailed understanding of the effects of GLP-2 during...

  20. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin

    NARCIS (Netherlands)

    Ripken, D.; Wielen, N. van der; Wortelboer, H.M.; Meijerink, J.; Witkamp, R.F.; Hendriks, H.F.J.

    2016-01-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis fo

  1. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin

    NARCIS (Netherlands)

    Ripken, Dina; Wielen, van der Nikkie; Wortelboer, Heleen M.; Meijerink, Jocelijn; Witkamp, Renger F.; Hendriks, Henk F.J.

    2016-01-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis

  2. Oligomerization of a Glucagon-like Peptide 1 Analog: Bridging Experiment and Simulations

    DEFF Research Database (Denmark)

    Frederiksen, Tine Maja; Sønderby, Pernille; Ryberg, Line A.

    2015-01-01

    The glucagon-like peptide 1 (GLP-1) analog, liraglutide, is a GLP-1 agonist and is used in the treatment of type-2 diabetes mellitus and obesity. From a pharmaceutical perspective, it is important to know the oligomerization state of liraglutide with respect to stability. Compared to GLP-1...

  3. Small-molecule agonists for the glucagon-like peptide 1 receptor

    DEFF Research Database (Denmark)

    Knudsen, Lotte Bjerre; Kiel, Dan; Teng, Min

    2007-01-01

    The peptide hormone glucagon-like peptide (GLP)-1 has important actions resulting in glucose lowering along with weight loss in patients with type 2 diabetes. As a peptide hormone, GLP-1 has to be administered by injection. Only a few small-molecule agonists to peptide hormone receptors have been...

  4. Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats.

    Science.gov (United States)

    DellaValle, Brian; Brix, Gitte S; Brock, Birgitte; Gejl, Michael; Landau, Anne M; Møller, Arne; Rungby, Jørgen; Larsen, Agnete

    2016-01-01

    Introduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS) pathology and influence the susceptibility to treatment, directing attention toward anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1 (GLP-1) family, is also anti-diabetic and weight-reducing and is, moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing the experimental model, experimental autoimmune encephalitis (EAE). Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 μg/kg s.c.) or saline. Healthy controls were included (saline, n = 6, liraglutide, n = 7). Clinical score and weight were assessed daily by blinded observers. Animals were killed at peak disease severity (day 11) or if exceeding humane endpoint (clinical score ≥4). Protein levels of manganese superoxide dismutase (MnSOD), amyloid precursor protein (APP), and glial fibrillary acidic protein (GFAP) were determined. Results: Liraglutide treatment delayed disease onset (group clinical score significantly >0) by 2 days and markedly reduced disease severity (median clinical score 2 vs. 5; p = 0.0003). Fourteen of 15 (93%) of vehicle-treated rats reached the humane endpoint (clinical score ≥4) by day 11 compared to 5 of 15 (33%) of liraglutide-treated rats (p = 0.0004). Liraglutide substantially increased the mitochondrial antioxidant MnSOD (p drug treatment (p = 0.09). Conclusion: We demonstrate, for the first time, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1 receptor agonists should be investigated further as a potential therapy for MS.

  5. Dietary lipids and sweeteners regulate glucagon-like peptide-2 secretion.

    Science.gov (United States)

    Sato, Shingo; Hokari, Ryota; Kurihara, Chie; Sato, Hirokazu; Narimatsu, Kazuyuki; Hozumi, Hideaki; Ueda, Toshihide; Higashiyama, Masaaki; Okada, Yoshikiyo; Watanabe, Chikako; Komoto, Shunsuke; Tomita, Kengo; Kawaguchi, Atsushi; Nagao, Shigeaki; Miura, Soichiro

    2013-04-15

    Glucagon-like peptide-2 (GLP-2) is a potent intestinal growth factor derived from enteroendocrine L cells. Although food intake is known to increase GLP-2 secretion, its regulatory mechanisms are largely unknown as a result of its very short half-life in venules. The aims of this study were to compare the effects of luminal nutrients on the stimulation of GLP-2 secretion in vivo using lymph samples and to clarify the involvement of the sweet taste receptor in this process in vitro. Lymph samples were collected from the thoracic duct after bolus administration of dietary lipids or sweetening agents into the duodenum of rats. Human enteroendocrine NCI-H716 cells were also used to compare the effects of various nutrients on GLP-2 secretion. GLP-2 concentrations were measured by ELISA in vivo and in vitro. GLP-2 secretion was enhanced by polyunsaturated fatty acid- and monounsaturated fatty acid-rich dietary oils, dietary carbohydrates, and some kinds of sweeteners in rats; this effect was reproduced in NCI-H716 cells using α-linolenic acid (αLA), glucose, and sweeteners. GLP-2 secretion induced by sweetening agents was inhibited by lactisole, a sweetness-antagonizing inhibitor of T1R3. In contrast, lactisole was unable to inhibit GLP-2 secretion induced by αLA alone. Our results suggested that fatty acid- and sweetener-induced GLP-2 secretion may be mediated by two different pathways, with the sweet taste receptor involved in the regulation of the latter.

  6. Glucagon-Like Peptide-1 Regulates Cholecystokinin Production in β-Cells to Protect From Apoptosis.

    Science.gov (United States)

    Linnemann, Amelia K; Neuman, Joshua C; Battiola, Therese J; Wisinski, Jaclyn A; Kimple, Michelle E; Davis, Dawn Belt

    2015-07-01

    Cholecystokinin (CCK) is a classic gut hormone that is also expressed in the pancreatic islet, where it is highly up-regulated with obesity. Loss of CCK results in increased β-cell apoptosis in obese mice. Similarly, islet α-cells produce increased amounts of another gut peptide, glucagon-like peptide 1 (GLP-1), in response to cytokine and nutrient stimulation. GLP-1 also protects β-cells from apoptosis via cAMP-mediated mechanisms. Therefore, we hypothesized that the activation of islet-derived CCK and GLP-1 may be linked. We show here that both human and mouse islets secrete active GLP-1 as a function of body mass index/obesity. Furthermore, GLP-1 can rapidly stimulate β-cell CCK production and secretion through direct targeting by the cAMP-modulated transcription factor, cAMP response element binding protein (CREB). We find that cAMP-mediated signaling is required for Cck expression, but CCK regulation by cAMP does not require stimulatory levels of glucose or insulin secretion. We also show that CREB directly targets the Cck promoter in islets from obese (Leptin(ob/ob)) mice. Finally, we demonstrate that the ability of GLP-1 to protect β-cells from cytokine-induced apoptosis is partially dependent on CCK receptor signaling. Taken together, our work suggests that in obesity, active GLP-1 produced in the islet stimulates CCK production and secretion in a paracrine manner via cAMP and CREB. This intraislet incretin loop may be one mechanism whereby GLP-1 protects β-cells from apoptosis.

  7. FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease.

    Science.gov (United States)

    Lipson, David A; Barnacle, Helen; Birk, Ruby; Brealey, Noushin; Locantore, Nicholas; Lomas, David A; Ludwig-Sengpiel, Andrea; Mohindra, Rajat; Tabberer, Maggie; Zhu, Chang-Qing; Pascoe, Steven J

    2017-08-15

    Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited. We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD. The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 μg/62.5 μg/25 μg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 μg/12 μg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV1 and in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24. In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components. These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).

  8. Among once-daily regimens, single tablet regimens (STRs are associated with better adherence

    Directory of Open Access Journals (Sweden)

    R Murri

    2012-11-01

    Full Text Available Previous published evidences showed that taking HAART once-daily (OD is associated to better adherence when compared to BID or TID regimens. However, no further studies investigated whether, among OD regimens, adherence levels can be differently influenced. Aim of the study was to evaluate levels of self-reported adherence in HIV+ people according to type of HAART dosing (STR, OD with more than one pill or BID. To limit reporting biases, the study was performed in five different non-clinic settings covering North and Central Italy. A total of 230 patients on stable HAART were asked to complete a semi-structured, anonymous questionnaire reporting their attitude toward HAART, their adherence and the acceptability of their regimen. Self-perception of adherence was also investigated with a single item for comparison with real adherence behavior. Most of the subjects were males (66% with a mean age of 46 years, with higher education level (72% and a long history of HIV infection (mean 13.6 years. 17% of patients were on a first-line regimen. 21% reported to miss at least one dose during the past week (STR: 6%; OD >1 pill 23% and BID 21%; p<0.05. People taking STR and BID tend to report less discontinuations (all the drug of the day for at least 3 times in a month compared to OD>1 pill (6 and 4% vs 11%. People taking therapies other than HAART reported similar adherence levels of people taking only HAART, even when stratified for dosing groups. Even people judging their adherence as ‘optimal’ or ‘very good’, 10 and 17% respectively, reported having missed a dose during the last week. At stepwise regression model, optimal adherence was correlated to being male (OR: 2.38; 95% CI: 1.19–4.74, younger (OR: 3.04; 95% CI: 1.01–9.13 and with a shorter HIV infection (OR: 3.58; 95% CI: 1.04–12.38. People taking simpler once-daily STR tend to report better adherence than people taking OD>1 pill or BID. Perception of optimal adherence is largely

  9. Semaglutide, a Once-Weekly Human GLP-1 Analog, Does Not Reduce the Bioavailability of the Combined Oral Contraceptive, Ethinylestradiol/Levonorgestrel

    OpenAIRE

    Kapitza, Christoph; Nosek, Leszek; Jensen, Lene; Hartvig, Helle; Jensen, Christine B; Flint, Anne

    2015-01-01

    The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0....

  10. Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides

    DEFF Research Database (Denmark)

    Rehfeld, J F

    2011-01-01

    and neonatal islets express significant amounts of gastrin, and human as well as porcine islet cells express the gastrin/CCK-B receptor abundantly. Therefore, exogenous gastrin and CCK peptides stimulate insulin and glucagon secretion in man. Accordingly, endogenous hypergastrinaemia is accompanied by islet...... cell hyperplasia and increased insulin secretion. Conventionally, the effect of gastrointestinal hormones on insulin secretion (the incretin effect) has been defined and quantified in relation to oral versus intravenous glucose loadings. Under these unphysiological conditions, the release of gastrin...... and CCK and, hence, their effect on insulin secretion are modest in comparison with the effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 (GLP-1). Consequently, the interest of CCK and gastrin in incretin research has for decades been limited. A few years ago, however...

  11. Effect of alfaprostol, lasalocid, and once-daily suckling on postpartum interval in Brahman and Brahman crossbred cattle.

    Science.gov (United States)

    Del Vecchio, R P; Randel, R D; Neuendorff, D A; Peterson, L A

    1988-10-01

    Brahman cows (n = 49) and primiparous heifers (n = 11), Brahman x Hereford primiparous F1 heifers (n = 86) and Simmental x Brahman primiparous F1 heifers (n = 13) were randomly allotted by breed, age and date of calving to one of eight treatment groups: 1) control; 2) once-daily suckling; 3) lasalocid (200 mg/hd/d); 4) alfaprostol (5 mg intermuscular injections on Days 21 and 32 post partum); 5) lasalocid + once-daily suckling; 6) alfaprostol + once daily suckling; 7) alfaprostol + lasalocid; 8) alfaprostol + lasalocid + once daily suckling. All animals received 2.3 kg/hd/d of a concentrate (6 corn : 1 cottonseed meal) and lasalocid was mixed and fed in the concentrate. Body weights and condition scores were taken on Day 1 post partum and every 28 d thereafter. All animals were maintained with sterile marker bulls with Brahman and Simmental x Brahman cattle artificially inseminated at first estrus. Blood samples were collected at weekly intervals starting on Day 21 post partum until estrus and at nine to twelve days post estrus when the ovaries were palpated for corpora lutea. After the first postpartum estrus with a corpora lutea, cows were placed with fertile bulls. Mean serum progesterone concentrations were below 0.5 ng/ml prior to treatment. Calf weight gains to 90 d were not affected by age (P > 0.10) but were lower in the once-daily suckling group (P 0.10). Cows had a shorter postpartum interval (P 0.10) but did increase the cumulative frequency of return to estrus by 90 d post partum (P 0.10). Both once-daily suckling and alfaprostol were effective in increasing the numbers of animals inseminated by 90 d post partum. The once-daily suckling + alfaprostol treatment resulted in the shortest postpartum interval.

  12. Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Bateman Eric D

    2011-04-01

    Full Text Available Abstract Background The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD. Methods In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843 and II (n = 804, patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1/forced vital capacity ratio of ≤70% and FEV1 1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ and time to first moderate or severe COPD exacerbation. Results At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p Conclusion Aclidinium is effective and well tolerated in patients with moderate to severe COPD. Trial registration ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I and NCT00358436 (ACCLAIM/COPD II.

  13. The emergence of oral tadalafil as a once-daily treatment for pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Jeremy A Falk

    2010-04-01

    Full Text Available Jeremy A Falk, Kiran J Philip, Ernst R SchwarzCedars Sinai Women’s Guild Lung Institute, Cedars Sinai Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA, USAAbstract: Pulmonary hypertension (PH is found in a vast array of diseases, with a minority representing pulmonary arterial hypertension (PAH. Idiopathic PAH or PAH in association with other disorders has been associated with poor survival, poor exercise tolerance, progressive symptoms of dyspnea, and decreased quality of life. Left untreated, patients with PAH typically have a progressive decline in function with high morbidity ultimately leading to death. Advances in medical therapy for PAH over the past decade have made significant inroads into improved function, quality of life, and even survival in this patient population. Three classes of pulmonary artery-specific vasodilators are currently available in the United States. They include prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 (PDE5 inhibitors. In May 2009, the FDA approved tadalafil, the first once-daily PDE5 inhibitor for PAH. This review will outline the currently available data on tadalafil and its effects in patients with PAH.Keywords: PDE-5 inhibition, pulmonary hypertension, tadalafil

  14. Tafluprost once daily for treatment of elevated intraocular pressure in patients with open-angle glaucoma

    Directory of Open Access Journals (Sweden)

    Liu Y

    2012-12-01

    Full Text Available Yang Liu, Weiming MaoDepartment of Cell Biology and Anatomy, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TXAbstract: Glaucoma is a leading cause of visual loss worldwide. Current antiglaucoma therapy focuses on lowering intraocular pressure to a safe level. In recent years, prostaglandin analogs have become the first-line agents for treating open angle glaucoma. Tafluprost, which was first reported in 2003, is a novel prostaglandin analog, and has been shown to be a potent ocular hypotensive agent in a number of preclinical and clinical studies. Also, its unique preservative-free formulation helps to decrease preservative-associated ocular disorders and improve patient compliance. In this review, studies from 2003 to 2012 focusing on the structure, metabolism, efficacy, and safety of tafluprost are summarized. These studies suggested that application of tafluprost once daily is a safe and effective treatment for patients with open angle glaucoma.Keywords: tafluprost, prostaglandin analog, glaucoma, intraocular pressure, preservative-free formulation

  15. Randomized Trial of Once-Daily Fluticasone Furoate in Children with Inadequately Controlled Asthma

    DEFF Research Database (Denmark)

    Oliver, Amanda J.; Covar, Ronina A.; Goldfrad, Caroline H.

    2016-01-01

    Objective To evaluate the dose-response, efficacy, and safety of fluticasone furoate (FF; 25 µg, 50 µg, and 100 µg), administered once daily in the evening during a 12-week treatment period to children with inadequately controlled asthma. Study design This was a Phase IIb, multicenter, stratified......, randomized, double-blind, double-dummy, parallel-group, placebo- and active-controlled study in children aged 5-11 years with inadequately controlled asthma. The study comprised a 4-week run-in period, 12-week treatment period, and 1-week follow-up period. Children were randomized to receive either placebo...... In total, 593 children were included in the intent-to-treat population. The difference vs placebo in change from baseline daily morning PEF averaged over weeks 1-12 was statistically significant for the FF 25, FF 50, FF 100, and FP 100 groups (18.6 L/min, 19.5 L/min, 12.5 L/min, and 14.0 L...

  16. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD.

    Science.gov (United States)

    Buhl, R; Dunn, L J; Disdier, C; Lassen, C; Amos, C; Henley, M; Kramer, B

    2011-10-01

    Two, once daily (q.d.) inhaled bronchodilators are available for the treatment of chronic obstructive pulmonary disease (COPD): the β(2)-agonist indacaterol and the anticholinergic tiotropium. This blinded study compared the efficacy of these two agents and assessed their safety and tolerability. Patients with moderate-to-severe COPD were randomised to treatment with indacaterol 150 μg q.d. (n=797) or tiotropium 18 μg q.d. (n=801) for 12 weeks. After 12 weeks, the two treatments had similar overall effects on "trough" (24 h post-dose) forced expiratory volume in 1 s. Indacaterol-treated patients had greater improvements in transition dyspnoea index (TDI) total score (least squares means 2.01 versus 1.43; pindacaterol versus tiotropium odds ratios of 1.49 for TDI and 1.43 for SGRQ, both pindacaterol and tiotropium treatment groups, respectively. The most frequent adverse events were COPD worsening, cough and nasopharyngitis. Both bronchodilators demonstrated spirometric efficacy. The two treatments were well tolerated with similar adverse event profiles. Compared with tiotropium, indacaterol provided significantly greater improvements in clinical outcomes.

  17. Formulation and evaluation of once daily minocycline hydrochloride extended release matrix tablets

    Directory of Open Access Journals (Sweden)

    Keny R

    2009-01-01

    Full Text Available The present study was aimed to develop once daily extended release matrix tablets of minocycline hydrochloride, using hydroxypropylmethylcellulose either alone or in combination with ethyl cellulose as the matrix material in different proportions. The formulated tablets were also compared with a marketed product. The results of the dissolution study indicate that formulations FC-IV, FC-V and FC-VI showed maximum drug release upto 24 h, whereas the marketed product was found to extend the release only up to 14 h. Incase of formulations containing combination of hydroxypropylmethylcellulose and ethyl cellulose (FC-I to FC-IX, the release of the drug was found to be dependent on the relative proportions of hydroxypropylmethylcellulose and ethyl cellulose used in the tablet matrix. Mathematical treatment of the in vitro drug release data suggests that, all the formulations best fitted into first order release kinetics. Drug release from the matrix occurred by combination of two mechanisms, diffusion of drug from tablet matrix and erosion of tablet surface, which was reflected from Higuchi′s model and Erosion plot.

  18. Evaluation of once daily treatment with cyclosporine for anal furunculosis in dogs.

    Science.gov (United States)

    Doust, R; Griffiths, L G; Sullivan, M

    2003-02-22

    Twenty-four dogs with anal furunculosis were treated with cyclosporine once daily for 13 weeks at dosages of 1.5, 3.0, 5.0 or 7.5 mg/kg, and re-examined after six and 12 months. After 13 weeks the disease in six of the dogs was in remission, 11 were controlled or improved and seven had failed to respond. The response of the dogs given the highest dose was significantly better than the response of the other groups taken together (P dogs improved clinically during the treatment, most rapidly during the first five weeks. Of the six dogs that were in remission after 13 weeks, three relapsed after one, two and six months. The 11 dogs that were improved or controlled after 13 weeks were either left untreated or were continued on cyclosporine medication for one to three months at a dosage of 1.5 to 7.5 mg/kg; the disease went into remission in four cases and remained controlled in the other seven, but four of the 11 cases relapsed during the 12 months following the treatment. The side effects observed included increased coat turnover and transient vomiting.

  19. Role of Central Glucagon-like Peptide-1 in Stress Regulation

    OpenAIRE

    Ghosal, Sriparna; Myers, Brent; Herman, James P.

    2013-01-01

    Glucagon-like peptide 1 (GLP-1) is best known as an incretin hormone, secreted from L cells in the intestine in response to nutrient ingestion to stimulate glucose-dependent insulin secretion. However, GLP-1 is also expressed in neurons, and plays a major role in regulation of homeostatic function within the central nervous system (CNS). This review summarizes our current state of knowledge on the role GLP-1 plays in neural coordination of the organismal stress response. In brain, the primary...

  20. Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1)

    DEFF Research Database (Denmark)

    Bak, Monika Judyta; Albrechtsen, Nicolai Jacob Wewer; Pedersen, Jens;

    2014-01-01

    AIMS: To evaluate performances of commercially available glucagon-like peptide-1 (GLP-1) assays and implications for clinical studies. MATERIALS AND METHODS: Known concentrations (5-300 pmol/l) of synthetic GLP-1 isoforms (GLP-1 1-36NH2 , 7-36NH2 , 9-36NH2 , 1-37, 7-37 and 9-37) were added to the...

  1. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin

    OpenAIRE

    Ripken, Dina; Wielen, van der, S.; Wortelboer, Heleen M.; Meijerink, Jocelijn; Witkamp, Renger F.; Henk F J Hendriks

    2016-01-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects...

  2. A once-daily dose of tadalafil for erectile dysfunction: compliance and efficacy

    Directory of Open Access Journals (Sweden)

    Samuel L Washington III

    2010-08-01

    Full Text Available Samuel L Washington III1, Alan W Shindel21School of Medicine, University of California at San Francisco, San Francisco, California, USA; 2Department of Urology, University of California at San Francisco, San Francisco, California, USAAbstract: Selective phosphodiesterase type 5 inhibitors (PDE5Is have revolutionized the ­treatment of erectile dysfunction (ED in men. As an on-demand treatment, PDE5Is have excellent efficacy and safety in the treatment of ED due to a broad spectrum of etiologies. Nevertheless, these drugs do have side-effect profiles that are troublesome to some patients, eg, headache, dyspepsia, myalgia, etc. Furthermore, many patients and their partners dislike the necessity of on-demand treatment for ED, citing a desire for greater spontaneity with sexual interactions. In 2008, approximately 10 years after the release of the first commercially available PDE5I, a paradigm shift in the management of ED occurred with the approval of once-daily dose of tadalafil by the US Food and Drug Administration for the management of ED. The prolonged half-life of tadalafil lends itself well to this dosing regimen and conveys the advantage of separating medication from sexual interactions; lower dose therapy also carries the theoretical benefit of lower incidence of side effects. In this study, we review the current state of the art with respect to this new management strategy for ED, highlighting published reports of the efficacy and tolerability of the daily dose tadalafil regimen.Keywords: PDE5 inhibitor, on-demand therapy, side effects, daily dosing

  3. Efficacy and safety of recombinant human glucagon-like peptide-1 in combination with metformin in patients with type 2 diabetes mellitus%重组人胰高血糖素样肽-1联合二甲双胍治疗2型糖尿病的有效性和安全性评价

    Institute of Scientific and Technical Information of China (English)

    侯新国; 周克华; 甄晓慧; 宋君; 张亮; 矫磊; 陈丽

    2011-01-01

    目的 评价在口服降糖药二甲双胍的基础上餐前皮下注射重组人胰高血糖素样肽-1(rhGLP-1)治疗2型糖尿病的有效性和安全性.方法 在随机、双盲、安慰剂对照的临床试验中,选取42例二甲双胍单药治疗的2型糖尿病患者,随机分为观察组和对照组,每组21例.在口服原剂量二甲双胍的基础上分别接受rhGLP-1 0.2 mg(观察组)或安慰剂(对照组)三餐前皮下注射治疗,随访12周,观察空腹血糖、餐后2h血糖和糖化血红蛋白(HbAlc)等有效性指标及低血糖、不良反应和肝肾功能等安全性指标.结果 观察组治疗后HbAlc、空腹及餐后血糖水平较前明显下降(P<0.05),且较对照组下降更为显著(P<0.05).两组治疗后体质量指数均显著下降(P<0.05),但组间比较无统计学差异(P>0.05);观察组体质量指数下降程度与基线值呈正相关(P<0.01).观察组和对照组均无确切证据的低血糖发生,两组间胃肠道不良反应发生率无统计学差异(P>0.05).结论 在口服二甲双胍的基础上给予rhGLP-1三餐前皮下注射治疗可有效降低2型糖尿病患者的空腹及餐后血糖,而不增加低血糖及其他不良事件的发生率.%Objective To evaluate the efficacy and safety of recombinant human glucagon-like peptide-1 (rhGLP-1) subcutaneously administered before meals in combination with oral metformin in patients with type 2 diabetes mellitus. Methods In this randomized, double-blind and placebo-controlled study, 42 patients with type 2 diabetes were randomly divided into the study group and the control group, 21 patients in each group. They were subcutaneously administrated with 0.2 mg of rhGLP-1 (7-36) or a placebo in addition to an original dose of metformin, and then they were followed for 12 weeks. The changes of glucose, HbAlc and other safety indexes from the baseline to the endpoint were observed. Results The levels of HbAlc, and fasting and postprandial blood glucose

  4. Twice-Daily versus Once-Daily Pramipexole Extended Release Dosage Regimens in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Ji Young Yun

    2017-01-01

    Full Text Available This open-label study aimed to compare once-daily and twice-daily pramipexole extended release (PER treatment in Parkinson’s disease (PD. PD patients on dopamine agonist therapy, but with unsatisfactory control, were enrolled. Existing agonist doses were switched into equivalent PER doses. Subjects were consecutively enrolled into either once-daily-first or twice-daily-first groups and received the prescribed amount in one or two, respectively, daily doses for 8 weeks. For the second period, subjects switched regimens in a crossover manner. The forty-four patients completed a questionnaire requesting preference during their last visit. We measured the UPDRS-III, Hoehn and Yahr stages (H&Y in medication-on state, Parkinson’s disease sleep scale (PDSS, and Epworth Sleepiness Scale. Eighteen patients preferred a twice-daily regimen, 12 preferred a once-daily regimen, and 14 had no preference. After the trial, 14 subjects wanted to be on a once-daily regimen, 25 chose a twice-daily regimen, and 5 wanted to maintain the prestudy regimen. Main reasons for choosing the twice-daily regimen were decreased off-duration, more tolerable off-symptoms, and psychological stability. The mean UPDRS-III, H&Y, and PDSS were not different. Daytime sleepiness was significantly high in the once-daily regimen, whereas nocturnal hallucinations were more common in the twice-daily. Multiple dosing should be considered if once-daily dosing is unsatisfactory. This study is registered as NCT01515774 at ClinicalTrials.gov.

  5. Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats

    Science.gov (United States)

    DellaValle, Brian; Brix, Gitte S.; Brock, Birgitte; Gejl, Michael; Landau, Anne M.; Møller, Arne; Rungby, Jørgen; Larsen, Agnete

    2016-01-01

    Introduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS) pathology and influence the susceptibility to treatment, directing attention toward anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1 (GLP-1) family, is also anti-diabetic and weight-reducing and is, moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing the experimental model, experimental autoimmune encephalitis (EAE). Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 μg/kg s.c.) or saline. Healthy controls were included (saline, n = 6, liraglutide, n = 7). Clinical score and weight were assessed daily by blinded observers. Animals were killed at peak disease severity (day 11) or if exceeding humane endpoint (clinical score ≥4). Protein levels of manganese superoxide dismutase (MnSOD), amyloid precursor protein (APP), and glial fibrillary acidic protein (GFAP) were determined. Results: Liraglutide treatment delayed disease onset (group clinical score significantly >0) by 2 days and markedly reduced disease severity (median clinical score 2 vs. 5; p = 0.0003). Fourteen of 15 (93%) of vehicle-treated rats reached the humane endpoint (clinical score ≥4) by day 11 compared to 5 of 15 (33%) of liraglutide-treated rats (p = 0.0004). Liraglutide substantially increased the mitochondrial antioxidant MnSOD (p < 0.01) and reduced the neurodegenerative marker APP (p = 0.036) in the brain. GFAP levels were not significantly changed with drug treatment (p = 0.09). Conclusion: We demonstrate, for the first time, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1

  6. Fluticasone furoate: once-daily evening treatment versus twice-daily treatment in moderate asthma

    Directory of Open Access Journals (Sweden)

    Woodcock Ashley

    2011-12-01

    Full Text Available Abstract Background Inhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD evening and twice-daily (BD regimens of the novel inhaled corticosteroid fluticasone furoate (FF in asthma patients. Methods Patients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV1 40-85% predicted; FEV1 reversibility of ≥ 12% and ≥ 200 ml were randomized to FF or fluticasone propionate (FP regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 μg OD, FF or FP 100 μg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough FEV1; non-inferiority of FF 200 μg OD and FF 100 μg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs and 24-hour urinary cortisol excretion were assessed. Results The intent-to-treat population comprised 147 (FF and 43 (FP patients. On Day 28, pre-dose FEV1 showed FF 200 μg OD to be non-inferior (pre-defined limit -110 ml to FF 100 μg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml; all FF and FP regimens were significantly superior to placebo (p ≤ 0.02. AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 μg OD, 0.75; 100 μg BD, 0.84; p ≤ 0.02. Conclusions FF 200 μg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose. Trial registration Clinicaltrials.gov; NCT00766090.

  7. Comparison of once daily versus twice daily olmesartan in patients with chronic kidney disease

    Directory of Open Access Journals (Sweden)

    Sakai Y

    2013-10-01

    Full Text Available Yukinao Sakai,1 Anna Suzuki,1 Koji Mugishima,1 Yuichiro Sumi,1 Yusuke Otsuka,1 Tomoyuki Otsuka,1 Dai Ohno,1 Tsuneo Murasawa,1 Shuichi Tsuruoka21Department of Nephrology, Nippon Medical School Musashikosugi Hospital, Kawasaki, Japan; 2Division of Nephrology, Department of Internal Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, JapanBackground: The effects of olmesartan (OLM on blood pressure and kidney function in Japanese patients with chronic kidney disease (CKD were compared between 20 mg twice daily (BID and 40 mg once daily (QD treatments.Methods: The subjects were Japanese CKD patients with concurrent hypertension who had been treated with OLM 20 mg BID for at least 3 months on an outpatient basis (n=39. After a change in the treatment regimen to 40 mg OLM QD (after breakfast, blood pressure (BP (n=39, morning home BP (n=13, estimated glomerular filtration rate (n=39, and urinary albumin-to-creatinine ratio (n=17 were monitored for 2 months.Results: No significant change in office (mean ± standard deviation [SD] [mmHg], 143.9 ± 18.8/75.7 ± 12.0 to 141.6 ± 16.1/74.7 ± 11.7, not significant [ns] or early morning home (mean ± SD [mmHg], 133.8 ± 15.9/71.2 ± 11.5 to 133.8 ± 13.9/74.5 ± 10.5, ns BP was observed 2 months after the change in dose. The estimated glomerular filtration rate increased significantly (mean ± SD, 49.0 ± 28.0 to 51.8 ± 27.0, P<0.05, whereas urinary albumin-to-creatinine ratio did not change significantly (mean ± SD, 0.551 ± 0.445 to 0.364 ± 0.5194, ns.Conclusion: High-dose OLM administered BID and QD had similar effects on outpatient and early morning home BP in CKD patients, suggesting that the BID regimen can be safely changed to a QD regimen. For CKD patients with hypertension requiring continuous long-term treatment, the possibility that the QD regimen might bring a greater therapeutic effect was suggested. However, recognizing the best blood pressure control level for a CKD

  8. [Protective effects of glucagon-like peptide-1 on beta-cells: preclinical and clinical data].

    Science.gov (United States)

    Consoli, Agostino; Di Biagio, Rosamaria

    2011-12-01

    Dipartimento di Medicina Interna e Scienze dell'Invecchiamento, Università degli Studi "G. d'Annunzio", Chieti Continuing b-cell mass and function loss represents the key mechanism for the pathogenesis and the progression of type 2 diabetes mellitus. Drugs capable of arresting b-cell loss and eventually able to bring b-cell function close to be back to normal would then be a formidable help in type 2 diabetes mellitus treatment. The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide and liraglutide can stimulate in vitro neogenesis and prevent apoptosis in b-cell-like cell lines. Consistently, treatment with GLP-1 receptor agonists ameliorates glucose metabolism, preserves b-cell mass and improves b-cell function in several animal models of diabetes. For instance, in the db/db mice, liraglutide protects the b-cell from oxidative stress and endoplasmic reticulum stress-related damage. Data in humans, in vivo, are less definitive and often based on scarcely reliable indexes of b-cell function. However, short-term treatment (14 weeks) with liraglutide increased b-cell maximal response capacity in a dose-response fashion. A longer (1 year) exenatide treatment also was able to increase b-cell maximal response capacity, but the effect was no longer there after a 4-week washout period. However, a marginal, although significant as compared to glargine treatment, improvement in another b-cell function index (disposition index) was observed after a 4-week washout period following 3-year exenatide treatment. Finally, although no clinical trials with a long enough follow-up period are presently available, durable glucose control has been obtained during 2 years of liraglutide treatment in monotherapy. Since the durability of good control is strictly dependent upon a lack of further b-cell function deterioration, these clinical data may foster hope that GLP-1 receptor antagonist treatment might help preserving b-cell function also in individuals affected by type 2

  9. Glucagon-like peptide 2 treatment may improve intestinal adaptation during weaning

    DEFF Research Database (Denmark)

    Thymann, Thomas; Le Huërou-Luron, I; Petersen, Y M;

    2014-01-01

    Transition from sow’s milk to solid feed is associated with intestinal atrophy and diarrhea. We hypothesized that the intestinotrophic hormone glucagon-like peptide 2 (GLP-2) would induce a dose- and health status-dependent effect on gut adaptation. In Exp. 1, weaned pigs (average BW at weaning 4......) were kept in a low-sanitary environment, leading to weaning diarrhea, and injected with saline or short-acting GLP-2 (200 µg/(kg BW·12 h); n = 11). Treatment with GLP-2 increased goblet cell density (P

  10. The effects of glucagon-like peptide-1 on the beta cell

    DEFF Research Database (Denmark)

    Vilsbøll, Tina

    2009-01-01

    to stimulate glucose-dependent insulin secretion. Furthermore, GLP-1 appears to have multiple positive effects on beta cells. However, GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4), which limits the clinical relevance of GLP-1 for the treatment of type 2 diabetes. Two main classes of GLP-1-based......Type 2 diabetes is a progressive disease characterized by insulin resistance and impaired beta-cell function. Treatments that prevent further beta-cell decline are therefore essential for the management of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is known...

  11. Glucagon-like peptide-2 induces rapid digestive adaptation following intestinal resection in preterm neonates

    DEFF Research Database (Denmark)

    Vegge, Andreas; Thymann, Thomas; Lund, Pernille;

    2013-01-01

    Short bowel syndrome (SBS) is a frequent complication after intestinal resection in infants suffering from intestinal disease. We tested whether treatment with the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) increases intestinal volume and function in the period immediately following...... and protein contents and increased total protein synthesis rate in SBS+GLP-2 vs. SBS pigs (+100%, P fluid and macronutrients. GLP-2 treatment may...... be a promising therapy to enhance intestinal adaptation and improve digestive function in preterm infants with jejunostomy following intestinal resection....

  12. Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level.

    Science.gov (United States)

    Ishibashi, Yuji; Nishino, Yuri; Matsui, Takanori; Takeuchi, Masayoshi; Yamagishi, Sho-ichi

    2011-09-01

    Advanced glycation end products (AGE) and receptor for AGE (RAGE) interaction elicits reactive oxygen species (ROS) generation and inflammatory reactions, thereby being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, found that glucagon-like peptide-1 (GLP-1), one of the incretins and a gut hormone secreted from L cells in the intestine in response to food intake, could have anti-inflammatory and antithrombogenic properties in cultured endothelial cells. However, the effects of GLP-1 on renal mesangial cells are largely unknown. Therefore, to elucidate the role of GLP-1 in diabetic nephropathy, this study investigated whether and how GLP-1 blocked AGE-induced monocyte chemoattractant protein-1 expression in human cultured mesangial cells. Gene and protein expression was analyzed by quantitative real-time reverse transcription polymerase chain reactions, Western blots, and enzyme-linked immunosorbent assay. The ROS generation was measured with dihydroethidium staining. Glucagon-like peptide-1 receptor (GLP-1R) was expressed in mesangial cells. Glucagon-like peptide-1 inhibited RAGE gene expression in mesangial cells, which was blocked by small interfering RNAs raised against GLP-1R. Furthermore, GLP-1 decreased ROS generation and subsequently reduced monocyte chemoattractant protein-1 gene and protein expression in AGE-exposed mesangial cells. An analogue of cyclic adenosine monophosphate mimicked the effects of GLP-1 on mesangial cells. Our present study suggests that GLP-1 may directly act on mesangial cells via GLP-1R and that it could work as an anti-inflammatory agent against AGE by reducing RAGE expression via activation of cyclic adenosine monophosphate pathway.

  13. Crystal Structure of Glucagon-like Peptide-1 in Complex with the Extracellular Domain of the Glucagon-like Peptide-1 Receptor

    DEFF Research Database (Denmark)

    Underwood, Christina Rye; Garibay, P.; Knudsen, L.B.;

    2010-01-01

    GLP-1 (glucagon-like peptide-1) is an incretin released from intestinal L-cells in response to food intake. Activation of the GLP-1 receptor potentiates the synthesis and release of insulin from pancreatic beta-cells in a glucose-dependent manner. The GLP-1 receptor belongs to class B of the G......-protein-coupled receptors, a subfamily characterized by a large N-terminal extracellular ligand binding domain. Exendin-4 and GLP-1 are 50% identical, and exendin-4 is a full agonist with similar affinity and potency for the GLP-1 receptor. We recently solved the crystal structure of the GLP-1 receptor extracellular domain...... in complex with the competitive antagonist exendin-4(9-39). Interestingly, the isolated extra-cellular domain binds exendin-4 with much higher affinity than the endogenous agonist GLP-1. Here, we have solved the crystal structure of the extracellular domain in complex with GLP-1 to 2.1 angstrom resolution...

  14. Once-daily glycopyrronium bromide (Seebri Breezhaler(®)) for the treatment of chronic obstructive pulmonary disease (COPD)

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli

    2015-01-01

    glycopyrronium bromide (Seebri Breezhaler®) is a well-tolerated long-acting anti-muscarinic agent (LAMA) with a fast onset of action. In patients with moderate to severe COPD, glycopyrronium bromide has clinically important effects on level of FEV1, use of relief medication, day-time dyspnea scores, and probably...... also on health status. Furthermore, glycopyrronium bromide also has beneficial effects on dynamic hyperinflation and, probably by that, exercise tolerance. Glycopyrronium bromide has been shown to reduce the rate of exacerbations in patients with moderate to severe COPD, although as a secondary outcome...... only. EXPERT OPINION: Once-daily inhaled glycopyrronium bromide has positive impact on important COPD outcomes, comparable to the effects of other marketed LAMAs. Once-daily administration may improve adherence, and glycopyrronium bromide has the potential for a role in the future management of COPD...

  15. Intracerebroventricular administration of novel glucagon-like peptide suppresses food intake in chicks.

    Science.gov (United States)

    Honda, Kazuhisa; Saneyasu, Takaoki; Yamaguchi, Takuya; Shimatani, Tomohiko; Aoki, Koji; Nakanishi, Kiwako; Kamisoyama, Hiroshi

    2014-02-01

    Glucagon-related peptides such as glucagon, glucagon-like peptide-1, and oxyntomodulin suppress food intake in mammals and birds. Recently, novel glucagon-like peptide (GCGL) was identified from chicken brain, and a comparatively high mRNA expression level of GCGL was detected in the hypothalamus. A number of studies suggest that the hypothalamus plays a critical role in the regulation of food intake in mammals and birds. In the present study, we investigated whether GCGL is involved in the central regulation of food intake in chicks. Male 8-day-old chicks (Gallus gallus) were used in all experiments. Intracerebroventricular administration of GCGL in chicks significantly suppressed food intake. Plasma glucose level was significantly decreased by GCGL, whereas plasma corticosterone level was not affected. Central administration of a corticotrophin-releasing factor (CRF) receptor antagonist, α-helical CRF, attenuated GCGL-suppressed food intake. It seems likely that CRF receptor is involved in the GCGL-induced anorexigenic pathway. All our findings suggest that GCGL functions as an anorexigenic peptide in the central nervous system of chicks.

  16. Once-daily application of calcipotriene 0.005%-betamethasone dipropionate 0.064% ointment for repigmentation of facial vitiligo.

    Science.gov (United States)

    Newman, Marissa D; Silverberg, Nanette B

    2011-11-01

    Vitiligo vulgaris is an autoimmune pigmentary disorder with no universally efficacious therapeutic options. Separate applications of calcipotriene ointment 0.005% and topical corticosteroid ointments have been successful in the repigmentation of vitiligo. We sought to examine the efficacy of a combination calcipotriene 0.005%-betamethasone dipropionate 0.064% ointment in the repigmentation of vitiligo. An institutional review board-approved retrospective chart review was conducted in 13 pediatric and adult patients with vitiligo treated with calcipotriene 0.005%-betamethasone dipropionate 0.064% ointment once daily for at least 2 months. Two of 3 children had 76% to 100% repigmentation of facial vitiligo with once-daily usage after 2 months. Of the 10 adults (aged 28-55 years), 1 had 100% facial repigmentation in 3 months, 1 had 76% to 99% facial repigmentation in 5 to 9 months, and 2 had 26% to 50% repigmentation in 3 months. Twelve patients developed some facial repigmentation. No patients experienced atrophy, telangiectases, or lesion enlargement during treatment. Combination calcipotriene 0.005%-betamethasone dipropionate 0.064% ointment shows promise as a once-daily vitiligo therapy. Adult and pediatric facial vitiligo patients may see repigmentation as early as 2 months after initiation of therapy. Children may experience a better response, but larger studies are needed.

  17. Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial).

    Science.gov (United States)

    Molina, Jean-Michel; Journot, Valérie; Furco, André; Palmer, Pierre; De Castro, Nathalie; Raffi, François; Morlat, Philippe; May, Thierry; Rancinan, Corinne; Chêne, Geneviève

    2007-01-01

    Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported. This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability. After 5 years, 73% and 68% of patients had plasma HIV RNA levels < 400 and < 50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294 x 10(6) cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol. A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.

  18. The Role of the Pharmacist in Managing Type 2 Diabetes with Glucagon-Like Peptide-1 Receptor Agonists as Add-On Therapy.

    Science.gov (United States)

    Meece, Jerry

    2017-02-16

    The prevalence and associated clinical burden of type 2 diabetes (T2D) is increasing in the USA and other countries. As a consequence, the role of the pharmacist in managing T2D is expanding, and it is becoming increasingly important for pharmacists to have a complete understanding of the disease course and treatment options. Pharmacists have a key role in the use of injectable therapies, including incretin-based treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This article discusses the role of the pharmacist in the management of patients with T2D, particularly with respect to the use of GLP-1RAs to achieve glycemic control. GLP-1RAs are a class of injectable agents used as an adjunct to diet and exercise to improve glycemic control in adults with T2D. GLP-1RAs have been shown to lower glucose levels, slow gastric emptying, enhance satiety, and reduce body weight without increasing the risk of hypoglycemia. GLP-1RAs currently approved in the USA include exenatide twice daily, liraglutide once daily, and albiglutide, dulaglutide, and exenatide once weekly. Pharmacists can work with physicians to help identify patients for whom GLP-1RA therapy is appropriate. In addition, pharmacists can educate patients regarding medication storage, preparation, and injection techniques, glycated hemoglobin (HbA1c) targets, pre- and post-meal blood glucose goals, adverse events and management strategies, and the long-term benefits of reducing HbA1c. As members of the diabetes care team, pharmacists play an important role in improving patient outcomes.

  19. 胰高糖素样肽-1受体激动剂对人甲状腺髓样癌细胞生长和能量代谢的影响%Effect of glucagon-like peptide-1 receptor agonists on growth and energy metabolism in human medullary thyroid cancer cells

    Institute of Scientific and Technical Information of China (English)

    王红; 张斯亮; 关海霞

    2016-01-01

    背景与目的:胰高糖素样肽-1(glucagon like peptide-1,GLP-1)受体激动剂是一种新型降糖药。在研发过程中,发现其可增加啮齿类动物患甲状腺C细胞肿瘤的风险。因此,该药物对人类甲状腺的影响引人关注。本研究旨在探讨GLP-1受体激动剂对人甲状腺髓样癌(medullary thyroid cancer,MTC)细胞增殖、降钙素的分泌和能量代谢的影响。方法:体外培养人MTC细胞系(TT)。分别以0、1、10和100 nmol/L艾塞那肽和利拉鲁肽处理细胞24、48和72 h后,采用细胞计数试剂盒(cell counting kit-8,CCK-8)检测GLP-1受体激动剂艾塞那肽和利拉鲁肽处理后细胞增殖情况;采用降钙素试剂盒测定细胞培养上清液中降钙素水平的变化;采用Seahorse能量代谢分析仪检测细胞糖酵解及线粒体呼吸的变化。结果:实验组细胞增殖率与对照组相比,差异无统计学意义(P>0.05),降钙素的量与对照组相比,差异无统计学意义(P>0.05),不同浓度艾塞那肽和利拉鲁肽处理细胞24 h后,与对照组相比,实验组艾塞那肽和利拉鲁肽对MTC细胞能量代谢并无明显影响(P>0.05),随着艾塞那肽和利拉鲁肽处理时间延长,TT细胞糖酵解和线粒体呼吸并无明显改变(P>0.05)。结论:GLP-1受体激动剂对人MTC发生、发展无明显促进作用,未来仍需大规模临床数据进一步证实GLP-1受体激动剂的安全性。%Background and purpose:This study aimed to investigate the effect of glucagon-like peptide-1 receptor agonists on proliferation, secretion of calcitonin and energy metabolism of medullary thyroid cancer (MTC) cell.Methods:The MTC cell line (TT) was culturedin vitro. After treatment with exenatide and liraglutide (0, 1, 10 and 100 nmol/L) for 24, 48 and 72 h, the proliferation of TT was analyzed by CCK-8 kit, the calcitonin was measured by calcitonin assay kits, and the energy metabolism of TT was measured by Seahorse XF

  20. Once-daily dose regimen of ribavirin is interchangeable with a twice-daily dose regimen: randomized open clinical trial

    Directory of Open Access Journals (Sweden)

    Balk JM

    2015-08-01

    Full Text Available Jiska M Balk,1 Guido RMM Haenen,1 Özgür M Koc,2 Ron Peters,3 Aalt Bast,1 Wim JF van der Vijgh,1 Ger H Koek,4 1Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, 2Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, 3DSM Resolve, Geleen, 4Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands Background: The combination of ribavirin (RBV and pegylated interferon (PEG-IFN is effective in the treatment of chronic hepatitis C infection. Reducing the frequency of RBV intake from twice to once a day will improve compliance and opens up the opportunity to combine RBV with new and more specific direct-acting agents in one pill. Therefore, the purpose of this study was to evaluate the pharmacokinetic profile of RBV in a once-daily to twice-daily regimen. The secondary aim was to determine tolerability as well as the severity and differences in side effects of both treatment regimens. Methods: In this randomized open-label crossover study, twelve patients with chronic type 1 hepatitis C infection and weighing more than 75 kg were treated with 180 µg of PEG-IFN weekly and 1,200 mg RBV daily for 24 weeks. The patients received RBV dosed as 1,200 mg once-daily for 12 weeks followed by RBV dosed as 600 mg twice-daily for 12 weeks, or vice versa. In addition to the pharmacokinetic profile, the hematological profile and side effects were recorded. The RBV concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Results: Eight of twelve patients completed the study. Neither the time taken for RBV to reach peak plasma concentration nor the AUC0-last (adjusted for difference in dose was significantly different between the two groups (P>0.05. Furthermore, the once-daily regimen did not give more side effects than the twice-daily regimen (P>0

  1. Adaptations of mammary uptake and nutrient use to once-daily milking and feed restriction in dairy cows.

    Science.gov (United States)

    Guinard-Flament, J; Delamaire, E; Lamberton, P; Peyraud, J L

    2007-11-01

    The aim of this study was to gain a clearer understanding of the different levels of regulation involved in the reduction in milk yield in response to once-daily milking and feed restriction. The treatments were designed as a 2 x 2 factorial arrangement of 2 milking frequencies (once- or twice-daily milking) and 2 feeding levels (70 or 98% of requirements determined 1 wk before the trial). The cows were surgically prepared to study the net mammary balance of the nutrients that are precursors of milk components. Mammary efficiency in synthesizing milk components was estimated using a milk output:mammary uptake ratio. No interaction was observed between the effects of milking frequency and feeding level on milk and blood parameters except for milk protein yield, milk fatty acid profile, and nonesterified fatty acids metabolism. Once-daily milking and feed restriction reduced milk yield by 5.1 and 2.9 kg/d and fat-corrected milk yield by 4.2 and 4.1 kg/d, respectively. Both treatments induced a decrease in mammary blood flow. Once-daily milking led to a reduction in the extraction rate of glucose but no changes to the lactose output:glucose uptake ratio. Feed restriction did not change the glucose extraction rate but tended to improve the lactose output:glucose uptake ratio. Under once-daily milking, the slight increase in milk fat content (0.34 percentage units) was linked to a depressed uptake of glucose and acetate but without any variations in the uptake of beta-hydroxybutyrate and total glycerol and in the efficiency of acetate and beta-hydroxybutyrate conversion to short- and medium-chain fatty acids in milk. The decline in milk fat and protein contents (-0.43 and -0.23 percentage units, respectively) under feed restriction was associated with relatively similar reductions in the mammary uptake of all nutrients and with enhanced conversion of the glucose taken up by the mammary gland and used for lactose synthesis. As a result, once-daily milking and feed

  2. Simultaneous population pharmacokinetic modelling of darunavir and ritonavir Once daily in HIV-infected patients: evaluation of lower ritonavir dose

    Directory of Open Access Journals (Sweden)

    L Dickinson

    2012-11-01

    Full Text Available Purpose of study: Once-daily ritonavir-boosted darunavir (DRV/RTV is a preferred antiretroviral regimen for treatment-naïve patients. Population pharmacokinetic modelling of the interaction between DRV and RTV allows evaluation of alternative dosing strategies, particularly lower RTV doses (e.g. 800/50 mg once daily and assessment of factors that may influence DRV/RTV PK. Methods: Data were pooled from 3 DRV/RTV PK studies. Fifty-one HIV-infected patients (7 female stable on DRV/RTV (800/100 mg or 900/100 mg once daily; n=32 and 19, respectively were included. Median age, weight and baseline CD4 cell count were 39 yr (21–63, 74 kg (57–105 and 500 cells/mm3 (227–1129, respectively; 49 had undetectable viral load. Nonlinear mixed effects modelling (Monolix v.4.1.2 was applied simultaneously to DRV and RTV to determine PK parameters, interindividual variability and residual error. Covariates evaluated included: age, weight, sex and study. The model was validated by simulation and visual predictive check. DRV/RTV 800/50 mg once daily was simulated. Summary of results: RTV and DRV were described by a 1 and 2-compartment model, respectively with first-order absorption and lag-time. A maximum effect model, in which RTV inhibited DRV clearance (CL/F, best described the relationship between the two drugs. A RTV concentration of 0.33 mg/L was associated with 50% maximum inhibition of DRV CL/F with the maximum inhibitory effect fixed at 1. The population CL/F of DRV in the absence of RTV was 13.7L/h. Inclusion of weight on RTV CL/F and volume and age on DRV CL/F and study on DRV CL/F, volume and absorption improved the fit. Based on visual predictive check 93% and 91% of observed RTV and DRV concentrations were within the 95% prediction interval, indicative of an adequate model. Of 1000 simulated DRV troughs, 10% and 0% were below the MEC for treatment-experienced (<0.55 mg/L and naïve patients (<0.055 mg/L, respectively. For DRV/RTV 800/50 mg once

  3. A critical appraisal of antihyperglycemic and cardioprotective activities of liraglutide: A glucagon-like peptide-1 analog

    Directory of Open Access Journals (Sweden)

    Sayed Aliul Hasan Abdi

    2014-04-01

    Full Text Available Diabetes is leading cause for cardiovascular complication, drugs having cardioprotective and antihyperglycemic actions are constantly in search. Oral glucose elicits a three to four times higher peak insulin response compared with an equivalent dose of glucose, if infused intravenously. This is due to the reasons behind, the oral glucose causes a secretion of gut hormones, mainly the glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP which enhance the glucose-induced insulin release. In patients with type 2 diabetes mellitus (type 2 DM, glucose-induced insulin release is unsatisfactory or absent. Because of this type 2 DM patients are unable to adjust their insulin secretion as per the need exist. GLP-1 secretion (but not GIP secretion is diminished in patients with type 2 diabetes. However, when the GLP-1 and GIP agonist are administered in patients with type 2 diabetes, they elicit insulin secretion resulting in lowering of blood glucose level. In addition to its insulin stimulatory effect, GLP-1 agonist also induces cardioprotective effects. It increases nuclear respiratory factor-2 (Nrf2 and heamoxigenase-1(Ho-1 in cell which have antioxidant and cardioprotective property. GLP-1 maintains islets integrity and reduces apoptotic cell death of human islet cells in culture. Improved understanding of the mechanism of action and clinical effects of incretin-based therapies would be useful in advancement of its appropriate use in clinical practices.

  4. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    DEFF Research Database (Denmark)

    Kielgast, Urd; Holst, Jens Juul; Madsbad, Sten

    2009-01-01

    for a beta-cell preserving effect. This review summarizes the present knowledge of GLP-1 and its analogues regarding its role as a possible treatment in patients with type 1 diabetes. The studies that address the effect of GLP-1 and GLP-1 analogues on beta-cell mass in both type 2 and type 1 diabetes...... appetite and bodyweight in obese subjects. In vivo studies using animal models of type 2 diabetes and in vitro studies using human islet cells have suggested that GLP-1 or GLP-1 analogues are also able to increase beta-cell mass, but in animal models of type 1 diabetes, there is much less evidence......GLP-1 (glucagon-like peptide-1) is a peptide hormone secreted from endocrine cells in the intestinal mucosa in response to meals. The major effects of GLP-1 are to increase glucose-induced insulin secretion and reduce glucagon release, but GLP-1 also inhibits gastric emptying rate and reduces...

  5. Glucagon-like Peptide-1 Protects Pancreatic Beta-cells from Death by Increasing Autophagic Flux and Restoring Lysosomal Function.

    Science.gov (United States)

    Zummo, Francesco P; Cullen, Kirsty S; Honkanen-Scott, Minna; Shaw, James Am; Lovat, Penny E; Arden, Catherine

    2017-02-23

    Studies in animal models of type 2 diabetes have shown that glucagon-like peptide-1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown.Here we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5mmol/l palmitate, 25mmol/l glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilisation (LMP) and release of Cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Co-treatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. siRNA knockdown showed the restoration of autophagic flux is also essential for the protective effects of exendin-4.Collectively, our data highlights lysosomal dysfunction as a critical mediator of β-cell loss and shows that exendin-4 improves cell survival via restoration of lysosomal function and autophagic flux. Modulation of autophagy / lysosomal homeostasis may thus define a novel therapeutic strategy for type 2 diabetes, with the GLP-1 signalling pathway as a potential focus.

  6. Glucagon-Like Peptide-1 as Predictor of Body Mass Index and Dentate Gyrus Neurogenesis: Neuroplasticity and the Metabolic Milieu

    Directory of Open Access Journals (Sweden)

    Jeremy D. Coplan

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1, and body mass index (BMI in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge—high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

  7. Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome.

    Science.gov (United States)

    Thymann, Thomas; Stoll, Barbara; Mecklenburg, Lars; Burrin, Douglas G; Vegge, Andreas; Qvist, Niels; Eriksen, Thomas; Jeppesen, Palle B; Sangild, Per T

    2014-06-01

    Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our objective was to test the efficacy of the long-acting synthetic human GLP-2 analogue, teduglutide (ALX-0600), in a neonatal piglet jejunostomy model. Two-day-old pigs were subjected to resection of 50% of the small intestine (distal part), and the remnant intestine was exteriorized on the abdominal wall as a jejunostomy. All pigs were given total parenteral nutrition for 7 days and a single daily injection of the following doses of teduglutide: 0.01 (n = 6), 0.02 (n = 6), 0.1 (n = 5), or 0.2 mg · kg · day (n = 6), and compared with placebo (n = 9). Body weight increment was similar for all 4 teduglutide groups but higher than placebo (P short bowel syndrome.

  8. Spergularia marina induces glucagon-like peptide-1 secretion in NCI-H716 cells through bile acid receptor activation.

    Science.gov (United States)

    Kim, Kyong; Lee, Yu Mi; Rhyu, Mee-Ra; Kim, Hye Young

    2014-11-01

    Spergularia marina Griseb. (SM) is a halophyte that grows in mud flats. The aerial portions of SM have been eaten as vegetables and traditionally used to prevent chronic diseases in Korea. However, there has been no scientific report that demonstrates the pharmacological effects of SM. Glucagon-like peptide-1 (GLP-1) is important for the maintenance of glucose and energy homeostasis through acting as a signal in peripheral and neural systems. To discover a functional food for regulating glucose and energy homeostasis, we evaluated the effect of an aqueous ethanolic extract (AEE) of SM on GLP-1 release from enteroendocrine NCI-H716 cells. In addition, we explored the Takeda G-protein-coupled receptor 5 (TGR5) agonist activity of AEE-SM in Chinese hamster ovary (CHO)-K1 cells transiently transfected with human TGR5. As a result, treatment of NCI-H716 cells with AEE-SM increased GLP-1 secretion and intracellular Ca(2+) and cyclic AMP (cAMP) levels in a dose-dependent manner. Transfection of NCI-H716 cells with TGR5-specific small interference RNA inhibited AEE-SM-induced GLP-1 secretion and the increase in Ca(2+) and cAMP levels. Moreover, AEE-SM showed that the TGR5 agonist activity in CHO-K1 cells transiently transfected with TGR5. The results suggest that AEE-SM might be a candidate for a functional food to regulate glucose and energy homeostasis.

  9. Effects of glucagon-like peptide-1 and feeding on gastric volumes in diabetes mellitus with cardio-vagal dysfunction.

    Science.gov (United States)

    Delgado-Aros, S; Vella, A; Camilleri, M; Low, P A; Burton, D D; Thomforde, G M; Stephens, D

    2003-08-01

    Glucagon-like peptide-1 (GLP-1) increases gastric volume in humans possibly through the vagus nerve. Gastric volume response to feeding is preserved after vagal denervation in animals. We evaluated gastric volume responses to GLP-1 and placebo in seven diabetic patients with vagal neuropathy in a crossover study. We also compared gastric volume response to feeding in diabetes with that in healthy controls. We measured gastric volume using SPECT imaging. Data are median (interquartile range). In diabetic patients, GLP-1 did not increase gastric volume during fasting [5 mL (-3; 30)] relative to placebo [4 mL (-14; 50) P = 0.5], or postprandially [Delta postprandial minus fasting volume 469 mL (383; 563) with GLP-1 and 452 mL (400; 493) with placebo P = 0.3]. Change in gastric volume over fasting in diabetic patients on placebo was comparable to that of healthy controls [452 mL (400; 493)], P = 0.5. In contrast to effects in health, GLP-1 did not increase gastric volume in diabetics with vagal neuropathy, suggesting GLP-1's effects on stomach volume are vagally mediated. Normal gastric volume response to feeding in diabetics with vagal neuropathy suggests that other mechanisms compensate for vagal denervation.

  10. Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest

    DEFF Research Database (Denmark)

    Wiberg, Sebastian; Hassager, Christian; Schmidt, Henrik

    2016-01-01

    BACKGROUND: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes...... mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients. METHODS: We randomly...

  11. Glucagon-like peptide-1 (GLP-1) receptor agonists, obesity and psoriasis: diabetes meets dermatology.

    Science.gov (United States)

    Drucker, D J; Rosen, C F

    2011-11-01

    Type 2 diabetes mellitus is characterised by beta cell failure, which frequently develops in the setting of insulin resistance. Inflammation contributes to the pathophysiology of type 2 diabetes by impairing insulin action in peripheral tissues and via reduction of beta cell function. Inflammation may also play an important role in the development of complications that arise in patients with type 2 diabetes. Hence, the anti-inflammatory actions of commonly used glucose-lowering drugs may contribute, indirectly, to their mechanisms of action and therapeutic benefit. Herein we highlight the anti-inflammatory actions of glucagon-like peptide-1 (GLP-1), which exerts direct and indirect actions on immune function. The observations that GLP-1 receptor agonists exert anti-inflammatory actions in preclinical studies, taken together with case reports linking improvements in psoriasis with GLP-1 receptor agonist therapy, illustrates the emerging clinical implications of non-classical anti-inflammatory actions of incretin-based therapeutics.

  12. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes

    DEFF Research Database (Denmark)

    Lund, Asger; Knop, Filip K; Vilsbøll, Tina

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone, secreted in response to ingestion of nutrients, and has important effects on several of the pathophysiological features of type 2 diabetes (T2D). The effects include potentiation of insulin secretion, suppression of glucagon secretion...... developed. At the moment four different compounds are available for the treatment of T2D and many more are in clinical development. These compounds, although all based on the effects of native GLP-1, differ with regards to structure, pharmacokinetics and size, which ultimately leads to different clinical...... effects. This review gives an overview of the clinical data on GLP-1R agonists that have been compared in head-to-head studies and focuses on relevant differences between the compounds. Highlighting these similarities and differences could be beneficial for physicians in choosing the best treatment...

  13. Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

    Directory of Open Access Journals (Sweden)

    Francis S. Willard

    2012-01-01

    Full Text Available The therapeutic success of peptide glucagon-like peptide-1 (GLP-1 receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of “ligand bias” and “probe dependency” for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.

  14. Bile-induced secretion of glucagon-like peptide-1: pathophysiological implications in type 2 diabetes?

    DEFF Research Database (Denmark)

    Knop, Filip Krag

    2010-01-01

    During the last decades it has become clear that bile acids not only act as simple fat solubilizers, but additionally represent complex hormonal metabolic integrators. Bile acids activate both nuclear receptors (controlling transcription of genes involved in for example bile acid, cholesterol......, and glucose metabolism) and the cell surface G protein-coupled receptor TGR5 (modulating energy expenditure in brown fat and muscle cells). It has been shown that TGR5 is expressed in enteroendocrine L cells, which secrete the potent glucose-lowering incretin hormone glucagon-like peptide-1 (GLP-1). Recently...... it was shown that bile acid-induced activation of TGR5 results in intestinal secretion of GLP-1 and that enhanced TGR5 signaling improves postprandial glucose tolerance in diet-induced obese mice. This Perspectives article presents these novel findings in the context of prior studies on nutrient-induced GLP-1...

  15. Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice

    DEFF Research Database (Denmark)

    Arora, Tulika; Wegmann, Udo; Bobhate, Anup

    2016-01-01

    OBJECTIVE: The enteroendocrine hormone glucagon-like peptide 1 (GLP-1) is an attractive anti-diabetic therapy. Here, we generated a recombinant Lactococcus lactis strain genetically modified to produce GLP-1 and investigated its ability to improve glucose tolerance in mice on chow or high-fat diet...... (HFD). METHODS: We transformed L. lactis FI5876 with either empty vector (pUK200) or murine GLP-1 expression vector to generate LL-UK200 and LL-GLP1, respectively, and determined their potential to induce insulin secretion by incubating primary islets from wild-type (WT) and GLP-1 receptor knockout...... (GLP1R-KO) mice with culture supernatant of these strains. In addition, we administered these strains to mice on chow or HFD. At the end of the study period, we measured plasma GLP-1 levels, performed intraperitoneal glucose tolerance and insulin tolerance tests, and determined hepatic expression...

  16. Neural regulation of glucagon-like peptide-1 secretion in pigs

    DEFF Research Database (Denmark)

    Hansen, Lene; Lampert, Sarah; Mineo, Hitoshi

    2004-01-01

    Glucagon-like peptide (GLP)-1 is secreted rapidly from the intestine postprandially. We therefore investigated its possible neural regulation. With the use of isolated perfused porcine ileum, GLP-1 secretion was measured in response to electrical stimulation of the mixed, perivascular nerve supply...... and infusions of neuroactive agents alone and in combination with different blocking agents. Electrical nerve stimulation inhibited GLP-1 secretion, an effect abolished by phentolamine. Norepinephrine inhibited secretion, and phentolamine abolished this effect. GLP-1 secretion was stimulated by isoproterenol...... and weak effects on glucose-dependent insulinotropic peptide and somatostatin secretion, although this elicited a marked atropine-resistant release of the neuropeptide vasoactive intestinal polypeptide to the portal circulation. Thus GLP-1 secretion is inhibited by the sympathetic nerves to the gut and may...

  17. Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin

    DEFF Research Database (Denmark)

    Bahne, Emilie; Hansen, Morten; Brønden, Andreas;

    2016-01-01

    Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes. Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously...... administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin......-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target...

  18. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes

    DEFF Research Database (Denmark)

    Nauck, M A; Vardarli, I; Deacon, C F;

    2011-01-01

    The incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP......-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency...... with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual incretin secretory responses and explain some...

  19. Treatment of type 2 diabetes with glucagon-like peptide-1 receptor agonists

    DEFF Research Database (Denmark)

    Hansen, K B; Knop, F K; Holst, Jens Juul;

    2009-01-01

    ongoing decline in pancreatic beta-cell function and, lastly, they have a number of side effects including hypoglycaemia and weight gain. Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of pharmacological agents, which improve glucose homeostasis in a multifaceted way. Their effects...... of hypoglycaemia with GLP-1 receptor agonists is low, the compounds have clinically relevant effects on body weight, and data are suggesting beneficial effects on cardiovascular risk factors. Exenatide was released in 2005 for the treatment of type 2 diabetes and liraglutide is expected to be approved by the Food...... and Drug Administration in US and the European Medical Agency in Europe for use in 2009. In this review, the available data on the two drugs are presented and discussed....

  20. Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months

    DEFF Research Database (Denmark)

    NN, NN; Valerius, Niels Henrik

    2010-01-01

    BACKGROUND: Once-daily dosing of abacavir and lamivudine has been approved for adults, but paediatric data are insufficient. We conducted a pharmacokinetic study of once-daily and twice-daily abacavir and lamivudine in children aged 3-... levels after 12 weeks treatment with twice-daily abacavir (8 mg/kg) with or without lamivudine (4 mg/kg) underwent plasma pharmacokinetic sampling. Children then switched to once-daily abacavir (16 mg/kg) with or without lamivudine (8 mg/kg), and sampling was repeated 4 weeks later. The area under......-abacavir (17 for lamivudine). The GMR of AUC(0-24), once-daily versus twice-daily, was 1.07 (90% CI 0.92-1.23) for abacavir and 0.91 (90% CI 0.79-1.06) for lamivudine. C(max) almost doubled on once-daily versus twice...

  1. Clinical impact of laboratory error on therapeutic drug monitoring of once-daily tobramycin in cystic fibrosis: Case series

    Directory of Open Access Journals (Sweden)

    William A Prescott

    2014-01-01

    Full Text Available Once-daily dosing intravenous tobramycin is commonly used to treat cystic fibrosis pulmonary exacerbations. Clinicians often utilize historical therapeutic drug monitoring data to individualize the dose among patients who have been treated with tobramycin previously. This case series involves three patients with cystic fibrosis who had supra-therapeutic tobramycin levels despite use of a once-daily dosing that produced therapeutic drug levels during a previous hospital admission, raising questions about the validity of these levels. Investigation into several potential sources of error led to the discovery of an analyzer error in the laboratory. Once the laboratory’s tobramycin analyzer was recalibrated, the reported levels were comparable to historical levels. This case series emphasizes the clinical importance of critically analyzing reported levels, and specifically, the importance of utilizing past therapeutic drug monitoring data, if available, for all patients treated with intravenous tobramycin. If a patient was therapeutic on a similar dose of tobramycin during a previous admission, a dose adjustment may not be necessary, and clinicians should consider repeating levels while pursuing alternative explanations for the discrepant serum levels.

  2. Randomized efficacy and safety trial of once-daily remogliflozin etabonate for the treatment of type 2 diabetes.

    Science.gov (United States)

    Sykes, A P; Kemp, G L; Dobbins, R; O'Connor-Semmes, R; Almond, S R; Wilkison, W O; Walker, S; Kler, L

    2015-01-01

    The sodium-dependent glucose transporter 2 (SGLT2) inhibitor remogliflozin etabonate (RE) was evaluated in a 12-week, double-blind, randomized, placebo- and active-controlled, parallel-group study. A total of 252 newly diagnosed and drug-naïve people with type 2 diabetes and glycated haemoglobin (HbA1c) concentrations of 7.0-≤9.5% (53-80 mmol/mol) were recruited. Participants were randomized to RE (100, 250, 500 or 1000 mg once daily or 250 mg twice daily), placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c concentration from baseline. Secondary endpoints included changes in fasting plasma glucose, body weight and lipid profiles, safety and tolerability. We observed a statistically significant trend in the RE dose-response relationship for change from baseline in HbA1c at week 12 (p < 0.047). RE was generally well tolerated and no effects on LDL cholesterol were observed.

  3. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats

    DEFF Research Database (Denmark)

    Hoelmkjaer, Kirsten M.; Albrechtsen, Nicolai J. Wewer; Holst, Jens J.;

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment...... with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose...... by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean...

  4. A Placebo-Controlled Study on the Effects of the Glucagon-Like Peptide-1 Mimetic, Exenatide, on Insulin Secretion, Body Composition and Adipokines in Obese, Client-Owned Cats

    DEFF Research Database (Denmark)

    Hoelmkjaer, Kirsten M.; Albrechtsen, Nicolai Jacob Wewer; Holst, Jens Juul

    2016-01-01

    Glucagon-like Peptide-1 mimetics increase insulin secretion and reduces body weight in humans. In lean, healthy cats, short-term treatment has produced similar results, whereas the effect in obese cats or with extended duration of treatment is unknown. Here, prolonged (12 weeks) treatment...... with the Glucagon-like Peptide-1 mimetic, exenatide, was evaluated in 12 obese, but otherwise healthy, client-owned cats. Cats were randomized to exenatide (1.0 μg/kg) or placebo treatment twice daily for 12 weeks. The primary endpoint was changes in insulin concentration; the secondary endpoints were glucose...... by exenatide (P>0.05). Twelve weeks of exenatide was well-tolerated, with only two cases of mild, self-limiting gastrointestinal signs and a single case of mild hypoglycemia. The long-term insulinotropic effect of exenatide appeared less pronounced in obese cats compared to previous short-term studies in lean...

  5. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes

    DEFF Research Database (Denmark)

    Zander, M; Taskiran, M; Toft-Nielsen, M B;

    2001-01-01

    OBJECTIVE: The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted...

  6. A safety and pharmacokinetic dosing study of glucagon-like peptide 2 in infants with intestinal failure

    DEFF Research Database (Denmark)

    Sigalet, David L; Brindle, Mary E; Boctor, Dana

    2017-01-01

    BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) analogues are approved for adults with intestinal failure (IF), but no studies have included infants. This study examined the pharmacokinetics (PK), safety, and nutritional effects of GLP-2 in infants with IF. METHODS: With parental consent (Heal...

  7. Reduction in bone resorption by exogenous glucagon-like peptide-2 administration requires an intact gastrointestinal tract

    DEFF Research Database (Denmark)

    Gottschalck, Ida B; Jeppesen, Palle B; Holst, Jens Juul

    2008-01-01

    OBJECTIVE: Biochemical markers for bone resorption (s-CTX) are reduced by food intake, whereas markers for bone formation seem to be unaffected by meal status. Glucagon-like peptide-2 (GLP-2) is a peptide secreted from endocrine L cells in the intestinal mucosa in relation to food-intake. Subcuta...

  8. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon

    DEFF Research Database (Denmark)

    Jeppesen, P B; Hartmann, B; Thulesen, J

    2001-01-01

    Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a ...

  9. Involvement of endogenous glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine secretion

    DEFF Research Database (Denmark)

    Witte, Anne-Barbara; Grybäck, Per; Jacobsson, Hans;

    2011-01-01

    Objective. To study the role of endogenous glucagon-like peptide-1 (GLP-1) on gastric emptying rates of a solid meal as well as postprandial hormone secretion and glucose disposal. Material and methods. In nine healthy subjects, gastric emptying of a 310-kcal radio-labelled solid meal and plasma...

  10. Glucagon-like peptide-2 increases splanchnic blood flow acutely in calves but loses effectiveness with chronic exposure

    Science.gov (United States)

    Glucagon-like peptide-2 (GLP-2) is a 33-amino acid hormone secreted from the gastrointestinal tract that rapidly increases small intestinal blood flow. No experiments have been conducted evaluating the blood flow response to GLP-2 after extended administration, nor have investigations been performed...

  11. Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome

    Science.gov (United States)

    Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our object...

  12. Glucagon-like peptide 2 therapy reduces the negative impacts the proinflammatory response in the gut of calves with coccidiosis

    Science.gov (United States)

    Damage to the intestinal epithelium reduces nutrient absorption and animal growth, and can have negative long-term health effects on livestock. The intestinotropic hormone glucagon-like peptide 2 (GLP-2) contributes to gut integrity, reduces inflammation, and improves nutrient absorption. The presen...

  13. Oxyntomodulin differentially affects glucagon-like peptide-1 receptor beta-arrestin recruitment and signaling through Galpha(s)

    DEFF Research Database (Denmark)

    Jorgensen, Rasmus; Kubale, Valentina; Vrecl, Milka

    2007-01-01

    The glucagon-like peptide (GLP)-1 receptor is a promising target for the treatment of type 2 diabetes and obesity, and there is great interest in characterizing the pharmacology of the GLP-1 receptor and its ligands. In the present report, we have applied bioluminescence resonance energy transfer...

  14. Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease

    DEFF Research Database (Denmark)

    Junker, Anders E; Gluud, Lise L; van Hall, Gerrit

    2016-01-01

    BACKGROUND & AIMS: We evaluated the glucagon-suppressive effect of glucagon-like peptide-1 (GLP-1) and its potential effects on endogenous glucose production and whole body lipolysis in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD). METHODS: On two separate days 10 non...

  15. Glucagon-like peptide 2 dose-dependently activates intestinal cell survival and proliferation in neonatal piglets

    DEFF Research Database (Denmark)

    Burrin, Douglas G; Stoll, Barbara; Guan, Xinfu;

    2005-01-01

    Glucagon-like peptide 2 (GLP-2) is a gut hormone that stimulates mucosal growth in total parenteral nutrition (TPN)-fed piglets; however, the dose-dependent effects on apoptosis, cell proliferation, and protein synthesis are unknown. We studied 38 TPN-fed neonatal piglets infused iv with either s...

  16. Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice

    DEFF Research Database (Denmark)

    Kissow, Hannelouise; Hartmann, Bolette; Holst, Jens Juul

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel from the intestinal endocrine cells after nutrient intake. GLP-1 is an incretin hormone and analogues are available for the treatment of type 2 diabetes mellitus (T2DM). GLP-2 is an intestinal growth horm...

  17. Liraglutide: A Glucagon-Like Peptide-1 Agonist for Chronic Weight Management.

    Science.gov (United States)

    Manigault, Kendra R; Thurston, Maria Miller

    2016-12-01

    To review the efficacy and safety of liraglutide 3.0 mg for weight loss. A literature search was performed using PubMed and MEDLINE from 2000 to 2016. The following key terms were used alone or in combination: glucagon-like peptide-1 agonist, liraglutide, obesity, overweight, and weight loss. Additional supporting literature was identified utilizing the reference lists of the preceding articles. Analyzed studies were published in English and investigated use of liraglutide and its impact on weight loss. Clinical studies with a primary focus of liraglutide use in weight loss were included in this review. Author consensus determined final study inclusion. Management of obesity centers on behavior modification that includes diet and exercise; however, pharmacologic therapy may be used. Several studies have indicated that GLP-1 receptor agonists promote weight loss in patients with type 2 diabetes mellitus (T2DM). The efficacy of liraglutide 3.0 mg as a weight-loss agent in patients with and without T2DM was established in three SCALE™ clinical trials. Liraglutide 3.0 mg was generally well tolerated during clinical trials. Common adverse events were typically related to the gastrointestinal system (i.e., nausea, vomiting). Based on available evidence, liraglutide 3.0 mg appears to be a safe and effective addition to the pharmacologic armamentarium available for chronic weight management in the general population. However, there are limited data within the geriatric population. Clinicians should consider liraglutide's cost, route of administration, and concomitant drug therapy when deciding which patients are appropriate candidates for liraglutide therapy. AE = Adverse events, AHA/ACC/TOS = American Heart Association/American College of Cardiology/ The Obesity Society, BMI = Body mass index, CV = Cardiovascular, FDA = Food and Drug Administration, GI = Gastrointestinal, GLP-1 = Glucagon-like peptide-1, HbA1c = Hemoglobin A1c, Kcal = Kilocalorie, LCD = Low-calorie diet

  18. Safety and efficacy of bromfenac ophthalmic solution (Bromday) dosed once daily for postoperative ocular inflammation and pain.

    Science.gov (United States)

    Henderson, Bonnie A; Gayton, Johnny L; Chandler, Simon P; Gow, James A; Klier, Sharon M; McNamara, Timothy R

    2011-11-01

    To evaluate the efficacy and ocular safety of bromfenac ophthalmic solution (bromfenac) 0.09% dosed once daily for the treatment of ocular inflammation and pain after cataract surgery with posterior chamber intraocular lens implantation. Randomized, double-masked, vehicle-controlled or active-controlled, multicenter, clinical trials. A total of 872 subjects (872 study eyes: bromfenac in 584, placebo in 288). Four randomized, double-masked, vehicle or active-controlled, clinical trials were conducted at 134 ophthalmology clinics in the United States. Subjects aged ≥ 18 years were randomized to receive either bromfenac 0.09% or placebo dosed once daily beginning 1 day before cataract surgery (day -1), continuing on the day of surgery (day 0), and continuing for an additional postoperative 14 days. Subjects were evaluated for efficacy and safety on days 1, 3, 8, 15, and 22. The primary efficacy end point was cleared ocular inflammation, measured by the summed ocular inflammation score (SOIS; anterior chamber cells and flare) by day 15. The secondary efficacy end point was the number of subjects who were pain-free at day 1. The data from the 4 trials were pooled for analyses. The SOIS and ocular pain. The proportion of subjects who had cleared ocular inflammation by day 15 was significantly higher in the bromfenac 0.09% group than in the placebo group (P < 0.0001). The mean SOIS in the bromfenac 0.09% group was significantly lower than in the placebo group at days 3, 8, 15, and 22 (P < 0.0001). The proportion of subjects who were pain-free at days 1, 3, 8, and 15 was significantly higher in the bromfenac 0.09% group than in the placebo group (P < 0.0001). The incidence of adverse events reported in the bromfenac 0.09% group was significantly lower than in the placebo group (P < 0.0001). On day 15, 84.0% of the bromfenac subjects had ≥ 1-line improvement in visual acuity compared with 66.1% of placebo subjects (P < 0.0001). Bromfenac 0.09% dosed once daily was

  19. Validation and nephrotoxicity of a simplified once-daily aminoglycoside dosing schedule and guidelines for monitoring therapy.

    Science.gov (United States)

    Prins, J M; Weverling, G J; de Blok, K; van Ketel, R J; Speelman, P

    1996-11-01

    There is no established dosing schedule for once-daily aminoglycoside dosing regimens, and accepted guidelines for monitoring therapy are lacking. We derived a simplified schedule from the Hull and Sarubbi (J. H. Hull and F. A. Sarubbi, Ann. Intern. Med. 85:183-189, 1976) nomogram, for which efficacy and safety in a once-daily dosing regimen were previously demonstrated, and prospectively followed serum aminoglycoside levels in patients. The standard treatment was gentamicin or tobramycin at 4 mg/kg of body weight given intravenously once daily. When the renal function was decreased, the daily dose was reduced, as follows: for an estimated creatinine clearance of between 50 and 80 ml/min, the daily dose was 3.25 mg/kg, for an estimated creatinine clearance of between 30 and 50 ml/min, the daily dose was 2.5 mg/kg, and for an estimated creatinine clearance of below 30 ml/min, the daily dose was 2 mg/kg. A total of 221 patients were studied (184 received gentamicin and 37 received tobramycin). First trough levels above 2 mg/liter were recorded in 11% of the patients, and they all had a baseline creatinine clearance below 50 ml/min, or a substantial decrease in clearance between enrollment and the day that the trough level was obtained. A peak level below 6 mg/liter was recorded in 6% of the patients, and half of them received the lowest daily dose. Twenty-five of the 179 evaluable patients (14%; 95% confidence interval, 9 to 19%) fulfilled the criteria for nephrotoxicity. In a multiple regression analysis, the duration of treatment and the use of other nephrotoxic antibiotics or high-dose furosemide, but not trough levels, were significant risk factors. Since the meaning of low peak levels is unclear and since most studies with multiple daily regimens confirm the lack of an association between trough levels and toxicity, we believe that monitoring of serum drug levels can be restricted to monitoring of trough levels in patients with a creatinine clearance below 50 ml

  20. Efficacy and tolerability of once-daily barnidipine in the clinical management of patients with mild to moderate essential hypertension.

    Science.gov (United States)

    Spieker, C

    1998-01-01

    Four multicentre trials have investigated the efficacy and tolerability of treatment with once-daily, modified-release capsules of barnidipine, a long-acting dihydropyridine calcium antagonist, in patients with mild to moderate essential hypertension. In two of these trials, the clinical profile of barnidipine was compared with those of amlodipine and nitrendipine, which belong to the same class of drug as barnidipine, in a randomized, double-blind, parallel-group manner. In one study, 37 patients received amlodipine and 79 patients received barnidipine. In a second study, 46 patients received nitrendipine and 96 received barnidipine. In each trial, a 4-week placebo run-in phase was followed by a 12-week comparative phase. Changes in sitting and standing diastolic and systolic blood pressures were assessed, and adverse events were recorded. Both studies demonstrated that the antihypertensive efficacy of barnidipine was equivalent to each comparator agent, but barnidipine tended to produce fewer class I adverse reactions. The long-term efficacy and safety of barnidipine were demonstrated in an open-label study. In total, 106 patients were followed for the first year of the study, during which time they received barnidipine at a dose titrated to achieve a sitting diastolic blood pressure of less than 90 mm Hg; if necessary, another antihypertensive agent was added to achieve normalization of blood pressure. Seventy-nine of these patients, most of whom were maintained on barnidipine monotherapy, were followed for a second year, and 32 patients, all of whom received barnidipine monotherapy throughout the study period, were followed for a third year. Blood pressure normalization after 1 year of follow-up was achieved in 91% of patients, and was maintained for the second and third years in 91% and 81% of patients, respectively. The incidence of adverse events, possibly or probably attributable to barnidipine, was 22%, 14% and 3%, respectively, during each successive year

  1. Once-daily NVA237 improves exercise tolerance from the first dose in patients with COPD: the GLOW3 trial

    Directory of Open Access Journals (Sweden)

    Beeh KM

    2012-07-01

    Full Text Available Kai M Beeh,1 Dave Singh,2 Lilla Di Scala,3 Anton Drollmann31insaf Respiratory Research Institute, Wiesbaden, Germany; 2University Of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester, Manchester, UK; 3Novartis Pharma AG, Basel, SwitzerlandIntroduction: Exercise limitation, dynamic hyperinflation, and exertional dyspnea are key features of symptomatic chronic obstructive pulmonary disease (COPD. We assessed the effects of glycopyrronium bromide (NVA237, a once-daily, long-acting muscarinic antagonist, on exercise tolerance in patients with moderate to severe COPD.Methods: Patients were randomized to a cross-over design of once-daily NVA237 50 µg or placebo for 3 weeks, with a 14-day washout. Exercise endurance, inspiratory capacity (IC during exercise, IC and expiratory volumes from spirometry, plethysmographic lung volumes, leg discomfort and dyspnea under exercise (Borg scales, and transition dyspnea index were measured on Days 1 and 21 of treatment. The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test on Day 21.Results: A total of 108 patients were randomized to different treatment groups (mean age, 60.5 years; mean post-bronchodilator, forced expiratory volume in 1 second [FEV1] 57.1% predicted. Ninety-five patients completed the study. On Day 21, a 21% difference in endurance time was observed between patients treated with NVA237 and those treated with placebo (P < 0.001; the effect was also significant from Day 1, with an increase of 10%. Dynamic IC at exercise isotime and trough FEV1 showed significant and clinically relevant improvements from Day 1 of treatment that were maintained throughout the study. This was accompanied by inverse decreases in residual volume and functional residual capacity. NVA237 was superior to placebo (P < 0.05 in decreasing leg discomfort (Borg CR10 scale on Day 21 and exertional dyspnea on Days 1 and 21 (transition dyspnea index and Borg CR

  2. Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway.

    Science.gov (United States)

    Thompson, Aiysha; Kanamarlapudi, Venkateswarlu

    2015-01-01

    The glucagon-like peptide-1 receptor (GLP-1R) is a G-protein-coupled receptor (GPCR) and an important target in the treatment of type 2 diabetes mellitus (T2DM). Upon stimulation with agonist, the GLP-1R signals through both Gαs and Gαq coupled pathways to stimulate insulin secretion. The agonist-induced GLP-1R internalisation has recently been shown to be important for insulin secretion. However, the molecular mechanisms underlying GLP-1R internalisation remain unknown. The aim of this study was to determine the role of GLP-1R downstream signalling pathways in its internalisation. Agonist-induced human GLP-1R (hGLP-1R) internalisation and activity were examined using a number of techniques including immunoblotting, ELISA, immunofluorescence and luciferase assays to determine cAMP production, intracellular Ca(2+) accumulation and ERK phosphorylation. Agonist-induced hGLP-1R internalisation is dependent on caveolin-1 and dynamin. Inhibition of the Gαq pathway but not the Gαs pathway affected hGLP-1R internalisation. Consistent with this, hGLP-1R mutant T149M and small-molecule agonists (compound 2 and compound B), which activate only the Gαs pathway, failed to induce internalisation of the receptor. Chemical inhibitors of the Gαq pathway, PKC and ERK phosphorylation significantly reduced agonist-induced hGLP-1R internalisation. These inhibitors also suppressed agonist-induced ERK1/2 phosphorylation demonstrating that the phosphorylated ERK acts downstream of the Gαq pathway in the hGLP-1R internalisation. In summary, agonist-induced hGLP-1R internalisation is mediated by the Gαq pathway. The internalised hGLP-1R stimulates insulin secretion from pancreatic β-cells, indicating the importance of GLP-1 internalisation for insulin secretion.

  3. Effect of the Glucagon-like Peptide-1 Analogue Exenatide Extended Release in Cats with Newly Diagnosed Diabetes Mellitus.

    Science.gov (United States)

    Riederer, A; Zini, E; Salesov, E; Fracassi, F; Padrutt, I; Macha, K; Stöckle, T M; Lutz, T A; Reusch, C E

    2016-01-01

    Exenatide extended release (ER) is a glucagon-like peptide-1 analogue that increases insulin secretion, inhibits glucagon secretion and induces satiation in humans with type 2 diabetes mellitus. The use of exenatide ER is safe and stimulates insulin secretion in healthy cats. The objective of this study is to assess the safety of exenatide ER and its effect on body weight, remission and metabolic control in newly diagnosed diabetic cats receiving insulin and a low-carbohydrate diet. Thirty client-owned cats. Prospective placebo-controlled clinical trial. Cats were treated with exenatide ER or 0.9% saline, administered SC, once weekly. Both groups received insulin glargine and a low-carbohydrate diet. Exenatide ER was administered for 16 weeks, or in cats that achieved remission it was given for 4 weeks after discontinuing insulin treatment. Nonparametric tests were used for statistical analysis. Cats in the exenatide ER and placebo groups had transient adverse signs including decreased appetite (60% vs. 20%, respectively, P = .06) and vomiting (53% vs. 40%, respectively, P = .715). Body weight increased significantly in the placebo group (P = .002), but not in cats receiving exenatide ER. Cats on exenatide ER achieved remission or good metabolic control in 40% or 89%, respectively, whereas in control cats percentages were 20% or 58% (P = .427 and P = .178, respectively). Exenatide ER is safe in diabetic cats and does not result in weight gain. Our pilot study suggests that, should there be an additional clinically relevant beneficial effect of exenatide ER in insulin-treated cats on rate of remission and good metabolic control, it would likely approximate 20% and 30%, respectively. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  4. Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed.

    Science.gov (United States)

    King, Klim; Lin, Nai-Pin; Cheng, Yu-Hong; Chen, Gao-Hui; Chein, Rong-Jie

    2015-10-23

    The glucagon-like peptide-1 receptor (GLP-1R) is expressed in many tissues and has been implicated in diverse physiological functions, such as energy homeostasis and cognition. GLP-1 analogs are approved for treatment of type 2 diabetes and are undergoing clinical trials for other disorders, including neurodegenerative diseases. GLP-1 analog therapies maintain chronically high plasma levels of the analog and can lead to loss of spatiotemporal control of GLP-1R activation. To avoid adverse effects associated with current therapies, we characterized positive modulators of GLP-1R signaling. We screened extracts from edible plants using an intracellular cAMP biosensor and GLP-1R endocytosis assays. Ethanol extracts from fenugreek seeds enhanced GLP-1 signaling. These seeds have previously been found to reduce glucose and glycated hemoglobin levels in humans. An active compound (N55) with a new N-linoleoyl-2-amino-γ-butyrolactone structure was purified from fenugreek seeds. N55 promoted GLP-1-dependent cAMP production and GLP-1R endocytosis in a dose-dependent and saturable manner. N55 specifically enhanced GLP-1 potency more than 40-fold, but not that of exendin 4, to stimulate cAMP production. In contrast to the current allosteric modulators that bind to GLP-1R, N55 binds to GLP-1 peptide and facilitates trypsin-mediated GLP-1 inactivation. These findings identify a new class of modulators of GLP-1R signaling and suggest that GLP-1 might be a viable target for drug discovery. Our results also highlight a feasible approach for screening bioactive activity of plant extracts.

  5. Once-daily atomoxetine for treating pediatric attention-deficit/hyperactivity disorder: comparison of morning and evening dosing.

    Science.gov (United States)

    Block, Stan L; Kelsey, Douglas; Coury, Daniel; Lewis, Donald; Quintana, Humberto; Sutton, Virginia; Schuh, Kory; Allen, Albert J; Sumner, Calvin

    2009-09-01

    In this 3-arm, randomized, double-blind trial, once-daily morning-dosed atomoxetine, evening-dosed atomoxetine, and placebo were compared for treating pediatric attention-deficit/hyperactivity disorder (ADHD). Patients received morning atomoxetine/evening placebo (n = 102), morning placebo/evening atomoxetine (n = 93), or morning placebo/evening placebo (n = 93) for about 6 weeks. Core symptom efficacy was measured at weeks 0, 1, 3, and 6. Parent assessments of the child's home behaviors in the evening and early morning were collected daily during the first 2 weeks of treatment. Morning-dosed and evening-dosed atomoxetine significantly decreased core ADHD symptoms relative to placebo and produced symptom improvements that were measured up to 24 hours later. Morning dosing was superior to evening dosing on some efficacy measures. Evening dosing showed greater tolerability with significantly more patients receiving morning atomoxetine reporting at least 1 adverse event than those receiving evening atomoxetine.

  6. Effect of once-daily generic ciclesonide on exhaled nitric oxide in atopic children with persistent asthma.

    Science.gov (United States)

    Mallol, J; Aguirre, V; Gallardo, A; Cortez, E; Sánchez, C; Riquelme, C; Córdova, P; Martínez, M; Galindo, A

    2016-01-01

    Ciclesonide (CIC) is an effective inhaled corticosteroid for treating asthmatic children. However, its effect on airway inflammation assessed by the fraction of exhaled nitric oxide (FENO) in children with persistent asthma is virtually unknown. We aimed to assess the effect of once-daily generic CIC, 80 or 160 μg, on FENO, lung function, asthma control and bronchial hyperresponsiveness, in atopic children with persistent asthma. This was a 12-week, randomised, double-blind, parallel-group study. Sixty children with mild-to-moderate persistent asthma were recruited. Changes in FENO, asthma control score, lung function (FEV1) and bronchial hyperresponsiveness to methacholine (BHR) were used to assess the effects of both CIC doses. Non-normally distributed variables were log-transformed to approximate normality, and parametric tests were used for comparisons within and between groups at baseline and after 12 weeks of treatment. In the CIC 80 μg group, FENO decreased from 45.0 ppb (95% CI 37.8-53.7) to 32.7 ppb (95% CI 21.0-47.3) at the end of study (P=0.021), whereas in the CIC 160 μg group, FENO decreased from 47.3 ppb (95% CI 40.4-55.3) to 30.5 ppb (95% CI 24.1-38.7) (Pasthma control with both CIC doses but there was no significant change in BHR or FEV1 in either group. Once-daily generic ciclesonide (80 μg or 160 μg), for 12 weeks, is effective to improve airway inflammation and asthma control in atopic children with persistent asthma. Copyright © 2014 SEICAP. Published by Elsevier Espana. All rights reserved.

  7. Indacaterol once-daily provides superior efficacy to salmeterol twice-daily in COPD: a 12-week study.

    Science.gov (United States)

    Korn, Stephanie; Kerwin, Edward; Atis, Sibel; Amos, Carolynn; Owen, Roger; Lassen, Cheryl

    2011-05-01

    Indacaterol is a novel, inhaled once-daily ultra-long-acting β(2)-agonist for the treatment of COPD. This 12-week randomised, parallel-group study compared the efficacy of indacaterol 150 μg once-daily to salmeterol 50 μg twice-daily in patients with moderate-to-severe COPD. Assessments included FEV(1) standardised area under curve (AUC) from 5 min to 11 h 45 min at Week 12 (primary endpoint), 24-h trough FEV(1) (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (key secondary endpoint), FEV(1) and FVC measured over 24-h, transition dyspnoea index (TDI) and rescue medication use. Of 1123 patients randomised 92.1% completed. Mean ± SD age was 62.8±8.78 years, post-bronchodilator FEV(1) 51.8±12.32% predicted, FEV(1)/FVC 50.6±9.54%. At Week 12, FEV(1) AUC(5 min-11 h 45 min) for indacaterol was statistically superior (pIndacaterol also showed statistical superiority over salmeterol in terms of FEV(1) and FVC measured over 24-h at Week 12. For TDI at Week 12, the mean total score was statistically superior for indacaterol versus salmeterol (difference 0.63 [0.30, 0.97], pindacaterol used fewer puffs/day (difference -0.18 [-0.36, 0.00] puffs/day, pindacaterol provided statistically superior bronchodilation with an improvement in breathlessness and rescue use compared with twice-daily salmeterol. ClinicalTrials.gov NCT00821093. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. The efficacy and safety of high-dose arbekacin sulfate therapy (once-daily treatment) in patients with MRSA infection.

    Science.gov (United States)

    Yamamoto, Yoshihiro; Izumikawa, Koichi; Hashiguchi, Koji; Fukuda, Yuichi; Kobayashi, Tsutomu; Kondo, Akira; Inoue, Yuichi; Morinaga, Yoshitomo; Nakamura, Shigeki; Imamura, Yoshifumi; Miyazaki, Taiga; Kakeya, Hiroshi; Yanagihara, Katsunori; Kohno, Shigeru

    2012-04-01

    The efficacy and safety of once-daily high-dose arbekacin sulfate therapy for methicillin-resistant Staphylococcus aureus (MRSA) infection were evaluated, with analysis of their relationship to blood drug levels. The study was conducted in patients with pneumonia or sepsis, the cause of which was suspected to be MRSA, who were admitted to the Nagasaki University Hospital or its affiliated hospitals between January 2009 and December 2010. The initial drug dose was set at a level expected to yield the goal peak of 20 μg/ml and a trough level of less than 2 μg/ml, using the Habekacin Therapeutic Drug Monitoring analysis software. Thirteen patients were enrolled: 10 patients had pneumonia and 3 patients had sepsis. Patient mean age was 72.0 years; mean initial drug dose was 269.2 mg. Clinical efficacy at completion of treatment and bacterial eradication-reduction were achieved in 66.7% (6/9) and 62.5% (5/8) of patients, respectively. Incidence of adverse reactions was 38.5% (5/13). In analysis of efficacy in relationship to serum drug levels, the peak drug level was 22.7 ± 5.50 μg/ml, on average, and 15 μg/ml or higher in all 6 responders. Also, in patients with renal dysfunction, it seemed to be essential to ensure a certain peak drug level and to control the trough level appropriately. Although the number of patients was limited, once-daily high-dose arbekacin sulfate therapy may be highly effective, without posing any major safety problems. Further larger-scale studies are needed.

  9. Efficacy, safety, and tolerability of overnight switching from immediate- to once daily extended-release pramipexole in early Parkinson's disease.

    Science.gov (United States)

    Rascol, Olivier; Barone, Paolo; Hauser, Robert A; Mizuno, Yoshikuni; Poewe, Werner; Schapira, Anthony H V; Salin, Laurence; Sohr, Mandy; Debieuvre, Catherine

    2010-10-30

    The aim of this article is to test the feasibility, in early Parkinson's disease (PD), of an overnight switch from immediate-release (IR) pramipexole to a new once-daily extended-release (ER) formulation. Nonfluctuating patients on pramipexole IR three-times daily, alone or with levodopa, for early PD were randomly switched overnight to double-blind IR three-times daily (N = 52) or ER once-daily (N = 104) at initially unchanged daily dosage. Successful switching (defined as no worsening >15% of baseline UPDRS II+III score and no drug-related adverse event withdrawal) was assessed at 9 weeks, after optional dosage adjustments (primary endpoint), and at 4 weeks, before adjustment. Other secondary endpoints included adjusted mean changes from baseline in UPDRS scores and proportion of responders based on Clinical or Patient Global Impression (CGI/PGI). Absolute difference between percentage of successful switch to ER versus IR was tested for ER noninferiority, defined as a 95% confidence-interval lower bound not exceeding -15%. At 9 weeks, 84.5% of the ER group had been successfully switched, versus 94.2% for IR. Noninferiority was not demonstrated, with a difference of -9.76% (95% CI: [-18.81%, +1.66%]). At 4 weeks, 81.6% of the ER group had been successfully switched, versus 92.3% for IR, a difference of -10.75% (95% CI: [-20.51%, +1.48%]). UPDRS changes and CGI/PGI analyses showed no differences between the groups. Both formulations were safe and well tolerated. Pramipexole ER was not equivalent to IR, but the difference was marginal. The fact that >80% of the patients successfully switched overnight at unchanged dosage shows that this practice was feasible in most patients.

  10. Pharmacokinetics of tacrolimus converted from twice-daily formulation to once-daily formulation in Chinese stable liver transplant recipients

    Institute of Scientific and Technical Information of China (English)

    Yi-fan ZHANG; Xiao-yan CHEN; Xiao-jian DAI; Xi-sheng LENG; Da-fang ZHONG

    2011-01-01

    Aim:To evaluate the pharmacokinetics of tacrolimus in Chinese stable liver transplant recipients converted from immediate release (IR) tacrolimus-based immunosuppression to modified release (MR) tacrolimus-based immunosuppression.Methods:Open-label,multi-center study with a one-way conversion design was conducted.Eighty-three stable liver recipients (6-24 months post-transplant) with normal renal and stable hepatic function were converted from IR tacrolimus twice-daily treatment to MR tacrolimus once-daily treatment on a 1:1 (mg:mg) total daily dose basis.Twenty-four hour pharmacokinetic studies were carried out on d 0 (pre-conversion),d 1,and d 84 (post-conversion).Results:The area under the blood concentration-time curve of MR tacrolimus from 0 to 24 h (AUC0-24) on d 1 was comparable to that of IR tacrolimus on d 0,with a 90% confidence interval (CI) for MR/IR tacrolimus of 92%-97%.The AUC0-24 value for MR tacrolimus on d 84 with the daily dose increased by 14% was approximately 17% lower than that for IR tacrolimus.The 90% CI was 77%-90%,outside the bioequivalence range of 80%-125%.There was a good correlation between AUC0-24 and concentration at 24 h (C24) for IR tacrolimus (d 0,r=0.930) and MR tacrolimus (d 1,r=0.936; d 84,r=0.903).Conclusion:The exposure to tacrolimus when administered MR tacrolimus once daily is not equivalent to that for IR tacrolimus twice daily after an 84-day conversion in Chinese stable liver transplant recipients.The dose should be adjusted on the basis of trough levels.The therapeutic drug monitoring for patients treated with IR tacrolimus is considered to be applicable to MR tacrolimus.

  11. Design of Glucagon-Like Peptide-1 Receptor Agonist for Diabetes Mellitus from Traditional Chinese Medicine

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    Hsin-Chieh Tang

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a promising target for diabetes mellitus (DM therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4. We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD, solvent accessible surface (SAS, mean square deviation (MSD, Gyrate, total energy, root mean square fluctuation (RMSF, matrices of smallest distance of residues, database of secondary structure assignment (DSSP, cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists.

  12. [Albiglutide (Eperzan): a new once-weekly agonist of glucagon-like peptide-1 receptors].

    Science.gov (United States)

    Scheen, A J

    2015-04-01

    Albiglutide (Eperzan) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors that is indicated in the treatment of type 2 diabetes. Two doses are available, 30 mg and 50 mg, to be injected subcutaneously once a week. It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes, in comparison with placebo or an active comparator. The endocrine and metabolic effects of albiglutide are similar to those of other GLP-1 receptor agonists: stimulation of insulin secretion (incretin effect) and inhibition of glucagon secretion, both in a glucose-dependent manner, retardation of gastric emptying and increase of satiety. These effects lead to a reduction in glycated haemoglobin (HbA(1c)) levels, combined with a weight reduction. The overall tolerance profile is good. Albiglutide is currently reimbursed in Belgium after failure (HbA(1c) > 7.5%) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin (with or without oral antidiabetic drugs). To avoid hypoglycaemia, a reduction in the dose of sulfonylurea or insulin may be recommended. A once-weekly administration should increase patient's acceptance of injectable therapy and improve compliance.

  13. Glucagon-like peptide 1 improves insulin resistance in vitro through anti-inflammation of macrophages

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    C. Guo

    Full Text Available Glucagon-like peptide 1 (GLP-1, a kind of gut hormone, is used in the treatment of type 2 diabetes (T2D. Emerging evidence indicates that GLP-1 has anti-inflammatory activity. Chronic inflammation in the adipose tissue of obese individuals is a cause of insulin resistance and T2D. We hypothesized that GLP-1 analogue therapy in patients with T2D could suppress the inflammatory response of macrophages, and therefore inhibit insulin resistance. Our results showed that GLP-1 agonist (exendin-4 not only attenuated macrophage infiltration, but also inhibited the macrophage secretion of inflammatory cytokines including TNF-β, IL-6, and IL-1β. Furthermore, we observed that lipopolysaccharide (LPS-induced macrophage conditioned media could impair insulin-stimulated glucose uptake. This effect was compensated by treatment with the conditioned media from macrophages treated with the combination of LPS and exendin-4. It was also observed that exendin-4 directly inhibited the activation of NF-κB in macrophages. In conclusion, our results indicated that GLP-1 improved inflammatory macrophage-derived insulin resistance by inhibiting NF-κB pathway and secretion of inflammatory cytokines in macrophages. Furthermore, our observations suggested that the anti-inflammatory effect of GLP-1 on macrophages can contribute to GLP-1 analogue therapy of T2D.

  14. Glucagon-like peptide 1 and dysglycemia: Conflict in incretin science

    Directory of Open Access Journals (Sweden)

    Awadhesh Kumar Singh

    2015-01-01

    Full Text Available Although GLP-1 (glucagon like peptide-1 based therapies (GLP-1 agonists and dipeptidyl peptidase-4 inhibitors is currently playing a cornerstone role in the treatment of type 2 diabetes, dilemma does exist about some of its basic physiology. So far, we know that GLP-1 is secreted by the direct actions of luminal contents on the L cells in distal jejunum and proximal ileum. However, there is growing evidence now, which suggest that other mechanism via "neural" or "upper gut" signals may be playing a second fiddle and could stimulate GLP-1 secretion even before the luminal contents have reached into the proximities of L cells. Therefore, the contribution of direct and indirect mechanism to GLP-1 secretion remains elusive. Furthermore, no clear consensus exists about the pattern of GLP-1 secretion, although many believe it is monophasic. One of the most exciting issues in incretin science is GLP-1 level and GLP-1 responsiveness. It is not exactly known as to what happens to endogenous GLP-1 with progressive worsening of dysglycemia from normal glucose tolerance to impaired glucose to frank diabetes and furthermore with increasing duration of diabetes. Although, conventional wisdom suggests that there may be a decrease in endogenous GLP-1 level with the worsening of dysglycemia, literature showed discordant results. Furthermore, there is emerging evidence to suggest that GLP-1 response can vary with ethnicity. This mini review is an attempt to put a brief perspective on all these issues.

  15. Combining basal insulin analogs with glucagon-like peptide-1 mimetics.

    Science.gov (United States)

    Perfetti, Riccardo

    2011-09-01

    Basal insulin analogs are recognized as an effective method of achieving and maintaining glycemic control for patients with type 2 diabetes. However, the progressive nature of the disease means that some individuals may require additional ways to maintain their glycemic goals. Intensification in these circumstances has traditionally been achieved by the addition of short-acting insulin to cover postprandial glucose excursions that are not targeted by basal insulin. However, intensive insulin regimens are associated with a higher risk of hypoglycemia and weight gain, which can contribute to a greater burden on patients. The combination of basal insulin with a glucagon-like peptide-1 (GLP-1) mimetic is a potentially attractive solution to this problem for some patients with type 2 diabetes. GLP-1 mimetics target postprandial glucose and should complement the activity of basal insulins; they are also associated with a relatively low risk of associated hypoglycemia and moderate, but significant, weight loss. Although the combination has not been approved by regulatory authorities, preliminary evidence from mostly small-scale studies suggests that basal insulins in combination with GLP-1 mimetics do provide improvements in A1c and postprandial glucose with concomitant weight loss and no marked increase in the risk of hypoglycemia. These results are promising, but further studies are required, including comparisons with basal-bolus therapy, before the complex value of this association can be fully appreciated.

  16. Glucagon-like peptide-2-induced memory improvement and anxiolytic effects in mice.

    Science.gov (United States)

    Iwai, Takashi; Jin, Kazushi; Ohnuki, Tomoko; Sasaki-Hamada, Sachie; Nakamura, Minami; Saitoh, Akiyoshi; Sugiyama, Azusa; Ikeda, Masaatsu; Tanabe, Mitsuo; Oka, Jun-Ichiro

    2015-02-01

    We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) on memory impairment in lipopolysaccharide (LPS)-treated mice, and anxiety-like behavior in adrenocorticotropic hormone (ACTH)-treated mice. In the Y-maze test, LPS (10 µg/mouse, i.c.v.) significantly decreased spontaneous alternation, which was prevented by pretreatment with GLP-2 (0.01-0.3 µg/mouse, i.c.v.). The GLP-2 treatment just before the Y-maze test also improved LPS-induced memory impairment. Continuous treatment with GLP-2 (3 µg/mouse, i.c.v.) had no effect on the open-field test in saline-treated or ACTH-treated mice. Chronic ACTH treatment did not cause anxiogenic effects in the elevated plus-maze test. GLP-2 showed weak anxiolytic-like effects in the elevated plus-maze test in ACTH-treated, but not saline-treated mice. Moreover, GLP-2 increased 5-HT, but not 5-HIAA and tryptophan hydroxylase 2 levels in the amygdala of ACTH-treated mice. Pharmacological depletion of 5-HT prevented the anxiolytic effects of GLP-2. These results suggest that GLP-2 protected and improved memory function in LPS-treated mice, and also had anxiolytic effects due to changes in the 5-HT system.

  17. A novel glucagon-like peptide 1 peptide identified from Ophisaurus harti.

    Science.gov (United States)

    Zhu, Jingjing; Huang, Xian; Gao, Hong; Bao, Qiuying; Zhao, Yun; Hu, Jin-Feng; Xia, Gang

    2013-09-01

    Glucagon-like peptide 1 receptor (GLP1R) is a promising target for the treatment of type 2 diabetes. Because of the short half-life of endogenous GLP1 peptide, other GLP1R agonists are considered to be appealing therapeutic candidates. A high-throughput assay has been established to screen for GLP1R agonists in a 60 000-well natural product compound library fractionated from 670 different herbs/materials widely used in traditional Chinese medicines (TCMs). The screening is based on primary screen of GLP1R⁺ reporter gene assay with the counter screen in GLP1R⁻ cell line. An active fraction, A089-147, was identified from the screening. Fraction A089-147 was isolated from dried Ophisaurus harti, and the fact that its GLP1R agonist activity was sensitive to trypsin treatment indicates its peptidic nature. The active ingredient of A089-147 was later identified as O. harti GLP1 through transcriptome analysis. Chemically synthesized O. harti GLP1 showed GLP1R agonist activity and sensitivity to dipeptidase IV digestion. This study illustrated a comprehensive screening strategy to identify novel GLP1R agonists from TCMs libraries and at the same time underlined the difficulty of identifying a non-peptidic GLP1R agonist. The novel O. harti GLP1 peptide yielded from this study confirmed broader application of TCMs libraries in active peptide identification. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.

  18. Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity.

    Science.gov (United States)

    Anandhakrishnan, Ananthi; Korbonits, Márta

    2016-12-15

    Though the pathophysiology of clinical obesity is undoubtedly multifaceted, several lines of clinical evidence implicate an important functional role for glucagon-like peptide 1 (GLP-1) signalling. Clinical studies assessing GLP-1 responses in normal weight and obese subjects suggest that weight gain may induce functional deficits in GLP-1 signalling that facilitates maintenance of the obesity phenotype. In addition, genetic studies implicate a possible role for altered GLP-1 signalling as a risk factor towards the development of obesity. As reductions in functional GLP-1 signalling seem to play a role in clinical obesity, the pharmacological replenishment seems a promising target for the medical management of obesity in clinical practice. GLP-1 analogue liraglutide at a high dose (3 mg/d) has shown promising results in achieving and maintaining greater weight loss in obese individuals compared to placebo control, and currently licensed anti-obesity medications. Generally well tolerated, provided that longer-term data in clinical practice supports the currently available evidence of superior short- and long-term weight loss efficacy, GLP-1 analogues provide promise towards achieving the successful, sustainable medical management of obesity that remains as yet, an unmet clinical need.

  19. Glucagon-like peptides 1 and 2: intestinal hormones implicated in the pathophysiology of mucositis.

    Science.gov (United States)

    Kissow, Hannelouise

    2015-06-01

    Chemotherapy often causes adverse effects, including pain, bloating, diarrhea, and inflammation and ulceration of the mucous membranes lining the digestive tract, which are collectively referred to as mucositis. Unfortunately, no remedy has been found yet to manage these side-effects. The intestinal glucagon-like peptide-2 (GLP-2) is secreted from the intestinal endocrine L cells after nutrient intake, but recent findings show that the peptide concentration in the plasma also rises after intestinal injury and that GLP-2 receptor activation is crucial for intestinal healing. The antidiabetic hormone GLP-1, cosecreted with GLP-2, diminished mucositis in an animal model of the condition. Therefore, both peptides could be involved in the pathophysiology of mucositis. The intestinal GLPs have shown beneficial effects in experimental trials and have potential for therapeutic use. In type 2 diabetic and obese patients, GLP secretion is impaired. Elucidating the role of these endogenous hormones could lead to the identification of mucositis risk factors and an alternative preventive therapy for these patients.

  20. Intracerebroventricular administration of chicken glucagon-like peptide-2 potently suppresses food intake in chicks.

    Science.gov (United States)

    Honda, Kazuhisa; Saneyasu, Takaoki; Shimatani, Tomohiko; Aoki, Koji; Yamaguchi, Takuya; Nakanishi, Kiwako; Kamisoyama, Hiroshi

    2015-03-01

    Glucagon-related peptides, such as glucagon-like peptide (GLP)-1, GLP-2 and oxyntomodulin (OXM), are processed from an identical precursor proglucagon. In mammals, all of these peptides are suggested to be involved in the central regulation of food intake. We previously showed that intracerebroventricular administration of chicken OXM and GLP-1 significantly suppressed food intake in chicks. Here, we show that central administration of chicken GLP-2 potently suppresses food intake in chicks. Male 8-day-old chicks (Gallus gallus domesticus) were used in all experiments. Intracerebroventricular administration of chicken GLP-2 significantly suppressed food intake in chicks. Plasma glucose concentration was significantly decreased by chicken GLP-2, whereas plasma nonesterified fatty acid concentration was significantly increased. Intracerebroventricular administration of chicken GLP-2 did not affect plasma corticosterone concentration. In addition, the anorexigenic effect of GLP-2 was not reversed by the corticotropin-releasing factor (CRF) receptor antagonist α-helical CRF, suggesting that CRF is not a downstream mediator of the anorexigenic pathway of GLP-2 in chicks. Intracerebroventricular administration of an equimolar amount of GLP-1 and GLP-2, but not OXM, significantly suppressed food intake in both broiler and layer chicks. All our findings suggest that GLP-2 functions as a potent anorexigenic peptide in the brain, as well as GLP-1, in chicks.

  1. Osteocalcin induces release of glucagon-like peptide-1 and thereby stimulates insulin secretion in mice.

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    Akiko Mizokami

    Full Text Available The uncarboxylated form (ucOC, but not the γ-carboxylated form (GlaOC, of the bone-derived protein osteocalcin stimulates insulin secretion and regulates energy metabolism in insulin target tissues. Glucagon-like peptide-1 (GLP-1 is an insulin secretagogue that is released from the gut in response to food intake. We have now found that Gprc6a, a putative ucOC receptor, is expressed in epithelial cells of the mouse small intestine as well as in STC-1 enteroendocrine cells. Secretion of GLP-1 by STC-1 cells was stimulated by ucOC but not by GlaOC. The serum GLP-1 concentration in mice was increased by intraperitoneal or oral administration of ucOC, whereas GlaOC was effective in this regard only after oral application. Serum insulin levels were also increased by ucOC, and this effect was potentiated by an inhibitor of dipeptidyl peptidase IV and blocked by a GLP-1 receptor antagonist. Intravenous injection of ucOC in mice increased the serum GLP-1 concentration, and also increased the serum level of insulin. Our results suggest that ucOC acts via Gprc6a to induce GLP-1 release from the gut, and that the stimulatory effect of ucOC on insulin secretion is largely mediated by GLP-1.

  2. GLUCAGON LIKE PEPTIDE – 1: A NEW ERA IN TREATMENT OF TYPE- 2 DIABETES MELLITUS

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    Singhal Manmohan

    2010-09-01

    Full Text Available Therapies based on the incretin hormone glucagon-like peptide 1 (GLP-1 are novel treatment options for type 2 diabetes that act through a variety of complementary mechanisms. GLP-1 is produced by the proglucagon gene in L-cells of the small intestine in response to nutrients. It stimulates glucose-dependent insulin release from the pancreatic islets. In addition to its insulinotropic effects, it is thought to exert ant hyperglycemic effects by slowing gastric emptying, inhibiting inappropriate glucagon release, stimulating β-cell proliferation and differentiation, and improving satiety. GLP-1 secretion is decreased in type 2 diabetes, thus making it a logical target for novel treatments of type 2 diabetes. In clinical trials, GLP-1 effects are evident regardless of the duration or severity of diabetes. Thus, modulating GLP-1 levels and GLP-1 activity through administration of the native hormone, analogs, and mimetics or by inhibiting its degradation has become a major focus of investigation for treating type 2 diabetes over the past decade.

  3. Structural insight into antibody-mediated antagonism of the Glucagon-like peptide-1 Receptor.

    Science.gov (United States)

    Hennen, Stephanie; Kodra, János T; Soroka, Vladyslav; Krogh, Berit O; Wu, Xiaoai; Kaastrup, Peter; Ørskov, Cathrine; Rønn, Sif G; Schluckebier, Gerd; Barbateskovic, Silvia; Gandhi, Prafull S; Reedtz-Runge, Steffen

    2016-05-19

    The Glucagon-like peptide-1 receptor (GLP-1R) is a member of the class B G protein-coupled receptor (GPCR) family and a well-established target for the treatment of type 2 diabetes. The N-terminal extracellular domain (ECD) of GLP-1R is important for GLP-1 binding and the crystal structure of the GLP-1/ECD complex was reported previously. The first structure of a class B GPCR transmembrane (TM) domain was solved recently, but the full length receptor structure is still not well understood. Here we describe the molecular details of antibody-mediated antagonism of the GLP-1R using both in vitro pharmacology and x-ray crystallography. We showed that the antibody Fab fragment (Fab 3F52) blocked the GLP-1 binding site of the ECD directly and thereby acts as a competitive antagonist of native GLP-1. Interestingly, Fab 3F52 also blocked a short peptide agonist believed to engage primarily the transmembrane and extracellular loop region of GLP-1R, whereas functionality of an allosteric small-molecule agonist was not inhibited. This study has implications for the structural understanding of the GLP-1R and related class B GPCRs, which is important for the development of new and improved therapeutics targeting these receptors.

  4. Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis.

    Science.gov (United States)

    Koehler, Jacqueline A; Baggio, Laurie L; Cao, Xiemin; Abdulla, Tahmid; Campbell, Jonathan E; Secher, Thomas; Jelsing, Jacob; Larsen, Brett; Drucker, Daniel J

    2015-03-01

    Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67(+) cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice.

  5. Effects of glucagon-like peptide-1 receptor agonists on renal function

    Institute of Scientific and Technical Information of China (English)

    Theodosios; D; Filippatos; Moses; S; Elisaf

    2013-01-01

    Glucagon-like peptide-1(GLP-1)receptor agonists result in greater improvements in glycemic control than placebo and promote weight loss with minimal hypoglycemia in patients with type 2 diabetes mellitus.A number of case reports show an association of GLP-1receptor agonists,mainly exenatide,with the development of acute kidney injury.The present review aims to present the available data regarding the effects of GLP-1 receptor agonists on renal function,their use in subjects with chronic renal failure and their possible association with acute kidney injury.Based on the current evidence,exenatide is eliminated by renal mechanisms and should not be given in patients with severe renal impairment or end stage renal disease.Liraglutide is not eliminated by renal or hepatic mechanisms,but it should be used with caution since there are only limited data in patients with renal or hepatic impairment.There is evidence from animal studies that GLP-1 receptor agonists exert protective role in diabetic nephropathy with mechanisms that seem to be independent of their glucose-lowering effect.Additionally,there is evidence that GLP-1 receptor agonists influence water and electrolyte balance.These effects may represent new ways to improve or even prevent diabetic nephropathy.

  6. [Glucagon-like peptide-1 (GLP-1) mimetics: a new treatment for Alzheimer's disease?].

    Science.gov (United States)

    García-Casares, Natalia; García-Arnés, Juan Antonio; Gómez-Huelgas, Ricardo; Valdivielso-Felices, Pedro; García-Arias, Carlota; González-Santos, Pedro

    2014-12-01

    Introduccion. Los analogos del glucagon-like peptide-1 (GLP-1) son una opcion terapeutica establecida en los pacientes con diabetes tipo 2. Sin embargo, las propiedades de los analogos del GLP-1 van mas alla del control estrictamente metabolico del paciente diabetico. Los efectos neuroprotectores de los analogos del GLP-1 se han puesto de manifiesto en estudios recientes y han abierto nuevos campos de investigacion en trastornos neurodegenerativos como la enfermedad de Alzheimer (EA), entre otros. Objetivo. Revision sistematica de los estudios experimentales y ensayos clinicos en humanos que demuestran las propiedades neuroprotectoras de los analogos del GLP-1 en la EA. Desarrollo. Los estudios experimentales que se han llevado a cabo en modelos de roedores con EA demuestran las propiedades neuroprotectoras de los analogos del GLP-1 sobre el sistema nervioso central que reducen las placas de beta-amiloide, el estres oxidativo y la respuesta inflamatoria cerebral. Recientemente se han puesto en marcha estudios con analogos del GLP-1 en humanos con deterioro cognitivo y EA. Conclusiones. Los analogos del GLP-1 presentan propiedades neuroprotectoras. Al considerarse la diabetes tipo 2 un factor de riesgo para el deterioro cognitivo y la demencia, deben considerarse los beneficios de los analogos del GLP-1 sobre la cognicion. Del mismo modo, los analogos del GLP-1 suponen un tratamiento prometedor en la EA.

  7. Alveolar Rhabdomyosarcoma in a 69-Year-Old Woman Receiving Glucagon-Like Peptide-2 Therapy

    Directory of Open Access Journals (Sweden)

    Laura E. Zyczynski

    2015-01-01

    Full Text Available A 69-year-old woman was diagnosed with alveolar rhabdomyosarcoma (ARMS of the nasopharynx. She has a history of catastrophic thromboembolic event in the abdomen that caused short-gut syndrome and dependence on total parenteral nutrition (TPN twelve hours per day. She was treated for short-gut syndrome with teduglutide, a glucagon-like peptide-2 (GLP-2 analog, which led to reduction of TPN requirements. However, a few months later, she developed metastatic alveolar rhabdomyosarcoma. Though a causative relationship is unlikely between the peptide and ARMS due to the brief time course between teduglutide therapy and sarcoma diagnosis, neoplastic growth may have been accelerated by the GLP-2 analog, causing release of IGF-1. The transmembrane receptor for IGF-1 is frequently overexpressed in ARMS and is implicated in cell proliferation and metastatic behavior. This case describes a rare incidence of metastatic alveolar rhabdomyosarcoma in a sexagenarian and possibly the first case reported associated with the use of teduglutide. Teduglutide was discontinued due to a potential theoretical risk of acceleration of sarcoma growth, and the patient’s rhabdomyosarcoma is in remission following sarcoma chemotherapy.

  8. Effect of exercise combined with glucagon-like peptide-1 receptor agonist treatment on cardiac function

    DEFF Research Database (Denmark)

    Jørgensen, Peter G; Jensen, Magnus T; Mensberg, Pernille

    2017-01-01

    groups, P  = .03). We found no significant differences in heart rate, left ventricular (LV) structure or function within or between the groups. In conclusion, the addition of liraglutide to exercise in sedentary patients with dysregulated type 2 diabetes may blunt the suggested beneficial effect......In patients with type 2 diabetes, both supervised exercise and treatment with the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) liraglutide may improve cardiac function. We evaluated cardiac function before and after 16 weeks of treatment with the GLP-1RA liraglutide or placebo......, combined with supervised exercise, in 33 dysregulated patients with type 2 diabetes on diet and/or metformin. Early diastolic myocardial tissue velocity was improved by exercise in the placebo group (mean ± standard deviation [s.d.] -7.1 ± 1.6 to -7.7 ± 1.8 cm/s, P  = .01), but not in the liraglutide group...

  9. Imaging exocytosis of single glucagon-like peptide-1 containing granules in a murine enteroendocrine cell line with total internal reflection fluorescent microscopy

    Energy Technology Data Exchange (ETDEWEB)

    Ohara-Imaizumi, Mica; Aoyagi, Kyota [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Akimoto, Yoshihiro [Department of Anatomy, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Nakamichi, Yoko; Nishiwaki, Chiyono [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Kawakami, Hayato [Department of Anatomy, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan); Nagamatsu, Shinya, E-mail: shinya@ks.kyorin-u.ac.jp [Department of Biochemistry, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611 (Japan)

    2009-12-04

    To analyze the exocytosis of glucagon-like peptide-1 (GLP-1) granules, we imaged the motion of GLP-1 granules labeled with enhanced yellow fluorescent protein (Venus) fused to human growth hormone (hGH-Venus) in an enteroendocrine cell line, STC-1 cells, by total internal reflection fluorescent (TIRF) microscopy. We found glucose stimulation caused biphasic GLP-1 granule exocytosis: during the first phase, fusion events occurred from two types of granules (previously docked granules and newcomers), and thereafter continuous fusion was observed mostly from newcomers during the second phase. Closely similar to the insulin granule fusion from pancreatic {beta} cells, the regulated biphasic exocytosis from two types of granules may be a common mechanism in glucose-evoked hormone release from endocrine cells.

  10. Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations

    DEFF Research Database (Denmark)

    Ellrichmann, Mark; Kapelle, Mario; Ritter, Peter R;

    2008-01-01

    INTRODUCTION: Intestinal lipase inhibition using tetrahydrolipstatin (Orlistat) has been widely used in the pharmacotherapy of morbid obesity. However, the effects of Orlistat on the secretion of appetite regulating gastrointestinal hormones and appetite sensations are still debated. We addressed...... whether Orlistat alters the secretion of glucagon-like peptide-1-(7-36)-amide (GLP-1), cholecystokinin (CCK), peptide YY (PYY), and ghrelin as well as postprandial appetite sensations. METHODS: Twenty-five healthy human volunteers were examined with a solid-liquid test meal after the oral administration...... of Orlistat or placebo. Gastric emptying, gallbladder volume and the plasma levels of CCK, PYY, GLP-1, and ghrelin were determined and appetite sensations were measured using visual analogue scales. RESULTS: Gastric emptying was accelerated by Orlistat administration (P

  11. An overview of once-weekly glucagon-like peptide-1 receptor agonists--available efficacy and safety data and perspectives for the future

    DEFF Research Database (Denmark)

    Madsbad, S; Kielgast, U; Asmar, M;

    2011-01-01

    Incretin-based therapies, such as the injectable glucagon-like peptide-1 (GLP-1) receptor agonists and orally administered dipeptidyl peptidase-4 (DPP-4) inhibitors, have recently been introduced into clinical practice. At present, the GLP-1 receptor agonists need to be administered once or twice...... daily. Several once-weekly GLP-1 receptor agonists are in phase 3 development. This review examines the efficacy, safety and perspective for the future of the once-weekly GLP-1 receptor agonists: exenatide once weekly, taspoglutide, albiglutide, LY2189265 and CJC-1134-PC, and compared them...... with exenatide BID and liraglutide. In humans, no signal has been found indicating an association between the once-weekly agonists and C-cell cancer. The cardiovascular safety, durability of glucose control and effect on weight will emerge from several ongoing major long-term trials. The once-weekly GLP-1...

  12. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    OpenAIRE

    Julio, Montaner SG; Schutz, Malte; Schwartz, Robert; Jayaweera, Dushyantha T; Burnside, Alfred F; Walmsley, Sharon; Saag, Michael S.

    2006-01-01

    Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infected indiv...

  13. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    OpenAIRE

    Julio SG Montaner; Schutz Malte; Schwartz Robert; Jayaweera Dushyantha T; Burnside Alfred F; Walmsley Sharon; Saag Michael S

    2006-01-01

    Abstract Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infec...

  14. Bile acids induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weaned pigs

    DEFF Research Database (Denmark)

    Ipharraguerre, Ignacio R; Tedó, Gemma; Menoyo, David

    2013-01-01

    Early weaning is a stressful event characterized by a transient period of intestinal atrophy that may be mediated by reduced secretion of glucagon-like peptide (GLP) 2. We tested whether enterally fed bile acids or plant sterols could increase nutrient-dependent GLP-2 secretion and improve.......05) but did not affect plasma GLP-1 and feed intake. The intestinal expression of glucagon-like peptide 2 receptor, sodium-dependent bile acid transporter, farnesoid X receptor, and guanosine protein-coupled bile acid receptor genes were not affected by CDC treatment. The intragastric administration of CDC...... did not alter the weight and length of the intestine, yet increased the activation of caspase-3 in ileal villi (P affect any of the variables that were measured. Our results show that the enteral...

  15. Differences in the Central Anorectic Effects of Glucagon-Like Peptide-1 and Exendin-4 in Rats

    OpenAIRE

    Barrera, Jason G.; D'Alessio, David A.; Drucker, Daniel J.; Woods, Stephen C.; Seeley, Randy J

    2009-01-01

    OBJECTIVE Glucagon-like peptide (GLP)-1 is a regulatory peptide synthesized in the gut and the brain that plays an important role in the regulation of food intake. Both GLP-1 and exendin (Ex)-4, a long-acting GLP-1 receptor (GLP-1r) agonist, reduce food intake when administered intracerebroventricularly, whereas Ex4 is much more potent at suppressing food intake when given peripherally. It has generally been hypothesized that this difference is due to the relative pharmacokinetic profiles of ...

  16. Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes:A Clinical Update of Safety and Efficacy

    OpenAIRE

    Drab, Scott R.

    2016-01-01

    Abstract: Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer. Methods A MEDLINE search (2010-2015) ident...

  17. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future

    OpenAIRE

    Sanjay Kalra; Baruah, Manash P.; Rakesh K Sahay; Ambika Gopalakrishnan Unnikrishnan; Shweta Uppal; Omolara Adetunji

    2016-01-01

    Glucagon-like peptide-1 (GLP-1)–based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs) continue to become available, physicians will soon face the challenge of selec...

  18. Accelerated partial breast irradiation using once-daily fractionation: analysis of 312 cases with four years median follow-up

    Directory of Open Access Journals (Sweden)

    Shaikh Arif Y

    2012-02-01

    Full Text Available Abstract Background There are limited data on accelerated partial breast irradiation (APBI using external beam techniques. Moreover, there are recent reports of increased fibrosis and unacceptable cosmesis with APBI using external beam with BID fractionation. We adopted a once daily regimen of APBI with fractionation similar to that shown to be effective in a Canadian randomized trial of whole breast irradiation. It is unclear whether patients with DCIS or invasive lobular carcinoma (ILC are suitable for APBI. Methods The retrospective cohort included 310 patients with 312 tumors of T1-T2N0-N1micM0 invasive ductal carcinoma (IDC, ILC, or Tis (DCIS treated with APBI via external beam. Most patients were treated using IMRT with 16 daily fractions of 270 cGy to a dose of 4320 cGy. The target volume included the lumpectomy cavity plus 1.0 cm to account for microscopic disease and an additional 0.5 to 1.0 cm for setup uncertainty and breathing motion. Ipsilateral breast failure (IBF was pathologically confirmed as a local failure (LF or an elsewhere failure (EF. Results Median follow-up was 49 months. Among the 312 cases, 213 were IDC, 31 ILC, and 68 DCIS. Median tumor size was 1.0 cm. There were 9 IBFs (2.9% including 5 LFs and 4 EFs. The IBF rates among patients with IDC, ILC, and DCIS were 2.4%, 3.2%, and 4.4%, respectively, with no significant difference between histologies. When patients were analyzed by the ASTRO APBI consensus statement risk groups, 32% of treated cases were considered suitable, 50% cautionary, and 18% unsuitable. The IBF rates among suitable, cautionary, and unsuitable patients were 4.0%, 2.6%, and 1.8%, respectively, with no significant difference between risk groups. Acute skin reactions were rare and long-term cosmetic outcome was very good to excellent. Conclusions External beam APBI with once daily fractionation has a low rate of IBF consistent with other published APBI studies. The ASTRO risk stratification did not

  19. Bronchodilator efficacy and safety of indacaterol 150 µg once daily in patients with COPD: an analysis of pooled data

    Directory of Open Access Journals (Sweden)

    Bleecker ER

    2011-08-01

    Full Text Available Eugene R Bleecker1, Thomas Siler2, Roger Owen3, Benjamin Kramer41Center for Genomics and Personalized Medicine Research and Translational Medicine Institute, Wake Forest University Health Sciences, Winston-Salem, NC, USA; 2Midwest Chest Consultants, Saint Charles, MO, USA; 3Novartis Horsham Research Centre, Horsham, West Sussex, UK; 4Respiratory Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USABackground: Indacaterol is an inhaled, once-daily long-acting β2-agonist bronchodilator for regular use in patients with chronic obstructive pulmonary disease (COPD. As indacaterol is the first once-daily β2-agonist to be developed, it is relevant to evaluate its bronchodilator efficacy, safety, and tolerability.Methods: Data were pooled from three randomized, double-blind, clinical studies in patients with moderate-to-severe COPD treated with indacaterol 150 µg qd (n = 627 or placebo (n = 1021. Bronchodilator efficacy was assessed as trough (24-hour post-dose forced expiratory volume in 1 second (FEV1 after 12 weeks (primary endpoint in individual studies and FEV1 measured serially post-dose. Rescue use of albuterol was monitored.Results: At week 12, indacaterol increased trough FEV1 by 160 mL compared with placebo (P < 0.001, exceeding the 120 mL level prespecified as clinically important. FEV1 during the first 12-hour post-dose at week 12 averaged 210 mL higher with indacaterol than with placebo (P < 0.001. Patients receiving indacaterol recorded 53% of days without use of rescue albuterol, compared with 38% of days in the placebo group (P < 0.001. Adverse events (mostly mild or moderate were reported for 52% and 46% of patients receiving indacaterol and placebo, respectively, and serious adverse events for 4% and 5%. Worsening of COPD was the most frequent adverse event (10% indacaterol; 15% placebo. Indacaterol had little effect on pulse or blood pressure or measures of systemic β2-adrenoceptor activity (blood glucose, serum

  20. Long-term management of type 2 diabetes with glucagon-like peptide-1 receptor agonists

    Science.gov (United States)

    Courtney, Hamish; Nayar, Rahul; Rajeswaran, Chinnadorai; Jandhyala, Ravi

    2017-01-01

    Continuously reducing excess blood glucose is a primary goal for the management of type 2 diabetes (T2D). Most patients with T2D require glucose-lowering medications to achieve and maintain adequate glycemic control; however, treatment failure may occur, limiting treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an emerging therapeutic class that can be prescribed for patients instead of basal insulin after the failure of oral therapies. Recent studies have focused on the durability and tolerability of long-term GLP-1RA therapy. This review summarizes the key efficacy and safety findings from prospective phase 3 clinical studies of at least 76 weeks’ duration for the GLP-1RAs currently approved in the United States and the European Union (albiglutide, dulaglutide, exenatide twice daily [BID], exenatide once weekly [QW], liraglutide, and lixisenatide). Currently, most of the long-term data are from uncontrolled extension studies, and continuous patient benefit has been observed for up to 3 years with multiple GLP-1RAs. Four-year comparative data demonstrated a longer time to treatment failure for exenatide BID than for sulfonylurea, and 3-year comparative extension data demonstrated greater glycated hemoglobin (HbA1c) reductions and weight loss with exenatide QW than with insulin glargine. Currently, the longest extension study for a GLP-1RA is the DURATION-1 study of exenatide QW, with >7 years of clinical data available. Data from DURATION-1 demonstrated that continuous HbA1c reductions and weight loss were observed for the patients continuing on the treatment, with no unexpected adverse events. Taken together, these data support GLP-1RAs as a long-term noninsulin treatment option after the failure of oral therapies.

  1. Whey protein potentiates the intestinotrophic action of glucagon-like peptide-2 in parenterally fed rats.

    Science.gov (United States)

    Liu, Xiaowen; Murali, Sangita G; Holst, Jens J; Ney, Denise M

    2009-11-01

    Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral protein component, casein, soy, or whey protein, potentiates the intestinal growth response to GLP-2 in rats with PN-induced mucosal hypoplasia. Rats received PN and continuous intravenous infusion of GLP-2 (100 microg/kg/day) for 7 days. Six EN groups received PN+GLP-2 for days 1-3 and partial PN+GLP-2 plus EN for days 4-7. EN was provided by ad libitum intake of a semielemental liquid diet with different protein sources: casein, hydrolyzed soy, whey protein concentrate (WPC), and hydrolyzed WPC+casein. Controls received PN+GLP-2 alone. EN induced significantly greater jejunal sucrase activity and gain of body weight, and improved feed efficiency compared with PN+GLP-2 alone. EN induced greater ileal proglucagon expression, increased plasma concentration of bioactive GLP-2 by 35%, and reduced plasma dipeptidyl peptidase IV (DPP-IV) activity compared with PN+GLP-2 alone, P whey protein, and not casein or soy, potentiated the ability of GLP-2 to reverse PN-induced mucosal hypoplasia and further increase ileal villus height, crypt depth, and mucosa cellularity compared with PN+GLP-2 alone, P whey protein to induce greater mucosal surface area was associated with decreased DPP-IV activity in ileum and colon compared with casein, soy, or PN+GLP-2 alone, P whey protein potentiates the action of GLP-2 to reverse PN-induced mucosal hypoplasia in association with decreased intestinal DPP-IV activity.

  2. Nutrient-induced glucagon like peptide-1 release is modulated by serotonin.

    Science.gov (United States)

    Ripken, Dina; van der Wielen, Nikkie; Wortelboer, Heleen M; Meijerink, Jocelijn; Witkamp, Renger F; Hendriks, Henk F J

    2016-06-01

    Glucagon like peptide-1 (GLP-1) and serotonin are both involved in food intake regulation. GLP-1 release is stimulated upon nutrient interaction with G-protein coupled receptors by enteroendocrine cells (EEC), whereas serotonin is released from enterochromaffin cells (ECC). The central hypothesis for the current study was that nutrient-induced GLP-1 release from EECs is modulated by serotonin through a process involving serotonin receptor interaction. This was studied by assessing the effects of serotonin reuptake inhibition by fluoxetine on nutrient-induced GLP-1, PYY and CCK release from isolated pig intestinal segments. Next, serotonin-induced GLP-1 release was studied in enteroendocrine STC-1 cells, where effects of serotonin receptor inhibition were studied using specific and non-specific antagonists. Casein (1% w/v), safflower oil (3.35% w/v), sucrose (50mM) and rebaudioside A (12.5mM) stimulated GLP-1 release from intestinal segments, whereas casein only stimulated PYY and CCK release. Combining nutrients with fluoxetine further increased nutrient-induced GLP-1, PYY and CCK release. Serotonin release from intestinal tissue segments was stimulated by casein and safflower oil while sucrose and rebaudioside A had no effect. The combination with fluoxetine (0.155μM) further enhanced casein and safflower oil induced-serotonin release. Exposure of ileal tissue segments to serotonin (30μM) stimulated GLP-1 release whereas it did not induce PYY and CCK release. Serotonin (30 and 100μM) also stimulated GLP-1 release from STC-1 cells, which was inhibited by the non-specific 5HT receptor antagonist asenapine (1 and 10μM). These data suggest that nutrient-induced GLP-1 release is modulated by serotonin through a receptor mediated process.

  3. Does Glucagon-Like Peptide-1 Have a Role in the Etiopathogenesis of Gestational Diabetes?

    Directory of Open Access Journals (Sweden)

    Mustafa Demirpençe

    2016-06-01

    Full Text Available Purpose: The aim of this study was to evaluate glucagon-like peptide-1 (GLP-1 levels, lipid parameters, thyroid-stimulating hormone (TSH, c peptide and glycated hemoglobin (A1C values in pregnant women at high-risk for gestational diabetes mellitus (GDM. Material and Method: In this cross-sectional study, we included pregnant women at high-risk for GDM who attended the endocrinology and metabolic diseases outpatient clinics at İzmir Katip Çelebi University Atatürk Training and Research Hospital between January 2013 and April 2013. Twenty pregnant women with GDM and eleven without GDM participated in the study. The dependent variable in the study was GDM that was evaluated by 75 mg oral glucose tolerance test (OGTT. Independent variables were the levels of glucose, A1C, insulin, c-peptide, GLP-1, TSH, and lipid parameters, all evaluated in fasting blood samples. Besides, glucose, insulin, c-peptide, GLP-1 levels during OGTT were also evaluated in blood samples collected at 60 and 120 minutes. Results: While fasting insulin levels were statistically significantly higher among women with GDM, there was no statistically significant difference in the levels at 60 and 120 minutes between the two groups. There was no significant difference in fasting c-peptide levels and c-peptide levels at 60 minutes during OGTT between the two groups, however, c-peptide levels at 120 minutes were higher in women with GDM. The women with GDM was found to have lower fasting GLP-1 levels than women without GDM. Although it was not significant, GLP-1 levels at 60 and 120 minutes were also lower among women with GDM. Discussion: A decrease in GLP-1 levels may have a role in the etiopathogenesis of GDM and type 2 diabetes mellitus.

  4. Acarbose improves hypoglycaemia following gastric bypass surgery without increasing glucagon-like peptide 1 levels.

    Science.gov (United States)

    Valderas, Juan Patricio; Ahuad, Jessica; Rubio, Lorena; Escalona, Manuel; Pollak, Felipe; Maiz, Alberto

    2012-04-01

    Postprandial hypoglycaemia is a severe complication of Roux-en-Y gastric bypass (RYGBP). Acarbose, an α-glucosidase inhibitor (AGI), is employed in its treatment. Several studies have shown that AGIs increase the postprandial levels of glucagon-like peptide 1 (GLP-1). However, an excessive level of GLP-1 is one of the factors involved in the physiopathology of this condition. We analysed the effect of acarbose oral administration in eight RYBGP patients with clinically significant hypoglycaemia or dumping syndrome. Glucose, insulin and GLP-1 plasma levels in fasting and after ingestion of a standard meal (Ensure Plus®; 13 g protein, 50 g carbohydrate, 11 g fat) were measured. The test was repeated the following week with the oral administration of 100 mg of acarbose 15 min prior to the meal. Five patients developed asymptomatic hypoglycaemia during the test (glucose level <50 mg/dl) with inappropriately high insulin levels and exaggerated GLP-1 response. Acarbose ingestion avoided hypoglycaemia in all of the patients and increased the lowest plasma glucose level (46.4 ± 4.8 vs. 59.0 ± 2.6 mg/dl, p < 0.01). Acarbose ingestion decreased the area under the curve for serum insulin and GLP-1 levels at 15 min after the meal. Acarbose avoided postprandial hypoglycaemia following RYGBP by decreasing the hyperinsulinemic response. This was associated with a decrease in early GLP-1 secretion, in contrast to that observed in non-surgical subjects. This finding could be explained by the reduction of glucose load in the jejunum produced by the α-glucosidase inhibition, which is the main stimulus for GLP-1 secretion.

  5. Optogenetic analysis of depolarization dependent glucagon-like peptide-1 release.

    Science.gov (United States)

    Chimerel, Catalin; Riccio, Cristian; Murison, Keir; Gribble, Fiona M; Reimann, Frank

    2017-07-28

    Incretin hormones play an important role in the regulation of food intake and glucose homeostasis. Glucagon-like peptide-1 (GLP-1) secreting cells have been demonstrated to be electrically excitable and to fire action potentials (APs) with increased frequency in response to nutrient exposure. However, nutrients can also be metabolised or activate G-protein-coupled receptors, thus potentially stimulate GLP-1 secretion independent of their effects on the plasma membrane potential. Here we used channelrhodopsins to manipulate the membrane potential of GLUTag cells, a well established model of GLP-1 secreting enteroendocrine L-cells. Using channelrhodopsins with fast or slow on/off kinetics (CheTA and SSFO, respectively), we found that trains of light pulses could trigger APs and calcium elevation in GLUTag cells stably expressing either CheTA or SSFO. Tetrodotoxin reduced light-triggered AP frequency but did not impair calcium responses, whereas further addition of the calcium channel blockers nifedipine and ω-conotoxin GVIA abolished both APs and calcium transients. Light pulse trains did not trigger GLP-1 secretion from CheTA-expressing cells under basal conditions, but were an effective stimulus when cAMP concentrations were elevated by forskolin plus IBMX. In SSFO-expressing cells, light-stimulated GLP-1 release was observed at resting and elevated cAMP concentrations and was blocked by nifedipine plus ω-conotoxin GVIA but not tetrodotoxin. We conclude that cAMP elevation or cumulative membrane depolarisation triggered by SSFO enhance the efficiency of light-triggered action potential firing, voltage gated calcium entry and GLP-1 secretion. Copyright © 2017 Endocrine Society.

  6. A sandwich ELISA for measurement of the primary glucagon-like peptide-1 metabolite.

    Science.gov (United States)

    Wewer Albrechtsen, Nicolai J; Asmar, Ali; Jensen, Frederik; Törang, Signe; Simonsen, Lene; Kuhre, Rune E; Asmar, Meena; Veedfald, Simon; Plamboeck, Astrid; Knop, Filip K; Vilsbøll, Tina; Madsbad, Sten; Nauck, Michael A; Deacon, Carolyn F; Bülow, Jens; Holst, Jens J; Hartmann, Bolette

    2017-09-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract. It is best known for its glucose-dependent insulinotropic effects. GLP-1 is secreted in its intact (active) form (7-36NH2) but is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme, converting >90% to the primary metabolite (9-36NH2) before reaching the targets via the circulation. Although originally thought to be inactive or antagonistic, GLP-1 9-36NH2 may have independent actions, and it is therefore relevant to be able to measure it. Because reliable assays were not available, we developed a sandwich ELISA recognizing both GLP-1 9-36NH2 and nonamidated GLP-1 9-37. The ELISA was validated using analytical assay validation guidelines and by comparing it to a subtraction-based method, hitherto employed for estimation of GLP-1 9-36NH2 Its accuracy was evaluated from measurements of plasma obtained during intravenous infusions (1.5 pmol × kg(-1) × min(-1)) of GLP-1 7-36NH2 in healthy subjects and patients with type 2 diabetes. Plasma levels of the endogenous GLP-1 metabolite increased during a meal challenge in patients with type 2 diabetes, and treatment with a DPP-4 inhibitor fully blocked its formation. Accurate measurements of the GLP-1 metabolite may contribute to understanding its physiology and role of GLP-1 in diabetes. Copyright © 2017 the American Physiological Society.

  7. Glucagon-like peptide-2 and mouse intestinal adaptation to a high-fat diet.

    Science.gov (United States)

    Baldassano, Sara; Amato, Antonella; Cappello, Francesco; Rappa, Francesca; Mulè, Flavia

    2013-04-01

    Endogenous glucagon-like peptide-2 (GLP2) is a key mediator of refeeding-induced and resection-induced intestinal adaptive growth. This study investigated the potential role of GLP2 in mediating the mucosal responses to a chronic high-fat diet (HFD). In this view, the murine small intestine adaptive response to a HFD was analyzed and a possible involvement of endogenous GLP2 was verified using GLP2 (3-33) as GLP2 receptor (GLP2R) antagonist. In comparison with animals fed a standard diet, mice fed a HFD for 14 weeks exhibited an increase in crypt-villus mean height (duodenum, 27.5±3.0%; jejunum, 36.5±2.9%; P<0.01), in the cell number per villus (duodenum, 28.4±2.2%; jejunum, 32.0±2.9%; P<0.01), and in Ki67-positive cell number per crypt. No change in the percent of caspase-3-positive cell in the villus-crypt was observed. The chronic exposure to a HFD also caused a significant increase in GLP2 plasma levels and in GLP2R intestinal expression. Daily administration of GLP2 (3-33) (30-60  ng) for 4 weeks did not modify the crypt-villus height in control mice. In HFD-fed mice, chronic treatment with GLP2 (3-33) reduced the increase in crypt-villus height and in the cell number per villus through reduction of cell proliferation and increase in apoptosis. This study provides the first experimental evidence for a role of endogenous GLP2 in the intestinal adaptation to HFD in obese mice and for a dysregulation of the GLP2/GLP2R system after a prolonged HFD.

  8. Oral Delivery of Pentameric Glucagon-Like Peptide-1 by Recombinant Lactobacillus in Diabetic Rats

    Science.gov (United States)

    Krogh-Andersen, Kasper; Pelletier, Julien; Marcotte, Harold; Östenson, Claes-Göran; Hammarström, Lennart

    2016-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by intestinal cells and stimulates insulin secretion from the pancreas in a glucose-dependent manner. Exogenously supplied GLP-1 analogues are used in the treatment of type 2 diabetes. An anti-diabetic effect of Lactobacillus in lowering plasma glucose levels and its use as a vehicle for delivery of protein and antibody fragments has been shown previously. The aim of this study was to employ lactobacilli as a vehicle for in situ production and delivery of GLP-1 analogue to normalize blood glucose level in diabetic GK (Goto-Kakizaki) rats. In this study, we designed pentameric GLP-1 (5×GLP-1) analogues which were both expressed in a secreted form and anchored to the surface of lactobacilli. Intestinal trypsin sites were introduced within 5×GLP-1, leading to digestion of the pentamer into an active monomeric form. The E. coli-produced 5×GLP-1 peptides delivered by intestinal intubation to GK rats resulted in a significant improvement of glycemic control demonstrated by an intraperitoneal glucose tolerance test. Meanwhile, the purified 5×GLP-1 (trypsin-digested) from the Lactobacillus cultures stimulated insulin secretion from HIT-T15 cells, similar to the E. coli-produced 5×GLP-1 peptides. When delivered by gavage to GK rats, non-expressor L. paracasei significantly lowered the blood glucose level but 5×GLP-1 expression did not provide an additional anti-diabetic effect, possibly due to the low levels produced. Our results indicate that lactobacilli themselves might be used as an alternative treatment method for type 2 diabetes, but further work is needed to increase the expression level of GLP-1 by lactobacilli in order to obtain a significant insulinotropic effect in vivo. PMID:27610615

  9. Glucagon-like peptide receptor agonists and dipeptidyl peptidase-4 inhibitors in the treatment of diabetes: a review of clinical trials

    DEFF Research Database (Denmark)

    Madsbad, Sten; Krarup, Thure; Deacon, Carolyn F;

    2008-01-01

    PURPOSE OF REVIEW: To discuss the virtues and shortcomings of the glucagon-like peptide-1 receptor agonists and the dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes. RECENT FINDINGS: The injectable glucagon-like peptide-1 receptor agonists exenatide significantly improves......-acting glucagon-like peptide-1 receptor agonists liraglutide and exenatide long-acting release reduce haemoglobin A1c by about 1.0-2.0% and have fewer gastrointestinal side-effects. The orally available dipeptidyl peptidase-4 inhibitors, that is sitagliptin and vildagliptin reduce haemoglobin A1c by 0...

  10. Profile of once-daily darunavir/cobicistat fixed-dose combination for the treatment of HIV/AIDS

    Science.gov (United States)

    Navarro, Jordi; Curran, Adrian

    2016-01-01

    Efficacy is the main objective of antiretroviral treatment and adherence is one of the cornerstones to achieve it. For this reason, treatment simplification is of key importance with regard to antiretroviral regimens. Rezolsta® (darunavir/cobicistat) is the first fixed-dose combination containing a protease inhibitor approved for HIV treatment. This coformulation includes darunavir, a protease inhibitor that has shown its efficacy and safety in naïve and treatment-experienced patients, and cobicistat, the new pharmacokinetic enhancer that is expected to replace ritonavir. Bioequivalence between ritonavir and cobicistat as darunavir boosters has been shown in studies involving healthy volunteers. Furthermore, efficacy and safety of darunavir/cobicistat observed in phase III studies, including naïve and pretreated patients without darunavir-associated resistance mutations, are comparable to historical data of darunavir/ritonavir 800/100 mg once-daily formulation. Adverse events with darunavir/cobicistat are scarce and mild, and basically include skin reactions and gastrointestinal disturbances. Although small increases in plasma creatinine are expected in patients receiving cobicistat due to the inhibition of creatinine transporters in kidney tubules, actual glomerular filtrate rate remains unaltered. Cobicistat does not have an inducer effect on metabolic pathways and shows much more selective inhibition than ritonavir. Therefore, isoenzyms different from CYP3A4 are supposed to be less affected by cobicistat, and thus fewer drug–drug interactions are expected. PMID:27843352

  11. Once-daily rupatadine improves the symptoms of chronic idiopathic urticaria: a randomised, double-blind, placebo-controlled study.

    Science.gov (United States)

    Dubertret, Louis; Zalupca, Lavinia; Cristodoulo, Tania; Benea, Vasile; Medina, Iris; Fantin, Sara; Lahfa, Morad; Pérez, Iñaki; Izquierdo, Iñaki; Arnaiz, Eva

    2007-01-01

    This randomised, double-blind, placebo-controlled, parallel-group, international, dose-ranging study investigated the effect of treatment with rupatadine 5, 10 and 20 mg once daily for 4 weeks on symptoms and interference with daily activities and sleep in 12-65 years-old patients with moderate-to-severe chronic idiopathic urticaria (CIU). Rupatadine 10 and 20 mg significantly reduced pruritus severity by 62.05% and 71.87% respectively, from baseline, over a period of 4 weeks compared to reduction with placebo by 46.59% (p < 0.05). Linear trends were noted for reductions in mean number of wheals and interference with daily activities and sleep with rupatadine 10 and 20 mg over the 4-week treatment period. The two most frequently reported AEs were somnolence (2.90% for placebo, 4.29% for 5 mg-, 5.41% for 10 mg- and 21.43% for 20 mg-rupatadine-treated group) and headache (4.35% for placebo, 2.86% for 5 mg-, 4.05% for 10 mg- and 4.29% for 20 mg-rupatadine-treated group). These findings suggest that rupatadine 10 and 20 mg is a fast-acting, efficacious and safe treatment for the management of patients with moderate-to-severe CIU. Rupatadine decreased pruritus severity, in a dose- and time-dependent manner.

  12. Glucagon-like peptide-1 analogue, liraglutide, delays onset and reduces severity of experimental autoimmune encephalitis in Lewis rats

    Directory of Open Access Journals (Sweden)

    Brian DellaValle

    2016-11-01

    Full Text Available AbstractIntroduction: Recent findings indicate that metabolic disturbances are involved in multiple sclerosis (MS pathology and influence the susceptibility to treatment, directing attention towards anti-diabetic drugs such as metformin and pioglitazone. Liraglutide, a drug of the glucagon-like peptide-1 (GLP-1 family, is also anti-diabetic and weight-reducing and is moreover, directly neuroprotective and anti-inflammatory in a broad spectrum of experimental models of brain disease. In this study we investigate the potential for this FDA-approved drug, liraglutide, as a treatment for MS by utilizing the experimental model, experimental autoimmune encephalitis (EAE.Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 µg/kg s.c. or saline. Healthy controls were included (saline, n=6, liraglutide, n=7. Clinical score and weight were assessed daily by blinded observers. Animals were killed at peak disease severity (day 11 or if exceeding humane endpoint (clinical score ≥4. Protein levels of manganese superoxide dismutase (MnSOD, amyloid precursor protein (APP, and glial fibrillary acidic protein (GFAP were determined.Results: Liraglutide treatment delayed disease onset (group clinical score significantly >0 by two days and markedly reduced disease severity (median clinical score 2 vs. 5; p=0.0003. Fourteen of 15 (93% of vehicle-treated rats reached the humane endpoint (clinical score ≥4 by day 11 compared to 5 of 15 (33% of liraglutide-treated rats (p=0.0004. Liraglutide substantially increased the mitochondrial antioxidant MnSOD (p<0.01 and reduced the neurodegenerative marker APP (p=0.036 in the brain. GFAP levels were not significantly changed with drug treatment (p=0.09Conclusion: We demonstrate, for the first time, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1 receptor

  13. Comparison of health care resource utilization and costs among patients with GERD on once-daily or twice-daily proton pump inhibitor therapy

    Directory of Open Access Journals (Sweden)

    Mody R

    2013-04-01

    Full Text Available Reema Mody,1 Debra Eisenberg,2 Likun Hou,2 Siddhesh Kamat,2 Joseph Singer,2 Lauren B Gerson3 1Takeda Pharmaceuticals International Inc, Deerfield, IL, 2HealthCore Inc, Wilmington, DE, 3Stanford University School of Medicine, Stanford, CA, USA Background: The purpose of this study was to assess differences in health care resource utilization and costs associated with once-daily and twice-daily proton pump inhibitor (PPI therapy. Most patients with gastroesophageal reflux disease (GERD achieve symptom control on once-daily PPI therapy, but approximately 20%–30% require twice-daily dosing. Methods: Patients were ≥18 years of age with at least one medical claim for GERD and at least two PPI claims from HealthCore's Integrated Research Database (HIRDSM during 2004–2009. Patients were continuously eligible for 12 months before and after the index date (date of first PPI claim. Based on PPI dosing throughout the post-index period (quantity of medication dispensed/number of days supply, patients were classified as once-daily (dose ≤ 1.5 pills per day or twice-daily (≥1.5 PPI users. Results: The study cohort included 248,386 patients with GERD (mean age 52.8 ± 13.93 years, 56% females of whom 90% were once-daily and 10% were twice-daily PPI users. The Deyo-Charlson Comorbidity Index for once-daily and twice-daily PPI users was 0.70 ± 1.37 and 0.89 ± 1.54, respectively (P < 0.05. More once-daily patients had claims for Barrett's esophagus (5% versus 2%, P < 0.0001 than twice-daily patients. Post-index, higher proportions of twice-daily patients had at least one GERD-related inpatient visit (7% versus 5%, outpatient visit (60% versus 49%, and office visit (48% versus 38% versus once-daily patients (P < 0.0001. Mean total GERD-related health care costs were $2065 ± $6636 versus $3749 ± $11,081 for once-daily and twice-daily PPI users, respectively (P < 0.0001. Conclusion: Patients receiving twice-daily PPI therapy were likely to have more

  14. Twice-daily versus once-daily antiretroviral therapy and coformulation strategies in HIV-infected adults: benefits, risks, or burden?

    Science.gov (United States)

    Nachega, Jean B; Rosenkranz, Bernd; Pham, Paul A

    2011-01-01

    The recent development of once-daily antiretroviral agents and fixed-dose combination formulations has been an important development in antiretroviral regimen simplification. Recent studies indicate that once-daily antiretroviral regimens improve adherence, especially in antiretroviral-naïve patients and in difficult-to-treat populations, such as the homeless or marginally housed. However, there are potential risks with the higher peak and lower trough plasma drug concentrations that may result from certain once-daily formulations. Due to the multifactorial and complex nature of adherence behavior, clinicians’ efforts to improve patient adherence should not be limited to prescribing once-daily regimens, but should also consider social support, side effect management, and adherence support tools, such as pillbox organizers and other targeted interventions. Additional research will clarify the benefits of once-daily and fixed-dose combination regimens on clinical and virologic outcomes. Comprehensive cost-benefit analysis of regimen simplification could help facilitate evidence-based decisions regarding antiretroviral regimen choices. PMID:22259241

  15. Glucagon-Like Peptide-1 Receptor Activation Modulates Pancreatitis-Associated Gene Expression But Does Not Modify the Susceptibility to Experimental Pancreatitis in Mice

    National Research Council Canada - National Science Library

    Jacqueline A. Koehler; Laurie L. Baggio; Benjamin J. Lamont; Safina Ali; Daniel J. Drucker

    2009-01-01

    Glucagon-Like Peptide-1 Receptor Activation Modulates Pancreatitis-Associated Gene Expression But Does Not Modify the Susceptibility to Experimental Pancreatitis in Mice Jacqueline A. Koehler , Laurie L...

  16. Differential effects of glucagon-like peptide-1 receptor agonists on heart rate.

    Science.gov (United States)

    Lorenz, Martin; Lawson, Francesca; Owens, David; Raccah, Denis; Roy-Duval, Christine; Lehmann, Anne; Perfetti, Riccardo; Blonde, Lawrence

    2017-01-13

    While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1-12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1-3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6-10 bpm compared with dulaglutide and exenatide LAR at 3-4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained

  17. Enteroendocrine-derived glucagon-like peptide-2 controls intestinal amino acid transport.

    Science.gov (United States)

    Lee, Jennifer; Koehler, Jacqueline; Yusta, Bernardo; Bahrami, Jasmine; Matthews, Dianne; Rafii, Mahroukh; Pencharz, Paul B; Drucker, Daniel J

    2017-03-01

    Glucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 from gut endocrine cells, and both peptides act as growth factors to expand the surface area of the mucosal epithelium. Notably, GLP-2 also enhances glucose and lipid transport in enterocytes; however, its actions on control of amino acid (AA) transport remain unclear. Here we examined the mechanisms linking gain and loss of GLP-2 receptor (GLP-2R) signaling to control of intestinal amino acid absorption in mice. Absorption, transport, and clearance of essential AAs, specifically lysine, were measured in vivo by Liquid Chromatography triple quadrupole Mass Spectrometry (LC-MS/MS) and ex vivo with Ussing chambers using intestinal preparations from Glp2r(+/+) and Glp2r(-/-) mice. Immunoblotting determined jejunal levels of protein components of signaling pathways (PI3K-AKT, and mTORC1-pS6-p4E-BP1) following administration of GLP-2, protein gavage, and rapamycin to fasted Glp2r(+/+) and Glp2r(-/-) mice. Expression of AA transporters from full thickness jejunum and 4F2hc from brush border membrane vesicles (BBMVs) was measured by real-time PCR and immunoblotting, respectively. Acute administration of GLP-2 increased basal AA absorption in vivo and augmented basal lysine transport ex vivo. GLP-2-stimulated lysine transport was attenuated by co-incubation with wortmannin, rapamycin, or tetrodotoxin ex vivo. Phosphorylation of mTORC1 effector proteins S6 and 4E-BP1 was significantly increased in wild-type mice in response to GLP-2 alone, or when co-administered with protein gavage, and abolished following oral gavage of rapamycin. In contrast, activation of GLP-1R signaling did not enhance S6 phosphorylation. Disruption of GLP-2 action in Glp2r(-/-) mice reduced lysine transport ex vivo and attenuated the phosphorylation of S6 and 4E-BP1 in response to oral protein. Moreover, the expression of cationic AA transporter slc7a9 in response to refeeding, and the abundance of 4F2hc in BBMVs following protein gavage

  18. Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Sharma Pawana

    2010-12-01

    Full Text Available Abstract Background Glucagon-like peptide (GLP-1 analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs. Methods MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events. Results Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 μg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily. Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists

  19. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Christensen, Mikkel; Junker, Anders E;

    2012-01-01

    To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.......To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus....

  20. Cost-utility analysis of indacaterol in Germany: a once-daily maintenance bronchodilator for patients with COPD.

    Science.gov (United States)

    Price, David; Gray, Alastair; Gale, Rupert; Asukai, Yumi; Mungapen, Laura; Lloyd, Adam; Peters, Lars; Neidhardt, Katja; Gantner, Tobias

    2011-11-01

    Indacaterol is a novel inhaled once-daily long-acting beta(2)-agonist (LABA) for the maintenance treatment of COPD that has been compared to existing inhaled monotherapies on a number of symptomatic endpoints in clinical studies. With constrained healthcare budgets, the objective of this analysis was to evaluate the cost-effectiveness of indacaterol 150 μg, the approved starting dose for maintenance therapy, from a German heath service perspective against the most widely used bronchodilator tiotropium, and the twice-daily LABA, salmeterol. A Markov model was developed with the following main health states: Mild, Moderate, Severe, and Very Severe COPD, based on pre-bronchodilator FEV(1) measures reported in the indacaterol clinical trials, and death. Each disease severity health state had two associated health states for severe or non-severe exacerbation. The model considered patients with moderate to severe COPD, with a mean age of 64 years. The base case time horizon was three years, with discounting set at 3% for costs and benefits. Selected clinical inputs and health state utilities were derived from indacaterol clinical trials, while costs were based on publicly available drug prices and tariffs or published sources. Inputs describing disease progression were based on published data on the rate of FEV(1) decline. Point-estimates show that indacaterol 150 μg is dominant (lower total costs and better outcomes) against tiotropium and salmeterol. An alternative analysis comparing indacaterol 300 μg (maximum dose) against tiotropium, showed an incremental cost-effectiveness ratio (ICER) of approximately €28,300 per QALY. Indacaterol is cost-effective compared to tiotropium and salmeterol. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. Automated telecommunication-based reminders and adherence with once-daily glaucoma medication dosing: the automated dosing reminder study.

    Science.gov (United States)

    Boland, Michael V; Chang, Dolly S; Frazier, Travis; Plyler, Ryan; Jefferys, Joan L; Friedman, David S

    2014-07-01

    Topical glaucoma medications lower intraocular pressure and alter the course of the disease. Because adherence with glaucoma medications is a known problem, interventions are needed to help those patients who do not take their medications as prescribed. To assess the ability of an automated telecommunication-based intervention to improve adherence with glaucoma medications. We performed a prospective cohort study of medication adherence, followed by a randomized intervention for those found to be nonadherent, of individuals recruited from a university-based glaucoma subspecialty clinic. A total of 491 participants were enrolled in the initial assessment of adherence. Of those, 70 were nonadherent with their medications after 3 months of electronic monitoring and randomized to intervention and control groups. A personal health record was used to store the list of patient medications and reminder preferences. On the basis of those data, participants randomized to the intervention received daily messages, either text or voice, reminding them to take their medication. Participants randomized to the control group received usual care. Difference in adherence before and after initiation of the intervention. Using an intent-to-treat analysis, we found that the median adherence rate in the 38 participants randomized to the intervention increased from 53% to 64% (P telecommunication-based reminders linked to data in a personal health record improved adherence with once-daily glaucoma medications. This is an effective method to improve adherence that could realistically be implemented in ophthalmology practices with a minimum amount of effort on the part of the practice or the patient.

  2. Effects of once-daily extended release quetiapine fumarate on patient-reported outcomes in patients with generalized anxiety disorder

    Directory of Open Access Journals (Sweden)

    Endicott J

    2012-07-01

    Full Text Available Jean Endicott,1 Henrik Svedsäter,2 Julie C Locklear21Department of Psychiatry, Columbia University, New York, NY; 2AstraZeneca Pharmaceuticals, Wilmington, DE, USABackground: We evaluated the effects of once-daily extended-release quetiapine fumarate (quetiapine XR on patient-reported outcomes in generalized anxiety disorder (GAD.Methods: This is a report of a pooled analysis from three acute 8-week, randomized, placebo-controlled, fixed-dose (50, 150, 300 mg/day studies and a 52-week maintenance flexible dose (50–300 mg/day study of quetiapine XR monotherapy in patients with GAD. Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF percent maximum total scores (items 1–14, item 15 ("satisfaction with medication", item 16 ("overall life satisfaction", and Pittsburgh Sleep Quality Index (PSQI global scores are reported. Sheehan Disability Scale (SDS total scores were also assessed (maintenance study only.Results: The acute studies showed significant improvements at week 8 in Q-LES-Q-SF percent maximum total score with quetiapine XR 150 mg/day (P < 0.001 and item 16 with quetiapine XR 50 (P < 0.05 and 150 mg/day (P < 0.001 versus placebo; PSQI global scores significantly improved with quetiapine XR 50, 150, and 300 mg/day versus placebo (P < 0.001. The maintenance study showed significant benefits versus placebo with quetiapine XR 50–300 mg/day in Q-LES-Q-SF percent total score, item 15 and item 16 scores, PSQI global score, and SDS total score.Conclusion: Quetiapine XR 150 mg/day (acute studies and 50–300 mg/day (maintenance study improved quality of life, overall functioning, and sleep quality in patients with GAD.Keywords: atypical antipsychotic, anxiety disorders, quality of life, sleep quality, functioning, randomized studies

  3. Profile of once-daily darunavir/cobicistat fixed-dose combination for the treatment of HIV/AIDS

    Directory of Open Access Journals (Sweden)

    Navarro J

    2016-10-01

    Full Text Available Jordi Navarro, Adrian Curran Infectious Diseases Department, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain Abstract: Efficacy is the main objective of antiretroviral treatment and adherence is one of the cornerstones to achieve it. For this reason, treatment simplification is of key importance with regard to antiretroviral regimens. Rezolsta® (darunavir/cobicistat is the first fixed-dose combination containing a protease inhibitor approved for HIV treatment. This coformulation includes darunavir, a protease inhibitor that has shown its efficacy and safety in naïve and treatment-experienced patients, and cobicistat, the new pharmacokinetic enhancer that is expected to replace ritonavir. Bioequivalence between ritonavir and cobicistat as darunavir boosters has been shown in studies involving healthy volunteers. Furthermore, efficacy and safety of darunavir/cobicistat observed in phase III studies, including naïve and pretreated patients without darunavir-associated resistance mutations, are comparable to historical data of darunavir/ritonavir 800/100 mg once-daily formulation. Adverse events with darunavir/cobicistat are scarce and mild, and basically include skin reactions and gastrointestinal disturbances. Although small increases in plasma creatinine are expected in patients receiving cobicistat due to the inhibition of creatinine transporters in kidney tubules, actual glomerular filtrate rate remains unaltered. Cobicistat does not have an inducer effect on metabolic pathways and shows much more selective inhibition than ritonavir. Therefore, isoenzyms different from CYP3A4 are supposed to be less affected by cobicistat, and thus fewer drug–drug interactions are expected. Keywords: darunavir, cobicistat, fixed-dose combination, HIV infection, antiretroviral treatment

  4. Twice-daily versus once-daily antiretroviral therapy and coformulation strategies in HIV-infected adults: benefits, risks, or burden?

    Directory of Open Access Journals (Sweden)

    Nachega JB

    2011-12-01

    Full Text Available Jean B Nachega1–3, Bernd Rosenkranz4, Paul A Pham51Department of International Health, 2Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; 3Department of Medicine and Centre for Infectious Diseases, 4Division of Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Stellenbosch, Capetown, South Africa; 5Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: The recent development of once-daily antiretroviral agents and fixed-dose combination formulations has been an important development in antiretroviral regimen simplification. Recent studies indicate that once-daily antiretroviral regimens improve adherence, especially in antiretroviral-naïve patients and in difficult-to-treat populations, such as the homeless or marginally housed. However, there are potential risks with the higher peak and lower trough plasma drug concentrations that may result from certain once-daily formulations. Due to the multifactorial and complex nature of adherence behavior, clinicians’ efforts to improve patient adherence should not be limited to prescribing once-daily regimens, but should also consider social support, side effect management, and adherence support tools, such as pillbox organizers and other targeted interventions. Additional research will clarify the benefits of once-daily and fixed-dose combination regimens on clinical and virologic outcomes. Comprehensive cost-benefit analysis of regimen simplification could help facilitate evidence-based decisions regarding antiretroviral regimen choices.Keywords: regimen adherence, regimen simplification, health care costs, fixed-dose combination, once-daily antiretroviral drugs

  5. Once-daily or twice-daily delivery of inhaled corticosteroids: assessment of the efficacy and of influence of the long term treatment on growth in asthmatic children

    Directory of Open Access Journals (Sweden)

    Lilijana Besednjak-Kocijančič

    2006-03-01

    Full Text Available Background: Inhaled corticosteroids are recommended drugs for asthma treatment. Their growth suppressive potential is well-known. Twice-daily delivery is usually used in children, but poor compliance of such long-term treatment may represent a problem which can be resolved with once-daily regimen. The aim of this prospective study was to asses the efficacy and the influence on growth of long term once-daily administration of inhaled fluticasone propionate (FP in asthmatic Slovene children under 5 years.Methods: Children with mild persistent asthma took part in parallel group trial. Their parents recorded asthma symptoms, β 2-agonist usage, and PEF using a form for asthma control on a daily basis for a period of one year. According twice or once-daily treatment they were divided in two groups: group A – children receiving FP 100 μg twice-daily and group B – children receiving FP 200 μg once-daily at bedtime. Mean height of 26 children of the same sex and age from each group and of 26 healthy children (groups A1, B1, C was observed. Chi-square analysis with Yates’ correction and t-tests were employed for between – group analyses (SPSS software 11.0.Results: FP given once-daily was as effective and tolerated as the same total dose given twice-daily. PEF, asthma symptoms and bronchodilator use of children from group B were not significantly different from those from group A (p > 0.05. The mean height increase of children receiving FP once-daily was smaller for 0.22 cm than of children receiving FP twice-daily and for 0.98 cm than of healthy children (t = 1.56, p = 0.132; DF: 24.Conclusions: Once-daily administration of inhaled FP in asthmatic children is safe and as effective as twice-daily administration. The suppressive potential is greater when it is given once-daily.

  6. Unprecedented high insulin secretion in a healthy human subject after intravenous glucagon-like peptide-1

    DEFF Research Database (Denmark)

    Knop, Filip K; Lund, Asger; Madsbad, Sten

    2014-01-01

    to as one of the most insulinotropic substances known. CASE PRESENTATION: Plasma insulin and C-peptide concentrations were measured in a healthy Caucasian male (age: 53 years; body mass index: 28.6 kg/m2; fasting plasma glucose: 5.7 mM; 2 h plasma glucose value following 75 g-oral glucose tolerance test: 3...... insulin and C-peptide responses were observed during meal test (peak concentrations: 300 and 3,278 pM) and glucagon test (peak concentrations: 250 and 2,483 pM). During the hyperglycaemic clamp with continuous intravenous infusion of GLP-1 the subject exhibited plasma insulin and C-peptide concentrations...

  7. The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes.

    Science.gov (United States)

    Moon, Ho-Sang; Kim, Mi-Kyung; Son, Moon-Ho

    2011-07-01

    Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic β-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864.

  8. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients

    DEFF Research Database (Denmark)

    Toft-Nielsen, M B; Madsbad, Sten; Holst, J J

    1999-01-01

    under the curve for insulin and C-peptide levels were significantly higher during the GLP-1 administration, whereas glucagon levels were unchanged. Neither triglycerides nor free fatty acids were affected. GLP-1 administration decreased hunger and prospective food intake and increased satiety, whereas......OBJECTIVE: The gut hormone glucagon-like peptide 1 (GLP-1) has insulinotropic and anorectic effects during intravenous infusion and has been proposed as a new treatment for type 2 diabetes and obesity. The effect of a single subcutaneous injection is brief because of rapid degradation. We therefore...

  9. The glucagon-like peptide 2 receptor is expressed in enteric neurons and not in the epithelium of the intestine

    DEFF Research Database (Denmark)

    Pedersen, Jens; B. Pedersen, Nis; Brix, Sophie W.

    2015-01-01

    Glucagon-like peptide 2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential in the treatment of intestinal deficiencies. It has recently been approved for the treatment of short bowel syndrome. The effects of GLP-2 are mediated by specific binding of the hormone to the GLP......-2 receptor (GLP-2R) which was cloned in 1999. However, consensus about the exact receptor localization in the intestine has never been established. By physical, chemical and enzymatic tissue fragmentation, we were able to divide rat jejunum into different compartments consisting of: (1) epithelium...... compartments rich in enteric neurons and, importantly they exclude significant expression in the epithelium of rat jejunal mucosa....

  10. Plasma glucagon-like peptide 1 and peptide YY levels are not altered in symptomatic fructose-sorbitol malabsorption

    DEFF Research Database (Denmark)

    Valeur, Jørgen; Øines, Eliann; Morken, Mette Helvik

    2008-01-01

    consecutive patients with functional abdominal complaints, referred to our clinic for investigation of self-reported food hypersensitivity, were included in the study and compared with 15 healthy volunteers. All subjects ingested a mixture of 25 g fructose and 5 g sorbitol. Pulmonary hydrogen and methane...... excretion and plasma glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) levels were measured during the next 3 h. Both habitual and post-test symptoms were assessed. RESULTS: Malabsorption of fructose and sorbitol was present in 61% of the patients and 73% of the controls. Nevertheless, the patients...

  11. Glucagon like peptide-1 and its receptor agonists: Their roles in management of Type 2 diabetes mellitus.

    Science.gov (United States)

    Gupta, Ankit; Jelinek, Herbert F; Al-Aubaidy, Hayder

    This study summarizes major work which investigated the roles of glucagon like peptide-1 (GLP-1) and its receptor (GLP-1R); the use of GLP-1-R agonists and dipeptidyl peptidase 4 inhibitor in the management of type 2 diabetes mellitus. It focuses on the recent therapeutic development which has occurred in this field, and also discusses the potential treatments which can be discovered and implemented in the near future to design an effective therapy for type 2 diabetes mellitus. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  12. Apelin stimulates both cholecystokinin and glucagon-like peptide 1 secretions in vitro and in vivo in rodents.

    Science.gov (United States)

    Wattez, Jean-Sébastien; Ravallec, Rozenn; Cudennec, Benoit; Knauf, Claude; Dhulster, Pascal; Valet, Philippe; Breton, Christophe; Vieau, Didier; Lesage, Jean

    2013-10-01

    Apelin is an enteric peptide that exerts several digestive functions such as stimulation of cell proliferation and cholecystokinin (CCK) secretion. We investigated using murine enteroendocrine cell line (STC-1) and rats if apelin-13 stimulates both CCK and glucagon-like peptide 1 (GLP-1) secretions. We demonstrated that, in vitro and in vivo, apelin-13 increases the release of these two hormones in a dose-dependent manner. Present data suggest that apelin may modulate digestive functions, food intake behavior and glucose homoeostasis via apelin-induced release of enteric CCK but also through a new incretin-releasing activity on enteric GLP-1.

  13. Treatment of type 1 diabetic patients with glucagon-like peptide-1 (GLP-1) and GLP-1R agonists

    DEFF Research Database (Denmark)

    Holst, JJ; Kielgast, Urd; Holst, Jens J

    2009-01-01

    GLP-1 (glucagon-like peptide-1) is a peptide hormone secreted from endocrine cells in the intestinal mucosa in response to meals. The major effects of GLP-1 are to increase glucose-induced insulin secretion and reduce glucagon release, but GLP-1 also inhibits gastric emptying rate and reduces......, as well as the potential of GLP-1 as an adjuvant therapy in islet cell transplantation, will be reviewed. Suggestions for future studies of GLP-1 treatment in type 1 diabetes may include early treatment in order to preserve beta-cell mass and prolong the remission period, but should also take a potential...

  14. Clinical benefit of fixed-dose dual bronchodilation with glycopyrronium and indacaterol once daily in patients with chronic obstructive pulmonary disease

    DEFF Research Database (Denmark)

    Ulrik, Charlotte Suppli

    2014-01-01

    (salmeterol/fluticasone twice daily), once-daily fixed-dose indacaterol/glycopyrronium has clinically important effects on symptoms, including dyspnea score, health status, level of lung function, and rate of moderate or severe exacerbations in patients with moderate-to-very severe COPD (Global initiative...

  15. Indacaterol 75 μg once daily for the treatment of patients with chronic obstructive pulmonary disease: a North American perspective.

    Science.gov (United States)

    Kerwin, Edward M; Williams, James

    2013-02-01

    Chronic obstructive pulmonary disease (COPD) is a progressive disease in which patients become increasingly disabled by their symptoms and limited in their activities. Health-related quality of life may be profoundly impaired even in the early stages of the disease. Treatment with long-acting inhaled bronchodilators can improve lung function, symptoms and health status and reduce exacerbations of COPD. This review profiles the efficacy, safety and tolerability of indacaterol, an inhaled β(2)-agonist bronchodilator for once-daily maintenance treatment of patients with COPD. After 12 weeks of treatment with a once-daily dose of 75 µg (the dose approved in the USA and Canada) in patients with moderate to severe COPD, compared with placebo, indacaterol provided significant and clinically relevant levels of bronchodilation [difference in trough forced expiratory volume in 1 s: 131 ml; 95% confidence interval (CI) 104-159; p indacaterol 75 µg for 12 weeks did not differ in any substantial aspect from placebo treatment. Indirect comparisons analyzing pooled clinical data and meta-analyses suggest that treatment with indacaterol 75 µg once daily may be effective in reducing exacerbations of COPD, and that its effects on lung function and health status will be comparable with other currently available inhaled long-acting bronchodilators used for COPD. Treatment with indacaterol 75 µg once daily provides effective bronchodilation, improves dyspnea and health status, and has a well characterized profile of safety and tolerability.

  16. The safety and effectiveness of once daily detemir in patients with type 2 diabetes previously failing oral agents:the Chinese cohort from SOL-VETM observational study

    Institute of Scientific and Technical Information of China (English)

    潘长玉

    2013-01-01

    Objective To evaluate the safety and effectiveness of initiating once-daily insulin detemir(Levemir) as add-on therapy in patients with type 2 diabetes mellitus(T2DM) who failed treatment of oral anti-diabetic drugs(OAD).Methods The present study was derived from the data of

  17. Once daily versus conventional dosing of pH-dependent mesalamine long-term to maintain quiescent ulcerative colitis: Preliminary results from a randomized trial

    Directory of Open Access Journals (Sweden)

    Sunanda Kane

    2008-09-01

    Full Text Available Sunanda Kane1, William Holderman2, Peter Jacques2, Todd Miodek31Mayo Clinic College of Medicine, Rochester, MN, USA; 2Digestive Health Specialists, Tacoma, WA, USA; 3University of Chicago, Chicago, IL, USABackground and Aims: Multiple studies have demonstrated the efficacy of aminosalicylates in maintaining remission in ulcerative colitis (UC. A newer formulation of mesalamine can be administered once daily. We aimed to examine the efficacy and tolerability of pH-dependent mesalamine for long-term maintenance, and compare the rates of medication consumption between groups over a prolonged period.Methods: Subjects whose UC had been quiescent for at least 4 months, and who had been receiving mesalamine for maintenance only, were randomized to once daily or conventional dosing for 12 months. Disease activity and medication consumption was assessed every 3 months. The primary endpoint was the percentage of those with quiescent disease at 12 months.Results: We enrolled 20 patients, 12 to once daily and 8 to conventional dosing. Six of the 12 patients (50% in the once daily group compared with 5 of the 8 patients (62.5% in the conventional group experienced a flare (p = 0.31. Only 5 of the 12 (42% patients in the once daily group were adherent compared with 3 of 8 patients (37.5% in the conventional dosing group (p = NS. Median amount consumed in the once daily group was 63% (range 0%–100% and in the conventional group 55% (range 0%–100%, (p > 0.5. None of the adherent subjects in the once daily group experienced a flare, while 6 out of 7 (86% who were non-adherent experienced a flare (p < 0.01. In the conventional dosing group, 1 in 3 adherent patients (33% experienced a fl are compared with 4 out of 5 (80% in the non-adherent group (p < 0.01.Conclusion: Adherence, rather than medication regimen, appeared to be important in disease outcome at 12 months.Keywords: ulcerative colitis, mesalamine, aminosalicylates, remission

  18. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers.

    Science.gov (United States)

    Benvenuto, Mark; Benziger, David P; Yankelev, Sara; Vigliani, Gloria

    2006-10-01

    Daptomycin, a novel lipopeptide, is bactericidal against a broad range of gram-positive strains, including methicillin- (MRSA) and vancomycin-resistant Staphylococcus aureus. Daptomycin is approved at 4 mg/kg of body weight given intravenously once daily for the treatment of complicated skin and skin structure infections and at 6 mg/kg for the treatment of S. aureus bloodstream infections (bacteremia), including right-sided endocarditis caused by methicillin-susceptible S. aureus and MRSA. The present study was designed to evaluate the multiple-dose pharmacokinetics and safety of daptomycin at doses of 6 to 12 mg/kg in healthy volunteers. Three cohorts of 12 subjects each were given daptomycin (10 mg/kg) or placebo once daily for 14 days, daptomycin (12 mg/kg) or placebo once daily for 14 days, or daptomycin (6 or 8 mg/kg) once daily for 4 days. Daptomycin produced dose-proportional increases in the area under the plasma concentration-time curve and in trough daptomycin levels and nearly dose-proportional increases in peak daptomycin concentrations. Other pharmacokinetic parameters measured on day 1 and at steady state were independent of the dose, including the half-life (approximately 8 h), weight-normalized plasma clearance (9 to 10 ml/h/kg), and volume of distribution (approximately 100 ml/kg). Plasma protein binding was 90% to 93% and was independent of the daptomycin concentration. Daptomycin did not produce electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity. Daptomycin was well tolerated in subjects dosed with up to 12 mg/kg intravenously for 14 days. Doses of daptomycin higher than 6 mg/kg once daily may be considered in further studies to evaluate the safety and efficacy of daptomycin in difficult-to-treat infections.

  19. Turning a molecule into a medicine: the development of indacaterol as a novel once-daily bronchodilator treatment for patients with COPD.

    Science.gov (United States)

    Murphy, Lorraine; Rennard, Stephen; Donohue, James; Molimard, Mathieu; Dahl, Ronald; Beeh, Kai-Michael; Dederichs, Juergen; Fülle, Hans-Jürgen; Higgins, Mark; Young, David

    2014-09-01

    Indacaterol is the first once-daily, long-acting β2-adrenergic agonist (LABA) approved for the treatment of chronic obstructive pulmonary disease (COPD). Indacaterol was developed using a combination of informed drug design and molecular chemistry to generate a β2-adrenergic agonist with a fast onset and long duration of action, enabling once-daily dosing with an acceptable safety profile. Early preclinical studies with indacaterol demonstrated these characteristics, and this promising molecule was taken into clinical development, originally for asthma treatment. Subsequent safety concerns over LABA monotherapy in patients with asthma redirected indacaterol's development to centre on COPD, where a good evidence base and guideline recommendations for bronchodilator monotherapy existed. Clinical development was initially complicated by different inhaler devices and differing doses of indacaterol. Using a phase III innovative adaptive-design clinical trial (INHANCE), indacaterol 150 and 300 μg once-daily doses were selected to be taken forward into the phase III INERGIZE programme. This programme delivered placebo-controlled and active-comparator data, including comparisons with formoterol, tiotropium and salmeterol/fluticasone, as well as the use of indacaterol in combination with tiotropium. Together, these studies provided a comprehensive assessment of the benefit-risk profile of indacaterol, allowing for regulatory submission. Indacaterol was first approved at once-daily doses of 150 and 300 μg in the European Union in 2009, followed by 150 µg in Japan (2011) and China (2012), and 75 μg in the United States (2011). To date, indacaterol is approved and marketed in more than 100 countries worldwide for once-daily maintenance treatment of COPD.

  20. Pharmacodynamics and Pharmacokinetics Following Once-Daily and Twice-Daily Dosing of Tiotropium Respimat® in Asthma Using Standardized Sample-Contamination Avoidance

    Science.gov (United States)

    Kirsten, Anne-Marie; Dusser, Daniel; Sharma, Ashish; Cornelissen, Piet; Sigmund, Ralf; Moroni-Zentgraf, Petra; Dahl, Ronald

    2016-01-01

    Abstract Background: This study was conducted to confirm the 24-hour bronchodilator efficacy and pharmacokinetic profile of once-daily tiotropium Respimat® 5 μg add-on to inhaled corticosteroids (ICS) in adults with symptomatic asthma. It used a trial protocol designed to minimize the risk of pharmacokinetic sample contamination resulting from improper sampling procedure, sample handling, or device handling during priming and subsequent inhalation procedure. Methods: A Phase II, randomized, double-blind, two-way crossover study (NCT01696071) comparing two daily dosing regimens of tiotropium for 4 weeks, once-daily 5 μg (evening dosing) or twice-daily 2.5 μg (morning and evening dosing), as add-on to maintenance therapy with ICS (400–800 μg budesonide or equivalent) as controller medication. There was no washout between treatment periods. Results: An increase in the area under the curve of the 24-hour forced expiratory volume in 1 second profile from study baseline was observed following once-daily tiotropium 5 μg (217 mL) and twice-daily 2.5 μg (219 mL), with no difference between the two regimens (−2 mL [95% confidence interval: −38, 34]). In a subset of the study population, total tiotropium exposure, expressed as area under the plasma concentration versus time curve over 24 hours, was comparable between dosing regimens. Unexpected tiotropium plasma levels were observed in two patients, possibly because of contamination. Conclusions: The observed bronchodilator efficacy over 24 hours was similar with once-daily tiotropium 5 μg and twice-daily 2.5 μg as add-on to ICS therapy, supporting the suitability of once-daily dosing to provide sustained improvements in lung function in adults with symptomatic asthma. PMID:26859538

  1. The alpha cell expresses glucagon-like peptide-2 receptors and glucagon-like peptide-2 stimulates glucagon secretion from the rat pancreas

    DEFF Research Database (Denmark)

    de Heer, J; Pedersen, J; Orskov, C

    2007-01-01

    . MATERIALS AND METHODS: The expression of the GLP-2 receptor gene, Glpr2, and the localisation of the protein were evaluated by real-time PCR on cDNA from isolated rat islets and by immunohistochemistry in rat and human pancreas. The glucagon, insulin and somatostatin responses to 0.1, 1 and 10 nmol/l GLP-2...... from a pre-infusion level of 0.314 +/- 0.07 to 0.508 +/- 0.09 pmol/min (p insulin nor somatostatin output was influenced. During simultaneous administration of GLP-1 and GLP-2, net glucagon release was no longer reduced by 0.1, 1...

  2. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects

    DEFF Research Database (Denmark)

    Vilsbøll, T; Agersø, H; Krarup, T

    2003-01-01

    We have previously shown that type 2 diabetic patients have decreased plasma concentrations of glucagon-like peptide 1 (GLP-1) compared with healthy subjects after ingestion of a standard mixed meal. This decrease could be caused by differences in the metabolism of GLP-1. The objective of this st......We have previously shown that type 2 diabetic patients have decreased plasma concentrations of glucagon-like peptide 1 (GLP-1) compared with healthy subjects after ingestion of a standard mixed meal. This decrease could be caused by differences in the metabolism of GLP-1. The objective...... of this study was to examine the pharmacokinetics of GLP-1 in healthy subjects and type 2 diabetic patients after iv bolus doses ranging from 2.5-25 nmol/subject. Bolus injections iv of 2.5, 5, 15, and 25 nmol of GLP-1 and a meal test were performed in six type 2 diabetic patients [age, mean (range): 56 (48......-67) yr; body mass index: 31.2 (27.0-37.7) kg/m(2); fasting plasma glucose: 11.9 (8.3-14.3) mmol/liter; hemoglobin A(1C): 9.6 (7.0-12.5)%]. For comparison, six matched healthy subjects were examined. Peak plasma GLP-1 concentrations increased linearly with increasing doses of GLP-1 and were similar...

  3. Glucagon-like peptide 1 receptor playsa critical role in geniposide-regulated insulin secretion in INS-1 cells

    Institute of Scientific and Technical Information of China (English)

    Li-xia GUO; Zhi-ning XIA; Xue GAO; Fei YIN; Jian-hui LIU

    2012-01-01

    Aim:To explore the role of the glucagon-like peptide 1 receptor (GLP-1R) in geniposide regulated insulin secretion in rat INS-1 insulinoma cells.Methods:Rat INS-1 insulinoma cells were cultured.The content of insulin in the culture medium was measured with ELISA assay.GLP-1R gene in INS-1 cells was knocked down with shRNA interference.The level of GLP-1R protein in INS-1 cells was measured with Western blotting.Results:Geniposide (0.01-100 μmol/L) increased insulin secretion from INS-1 cells in a concentration-dependent manner.Geniposide (10 μmol/L) enhanced acute insulin secretion in response to both the low (5.5 mmol/L) and moderately high levels (11 mmol/L) of glucose.Blockade of GLP-1R with the GLP-1R antagonist exendin (9-39) (200 nmol/L) or knock-down of GLP-1R with shRNA interference in INS-1 cells decreased the effect of geniposide (10 μmol/L) on insulin secretion stimulated by glucose (5.5 mmol/L).Conclusion:Geniposide increases insulin secretion through glucagon-like peptide 1 receptors in rat INS-1 insulinoma cells.

  4. Long-term efficacy and safety of once-daily mesalazine granules for the treatment of active ulcerative colitis

    Directory of Open Access Journals (Sweden)

    Böhm SK

    2014-09-01

    Full Text Available Stephan Karl Böhm,1 Wolfgang Kruis2 1Kantonsspital Baselland, Medizinische Universitätsklinik, Bruderholz, Switzerland; 2Evangelisches Krankenhaus Kalk, University of Cologne, Cologne, Germany Abstract: In 1977, 5-aminosalicylic acid (5-ASA was discovered as a therapeutically active moiety of sulfasalazine (SASP and was launched for topical and oral therapy of ulcerative colitis (UC in 1984. As a first-step, delivery systems had to be developed to protect 5-ASA against absorption in the upper gastrointestinal tract, resulting in different and competing strategies (azo compounds, controlled release, and pH-dependent release. In a second step, at the beginning of the new century, coinciding with the expiration of patent protection for the first 5-ASA formulations, two component composite release mechanisms (pH-dependent and controlled release were developed. Furthermore, the drug was formulated as granules instead of tablets, allowing higher unit strengths compared with tablets. Neither Salofalk Granu-Stix®, nor MMX 5-ASA, nor Pentasa® granules have initially been developed for once-daily (OD dosing. A review of the achievements of 20 years of 5-ASA development has demonstrated that 5-ASA has equal efficacy compared with SASP at best, that there are no measurable differences in efficacy between various 5-ASA preparations, and that in a group of patients tolerating SASP, adverse event profiles of SASP and 5-ASA did not differ significantly, with SASP being the far cheaper substance. Therefore, drug adherence came into focus as a new goal for improving UC therapy. Although adherence is a complex and multifactorial construct, a simple dosing schedule may contribute to higher drug adherence and better efficacy of treatment. Simultaneously, the US 5-ASA market, estimated to be worth US$1.4 billion, is expected to grow continuously. Naturally, this very competitive market is not only driven by scientific progress but also by commercial interests

  5. Long-term efficacy and safety of once-daily mesalazine granules for the treatment of active ulcerative colitis.

    Science.gov (United States)

    Böhm, Stephan Karl; Kruis, Wolfgang

    2014-01-01

    In 1977, 5-aminosalicylic acid (5-ASA) was discovered as a therapeutically active moiety of sulfasalazine (SASP) and was launched for topical and oral therapy of ulcerative colitis (UC) in 1984. As a first-step, delivery systems had to be developed to protect 5-ASA against absorption in the upper gastrointestinal tract, resulting in different and competing strategies (azo compounds, controlled release, and pH-dependent release). In a second step, at the beginning of the new century, coinciding with the expiration of patent protection for the first 5-ASA formulations, two component composite release mechanisms (pH-dependent and controlled release) were developed. Furthermore, the drug was formulated as granules instead of tablets, allowing higher unit strengths compared with tablets. Neither Salofalk Granu-Stix(®), nor MMX 5-ASA, nor Pentasa(®) granules have initially been developed for once-daily (OD) dosing. A review of the achievements of 20 years of 5-ASA development has demonstrated that 5-ASA has equal efficacy compared with SASP at best, that there are no measurable differences in efficacy between various 5-ASA preparations, and that in a group of patients tolerating SASP, adverse event profiles of SASP and 5-ASA did not differ significantly, with SASP being the far cheaper substance. Therefore, drug adherence came into focus as a new goal for improving UC therapy. Although adherence is a complex and multifactorial construct, a simple dosing schedule may contribute to higher drug adherence and better efficacy of treatment. Simultaneously, the US 5-ASA market, estimated to be worth US$1.4 billion, is expected to grow continuously. Naturally, this very competitive market is not only driven by scientific progress but also by commercial interests. Thus, patents for minor changes to the formulation may serve as protection against drug companies trying to launch generic versions. Randomized controlled trials performed on OD dosing in induction of remission have

  6. CSF LPV concentrations and viral load in viral suppressed patients on LPV/r monotherapy given once daily

    Directory of Open Access Journals (Sweden)

    Juan Tiraboschi

    2014-11-01

    Full Text Available Introduction: Plasma trough concentrations of lopinavir (LPV given as LPV/r 800/200 mg once daily (OD are reduced in comparison with 400/100 mg twice daily (BID. While OD dosage of LPV/r is sufficient to achieve viral suppression in plasma, data about drug penetration and viral suppression in central nervous system (CNS is needed, mainly if LPVr is used as maintenance monotherapy strategy in selected patients. The objective of this study was to evaluate CSF HIV-1 RNA and CSF LPV concentrations in patients receiving LPV/r monotherapy OD (LPVrMOD. Material and Methods: This is a cross-sectional sub-study within a prospective, open-label pilot simplification study to evaluate the efficacy and safety of LPV/rMOD in virologically suppressed patients previously receiving a BID LPV/r monotherapy regimen (LPV/rMBID, the “Kmon study” (NCT01581853. To assess LPV concentrations and HIV-1 RNA in CSF, a lumbar puncture (LP was performed in a subgroup of patients after at least one month of LPVrMOD treatment. Plasma-paired samples of all patients were also obtained. HIV-1 RNA was determined by real-time PCR (limit of detection 40 copies/mL. Liquid chromatography-tandem mass spectrometry (Tandem labs, NJ was used to determine CSF and blood plasma LPV concentrations. Results: Nine patients were included. Median (range age was 48 (34–56 years, median CD4 cell count 672 (252–1,408 cells/mL, median nadir CD4 count 125 (35–537 cells/mL and 40% of subjects were HCV-positive. Before starting LPV/rMOD median time on a LPV/r-containing regimen and on LPV/rMBID were 9 (4–11 years and 15 (7–24 months respectively, median time with undetectable HIV viral load was 5 (3–12 years and 2 patients had a previous documented blip. LP was performed a median of 24 (8–36 weeks after starting LPV/rMOD and 24 (11–28 hours after the last LPV/rMOD dose CSF and plasma HIV RNA was 40 copies/mL in all patients. Median LPV CSF concentration was 9.78 (1.93–78.3 ng

  7. Therapeutic concentrations of glucagon-like peptide-1 in cerebrospinal fluid following cell-based delivery into the cerebral ventricles of cats

    Directory of Open Access Journals (Sweden)

    Glage Silke

    2011-05-01

    Full Text Available Abstract Background Neuropeptides may have considerable potential in the treatment of acute and chronic neurological diseases. Encapsulated genetically engineered cells have been suggested as a means for sustained local delivery of such peptides to the brain. In our experiments, we studied human mesenchymal stem cells which were transfected to produce glucagon-like peptide-1 (GLP-1. Methods Cells were packed in a water-permeable mesh bag containing 400 polymeric microcapsules, each containing 3000 cells. The mesh bags were either transplanted into the subdural space, into the brain parenchyma or into the cerebral ventricles of the cat brain. Mesh bags were explanted after two weeks, and cell viability, as well as GLP-1 concentration in the cerebrospinal fluid (CSF, was measured. Results Viability of cells did not significantly differ between the three implantation sites. However, CSF concentration of GLP-1 was significantly elevated only after ventricular transplantation with a maximum concentration of 73 pM (binding constant = 70 pM. Conclusions This study showed that ventricular cell-based delivery of soluble factors has the capability to achieve concentrations in the CSF which may become pharmacologically active. Despite the controversy about the pharmacokinetic limitations of ventricular drug delivery, there might be a niche in this for encapsulated cell biodelivery of soluble, highly biologically-effective neuropeptides of low molecular weight like GLP-1.

  8. POSSIBLE ADVERSE EFFECTS OF ONCE-DAILY ORAL THERAPEUTIC DOSE OF EITHER GLUCOSAMINE SULFATE OR GLUCOSAMINE/CHONDROITIN SULFATE ON BLOOD CELLS COUNT IN RATS

    Directory of Open Access Journals (Sweden)

    Noushi Abeer Amer

    2013-10-01

    Full Text Available This study was designed to investigate the possible adverse effects that may be induced by once-daily therapeutic doses of either glucosamine sulfate or glucosamine/chondroitin sulfate administered orally to rats for 30 days on blood cells (RBCs, WBCs and platelets counts. Forty three white healthy adult Albino rats of both sexes were selected randomly for this study. They were divided into three groups (І, ІІ, ІІІ. Group І received 0.05 ml distilled water, group ІІ received once daily therapeutic dose of glucosamine sulphate and group ІІІ received once daily therapeutic dose of glucosamine sulphate/chondroitin sulphate orally. The treatment period was for 30 days. At day 31, the animals were subjected to light ether anaesthesia and blood was withdrawn from the eye by retro-orbital puncture for the estimation of blood cells (RBCs, WBCs and platelets count. Treatment with single daily therapeutic dose of either GS alone or GS/CS for 30 days on blood cells count in rats produced a non significant change in RBCs counts compared to control and to each other. There were no statistically significant differences in total WBCs count at day 31 in animals administered once daily therapeutic dose of either GS or GS/CS orally compared to control group. In contrast, there was a statistically significant elevation in total WBCs count in GS/CS- treated rats compared to that in the GS-treated rats. The results of this study also showed that there was statistically significant decrease in neutrophils percentage in both drug treatment groups compared to control group. A statistically significant reduction in the percentage of monocytes was observed in GS/CS group compared to the corresponding percentage in animals of control group; while, there were non-significant differences in the percentage of monocytes in GS treated rats compared to that in the control group. There were no significant differences in the percentage of monocytes at day 31 of GS

  9. Changes in mammary uptake and metabolic fate of glucose with once-daily milking and feed restriction in dairy cows

    OpenAIRE

    Guinard-Flament, Jocelyne; Delamaire, Eloise; Lemosquet, Sophie; Boutinaud, Marion; David, Yolande

    2006-01-01

    International audience; The aim of this review is to better understand the regulation of milk yield in response to once-daily milking and feed restriction. Glucose is the principal precursor for the synthesis of lactose (a major osmotic agent in milk), and participates in determining the milk volume produced. When applying these two breeding factors, reductions in milk yield are associated with a reduction in milk lactose yield and in the arterial flow of glucose, due to a decrease in the mam...

  10. Efficacy of indacaterol 75 μg once-daily on dyspnea and health status: results of two double-blind, placebo-controlled 12-week studies.

    Science.gov (United States)

    Gotfried, Mark H; Kerwin, Edward M; Lawrence, David; Lassen, Cheryl; Kramer, Benjamin

    2012-12-01

    Indacaterol is an inhaled, once-daily, long-acting ®(2)-agonist for the treatment of COPD. Most previous studies were conducted with doses of 150 and/or 300 μg once-daily, and data with the 75 μg dose are limited. Two identically designed studies were, therefore, conducted to evaluate the efficacy and safety of the 75 μg once-daily dose. In two double-blind studies conducted in the USA, patients with moderate-to-severe COPD were randomized to treatment with indacaterol 75 μg once-daily (n = 163 and 159) or matching placebo (n = 160 and 159) for 12 weeks. The primary variable was forced expiratory volume in 1 s measured 24 h post-dose after 12 weeks (reported elsewhere). This report describes secondary efficacy endpoints, including transition dyspnea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores, and the percentages of patients with improvements of or above the minimal clinically important difference (MCID; ≥1 in TDI score and ≥4 in SGRQ score). Differences between indacaterol and placebo for TDI total score at week 12 were 1.23 (p indacaterol at week 12 (2.0 and 0.9 with placebo), with odds ratios for achieving the MCID of 1.80 (p = 0.024) and 1.71 (p = 0.031). Patients receiving indacaterol had statistically significant or numerical improvements in diary-derived symptom variables compared with placebo. Treatment with indacaterol 75 μg may provide useful improvements in patient-reported outcomes in patients with moderate-to-severe COPD.

  11. Sustained 24-hour efficacy of once daily indacaterol (300 μg) in patients with chronic obstructive pulmonary disease: a randomized, crossover study.

    Science.gov (United States)

    Laforce, Craig; Aumann, Joseph; de Teresa Parreño, Luis; Iqbal, Amir; Young, David; Owen, Roger; Higgins, Mark; Kramer, Benjamin

    2011-02-01

    Indacaterol is a novel, once daily, inhaled ultra-long-acting β₂-agonist for the treatment of chronic obstructive pulmonary disease (COPD). Here we compared the 24-h spirometry profile of once daily indacaterol 300 μg with that of placebo and twice daily salmeterol 50 μg in patients with COPD. This randomized, multicenter, placebo-controlled, crossover study comprised three 14-day treatment periods (with 14-day washouts). Patients (male/female ≥ 40 years) with moderate-to-severe COPD were randomized to receive double-blind indacaterol 300 μg or placebo once daily, or open-label salmeterol 50 μg twice daily. The primary outcome measure was 24-h post-dose (trough) FEV₁ (mean of FEV₁ at 23 h 10 min and 23 h 45 min post-indacaterol dose) after 14 days. FEV₁ was assessed at multiple time points on Days 1 and 14 of each treatment period. Safety and tolerability were also monitored. Of 68 randomized patients, 61 completed. Trough FEV₁ (primary endpoint) on Day 14 for indacaterol was 200 mL higher than placebo (p indacaterol was 150 mL higher than placebo (p Indacaterol provided superior bronchodilation compared with placebo (p indacaterol provided superior FEV₁ compared with salmeterol (p indacaterol 300 μg produced effective sustained 24-h bronchodilation from the first dose, an efficacy profile superior to placebo and twice daily salmeterol. Given its effective bronchodilation with once daily dosing, indacaterol is likely to be a useful treatment option for patients with moderate-to-severe COPD. Copyright © 2010 Elsevier Ltd. All rights reserved.

  12. Efficacy, Safety and Pharmacokinetics of Once-Daily Saquinavir Soft-Gelatin Capsule/Ritonavir in Antiretroviral-Naive, HIV-Infected Patients

    Directory of Open Access Journals (Sweden)

    Julio Montaner SG

    2006-05-01

    Full Text Available Abstract Context Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective To evaluate the efficacy and safety of saquinavir-soft-gelatin capsule (SGC/ritonavir combination (1600 mg/100 mg vs efavirenz (600 mg both once daily and combined with 2 nucleoside analogs twice daily. Setting Twenty-six centers in the United States, Canada, and Puerto Rico. Patients A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study. Main Outcome Measure Proportion of patients with HIV-RNA levels Results In the primary intent-to-treat population at week 48, 51% (38/75 and 71% (55/77 of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression P = .5392, 95% 1-sided confidence interval [CI] = -33.5%. In the on-treatment (OT population, 73% (38/52 and 93% (54/58 of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression P = .5015, 95% 1-sided CI = -33.4%. Mean CD4+ cell counts increased by 239 and 204 cells/microliters (mcL, in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058. Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinetic profiles in 6 patients showed an observed median Cmin at 24 hours of 429 ng/mL (range, 68-1750 ng/mL. Conclusion Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ritonavir arm of the study.

  13. A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women.

    Science.gov (United States)

    Blume-Peytavi, Ulrike; Hillmann, Kathrin; Dietz, Ekkehart; Canfield, Douglas; Garcia Bartels, Natalie

    2011-12-01

    Although twice-daily application of propylene glycol-containing 2% minoxidil topical solution (MTS) stimulates new hair growth, higher concentrations of minoxidil in a once-daily, propylene glycol-free formulation may improve efficacy and reduce unpleasant side effects. We sought to compare the efficacy, safety, and acceptability and to show noninferiority of once-daily 5% minoxidil topical foam (MTF) with twice-daily 2% MTS in women with androgenetic alopecia. A total of 113 women with androgenetic alopecia were randomized to 24 weeks of treatment with 5% MTF or 2% MTS. The primary efficacy parameter was change from baseline in nonvellus target area hair count at week 24. Secondary end points included change in nonvellus target area hair width, overall efficacy by global photographic review as assessed by treatment-blinded evaluators and the subject herself, adverse events, and participants' assessment of product aesthetics. After 24 weeks, women randomized to 5% MTF once daily showed noninferior target area hair count and target area hair width and experienced greater, but nonsignificant, improvements in target area hair count, target area hair width, and overall efficacy by global photographic review than those randomized to 2% MTS used twice daily. 5% MTF was significantly superior to 2% MTS in participants' agreement with "the treatment does not interfere with styling my hair" (P = .002). Women randomized to 5% MTF experienced significantly lower rates of local intolerance (P = .046) especially in pruritus and dandruff compared with 2% MTS. Because of differences in the formulations tested, study participants were not blinded to treatment. Once-daily 5% MTF is noninferior and as effective for stimulating hair growth as twice-daily 2% MTS in women with androgenetic alopecia and is associated with several aesthetic and practical advantages. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  14. Clinical trial: a novel high-dose 1 g mesalamine suppository (Salofalk) once daily is as efficacious as a 500-mg suppository thrice daily in active ulcerative proctitis.

    Science.gov (United States)

    Andus, Tilo; Kocjan, Andreas; Müser, Moritz; Baranovsky, Andrey; Mikhailova, Tatyana L; Zvyagintseva, Tatyana D; Dorofeyev, Andrey E; Lozynskyy, Yurii S; Cascorbi, Ingolf; Stolte, Manfred; Vieth, Michael; Dilger, Karin; Mohrbacher, Ralf; Greinwald, Roland

    2010-11-01

    Mesalamine suppositories are first-line therapy in active ulcerative proctitis; the standard regime still recommends multiple doses per day. The primary objective of this study was to show the noninferiority of once-daily administration of a novel 1 g mesalamine suppository versus thrice-daily administration of the 0.5 g mesalamine suppository. This was a single-blind (investigator-blinded), randomized, multicenter, comparative, Phase III clinical trial. Patients with mild to moderately active ulcerative proctitis inserted either one mesalamine 1 g suppository at bedtime or one mesalamine 0.5 g suppository thrice daily over a 6-week period. The primary endpoint was rate of remission (Disease Activity Index below 4). In all, 354 patients were evaluable for safety and per-protocol analysis. The new regimen demonstrated noninferiority: The percentage of patients with remission was 87.9% for the once-daily 1 g mesalamine suppository and 90.7% for the thrice-daily 0.5 g mesalamine suppository. Each regimen resulted in prompt cessation of clinical symptoms (e.g., median time to ≤3 stools per day (all without blood): 5 days in the 1 g mesalamine once-daily and 7 days in the 0.5 g mesalamine thrice-daily group). Patients preferred applying suppositories once a day. In active ulcerative proctitis the once-daily administration of a 1 g mesalamine suppository is as effective and safe, yet considerably more convenient, than the standard thrice-daily administration of a 0.5 g mesalamine suppository.

  15. Once-daily oral administration of cyclosporine in a lung transplant patient with a history of renal toxicity of calcineurin inhibitors.

    Science.gov (United States)

    Matsuda, Yuya; Chen, Fengshi; Miyata, Hitomi; Date, Hiroshi

    2014-07-01

    Cyclosporine is usually administered orally in two divided doses every 12 h in transplant patients. However, some patients have difficulty in achieving therapeutic levels after transplantation. In fact, cyclosporine is reportedly administered once daily in renal and liver transplantation cases, but not in lung transplantation cases. We report a patient with a history of calcineurin inhibitor-induced renal toxicity who successfully underwent living-donor lobar lung transplantation (LDLLT) with the novel immunosuppressive strategy of once-daily administration of cyclosporine. An 18-year old man with progressive respiratory insufficiency after bone marrow transplantation was referred to our hospital for lung transplantation. He had a history of renal toxicity due to calcineurin inhibitors. Based on his history of tacrolimus- and cyclosporine-induced renal toxicity, we decided to initiate basiliximab as induction therapy, followed by once-daily cyclosporine administration to obtain high enough blood cyclosporine concentrations at 2 h post-dose (C2) and lowered trough blood concentrations (C0) for protection of renal function as maintenance therapy. LDLLT was successfully performed, and the postoperative course was uneventful and free of rejection episodes. Cyclosporine dosing was adjusted with intensive therapeutic drug monitoring of blood cyclosporine levels. One year after LDLLT, the patient is alive and well with no problems with daily life activities. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

  16. Expression of mRNA for proglucagon and glucagon-like peptide-2 (GLP-2) receptor in the ruminant gastrointestinal tract and the influence of energy intake

    DEFF Research Database (Denmark)

    Taylor-Edwards, C C; Burrin, D G; Matthews, J C

    2010-01-01

    Glucagon-like peptide-2 (GLP-2) is a potent trophic gut hormone, yet its function in ruminants is relatively unknown. Experiment 1 was conducted as a pilot study to establish the presence of GLP-2 in ruminants and to ascertain whether it was responsive to increased nutrition, as in non-ruminants.......Glucagon-like peptide-2 (GLP-2) is a potent trophic gut hormone, yet its function in ruminants is relatively unknown. Experiment 1 was conducted as a pilot study to establish the presence of GLP-2 in ruminants and to ascertain whether it was responsive to increased nutrition, as in non...

  17. Truncated glucagon-like peptide-1 (proglucagon 78-107 amide), an intestinal insulin-releasing peptide, has specific receptors on rat insulinoma cells (RIN 5AH)

    DEFF Research Database (Denmark)

    Orskov, C; Nielsen, Jens Høiriis

    1988-01-01

    We studied binding of 125I-labelled truncated-glucagon-like peptide-1 (proglucagon 78-107 amide) to a cloned rat insulin-producing cell line, RIN 5AH, in monolayer culture. Interaction of the peptide with pancreatic insulinoma cells was saturable and time dependent. Half-maximal binding was obtai......We studied binding of 125I-labelled truncated-glucagon-like peptide-1 (proglucagon 78-107 amide) to a cloned rat insulin-producing cell line, RIN 5AH, in monolayer culture. Interaction of the peptide with pancreatic insulinoma cells was saturable and time dependent. Half-maximal binding...

  18. Increased Postprandial Response of Glucagon-Like Peptide-2 in Patients with Chronic Pancreatitis and Pancreatic Exocrine Insufficiency

    DEFF Research Database (Denmark)

    Hornum, Mads; Pedersen, Jan F; Larsen, Steen

    2010-01-01

    Background/Aims: Glucagon-like peptide-2 (GLP-2) is a nutrient-released gastrointestinal (GI) hormone that acts as an intestinal growth factor, and exogenous GLP-2 has been shown to increase superior mesenteric artery (SMA) blood flow. We aimed to investigate how assimilation of nutrients affects...... postprandial GLP-2 responses and to correlate these with postprandial SMA blood flow. Methods: Responses of the GI hormone glucose-dependent insulinotropic polypeptide (GIP) and GLP-2 were measured following an 80-min liquid meal test in 8 patients (6 males) with chronic pancreatitis (CP) and pancreatic...... exocrine insufficiency (PEI) and 8 healthy control subjects (5 males). Postprandial GI hormone responses were correlated with change in SMA flow as assessed by the resistance index. Results: Patients with CP and PEI exhibited the greatest postprandial GLP-2 responses (1,870 +/- 249 vs. 1,199 +/- 108 pM.80...

  19. Synaptotagmin-7 as a positive regulator of glucose-induced glucagon-like peptide-1 secretion in mice

    DEFF Research Database (Denmark)

    Gustavsson, N; Wang, Y; Kang, Y

    2011-01-01

    . Lentiviral knockdown (KD) of synaptotagmin-7 in GLUTag cells led to similar reductions in GLP-1 secretion, as determined by biochemical assays and by membrane capacitance measurements. Calcium response was not altered in synaptotagmin-7 KD cells. CONCLUSIONS/INTERPRETATION: These results demonstrate......AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1), a hormone with potent antihyperglycaemic effects, is produced and secreted from highly specialised gut endocrine L-cells. It regulates glucose homeostasis by promoting glucose-dependent insulin secretion, suppressing glucagon secretion and enhancing...... insulin sensitivity. Similar to islet alpha and beta cells, L-cells are electrically excitable, and express calcium channels and ATP-sensitive potassium channels. GLP-1 is also stored in secretory granules, the exocytosis of which is triggered by increased intracellular calcium levels. Although...

  20. Intestinal growth adaptation and glucagon-like peptide 2 in rats with ileal--jejunal transposition or small bowel resection

    DEFF Research Database (Denmark)

    Thulesen, J; Hartmann, B; Kissow, Hannelouise;

    2001-01-01

    , and twofold in the distally resected group. Tissue GLP-2 levels were unchanged in resected rats. The data indicate that transposition of a distal part of the small intestine, and thereby exposure of L cells to a more nutrient-rich chyme, leads to intestinal growth. The adaptive intestinal growth is associated......Glucagon-like peptide 2 (GLP-2), produced by enteroendocrine L-cells, regulates intestinal growth. This study investigates circulating and intestinal GLP-2 levels in conditions with altered L-cell exposure to nutrients. Rats were allocated to the following experimental groups: ileal...... GLP-2 levels in the intestinal segments were unchanged. In resected rats with reduced intestinal capacity, adaptive small bowel growth was more pronounced following proximal resection than distal small bowel resection. Circulating GLP-2 levels increased threefold in proximally resected animals...

  1. Glucagon-like peptide-1 decreases intracerebral glucose content by activating hexokinase and changing glucose clearance during hyperglycemia

    DEFF Research Database (Denmark)

    Jensen, Michael Gejl; Egefjord, Lærke; Lerche, Susanne

    2012-01-01

    and stroke: Although the mechanism is unclear, glucose homeostasis appears to be important. We conducted a randomized, double-blinded, placebo-controlled crossover study in nine healthy males. Positron emission tomography was used to determine the effect of GLP-1 on cerebral glucose transport and metabolism...... across the blood–brain barrier remained unchanged (P=0.099) in all regions, while the unidirectional clearance and the phosphorylation rate increased (P=0.013 and 0.017), leading to increased net clearance of the glucose tracer (P=0.006). We show that GLP-1 plays a role in a regulatory mechanism involved......Type 2 diabetes and hyperglycemia with the resulting increase of glucose concentrations in the brain impair the outcome of ischemic stroke, and may increase the risk of developing Alzheimer's disease (AD). Reports indicate that glucagon-like peptide-1 (GLP-1) may be neuroprotective in models of AD...

  2. [The physiology of glucagon-like peptide-1 and its role in the pathophysiology of type 2 diabetes mellitus].

    Science.gov (United States)

    Escalada, Francisco Javier

    2014-09-01

    The hormone glucagon-like peptide-1 (GLP-1) is synthesized and secreted by L cells in the small intestine in response to food ingestion. After reaching the general circulation it has a half-life of 2-3 minutes due to degradation by the enzyme dipeptidyl peptidase-4. Its physiological role is directed to control plasma glucose concentration, though GLP-1 also plays other different metabolic functions following nutrient absorption. Biological activities of GLP-1 include stimulation of insulin biosynthesis and glucose-dependent insulin secretion by pancreatic beta cell, inhibition of glucagon secretion, delay of gastric emptying and inhibition of food intake. GLP-1 is able to reduce plasma glucose levels in patients with type 2 diabetes and also can restore beta cell sensitivity to exogenous secretagogues, suggesting that the increasing GLP-1 concentration may be an useful therapeutic strategy for the treatment of patients with type 2 diabetes.

  3. TREATMENT OF DIABETES MELLITUS IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA) WITH THE GLUCAGON-LIKE PEPTIDE-1 MIMETIC EXENATIDE.

    Science.gov (United States)

    Johnson, James G; Langan, Jennifer N; Gilor, Chen

    2016-09-01

    An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.

  4. Effect of glucagon-like peptide-1 (proglucagon 78-107amide) on hepatic glucose production in healthy man

    DEFF Research Database (Denmark)

    Hvidberg, A; Nielsen, M T; Hilsted, J;

    1994-01-01

    The newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1) (proglucagon 78-107amide), stimulates insulin secretion and inhibits glucagon secretion in man and may therefore be anticipated to influence hepatic glucose production. To study this, we infused synthetic GLP-1 sequentially......-1 infusion. Glucose disappearance rate (Rd) did not change significantly, but glucose clearance increased significantly compared with saline. All parameters of glucose turnover remained constant during saline infusion. We conclude that GLP-1 may potently control hepatic glucose production...... and glucose clearance through its effects on the pancreatic glucoregulatory hormones. The effect of GLP-1 on glucose production is consistent with its proposed use in the treatment of type II diabetes....

  5. Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat

    DEFF Research Database (Denmark)

    Bucinskaite, V; Tolessa, T; Pedersen, J

    2009-01-01

    The vagus nerve plays a role in mediating effects of the two glucagon-like peptides GLP-1 and GLP-2 on gastrointestinal growth, functions and eating behaviour. To obtain electrophysiological and molecular evidence for the contribution of afferent pathways in chemoreception from the gastrointestinal...... tract, afferent mass activity in the ventral gastric branch of the vagus nerve and gene expression of GLP-1 receptors and GLP-2 receptors in the nodose ganglion were examined in Sprague-Dawley rats. Intravenous administration of GLP-1 (30-1000 pmol kg(-1)), reaching high physiological plasma...... afferent nerves mediate sensory input from the gastrointestinal tract or pancreas; either directly or indirectly via the release of another mediator. GLP-2 receptors appear not be functionally expressed on vagal afferents....

  6. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes

    DEFF Research Database (Denmark)

    Zander, M; Taskiran, M; Toft-Nielsen, M B;

    2001-01-01

    OBJECTIVE: The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted...... this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally......) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol x kg(-1) x min(-1)) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite. RESULTS: Fasting plasma glucose (day 2...

  7. Glucagon-like peptide-2 (GLP-2) response to enteral intake in children during anti-cancer treatment

    DEFF Research Database (Denmark)

    Andreassen, B U; Paerregaard, A; Schmiegelow, K

    2005-01-01

    BACKGROUND: Intestinal dysfunction is frequent in cancer and during anti-cancer treatment. Glucagon-like peptide-2 (GLP-2) is secreted in a nutrition-dependent manner from the intestinal enteroendocrine L-cells. It accelerates crypt cell proliferation and nutrient absorption, inhibits enterocyte...... apoptosis and decreases mucosal permeability. Lack of GLP-2 may increase the risk of malabsorption and intestinal bacterial translocation. The aim of this study is to evaluate meal stimulated secretion of GLP-2 in children with cancer undergoing anti-cancer treatment. METHODS: Plasma-GLP-2 analysis after...... an overnight fast and 1 hour after intake of a mixed test meal. Data on gastrointestinal toxicity, blood neutrophile counts and food records were included in the analysis. RESULTS: Forty-four meal stimulation tests were performed in 25 children (median age, 6.0 years; range, 2.5-19) during anti-cancer...

  8. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients

    DEFF Research Database (Denmark)

    Toft-Nielsen, M B; Madsbad, Sten; Holst, J J

    1999-01-01

    OBJECTIVE: The gut hormone glucagon-like peptide 1 (GLP-1) has insulinotropic and anorectic effects during intravenous infusion and has been proposed as a new treatment for type 2 diabetes and obesity. The effect of a single subcutaneous injection is brief because of rapid degradation. We therefore...... sought to evaluate the effect of infusion of GLP-1 for 48 h in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We infused GLP-1 (2.4 pmol.kg-1.min-1) or saline subcutaneously for 48 h in randomized order in six patients with type 2 diabetes to evaluate the effect on appetite during fixed....... CONCLUSIONS: We conclude that 48-h continuous subcutaneous infusion of GLP-1 in type 2 diabetic patients 1) lowers fasting as well as meal-related plasma glucose, 2) reduces appetite, 3) has no gastrointestinal side effects, and 4) has no negative effect on blood pressure....

  9. Effects of exogenous glucagon-like peptide-2 and distal bowel resection on intestinal and systemic adaptive responses in rats

    DEFF Research Database (Denmark)

    Lai, Sarah W; de Heuvel, Elaine; Wallace, Laurie E

    2017-01-01

    OBJECTIVE: To determine the effects of exogenous glucagon-like peptide-2 (GLP-2), with or without massive distal bowel resection, on adaptation of jejunal mucosa, enteric neurons, gut hormones and tissue reserves in rats. BACKGROUND: GLP-2 is a gut hormone known to be trophic for small bowel mucosa......-2 attenuated resection-induced increases in blood glucose and body fat loss. CONCLUSIONS: Exogenous GLP-2 stimulates jejunal adaptation independent of enteric neuronal VIP or nNOS changes, and has divergent effects on plasma amylin and peptide YY concentrations. The novel ability of exogenous GLP-2......, and to mimic intestinal adaptation in short bowel syndrome (SBS). However, the effects of exogenous GLP-2 and SBS on enteric neurons are unclear. METHODS: Sprague Dawley rats were randomized to four treatments: Transected Bowel (TB) (n = 8), TB + GLP-2 (2.5 nmol/kg/h, n = 8), SBS (n = 5), or SBS + GLP-2 (2...

  10. Glucagon-like peptide 2 has limited efficacy to increase nutrient absorption in fetal and preterm pigs

    DEFF Research Database (Denmark)

    Sangild, Per Torp; Malo, Christiane; Schmidt, Mette;

    2007-01-01

    to exogenous GLP-2. This was accomplished using catheterized fetal pigs infused for 6 days (87-91% of gestation) with GLP-2 (25 nmol.kg(-1).day(-1) iv; n = 7) or saline (n = 7), and cesarean-delivered preterm pigs (92% of gestation) that received TPN with GLP-2 (25 nmol.kg(-1).day(-1) iv; n = 8) or saline (n......Exogenous glucagon-like peptide 2 (GLP-2) prevents intestinal atrophy and increases nutrient absorption in term newborn pigs receiving total parenteral nutrition (TPN). We tested the hypothesis that the immature intestine of fetuses and preterm neonates has a diminished nutrient absorption response...... circulating GLP-2 levels in fetuses, but did not increase intestinal mass or absorption of nutrients by intact tissues and brush border membrane vesicles, except for lysine. Administration of exogenous GLP-2 to preterm TPN-fed pigs similarly did not increase rates of nutrient absorption, yet nutrient...

  11. Glucagon-like peptide-1 and cholecystokinin production and signaling in the pancreatic islet as an adaptive response to obesity.

    Science.gov (United States)

    Linnemann, Amelia K; Davis, Dawn Belt

    2016-04-01

    Precise control of blood glucose is dependent on adequate β-cell mass and function. Thus, reductions in β-cell mass and function lead to insufficient insulin production to meet demand, and result in diabetes. Recent evidence suggests that paracrine signaling in the islet might be important in obesity, and disruption of this signaling could play a role in the pathogenesis of diabetes. For example, we recently discovered a novel islet incretin axis where glucagon-like peptide-1 regulates β-cell production of another classic gut hormone, cholecystokinin. This axis is stimulated by obesity, and plays a role in enhancing β-cell survival. In the present review, we place our observations in the wider context of the literature on incretin regulation in the islet, and discuss the potential for therapeutic targeting of these pathways.

  12. Glucagon-like peptide-1 receptor ligand interactions: structural cross talk between ligands and the extracellular domain.

    Directory of Open Access Journals (Sweden)

    Graham M West

    Full Text Available Activation of the glucagon-like peptide-1 receptor (GLP-1R in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM. Like other class B G protein-coupled receptors (GPCRs, the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R. In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands.

  13. Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once-daily betaxolol versus twice daily metoprolol: a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Przemyslaw Kardas

    2007-05-01

    Full Text Available Przemyslaw KardasThe First Department of Family Medicine, Medical University of LodzBackground: A randomized, controlled trial was conducted in an outpatient setting to examine the effect of beta-blocker dosing frequency on patient compliance, clinical outcome, and health-related quality of life in patients with stable angina pectoris.Methods: One hundred and twelve beta-blockers-naive outpatients with stable angina pectoris were randomized to receive betaxolol, 20 mg once daily or metoprolol tartrate, 50 mg twice daily for 8 weeks. The principal outcome measure was overall compliance measured electronically, whereas secondary outcome measures were drug effectiveness and health-related quality of life.Results: The overall compliance was 86.5 ± 21.3% in the betaxolol group versus 76.1 ± 26.3% in the metoprolol group (p < 0.01, and the correct number of doses was taken on 84.4 ± 21.6% and 64.0 ± 31.7% of treatment days, respectively (p < 0.0001. The percentage of missed doses was 14.5 ± 21.5% in the once-daily group and 24.8 ± 26.4% in the twice-daily group (p < 0.01. The percentage of doses taken in the correct time window (58.6% vs 42.0%, p = 0.01, correct interdose intervals (77.4% v 53.1%, p < 0.0001, and therapeutic coverage (85.6% vs 73.7%, p < 0.001 were significantly higher in the once-daily group. Both studied drugs had similar antianginal effectiveness. Health-related quality of life improved in both groups, but this increase was more pronounced in the betaxolol arm in some dimensions.Conclusions: The study demonstrates that patient compliance with once-daily betaxolol is significantly better than with twice daily metoprolol. Similarly, this treatment provides better quality of life. These results demonstrate possible therapeutic advantages of once-daily over twice-daily beta-blockers in the treatment of stable angina pectoris.Keywords: patient compliance, quality of life, stable angina pectoris, randomized controlled trial

  14. Effect of glucagon like peptide-1 receptor agonist combined human umbilical cord mesenchymal stem cells on the glucose metabolism and the islet β cell function in type 2 diabetic SD rats%胰高血糖素样肽1受体激动剂和脐带间充质干细胞联合治疗对2型糖尿病大鼠糖代谢和胰岛分泌功能的作用

    Institute of Scientific and Technical Information of China (English)

    陈频; 徐向进; 黄勤; 温代芬; 邵珠林; 黄梁浒; 陈晨

    2015-01-01

    Objective To observe the efficacy of glucagon like peptide-1(GLP-1) receptor agonist liraglutide(LIRA) combined with umbilical cord mesenchymal stem cells(UC-MSCs) on the glucose metabolism and isletβcell function in type 2 diabetic SD rats. Methods Type 2 diabetic SD rats models were established by giving high-carbonhydrate-fat diet and then intraperitoneal injecting of streptozotocin. The rats models were randomly divided into four groups according the table of random number: type 2 diabetes mellitus(T2DM), T2DM+UC-MSC, T2DM+LIRA, T2DM+LIRA+UC-MSCs, 10 rats in each group. Rats of each group were given the appropriate drug therapy for 8 weeks respectively. Liraglutide was given by subcutaneous injection with 200 μg/kg dosage. UC-MSCs were given by tail vein injection with 5 × 106 cells. During the treatment period, the general condition indexs of each group were monitored. The serum glycated hemoglobin A1c(HbA1c), peptide C(C-P), glucagon(Glu), GLP-1, gastrin(GAS) and cholecystokinin (CCK) were measured respectively. Mean data between groups was compared with one-way ANOVA. Results After 8-week of treatment, compared with T2DM group, HbA1c of the T2DM+UC-MSCs, T2DM+LIRA and T2DM+LIRA+UC-MSCs group decreased significantly((9.1±0.4)% vs (7.2±0.4)%, (3.9± 0.3)%, (3.1±0.3)%, respectively, F=815.220, P0.05);but the C-P, GLP-1, GAS and CCK in T2DM+LIRA group and T2DM+LIRA+UC-MSCs group increased markably(t=-18.115-35.732, all P0.05);T2DM+LIRA组和T2DM+LIRA+UC-MSCs组C-P、GLP-1、GAS和CCK水平均明显升高(t=-18.115~35.732,均P<0.05),GLu降低(t=3.022、11.859,均P<0.05);与T2DM+LIRA组比较,T2DM+LIRA+UC-MSCs组C-P、GLP-1、GAS和CCK明显升高(t=-9.107、7.635、9.870、19.152,均P<0.05),Glu降低(t=-13.976,P<0.05).Pearson双变量分析发现,大鼠空腹血清C-P与GLP-1、GAS及CCK呈正相关(r=0.401、0.628、0.619,均P<0.01),与Glu呈负相关(r=-0.603,P<0.01).大鼠空腹血清GLu水平与GLP-1、GAS及CCK呈负相关(r=-0.827、-0.583、-0.516,

  15. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    Science.gov (United States)

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways.

  16. Glucagon-like peptide-2 intracellularly stimulates eNOS phosphorylation and specifically induces submucosal arteriole vasodilation via a sheer stress-independent, local neural mechanism

    Science.gov (United States)

    Glucagon-like peptide-2 (GLP-2) is a nutrient-responsive neuropeptide that exerts diverse actions in the gastrointestinal tract, including enhancing mucosal cell survival and proliferation, mucosal blood flow, luminal nutrient uptake, and suppressing gastric motility and secretion. We have shown th...

  17. Steviol glycoside rebaudioside A induces glucagon-like peptide-1 and peptide YY release in a porcine ex vivo intestinal model

    NARCIS (Netherlands)

    Ripken, D.; Wielen, van der N.; Wortelboer, H.M.; Meijerink, J.; Witkamp, R.F.; Hendriks, H.F.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are hormones important for satiation and are involved in the process called "ileal brake". The aim of this study was to investigate the GLP-1- and PYY-stimulating efficacy of rebaudioside A, casein, and sucrose. This was studied using tissue segme

  18. Synergistic effect of supplemental enteral nutrients and exogenous glucagon-like peptide 2 on intestinal adaptation in a rat model of short bowel syndrome

    DEFF Research Database (Denmark)

    Liu, Xiaowen; Nelson, David W; Holst, Jens Juul

    2006-01-01

    BACKGROUND: Short bowel syndrome (SBS) can lead to intestinal failure and require total or supplemental parenteral nutrition (TPN or PN, respectively). Glucagon-like peptide 2 (GLP-2) is a nutrient-dependent, proglucagon-derived gut hormone that stimulates intestinal adaptation. OBJECTIVE: Our...... of GLP-2 (SEN x GLP-2 interaction, P cellularity and digestive capacity in parenterally fed rats with SBS...

  19. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue, improves intestinal function in short bowel syndrome patients

    OpenAIRE

    Jeppesen, P B; Sanguinetti, E L; A. Buchman; Howard, L; Scolapio, J S; Ziegler, T R; Gregory, J; Tappenden, K A; Holst, J; Mortensen, P. B.

    2005-01-01

    Background and aims: Glucagon-like peptide 2 (GLP-2) may improve intestinal absorption in short bowel syndrome (SBS) patients with an end jejunostomy. Teduglutide (ALX-0600), a dipeptidyl peptidase IV resistant GLP-2 analogue, prolongs the intestinotrophic properties of GLP-2 in animal models. The safety and effect of teduglutide were investigated in SBS patients with and without a colon in continuity.

  20. CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice

    NARCIS (Netherlands)

    Parlevliet, E.T.; Schröder-van der Elst, J.P.; Corssmit, E.P.M.; Picha, K.; O'Neil, K.; Stojanovic-Susulic, V.; Ort, T.; Havekes, L.M.; Romijn, J.A.; Pijl, H.

    2009-01-01

    CNTO736 is a glucagon-like peptide (GLP) 1 receptor agonist that incorporates a GLP-1 peptide analog linked to the Mimeti-body platform. We evaluate the potential of acute and chronic CNTO736 treatment on insulin sensitivity and very low-density lipoprotein (VLDL) metabolism. For acute studies, diet

  1. No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis

    DEFF Research Database (Denmark)

    Knop, Filip K; Vilsbøll, Tina; Larsen, Steen;

    2003-01-01

    Glucagon-like peptide 1 (GLP-1) is a proglucagon derivative secreted primarily from the L-cells of the small intestinal mucosa in response to the ingestion of meals. GLP-1 stimulates insulin secretion and inhibits glucagon secretion. It has previously been shown that intravenous or subcutaneous...

  2. Insulin-like growth factor I and glucagon-like peptide-2 responses to fasting followed by controlled or ad libitum refeeding in rats

    DEFF Research Database (Denmark)

    Nelson, David W; Murali, Sangita G; Liu, Xiaowen

    2008-01-01

    Luminal nutrients stimulate structural and functional regeneration in the intestine through mechanisms thought to involve insulin-like growth factor I (IGF-I) and glucagon-like peptide-2 (GLP-2). We investigated the relationship between IGF-I and GLP-2 responses and mucosal growth in rats fasted ...

  3. Elimination and Degradation of Glucagon-like Peptide-1 and Glucose-Dependent Insulinotropic Polypeptide in Patients with End-Stage Renal Disease

    DEFF Research Database (Denmark)

    Idorn, Thomas; Knop, Filip K; Jørgensen, Morten B;

    2014-01-01

    Context: The affect of the kidneys in elimination and degradation of intact incretin hormones and their truncated metabolites is unclear. Objective: To evaluate elimination and degradation of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in patients with d...

  4. Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms

    DEFF Research Database (Denmark)

    Schäfer, S A; Tschritter, O; Machicao, F;

    2007-01-01

    AIMS/HYPOTHESIS: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes and reduced insulin secretion. The transcription factor TCF7L2 is an essential factor for glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells. We studied whether a d...

  5. Steviol Glycoside Rebaudioside A Induces Glucagon-like Peptide-1 and Peptide YY Release in a Porcine ex Vivo Intestinal Model

    NARCIS (Netherlands)

    Ripken, D.; Wielen, N. van der; Wortelboer, H.M.; Meijerink, J.; Witkamp, R.F.; Hendriks, H.F.J.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are hormones important for satiation and are involved in the process called “ileal brake”. The aim of this study was to investigate the GLP-1- and PYY-stimulating efficacy of rebaudioside A, casein, and sucrose. This was studied using tissue segme

  6. Glucagon-Like Peptide 1 Prevents Reactive Oxygen Species-Induced Endothelial Cell Senescence Through the Activation of Protein Kinase A

    NARCIS (Netherlands)

    Oeseburg, Hisko; de Boer, Rudolf A.; Buikema, Hendrik; van der Harst, Pim; van Gilst, Wiek H.; Sillje, Herman H. W.

    2010-01-01

    Objective-Endothelial cell senescence is an important contributor to vascular aging and is increased under diabetic conditions. Here we investigated whether the antidiabetic hormone glucagon-like peptide 1 (GLP-1) could prevent oxidative stress-induced cellular senescence in endothelial cells. Metho

  7. Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery

    DEFF Research Database (Denmark)

    Svane, M S; Jørgensen, N B; Bojsen-Møller, K N;

    2016-01-01

    BACKGROUND/OBJECTIVES: Exaggerated postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) may explain appetite reduction and weight loss after Roux-en-Y gastric bypass (RYGB), but causality has not been established. We hypothesized that food intake decreases after surgery...

  8. Exaggerated release and preserved insulinotropic action of glucagon-like peptide-1 underlie insulin hypersecretion in glucose-tolerant individuals after Roux-en-Y gastric bypass

    DEFF Research Database (Denmark)

    Dirksen, Carsten; Bojsen-Møller, Kirstine N; Jørgensen, Nils Bruun;

    2013-01-01

    Roux-en-Y gastric bypass (RYGB) improves glycaemic control in part by increasing postprandial insulin secretion through exaggerated glucagon-like peptide (GLP)-1 release. However, it is unknown whether islet cell responsiveness to i.v. glucose, non-glucose (arginine) and incretin hormones...

  9. Comparison of two once-daily regimens with a regimen consisting of nelfinavir, didanosine, and stavudine in antiretroviral therapy-naive adults : 48-week results from the antiretroviral regimen evaluation study (ARES)

    NARCIS (Netherlands)

    Lowe, SH; Wensing, AMJ; Hassink, EAM; ten Kate, RW; Richter, C; Schreij, G; Koopmans, PP; Juttmann, J.; van der Tweel, I.; Lange, JMA; Borleffs, JCC

    2005-01-01

    Background: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. Method: HIV-1-infected, antiretroviral drug-naive adults were randomized to either twice-daily nelfinavir and stavudine and once-daily dida

  10. Comparison of two once-daily regimens with a regimen consisting of nelfinavir, didanosine, and stavudine in antiretroviral therapy-naive adults: 48-week results from the Antiretroviral Regimen Evaluation Study (ARES).

    NARCIS (Netherlands)

    Lowe, S.H.; Wensing, B.M.; Hassink, E.A.M.; Kate, R.W. ten; Richter, C.; Schreij, G.; Koopmans, P.P.; Juttmann, J.R.; Tweel, I. van de; Lange, J.M.A.; Borleffs, J.C.

    2005-01-01

    BACKGROUND: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. METHOD: HIV-1-infected, antiretroviral drug-naive adults were randomized to either twice-daily nelfinavir and stavudine and once-daily dida

  11. Tadalafil once daily and extracorporeal shock wave therapy in the management of patients with Peyronie's disease and erectile dysfunction: results from a prospective randomized trial.

    Science.gov (United States)

    Palmieri, A; Imbimbo, C; Creta, M; Verze, P; Fusco, F; Mirone, V

    2012-04-01

    Extracorporeal shock wave therapy improves erectile function in patients with Peyronie's disease. However, erectile dysfunction still persists in many cases. We aimed to investigate the effects of extracorporeal shock wave therapy plus tadalafil 5 mg once daily in the management of patients with Peyronie's disease and erectile dysfunction not previously treated. One hundred patients were enrolled in a prospective, randomized, controlled study. Patients were randomly allocated to receive either extracorporeal shock wave therapy alone for 4 weeks (n = 50) or extracorporeal shock wave therapy plus tadalafil 5 mg once daily for 4 weeks (n = 50). Main outcome measures were: erectile function (evaluated through the shortened version of the International Index of Erectile Function), pain during erection (evaluated through a Visual Analog Scale), plaque size, penile curvature and quality of life (evaluated through an internal questionnaire). Follow-up evaluations were performed after 12 and 24 weeks. In both groups, at 12 weeks follow-up, mean Visual Analog Scale score, mean International Index of Erectile Function score and mean quality of life score ameliorated significantly while mean plaque size and mean curvature degree were unchanged. Intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and quality of life score in patients receiving the combination. After 24 weeks, intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and mean quality of life score in patients that received extracorporeal shock wave therapy plus tadalafil. In conclusion extracorporeal shock wave therapy plus tadalafil 5 mg once daily may represent a valid conservative strategy for the management of patients with Peyronie's disease and erectile dysfunction.

  12. Clinical benefit of fixed-dose dual bronchodilation with glycopyrronium and indacaterol once daily in patients with chronic obstructive pulmonary disease: a systematic review

    Directory of Open Access Journals (Sweden)

    Ulrik CS

    2014-04-01

    Full Text Available Charlotte Suppli UlrikDepartment of Respiratory Medicine, Hvidovre Hospital and University of Copenhagen, Hvidovre, DenmarkBackground and aim: Long-acting bronchodilators are the preferred option for maintenance therapy of patients with chronic obstructive pulmonary disease (COPD. The aim of this review is to provide an overview of the clinical studies evaluating the clinical efficacy of the once-daily fixed-dose dual bronchodilator combination of indacaterol and glycopyrronium bromide in patients suffering from COPD.Methods: This study comprised a systematic review of randomized controlled trials identified through systematic searches of different databases of published trials.Results: Nine trials (6,166 participants were included. Fixed-dose once-daily indacaterol/glycopyrronium seems to be safe and well tolerated in patients with COPD. Compared with single therapy with other long-acting bronchodilators (indacaterol, glycopyrronium, and tiotropium and fixed-combination long-acting β2-agonist/inhaled corticosteroid (salmeterol/fluticasone twice daily, once-daily fixed-dose indacaterol/glycopyrronium has clinically important effects on symptoms, including dyspnea score, health status, level of lung function, and rate of moderate or severe exacerbations in patients with moderate-to-very severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] spirometric criteria. Furthermore, a very recent study has shown that fixed-dose indacaterol/glycopyrronium improves exercise endurance time compared with placebo, although no significant difference was observed between fixed-dose indacaterol/glycopyrronium and tiotropium.Conclusion: Fixed-dose indacaterol/glycopyrronium has clinically relevant effects on important COPD outcome measures and is, in general, superior to therapy with a single long-acting bronchodilator (with or without inhaled corticosteroid indicating long-acting dual bronchodilation as a potential important maintenance

  13. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD.

    Science.gov (United States)

    Dahl, Ronald; Chung, Kian Fan; Buhl, Roland; Magnussen, Helgo; Nonikov, Vladimir; Jack, Damon; Bleasdale, Patricia; Owen, Roger; Higgins, Mark; Kramer, Benjamin

    2010-06-01

    Indacaterol is a long-acting inhaled beta(2)-agonist (LABA) for the treatment of chronic obstructive pulmonary disease (COPD). In previous studies, indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action. This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year. Patients with moderate to severe COPD were randomised to receive once-daily indacaterol 300 microg (n=437) or 600 microg (n=428), twice-daily formoterol 12 microg (n=435) or placebo (n=432) for 52 weeks in a double-blind double-dummy parallel group study. The primary efficacy variable was forced expiratory volume in 1 s (FEV(1)) measured 24 h postdose after 12 weeks (indacaterol vs placebo). Other outcomes included dyspnoea (transition dyspnoea index, TDI), use of as-needed salbutamol, symptom-based measures recorded on diary cards, exacerbations, health status (St George's Respiratory Questionnaire), BODE index (body mass index, obstruction, dyspnoea, exercise), safety and tolerability. Indacaterol increased 24 h postdose FEV(1) after 12 weeks by 170 ml (both doses) versus placebo and by 100 ml versus formoterol (all pindacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol. Indacaterol was well tolerated and had a good overall safety profile, including minimal impact on QTc interval and systemic beta(2)-mediated events. Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD. NCT 00393458.

  14. Clinical benefit of fixed-dose dual bronchodilation with glycopyrronium and indacaterol once daily in patients with chronic obstructive pulmonary disease: a systematic review.

    Science.gov (United States)

    Ulrik, Charlotte Suppli

    2014-01-01

    Long-acting bronchodilators are the preferred option for maintenance therapy of patients with chronic obstructive pulmonary disease (COPD). The aim of this review is to provide an overview of the clinical studies evaluating the clinical efficacy of the once-daily fixed-dose dual bronchodilator combination of indacaterol and glycopyrronium bromide in patients suffering from COPD. This study comprised a systematic review of randomized controlled trials identified through systematic searches of different databases of published trials. Nine trials (6,166 participants) were included. Fixed-dose once-daily indacaterol/glycopyrronium seems to be safe and well tolerated in patients with COPD. Compared with single therapy with other long-acting bronchodilators (indacaterol, glycopyrronium, and tiotropium) and fixed-combination long-acting β2-agonist/inhaled corticosteroid (salmeterol/fluticasone twice daily), once-daily fixed-dose indacaterol/glycopyrronium has clinically important effects on symptoms, including dyspnea score, health status, level of lung function, and rate of moderate or severe exacerbations in patients with moderate-to-very severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] spirometric criteria). Furthermore, a very recent study has shown that fixed-dose indacaterol/glycopyrronium improves exercise endurance time compared with placebo, although no significant difference was observed between fixed-dose indacaterol/glycopyrronium and tiotropium. Fixed-dose indacaterol/glycopyrronium has clinically relevant effects on important COPD outcome measures and is, in general, superior to therapy with a single long-acting bronchodilator (with or without inhaled corticosteroid) indicating long-acting dual bronchodilation as a potential important maintenance therapeutic option for patients with symptomatic COPD, possibly also for the treatment of naïve patients.

  15. Ingestion of coffee polyphenols increases postprandial release of the active glucagon-like peptide-1 (GLP-1(7-36)) amide in C57BL/6J mice.

    Science.gov (United States)

    Fujii, Yoshie; Osaki, Noriko; Hase, Tadashi; Shimotoyodome, Akira

    2015-01-01

    The widespread prevalence of diabetes, caused by impaired insulin secretion and insulin resistance, is now a worldwide health problem. Glucagon-like peptide 1 (GLP-1) is a major intestinal hormone that stimulates glucose-induced insulin secretion from β cells. Prolonged activation of the GLP-1 signal has been shown to attenuate diabetes in animals and human subjects. Therefore, GLP-1 secretagogues are attractive targets for the treatment of diabetes. Recent epidemiological studies have reported that an increase in daily coffee consumption lowers diabetes risk. The present study examined the hypothesis that the reduction in diabetes risk associated with coffee consumption may be mediated by the stimulation of GLP-1 release by coffee polyphenol extract (CPE). GLP-1 secretion by human enteroendocrine NCI-H716 cells was augmented in a dose-dependent manner by the addition of CPE, and was compatible with the increase in observed active GLP-1(7-36) amide levels in the portal blood after administration with CPE alone in mice. CPE increased intracellular cyclic AMP (cAMP) levels in a dose-dependent manner, but this was not mediated by G protein-coupled receptor 119 (GPR119). The oral administration of CPE increased diet (starch and glyceryl trioleate)-induced active GLP-1 secretion and decreased glucose-dependent insulinotropic polypeptide release. Although CPE administration did not affect diet-induced insulin secretion, it decreased postprandial hyperglycaemia, which indicates that higher GLP-1 levels after the ingestion of CPE may improve insulin sensitivity. We conclude that dietary coffee polyphenols augment gut-derived active GLP-1 secretion via the cAMP-dependent pathway, which may contribute to the reduced risk of type 2 diabetes associated with daily coffee consumption.

  16. The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Jessica E Potts

    Full Text Available To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus.Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo in adults with type 2 diabetes and a mean body mass index ≥ 25 kg/m2. Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator.In the mixed treatment comparison (27 trials, the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2 mg/week: -1.62 kg (95% CrI: -2.95 kg, -0.30 kg, exenatide 20 μg: -1.37 kg (95% CI: -222 kg, -0.52 kg, liraglutide 1.2 mg: -1.01 kg (95%CrI: -2.41 kg, 0.38 kg and liraglutide 1.8 mg: -1.51 kg (95% CI: -2.67 kg, -0.37 kg compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss.This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed.

  17. Pharmacodynamics and Pharmacokinetics Following Once-Daily and Twice-Daily Dosing of Tiotropium Respimat(®) in Asthma Using Standardized Sample-Contamination Avoidance

    DEFF Research Database (Denmark)

    Beeh, Kai-Michael; Kirsten, Anne-Marie; Dusser, Daniel;

    2016-01-01

    BACKGROUND: This study was conducted to confirm the 24-hour bronchodilator efficacy and pharmacokinetic profile of once-daily tiotropium Respimat(®) 5 μg add-on to inhaled corticosteroids (ICS) in adults with symptomatic asthma. It used a trial protocol designed to minimize the risk...... of pharmacokinetic sample contamination resulting from improper sampling procedure, sample handling, or device handling during priming and subsequent inhalation procedure. METHODS: A Phase II, randomized, double-blind, two-way crossover study (NCT01696071) comparing two daily dosing regimens of tiotropium for 4...

  18. Increased expression of glucagon-like peptide-1 receptors in psoriasis plaques

    DEFF Research Database (Denmark)

    Faurschou, Annesofie; Pedersen, Jens; Gyldenløve, Mette

    2013-01-01

    in either stimulated or unstimulated cultured human keratinocytes. Our results show increased presence of GLP-1Rs in psoriasis plaques and that this most likely is due to infiltration with immune cells. This offers a possible explanation for the positive effect of treatment with GLP-1R agonists in patients...

  19. Real-time trafficking and signaling of the glucagon-like peptide-1 receptor

    DEFF Research Database (Denmark)

    Roed, Sarah Noerklit; Wismann, Pernille; Underwood, Christina Rye

    2014-01-01

    . A fundamental mechanism controlling the signaling capacity of GPCRs is the post-endocytic trafficking of receptors between recycling and degradative fates. Here, we combined microscopy with novel real-time assays to monitor both receptor trafficking and signaling in living cells. We find that the human GLP-1R...

  20. Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1 metabolite GLP-1 9-36 amide at the GLP-1 receptor.

    Directory of Open Access Journals (Sweden)

    Naichang Li

    Full Text Available Glucagon-like peptide-1 (GLP-1 released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R. GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compound 2' has been described as both an agonist and positive allosteric modulator of GLP-1 7-36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9-39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa at the GLP-1R. Given that GLP-1 9-36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9-36 amide for key cellular responses including AMP generation, Ca(2+ signaling and extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy.

  1. Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1) metabolite GLP-1 9-36 amide at the GLP-1 receptor.

    Science.gov (United States)

    Li, Naichang; Lu, Jing; Willars, Gary B

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compound 2' has been described as both an agonist and positive allosteric modulator of GLP-1 7-36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9-39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa) at the GLP-1R. Given that GLP-1 9-36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9-36 amide for key cellular responses including AMP generation, Ca(2+) signaling and extracellular signal-regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy.

  2. Progesterone receptor membrane component 1 is a functional part of the glucagon-like peptide-1 (GLP-1) receptor complex in pancreatic β cells.

    Science.gov (United States)

    Zhang, Ming; Robitaille, Mélanie; Showalter, Aaron D; Huang, Xinyi; Liu, Ying; Bhattacharjee, Alpana; Willard, Francis S; Han, Junfeng; Froese, Sean; Wei, Li; Gaisano, Herbert Y; Angers, Stéphane; Sloop, Kyle W; Dai, Feihan F; Wheeler, Michael B

    2014-11-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates glucose homeostasis. Because of their direct stimulation of insulin secretion from pancreatic β cells, GLP-1 receptor (GLP-1R) agonists are now important therapeutic options for the treatment of type 2 diabetes. To better understand the mechanisms that control the insulinotropic actions of GLP-1, affinity purification and mass spectrometry (AP-MS) were employed to uncover potential proteins that functionally interact with the GLP-1R. AP-MS performed on Chinese hamster ovary cells or MIN6 β cells, both expressing the human GLP-1R, revealed 99 proteins potentially associated with the GLP-1R. Three novel GLP-1R interactors (PGRMC1, Rab5b, and Rab5c) were further validated through co-immunoprecipitation/immunoblotting, fluorescence resonance energy transfer, and immunofluorescence. Functional studies revealed that overexpression of PGRMC1, a novel cell surface receptor that associated with liganded GLP-1R, enhanced GLP-1-induced insulin secretion (GIIS) with the most robust effect. Knockdown of PGRMC1 in β cells decreased GIIS, indicative of positive interaction with GLP-1R. To gain insight mechanistically, we demonstrated that the cell surface PGRMC1 ligand P4-BSA increased GIIS, whereas its antagonist AG-205 decreased GIIS. It was then found that PGRMC1 increased GLP-1-induced cAMP accumulation. PGRMC1 activation and GIIS induced by P4-BSA could be blocked by inhibition of adenylyl cyclase/EPAC signaling or the EGF receptor-PI3K signal transduction pathway. These data reveal a dual mechanism for PGRMC1-increased GIIS mediated through cAMP and EGF receptor signaling. In conclusion, we identified several novel GLP-1R interacting proteins. PGRMC1 expressed on the cell surface of β cells was shown to interact with the activated GLP-1R to enhance the insulinotropic actions of GLP-1.

  3. The pivotal role of high glucose-induced overexpression of PKCβ in the appearance of glucagon-like peptide-1 resistance in endothelial cells.

    Science.gov (United States)

    Pujadas, Gemma; De Nigris, Valeria; La Sala, Lucia; Testa, Roberto; Genovese, Stefano; Ceriello, Antonio

    2016-11-01

    Recently, it has been demonstrated that Glucagon-like peptide-1 (GLP-1) has a protective effect on endothelial cells. Our hypothesis is that this GLP-1 protective effect is partly lost when the cells are exposed to sustained high glucose concentrations. Human umbilical vein endothelial cells (HUVECs) were cultured for 21 days in normal glucose (5 mmol/L, NG) or high glucose (25 mmol/L glucose, HG). GLP-1 (7-37) and Ruboxistaurin were added at 50 and 500 nM, respectively, alone or in combination, 1 h before cell harvesting. Analysis of GLP-1 receptor protein levels, as well as of the gene expression of different ER stress-related genes, proliferation markers, antioxidant cell response-related genes, and PKA subunits, was performed. ROS production was also measured in HUVECs exposed to mentioned treatments. GLP-1 receptor expression was reduced in HUVECs exposed to chronic high glucose concentrations but was partially restored by a chemical PKCβ-specific inhibitor. GLP-1, added as an acute treatment in endothelial cells, had the capacity to induce the expression of Nrf2-detoxifying enzyme targets, to increase transcription levels of scavenger genes, to attenuate the expression of high glucose-induced PKA subunits, ER stress and also the apoptotic phenotype of HUVECs; these effects occured only when high glucose-induced PKCβ overexpression was reduced by Ruboxistaurin. In a similar manner, ROS production induced by high glucose was reduced by GLP-1 in the presence of PKCβ inhibitor. This study suggests that an increase in PKCβ, induced by high glucose, could have a role in endothelial GLP-1 resistance, reducing GLP-1 receptor levels and disrupting the GLP-1 canonical pathway.

  4. Use of new once-daily 5-aminosalicylic acid preparations in the treatment of ulcerative colitis: Is there anything new under the sun?

    Institute of Scientific and Technical Information of China (English)

    Peter Laszlo Lakatos

    2009-01-01

    5-aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents are commercially available, including azobond pro-drugs, as well as delayed- and controlledrelease forms of mesalazine. However, poor adherence due to frequent daily dosing and a large number of tablets has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine, including the unique multi-matrix delivery system and mesalazine granules, were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of a low pill burden and might contribute to increased long-term compliance and treatment success in clinical practice. This editorial summarizes the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.

  5. Bronchodilator efficacy and safety of indacaterol 150 μg once daily in patients with COPD: an analysis of pooled data.

    Science.gov (United States)

    Bleecker, Eugene R; Siler, Thomas; Owen, Roger; Kramer, Benjamin

    2011-01-01

    Indacaterol is an inhaled, once-daily long-acting β(2)-agonist bronchodilator for regular use in patients with chronic obstructive pulmonary disease (COPD). As indacaterol is the first once-daily β(2)-agonist to be developed, it is relevant to evaluate its bronchodilator efficacy, safety, and tolerability. Data were pooled from three randomized, double-blind, clinical studies in patients with moderate-to-severe COPD treated with indacaterol 150 μg qd (n = 627) or placebo (n = 1021). Bronchodilator efficacy was assessed as trough (24-hour post-dose) forced expiratory volume in 1 second (FEV(1)) after 12 weeks (primary endpoint in individual studies) and FEV(1) measured serially post-dose. Rescue use of albuterol was monitored. At week 12, indacaterol increased trough FEV(1) by 160 mL compared with placebo (P indacaterol than with placebo (P indacaterol recorded 53% of days without use of rescue albuterol, compared with 38% of days in the placebo group (P indacaterol and placebo, respectively, and serious adverse events for 4% and 5%. Worsening of COPD was the most frequent adverse event (10% indacaterol; 15% placebo). Indacaterol had little effect on pulse or blood pressure or measures of systemic β(2)-adrenoceptor activity (blood glucose, serum potassium, and corrected QT interval). Indacaterol was an effective bronchodilator and was well tolerated, with a good safety profile over 12 weeks of treatment. It should prove a useful treatment for patients with moderate-to-severe COPD.

  6. Comparison of airway dimensions with once daily tiotropium plus indacaterol versus twice daily Advair(®) in chronic obstructive pulmonary disease.

    Science.gov (United States)

    Hoshino, Makoto; Ohtawa, Junichi; Akitsu, Kenta

    2015-02-01

    Current guidelines recommend combining long-acting bronchodilators with different modes of action in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). We evaluated the effects of airway dimensions and pulmonary function with tiotropium plus indacaterol versus Advair(®). Subjects (n = 46) were randomized to receive tiotropium (18 μg once daily) plus indacaterol (150 μg once daily) or Advair(®) (50/250 μg twice daily) for 16 weeks. Airway geometry was determined by quantitative computed tomography (luminal area, Ai; total area of the airway, Ao; wall area, WA; and percentage wall area, WA/Ao and wall thickness, T). Spirometry (forced expiratory volume in 1 s, FEV1; forced vital capacity, FVC and inspiratory capacity, IC) and St. George's Respiratory Questionnaire (SGRQ) were evaluated. Tiotropium plus indacaterol significantly increased CT-indices including Ai corrected for body surface area (Ai/BSA), and decreased WA/BSA, WA/Ao and T/√BSA compared with Advair(®) (p indacaterol than Advair(®) (p indacaterol than Advair(®). These findings suggest that dual bronchodilation with tiotropium plus indacaterol is superior in airway geometry and lung function compared with Advair(®) in COPD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy

    Science.gov (United States)

    Albertson, Timothy E; Bullick, Samuel W; Schivo, Michael; Sutter, Mark E

    2016-01-01

    The use of inhaled corticosteroids (ICSs) plays a key role in the treatment of asthmatic patients, and international guidelines have designated ICSs as an early maintenance therapy in controlling asthma symptoms. When asthmatic patients remain symptomatic on ICSs, one common option is to add a long-acting beta2 agonist (LABA) to the maintenance treatment. Fixed combination inhalers that contain both an ICS and a LABA have been popular for both chronic obstructive pulmonary disease (COPD) and asthma. Historically, these inhalers have been dosed twice daily. However, currently, there is a once-daily combination therapy with the ICS fluticasone furoate (FF) and the LABA vilanterol trifenatate (VI) with indications for use in both COPD and asthma. This dry powder inhaler (DPI) comes in two doses of FF (100 or 200 μg) both combined with VI (25 μg). This article reviews the clinical trial data for FF, VI and FF/VI combination inhalers and documents the efficacy and safety of once-daily inhaled maintenance therapy by DPI in asthmatic patients. PMID:28008228

  8. Efficacy and safety of telithromycin 800 mg once daily for 7 days in community-acquired pneumonia: an open-label, multicenter study

    Directory of Open Access Journals (Sweden)

    Dunbar Lala M

    2005-05-01

    Full Text Available Abstract Background Community-acquired pneumonia (CAP remains a major cause of morbidity and mortality throughout the world. Telithromycin (a new ketolide has shown good in vitro activity against the key causative pathogens of CAP, including S pneumoniae resistant to penicillin and/or macrolides. Methods The efficacy and safety of telithromycin 800 mg orally once daily for 7 days in the treatment of CAP were assessed in an open-label, multicenter study of 442 adults. Results Of 149 microbiologically evaluable patients, 57 (9 bacteremic had Streptococcus pneumoniae. Of the 57 S pneumoniae pathogens isolated in these patients, 9 (2 bacteremic were penicillin- or erythromycin-resistant; all 57 were susceptible to telithromycin and were eradicated. Other pathogens and their eradication rates were: Haemophilus influenzae (96%, Moraxella catarrhalis (100%, Staphylococcus aureus (80%, and Legionella spp. (100%. The overall bacteriologic eradication rate was 91.9%. Of the 357 clinically evaluable patients, clinical cure was achieved in 332 (93%. In the 430 patients evaluable for safety, the most common drug-related adverse events were diarrhea (8.1% and nausea (5.8%. Conclusion Telithromycin 800 mg once daily for 7 days is an effective and well-tolerated oral monotherapy and offers a new treatment option for CAP patients, including those with resistant S pneumoniae.

  9. Use of new once-daily 5-aminosalicylic acid preparations in the treatment of ulcerative colitis: Is there anything new under the sun?

    Science.gov (United States)

    Lakatos, Peter Laszlo

    2009-04-21

    5-aminosalicylate (5-ASA) agents remain the mainstay treatment in ulcerative colitis (UC). A number of oral 5-ASA agents are commercially available, including azobond pro-drugs, as well as delayed- and controlled-release forms of mesalazine. However, poor adherence due to frequent daily dosing and a large number of tablets has been shown to be an important barrier to successful management of patients with UC. Recently, new, once-daily formulations of mesalazine, including the unique multi-matrix delivery system and mesalazine granules, were proven to be efficacious in inducing and maintaining remission in mild-to-moderate UC, with a good safety profile comparable to that of other oral mesalazine formulations. In addition, they offer the advantage of a low pill burden and might contribute to increased long-term compliance and treatment success in clinical practice. This editorial summarizes the available literature on the short- and medium-term efficacy and safety of the new once-daily mesalazine formulations.

  10. Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Minglin Pan

    2011-01-01

    Full Text Available The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1 receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX- sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

  11. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice.

    Science.gov (United States)

    Sørensen, Gunnar; Reddy, India A; Weikop, Pia; Graham, Devon L; Stanwood, Gregg D; Wortwein, Gitta; Galli, Aurelio; Fink-Jensen, Anders

    2015-10-01

    Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.

  12. Exendin-4, a glucagon-like peptide-1 receptor agonist, provides neuroprotection in mice transient focal cerebral ischemia.

    Science.gov (United States)

    Teramoto, Shinichiro; Miyamoto, Nobukazu; Yatomi, Kenji; Tanaka, Yasutaka; Oishi, Hidenori; Arai, Hajime; Hattori, Nobutaka; Urabe, Takao

    2011-08-01

    Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate glucose-dependent insulin secretion. The GLP-1 receptor agonist, exendin-4, has similar properties to GLP-1 and is currently in clinical use for type 2 diabetes mellitus. As GLP-1 and exendin-4 confer cardioprotection after myocardial infarction, this study was designed to assess the neuroprotective effects of exendin-4 against cerebral ischemia-reperfusion injury. Mice received a transvenous injection of exendin-4, after a 60-minute focal cerebral ischemia. Exendin-4-treated vehicle and sham groups were evaluated for infarct volume, neurologic deficit score, various physiologic parameters, and immunohistochemical analyses at several time points after ischemia. Exendin-4 treatment significantly reduced infarct volume and improved functional deficit. It also significantly suppressed oxidative stress, inflammatory response, and cell death after reperfusion. Furthermore, intracellular cyclic AMP (cAMP) levels were slightly higher in the exendin-4 group than in the vehicle group. No serial changes were noted in insulin and glucose levels in both groups. This study suggested that exendin-4 provides neuroprotection against ischemic injury and that this action is probably mediated through increased intracellular cAMP levels. Exendin-4 is potentially useful in the treatment of acute ischemic stroke.

  13. REVIEW: Role of cyclic AMP signaling in the production and function of the incretin hormone glucagon-like peptide-1

    Science.gov (United States)

    Yu, Zhiwen; Jin, Tianru

    2008-01-01

    Pancreatic cells express the proglucagon gene (gcg) and thereby produce the peptide hormone glucagon, which stimulates hepatic glucose production and thereby increases blood glucose levels. The same gcg gene is also expressed in the intestinal endocrine L cells and certain neural cells in the brain. In the gut, gcg expression leads to the production of glucagon-like peptide-1 (GLP-1). This incretin hormone stimulates insulin secretion when blood glucose level is high. In addition, GLP-1 stimulates pancreatic cell proliferation, inhibits cell apoptosis, and has been utilized in the trans-differentiation of insulin producing cells. Today, a long-term effective GLP-1 receptor agonist has been developed as a drug in treating diabetes and potentially other metabolic disorders. Extensive investigations have shown that the expression of gcg and the production of GLP-1 can be activated by the elevation of the second messenger cyclic AMP (cAMP). Recent studies suggest that in addition to protein kinase A (PKA), exchange protein activated by cAMP (Epac), another effector of cAMP signaling, and the crosstalk between PKA and Wnt signaling pathway, are also involved in cAMP-stimulated gcg expression and GLP-1 production. Furthermore, functions of GLP-1 in pancreatic cells are mainly mediated by cAMP-PKA, cAMP-Epac and Wnt signaling pathways as well.

  14. Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation.

    Science.gov (United States)

    Chen, S; An, F-M; Yin, L; Liu, A-R; Yin, D-K; Yao, W-B; Gao, X-D

    2014-01-03

    We have previously demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonist ameliorated neurodegenerative changes in rat models of diabetes-related Alzheimer's disease (AD), and protected neurons from glucose toxicity in vitro. Herein, we investigated the effects of GLP-1 receptor mediates on cell toxicity and tau hyperphosphorylation induced by advanced glycation end products (AGEs), which are associated with glucose toxicity, and the molecular mechanism in PC12 cells and the primary hippocampal neurons. Our study demonstrated that the similar protection effects of GLP-1 existed in PC12 cells treated with glucose-bovine serum albumin (BSA) in hyperglycemic conditions or with glycoaldehyde-BSA alone. Additionally, glucose-BSA alone did not induce significant cytotoxicity in PC12 cells, but resulted in tau hyperphosphorylation in primary hippocampal neurons in 24h. And we found that GLP-1 could reduce cell tau phosphorylation induced by high glucose or glucose-BSA. Furthermore, our data in the present study suggested that GLP-1 regulated tau phosphorylation induced by AGEs through a signaling pathway involving glycogen synthase kinase 3β (GSK-3β), similarly to the GSK-3β inhibitor, lithium chloride. Our findings suggest that GLP-1 can protect neurons from diabetes-associated AGE insults in vitro, and provide new evidence for a potential therapeutic value of GLP-1 receptor agonist in the treatment of AD especially diabetes-related AD.

  15. The glucagon-like peptide 1 analogue, exendin-4, attenuates the rewarding properties of psychostimulant drugs in mice.

    Directory of Open Access Journals (Sweden)

    Emil Egecioglu

    Full Text Available Glucagon-like peptide 1 (GLP-1 is an incretine hormone that controls consummatory behavior and glucose homeostasis. It is released in response to nutrient ingestion from the intestine and production in the brain has also been identified. Given that GLP-1 receptors are expressed in reward areas, such as the nucleus accumbens and ventral tegmental area, and that common mechanisms regulate food and drug-induced reward we hypothesize that GLP-1 receptors are involved in reward regulation. Herein the effect of the GLP-1 receptor agonist Exendin-4 (Ex4, on amphetamine- and cocaine-induced activation of the mesolimbic dopamine system was investigated in mice. In a series of experiments we show that treatment with Ex4, at a dose with no effect per se, reduce amphetamine- as well as cocaine-induced locomotor stimulation, accumbal dopamine release as well as conditioned place preference in mice. Collectively these data propose a role for GLP-1 receptors in regulating drug reward. Moreover, the GLP-1 signaling system may be involved in the development of drug dependence since the rewarding effects of addictive drugs involves interferences with the mesolimbic dopamine system. Given that GLP-1 analogues, such as exenatide and liraglutide, are clinically available for treatment of type II diabetes, we propose that these should be elucidated as treatments of drug dependence.

  16. The glucagon-like peptide 1 receptor agonist enhances intrinsic peroxisome proliferator-activated receptor γ activity in endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Onuma, Hirohisa; Inukai, Kouichi, E-mail: kinukai@ks.kyorin-u.ac.jp; Kitahara, Atsuko; Moriya, Rie; Nishida, Susumu; Tanaka, Toshiaki; Katsuta, Hidenori; Takahashi, Kazuto; Sumitani, Yoshikazu; Hosaka, Toshio; Ishida, Hitoshi

    2014-08-22

    Highlights: • PPARγ activation was involved in the GLP-1-mediated anti-inflammatory action. • Exendin-4 enhanced endogenous PPARγ transcriptional activity in HUVECs. • H89, a PKA inhibitor, abolished GLP-1-induced PPARγ enhancement. • The anti-inflammatory effects of GLP-1 may be explained by PPARγ activation. - Abstract: Recent studies have suggested glucagon-like peptide-1 (GLP-1) signaling to exert anti-inflammatory effects on endothelial cells, although the precise underlying mechanism remains to be elucidated. In the present study, we investigated whether PPARγ activation is involved in the GLP-1-mediated anti-inflammatory action on endothelial cells. When we treated HUVEC cells with 0.2 ng/ml exendin-4, a GLP-1 receptor agonist, endogenous PPARγ transcriptional activity was significantly elevated, by approximately 20%, as compared with control cells. The maximum PPARγ activity enhancing effect of exendin-4 was observed 12 h after the initiation of incubation with exendin-4. As H89, a PKA inhibitor, abolished GLP-1-induced PPARγ enhancement, the signaling downstream from GLP-1 cross-talk must have been involved in PPARγ activation. In conclusion, our results suggest that GLP-1 has the potential to induce PPARγ activity, partially explaining the anti-inflammatory effects of GLP-1 on endothelial cells. Cross-talk between GLP-1 signaling and PPARγ activation would have major impacts on treatments for patients at high risk for cardiovascular disease.

  17. Chenodeoxycholic acid stimulates glucagon-like peptide-1 secretion in patients after Roux-en-Y gastric bypass

    DEFF Research Database (Denmark)

    Nielsen, Signe; Svane, Maria S; Kuhre, Rune E

    2017-01-01

    (BMI 29.1 ± 1.2, age 37.0 ± 3.2 years, time from RYGB 32.3 ± 1.1 months, weight loss after RYGB 37.0 ± 3.1 kg) were studied in a placebo-controlled, crossover-study. On three different days, participants ingested (1) placebo (water), (2) UDCA 750 mg, (3) CDCA 1250 mg (highest recommended doses). Oral......Postprandial secretion of glucagon-like peptide-1 (GLP-1) is enhanced after Roux-en-Y gastric bypass (RYGB), but the precise molecular mechanisms explaining this remain poorly understood. Plasma concentrations of bile acids (BAs) increase after RYGB, and BAs may act as molecular enhancers of GLP-1...... secretion through activation of TGR5-receptors. We aimed to evaluate GLP-1 secretion after oral administration of the primary bile acid chenodeoxycholic acid (CDCA) and the secondary bile acid ursodeoxycholic acid (UDCA) (which are available for oral use) in RYGB-operated participants. Eleven participants...

  18. Grape-seed procyanidins prevent the cafeteria-diet-induced decrease of glucagon-like peptide-1 production.

    Science.gov (United States)

    González-Abuín, Noemi; Martínez-Micaelo, Neus; Blay, Mayte; Ardévol, Anna; Pinent, Montserrat

    2014-02-05

    Grape-seed procyanidin extract (GSPE) has been reported to improve insulin resistance in cafeteria rats. Because glucagon-like peptide-1 (GLP-1) is involved in glucose homeostasis, the preventive effects of GSPE on GLP-1 production, secretion, and elimination were evaluated in a model of diet-induced insulin resistance. Rats were fed a cafeteria diet for 12 weeks, and 25 mg of GSPE/kg of body weight was administered concomitantly. Vehicle-treated cafeteria-fed rats and chow-fed rats were used as controls. The cafeteria diet decreased active GLP-1 plasma levels, which is attributed to a decreased intestinal GLP-1 production, linked to reduced colonic enteroendocrine cell populations. Such effects were prevented by GSPE. In the same context, GSPE avoided the decrease on intestinal dipeptidyl-peptidase 4 (DPP4) activity and modulated the gene expression of GLP-1 and its receptor in the hypothalamus. In conclusion, the preventive treatment with GSPE abrogates the effects of the cafeteria diet on intestinal GLP-1 production and DPP4 activity.

  19. Preliminary Examination of Glucagon-Like Peptide-1 Levels in Women with Purging Disorder and Bulimia Nervosa

    Science.gov (United States)

    Dossat, Amanda M.; Bodell, Lindsay P.; Williams, Diana L.; Eckel, Lisa A.; Keel, Pamela K.

    2014-01-01

    Objective This study examined pre- and post-prandial glucagon-like peptide 1 (GLP-1) levels in women with bulimia nervosa (BN), purging disorder (PD), and non-eating disorder control women to better understand whether alterations in satiation-related hormones in BN may be linked to binge-eating episodes or other altered ingestive behaviors. Method Participants included women with BN (n = 19), PD (n = 14), or controls (n = 14). Participants provided subjective ratings for hunger and fullness and plasma samples before and after consumption of a standardized test meal. Results As expected, GLP-1 levels increased significantly following test meal consumption; however, participants with BN displayed significantly lower GLP-1 levels compared to PD and control participants both before and after consumption of the test meal. There were no significant differences between PD and control participants in GLP-1 levels, but individuals with PD displayed significantly higher levels of fullness throughout the test meal as compared to both control and BN participants. Discussion Our findings provide preliminary evidence that reduced GLP-1 levels in individuals with BN may be associated with binge-eating episodes. Additionally, increased fullness in individuals with PD does not appear to be accounted for by exaggerated post-prandial GLP-1 release. PMID:24590464

  20. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients

    DEFF Research Database (Denmark)

    Toft-Nielsen, M B; Madsbad, Sten; Holst, J J

    1999-01-01

    OBJECTIVE: The gut hormone glucagon-like peptide 1 (GLP-1) has insulinotropic and anorectic effects during intravenous infusion and has been proposed as a new treatment for type 2 diabetes and obesity. The effect of a single subcutaneous injection is brief because of rapid degradation. We therefore......, previously shown to lower blood glucose effectively in type 2 diabetic patients. Fasting plasma glucose (day 2) decreased from 14.1 +/- 0.9 (saline) to 12.2 +/- 0.7 mmol/l (GLP-1), P = 0.009, and 24-h mean plasma glucose decreased from 15.4 +/- 1.0 to 13.0 +/- 1.0 mmol/l, P = 0.0009. Fasting and total area...... under the curve for insulin and C-peptide levels were significantly higher during the GLP-1 administration, whereas glucagon levels were unchanged. Neither triglycerides nor free fatty acids were affected. GLP-1 administration decreased hunger and prospective food intake and increased satiety, whereas...

  1. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2016-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1–based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs continue to become available, physicians will soon face the challenge of selecting the right option customized to their patient's needs. The following discussion, derived from an extensive literature search using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide, provides a comprehensive review of existing and upcoming molecules in the GLP-1 RA class in terms of their structure, pharmacological profiles, efficacy, safety, and convenience. Search Methodology: A literature search was conducted using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide. Relevant articles were those that discussed structural, pharmacokinetic and pharmacodynamic differences, classification, long-acting and short-acting GLP-1 RAs, phase 3 trials, and expert opinions. Additional targeted searches were conducted on diabetes treatment guidelines and reviews on safety, as well as the American Diabetes Association/European Society for Study of Diabetes (ADA/EASD statement on pancreatic safety.

  2. Glucagon-like peptide-1 receptor agonists in the treatment of type 2 diabetes: Past, present, and future.

    Science.gov (United States)

    Kalra, Sanjay; Baruah, Manash P; Sahay, Rakesh K; Unnikrishnan, Ambika Gopalakrishnan; Uppal, Shweta; Adetunji, Omolara

    2016-01-01

    Glucagon-like peptide-1 (GLP-1)-based therapy improves glycaemic control through multiple mechanisms, with a low risk of hypoglycaemia and the additional benefit of clinically relevant weight loss. Since Starling and Bayliss first proposed the existence of intestinal secretions that stimulate the pancreas, tremendous progress has been made in the area of incretins. As a number of GLP-1 receptor agonists (GLP-1 RAs) continue to become available, physicians will soon face the challenge of selecting the right option customized to their patient's needs. The following discussion, derived from an extensive literature search using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide, provides a comprehensive review of existing and upcoming molecules in the GLP-1 RA class in terms of their structure, pharmacological profiles, efficacy, safety, and convenience. Search Methodology: A literature search was conducted using the PubMed database, applying the terms incretin, GLP-1, exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and taspoglutide. Relevant articles were those that discussed structural, pharmacokinetic and pharmacodynamic differences, classification, long-acting and short-acting GLP-1 RAs, phase 3 trials, and expert opinions. Additional targeted searches were conducted on diabetes treatment guidelines and reviews on safety, as well as the American Diabetes Association/European Society for Study of Diabetes (ADA/EASD) statement on pancreatic safety.

  3. Brain glucagon-like peptide–1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

    Science.gov (United States)

    Knauf, Claude; Cani, Patrice D.; Perrin, Christophe; Iglesias, Miguel A.; Maury, Jean François; Bernard, Elodie; Benhamed, Fadilha; Grémeaux, Thierry; Drucker, Daniel J.; Kahn, C. Ronald; Girard, Jean; Tanti, Jean François; Delzenne, Nathalie M.; Postic, Catherine; Burcelin, Rémy

    2005-01-01

    Intestinal glucagon-like peptide–1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9–39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state. PMID:16322793

  4. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage.

    Science.gov (United States)

    Knauf, Claude; Cani, Patrice D; Perrin, Christophe; Iglesias, Miguel A; Maury, Jean François; Bernard, Elodie; Benhamed, Fadilha; Grémeaux, Thierry; Drucker, Daniel J; Kahn, C Ronald; Girard, Jean; Tanti, Jean François; Delzenne, Nathalie M; Postic, Catherine; Burcelin, Rémy

    2005-12-01

    Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

  5. Serum levels of glucagon-like peptide (GLP-1 and GLP-2 in patients with Hashimoto′s thyroiditis

    Directory of Open Access Journals (Sweden)

    Yue Jin

    2015-01-01

    Full Text Available Background: The influence of Hashimoto′s thyroiditis (HT with subclinical hypothyroidism or euthyroid status on the alteration of glucagon-like peptide (GLP-1 and GLP-2 levels remains uncertain. Materials and Methods: Twenty-four untreated HT patients with subclinical hypothyroidism, 24 euthyroid HT patients, and 24 age- and gender-matched controls were enrolled in the study. The levels of GLP-1, GLP-2, glucose, glycated albumin, insulin, thyroid hormone, and thyroid autoantibodies were measured and evaluated. Results: The levels of GLP-1, blood glucose, and triglyceride were higher in HT patients with subclinical hypothyroidism than in controls (all P < 0.05, respectively. However, the above variables, including GLP-2, were similar in euthyroid patients and controls. Neither GLP-1 nor GLP-2 was correlated with thyroid hormone, thyroid autoantibodies or metabolic parameters. Conclusion: The serum levels of GLP-1, not GLP-2, were increased in patients with subclinical hypothyroidism. Our data suggest that subclinical hypothyroidism affects circulating GLP-1 levels.

  6. Diuretic and Natriuretic Effects of Dipeptidyl Peptidase-4 Inhibitor Teneligliptin: The Contribution of Glucagon-like Peptide-1.

    Science.gov (United States)

    Moroi, Masao; Kubota, Tetsuya

    2015-08-01

    Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents; however, their mechanisms of action are different. GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they regulate Na reabsorption. We investigated whether the DPP-4 inhibitor, teneligliptin, has diuretic and natriuretic effects and whether these are associated with the stimulation of the GLP-1R in rats. Oral administration of teneligliptin resulted in a reduction of plasma DPP-4 activity over 6 hours, as well as an induction of diuresis and natriuresis. Although teneligliptin did not change the increase in blood glucose levels by glucose loading, percentage of urine volume and Na/K ratio with teneligliptin to vehicle were augmented by glucose loading. Peak levels of plasma GLP-1 did not change after oral administration of teneligliptin when glucose was not loaded but increased at least 2-fold with glucose loading. Furthermore, the natriuretic effect of teneligliptin was inhibited by the GLP-1R antagonist, exendin9-39, whereas the diuresis was not affected. These results suggest that the mechanism of natriuresis was different from that of diuresis, and the natriuresis is associated with the stimulation of GLP-1R. There may be mechanistic differences in DPP-4 inhibition between diuresis and natriuresis.

  7. Glucagon-like peptide-2 but not imipramine exhibits antidepressant-like effects in ACTH-treated mice.

    Science.gov (United States)

    Iwai, Takashi; Ohnuki, Tomoko; Sasaki-Hamada, Sachie; Saitoh, Akiyoshi; Sugiyama, Azusa; Oka, Jun-Ichiro

    2013-04-15

    We investigated the effectiveness of glucagon-like peptide-2 (GLP-2) against refractory depression in adrenocorticotropic hormone (ACTH)-treated mice as a model of tricyclic antidepressant (TCA)-resistant depression. Chronic ACTH treatment (0.45 mg/kg, s.c., 14 days) weakened the antidepressant-like effects of imipramine (20 mg/kg, i.p., 6 days) in the forced-swim test (FST). Conversely, GLP-2 (3 μg/mice, i.c.v., 6 days) induced antidepressant-like effects in the ACTH-treated mice in the FST. ACTH-treatment increased basal serum corticosterone levels, with an additional increase induced by the FST. Imipramine or GLP-2 had no effect on the basal corticosterone level, but GLP-2 attenuated the additional increase caused by the FST. Moreover, GLP-2 increased 5-HT levels, but not 5-HIAA. These results suggest that GLP-2 induced antidepressant-like effects under imipramine-resistant conditions through increase in 5-HT levels.

  8. The influence of restricted feeding on glucagon-like peptide-1 (GLP-1)-containing cells in the chicken small intestine.

    Science.gov (United States)

    Monir, M M; Hiramatsu, K; Yamasaki, A; Nishimura, K; Watanabe, T

    2014-04-01

    The influence of restricted feeding on the distribution of glucagon-like peptide-1 (GLP-1)-containing endocrine cells in the chicken small intestine was investigated using immunohistochemical and morphometrical techniques. This study demonstrated that the restricted feeding had an influence on the activity of GLP-1-immunoreactive cells in the chicken small intestine. There were differences in the localization and the frequency of occurrence of GLP-1-immunoreactive cells in the small intestine between control and restricted groups, especially 25% feed supply group provided with 25% of the intake during the adapting period. GLP-1-immunoreactive cells in the control chickens were mainly located in epithelium from crypts to the lower part of intestinal villi. Those in restricted groups, however, tended to be located from crypts to the middle part of intestinal villi. The frequency of occurrence of GLP-1-immunoreactive cells was lowest in the control group, medium in 50% feed supply group and highest in 25% feed supply group at each intestinal region examined in this study, that is, increased with the advancement of restricting the amount of feed supply. These data show that the quantity of food intake is one of signals that have an influence on the secretion of GLP-1 from L cells in the chicken small intestine.

  9. An Emerging Role of Glucagon-Like Peptide-1 in Preventing Advanced-Glycation-End-Product-Mediated Damages in Diabetes

    Directory of Open Access Journals (Sweden)

    Alessandra Puddu

    2013-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a gut hormone produced in the intestinal epithelial endocrine L cells by differential processing of the proglucagon gene. Released in response to the nutrient ingestion, GLP-1 plays an important role in maintaining glucose homeostasis. GLP-1 has been shown to regulate blood glucose levels by stimulating glucose-dependent insulin secretion and inhibiting glucagon secretion, gastric emptying, and food intake. These antidiabetic activities highlight GLP-1 as a potential therapeutic molecule in the clinical management of type 2 diabetes, (a disease characterized by progressive decline of beta-cell function and mass, increased insulin resistance, and final hyperglycemia. Since chronic hyperglycemia contributed to the acceleration of the formation of Advanced Glycation End-Products (AGEs, a heterogeneous group of compounds derived from the nonenzymatic reaction of reducing sugars with free amino groups of proteins implicated in vascular diabetic complications, the administration of GLP-1 might directly counteract diabetes pathophysiological processes (such as pancreatic β-cell dysfunction. This paper outlines evidence on the protective role of GLP-1 in preventing the deleterious effects mediated by AGEs in type 2 diabetes.

  10. Potential roles of glucagon-like peptide-1-based therapies in treating non-alcoholic fatty liver disease.

    Science.gov (United States)

    Liu, Ye; Wei, Rui; Hong, Tian-Pei

    2014-07-21

    Glucagon-like peptide-1 (GLP-1)-based therapies have demonstrated efficacy and safety in treating type 2 diabetes, which shares a similar pathophysiological mechanism with non-alcoholic fatty liver disease (NAFLD). Recent studies showed that glucose-induced GLP-1 secretion was decreased in patients with NAFLD and that the level of dipeptidyl peptidase-4, which inactivates intact GLP-1, was upregulated. Moreover, the expression of the GLP-1 receptor was downregulated in livers from patients with NAFLD, indicating an association of defective GLP-1 signalling with NAFLD. Notably, GLP-1-based therapies are reported to be effective in improving hepatic endpoints in patients with NAFLD, such as reducing hepatic fat content, hepatic steatosis and plasma transaminase levels, and preventing fibrosis. GLP-1-based therapies are beneficial for body weight control and glycaemic normalisation, which are important for the management of NAFLD. Moreover, clinical and preclinical studies showed that GLP-1-based agents might directly exert their actions on the liver through activation of functional GLP-1 receptors in hepatocytes. The possible mechanisms involve regulating gene expression that is associated with insulin resistance and lipid metabolism, and suppressing oxidative stress in the liver cells, thus preventing the development and progression of NAFLD. Based on these promising data, large-scale randomised controlled trials are warranted to assess the efficacy and safety of GLP-1-based therapies in treating NAFLD.

  11. Dietary Mannoheptulose Increases Fasting Serum Glucagon Like Peptide-1 and Post-Prandial Serum Ghrelin Concentrations in Adult Beagle Dogs.

    Science.gov (United States)

    McKnight, Leslie L; Eyre, Ryan; Gooding, Margaret A; Davenport, Gary M; Shoveller, Anna Kate

    2015-06-16

    There is a growing interest in the use of nutraceuticals for weight management in companion animals. The purpose of this study was to determine the effects of mannoheptulose (MH), a sugar in avocados that inhibits glycolysis, on energy metabolism in adult Beagle dogs. The study was a double-blind, randomized controlled trial where dogs were allocated to a control (CON, n = 10, 10.1 ± 0.4 kg) or MH containing diet (168 mg/kg, n = 10, 10.3 ± 0.4 kg). Blood was collected after an overnight fast and 1 h post-feeding (week 12) to determine serum satiety related hormones and biochemistry. Resting and post-prandial energy expenditure and respiratory quotient were determined by indirect calorimetry (weeks 4 and 8). Physical activity was measured using an accelerometer (weeks 3, 7, 11). Body composition was assessed using dual X-ray absorptiometry (week 12). MH significantly (p < 0.05) increased fasting serum glucagon-like peptide-1 and post-prandial serum ghrelin. MH tended (p < 0.1) to increase fasting serum gastric inhibitory peptide and decrease physical activity. Together, these findings suggest that dietary MH has the ability to promote satiation and lowers daily energy expenditure.

  12. The Antidiabetic Mechanisms of Polyphenols Related to Increased Glucagon-Like Peptide-1 (GLP1 and Insulin Signaling

    Directory of Open Access Journals (Sweden)

    J. Abraham Domínguez Avila

    2017-05-01

    Full Text Available Type-2 diabetes mellitus (T2DM is an endocrine disease related to impaired/absent insulin signaling. Dietary habits can either promote or mitigate the onset and severity of T2DM. Diets rich in fruits and vegetables have been correlated with a decreased incidence of T2DM, apparently due to their high polyphenol content. Polyphenols are compounds of plant origin with several documented bioactivities related to health promotion. The present review describes the antidiabetic effects of polyphenols, specifically related to the secretion and effects of insulin and glucagon-like peptide 1 (GLP1, an enteric hormone that stimulates postprandial insulin secretion. The evidence suggests that polyphenols from various sources stimulate L-cells to secrete GLP1, increase its half-life by inhibiting dipeptidyl peptidase-4 (DPP4, stimulate β-cells to secrete insulin and stimulate the peripheral response to insulin, increasing the overall effects of the GLP1-insulin axis. The glucose-lowering potential of polyphenols has been evidenced in various acute and chronic models of healthy and diabetic organisms. Some polyphenols appear to exert their effects similarly to pharmaceutical antidiabetics; thus, rigorous clinical trials are needed to fully validate this claim. The broad diversity of polyphenols has not allowed for entirely describing their mechanisms of action, but the evidence advocates for their regular consumption.

  13. Glucagon-Like Peptide-1 Triggers Protective Pathways in Pancreatic Beta-Cells Exposed to Glycated Serum

    Directory of Open Access Journals (Sweden)

    Alessandra Puddu

    2013-01-01

    Full Text Available Advanced glycation end products (AGEs might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1, an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs, in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid-derived 2 (Nrf2, glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS.

  14. Teduglutide, a glucagon-like peptide-2 analog for the treatment of gastrointestinal diseases, including short bowel syndrome.

    Science.gov (United States)

    Yazbeck, Roger

    2010-12-01

    Glucagon-like peptide-2 (GLP-2) is a potent intestinotrophic growth factor with therapeutic potential for the prevention or treatment of an expanding number of gastrointestinal diseases, including short bowel syndrome (SBS). Teduglutide, being developed by NPS Allelix and licensee Nycomed, is a protease-resistant analog of GLP-2 for the potential treatment of gastrointestinal disease. Teduglutide has prolonged biological activity compared with native GLP-2, and preclinical studies demonstrated significant intestinotrophic activity in models of SBS, experimental colitis and chemotherapy-induced intestinal mucositis. Patients with SBS rely on parenteral nutrition (PN) following bowel resection, and in a phase III clinical trial with teduglutide, > 20% reduction in PN was observed in patients with SBS receiving teduglutide. A phase II clinical trial for teduglutide in Crohn's disease observed remission rates of 55.6% in patients. At the time of publication, phase III clinical trials for SBS were ongoing, as were preclinical studies for chemotherapy-induced mucositis and pediatric indications. Teduglutide represents a novel, efficacious drug capable of increasing intestinal growth and improving intestinal function, and may change clinical management of intestinal disease and damage.

  15. Glucagon-like peptide (GLP-1) is involved in the central modulation of fecal output in rats.

    Science.gov (United States)

    Gülpinar, M A; Bozkurt, A; Coşkun, T; Ulusoy, N B; Yegen, B C

    2000-06-01

    In addition to its insulinotropic action, exogenously administered glucagon-like peptide (GLP-1) inhibits gastropancreatic motility and secretion via central pathways. The aims of the present study were to evaluate the effects of exogenous GLP-1-(7-36) amide on fecal output and to investigate the role of endogenous GLP-1 on stress-induced colonic activity. With the use of a stereotaxic instrument, adult male Sprague-Dawley rats weighing 200-250 g were fitted with stainless steel cerebroventricular guide cannulas under ketamine anesthesia. A group of rats were placed in Bollman-type cages to induce restraint stress. Fecal output monitored for 2 h was increased significantly by intracerebroventricular GLP-1 to 500, 1, 000, and 3,000 pmol/rat (P corticotropin-releasing factor receptor antagonist astressin (10 microg/rat icv). The significant increase in fecal pellet output induced by restraint stress was also decreased by both intracerebroventricular exendin (10 nmol/rat) and astressin (10 microg/rat; Pmotility via its own receptor and that GLP-1 is likely to be a candidate brain-gut peptide that acts as a physiological modulator of stress-induced colonic motility.

  16. Glucagon-Like Peptide-1 Analog, Liraglutide, Delays Onset of Experimental Autoimmune Encephalitis in Lewis Rats

    DEFF Research Database (Denmark)

    DellaValle, Brian; Brix, Gitte S; Brock, Birgitte

    2016-01-01

    the experimental model, experimental autoimmune encephalitis (EAE). Methods: EAE was induced in 30 female Lewis rats that subsequently received twice-daily liraglutide (200 μg/kg s.c.) or saline. Healthy controls were included (saline, n = 6, liraglutide, n = 7). Clinical score and weight were assessed daily...... by blinded observers. Animals were killed at peak disease severity (day 11) or if exceeding humane endpoint (clinical score ≥4). Protein levels of manganese superoxide dismutase (MnSOD), amyloid precursor protein (APP), and glial fibrillary acidic protein (GFAP) were determined. Results: Liraglutide......, that liraglutide treatment delays onset of EAE in Lewis rats and is associated with improved protective capacity against oxidative stress. These data suggest GLP-1 receptor agonists should be investigated further as a potential therapy for MS....

  17. Levofloxacin plus metronidazole administered once daily versus moxifloxacin monotherapy against a mixed infection of Escherichia coli and Bacteroides fragilis in an in vitro pharmacodynamic model.

    Science.gov (United States)

    Hermsen, Elizabeth D; Hovde, Laurie B; Sprandel, Kelly A; Rodvold, Keith A; Rotschafer, John C

    2005-02-01

    Moxifloxacin has been suggested as an option for monotherapy of intra-abdominal infections. Recent data support the use of a once-daily metronidazole regimen. The purpose of this study was to investigate the activity of levofloxacin (750 mg every 24 h [q24h]) plus metronidazole (1,500 mg q24h) compared with that of moxifloxacin (400 mg q24h) monotherapy in a mixed-infection model. By using an in vitro pharmacodynamic model in duplicate, Escherichia coli and Bacteroides fragilis were exposed to peak concentrations of 8.5 mg of levofloxacin/liter q24h, 32 mg of metronidazole/liter q24h, and 2 mg for moxifloxacin/liter q24h for 24 h. The activities of levofloxacin, metronidazole, moxifloxacin, and levofloxacin plus metronidazole were evaluated against E. coli, B. fragilis, and E. coli plus B. fragilis. The targeted half-lives of levofloxacin, metronidazole, and moxifloxacin were 8, 8, and 12 h, respectively. Time-kill curves were analyzed for time to 3-log killing, slope, and regrowth. Pre- and postexposure MICs were determined. The preexposure levofloxacin, metronidazole, and moxifloxacin MICs for E. coli and B. fragilis were 0.5 and 1, >64 and 0.5, and 1 and 0.25 mg/liter, respectively. Levofloxacin and moxifloxacin achieved a 3-log killing against E. coli and B. fragilis in all experiments, as did metronidazole against B. fragilis. Metronidazole did not decrease the starting inoculum of E. coli. The area under the concentration-time curve/MIC ratios for E. coli and B. fragilis were 171.7 and 85.9, respectively, for levofloxacin and 26 and 103.9, respectively, for moxifloxacin. Levofloxacin plus metronidazole exhibited the fastest rates of killing. The levofloxacin and moxifloxacin MICs for B. fragilis increased 8- to 16-fold after the organism was exposed to moxifloxacin. No other changes in the postexposure MICs were found. Levofloxacin plus metronidazole administered once daily exhibited activity similar to that of moxifloxacin against the mixed E. coli and B

  18. Increased adherence eight months after switch from twice daily calcineurin inhibitor based treatment to once daily modified released tacrolimus in heart transplantation

    Directory of Open Access Journals (Sweden)

    Doesch AO

    2013-10-01

    Full Text Available Andreas O Doesch,1 Susanne Mueller,1 Ceylan Akyol,1 Christian Erbel,1 Lutz Frankenstein,1 Arjang Ruhparwar,2 Philipp Ehlermann,1 Thomas J Dengler,3 Hugo A Katus11Department of Cardiology, University of Heidelberg, Heidelberg, Germany; 2Department of Cardiovascular Surgery, University of Heidelberg, Heidelberg, Germany; 3Department of Cardiology, SLK-Kliniken Heilbronn, Bad Friedrichshall, GermanyBackground: Modified-release tacrolimus (TAC is a new, once-daily oral formulation of the established immunosuppressive agent TAC. This study evaluated long-term patient adherence, as well as safety and efficacy, in stable patients after heart transplantation (HTx who switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA] to a once-daily modified-release TAC regimen.Methods: Stable patients were switched from conventional TAC or CsA (twice-daily dosing to modified-release TAC (once-daily dosing according to manufacturer's recommendations using a pre-experimental design. Self-reported adherence was assessed at baseline and 8 months after the switch with the Basel Assessment of Adherence with Immunosuppressive Medication Scale (BAASIS. Additionally, routine laboratory values were analyzed 8 months after switch.Results: Of 76 patients (58 male, 18 female initially included, 72 were available for statistical analysis, as modified-release TAC was discontinued due to diarrhea in one patient and gastrointestinal discomfort in three patients. Overall nonadherence at baseline for any of the four BAASIS items was 75.0% versus 40.3% after 8 months (P<0.0001. After 8 months, adherence was improved in 41 patients (56.9%, unchanged in 27 (37.5%, and reduced in four patients (5.6%. The BAASIS visual analog scale score improved significantly from 87.0% ± 13.5% to 97.5% ± 5.7% (P<0.0001. No significant changes were observed for hematological, renal, or liver function parameters after 8 months (all P=not significant

  19. Steady-state pharmacokinetics of once-daily cyclobenzaprine extended release: a randomized, double-blind, 2-period crossover study in healthy volunteers.

    Science.gov (United States)

    Darwish, Mona; Hellriegel, Edward T

    2011-06-01

    The single-dose pharmacokinetic profile of cyclobenzaprine extended-release (CER) has been previously characterized and compared with the pharmacokinetics of cyclobenzaprine immediate-release (CIR) administered 3 times daily for 3 doses. The objective of this study was to characterize the multiple-dose pharmacokinetic properties of once-daily CER 30 mg and CIR 10 mg TID formulations in healthy volunteers. In this double-blind, single-center, 2-period crossover study, healthy subjects were randomized to dosing sequences with once-daily CER 30 mg or CIR 10 mg TID for 7 days. Subjects crossed over to the alternative regimen following a 14-day washout period. Pharmacokinetic assessments at steady state included area under the plasma cyclobenzaprine concentration-time curve over the dosing interval (AUC(0-τ,ss)), peak plasma cyclobenzaprine concentration (C(max,ss)), time to observed C(max) (T(max,ss)), observed minimum cyclobenzaprine concentration (C(min,ss)), average cyclobenzaprine concentration (C(avg,ss)), accumulation ratio (R(ac)), and terminal elimination half-life (t(½)). Tolerability and safety assessments were conducted. A total of 36 subjects were randomized; 34 completed both dosing periods (1 subject was lost to follow-up, 1 withdrew consent). Steady state was reached for CER 30 mg on day 7. Mean C(max,ss), C(min,ss), and C(avg,ss) were 41.1, 21.4, and 31.4 ng/mL, respectively. The median T(max,ss) for CER 30 mg was 7.0 hours, with a mean t(½) of 34.8 hours. At steady state, CER produced a sustained plasma cyclobenzaprine concentration with a single peak in plasma concentration during the 24-hour dose interval. The R(ac) for CER was 2.65. Because of a protocol violation (insufficient data), no steady-state pharmacokinetic assessments could be performed for CIR. Most adverse events were mild or moderate in intensity. Somnolence was the most frequently reported adverse event (100% of subjects) in those receiving CER, followed by dry mouth (58

  20. Glucagon-like peptide-1 secretion is influenced by perfusate glucose concentration and by a feedback mechanism involving somatostatin in isolated perfused porcine ileum

    DEFF Research Database (Denmark)

    Hansen, Lene; Hartmann, Bolette; Mineo, Hitoshi;

    2004-01-01

    Glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells in response to ingestion of meals. The mechanisms regulating its secretion are not clear, but local somatostatin (SS) restrains GLP-1 secretion. We investigated feedback and substrate regulation of GLP-1 and SS secretion, using...... the effect of proglucagon products, glucagon (10 nM), GLP-1 and GLP-2 (0.1, 1, and 10 nM) on GLP-1 and SS secretion, as well as on glucagon-like peptide-2 (GLP-2), peptide YY (PYY) and GIP secretion, all possible product of L-cells or neighbour cells. Perfusate glucose concentration dose......-dependently stimulated GLP-1 secretion (p=0.011). Insulin had no effect. Glucagon weakly stimulated GIP secretion. GLP-1 stimulated SS secretion and motor activity, but inhibited GLP-2, GIP and PYY secretion and perfusion pressure. GLP-2 weakly stimulated SS secretion. We conclude (a) that GLP-1 secretion is influenced...

  1. A novel once daily microparticulate dosage form comprising lansoprazole to prevent nocturnal acid breakthrough in the case of gastro-esophageal reflux disease: preparation, pharmacokinetic and pharmacodynamic evaluation.

    Science.gov (United States)

    Alai, Milind; Lin, Wen Jen

    2013-01-01

    The objective of this study was to formulate and evaluate the lansoprazole (LPZ)-loaded microparticles to prevent nocturnal acid breakthrough in the case of gastro-esophageal reflux disease (GERD). The microparticulate delivery system was prepared by solvent evaporation method using Eudragit RS100 as a matrix polymer followed by enteric coated with Eudragit S100 and hydroxypropyl methylcellulose phthalate HP55 using spray drying method. The enteric coated microparticles were stable in gastric pH condition. In vivo pharmacokinetic and pharmacodynamic studies in male Wistar rats demonstrated that enteric coated microparticles sustained release of LPZ and promoted ulcer healing activity. In other words, the microparticulate dosage form provided effective drug concentration for a longer period as compared to conventional extended release dosage form, and showed sufficient anti-acid secretion activity to treat acid related disorders including the enrichment of nocturnal acid breakthrough event based on a once daily administration.

  2. A Prospective Open-Label Multicentre Trial on the Use of 1 G, Once Daily Ceftriaxone in Lower Respiratory Tract Infections

    Directory of Open Access Journals (Sweden)

    Donald E Low

    1994-01-01

    in the study. Clinical cure and clinical improvement were achieved in 64.6 and 28.3% of the evaluable patients. respectively. Relapse of infection occurred in two patients (1.8%. and treatment failure was recorded in six cases (5.3%. Twelve patients (8.8% died clue to reasons unrelated to the sludy treatment. Three adverse event (hives, diarrhea and phlebitis at the injection site were possibly related to the study drug. A cross-Canada in vitro susceptibility surveillance study of bacterial pathogens. frequently the cause of pneumonia. found ceftriaxone to have minimal inhibitory concentrations in 90% of isolates that would support such a dosing regimen. with the exception of Enterobacter species. These rcsults support the use of 1 g, once daily ceftriaxone for the empirical treatment of pneumonia in those patients requiring hospitalization.

  3. [Effects of once-daily low-dose administration of sustained-release theophylline on airway inflammation and airway hyperresponsiveness in patients with asthma].

    Science.gov (United States)

    Terao, Ichiro

    2002-04-01

    Bronchial asthma is eosinophilic airway inflammation with enhanced airway responsiveness induced by eosinophilic granule proteins such as eosinophilic cationic protein (ECP) that are released from eosinophils. In the present study using 30 outpatients with mild to moderate asthma who had no history of treatment with steroid inhalation, we examined the effects of 4-week low-dose (200 mg/day) treatment with Uniphyl Tablets, a sustained-release theophylline formulated for once-daily dosing, on airway inflammation and airway hyperresponsiveness, as well as on respiratory function. Uniphyl Tablets significantly (p statistically significant (p V50 also showed statistically significant (p < 0.05) improvement. Mean blood theophylline concentration at the time the improvements were seen was 3.95 mg/mL. These results suggest that low-dose administration of Uniphyl Tablets has anti-airway inflammatory and anti-airway hyperresponsiveness effects in mild to moderate asthmatic patients.

  4. Solid phase synthesis of fatty acid modified glucagon-like peptide-1(7-36) amide under thermal and controlled microwave irradiation

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Fatty acid modified glucagon-like peptide-1(7-36) amide was synthesized efficiently on Rink-Amide-MBHA resin by microwave-assisted solid phase method.The method of thermal and controlled microwave irradiation provided impressive enhancements in product yield,selectivity,and reaction rate.The coupling time was dramatically decreased to 6 min,and the desired products were obtained in high yield and purity.

  5. The effect of Glucagon-Like Peptide-2 on mesenteric blood flow and cardiac parameters in end-jejunostomy short bowel patients

    DEFF Research Database (Denmark)

    Bremholm, Lasse; Hornum, Mads; Andersen, Ulrik B;

    2011-01-01

    Exogenous Glucagon-Like Peptide-2 (GLP-2) treatment improves intestinal wet weight absorption in short bowel syndrome (SBS) patients. In healthy subjects, administration of GLP-2 increases small intestinal blood flow. The aim of the study was to evaluate the effect of GLP-2 on mesenteric blood flow...... and dynamic changes in cardiac parameters in SBS patients with jejunostomy and varying length of remnant small intestine....

  6. The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

    OpenAIRE

    2011-01-01

    The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason...

  7. Exogenous glucagon-like peptide-2 (GLP-2) augments GLP-2 receptor mRNA and maintains proglucagon mRNA levels in resected rats

    DEFF Research Database (Denmark)

    Koopmann, Matthew C; Nelson, David W; Murali, Sangita G;

    2008-01-01

    BACKGROUND: Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent proglucagon-derived hormone that stimulates intestinal adaptive growth. Our aim was to determine whether exogenous GLP-2 increases resection-induced adaptation without diminishing endogenous proglucagon and GLP-2 receptor...... augments adaptive growth and digestive capacity of the residual small intestine in a rat model of mid-small bowel resection by increasing plasma GLP-2 concentrations and GLP-2 receptor expression without diminishing endogenous proglucagon expression....

  8. The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion

    DEFF Research Database (Denmark)

    El-Ouaghlidi, Andrea; Rehring, Erika; Holst, Jens Juul

    2007-01-01

    BACKGROUND/AIMS: Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hy...... of glibenclamide is not accentuated by the coadministration of vildagliptin. This may be explained by a negative feedback regulation of GLP-1 and GIP secretion that limits the degree to which the active incretin levels are enhanced....

  9. Short-term administration of glucagon-like peptide-2. Effects on bone mineral density and markers of bone turnover in short-bowel patients with no colon

    DEFF Research Database (Denmark)

    Haderslev, K V; Jeppesen, P B; Hartmann, B

    2002-01-01

    Glucagon-like peptide 2 (GLP-2) is a newly discovered intestinotrophic hormone. We have recently reported that a 5-week GLP-2 treatment improved the intestinal absorptive capacity of short-bowel patients with no colon. Additionally, GLP-2 treatment was associated with changes in body composition ...... that included a significant increase in total body bone mass. This article describes the effect of GLP-2 on spinal and hip bone mineral density (BMD) and biochemical markers of bone turnover in these patients....

  10. Legal, ethical, and economic implications of breaking down once-daily fixed-dose antiretroviral combinations into their single components for cost reduction.

    Science.gov (United States)

    Ramiro, Miguel A; Llibre, Josep M

    2014-11-01

    The availability of generic lamivudine in the context of the current economic crisis has raised a new issue in some European countries: breaking up the once-daily fixed-dose antiretroviral combinations (FDAC) of efavirenz/tenofovir/emtricitabine, tenofovir/emtricitabine, or abacavir/lamivudine, in order to administer their components separately, thereby allowing the use of generic lamivudine instead of branded emtricitabine or lamivudine. The legal, ethical, and economic implications of this potential strategy are reviewed, particularly in those patients receiving a once-daily single-tablet regimen. An unfamiliar change in antiretroviral treatment from a successful patient-friendly FDAC into a more complex regimen including separately the components to allow the substitution of one (or some) of them for generic surrogates (in the absence of a generic bioequivalent FDAC) could be discriminatory because it does not guarantee access to equal excellence in healthcare to all citizens. Furthermore, it could violate the principle of non-maleficence by potentially causing harm both at the individual level (hindering adherence and favouring treatment failure and resistance), and at the community level (hampering control of disease transmission and transmission of HIV-1 resistance). Replacing a FDAC with the individual components of that combination should only be permitted when the substituting medication has the same qualitative and quantitative composition of active ingredients, pharmaceutical form, method of administration, dosage and presentation as the medication being replaced, and a randomized study has demonstrated its non-inferiority. Finally, a strict pharma-economic study supporting this change, comparing the effectiveness and the cost of a specific intervention with the best available alternative, should be undertaken before its potential implementation.

  11. Effectiveness and tolerance of single tablet versus once daily multiple tablet regimens as first-line antiretroviral therapy - Results from a large french multicenter cohort study

    Science.gov (United States)

    Cotte, Laurent; Ferry, Tristan; Pugliese, Pascal; Valantin, Marc-Antoine; Allavena, Clotilde; Cabié, André; Poizot-Martin, Isabelle; Rey, David; Duvivier, Claudine; Cheret, Antoine; Dellamonica, Pierre; Pradat, Pierre; Parienti, Jean-Jacques

    2017-01-01

    Objectives Pill burden during antiretroviral treatment (ART) is associated with worse adherence and impaired virological suppression. We compared the effectiveness, tolerance, and persistence on treatment of single tablet regimens (STRs) with non-STR once-daily regimens in patients receiving first-line ART. Methods Retrospective analysis of naïve HIV-1 infected patients prospectively enrolled in the French Dat’AIDS cohort and initiating first-line ART with STRs or once-daily non-STRs from 2004 to 2013. The primary outcome was time to treatment discontinuation defined by any change in the treatment regimen. STR and non-STR groups were compared controlling for baseline risk factors by inverse probability weighted treatment Cox analysis (IPWT) and propensity-score matching (PSM). Results Overall, 3212 patients (STR 499, non-STR 2713) were included. Median time to treatment discontinuation was shorter in non-STR patients than in STR patients, both in the IPWT (HR = 0.61, pPSM cohort (HR = 0.55, pPSM cohort (HR = 0.91, p = 0.33). A lower rate of virological failure was observed with STRs than with non-STRs in both cohorts (HR = 0.23; p = 0.002 and HR = 0.22, p = 0.003, respectively). A lower rate of treatment modification for adverse event was observed with non-STRs in the IPWT cohort (HR = 1.46, pPSM cohort (HR = 1.22, p = 0.11). Conclusion First-line therapy with STRs was associated with a longer time to treatment discontinuation than with non-STRs. However, when ART modification for simplification was not considered as a failure, STRs and non-STRs were similar. PMID:28152047

  12. Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy

    Directory of Open Access Journals (Sweden)

    Albertson TE

    2016-12-01

    Full Text Available Timothy E Albertson,1–3 Samuel W Bullick,1,3 Michael Schivo,1 Mark E Sutter2,3 1Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, 2Department of Emergency Medicine, School of Medicine, UC Davis, Sacramento, 3Department of Medicine, Veterans Administration Northern California Health Care System, Mather, CA, USA Abstract: The use of inhaled corticosteroids (ICSs plays a key role in the treatment of asthmatic patients, and international guidelines have designated ICSs as an early maintenance therapy in controlling asthma symptoms. When asthmatic patients remain symptomatic on ICSs, one common option is to add a long-acting beta2 agonist (LABA to the maintenance treatment. Fixed combination inhalers that contain both an ICS and a LABA have been popular for both chronic obstructive pulmonary disease (COPD and asthma. Historically, these inhalers have been dosed twice daily. However, currently, there is a once-daily combination therapy with the ICS fluticasone furoate (FF and the LABA vilanterol trifenatate (VI with indications for use in both COPD and asthma. This dry powder inhaler (DPI comes in two doses of FF (100 or 200 µg both combined with VI (25 µg. This article reviews the clinical trial data for FF, VI and FF/VI combination inhalers and documents the efficacy and safety of once-daily inhaled maintenance therapy by DPI in asthmatic patients. Keywords: fluticasone furoate/vilanterol trifenatate, asthma, long-acting beta2 agonist, inhaled corticosteroid, combined inhaler, persistent asthma, dry powder inhaler  

  13. Indirect effects of glucagon-like peptide-1 receptor agonist exendin-4 on the peripheral circadian clocks in mice.

    Science.gov (United States)

    Ando, Hitoshi; Ushijima, Kentarou; Fujimura, Akio

    2013-01-01

    Circadian clocks in peripheral tissues are powerfully entrained by feeding. The mechanisms underlying this food entrainment remain unclear, although various humoral and neural factors have been reported to affect peripheral clocks. Because glucagon-like peptide-1 (GLP-1), which is rapidly secreted in response to food ingestion, influences multiple humoral and neural signaling pathways, we suggest that GLP-1 plays a role in the food entrainment of peripheral clocks. To test this, we compared the effects of exendin-4, a GLP-1 receptor agonist, on mRNA expression of the clock genes (Clock, Bmal1, Nr1d1, Per1, Per2, and Cry1) with those of refeeding. In addition, we investigated whether exendin-4 could affect the rhythms of the peripheral clocks. In male C57BL/6J mice, although refeeding rapidly (within 2 h) altered mRNA levels of Per1 and Per2 in the liver and that of Per1 in adipose tissue, a single i.p. injection of exendin-4 did not cause such changes. However, unlike the GLP-1 receptor antagonist exendin-(9-39), exendin-4 significantly influenced Per1 mRNA levels in the liver at 12 h after injection. Moreover, pretreatment with exendin-4 affected the rapid-feeding-induced change in Per1 not only in the liver, but also in adipose tissue, without effect on food intake. Furthermore, during light-phase restricted feeding, repeated dosing of exendin-4 at the beginning of the dark phase profoundly influenced both the food intake and daily rhythms of clock gene expression in peripheral tissues. Thus, these results suggest that exendin-4 modulates peripheral clocks via multiple mechanisms different from those of refeeding.

  14. Neural effects of gut- and brain-derived glucagon-like peptide-1 and its receptor agonist.

    Science.gov (United States)

    Katsurada, Kenichi; Yada, Toshihiko

    2016-04-01

    Glucagon-like peptide-1 (GLP-1) is derived from both the enteroendocrine L cells and preproglucagon-expressing neurons in the nucleus tractus solitarius (NTS) of the brain stem. As GLP-1 is cleaved by dipeptidyl peptidase-4 yielding a half-life of less than 2 min, it is plausible that the gut-derived GLP-1, released postprandially, exerts its effects on the brain mainly by interacting with vagal afferent neurons located at the intestinal or hepatic portal area. GLP-1 neurons in the NTS widely project in the central nervous system and act as a neurotransmitter. One of the physiological roles of brain-derived GLP-1 is restriction of feeding. GLP-1 receptor agonists have recently been used to treat type 2 diabetic patients, and have been shown to exhibit pleiotropic effects beyond incretin action, which involve brain functions. GLP-1 receptor agonist administered in the periphery is stable because of its resistance to dipeptidyl peptidase-4, and is highly likely to act on the brain by passing through the blood-brain barrier (BBB), as well as interacting with vagal afferent nerves. Central actions of GLP-1 have various roles including regulation of feeding, weight, glucose and lipid metabolism, cardiovascular functions, cognitive functions, and stress and emotional responses. In the present review, we focus on the source of GLP-1 and the pathway by which peripheral GLP-1 informs the brain, and then discuss recent findings on the central effects of GLP-1 and GLP-1 receptor agonists.

  15. Dipeptidylpeptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) receptor agonists: yes.

    Science.gov (United States)

    Scheen, André J

    2012-03-01

    The pharmacological treatment of type 2 diabetes (T2DM) is becoming increasingly complex, especially since the availability of incretin-based therapies. Compared with other glucose-lowering strategies, these novel drugs offer some advantages such as an absence of weight gain and a negligible risk of hypoglycaemia and, possibly, better cardiovascular and β-cell protection. The physician has now multiple choices to manage his/her patient after secondary failure of metformin, and the question whether it is preferable to add an oral dipeptidylpeptidase-4 (DPP-4) inhibitor (gliptin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist will emerge. Obviously, DPP-4 inhibitors offer several advantages compared with GLP-1 receptor agonists, especially regarding easiness of use, tolerance profile and cost. However, because they can only increase endogenous GLP-1 concentrations to physiological (rather than pharmacological) levels, they are less potent to improve glucose control, promote weight reduction ("weight neutrality") and reduce blood pressure compared to GLP-1 receptor agonists. Of note, none of the two classes have proven long-term safety and positive impact on diabetic complications yet. The role of DPP-4 inhibitors and GLP-1 receptor agonists in the therapeutic armamentarium of T2DM is rapidly evolving, but their respective potential strengths and weaknesses should be better defined in long-term head-to-head comparative controlled trials. Instead of trying to answer the question whether DPP-4 inhibitors are favourable to GLP-1 receptor agonists (or vice versa), it is probably more clinically relevant to look at which T2DM patient will benefit more from one or the other therapy considering all his/her individual clinical characteristics ("personalized medicine").

  16. Distinct effects of dipeptidyl peptidase-4 inhibitor and glucagon-like peptide-1 receptor agonist on islet morphology and function.

    Science.gov (United States)

    Morita, Asuka; Mukai, Eri; Hiratsuka, Ayano; Takatani, Tomozumi; Iwanaga, Toshihiko; Lee, Eun Young; Miki, Takashi

    2016-03-01

    Although the two anti-diabetic drugs, dipeptidyl peptidase-4 inhibitors (DPP4is) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1RAs), have distinct effects on the dynamics of circulating incretins, little is known of the difference in their consequences on morphology and function of pancreatic islets. We examined these in a mouse model of β cell injury/regeneration. The model mice were generated so as to express diphtheria toxin (DT) receptor and a fluorescent protein (Tomato) specifically in β cells. The mice were treated with a DPP4i (MK-0626) and a GLP1RA (liraglutide), singly or doubly, and the morphology and function of the islets were compared. Prior administration of MK-0626 and/or liraglutide similarly protected β cells from DT-induced cell death, indicating that enhanced GLP-1 signaling can account for the cytoprotection. However, 2-week intervention of MK-0626 and/or liraglutide in DT-injected mice resulted in different islet morphology and function: β cell proliferation and glucose-stimulated insulin secretion (GSIS) were increased by MK-0626 but not by liraglutide; α cell mass was decreased by liraglutide but not by MK-0626. Although liraglutide administration nullified MK-0626-induced β cell proliferation, their co-administration resulted in increased GSIS, decreased α cell mass, and improved glucose tolerance. The pro-proliferative effect of MK-0626 was lost by co-administration of the GLP-1 receptor antagonist exendin-(9-39), indicating that GLP-1 signaling is required for this effect. Comparison of the effects of DPP4is and/or GLP1RAs treatment in a single mouse model shows that the two anti-diabetic drugs have distinct consequences on islet morphology and function.

  17. Indirect effects of glucagon-like peptide-1 receptor agonist exendin-4 on the peripheral circadian clocks in mice.

    Directory of Open Access Journals (Sweden)

    Hitoshi Ando

    Full Text Available Circadian clocks in peripheral tissues are powerfully entrained by feeding. The mechanisms underlying this food entrainment remain unclear, although various humoral and neural factors have been reported to affect peripheral clocks. Because glucagon-like peptide-1 (GLP-1, which is rapidly secreted in response to food ingestion, influences multiple humoral and neural signaling pathways, we suggest that GLP-1 plays a role in the food entrainment of peripheral clocks. To test this, we compared the effects of exendin-4, a GLP-1 receptor agonist, on mRNA expression of the clock genes (Clock, Bmal1, Nr1d1, Per1, Per2, and Cry1 with those of refeeding. In addition, we investigated whether exendin-4 could affect the rhythms of the peripheral clocks. In male C57BL/6J mice, although refeeding rapidly (within 2 h altered mRNA levels of Per1 and Per2 in the liver and that of Per1 in adipose tissue, a single i.p. injection of exendin-4 did not cause such changes. However, unlike the GLP-1 receptor antagonist exendin-(9-39, exendin-4 significantly influenced Per1 mRNA levels in the liver at 12 h after injection. Moreover, pretreatment with exendin-4 affected the rapid-feeding-induced change in Per1 not only in the liver, but also in adipose tissue, without effect on food intake. Furthermore, during light-phase restricted feeding, repeated dosing of exendin-4 at the beginning of the dark phase profoundly influenced both the food intake and daily rhythms of clock gene expression in peripheral tissues. Thus, these results suggest that exendin-4 modulates peripheral clocks via multiple mechanisms different from those of refeeding.

  18. Intestinal Sodium Glucose Cotransporter 1 Inhibition Enhances Glucagon-Like Peptide-1 Secretion in Normal and Diabetic Rodents.

    Science.gov (United States)

    Oguma, Takahiro; Nakayama, Keiko; Kuriyama, Chiaki; Matsushita, Yasuaki; Yoshida, Kumiko; Hikida, Kumiko; Obokata, Naoyuki; Tsuda-Tsukimoto, Minoru; Saito, Akira; Arakawa, Kenji; Ueta, Kiichiro; Shiotani, Masaharu

    2015-09-01

    The sodium glucose cotransporter (SGLT) 1 plays a major role in glucose absorption and incretin hormone release in the gastrointestinal tract; however, the impact of SGLT1 inhibition on plasma glucagon-like peptide-1 (GLP-1) levels in vivo is controversial. We analyzed the effects of SGLT1 inhibitors on GLP-1 secretion in normoglycemic and hyperglycemic rodents using phloridzin, CGMI [3-(4-cyclopropylphenylmethyl)-1-(β-d-glucopyranosyl)-4-methylindole], and canagliflozin. These compounds are SGLT2 inhibitors with moderate SGLT1 inhibitory activity, and their IC50 values against rat SGLT1 and mouse SGLT1 were 609 and 760 nM for phloridzin, 39.4 and 41.5 nM for CGMI, and 555 and 613 nM for canagliflozin, respectively. Oral administration of these inhibitors markedly enhanced and prolonged the glucose-induced plasma active GLP-1 (aGLP-1) increase in combination treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in normoglycemic mice and rats. CGMI, the most potent SGLT1 inhibitor among them, enhanced glucose-induced, but not fat-induced, plasma aGLP-1 increase at a lower dose compared with canagliflozin. Both CGMI and canagliflozin delayed intestinal glucose absorption after oral administration in normoglycemic rats. The combined treatment of canagliflozin and a DPP4 inhibitor increased plasma aGLP-1 levels and improved glucose tolerance compared with single treatment in both 8- and 13-week-old Zucker diabetic fatty rats. These results suggest that transient inhibition of intestinal SGLT1 promotes GLP-1 secretion by delaying glucose absorption and that concomitant inhibition of intestinal SGLT1 and DPP4 is a novel therapeutic option for glycemic control in type 2 diabetes mellitus. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  19. The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes.

    Science.gov (United States)

    Ali, Eunüs S; Hua, Jin; Wilson, Claire H; Tallis, George A; Zhou, Fiona H; Rychkov, Grigori Y; Barritt, Greg J

    2016-09-01

    The release of Ca(2+) from the endoplasmic reticulum (ER) and subsequent replenishment of ER Ca(2+) by Ca(2+) entry through store-operated Ca(2+) channels (SOCE) play critical roles in the regulation of liver metabolism by adrenaline, glucagon and other hormones. Both ER Ca(2+) release and Ca(2+) entry are severely inhibited in steatotic hepatocytes. Exendin-4, a slowly-metabolised glucagon-like peptide-1 (GLP-1) analogue, is known to reduce liver glucose output and liver lipid, but the mechanisms involved are not well understood. The aim of this study was to determine whether exendin-4 alters intracellular Ca(2+) homeostasis in steatotic hepatocytes, and to evaluate the mechanisms involved. Exendin-4 completely reversed lipid-induced inhibition of SOCE in steatotic liver cells, but did not reverse lipid-induced inhibition of ER Ca(2+) release. The action of exendin-4 on Ca(2+) entry was rapid in onset and was mimicked by GLP-1 or dibutyryl cyclic AMP. In steatotic liver cells, exendin-4 caused a rapid decrease in lipid (half time 6.5min), inhibited the accumulation of lipid in liver cells incubated in the presence of palmitate plus the SOCE inhibitor BTP-2, and enhanced the formation of cyclic AMP. Hormone-stimulated accumulation of extracellular glucose in glycogen replete steatotic liver cells was inhibited compared to that in non-steatotic cells, and this effect of lipid was reversed by exendin-4. It is concluded that, in steatotic hepatocytes, exendin-4 reverses the lipid-induced inhibition of SOCE leading to restoration of hormone-regulated cytoplasmic Ca(2+) signalling. The mechanism may involve GLP-1 receptors, cyclic AMP, lipolysis, decreased diacylglycerol and decreased activity of protein kinase C.

  20. Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Christine Bernsmeier

    Full Text Available BACKGROUND & AIMS: The incretins glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD. However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients. METHODS: N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH patients and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration. RESULTS: Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001. In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH. CONCLUSIONS: Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.

  1. Chronic liraglutide therapy induces an enhanced endogenous glucagon-like peptide-1 secretory response in early type 2 diabetes.

    Science.gov (United States)

    Kramer, Caroline K; Zinman, Bernard; Choi, Haysook; Connelly, Philip W; Retnakaran, Ravi

    2017-02-09

    Sustained exogenous stimulation of a hormone-specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon-like peptide-1 (GLP-1) agonists on the endogenous GLP-1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years' duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP-1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUCGIP between the groups. By contrast, although fasting GLP-1 was unaffected, the liraglutide arm had ~2-fold higher AUCGLP-1 at 12 weeks ( P  < .001), 24 weeks ( P  < .001), 36 weeks ( P  = .03) and 48 weeks ( P  = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP-1 response, highlighting the need for further study of the long-term effects of incretin mimetics on L-cell physiology.

  2. Hindbrain leptin and glucagon-like-peptide-1 receptor signaling interact to suppress food intake in an additive manner.

    Science.gov (United States)

    Zhao, S; Kanoski, S E; Yan, J; Grill, H J; Hayes, M R

    2012-12-01

    The physiological control of feeding behavior involves modulation of the intake inhibitory effects of gastrointestinal satiation signaling via endogenous hindbrain leptin receptor (LepR) and glucagon-like-peptide-1 receptor (GLP-1R) activation. Using a variety of dose-combinations of hindbrain delivered (4th intracerebroventricular; i.c.v.) leptin and the GLP-1R agonist exendin-4, experiments demonstrate that hindbrain LepR and GLP-1R signaling interact to control food intake and body weight in an additive manner. In addition, the maximum intake suppressive response that could be achieved by 4th i.c.v. leptin alone in non-obese rats (∼33%) was shown to be further suppressed when exendin-4 was co-administered. Importantly, it was determined that the interaction between hindbrain LepR signaling and GLP-1R signaling is relevant to endogenous food intake control, as hindbrain GLP-1R blockade by the selective antagonist exendin-(9-39) attenuated the intake inhibitory effects of hindbrain leptin delivery. Collectively, the findings reported here show that hindbrain LepR and GLP-1R activation interact in at least an additive manner to control food intake and body weight. As evidence is accumulating that combination pharmacotherapies offer greater sustained food intake and body weight suppression in obese individuals when compared with mono-drug therapies or lifestyle modifications alone, these findings highlight the need for further examination of combined central nervous system GLP-1R and LepR signaling as a potential drug target for obesity treatment.

  3. Elevated basal and post-feed glucagon-like peptide 1 (GLP-1) concentrations in the neonatal period.

    Science.gov (United States)

    Padidela, Raja; Patterson, Michael; Sharief, Nawfal; Ghatei, Mohammed; Hussain, Khalid

    2009-01-01

    Glucagon-like peptide 1 (GLP-1) is an incretin hormone that stimulates glucose-induced insulin secretion, increases beta-cell proliferation, neogenesis and beta-cell mass. In adults, plasma concentrations of amidated GLP-1 are typically within the 5-10 pmol/l range in the fasting state and increases to approximately 50 pmol/l after ingestion of a mixed meal. We measured plasma glucose, insulin and amidated forms of GLP-1 prefeed and then at 20 and 60 min post-feed following ingestion of a 60-70 ml of standard milk feed in preterm (n=10, 34-37 weeks) and term newborn infants (n=12, 37-42 weeks). Reverse-phase fast protein liquid chromatography was used to characterise the molecular nature of the circulating GLP-1. Mean birth weight was 3.18 kg and mean age at sampling for GLP-1 was 7.7 days. The mean basal GLP-1 concentration was 79.1 pmol/l, which increased to 156.6 pmol/l (+/-70.9, P75%) represented GLP-1 (7-36) amide and (9-36) amide. Basal and post-feed amidated GLP-1 concentrations in neonates are grossly raised with the major fractions of circulating GLP-1 being (7-36) amide and (9-36) amide. Elevated GLP-1 concentrations in the newborn period may have a role in regulating maturation of enteroendocrine system and also of increasing pancreatic beta-cell mass and regeneration. The high levels of GLP-1 may be due to immaturity of the dipeptidyl peptidase IV and or lower glomerular filtration rate in the neonatal period. Further studies are required to understand the role of GLP-1 in the neonatal period.

  4. Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats.

    Science.gov (United States)

    Darsalia, Vladimer; Mansouri, Shiva; Ortsäter, Henrik; Olverling, Anna; Nozadze, Nino; Kappe, Camilla; Iverfeldt, Kerstin; Tracy, Linda M; Grankvist, Nina; Sjöholm, Åke; Patrone, Cesare

    2012-05-01

    Diabetes is a strong risk factor for premature and severe stroke. The GLP-1R (glucagon-like peptide-1 receptor) agonist Ex-4 (exendin-4) is a drug for the treatment of T2D (Type 2 diabetes) that may also have neuroprotective effects. The aim of the present study was to determine the efficacy of Ex-4 against stroke in diabetes by using a diabetic animal model, a drug administration paradigm and a dose that mimics a diabetic patient on Ex-4 therapy. Furthermore, we investigated inflammation and neurogenesis as potential cellular mechanisms underlying the Ex-4 efficacy. A total of seven 9-month-old Type 2 diabetic Goto–Kakizaki rats were treated peripherally for 4 weeks with Ex-4 at 0.1, 1 or 5 μg/kg of body weight before inducing stroke by transient middle cerebral artery occlusion and for 2–4 weeks thereafter. The severity of ischaemic damage was measured by evaluation of stroke volume and by stereological counting of neurons in the striatum and cortex. We also quantitatively evaluated stroke-induced inflammation, stem cell proliferation and neurogenesis. We show a profound anti-stroke efficacy of the clinical dose of Ex-4 in diabetic rats, an arrested microglia infiltration and an increase of stroke-induced neural stem cell proliferation and neuroblast formation, while stroke-induced neurogenesis was not affected by Ex-4. The results show a pronounced anti-stroke, neuroprotective and anti-inflammatory effect of peripheral and chronic Ex-4 treatment in middle-aged diabetic animals in a preclinical setting that has the potential to mimic the clinical treatment. Our results should provide strong impetus to further investigate GLP-1R agonists for their neuroprotective action in diabetes, and for their possible use as anti-stroke medication in non-diabetic conditions.

  5. Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion.

    Directory of Open Access Journals (Sweden)

    Michela Riz

    2015-12-01

    Full Text Available Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1, peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT and ATP-sensitive K+-channels (K(ATP-channels to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release.

  6. Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus.

    Science.gov (United States)

    Holz, George G; Chepurny, Oleg G

    2003-11-01

    Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic beta-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing beta-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate beta-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted.

  7. Association of antidiabetic medications targeting the glucagon-like peptide 1 pathway and heart failure events in patients with diabetes.

    Science.gov (United States)

    Velez, Mauricio; Peterson, Edward L; Wells, Karen; Swadia, Tanmay; Sabbah, Hani N; Williams, L Keoki; Lanfear, David E

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors (GLP-1 agents) may be protective in heart failure (HF). We set out to determine whether GLP-1 agent use is associated with HF risk in diabetics. In this retrospective cohort study of members of a large health system, we identified >19,000 adult diabetics from January 1, 2000, to July 1, 2012. GLP-1 agent users were matched 1:2 to control subjects with the use of propensity matching based on age, race, sex, coronary disease, HF, diabetes duration, and number of antidiabetic medications. The association of GLP-1 agents with time to HF hospitalization was tested with multivariable Cox regression. All-cause hospitalization and mortality were secondary end points. We identified 1,426 users of GLP-1 agents and 2,798 control subjects. Both were similar except for angiotensin-converting enzyme inhibitors/angiotensin receptor blocker use, number of antidiabetic medications, and age. There were 199 hospitalizations, of which 128 were for HF, and 114 deaths. GLP-1 agents were associated with reduced risk of HF hospitalization (adjusted hazard ratio [aHR] 0.51, 95% confidence interval [CI] 0.34-0.77; P = .002), all-cause hospitalization (aHR 0.54, 95% CI 0.38-0.74; P = .001), and death (aHR 0.31, 95% CI 0.18-0.53; P = .001). GLP-1 agents may reduce the risk of HF events in diabetics. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Role of cholinergic neurons in the motor effects of glucagon-like peptide-2 in mouse colon.

    Science.gov (United States)

    Amato, Antonella; Rotondo, Alessandra; Cinci, Lorenzo; Baldassano, Sara; Vannucchi, Maria Giuliana; Mulè, Flavia

    2010-11-01

    Glucagon-like peptide-2 (GLP-2) reduces mouse gastric tone and small intestine transit, but its action on large intestine motility is still unknown. The purposes of the present study were 1) to examine the influence of GLP-2 on spontaneous mechanical activity and on neurally evoked responses, by recording intraluminal pressure from mouse isolated colonic segments; 2) to characterize GLP-2 mechanism of action; and 3) to determine the distribution of GLP-2 receptor (GLP-2R) in the mouse colonic muscle coat by immunohistochemistry. Exogenous GLP-2 (0.1-300 nM) induced a concentration-dependent reduction of the spontaneous mechanical activity, which was abolished by the desensitization of GLP-2 receptor or by tetrodotoxin, a voltage-dependent Na(+)-channel blocker. GLP-2 inhibitory effect was not affected by N(ω)-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor), apamin (a blocker of small conductance Ca(2+)-dependent K(+) channels), or [Lys1,Pro2,5,Arg3,4,Tyr6]VIP(7-28) (a VIP receptor antagonist), but it was prevented by atropine or pertussis toxin (PTX), a G(i/o) protein inhibitor. Proximal colon responses to electrical field stimulation were characterized by nitrergic relaxation, which was followed by cholinergic contraction. GLP-2 reduced only the cholinergic evoked contractions. This effect was almost abolished by GLP-2 receptor desensitization or PTX. GLP-2 failed to affect the contractile responses to exogenous carbachol. GLP-2R immunoreactivity (IR) was detected only in the neuronal cells of both plexuses of the colonic muscle coat. More than 50% of myenteric GLP-2R-IR neurons shared the choline acetyltransferase IR. In conclusion, the activation of GLP-2R located on cholinergic neurons may modulate negatively the colonic spontaneous and electrically evoked contractions through inhibition of acetylcholine release. The effect is mediated by G(i) protein.

  9. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice.

    Science.gov (United States)

    Valdecantos, M Pilar; Pardo, Virginia; Ruiz, Laura; Castro-Sánchez, Luis; Lanzón, Borja; Fernández-Millán, Elisa; García-Monzón, Carmelo; Arroba, Ana I; González-Rodríguez, Águeda; Escrivá, Fernando; Álvarez, Carmen; Rupérez, Francisco J; Barbas, Coral; Konkar, Anish; Naylor, Jacqui; Hornigold, David; Santos, Ana Dos; Bednarek, Maria; Grimsby, Joseph; Rondinone, Cristina M; Valverde, Ángela M

    2017-03-01

    Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon-like peptide-1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline-deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high-fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine-mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49.

  10. Resistant maltodextrin promotes fasting glucagon-like peptide-1 secretion and production together with glucose tolerance in rats.

    Science.gov (United States)

    Hira, Tohru; Ikee, Asuka; Kishimoto, Yuka; Kanahori, Sumiko; Hara, Hiroshi

    2015-07-14

    Glucagon-like peptide-1 (GLP-1), which is produced and released from enteroendocrine L cells, plays pivotal roles in postprandial glycaemia. The ingestion of resistant maltodextrin (RMD), a water-soluble non-digestible saccharide, improves the glycaemic response. In the present study, we examined whether the continuous feeding of RMD to rats affected GLP-1 levels and glycaemic control. Male Sprague-Dawley rats (6 weeks of age) were fed an American Institute of Nutrition (AIN)-93G-based diet containing either cellulose (5 %) as a control, RMD (2.5 or 5 %), or fructo-oligosaccharides (FOS, 2.5 or 5 %) for 7 weeks. During the test period, an intraperitoneal glucose tolerance test (IPGTT) was performed after 6 weeks. Fasting GLP-1 levels were significantly higher in the 5 % RMD group than in the control group after 6 weeks. The IPGTT results showed that the glycaemic response was lower in the 5 % RMD group than in the control group. Lower caecal pH, higher caecal tissue and content weights were observed in the RMD and FOS groups. Proglucagon mRNA levels were increased in the caecum and colon of both RMD and FOS groups, whereas caecal GLP-1 content was increased in the 5 % RMD group. In addition, a 1 h RMD exposure induced GLP-1 secretion in an enteroendocrine L-cell model, and single oral administration of RMD increased plasma GLP-1 levels in conscious rats. The present study demonstrates that continuous ingestion of RMD increased GLP-1 secretion and production in normal rats, which could be stimulated by its direct and indirect (enhanced gut fermentation) effects on GLP-1-producing cells, and contribute to improving glucose tolerance.

  11. Glucagon-like peptide-1 modulates neurally evoked mucosal chloride secretion in guinea pig small intestine in vitro.

    Science.gov (United States)

    Baldassano, Sara; Wang, Guo-Du; Mulè, Flavia; Wood, Jackie D

    2012-02-01

    Glucagon-like peptide-1 (GLP-1) acts at the G protein-coupled receptor, GLP-1R, to stimulate secretion of insulin and to inhibit secretion of glucagon and gastric acid. Involvement in mucosal secretory physiology has received negligible attention. We aimed to study involvement of GLP-1 in mucosal chloride secretion in the small intestine. Ussing chamber methods, in concert with transmural electrical field stimulation (EFS), were used to study actions on neurogenic chloride secretion. ELISA was used to study GLP-1R effects on neural release of acetylcholine (ACh). Intramural localization of GLP-1R was assessed with immunohistochemistry. Application of GLP-1 to serosal or mucosal sides of flat-sheet preparations in Ussing chambers did not change baseline short-circuit current (I(sc)), which served as a marker for chloride secretion. Transmural EFS evoked neurally mediated biphasic increases in I(sc) that had an initial spike-like rising phase followed by a sustained plateau-like phase. Blockade of the EFS-evoked responses by tetrodotoxin indicated that the responses were neurally mediated. Application of GLP-1 reduced the EFS-evoked biphasic responses in a concentration-dependent manner. The GLP-1 receptor antagonist exendin-(9-39) suppressed this action of GLP-1. The GLP-1 inhibitory action on EFS-evoked responses persisted in the presence of nicotinic or vasoactive intestinal peptide receptor antagonists but not in the presence of a muscarinic receptor antagonist. GLP-1 significantly reduced EFS-evoked ACh release. In the submucosal plexus, GLP-1R immunoreactivity (IR) was expressed by choline acetyltransferase-IR neurons, neuropeptide Y-IR neurons, somatostatin-IR neurons, and vasoactive intestinal peptide-IR neurons. Our results suggest that GLP-1R is expressed in guinea pig submucosal neurons and that its activation leads to a decrease in neurally evoked chloride secretion by suppressing release of ACh at neuroepithelial junctions in the enteric neural networks

  12. Glucagon-Like Peptide-1 Receptor Agonists for Type 2 Diabetes:A Clinical Update of Safety and Efficacy

    Science.gov (United States)

    Drab, Scott R.

    2016-01-01

    Abstract: Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly being used for the treatment of type 2 diabetes mellitus, but consideration of benefits and potential adverse events is required. This review examines the state of glycemic control, weight loss, blood pressure, and tolerability, as well as the current debate about the safety of GLP-1 RAs, including risk of pancreatitis, pancreatic cancer, and thyroid cancer. Methods A MEDLINE search (2010-2015) identified publications that discussed longer-acting GLP-1 RAs. Search terms included GLP-1 receptor agonists, liraglutide, exenatide, lixisenatide, semaglutide, dulaglutide, albiglutide, efficacy, safety, pancreatitis, pancreatic cancer, and thyroid cancer. Abstracts from the American Diabetes Association, European Association for the Study of Diabetes, and American Association of Clinical Endocrinologists from 2010 to 2015 were also searched. Efficacy and safety studies, pooled analyses, and meta-analyses were prioritized. Results Research has confirmed that GLP-1 RAs provide robust glycemic control, weight loss, and blood pressure re-duction. Current studies do not prove increased risk of pancreatitis, pancreatic cancer, or thyroid cancer but more trials are needed since publications that indicate safety or suggest increased risk have methodological flaws that prevent firm conclusions to be drawn about these rare, long-term events. Conclusion GLP-1 RA therapy in the context of individualized, patient-centered care continues to be supported by current literature. GLP-1 RA therapy provides robust glycemic control, blood pressure reduction, and weight loss, but studies are still needed to address concerns about tolerability and safety, including pancreatitis and cancer. PMID:26694823

  13. Mathematical Modeling of Interacting Glucose-Sensing Mechanisms and Electrical Activity Underlying Glucagon-Like Peptide 1 Secretion.

    Science.gov (United States)

    Riz, Michela; Pedersen, Morten Gram

    2015-12-01

    Intestinal L-cells sense glucose and other nutrients, and in response release glucagon-like peptide 1 (GLP-1), peptide YY and other hormones with anti-diabetic and weight-reducing effects. The stimulus-secretion pathway in L-cells is still poorly understood, although it is known that GLP-1 secreting cells use sodium-glucose co-transporters (SGLT) and ATP-sensitive K+-channels (K(ATP)-channels) to sense intestinal glucose levels. Electrical activity then transduces glucose sensing to Ca2+-stimulated exocytosis. This particular glucose-sensing arrangement with glucose triggering both a depolarizing SGLT current as well as leading to closure of the hyperpolarizing K(ATP) current is of more general interest for our understanding of glucose-sensing cells. To dissect the interactions of these two glucose-sensing mechanisms, we build a mathematical model of electrical activity underlying GLP-1 secretion. Two sets of model parameters are presented: one set represents primary mouse colonic L-cells; the other set is based on data from the GLP-1 secreting GLUTag cell line. The model is then used to obtain insight into the differences in glucose-sensing between primary L-cells and GLUTag cells. Our results illuminate how the two glucose-sensing mechanisms interact, and suggest that the depolarizing effect of SGLT currents is modulated by K(ATP)-channel activity. Based on our simulations, we propose that primary L-cells encode the glucose signal as changes in action potential amplitude, whereas GLUTag cells rely mainly on frequency modulation. The model should be useful for further basic, pharmacological and theoretical investigations of the cellular signals underlying endogenous GLP-1 and peptide YY release.

  14. Effects and mechanism of glucagon-like peptide-1 on injury of rats cardiomyocytes induced by hypoxia-reoxygenation

    Institute of Scientific and Technical Information of China (English)

    XIE Yun; WANG Shao-xin; SHA Wei-wei; ZHOU Xue; WANG Wei-lin; HAN Li-pin; LI Dai-qing; YU De-min

    2008-01-01

    Background Although the insulinotropic role of glucagon-like peptide-1 (GLP-1) in type 2 diabetes mellitus has been substantiated,its role in cardioprotection remains largely unknown.This study aimed to determine the effects of GLP-1 on injury of rats cardiac myocytes induced by hypoxia-reoxygenation (H/R) and the possible mechanisms.Methods The cultured neonatal rats cardiac myocytes were randomly divided into seven groups:the normal control group,the H/R group,the GLP-1+H/R group,the GLP-1+H/R+UO126 (the p42/44 mitogen-activated protein kinase (MAPK) inhibitor) group,the GLP-1+H/R+LY294002 (phosphatidylinositol 3-kinase (P13K) inhibitor) group,the H/R+UO126 group,and the H/R+LY294002 group.The lactate dehydrogenase (LDH) activity,apoptosis rate of cardiac myocytes,and caspase-3 activity were detected after the injury of H/R.Results Compared with the normal control group,the activity of LDH,cardiac myocyte apoptosis rate,and caspase-3 activity all increased significantly in the H/R group (P<0.01).Compared with the H/R group,these three indices all decreased in the H/R+GLP-1 group (P<0.01).However,the changes of LDH activity,apoptosis rate,and caspase-3 activity were inhibited by LY294002 and UO126 respectively.Conclusions GLP-1 can directly act on cardiac myocytes and protect them from H/R injury mainly by inhibiting their apoptosis.Its mechanism may be through the P13K-Akt pathway and the MAPK signaling pathway.

  15. Prediction of the effect on antihyperglycaemic action of sitagliptin by plasma active form glucagon-like peptide-1

    Institute of Scientific and Technical Information of China (English)

    Akifumi; Kushiyama; Takako; Kikuchi; Kentaro; Tanaka; Tazu; Tahara; Toshiko; Takao; Yukiko; Onishi; Yoko; Yoshida; Shoji; Kawazu; Yasuhiko; Iwamoto

    2016-01-01

    AIM: To investigate whether active glucagon-like peptide-1(GLP-1) is a prediction Factor of Effect of sitagliptin on patients with type 2 diabetes mellitus(GLP-1 FEST:UMIN000010645). METHODS: Seventy-six patients with type 2 diabetes, who had insufficient glycemic control [Hemoglobin A1c(Hb A1c) ≥ 7%] in spite of treatment with metformin and/or sulfonylurea, were included in the investigation. Patients were divided into three groups by tertiles of fasting plasma active GLP-1 level, before the administration of 50 mg sitagliptin. RESULTS: At baseline, body mass index, serum UA, insulin and HOMA-IR were higher in the high active GLP-1 group than in the other two groups. The high active GLP-1 group did not show any decline of Hb A1c(7.6% ± 1.4% to 7.5% ± 1.5%), whereas the middle and low groups indicated significant decline of Hb A1c(7.4 ± 0.7 to 6.8 ± 0.6 and 7.4 ± 1.2 to 6.9 ± 1.3, respectively) during six months. Only the low and middle groups showed a significant increment of active GLP-1, C-peptide level, a decreased log and proinsulin/insulin ratio after administration. In logistic analysis, the low or middle group is a significantexplanatory variable for an Hb A1 c decrease of ≥ 0.5%, and its odds ratio is 4.5(1.40-17.6)(P = 0.01) against the high active GLP-1 group. This remains independent when adjusted for Hb A1 c level before administration, patients’ medical history, medications, insulin secretion and insulin resistance.CONCLUSION: Plasma fasting active GLP-1 is an independent predictive marker for the efficacy of dipeptidyl peptidase 4 inhibitor sitagliptin.

  16. Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice.

    Directory of Open Access Journals (Sweden)

    Min He

    Full Text Available BACKGROUND: Glucagon-like peptide-1 (GLP-1 is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO mice, an animal model of human obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg for 12 weeks. Body weight, body mass index (BMI, food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various

  17. Use of the incretin hormone glucagon-like peptide-1 (GLP-1) for the detection of insulinomas: initial experimental results

    Energy Technology Data Exchange (ETDEWEB)

    Gotthardt, Martin; Fischer, Marc; Naeher, Inga; Holz, Josefin B.; Jungclas, Hartmut; Fritsch, Hans-Walter; Behe, Martin; Joseph, Klaus; Behr, Thomas M. [Department of Nuclear Medicine, Philipps-University of Marburg (Germany); Goeke, Burkhard [Department of Internal Medicine II, Ludwig-Maximilians-University of Munich (Germany)

    2002-05-01

    The non-invasive detection of insulinomas remains a diagnostic problem that is not solved by means of somatostatin receptor scintigraphy. We investigated the biokinetics and specificity of uptake and degradation of the incretin hormone glucagon-like peptide-1 (GLP-1) in a rat insulinoma cell line (RINm5F) in order to ascertain whether radiolabelled GLP-1 may be suitable for specific visualisation of insulinomas in vivo. GLP-1 (7-36)amide was radioiodinated according to the iodogen method. The specificity of the uptake of [{sup 125}I]GLP-1(7-36)amide by RINm5F cells was investigated. Degradation products of GLP-1 (7-36)amide in the cell medium were purified by HPLC. Their masses and amino acid sequences were determined by {sup 252}Cf-plasma desorption mass spectrometry. Lysosomal degradation was inhibited and after differential centrifugation the amount of radiotracer incorporated into lysosomes was determined. Biodistribution studies were performed in a rat insulinoma model (NEDH rats and RINm5F cells) with [{sup 123}I]GLP-1(7-36)amide and its more stable agonist [{sup 123}I]exendin 3. The uptake of radiotracer into insulinoma cells reached a maximum within 5 min. It was inhibited by an excess of unlabelled peptide. [{sup 125}I]GLP-1(7-36)amide accumulated in the cells if lysosomal degradation was inhibited. Degradation products of the peptide were found in the cell medium. We determined their mass and derived their amino acid sequence. Radiolabelling of exendin 3 was more difficult than that of GLP-1 because of the lack of tyrosine in its primary structure. Biodistribution studies showed rapid blood clearance and uptake of the radiotracer into the tumour and the pancreas. It was also possible to detect insulinomas in an animal model by external scintigraphy using radioiodinated GLP-1 (7-36)amide and exendin 3. GLP-1 (7-36)amide is specifically internalised into insulinoma cells by a receptor-mediated mechanism. Our results demonstrate that GLP-1 receptor

  18. GLP-1(28-36)amide, the Glucagon-like peptide-1 metabolite: friend, foe, or pharmacological folly?

    Science.gov (United States)

    Taing, Meng-Wong; Rose, Felicity J; Whitehead, Jonathan P

    2014-01-01

    The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes. GLP-1 mediates its key insulinotropic effects via a G-protein coupled receptor expressed on β-cells and other pancreatic cell types. The insulinotropic activity of GLP-1 is terminated via enzymatic cleavage by dipeptidyl peptidase-4. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive; however, accumulating evidence indicates some have biological activity that may contribute to the pleiotropic effects of GLP-1 independent of the GLP-1 receptor. Recent reports describing the putative effects of one such metabolite, the GLP-1-derived nonapeptide GLP-1(28-36) amide, are the focus of this review. Administration of the nonapeptide elevates cyclic adenosine monophosphate (cAMP) and activates protein kinase A, β-catenin, and cAMP response-element binding protein in pancreatic β-cells and hepatocytes. In stressed cells, the nonapeptide targets the mitochondria and, via poorly defined mechanisms, helps to maintain mitochondrial membrane potential and cellular adenosine triphosphate levels and to reduce cytotoxicity and apoptosis. In mouse models of diet-induced obesity, treatment with the nonapeptide reduces weight gain and ameliorates associated pathophysiology, including hyperglycemia, hyperinsulinemia, and hepatic steatosis. Nonapeptide administration in a streptozotocin-induced model of type 1 diabetes also improves glucose disposal concomitant with elevated insulin levels and increased β-cell mass and proliferation. Collectively, these results suggest some of the beneficial effects of GLP-1 receptor analogs may be mediated by the nonapeptide. However, the concentrations required to elicit some of these effects are in the micromolar range, leading to reservations about potentially related therapeutic benefits. Moreover, although controversial, concerns have been raised about the potential for incretin

  19. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Kingsbury Ann E

    2008-05-01

    Full Text Available Abstract Background It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD. This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R agonist exendin-4 (EX-4, which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD. Methods Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA and lipopolysaccaride (LPS, were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system. Results EX-4 (0.1 and 0.5 μg/kg was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats. Conclusion The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models

  20. Secretion of glucagon-like peptide-2 responds to nutrient intake but not glucose provision in milk-fed calves.

    Science.gov (United States)

    Castro, J J; Morrison, S Y; Hosseinni, A; Loor, J J; Drackley, J K; Ipharraguerre, I R

    2016-07-01

    Glucagon-like peptide 2 (GLP-2) is a peptide released by the lower gut that has potent trophic and restorative effects on the intestinal epithelium. Two experiments were conducted to assess the effects of feeding rate and either metabolizable or nonmetabolizable glucose supplementation on GLP-2 concentrations in plasma and intestinal development in Holstein calves. In the first experiment, 48 newborn calves were assigned to 12 treatments (n=4) corresponding to the factorial combination of 4 milk feeding amounts [1.75, 1.32, 0.88, and 0.44% of body weight (BW) as dry matter (DM)] and 3 oral supplementation treatments (nonsupplemented, glucose-supplemented, and 3-O-methyl glucose-supplemented). In the second experiment 30 newborn calves (n=10) were fed milk at a fixed rate of 1.75% of BW as DM and assigned to the same glucose supplementation treatments used in experiment 1 to investigate effects on intestinal development. In the first experiment, we found a saturating response of plasma GLP-2 to increasing feeding levels. The feeding rate at which 50% of the maximal GLP-2 release occurred was estimated to be 0.53% of BW as DM or 30.3% of the maximum feeding rate (1.75% of BW as DM), whereas maximal secretion was estimated to be about 98.6 pmol/L. In turn, feeding 75, 50, or 25% of the maximal feeding rate (i.e., 1.75% BW as DM) resulted in plasma GLP-2 concentrations 87, 72, and 49% of that in fully fed calves, respectively. Neither metabolizable nor nonmetabolizable glucose supplementation affected GLP-2 secretion and no interaction with feed intake level was detected. In the second experiment, no effect of glucose supplementation was observed on intestinal growth, mucosal cell proliferation, or expression of genes related to the actions of GLP-2. Nonetheless, we observed that a pool of genes of the GLP-2 signaling pathway was more abundantly and coordinately regulated in the colon than in the ileum of these animals, indicating an opportunity for dietary induction

  1. Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively.

    Science.gov (United States)

    Neary, Nicola M; Small, Caroline J; Druce, Maralyn R; Park, Adrian J; Ellis, Sandra M; Semjonous, Nina M; Dakin, Catherine L; Filipsson, Karin; Wang, Fang; Kent, Aysha S; Frost, Gary S; Ghatei, Mohammad A; Bloom, Stephen R

    2005-12-01

    Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY(3-36) and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY(3-36) with GLP-1(7-36) in rodents and man. Whereas high-dose PYY(3-36) (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY(3-36) (1 nmol/kg) and GLP-1(7-36) (10 nmol/kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY(3-36) or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY(3-36) and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg.min), PYY(3-36) (0.4 pmol/kg.min), and PYY(3-36) (0.4 pmol/kg.min) + GLP-1(7-36) (0.4 pmol/kg.min) on four separate days. Energy intake from a buffet meal after combined PYY(3-36) + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY(3-36) and GLP-1(7-36), cosecreted after a meal, may inhibit food intake additively.

  2. Positron emission tomography imaging of the glucagon-like peptide-1 receptor in healthy and streptozotocin-induced diabetic pigs

    Energy Technology Data Exchange (ETDEWEB)

    Nalin, Lovisa; Andreasson, Susanne; Wikstrand, Anna; Ryden, Anneli; Nyman, Goerel; Jensen-Waern, Marianne [Swedish University of Agricultural Sciences, Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Uppsala (Sweden); Selvaraju, Ram K.; Eriksson, Olof [Uppsala University, Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala (Sweden); Velikyan, Irina [Uppsala University, Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala (Sweden); Uppsala University, Department of Radiology, Oncology and Radiation Sciences, Uppsala (Sweden); Uppsala University Hospital, PET Centre, Centre for Medical Imaging, Uppsala (Sweden); Berglund, Marie [Uppsala University, Department of Medicinal Chemistry, Preclinical PET Platform, Uppsala (Sweden); Uppsala University, Department of Radiology, Oncology and Radiation Sciences, Uppsala (Sweden); Lubberink, Mark [Uppsala University, Department of Radiology, Oncology and Radiation Sciences, Uppsala (Sweden); Kandeel, Fouad [Beckman Research Institute of the City of Hope, Duarte, CA (United States); Korsgren, Olle [Uppsala University, Department of Immunology, Genetics and Pathology, Uppsala (Sweden)

    2014-09-15

    The glucagon-like peptide-1 receptor (GLP-1R) has been proposed as a target for molecular imaging of beta cells. The feasibility of non-invasive imaging and quantification of GLP-1R in pancreas using the positron emission tomography (PET) tracer [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 in non-diabetic and streptozotocin (STZ)-induced diabetic pigs treated with insulin was investigated. Non-diabetic (n = 4) and STZ-induced diabetic pigs (n = 3) from the same litter were examined. Development of diabetes was confirmed by blood glucose values, clinical examinations and insulin staining of pancreatic sections post mortem. Tissue perfusion in the pancreas and kidneys was evaluated by [{sup 15}O]water PET/computed tomography (CT) scans. The in vivo receptor specificity of [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 was assessed by administration of either tracer alone or by competition with 3-6.5 μg/kg of Exendin-4. Volume of distribution and occupancy in the pancreas were quantified with a single tissue compartment model. [{sup 15}O]water PET/CT examinations showed reduced perfusion in the pancreas and kidneys in diabetic pigs. [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 uptake in the pancreas of both non-diabetic and diabetic pigs was almost completely abolished by co-injection of unlabeled Exendin-4 peptide. [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 uptake did not differ between non-diabetic and diabetic pigs. In all animals, administration of the tracer resulted in an immediate increase in the heart rate (HR). Pancreatic uptake of [{sup 68}Ga]Ga-DO3A-VS-Cys{sup 40}-Exendin-4 was not reduced by destruction of beta cells in STZ-induced diabetic pigs. (orig.)

  3. Oleic acid and glucose regulate glucagon-like peptide 1 receptor expression in a rat pancreatic ductal cell line

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Leshuai W.; McMahon Tobin, Grainne A.; Rouse, Rodney L., E-mail: rodney.rouse@fda.hhs.gov

    2012-10-15

    The glucagon-like peptide 1 receptor (GLP1R) plays a critical role in glucose metabolism and has become an important target for a growing class of drugs designed to treat type 2 diabetes. In vitro studies were designed to investigate the effect of the GLP1R agonist, exenatide (Ex4), in “on-target” RIN-5mF (islet) cells as well as in “off-target” AR42J (acinar) and DSL-6A/C1 (ductal) cells in a diabetic environment. Ex4 increased islet cell proliferation but did not affect acinar cells or ductal cells at relevant concentrations. A high caloric, high fat diet is a risk factor for impaired glucose tolerance and type-2 diabetes. An in vitro Oleic acid (OA) model was used to investigate the effect of Ex4 in a high calorie, high fat environment. At 0.1 and 0.4 mM, OA mildly decreased the proliferation of all pancreatic cell types. Ex4 did not potentiate the inhibitory effect of OA on cell proliferation. Akt phosphorylation in response to Ex4 was diminished in OA-treated ductal cells. GLP1R protein detected by western blot was time and concentration dependently decreased after glucose stimulation in OA-treated ductal cells. In ductal cells, OA treatment altered the intracellular localization of GLP1R and its co-localization with early endosome and recycling endosomes. Chloroquine (lysosomal inhibitor), N-acetyl-L-cysteine (reactive oxygen species scavenger) and wortmannin (a phosphatidylinositol-3-kinase inhibitor), fully or partially, rescued GLP1R protein in OA-pretreated, glucose-stimulated ductal cells. The impact of altered regulation on phenotype/function is presently unknown. However, these data suggest that GLP1R regulation in ductal cells can be altered by a high fat, high calorie environment. -- Highlights: ► Exenatide did not inhibit islet, acinar or ductal cell proliferation. ► GLP1R protein decreased after glucose stimulation in oleic acid-treated ductal cells. ► Oleic acid treatment altered localization of GLP1R with early and recycling

  4. Importance of Large Intestine in Regulating Bile Acids and Glucagon-Like Peptide-1 in Germ-Free Mice.

    Science.gov (United States)

    Selwyn, Felcy Pavithra; Csanaky, Iván L; Zhang, Youcai; Klaassen, Curtis D

    2015-10-01

    It is known that 1) elevated serum bile acids (BAs) are associated with decreased body weight, 2) elevated glucagon-like peptide-1 (GLP-1) levels can decrease body weight, and 3) germ-free (GF) mice are resistant to diet-induced obesity. The purpose of this study was to test the hypothesis that a lack of intestinal microbiota results in more BAs in the body, resulting in increased BA-mediated transmembrane G protein-coupled receptor 5 (TGR5) signaling and increased serum GLP-1 as a mechanism of resistance of GF mice to diet-induced obesity. GF mice had 2- to 4-fold increased total BAs in the serum, liver, bile, and ileum. Fecal excretion of BAs was 63% less in GF mice. GF mice had decreased secondary BAs and increased taurine-conjugated BAs, as anticipated. Surprisingly, there was an increase in non-12α-OH BAs, namely, β-muricholic acid, ursodeoxycholic acid (UDCA), and their taurine conjugates, in GF mice. Further, in vitro experiments confirmed that UDCA is a primary BA in mice. There were minimal changes in the mRNA of farnesoid X receptor target genes in the ileum (Fibroblast growth factor 15, small heterodimer protein, and ileal bile acid-binding protein), in the liver (small heterodimer protein, liver receptor homolog-1, and cytochrome P450 7a1), and BA transporters (apical sodium dependent bile acid transporter, organic solute transporter α, and organic solute transporter β) in the ileum of GF mice. Surprisingly, there were marked increases in BA transporters in the large intestine. Increased GLP-1 levels and gallbladder size were observed in GF mice, suggesting activation of TGR5 signaling. In summary, the GF condition results in increased expression of BA transporters in the colon, resulting in 1) an increase in total BA concentrations in tissues, 2) a change in BA composition to favor an increase in non-12α-OH BAs, and 3) activation of TGR5 signaling with increased gallbladder size and GLP-1.

  5. Once daily baclofen sustained release or gastro-retentive system are acceptable alternatives to thrice daily baclofen immediate release at same daily dosage in patients

    Directory of Open Access Journals (Sweden)

    Sampat Nitin

    2009-01-01

    Full Text Available Background: Baclofen, a GABA-agonist, is currently available as an immediate release (IR formulation for relieving neurogenic spasticity in a variety of disorders. Baclofen IR requires to be administered three times a day which inadvertently increases the chances of medication noncompliance among patients and is also associated with side effects such as drowsiness and muscle weakness. Aim: To overcome the shortcomings of baclofen IR, two modified formulations, baclofen sustained release (SR and gastric retentive system (GRS, have been proposed to be equivalent in efficacy to baclofen IR with the administration of a single daily dose. Materials and Methods: Ninety patients with chronic neurogenic muscular spasticity were enrolled requiring 10-20 mg of baclofen IR every eight hours. The patients were randomized to two treatment arms: SR (n = 46 or GRS (n = 44 at the same once-daily dose for four weeks. Efficacy was measured by Ashworth score for muscle tone, spasm score, reflex score, 30-item functional independence score, and patient′s diary score for three most affected activities of daily life. Results: The mean Ashworth score changed significantly (P = 0.00 for patients in the SR group from 3.03-2.69 (-0.35 and 3.07-2.70 (-0.37 for patients in the GRS group. There was no significant difference (P = 0.87 between baseline-adjusted Ashworth score reductions on SR (-0.35 and GRS (-0.37. Similar results were obtained for spasm, reflex, and functional independence scores. The mean baseline-adjusted patient-diary scores did not differ significantly between 8 am, 12 pm, 4 pm, and 8 pm (P = 0.96, either on SR (-5.3 to -6.1 or GRS (-7.3 to -8.1, indicating a uniform effect round-the-day on both. Further, sedation scores (mean ± SEM decreased significantly (P < 0.05 on both SR (10.36 ± 1.37 to 6.18 ± 0.92 and GRS (8.14 ± 1.57 to 5.33 ± 1.11, suggesting better toleration. Conclusion: Once-daily baclofen SR and GRS are efficacious, convenient, and

  6. Similar risk reduction of death of extended-release metoprolol once daily and immediate-release metoprolol twice daily during 5 years after myocardial infarction.

    Science.gov (United States)

    Herlitz, J; Dellborg, M; Karlson, B W; Lindqvist, J; Sandèn, W; Svensson, H; Sjölin, M; Wedel, H

    1999-04-01

    The pooled results from five placebo-controlled postinfarction studies with metoprolol have shown a significant reduction in total mortality. All five studies used immediate-release metoprolol twice daily. An extended-release formulation of metoprolol for once-daily use has since been developed. The aim of the present study was to compare the two different forms of metoprolol with regard to the risk reduction of death for 5 years postinfarction and to analyze whether treatment with the beta-blocker metoprolol is associated with a reduced mortality after the introduction of modern therapies such as thrombolysis, aspirin, and ACE inhibitors. All patients discharged after an acute myocardial infarction (AMI) from Sahlgrenska University Hospital (SU) during 1986-1987 (n = 740, Period I) and during 1990-1991 (n = 1446, Period II) from both SU and Ostra Hospital, Göteborg, Sweden, were included in the study. During Period I, 56% were prescribed immediate-release metoprolol compared with 61% prescribed extended-release metoprolol during Period II. Immediate-release metoprolol was not available for outpatient use during Period II. In a multivariate analysis, all variables significantly associated with either increased or decreased postinfarction mortality during Periods I and II (univariate analysis of patient characteristics, medical history, complications during the AMI medication at discharge) studied were with Cox's proportional hazards model. Treatment with immediate-release metoprolol was significantly associated with reduced mortality over 5 years during Period I (relative risk reduction for total mortality, -34%, P = 0.003; 95% CI for RR, 0.51-0.87), and treatment with extended-release metoprolol was significantly associated with reduced mortality during Period II (-34%, P metoprolol given once daily was associated with a similar risk reduction of death over 5 years as immediate-release metoprolol given twice daily. The data, furthermore, indicate that the beta

  7. Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies

    Directory of Open Access Journals (Sweden)

    Ferguson GT

    2014-06-01

    Full Text Available Gary T Ferguson,1 Gregory J Feldman,2 Peter Hofbauer,3 Alan Hamilton,4 Lisa Allen,5 Lawrence Korducki,5 Paul Sachs6 1Pulmonary Research Institute of Southeast Michigan, Livonia, MI, 2S Carolina Pharmaceutical Research, Spartanburg, SC, USA; 3Pneumologie, Weinheim, Germany; 4Boehringer Ingelheim, Burlington, ON, Canada; 5Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 6Pulmonary Associates of Stamford, Stamford, CT, USA Background: Olodaterol is a long-acting β2-agonist with a 24-hour bronchodilator profile. Two replicate, randomized, double-blind, placebo-controlled, parallel-group, Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD receiving usual-care background therapy. Methods: Patients received olodaterol 5 µg or 10 µg or placebo once daily for 48 weeks. Coprimary end points were forced expiratory volume in 1 second (FEV1 area under the curve from 0 to 3 hours (AUC0–3 response (change from baseline, and trough FEV1 response at 12 weeks. Secondary end points included additional lung function assessments, use of rescue medications, FEV1 AUC response from 0 to 12 hours, and Patient Global Rating over 48 weeks. Results: Overall, 624 and 642 patients were evaluated in studies 1222.11 and 1222.12, respectively. In both studies, olodaterol 5 µg and 10 µg significantly improved the FEV1 AUC0–3 response (P<0.0001 and trough FEV1 (study 1222.11, P<0.0001; study 1222.12, P<0.05, post hoc at week 12, with an incidence of adverse events comparable with that of placebo. Secondary end points supported the efficacy of olodaterol. Conclusion: These studies demonstrate the long-term efficacy and safety of once-daily olodaterol 5 µg and 10 µg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy. Keywords: chronic obstructive

  8. Effects of changing milk replacer feedings from twice to once daily on Holstein calf innate immune responses before and after weaning.

    Science.gov (United States)

    Hulbert, L E; Cobb, C J; Carroll, J A; Ballou, M A

    2011-05-01

    The objectives of this study were to determine the effects of switching Holstein calves to once-daily feeding during the fourth week of life (24 ± 2.3 d of age; once-fed n=22; twice-fed n=22) on innate immune responses, and to evaluate whether carry-over effects occurred when the calves were weaned during the seventh week of life. Peripheral blood samples were taken immediately before the change in feeding strategy (24 d of age) and at 27, 31, 45, 48, 52, and 66 d of age and were analyzed for circulating cortisol, haptoglobin, total leukocyte counts, neutrophil:mononuclear cells, and hematocrit percentage. Heparinized whole blood was also stimulated with lipopolysaccharide (LPS) for 24h and the concentration of tumor necrosis factor-α (TNF-α) in the supernatant was analyzed. Neutrophil L-selectin and β(2)-integrin expression were analyzed by flow cytometry. Simultaneous neutrophil phagocytic and oxidative burst responses to a heat-killed Escherichia coli were quantified by dual-color flow-cytometry. Treatment (once-daily or twice daily feeding) had no effect on pre- or postweaning performance. Once-fed calves tended to have more circulating neutrophils at 27 d of age, greater expression of L-selectin on neutrophils at 31 and 45 d of age, and greater intensity of phagocytosis at 45 d of age. Once-fed calves secreted less TNF-α in LPS-stimulated whole blood cultures at 45 d of age compared with twice-fed calves and this tended to persist through the immediate postweaning period. None of the other immune parameters differed after weaning between the preweaning feeding strategies. Consolidating calf milk replacer into one feeding during the fourth week of life was likely a mild and acute stressor, as evidenced by transient neutrophilia in the absence of suppressed functional capacities of neutrophils. Future research should address the mechanism and immunological significance of the persistent decreased TNF-α response in once-fed calves.

  9. Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1

    DEFF Research Database (Denmark)

    Torekov, S S; Ma, L; Grarup, N;

    2011-01-01

    The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits.......The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and -2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits....

  10. Review of Efficacy and Safety of Duloxetine 40 to 60 mg Once Daily in Patients with Diabetic Peripheral Neuropathic Pain

    Directory of Open Access Journals (Sweden)

    Vladimir Skljarevski

    2012-01-01

    Full Text Available We summarize efficacy and safety findings from 4 double-blind, placebo-controlled, 12-week studies and 1 open-label, uncontrolled, 34-week maintenance-of-effect (MOE study that examine duloxetine 40 and 60 mg once daily (QD in patients with diabetic peripheral neuropathic pain (DPNP. In all placebo-controlled studies, duloxetine showed significantly (P≤.01 greater reduction in pain severity (weekly mean of 24-hour average pain severity ratings, primary outcome measure compared with placebo. In all placebo-controlled studies, duloxetine showed significantly (P≤.05 greater improvement on brief pain inventory-Interference ratings. Patient global impression of improvement ratings were superior to placebo (P≤.01 for duloxetine patients in all placebo-controlled studies. Response rates (based on 30% pain reduction ranged from 57% to 68% for duloxetine and from 35% to 47% for placebo and were statistically significantly different (P≤.01 between treatment groups in 3 out of 4 studies. The open-label study showed maintenance of analgesic effect of duloxetine in DPNP. In the duloxetine groups, 4.3% to 14.9% of patients discontinued because of adverse events (placebo groups: 2.6% to 7.4%. Most commonly reported treatment-emergent adverse events were nausea, somnolence, and headache. Duloxetine 40 and 60 mg QD was efficacious and well tolerated in the management of DPNP.

  11. Effect of once-daily indacaterol in a predominantly Chinese population with chronic obstructive pulmonary disease: a 26-week Asia-Pacific study.

    Science.gov (United States)

    Yao, Wanzhen; Wang, Changzheng; Zhong, Nanshan; Han, Xiaowen; Wu, Changgui; Yan, Xixin; Chen, Ping; Yang, Wei; Henley, Michelle; Kramer, Benjamin

    2014-02-01

    This study, in a predominantly Chinese population, investigated the efficacy and safety of a once-daily (o.d.) inhaled ultra-long-acting β2 -agonist indacaterol for the treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD). This is a 26-week, double-blind study on randomized patients who received indacaterol 150 μg or 300 μg or placebo o.d. The primary variable was trough forced expiratory volume in 1 s (FEV1 , average of 23 h 10 min and 23 h 45 min post-dose values) at Week 12. Health status (St George's Respiratory Questionnaire, SGRQ), dyspnoea (transition dyspnoea index, TDI) and safety were evaluated over 26 weeks. Of the 563 patients randomized, 561 (89.8% Chinese) received treatment and 482 completed. At Week 12, trough FEV1 improved significantly for indacaterol 150 and 300 μg versus placebo (1.32, 1.29 vs 1.17; P indacaterol 150 and 300 μg (0.82, 1.15; P Indacaterol delivered effective bronchodilation with significant improvements in breathlessness and health status in this predominantly Chinese population. © 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology.

  12. Once daily administration of the SGLT2 inhibitor, empagliflozin, attenuates markers of renal fibrosis without improving albuminuria in diabetic db/db mice.

    Science.gov (United States)

    Gallo, Linda A; Ward, Micheal S; Fotheringham, Amelia K; Zhuang, Aowen; Borg, Danielle J; Flemming, Nicole B; Harvie, Ben M; Kinneally, Toni L; Yeh, Shang-Ming; McCarthy, Domenica A; Koepsell, Hermann; Vallon, Volker; Pollock, Carol; Panchapakesan, Usha; Forbes, Josephine M

    2016-05-26

    Blood glucose control is the primary strategy to prevent complications in diabetes. At the onset of kidney disease, therapies that inhibit components of the renin angiotensin system (RAS) are also indicated, but these approaches are not wholly effective. Here, we show that once daily administration of the novel glucose lowering agent, empagliflozin, an SGLT2 inhibitor which targets the kidney to block glucose reabsorption, has the potential to improve kidney disease in type 2 diabetes. In male db/db mice, a 10-week treatment with empagliflozin attenuated the diabetes-induced upregulation of profibrotic gene markers, fibronectin and transforming-growth-factor-beta. Other molecular (collagen IV and connective tissue growth factor) and histological (tubulointerstitial total collagen and glomerular collagen IV accumulation) benefits were seen upon dual therapy with metformin. Albuminuria, urinary markers of tubule damage (kidney injury molecule-1, KIM-1 and neutrophil gelatinase-associated lipocalin, NGAL), kidney growth, and glomerulosclerosis, however, were not improved with empagliflozin or metformin, and plasma and intra-renal renin activity was enhanced with empagliflozin. In this model, blood glucose lowering with empagliflozin attenuated some molecular and histological markers of fibrosis but, as per treatment with metformin, did not provide complete renoprotection. Further research to refine the treatment regimen in type 2 diabetes and nephropathy is warranted.

  13. Effects of once-daily extended release quetiapine fumarate (quetiapine XR) on quality of life and sleep in elderly patients with major depressive disorder.

    Science.gov (United States)

    Locklear, Julie C; Svedsäter, Henrik; Datto, Catherine; Endicott, Jean

    2013-07-01

    Major depressive disorder (MDD) is frequently associated with reduced quality of life (QoL) and sleep disturbance. We investigated the effects of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy on QoL and sleep in elderly patients with MDD. Prospectively planned analysis of patient-reported data from an 11-week (9-week randomized; 2-week post-treatment), double-blind, placebo-controlled, Phase III study. Elderly patients (≥66 years; DSM-IV MDD; Hamilton Rating Scale for Depression [HAM-D] total score ≥22, HAM-D Item 1 score ≥2) were randomized to quetiapine XR (flexible dosing 50-300 mg/day) or placebo. MADRS total score change from randomization at Week 9. Patient-reported outcomes: Quality of Life, Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF) % of maximum total score (Items 1-14), Q-LES-Q-SF Item 15 ('satisfaction with medication'), Q-LES-Q-SF Item 16 ('overall life satisfaction'), and Pittsburgh Sleep Quality Index (PSQI) global score. In total, 338 patients were randomized (166 quetiapine XR; 172 placebo). At Week 9, quetiapine XR significantly reduced MADRS total score (-16.33; difference: -7.54; 95% CI: -9.23, -5.85; pelderly patients with MDD. Copyright © 2013. Published by Elsevier B.V.

  14. An observational study to monitor the efficacy and tolerability of levofloxacin 500 mg once daily for treatment of chronic bacterial prostatitis in Saudi Arabia

    Science.gov (United States)

    El Meliegy, Amr Ismail; Torky, Mohammed

    2015-01-01

    Introduction: Chronic prostatitis is a common urological problem in men <50-year-old. Untypical uropathogens and an intact blood prostate barrier cause difficulty in using antibiotics to treat the infection. Patients and Methods: In this open-label, observational study, levofloxacin 500 mg was given once daily for 28 days for treatment of chronic prostatitis. The primary efficacy measurement was the disappearance of all pre-treatment symptoms. Efficacy analysis is based on the per protocol population (PPP), all other analyses use the intent to treat (ITT) population. Results: The ITT included 154 men and the PPP included 151 (results are for the ITT unless otherwise indicated). Mean age was 42 ± 9 years, common concomitant conditions were diabetes mellitus (7%) and hypertension (5%). All symptoms decreased at day 28. Notably, the rate of dysuria decreased from 86.1% to 10.6%, painful ejaculation from 71% to 2.6% and perineal discomfort from 60.3% to 7.3%. A cure of condition was identified in 58.9%. No treatment failures were reported. Physician-reported adherence to study medication was 96.8%. Conclusion: Levofloxacin appears to be an effective antibiotic for treating symptoms of chronic bacterial prostatitis. Levofloxacin was well-tolerated in this population. PMID:25657549

  15. Efficacy and Safety of Once-Daily Minoxidil Foam 5% Versus Twice-Daily Minoxidil Solution 2% in Female Pattern Hair Loss: A Phase III, Randomized, Investigator-Blinded Study.

    Science.gov (United States)

    Blume-Peytavi, Ulrike; Shapiro, Jerry; Messenger, Andrew G; Hordinsky, Maria K; Zhang, Paul; Quiza, Carlos; Doshi, Uday; Olsen, Elise A

    2016-07-01

    A once-daily minoxidil topical foam (MTF) has been developed to treat female pattern hair loss. Determine noninferiority of once-daily 5% MTF versus twice-daily 2% minoxidil topical solution (MTS) based on the change from baseline in target area hair count (TAHC) at 24 weeks. In a randomized, phase III trial, women with female pattern hair loss received once-daily 5% MTF (n=161) or twice-daily 2% MTS (n=161) for 52 weeks. Primary endpoint was change from baseline in TAHC at 24 weeks. Secondary endpoint was change from baseline in TAHC at 12 weeks. Exploratory endpoints included change in total unit area density and change in overall scalp coverage. Once-daily 5% MTF increased TAHC from baseline (adjusted mean ± standard error) by 23.9 ± 2.1 hairs/cm2 at week 24. Twice-daily 2% MTS increased TAHC 24.2 ± 2.1 hairs/cm2 at week 24. The treatment difference was -0.3 hairs/cm2 (95% CI = -6.0, 5.4). Since the lower bound of the 95% CI was less than -5.0, the prespecified noninferiority goal was not met. Both treatments were well tolerated. Once-daily 5% MTF and twice-daily 2% MTS induced hair regrowth in female pattern hair loss, but prespecified noninferiority criteria were not met. ClinicalTrials.gov identifier: NCT01145625 J Drugs Dermatol. 2016;15(7):883-889.

  16. Treatment with liraglutide--a once-daily GLP-1 analog--does not reduce the bioavailability of ethinyl estradiol/levonorgestrel taken as an oral combination contraceptive drug.

    Science.gov (United States)

    Jacobsen, Lisbeth V; Vouis, Jan; Hindsberger, Charlotte; Zdravkovic, Milan

    2011-12-01

    Liraglutide is a once-daily human GLP-1 analog for treatment of type 2 diabetes. Like other GLP-1 analogs, liraglutide delays gastric emptying, which could potentially affect absorption of concomitantly administered oral drugs. This study investigated the effect of liraglutide on the pharmacokinetics of the components of an oral contraceptive (ethinyl estradiol/levonorgestrel). Postmeno-pausal healthy women (n = 21) were included. A single dose of this contraceptive was administered. Blood samples for ethinyl estradiol/levonorgestrel measurements were drawn until 74 hours post dosing of the contraceptive during liraglutide and placebo treatments. The 90% confidence interval (CI) of the ratio of the area under the curve (AUC) (1.06; 90% CI, 0.99-1.13) for ethinyl estradiol (during liraglutide and placebo) was within defined limits, demonstrating equivalence. The 90% CI for the ratio of AUC for levonorgestrel was not fully contained within the limits (1.18; 90% CI, 1.04-1.34) (levonorgestrel AUC was 18% greater with liraglutide vs placebo). However, equivalence was demonstrated for levonorgestrel AUC(0-t) (1.15; 90% CI, 1.06-1.24). Equivalence was not demonstrated for maximum concentration (C(max)); values for ethinyl estradiol and levonorgestrel C(max) were 12% and 13% lower with liraglutide versus placebo, respectively. Both reached C(max) ~1.5 hours later with liraglutide. No clinically relevant reduction in bioavailability of ethinyl estradiol/levonorgestrel occurred.

  17. Allosteric Modulation of the Activity of the Glucagon-like Peptide-1 (GLP-1) Metabolite GLP-1 9–36 Amide at the GLP-1 Receptor

    OpenAIRE

    Naichang Li; Jing Lu; Willars, Gary B

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose-dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compo...

  18. Negative Energy Balance Blocks Neural and Behavioral Responses to Acute Stress by “Silencing” Central Glucagon-Like Peptide 1 Signaling in Rats

    Science.gov (United States)

    Maniscalco, James W.; Zheng, Huiyuan; Gordon, Patrick J.

    2015-01-01

    Previous reports indicate that caloric restriction attenuates anxiety and other behavioral responses to acute stress, and blunts the ability of stress to increase anterior pituitary release of adrenocorticotropic hormone. Since hindbrain glucagon-like peptide-1 (GLP-1) neurons and noradrenergic prolactin-releasing peptide (PrRP) neurons participate in behavioral and endocrine stress responses, and are sensitive to the metabolic state, we examined whether overnight food deprivation blunts stress-induced recruitment of these neurons and their downstream hypothalamic and limbic forebrain targets. A single overnight fast reduced anxiety-like behavior assessed in the elevated-plus maze and acoustic startle test, including marked attenuation of light-enhanced startle. Acute stress [i.e., 30 min restraint (RES) or 5 min elevated platform exposure] robustly activated c-Fos in GLP-1 and PrRP neurons in fed rats, but not in fasted rats. Fasting also significantly blunted the ability of acute stress to activate c-Fos expression within the anterior ventrolateral bed nucleus of the stria terminalis (vlBST). Acute RES stress suppressed dark-onset food intake in rats that were fed ad libitum, whereas central infusion of a GLP-1 receptor antagonist blocked RES-induced hypophagia, and reduced the ability of RES to activate PrRP and anterior vlBST neurons in ad libitum-fed rats. Thus, an overnight fast “silences” GLP-1 and PrRP neurons, and reduces both anxiety-like and hypophagic responses to acute stress. The partial mimicking of these fasting-induced effects in ad libitum-fed rats after GLP-1 receptor antagonism suggests a potential mechanism by which short-term negative energy balance attenuates neuroendocrine and behavioral responses to acute stress. SIGNIFICANCE STATEMENT The results from this study reveal a potential central mechanism for the “metabolic tuning” of stress responsiveness. A single overnight fast, which markedly reduces anxiety-like behavior in rats

  19. Identification of potent 11mer glucagon-like peptide-1 receptor agonist peptides with novel C-terminal amino acids: Homohomophenylalanine analogs.

    Science.gov (United States)

    Haque, Tasir S; Lee, Ving G; Riexinger, Douglas; Lei, Ming; Malmstrom, Sarah; Xin, Li; Han, Songping; Mapelli, Claudio; Cooper, Christopher B; Zhang, Ge; Ewing, William R; Krupinski, John

    2010-05-01

    We report the identification of potent agonists of the Glucagon-Like Peptide-1 Receptor (GLP-1R). These compounds are short, 11 amino acid peptides containing several unnatural amino acids, including (in particular) analogs of homohomophenylalanine (hhPhe) at the C-terminal position. Typically the functional activity of the more potent peptides in this class is in the low picomolar range in an in vitro cAMP assay, with one example demonstrating excellent in vivo activity in an ob/ob mouse model of diabetes.

  20. Normal secretion of the incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 during gestational diabetes mellitus

    DEFF Research Database (Denmark)

    Cypryk, Katarzyna; Vilsbøll, Tina; Nadel, Iwona

    2007-01-01

    Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (DM2) are suggested to be caused by the same metabolic disorder. Defects in gut hormone-dependent regulation of beta-cell function (entero-insular axis) have been proposed to contribute to the pathogenesis of DM2. The aim of study...... was to evaluate whether an impaired secretion of glucagon-like peptide-1 (GLP-1) and/or glucose-dependent insulinotropic polypeptide (GIP) could play a role in the development of carbohydrate disorders during pregnancy....

  1. Expression and Distribution of Glucagon-Like Peptide-1 Receptor mRNA, Protein and Binding in the Male Nonhuman Primate (Macaca mulatta) Brain

    OpenAIRE

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract, where it acts as an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been...

  2. Effects of the glucagon-like peptide-1 receptor agonist liraglutide on 24-h ambulatory blood pressure in patients with type 2 diabetes and stable coronary artery disease

    DEFF Research Database (Denmark)

    Kumarathurai, Preman; Anholm, Christian; Fabricius-Bjerre, Andreas

    2017-01-01

    -one patients with type 2 diabetes and stable coronary artery disease were randomized to receive liraglutide or placebo to a backbone therapy of metformin in this double-blind, placebo-controlled 12 along with 12 weeks crossover study. Ambulatory blood pressure monitoring (ABPM) was performed at the start......OBJECTIVE: The glucagon-like peptide-1 receptor agonist liraglutide has been shown to reduce blood pressure (BP) in clinical trials using office BP measurements. However, the effects of liraglutide on 24-h BP and on the diurnal variation in BP have not been explored sufficiently. METHODS: Forty...

  3. Glucagon-like peptide-2 (GLP-2) increases net amino acid utilization by the portal-drained viscera of ruminating calves

    DEFF Research Database (Denmark)

    Taylor-Edwards, C C; Burrin, D G; Kristensen, Niels Bastian

    2012-01-01

    Glucagon-like peptide-2 (GLP-2) increases small intestinal mass and blood flow in ruminant calves, but its impact on nutrient metabolism across the portal-drained viscera (PDV) and liver is unknown. Eight Holstein calves with catheters in the carotid artery, mesenteric vein, portal vein and hepatic...... on days 0 and 10. Arterial concentrations and net fluxes of all amino acids and glucose metabolism using continuous intravenous infusion of [U13-C]glucose were measured on day 10 only. A 1-h infusion of GLP-2 increased blood flow in the portal and hepatic veins when administered to calves not previously...

  4. Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study

    Directory of Open Access Journals (Sweden)

    Vincken W

    2014-02-01

    Full Text Available Walter Vincken,1 Joseph Aumann,2 Hungta Chen,3 Michelle Henley,3 Danny McBryan,4 Pankaj Goyal4 1Respiratory Division, University Hospital, UZ Brussel, Free University of Brussels, Brussels, Belgium; 2Longartsenpraktijk, Prins Bisschopssingel, Hasselt, Belgium; 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 4Novartis Pharma AG, Basel, Switzerland Background: Addition of a second bronchodilator from a different pharmacological class may benefit patients with moderate-to-severe chronic obstructive pulmonary disease (COPD whose symptoms are insufficiently controlled by bronchodilator monotherapy. GLOW6 evaluated the efficacy and safety of once-daily coadministration of the long-acting β2-agonist indacaterol (IND and the long-acting muscarinic antagonist glycopyrronium (GLY versus IND alone in patients with moderate-to-severe COPD. Materials and methods: In this randomized, double-blind, parallel group, placebo-controlled, 12-week study, patients were randomized 1:1 to IND 150 µg and GLY 50 µg daily (IND + GLY or IND 150 µg daily and placebo (IND + PBO (all delivered via separate Breezhaler® devices. The primary objective was to demonstrate the superiority of IND + GLY versus IND + PBO for trough forced expiratory volume in 1 second (FEV1 at week 12. Other end points included trough FEV1 at day 1, FEV1 area under the curve from 30 minutes to 4 hours (AUC30min–4h, peak FEV1, inspiratory capacity and trough forced vital capacity (FVC at day 1 and week 12, and transition dyspnea index (TDI focal score, COPD symptoms, and rescue medication use over 12 weeks. Results: A total of 449 patients were randomized (IND + GLY, 226; IND + PBO, 223; 94% completed the study. On day 1 and at week 12, IND + GLY significantly improved trough FEV1 versus IND + PBO, with treatment differences of 74 mL (95% CI 46–101 mL and 64 mL (95% CI 28–99 mL, respectively (both P<0.001. IND + GLY significantly improved postdose peak FEV1, FEV1 AUC30min–4h

  5. Once-daily glycopyrronium bromide, a long-acting muscarinic antagonist, for chronic obstructive pulmonary disease: a systematic review of clinical benefit

    Directory of Open Access Journals (Sweden)

    Ulrik CS

    2012-09-01

    Full Text Available Charlotte Suppli UlrikDepartment of Pulmonary Medicine, Hvidovre Hospital and University of Copenhagen, Copenhagen, DenmarkBackground: Long-acting bronchodilators are central in the pharmacological management of patients with chronic obstructive pulmonary disease (COPD. The aim of this systematic review is to provide an overview of the studies evaluating the safety and clinical efficacy of inhaled glycopyrronium bromide, a novel long-acting muscarinic antagonist, in patients with COPD.Methods: This study was performed as a systematic literature review.Results: Inhaled glycopyrronium bromide seems to be a safe and well tolerated long-acting muscarinic antagonist with a fast onset of action. In patients suffering from moderate to severe COPD, glycopyrronium bromide has clinically important effects on level of forced expiratory volume in one second, use of relief medication, percentage of days with no use of rescue medication, daytime dyspnea scores, and probably also on health status. Furthermore, in this group of patients, glycopyrronium bromide has beneficial effects on dynamic hyperinflation and exercise tolerance. Glycopyrronium bromide has been shown to reduce the rate of exacerbations in patients with moderate to severe COPD, but long-term controlled trials with exacerbation rate as the primary outcome variable have not been published yet.Conclusion: Once-daily inhaled glycopyrronium bromide has characteristics important for use in COPD, including a fast onset of action, sustained 24-hour bronchodilatation, and improvement in exercise tolerance, and therefore appears to have the potential for a significant role in the future management of COPD.Keywords: chronic obstructive pulmonary disease, glycopyrronium bromide, long-acting bronchodilators

  6. Formulation and In Vitro and In Vivo Evaluation of Lipid-Based Terbutaline Sulphate Bi-layer Tablets for Once-Daily Administration.

    Science.gov (United States)

    Hashem, Fahima M; Nasr, Mohamed; Fathy, Gihan; Ismail, Aliaa

    2016-06-01

    The objective of this study was to prepare and evaluate terbutaline sulphate (TBS) bi-layer tablets for once-daily administration. The bi-layer tablets consisted of an immediate-release layer and a sustained-release layer containing 5 and 10 mg TBS, respectively. The sustained-release layer was developed by using Compritol®888 ATO, Precirol® ATO 5, stearic acid, and tristearin, separately, as slowly eroding lipid matrices. A full 4 × 2(2) factorial design was employed for optimization of the sustained-release layer and to explore the effect of lipid type (X 1), drug-lipid ratio (X 2), and filler type (X 3) on the percentage drug released at 8, 12, and 24 h (Y 1, Y 2, and Y 3) as dependent variables. Sixteen TBS sustained-release matrices (F1-F16) were prepared by melt solid dispersion method. None of the prepared matrices achieved the targeted release profile. However, F2 that showed a relatively promising drug release was subjected to trial and error optimization for the filler composition to develop two optimized matrices (F17 and F18). F18 which consisted of drug-Compritol®888 ATO at ratio (1:6 w/w) and Avicel PH 101/dibasic calcium phosphate mixture of 2:1 (w/w) was selected as sustained-release layer. TBS bi-layer tablets were evaluated for their physical properties, in vitro drug release, effect of storage on drug content, and in vivo performance in rabbits. The bi-layer tablets showed acceptable physical properties and release characteristics. In vivo absorption in rabbits revealed initial high TBS plasma levels followed by sustained levels over 24 h compared to immediate-release tablets.

  7. Once daily oral mesalamine compared to conventional dosing for induction and maintenance of remission in ulcerative colitis: a systematic review and meta-analysis.

    Science.gov (United States)

    Feagan, Brian G; MacDonald, John K

    2012-09-01

    We systematically reviewed and compared the efficacy and safety of once daily (OD) mesalamine to conventional dosing for induction and maintenance of remission in ulcerative colitis (UC). A literature search to January 2012 identified all applicable randomized trials. Study quality was evaluated using the Cochrane risk of bias tool. The GRADE criteria were used to assess the overall quality of the evidence. Studies were subgrouped by formulation for meta-analysis. Eleven studies that evaluated 4070 patients were identified. The risk of bias was low for most factors, although five studies were single-blind and one was open-label. No difference was observed between the dosing strategies in the proportion of patients with clinical remission (relative risk [RR] 0.95; 95% confidence interval [CI] 0.82-1.10), clinical improvement (RR 0.87 95% CI 0.68-1.10), or relapse at 6 (RR 1.10; 95% CI 0.83-1.46) or 12 months (RR 0.92; 95% CI 0.83-1.03). Subgroup analyses showed no important differences in efficacy. No significant difference was demonstrated in rates of medication adherence or adverse events between OD and conventional dosing. OD mesalamine appears to be as effective and safe as conventional dosing for both the treatment of mild to moderately active UC and for maintenance of remission in quiescent UC. The failure to demonstrate a superior rate of adherence to OD dosing may be due to the high rate of adherence observed in the clinical trials environment. Future research should assess the value of OD dosing in community settings.

  8. Effectiveness and safety of a long-acting, once-daily, two-phase release formulation of methylphenidate (Ritalin ® LA) in school children under daily practice conditions.

    Science.gov (United States)

    Haertling, Fabian; Mueller, Beate; Bilke-Hentsch, Oliver

    2015-06-01

    Long-acting (LA) preparations of methylphenidate allow for once-daily dosing; however, pharmacokinetics may vary and depend on food intake. The objective was to evaluate effectiveness of a two-phase release formulation (Ritalin(®) LA) under daily practice conditions. This was a prospective, multicenter, observational study in Germany. Eligibility and dosing were determined by the physician based on the drug label. Outcomes included changes over 3 months of treatment in assessments of effect duration, clinical global impression (CGI), and quality of life (ILK). In 101 sites, 262 patients (197 boys, 63 girls, and two unknown) with a mean age of 10.9 years were enrolled; 50 were treated for the first time; 212 switched medication to Ritalin(®) LA. After 3 months, CGI improved in 59.4 % of patients, and well-being overall was rated as good by 61.0 % of parents and 63.7 % of children. Based on parents' assessment, the proportion of children suffering from strong disease burden decreased from 40.7 to 15.1 %. In 123 insufficient responders to previous ADHD medications, benefit from Ritalin(®) LA was above average and effect duration was significantly prolonged as compared to pretreatment. Overall, 28 patients (10.7 %) had treatment-related adverse events with one case being serious; 23 patients (8.8 %) discontinued therapy, 7 (2.7 %) due to poor treatment response; and 212 patients (81 %) continued treatment beyond the study. In line with clinical trial data, Ritalin(®) LA provides significant benefit also under routine practice conditions.

  9. Once-daily indacaterol 75 μg in moderate- to-severe COPD: results of a Phase IV study assessing time until patients' perceived onset of effect.

    Science.gov (United States)

    Siler, Thomas M; LaForce, Craig F; Kianifard, Farid; Williams, James; Spangenthal, Selwyn

    2014-01-01

    Indacaterol 75 μg once daily is a long-acting β2 agonist approved for maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate patients' perception of onset of effect with a single dose. In this double-blind, crossover, Phase IV study, 40 patients were randomized to receive a single dose of indacaterol 75 μg or placebo via a dry powder inhaler device. The primary variable was time until patient's perception of onset of effect, using a simple self-administered (nonvalidated) questionnaire that patients answered at nine protocol-specified time points. Exploratory variables included change in forced expiratory volume in 1 second (FEV1) and change in percent predicted FEV1 from predose to postdose (determined 60-75 minutes postdose). The least-squares mean time to patient's perception of onset of effect was 25.4 minutes and 23.9 minutes for indacaterol and placebo, respectively. There was no significant effect for treatment, period, or sequence on the time to patient's perception. In addition, no statistically significant differences between treatments were observed for patient's global satisfaction with onset of effect and global expectation of treatment adherence. For the exploratory variable change in FEV1 from predose to postdose, indacaterol showed superiority over placebo with a clinically relevant least-squares mean treatment difference of 0.12 L (Pindacaterol 75 μg did not separate from placebo in terms of patient perception of onset, although there was an improvement in FEV1 for indacaterol compared with placebo. Development and use of a validated questionnaire may be needed to address the inconsistency in evaluating this patient-related outcome.

  10. Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol.

    Science.gov (United States)

    Roskell, Neil S; Anzueto, Antonio; Hamilton, Alan; Disse, Bernd; Becker, Karin

    2014-01-01

    In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD), an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, St George's Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol). Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters), the following mean differences (95% confidence interval) were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, -0.005 (-0.077 to 0.067), and indacaterol 150 mcg versus olodaterol 5 mcg, 0.020 (-0.036 to 0.077); trials with concomitant tiotropium: indacaterol 150 mcg versus olodaterol 5 mcg, 0.000 (-0.043 to 0.042). In sensitivity analyses of the full network, results for change from baseline in trough FEV1 favored indacaterol, but this dataset suffered from trial design heterogeneity. For the other endpoints investigated, no statistically significant differences were found when analyzed in the full network. When compared under similar trial conditions, olodaterol and indacaterol have

  11. Once-daily indacaterol 75 μg in moderate- to-severe COPD: results of a Phase IV study assessing time until patients’ perceived onset of effect

    Science.gov (United States)

    Siler, Thomas M; LaForce, Craig F; Kianifard, Farid; Williams, James; Spangenthal, Selwyn

    2014-01-01

    Background Indacaterol 75 μg once daily is a long-acting β2 agonist approved for maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate patients’ perception of onset of effect with a single dose. Methods In this double-blind, crossover, Phase IV study, 40 patients were randomized to receive a single dose of indacaterol 75 μg or placebo via a dry powder inhaler device. The primary variable was time until patient’s perception of onset of effect, using a simple self-administered (nonvalidated) questionnaire that patients answered at nine protocol-specified time points. Exploratory variables included change in forced expiratory volume in 1 second (FEV1) and change in percent predicted FEV1 from predose to postdose (determined 60–75 minutes postdose). Results The least-squares mean time to patient’s perception of onset of effect was 25.4 minutes and 23.9 minutes for indacaterol and placebo, respectively. There was no significant effect for treatment, period, or sequence on the time to patient’s perception. In addition, no statistically significant differences between treatments were observed for patient’s global satisfaction with onset of effect and global expectation of treatment adherence. For the exploratory variable change in FEV1 from predose to postdose, indacaterol showed superiority over placebo with a clinically relevant least-squares mean treatment difference of 0.12 L (Pindacaterol 75 μg did not separate from placebo in terms of patient perception of onset, although there was an improvement in FEV1 for indacaterol compared with placebo. Development and use of a validated questionnaire may be needed to address the inconsistency in evaluating this patient-related outcome. PMID:25214778

  12. Efficacy and safety of indacaterol 150 μg once-daily in COPD: a double-blind, randomised, 12-week study

    Directory of Open Access Journals (Sweden)

    Piggott Simon

    2010-03-01

    Full Text Available Abstract Background Indacaterol is a novel, once-daily (o.d. inhaled, long-acting β2-agonist in development for chronic obstructive pulmonary disease (COPD. This 12-week, double-blind study compared the efficacy, safety, and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD. Methods Efficacy variables included 24-h trough FEV1 (mean of 23 h 10 min and 23 h 45 min post-dose at Week 12 (primary endpoint and after Day 1, and the percentage of COPD days with poor control (i.e., worsening symptoms. Safety was assessed by adverse events (AEs, mean serum potassium and blood glucose, QTc (Fridericia, and vital signs. Results Patients were randomised (n = 416, mean age 63 years to receive either indacaterol 150 μg o.d. (n = 211 or placebo (n = 205 via a single-dose dry-powder inhaler; 87.5% completed the study. Trough FEV1 (LSM ± SEM at Week 12 was 1.48 ± 0.018 L for indacaterol and 1.35 ± 0.019 L for placebo, a clinically relevant difference of 130 ± 24 mL (p 1 after one dose was significantly higher with indacaterol than placebo (p 1 than placebo, both on Day 1 and at Week 12, with indacaterol-placebo differences (LSM ± SEM of 190 ± 28 (p 1 (between 5 min and 4 h, 5 min and 1 h, and 1 and 4 h post-dose at Week 12 were all significantly greater with indacaterol than placebo (p 500 ms. Conclusions Indacaterol 150 μg o.d. provided clinically significant and sustained bronchodilation, reduced rescue medication use, and had a safety and tolerability profile similar to placebo. Trial registration NCT00624286

  13. Improving treatment satisfaction and other patient-reported outcomes in people with type 2 diabetes: the role of once-daily insulin glargine.

    Science.gov (United States)

    Bradley, C; Gilbride, C J B

    2008-07-01

    Insulin therapy becomes essential for many people with type 2 diabetes. After starting insulin, people with diabetes that is poorly controlled with oral agents typically report improved well-being and treatment satisfaction. However, healthcare professionals and people with type 2 diabetes are often reluctant to begin insulin treatment, citing concerns such as time/resources needed to educate patients, increased risks of hypoglycaemia and fear of injections, which lead them to focus on intensifying conventional oral therapy. Insulin glargine, which offers people with diabetes a once-a-day injection regimen with low risk of hypoglycaemia, is more likely to overcome such initial barriers than other more complex insulin regimens. Once-daily insulin glargine, in combination with modern glucose-dependent oral agents that do not need to be chased with food to prevent hypoglycaemia, does not require the fixed mealtimes and set amounts of carbohydrates necessary with twice-daily injection mixes and older sulphonylureas. We know that it is such dietary restrictions that cause the most damage to quality of life (QoL). To avoid damaging QoL unnecessarily and to ensure optimal satisfaction with treatment, it is important to evaluate the effects of treatment on QoL, treatment satisfaction and other patient-reported outcomes (PROs) using questionnaires validated for this purpose, such as the widely used Diabetes Treatment Satisfaction Questionnaire and the Audit of Diabetes-Dependent Quality of Life measure. A systematic electronic literature search identified reports of studies evaluating PROs associated with insulin glargine in comparison with other treatments. The studies show that insulin glargine is usually associated with greater improvements in treatment satisfaction and other PROs compared with intensifying oral therapy or alternative insulin regimens.

  14. Immunovirological Efficacy of Once-Daily Maraviroc Plus Ritonavir-Boosted Atazanavir After 48 Weeks in Naive HIV-Infected Patients.

    Science.gov (United States)

    Pulido, Ildefonso; Genebat, Miguel; Alvarez-Rios, Ana I; De Pablo-Bernal, Rebeca S; Rafii-El-Idrissi Benhnia, Mohammed; Pacheco, Yolanda M; Ruiz-Mateos, Ezequiel; Leal, Manuel

    2016-10-01

    Toxicities related to the use of nucleoside analogues have increased the interest in developing nucleoside-sparing regimens, mainly combining protease inhibitors with raltegravir. However, data regarding the use of CCR5-antagonists in this setting and in the naive scenario are scarce. The main objective was to analyze the immunovirological efficacy and tolerability of a low-dose, once-daily, maraviroc (MVC)-containing, nucleoside reverse transcriptase inhibitor-sparing dual therapy compared with standard triple therapy after 48 weeks for naive HIV-infected patients in the routine clinical practice setting. All naive HIV-infected patients with stable clinical condition that started antiretroviral treatment since February 1, 2008 to May 30,h 2012 were included. MVC clinical test was used to select candidate subjects to MVC therapy. Thirty-two subjects with MVC + atazanavir/ritonavir (ATV/r) and 66 with standard triple therapy were analyzed. A comparable virological efficacy between groups was found after 48 weeks (87.5% vs. 80.3% of HIV undetectability, p = 0.37, MVC + ATV/r and triple therapy groups, respectively). The CD4 recovery after 48 weeks was similar and more than 200 cells/mm(3) in both groups. No need of therapy changes or treatment discontinuations was observed in the MVC + ATV/r group. Effect on lipid profile, high-sensitivity C reactive protein, and β2-microglobulin was similar for both groups. Noteworthy, a significant increase of erythrocyte mean corpuscular volume was observed only in the triple therapy group. A nucleoside-sparing MVC-containing dual therapy showed similar immunovirological efficacy and tolerability than standard triple therapy in naive HIV-infected patients.

  15. Sustained effects of once-daily memantine treatment on cognition and functional communication skills in patients with moderate to severe Alzheimer's disease: results of a 16-week open-label trial.

    Science.gov (United States)

    Schulz, Jörg B; Rainer, Michael; Klünemann, Hans-Hermann; Kurz, Alexander; Wolf, Stefanie; Sternberg, Kati; Tennigkeit, Frank

    2011-01-01

    The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer's disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE < 20; n = 97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. The primary efficacy endpoint was the change from baseline in the Consortium to Establish a Registry for Alzheimer's Disease -Neuropsychological Battery (CERAD-NP) total score. Secondary efficacy endpoints included change from baseline in Functional Communication Language Inventory (FLCI) and ADCS-ADL19 total score, and the response from baseline in Clinical Global Impression of Change (CGI-C). The CERAD-NP total score improved significantly after 12 weeks of once-daily memantine treatment compared with baseline (5.9 ± 8.8; p < 0.0001). The FLCI total score improved significantly after 12 weeks compared with baseline (4.4 ± 6.8; p < 0.0001). These significant improvements were already observed after 4 and 8 weeks of once-daily memantine treatment and persisted after a 4-week wash-out period. ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile.

  16. Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain

    DEFF Research Database (Denmark)

    Jensen, Michael Gejl; Lerche, Susanne; Egefjord, Lærke

    2013-01-01

    hypoglycemia study and our previous hyperglycemia study to estimate the Michaelis-Menten constants of glucose transport and metabolism. The GLP-1 treatment lowered the vascular volume of brain tissue. Loading data from hypo- to hyperglycemia into the Michaelis-Menten equation, we found increased maximum...

  17. Effects of treatment with glucagon-like peptide-2 on bone resorption in colectomized patients with distal ileostomy or jejunostomy and short-bowel syndrome

    DEFF Research Database (Denmark)

    Gottschalck, I.B.; Jeppesen, Palle Bekker; Hartmann, B.;

    2008-01-01

    OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome (...... and therefore precludes treatment of their osteopenia with GLP-2. The anti-resorptive response to GLP-2 seems to require an intact small intestine and may involve suppression of PTH secretion Udgivelsesdato: 2008......OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome...... (SBS) and they have reduced bone mineral density (BMD). The aim of the study was to investigate the anti-resorptive effect (assessed by s-CTX) of 14 days of GLP-2 treatment in these patients and to determine whether 56 days of treatment would improve BMD. PTH secretion in response to GLP-2 was also...

  18. Effects of treatment with glucagon-like peptide-2 on bone resorption in colectomized patients with distal ileostomy or jejunostomy and short-bowel syndrome

    DEFF Research Database (Denmark)

    Gottschalck, Ida B; Jeppesen, Palle B; Hartmann, Bolette;

    2008-01-01

    OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome (...... and therefore precludes treatment of their osteopenia with GLP-2. The anti-resorptive response to GLP-2 seems to require an intact small intestine and may involve suppression of PTH secretion.......OBJECTIVE: The gut hormone GLP-2 (glucagon-like peptide-2) seems to be involved in the circadian pattern of bone resorption, whereas parathyroid hormone (PTH) is an established key hormone in bone turnover. Endogenous GLP-2 secretion is lacking in colectomized patients with short-bowel syndrome...... (SBS) and they have reduced bone mineral density (BMD). The aim of the study was to investigate the anti-resorptive effect (assessed by s-CTX) of 14 days of GLP-2 treatment in these patients and to determine whether 56 days of treatment would improve BMD. PTH secretion in response to GLP-2 was also...

  19. Pharmacokinetics and metabolism studies on the glucagon-like peptide-1 (GLP-1)-derived metabolite GLP-1(9-36)amide in male Beagle dogs.

    Science.gov (United States)

    Eng, Heather; Sharma, Raman; McDonald, Thomas S; Landis, Margaret S; Stevens, Benjamin D; Kalgutkar, Amit S

    2014-09-01

    Glucagon-like peptide-1 (GLP-1)(7-36)amide is a 30-amino acid peptide hormone that is secreted from intestinal enteroendocrine L-cells in response to nutrients. GLP-1(7-36)amide possesses potent insulinotropic actions in the augmentation of glucose-dependent insulin secretion. GLP-1(7-36)amide is rapidly metabolized by dipeptidyl peptidase-IV to yield GLP-1(9-36)amide as the principal metabolite. Contrary to the earlier notion that peptide cleavage products of native GLP-1(7-36)amide [including GLP-1(9-36)amide] are pharmacologically inactive, recent studies have demonstrated cardioprotective and insulinomimetic effects with GLP-1(9-36)amide in mice, dogs and humans. In the present work, in vitro metabolism and pharmacokinetic properties of GLP-1(9-36)amide have been characterized in dogs, since this preclinical species has been used as an animal model to demonstrate the in vivo vasodilatory and cardioprotective effects of GLP-1(9-36)amide. A liquid chromatography tandem mass spectrometry assay was developed for the quantitation of the intact peptide in hepatocyte incubations as opposed to a previously reported enzyme-linked immunosorbent assay. Although GLP-1(9-36)amide was resistant to proteolytic cleavage in dog plasma and bovine serum albumin (t1/2>240 min), the peptide was rapidly metabolized in dog hepatocytes with a t1/2 of 110 min. Metabolite identification studies in dog hepatocytes revealed a variety of N-terminus cleavage products, most of which, have also been observed in human and mouse hepatocytes. Proteolysis at the C-terminus was not observed in GLP-1(9-36)amide. Following the administration of a single intravenous bolus dose (20 µg/kg) to male Beagle dogs, GLP-1(9-36)amide exhibited a mean plasma clearance of 15 ml/min/kg and a low steady state distribution volume of 0.05 l/kg, which translated into a short elimination half life of 0.05 h. Following subcutaneous administration of GLP-1(9-36)amide at 50 µg/kg, systemic exposure of

  20. The Impact of Pancreatic Enzyme Supplementation on Postprandial Responses of Glucagon-Like Peptide-2 in Patients with Chronic Pancreatitis and Pancreatic Exocrine Insufficiency

    Directory of Open Access Journals (Sweden)

    Filip K Knop

    2010-09-01

    Full Text Available Dear Sir, We have recently shown that patients with chronic pancreatitis and pancreatic exocrine insufficiency exhibit greater postprandial responses of the intestinal hormone glucagon-like peptide-2 (GLP-2 as compared to healthy control subjects [1]. GLP-2 is a 33-amino acid peptide hormone secreted by the endocrine L cells of the intestinal mucosa following meal ingestion [2]. It acts as a growth factor in the small intestine [3] and, in patients with functional short-bowel syndrome, GLP-2 has been shown to improve intestinal absorption [4]. Furthermore, GLP-2 seems to increase intestinal blood flow [5], including blood flow in the superior mesenteric artery of pigs [6] and humans [7]. Interestingly, our recent observation of increased postprandial GLP-2 responses in patients with chronic pancreatitis and pancreatic exocrine insufficiency correlated with increased postprandial blood flow in the superior mesenteric arteries of these patients [1]. However, the mechanisms behind the increased postprandial GLP-2 response in chronic pancreatitis patients with pancreatic exocrine insufficiency could only be speculated upon, with one explanation being that reduced assimilation of nutrients in the proximal part of the small intestine results in delivery of a larger nutrient load to the distal L cell-rich part of the small intestine. Reduced assimilation of nutrients in chronic pancreatitis patients with pancreatic exocrine insufficiency can be clinically modulated by the administration of pancreatic enzyme supplementation. In 2007, we reported that pancreatic enzyme supplementation in these patients resulted in increased postprandial secretion of GLP-2’s sister peptide, GLP-1, also released from intestinal L cells [8]. In order to investigate potential mechanisms behind exaggerated GLP-2 levels in chronic pancreatitis we evaluated the impact of pancreatic enzyme supplementation on postprandial GLP-2 responses in the chronic pancreatitis patients

  1. Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol

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    Roskell NS

    2014-07-01

    Full Text Available Neil S Roskell,1 Antonio Anzueto,2 Alan Hamilton,3 Bernd Disse,4 Karin Becker5 1Statistics, Bresmed Health Solutions Ltd, Sheffield, UK; 2School of Medicine, University of Texas Health Science Center, San Antonio, TX, USA; 3Medical Department, Boehringer Ingelheim (Canada Ltd, Burlington, ON, Canada; 4Medical Department, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany; 5Global Health Economics and Outcomes Research, Boehringer Ingelheim GmbH, Ingelheim am Rhein, Germany Purpose: In the absence of head-to-head clinical trials comparing the once-daily, long-acting beta2-agonists olodaterol and indacaterol for the treatment of chronic obstructive pulmonary disease (COPD, an indirect treatment comparison by systematic review and synthesis of the available clinical evidence was conducted. Methods: A systematic literature review of randomized, controlled clinical trials in patients with COPD was performed to evaluate the efficacy and safety of olodaterol and indacaterol. Network meta-analysis and adjusted indirect comparison methods were employed to evaluate treatment efficacy, using outcomes based on trough forced expiratory volume in 1 second (FEV1, Transition Dyspnea Index, St George’s Respiratory Questionnaire total score and response, rescue medication use, and proportion of patients with exacerbations. Results: Eighteen trials were identified for meta-analysis (eight, olodaterol; ten, indacaterol. Olodaterol trials included patients of all severities, whilst indacaterol trials excluded patients with very severe COPD. Concomitant maintenance bronchodilator use was allowed in most olodaterol trials, but not in indacaterol trials. When similarly designed trials/data were analyzed for change from baseline in trough FEV1 (liters, the following mean differences (95% confidence interval were observed: trials excluding concomitant bronchodilator: indacaterol 75 mcg versus olodaterol 5 mcg, –0.005 (–0.077 to 0.067, and indacaterol 150 mcg

  2. The decrease in milk yield during once daily milking is due to regulation of synthetic activity rather than apoptosis of mammary epithelial cells in goats.

    Science.gov (United States)

    Ben Chedly, H; Lacasse, P; Marnet, P-G; Boutinaud, M

    2013-01-01

    Once daily milking (ODM) is a management practice that can improve working conditions and reduce production costs in dairy farming compared with twice daily milking (TDM). However, ODM is associated with a decrease in milk yield. Previous research indicated that disruption of tight junctions in the mammary gland may be one of the regulatory factors involved in the milk yield decrease observed during ODM. The aim of this study was to investigate the involvement of mammary epithelium disruption in the regulation of the activity and dynamics of mammary epithelial cells (MEC) during 5 weeks of ODM in goats. Twelve alpine goats (producing 3.67 ± 0.64 kg/day and 47 ± 1.6 days in milk) were assigned to two groups that were milked once or twice a day during 5 weeks and then switched back to TDM. Mammary biopsies were collected before and on days 2 and 16 of both ODM and TDM switchback periods. Milk purified epithelial cells were collected before and on days 1, 7, 21 and 28 during ODM as well on days 1 and 7 of the TDM switchback period. The mRNA levels of genes involved in the regulation of synthetic activity and apoptosis were analysed by RT-PCR in milk MEC and mammary biopsies. ODM decreased yields of milk (-23%), lactose (-23%) and casein (-16%). Lactose synthesis was regulated at the transcriptional level by downregulation of α-lactalbumin mRNA levels in both biopsy samples (-30%) and milk MEC (-74%). TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling) staining of mammary gland biopsies did not show any increase in cell apoptosis after 2 and 16 days of ODM (0.8% and 1%, respectively) despite upregulation of Bax mRNA levels in milk MEC. This suggests that the decrease in milk yield observed during ODM is attributable to a decrease in synthetic activity rather than to induction of MEC cell death. ODM induced the disruption of tight junctions in the mammary gland only on the first day of the treatment as indicated by increased blood

  3. Efficacy and safety of indacaterol 150 μg once-daily in COPD: a double-blind, randomised, 12-week study

    Science.gov (United States)

    2010-01-01

    Background Indacaterol is a novel, once-daily (o.d.) inhaled, long-acting β2-agonist in development for chronic obstructive pulmonary disease (COPD). This 12-week, double-blind study compared the efficacy, safety, and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD. Methods Efficacy variables included 24-h trough FEV1 (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (primary endpoint) and after Day 1, and the percentage of COPD days with poor control (i.e., worsening symptoms). Safety was assessed by adverse events (AEs), mean serum potassium and blood glucose, QTc (Fridericia), and vital signs. Results Patients were randomised (n = 416, mean age 63 years) to receive either indacaterol 150 μg o.d. (n = 211) or placebo (n = 205) via a single-dose dry-powder inhaler; 87.5% completed the study. Trough FEV1 (LSM ± SEM) at Week 12 was 1.48 ± 0.018 L for indacaterol and 1.35 ± 0.019 L for placebo, a clinically relevant difference of 130 ± 24 mL (p indacaterol than placebo (p Indacaterol demonstrated significantly higher peak FEV1 than placebo, both on Day 1 and at Week 12, with indacaterol-placebo differences (LSM ± SEM) of 190 ± 28 (p indacaterol than placebo (p Indacaterol significantly reduced the percentage of days of poor control versus placebo by 22.5% (p indacaterol 49.3%, placebo 46.8%), with the most common AEs being COPD worsening (indacaterol 8.5%, placebo 12.2%) and cough (indacaterol 6.2%, placebo 7.3%). One patient died in the placebo group. Serum potassium and blood glucose levels did not differ significantly between the two groups, and no patient had QTc >500 ms. Conclusions Indacaterol 150 μg o.d. provided clinically significant and sustained bronchodilation, reduced rescue medication use, and had a safety and tolerability profile similar to placebo. Trial registration NCT00624286 PMID:20211002

  4. Once-daily indacaterol 75 µg in moderate- to-severe COPD: results of a Phase IV study assessing time until patients’ perceived onset of effect

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    Siler TM

    2014-09-01

    Full Text Available Thomas M Siler,1 Craig F LaForce,2 Farid Kianifard,3 James Williams,3 Selwyn Spangenthal4 1Midwest Chest Consultants, St Charles, MO, USA; 2North Carolina Clinical Research, Raleigh, NC, USA; 3Novartis Pharmaceuticals, East Hanover, NJ, USA; 4Charlotte Lung and Health Center, Charlotte, NC, USA Background: Indacaterol 75 µg once daily is a long-acting β2 agonist approved for maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD. The purpose of this study was to evaluate patients' perception of onset of effect with a single dose. Methods: In this double-blind, crossover, Phase IV study, 40 patients were randomized to receive a single dose of indacaterol 75 µg or placebo via a dry powder inhaler device. The primary variable was time until patient’s perception of onset of effect, using a simple self-administered (nonvalidated questionnaire that patients answered at nine protocol-specified time points. Exploratory variables included change in forced expiratory volume in 1 second (FEV1 and change in percent predicted FEV1 from predose to postdose (determined 60–75 minutes postdose. Results: The least-squares mean time to patient’s perception of onset of effect was 25.4 minutes and 23.9 minutes for indacaterol and placebo, respectively. There was no significant effect for treatment, period, or sequence on the time to patient's perception. In addition, no statistically significant differences between treatments were observed for patient's global satisfaction with onset of effect and global expectation of treatment adherence. For the exploratory variable change in FEV1 from predose to postdose, indacaterol showed superiority over placebo with a clinically relevant least-squares mean treatment difference of 0.12 L (P<0.0001. There was little or no association between patient’s perception of time to onset of effect and change in FEV1, or change in percent predicted FEV1. Both treatments were well

  5. A UK-based cost-utility analysis of indacaterol, a once-daily maintenance bronchodilator for patients with COPD, using real world evidence on resource use.

    Science.gov (United States)

    Price, David; Asukai, Yumi; Ananthapavan, Jaithri; Malcolm, Bill; Radwan, Amr; Keyzor, Ian

    2013-06-01

    Chronic Obstructive Pulmonary Disease (COPD) is a chronic, progressive disease that is not curable. However, there are effective treatments available. In the UK, long-acting bronchodilators are first-line treatments for COPD patients requiring maintenance therapy, and there are several options available. The aim of this study is to establish, from the UK National Health Service (NHS) perspective, the cost-effectiveness profile of indacaterol, the first once-daily long-acting beta2-agonist (LABA), compared with tiotropium and salmeterol, in patients with moderate to severe COPD. In assessing the cost-effectiveness of COPD therapies, this study has the advantage of using real world evidence on the resource use associated with COPD management across the spectrum of the disease. A Markov model was developed with four health states following the GOLD classification for severity of airflow limitation. The model time horizon was 3 years, and the cycle length was 3 months. From each state, patients could experience a severe or non-severe exacerbation, move to a different COPD state, remain in the current state or die. Transition probabilities were based on data from the indacaterol clinical trials. The majority of the resource use data was taken from the Optimum Patient Care Research Database (OPCRD), which contains data from over 20,000 COPD patients in England and Scotland. Cost data were taken from UK-based sources and published literature and presented for the cost year 2011. Health-related quality of life was the main outcome of interest and utility data for the COPD states were based on data from the indacaterol clinical trials and disutility due to exacerbations were taken from the literature. Both one way and probabilistic sensitivity analyses were performed to test the robustness of the results. Indacaterol dominated in the comparison with salmeterol producing an incremental QALY gain of 0.008 and cost savings of £110 per patient over a 3-year time horizon. In

  6. Prediction of efficacy for conversion from adjunctive therapy to monotherapy with eslicarbazepine acetate 800 mg once daily for partial-onset epilepsy

    Science.gov (United States)

    Sunkaraneni, Soujanya; Passarell, Julie A; Ludwig, Elizabeth A; Fiedler-Kelly, Jill; Pitner, Janet K; Grinnell, Todd A; Blum, David

    2017-01-01

    Purpose Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). Clinical studies of gradual conversion to ESL 1,200 and 1,600 mg QD monotherapies were previously conducted in patients with POS who were not well-controlled by 1 or 2 AEDs. This report describes modeling and simulation of plasma eslicarbazepine (primary active metabolite of ESL) concentrations and time to monotherapy study exit to predict efficacy for conversion to ESL monotherapy at a lower dose of 800 mg, as an option for patients requiring or not tolerating higher doses since this regimen is effective in adjunctive therapy for POS. Patients and methods A previously developed population pharmacokinetic model for ESL monotherapy was used to predict minimum plasma eslicarbazepine concentration (Cmin) in 1,500 virtual patients taking 1 (n=1,000) or 2 (n=500) AEDs at baseline, treated with ESL 400 mg QD for 1 week, followed by 800 mg QD for 17 weeks (similar to ESL monotherapy trials where the other AEDs were withdrawn during the first 6 weeks following titration to the randomized ESL dose). Model-predicted Cmin as a time-varying covariate and number of baseline AEDs were used to determine the weekly probability of each patient meeting exit criteria (65.3% threshold) indicative of worsening seizure control in 500 simulated ESL monotherapy trials. A previously developed extended Cox proportional hazards exposure–response model was used to relate time-varying eslicarbazepine exposure to the time to study exit. Results For virtual patients receiving ESL monotherapy (800 mg QD), the 95% upper prediction limit for exit rate at 112 days of 34.9% in patients taking 1 AED at baseline was well below the 65.3% threshold from historical control trials, while the estimate for patients taking 2 AEDs (70.6%) was slightly above the historical control threshold. Conclusion This model-based assessment supports conversion to ESL 800 mg QD monotherapy

  7. Indacaterol, a once-daily beta2-agonist, versus twice-daily beta₂-agonists or placebo for chronic obstructive pulmonary disease.

    Science.gov (United States)

    Geake, James B; Dabscheck, Eli J; Wood-Baker, Richard; Cates, Christopher J

    2015-01-10

    Indacaterol is an inhaled long-acting beta2-agonist that is administered once daily and has been investigated as a treatment for chronic obstructive pulmonary disease (COPD). Four different doses have been investigated (75 mcg, 150 mcg, 300 mcg and 600 mcg). The relative effects of different doses of once-daily indacaterol in the management of patients with COPD are uncertain. To compare the efficacy and safety of indacaterol versus placebo and alternative twice-daily long-acting beta2-agonists for the treatment of patients with stable COPD. We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), handsearched respiratory journals and meeting abstracts and searched the Novartis trials registry and ClinicalTrials.gov. The date of the most recent search was 8 November 2014. We included all randomised controlled trials comparing indacaterol at any dose versus placebo or alternative long-acting beta2-agonists. Trials were required to be of at least 12 weeks' duration and had to include adults older than 18 years with a confirmed spirometric diagnosis of COPD. Two review authors (JBG, EJD) independently assessed for possible inclusion all citations identified as a result of the search. Disagreements were resolved through discussion or, if required, through resolution by a third review author (RWB). One review author (JBG) extracted data from trials identified by the search and entered these data into Review Manager 5.1 for statistical analysis. Data entry was cross-checked by a second review author (EJD, CJC). A total of 13 trials with 9961 participants were included in the review. Ten trials with a total of 8562 participants involved an indacaterol versus placebo comparison. Five trials with a total of 4133 participants involved an indacaterol versus twice-daily beta2-agonist comparison. The comparator beta2-agonists were salmeterol, formoterol and eformoterol. One of these trials, with a total of 90 participants, provided no data

  8. Jejunal feeding is followed by a greater rise in plasma cholecystokinin, peptide YY, glucagon-like peptide 1, and glucagon-like peptide 2 concentrations compared with gastric feeding in vivo in humans

    DEFF Research Database (Denmark)

    Luttikhold, Joanna; van Norren, Klaske; Rijna, Herman;

    2016-01-01

    ± SD age: 21 ± 2 y) received continuous enteral nutrition that contained noncoagulating proteins for 12 h via a nasogastric tube or a nasojejunal tube placed 30-40 cm distal to the ligament of Treitz. Blood samples were collected during the 12-h postprandial period to assess the rise in plasma glucose...

  9. Effects of Tadalafil Once-Daily or On-Demand vs Placebo on Return to Baseline Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy - Results from a Randomized Controlled Trial (REACTT)

    DEFF Research Database (Denmark)

    Mulhall, John P; Brock, Gerald; Oelke, Matthias;

    2016-01-01

    INTRODUCTION AND AIM: The multicenter, randomized, double-blind, double-dummy, placebo-controlled REACTT trial suggested that treatment with tadalafil once daily (OaD) started early after bilateral nerve-sparing radical prostatectomy (nsRP) for prostate cancer may contribute to erectile function ...

  10. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial

    DEFF Research Database (Denmark)

    Bretzel, R.G.; Nuber, U.; Landgraf, W.

    2008-01-01

    BACKGROUND: As type 2 diabetes mellitus progresses, oral hypoglycaemic agents often fail to maintain blood glucose control and insulin is needed. We investigated whether the addition of once-daily insulin glargine is non-inferior to three-times daily prandial insulin lispro in overall glycaemic c...

  11. Functional ontogeny of the proglucagon-derived peptide axis in the premature human neonate

    DEFF Research Database (Denmark)

    Amin, Harish; Holst, Jens Juul; Hartmann, Bolette

    2008-01-01

    assimilation, intestinal growth, and function. OBJECTIVE: Our goal was to investigate the production of glucagon-like peptides 1 and 2 in premature human infants and examine the effects of prematurity and feeding on hormone release. PATIENTS AND METHODS: With informed consent, premature infants who were...... levels of both glucagon-like peptides 1 and 2 were elevated. There was no correlation between gestational age and glucagon-like peptide 2 output. However, both glucagon-like peptide 1 and 2 levels were correlated with the caloric value of feeds. CONCLUSIONS: The premature human neonate has significantly...... higher fasting levels of glucagon-like peptides 1 and 2 compared with adults; feeding increases these levels further. These findings suggest that the proglucagon-derived peptides may have a role in normal intestinal development and nutrient handling....

  12. Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice

    Directory of Open Access Journals (Sweden)

    Shaocong Hou

    2015-01-01

    Full Text Available Glucagon like peptide-1 (GLP-1 receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

  13. Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice.

    Science.gov (United States)

    Hou, Shaocong; Li, Caina; Huan, Yi; Liu, Shuainan; Liu, Quan; Sun, Sujuan; Jiang, Qian; Jia, Chunming; Shen, Zhufang

    2015-01-01

    Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increased β-cell area, improved islet morphology, and reduced β-cell apoptosis. In accordance with the promotion of β-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promoting β-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

  14. The glucagon-like peptide 1 analogue Exendin-4 attenuates the nicotine-induced locomotor stimulation, accumbal dopamine release, conditioned place preference as well as the expression of locomotor sensitization in mice.

    Directory of Open Access Journals (Sweden)

    Emil Egecioglu

    Full Text Available The gastrointestinal peptide glucagon-like peptide 1 (GLP-1 is known to regulate consummatory behavior and is released in response to nutrient ingestion. Analogues of this peptide recently emerged as novel pharmacotherapies for treatment of type II diabetes since they reduce gastric emptying, glucagon secretion as well as enhance glucose-dependent insulin secretion. The findings that GLP-1 targets reward related areas including mesolimbic dopamine areas indicate that the physiological role of GLP-1 extends beyond food intake and glucose homeostasis control to include reward regulation. The present series of experiments was therefore designed to investigate the effects of the GLP-1 receptor agonist, Exendin-4 (Ex4, on established nicotine-induced effects on the mesolimbic dopamine system in mice. Specifically, we show that treatment with Ex4, at a dose with no effect per se, attenuate nicotine-induced locomotor stimulation, accumbal dopamine release as well as the expression of conditioned place preference in mice. In accordance, Ex4 also blocks nicotine-induced expression of locomotor sensitization in mice. Given that development of nicotine addiction largely depends on the effects of nicotine on the mesolimbic dopamine system these findings indicate that the GLP-1 receptor may be a potential target for the development of novel treatment strategies for nicotine cessations in humans.

  15. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1.

    Science.gov (United States)

    den Besten, Gijs; Gerding, Albert; van Dijk, Theo H; Ciapaite, Jolita; Bleeker, Aycha; van Eunen, Karen; Havinga, Rick; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M

    2015-01-01

    The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

  16. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1.

    Directory of Open Access Journals (Sweden)

    Gijs den Besten

    Full Text Available The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs, have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR γ repression and AMP-activated protein kinase (AMPK activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

  17. Comparison of efficacies of once-daily dose multimatrix mesalazine and multiple-dose mesalazine for the maintenance of remission in ulcerative colitis: a randomized, double-blind study.

    Science.gov (United States)

    Ogata, Haruhiko; Ohori, Akihiro; Nishino, Haruo; Mizushima, Seiichi; Hagino, Atsushi; Hibi, Toshifumi

    2017-07-01

    This study compared the efficacy of once-daily administration of multimatrix mesalazine 2.4 g/day with multiple-dose mesalazine for the maintenance of remission. In this multicenter, randomized, double-blind study, 203 patients with ulcerative colitis in remission received multimatrix mesalazine 2.4 g/day once-daily or time-dependent (controlled-release) mesalazine 2.25 g/day 3 times-daily for 48 weeks. The primary efficacy endpoint was the proportion of patients without rectal bleeding. The proportion of patients without rectal bleeding during the 48-week treatment period in the per protocol set was 84.8% (84/99) in the multimatrix mesalazine 2.4 g/day group and 78.0% (78/100) in the controlled-release mesalazine 2.25 g/day group. The difference between the 2 treatment groups was 6.8% (two-sided 95% confidence interval, -3.9% to 17.6%). The noninferiority margin of -10% was met in the comparison of multimatrix mesalazine 2.4 g/day once-daily with controlled-release mesalazine 2.25 g/day. Multimatrix mesalazine 2.4 g/day once-daily demonstrated consistent efficacy in all subgroups. There was no difference between the 2 treatment groups with regard to safety. A once-daily dose of 2 multimatrix mesalazine tablets (2.4 g) was not inferior to controlled-release mesalazine 2.25 g/day 3 times-daily in maintaining absence of rectal bleeding in ulcerative colitis.

  18. Efficacy of once-daily indacaterol 75 μg relative to alternative bronchodilators in COPD: A study level and a patient level network meta-analysis

    Science.gov (United States)

    2012-01-01

    Background The objective of this study was to evaluate the comparative efficacy of indacaterol 75 μg once daily (OD), tiotropium 18 μg OD, salmeterol 50 μg twice daily (BID), formoterol 12 μg BID, and placebo for the treatment of chronic obstructive pulmonary disease (COPD) based on individual patient data (IPD) from randomized controlled trials (RCTs) from the indacaterol trial program and aggregate data (AD) identified from a systematic review of RCTs. Methods 22 RCTs were included in the AD analysis that evaluated: indacaterol 75 μg (n = 2 studies), indacaterol 150 μg n = 5 (i.e. salmeterol 50 μg) (n = 5), indacaterol 300 μg (n = 2), tiotropium 18 μg (n = 10), salmeterol 50 μg (n = 7), and formoterol 12 μg (n = 4). All of the studies except for one head-to-head comparison (tiotropium vs. salmeterol) were placebo controlled. Outcomes of interest were trough forced expiratory volume in 1 second (FEV1) and St. George’s Respiratory Questionnaire (SGRQ) total score at week 12. The AD from all trials was analysed simultaneously using a Bayesian network meta-analysis (NMA) and relative treatment effects between all regimens were obtained. In a separate analysis, the IPD available from the 6 indacaterol RCTs was analysed in a NMA. Treatment-by-covariate interactions were included in both analyses to improve similarity of the trials. Results All interventions compared were more efficacious than placebo regarding FEV1 at 12 weeks. Indacaterol 75 μg is expected to result in a comparable FEV1 at 12 weeks to tiotropium and salmeterol based on both IPD and AD analyses. In comparison to formoterol, the IPD and AD results indicate indacaterol 75 μg is more efficacious (IPD = 0.07 L difference; 95%Credible Interval (CrI) 0.02 to 0.11; AD = 0.05 L difference; 95%CrI 0.01; 0.09). In terms of SGRQ total score at 12 weeks, indacaterol 75 μg and formoterol were more efficacious than placebo

  19. Efficacy of once-daily indacaterol 75 μg relative to alternative bronchodilators in COPD: a study level and a patient level network meta-analysis.

    Science.gov (United States)

    Cope, Shannon; Zhang, Jie; Williams, James; Jansen, Jeroen P

    2012-06-25

    The objective of this study was to evaluate the comparative efficacy of indacaterol 75 μg once daily (OD), tiotropium 18 μg OD, salmeterol 50 μg twice daily (BID), formoterol 12 μg BID, and placebo for the treatment of chronic obstructive pulmonary disease (COPD) based on individual patient data (IPD) from randomized controlled trials (RCTs) from the indacaterol trial program and aggregate data (AD) identified from a systematic review of RCTs. 22 RCTs were included in the AD analysis that evaluated: indacaterol 75 μg (n = 2 studies), indacaterol 150 μg n = 5 (i.e. salmeterol 50 μg) (n = 5), indacaterol 300 μg (n = 2), tiotropium 18 μg (n = 10), salmeterol 50 μg (n = 7), and formoterol 12 μg (n = 4). All of the studies except for one head-to-head comparison (tiotropium vs. salmeterol) were placebo controlled. Outcomes of interest were trough forced expiratory volume in 1 second (FEV1) and St. George's Respiratory Questionnaire (SGRQ) total score at week 12. The AD from all trials was analysed simultaneously using a Bayesian network meta-analysis (NMA) and relative treatment effects between all regimens were obtained. In a separate analysis, the IPD available from the 6 indacaterol RCTs was analysed in a NMA. Treatment-by-covariate interactions were included in both analyses to improve similarity of the trials. All interventions compared were more efficacious than placebo regarding FEV1 at 12 weeks. Indacaterol 75 μg is expected to result in a comparable FEV1 at 12 weeks to tiotropium and salmeterol based on both IPD and AD analyses. In comparison to formoterol, the IPD and AD results indicate indacaterol 75 μg is more efficacious (IPD = 0.07 L difference; 95%Credible Interval (CrI) 0.02 to 0.11; AD = 0.05 L difference; 95%CrI 0.01; 0.09). In terms of SGRQ total score at 12 weeks, indacaterol 75 μg and formoterol were more efficacious than placebo, whereas for tiotropium and salmeterol the credible intervals included zero for the AD results only

  20. Efficacy of once-daily indacaterol 75 μg relative to alternative bronchodilators in COPD: A study level and a patient level network meta-analysis

    Directory of Open Access Journals (Sweden)

    Cope Shannon

    2012-06-01

    Full Text Available Abstract Background The objective of this study was to evaluate the comparative efficacy of indacaterol 75 μg once daily (OD, tiotropium 18 μg OD, salmeterol 50 μg twice daily (BID, formoterol 12 μg BID, and placebo for the treatment of chronic obstructive pulmonary disease (COPD based on individual patient data (IPD from randomized controlled trials (RCTs from the indacaterol trial program and aggregate data (AD identified from a systematic review of RCTs. Methods 22 RCTs were included in the AD analysis that evaluated: indacaterol 75 μg (n = 2 studies, indacaterol 150 μg n = 5 (i.e. salmeterol 50 μg (n = 5, indacaterol 300 μg (n = 2, tiotropium 18 μg (n = 10, salmeterol 50 μg (n = 7, and formoterol 12 μg (n = 4. All of the studies except for one head-to-head comparison (tiotropium vs. salmeterol were placebo controlled. Outcomes of interest were trough forced expiratory volume in 1 second (FEV1 and St. George’s Respiratory Questionnaire (SGRQ total score at week 12. The AD from all trials was analysed simultaneously using a Bayesian network meta-analysis (NMA and relative treatment effects between all regimens were obtained. In a separate analysis, the IPD available from the 6 indacaterol RCTs was analysed in a NMA. Treatment-by-covariate interactions were included in both analyses to improve similarity of the trials. Results All interventions compared were more efficacious than placebo regarding FEV1 at 12 weeks. Indacaterol 75 μg is expected to result in a comparable FEV1 at 12 weeks to tiotropium and salmeterol based on both IPD and AD analyses. In comparison to formoterol, the IPD and AD results indicate indacaterol 75 μg is more efficacious (IPD = 0.07 L difference; 95%Credible Interval (CrI 0.02 to 0.11; AD = 0.05 L difference; 95%CrI 0.01; 0.09. In terms of SGRQ total score at 12 weeks, indacaterol 75 μg and formoterol were more efficacious than