| 1. |
- Karling, Pontus, et al.
(författare)
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Function and dysfunction of the colon and anorectum in adults: working team report of the Swedish Motility Group (SMoG).
- 2009
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Ingår i: Scandinavian journal of gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 44:6, s. 646-60
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Forskningsöversikt (refereegranskat)abstract
- Symptoms of fecal incontinence and constipation are common in the general population. These can, however, be unreliably reported and are poorly discriminatory for underlying pathophysiology. Furthermore, both symptoms may coexist. In the elderly, fecal impaction always must be excluded. For patients with constipation, colon transit studies, anorectal manometry and defecography may help to identify patients with slow-transit constipation and/or pelvic floor dysfunction. The best documented medical treatments for constipation are the macrogols, lactulose and isphagula. Evolving drugs include lubiprostone, which enhances colonic secretion by activating chloride channels. Surgery is restricted for a highly selected group of patients with severe slow-transit constipation and for those with large rectoceles that demonstrably cause rectal evacuatory impairment. For patients with fecal incontinence that does not resolve on antidiarrheal treatment, functional and structural evaluation with anorectal manometry and endoanal ultrasound or magnetic resonance (MR) of the anal canal may help to guide management. Sacral nerve stimulation is a rapidly evolving alternative when other treatments such as biofeedback and direct sphincter repair have failed. Advances in understanding the pathophysiology as a guide to treatment of patients with constipation and fecal incontinence is a continuing important goal for translational research. The content of this article is a summary of presentations given by the authors at the Fourth Meeting of the Swedish Motility Group, held in Gothenburg in April 2007.
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| 2. |
- Bucinskaite, V, et al.
(författare)
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Receptor-mediated activation of gastric vagal afferents by glucagon-like peptide-1 in the rat
- 2009
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 21:9, s. 978-e78
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Tidskriftsartikel (refereegranskat)abstract
- 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 concentrations, increased vagal afferent mass activity peaking (13–52% above basal level, P < 0.05) 3–5 min after injection. Repeated administration of GLP-1 (1000 pmol kg−1; five times, 15 min intervals) elicited similar responses. Pretreatment with GLP-1 receptor antagonist exendin(9-39)amide (500 pmol kg−1) abolished the GLP-1 response to doses 30–300 pmol kg−1 but had no effect on the vagal response to gastric distension. For comparison, GLP-2 (1000 pmol kg−1) had no effect on vagal afferent activity. Vagal chemoreception of GLP-1 is supported by expression of the GLP-1 receptor gene in the nodose ganglion. However, the GLP-2 receptor was also expressed. To conclude, our results show that peripherally administered GLP-1, differently from GLP-2, activates vagal afferents, with no evidence of desensitisation. The GLP-1 effect was blocked by exendin(9-39)amide, suggesting that GLP-1 receptors on vagal 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.
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| 3. |
- Edholm, T, et al.
(författare)
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The incretin hormones GIP and GLP-1 in diabetic rats : effects on insulin secretion and small bowel motility
- 2009
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 21:3, s. 313-321
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Tidskriftsartikel (refereegranskat)abstract
- Incretin hormones often display inhibitory actions on gut motility. The aim of this study was to investigate if altered responsiveness to glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) as regards insulin release and small bowel motility could bring further clarity to the pathophysiology of diabetes in the Goto-Kakizaki (GK) rat. The isolated perfused pancreas was studied in male GK and Wistar rats (controls) under euglycemic and hyperglycemic conditions. Glucose-dependent insulinotropic peptide (10 nmol L−1) or GLP-1 (10 nmol L−1) were added to the medium and perfusate was collected and analysed for insulin. Moreover, GK and Wistar rats were supplied with bipolar electrodes in the small bowel and myoelectric activity was recorded during intravenous administration of GIP (1–400 pmol kg−1 min−1) or GLP-1 (0.1–20 pmol kg−1 min−1). Finally, tissue was collected from GK and Wistar rats for RNA extraction. Under euglycemia, GIP and GLP-1 stimulated the initial insulin response by 10-fold in GK rats (P < 0.05). At later hyperglycemia, the insulin response to GIP and GLP-1 was blunted to about one-third compared with controls (P < 0.05). In the bowel GLP-1 was about 2.6–16.7 times more potent than GIP in abolishing the migrating myoelectric complex in the GK and control rats. Polymerase chain reaction (PCR) showed GIP and GLP-1 receptor gene expression in pancreatic islets and in small bowel. The initially high, but later low insulin responsiveness to stimulation with GIP and GLP-1 along with inhibition of small bowel motility in the GK rat indicates a preserved incretin response on motility in diabetes type 2.
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| 4. |
- Ejskjaer, N, et al.
(författare)
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Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis
- 2009
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley. - 0269-2813 .- 1365-2036. ; 29:11, s. 1179-1187
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: TZP-101 is a synthetic, selective ghrelin agonist in development for gastroparesis. AIM: To assess safety and effects of TZP-101 in diabetes patients with symptomatic gastroparesis. METHODS: Adults with type 1 or type 2 diabetes mellitus received placebo and TZP-101 (80, 160, 320 or 600 microg/kg) infusions in a cross-over manner following a radiolabelled meal. Blood glucose levels were stabilized using a hyperinsulinemic-euglycemic clamp. Primary endpoints were gastric half emptying and latency times. Secondary measures included assessment of gastroparesis symptoms and endocrine responses. RESULTS: Ten patients with type 1 (n = 7) or 2 (n = 3) diabetes, moderate-to-severe gastroparesis symptoms and > or =29% retention 4 h after a radiolabelled solid meal were enrolled. TZP-101 produced significant reductions in solid meal half-emptying (20%, P = 0.043) and latency (34%, P = 0.037) times vs. placebo. Reductions in overall postmeal symptom intensity (24%) and postprandial fullness (37%) following TZP-101 infusion were not statistically significant. Most adverse events were mild and self-limiting and there were no identifiable differences in numbers or types of adverse events between TZP-101 and placebo. CONCLUSIONS: This proof-of-concept study demonstrates that the ghrelin agonist TZP-101 is well-tolerated in diabetes patients with moderate-to-severe chronic gastroparesis and shows statistically significant improvements in gastric emptying.
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| 5. |
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| 6. |
- Hellström, Per M., 1954-, et al.
(författare)
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Clinical trial : The glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome
- 2009
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley. - 0269-2813 .- 1365-2036. ; 29:2, s. 198-206
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is currently no treatment available to manage acute pain attacks in IBS patients regardless of subtype. AIMS: To evaluate efficacy and safety of the GLP-1 analogue ROSE-010 in patients with irritable bowel syndrome (IBS) through a randomized, double-blind, placebo-controlled study. METHODS: Eligible patients (n = 166) meeting Rome II criteria were randomly assigned to receive single subcutaneous injections of ROSE-010 100 microg, 300 microg and placebo in a cross-over design. Safety was assessed from spontaneously reported adverse events and measurement of vital signs. Patient-rated pain relief and intensity were measured on a 100-mm visual analogue scale. The primary efficacy variable was proportion of patients with >50% maximum total pain relief response from 10 to 60 min after treatment. Secondary endpoints included the maximum summed pain intensity difference, time to meaningful pain relief and patient ratings of satisfaction with treatment. RESULTS: Twice as many patients were responders in the primary efficacy endpoint after both ROSE-010 injections compared to placebo (24%P = 0.011, 23%P = 0.005, and 12% after 300 microg, 100 microg and placebo injections, respectively). Similar results were obtained for the proportion of patients with total pain intensity response. Times to meaningful and total pain relief were shorter for both doses of ROSE-010 compared with placebo. Compared with placebo, more patients (P < 0.05) were satisfied with ROSE-010 and considered ROSE-010 better than previous IBS medications used. CONCLUSION: ROSE-010 was well tolerated and provided fast and effective relief of acute pain attacks on demand in IBS patients.
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| 7. |
- Hellström, Per M., 1954-
(författare)
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Faces of ghrelin--research for the 21st century.
- 2009
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 21:1, s. 2-5
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Tidskriftsartikel (refereegranskat)abstract
- In this issue of Neurogastroenterology and Motility we find three new articles on different aspects of ghrelin, dealing with physiological and pathophysiological actions of the peptide. For the reader this is food for thoughts: Does this peptide do everything? Ghrelin is a gut peptide hormone well established to stimulate motility throughout most parts of the gastrointestinal (GI) tract and appetite. Ghrelin has been linked to various GI regulatory mechanisms, the most evident being hunger, over-eating and obesity. In this setting ghrelin has been studied under physiological conditions converging on obesity as a pathophysiological process where the peptide has been employed as an interesting tool for studying the development of obesity. With a widespread distribution of ghrelin receptors on various immune cells, it has been assumed that ghrelin also possesses immunoregulatory properties, thus also being of interest in intestinal inflammation research. Anti-inflammatory effects of exogenous ghrelin have been claimed in experimental colitis in mice. Further studies on this concept using ghrelin gene knock-out mice, however, show an increased inflammatory activity in experimental colitis in wild-type mice pointing to ghrelin as an enhancer of the inflammatory course of the disease. Taken together, recent studies on ghrelin indicate that the peptide is not only a regulatory agent in pathophysiological processes, but also participates in pathological disease conditions with actions that seem to even involve genetic mechanisms.
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| 8. |
- Hellström, Per M., 1954-
(författare)
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GLP-1 : broadening the incretin concept to involve gut motility
- 2009
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 156:1-3, s. 9-12
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Tidskriftsartikel (refereegranskat)abstract
- The incretin effect of the gut peptide hormone glucagon-like peptide-1 (GLP-1) is a combined result of inhibition of gastric emptying and stimulation of insulin secretion via an incretin mechanism. The temporal pattern of these events implicate that gastric emptying is primarily delayed, while later in the digestive process insulin is released for nutrient disposal. Since the inhibitory effect of GLP-1 on gastric motility is very outspoken, we considered it of value to study its effects on gut motility. Animal experimentation in the rat clearly showed that not only gastric emptying, but also small bowel motility with the migrating myoelectric complex was profoundly inhibited by GLP-1 at low doses. Similar effects were seen with analogues of the peptide. Extending the studies to man supported our earliest data indicating that the migrating motor complex of the small intestine was affected, and even more noticeable, the summarized motility index inhibited. Further extension of our studies to patients with irritable bowel syndrome (IBS) displayed similar results. This encouraged us to embark on a clinical pain-relief multi-centre study in IBS patients using a GLP-1 analogue, ROSE-010, with longer half-life than the native peptide. The outcome of the IBS study proved ROSE-010 to be superior to placebo with a pain-relief response rate of 24% for ROSE-010 compared to 12% for placebo. Taken together, the GLP-1 analogue ROSE-010 is believed to cause relaxation of the gut and can thereby relieve an acute pain attack of IBS, even though its precise mechanism is yet to be defined.
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| 9. |
- Kharaziha, Pedram, et al.
(författare)
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Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection : a phase I-II clinical trial
- 2009
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Ingår i: European Journal of Gastroenterology and Hepathology. - 0954-691X .- 1473-5687. ; 21:10, s. 1199-1205
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: End-stage liver disease is a medical problem with high morbidity and mortality. We have investigated the feasibility, safety, and efficacy of using autologous mesenchymal stem cells (MSCs) as a treatment. METHODS: Eight patients (four hepatitis B, one hepatitis C, one alcoholic, and two cryptogenic) with end-stage liver disease having Model for End-Stage Liver Disease score > or =10 were included. Autologous MSCs were taken from iliac crest. Approximately, 30-50 million MSCs were proliferated and injected into peripheral or the portal vein. Liver function and clinical features were evaluated at baseline and 1, 2, 4, 8, and 24 weeks after injection. RESULTS: Treatment was well tolerated by all patients. Liver function improved as verified by the Model for End-Stage Liver Disease score, which decreased from 17.9±5.6 to 10.7±6.3 (P<0.05) and prothrombin complex from international normalized ratio 1.9±0.4 to 1.4±0.5 (P<0.05). Serum creatinine decreased from 114±35 to 80±18 µmol/l (P<0.05). Serum albumin changed from 30±5 to 33±5 g/l and bilirubin from 46±29 to 41±31 µmol/l. No adverse effects were noted. CONCLUSION: Our data show that MSCs injection can be used for the treatment of end-stage liver disease with satisfactory tolerability. Furthermore, this treatment may improve clinical indices of liver function in end-stage liver disease.
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| 10. |
- Rudholm, Tobias, et al.
(författare)
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Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats
- 2009
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115 .- 1873-1686. ; 152:1-3, s. 8-12
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Tidskriftsartikel (refereegranskat)abstract
- The impact of exposure of the intestinal mucosa to acid and hyperosmolal solutions on the release of the inhibitory gut peptides somatostatin (SOM), neurotensin (NT) and vasoactive intestinal peptide (VIP) was studied in conscious rats during pentagastrin-stimulated gastric acid secretion. The animals were equipped with a chronic gastric fistula to measure acid secretion and a jejunal Thiry-Vella loop for intestinal challenge with saline, hydrochloric acid (HCl, 200 mmol L-1) or hyperosmolal polyethylene glycol (PEG, 1200 mOsm kg(-1)). Gut peptide concentrations were measured in intestinal perfusates, and in plasma samples collected during stimulated acid secretion, and at the end of experiments with luminal challenge of the loops. After pentagastrin-stimulation acid secretion was dose-dependently inhibited by intravenous administration of the gastrin receptor antagonist gastrazole, as well as ranitidine and esomeprazole by maximally 73 +/- 10%; 95 +/- 3%; 90 10%, respectively. Acid perfusion of the Thiry-Vella loop caused a prominent release of SOM both to the lumen (from 7.2 +/- 5.0 to 1279 +/- 580 pmol L-1) and to the circulation (from 18 +/- 5.2 to 51 +/- 9.0 pmol L-1) simultaneously with an inhibition of gastric acid secretion. The release of NTand VIP was not affected to the same extent. PEG perfusion of the loop caused a release of SOM as well as NT and VIP, but less. Simultaneously acid secretion was slightly decreased. In conclusion, intestinal perfusion with acid or hyperosmolal solutions mainly releases SOM, which seems to exert a major inhibitory action in the gut, as shown by inhibition of acid secretion. The other peptides NT and VIP also participate in this action but to a much lesser degree. The operative pathways of these gut peptides hence involve both endocrine (SOM) and paracrine actions (SOM, NT, VIP) in order to exert inhibitory functions on the stomach. The inhibitory action of gastrazole, was in a similar range as that of SOM implying that physiological acid-induced inhibition of gastric acid may primarily be exerted through inhibition of gastrin endocrine secretion.
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