ulimorelin and Ileus

The therapeutic potential of ghrelin and synthetic ghrelin receptor (GRLN-R) agonists for the treatment of gastrointestinal (GI) motility disorders is based on their ability to stimulate coordinated patterns of propulsive GI motility. This review focuses on the latest findings that support the therapeutic potential of GRLN-R agonists for the treatment of GI motility disorders. The review highlights the preclinical and clinical prokinetic effects of ghrelin and a series of novel ghrelin mimetics to exert prokinetic effects on the GI tract. We build upon a series of excellent reviews to critically discuss the evidence that supports the potential of GRLN-R agonists to normalize GI motility in patients with GI hypomotility disorders such as gastroparesis, post-operative ileus (POI), idiopathic chronic constipation and functional bowel disorders.

Topics: Animals; Chronic Disease; Constipation; Gastrointestinal Agents; Gastrointestinal Motility; Gastroparesis; Ghrelin; Guinea Pigs; Humans; Ileus; Inflammatory Bowel Diseases; Macrocyclic Compounds; Mice; Postoperative Complications; Receptors, Ghrelin

Gastrointestinal recovery is a critical milestone after bowel resection with postoperative ileus resulting in increased risk of complications and prolonged hospitalization.. The aim of this study is to evaluate the efficacy and safety of ulimorelin, a ghrelin receptor agonist given postoperatively in 2 identically designed phase 3 studies (ClinicalTrials.gov NCT01285570 and NCT01296620).. This investigation is designed as a multicenter, double-blind, randomized, parallel-group study.. This study involves hospital inpatients.. Adult patients undergoing partial bowel resection were included.. Thirty-minute intravenous infusions (160 µg/kg, 480 µg/kg ulimorelin, or placebo) once daily were started within 60 minutes after the end of surgery and ended at the first of the following: primary efficacy end point fulfilled (defined below), hospital discharge, or 7 days treatment.. The primary efficacy end point was the time from the end of surgery to the composite end point of the later of first bowel movement and tolerance of solid food. Safety was assessed with the use of standard assessments including adverse events and laboratory tests.. Ulimorelin Study of Efficacy and Safety 007, n = 332 patients; Ulimorelin Study of Efficacy and Safety 008, n = 330 patients: in both studies, the primary efficacy end point and the secondary efficacy outcomes, which included postsurgical time to first bowel movement, tolerance of solid food, and discharge eligibility, did not differ significantly among patients treated with either dose of ulimorelin versus placebo. Rates of serious adverse events were comparable across all treatment groups. There was no statistically significant difference from placebo in regard to events of interest, namely nausea, vomiting, ileus as an adverse event, nasogastric tube reinsertion, anastomotic complications, and infections.. A possible limitation is the variance inherent in surgery and comorbidities.. Although the efficacy of ulimorelin in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous ulimorelin at doses of 160 µg/kg and 480 µg/kg was generally well tolerated in postcolectomy patients. Similar to other promotility agents, ulimorelin may find an application in other indications better suited to its attributes.

Topics: Digestive System Surgical Procedures; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Gastrointestinal Motility; Humans; Ileus; Infusions, Intravenous; Macrocyclic Compounds; Male; Middle Aged; Postoperative Care; Postoperative Complications; Recovery of Function; Retrospective Studies; Treatment Outcome

Ghrelin agonist TZP-101 is a potent prokinetic. This phase 2b study evaluated TZP-101 safety and efficacy in postoperative ileus management.. Adults undergoing open partial colectomy were adaptively randomized to receive 20, 40, 80, 160, 320, 480 or 600 microg/kg TZP-101 (n = 168) or the placebo (n = 68) by 30-minute IV infusion within 1 hour of surgical closure and then daily for up to 7 days. The primary efficacy end point was the time to first bowel movement. Secondary end points included the percentage of patients with return of gastrointestinal function within 72 hours, and the time to readiness for discharge.. TZP-101 accelerated the time to first bowel movement in all groups, with Cox proportional hazard ratios of 1.57 (P = .056) for the low-efficacious dose (80 microg/kg) and 1.67 (P = .03) for the most efficacious dose (480 microg/kg). Using Kaplan-Meier analysis, the median time to first bowel movement was reduced in all TZP-101 groups by 10 to 22 hours vs. the placebo. A greater number of patients who received TZP-101 achieved recovery (P

Topics: Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Ghrelin; Humans; Ileus; Infusions, Intravenous; Macrocyclic Compounds; Male; Middle Aged; Postoperative Care; Proctocolectomy, Restorative; Retrospective Studies; Treatment Outcome

CHI's 17th International Tri-Conference on Molecular Medicine, held in San Francisco, included topics covering the drug discovery process, with an emphasis on lead optimization. This conference report highlights selected presentations on the development of several launched and investigational drugs, including Plerixafor, Trox-1 (CombinatoRX Inc), lorcaserin (Arena Pharmaceuticals Inc), vorapaxar (Merck & Co Inc) and ulimorelin (Tranzyme Pharma Inc).

Topics: Animals; Anti-HIV Agents; Benzazepines; Benzylamines; Calcium Channel Blockers; Chemistry, Pharmaceutical; Coronary Artery Disease; Cyclams; Drug Discovery; Heterocyclic Compounds; Humans; Ileus; Lactones; Macrocyclic Compounds; Obesity; Pyridines; Receptor, PAR-1; Receptors, CXCR4; Receptors, Ghrelin; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists

Ghrelin, the natural ligand of the growth hormone secretagogue receptor (ghrelin receptor), is an orexigenic gut hormone with prokinetic action in the upper gastrointestinal tract. Previously we have shown in a rodent model of postoperative ileus that the synthetic ghrelin receptor agonist TZP-101 prevents the delay in gastric emptying and improves small intestinal transit. The goal of the present study was to investigate whether TZP-101 affects colonic transit and food intake in rats with postoperative ileus. Fasted rats were treated with morphine and subjected to laparotomy under isoflurane anesthesia. Following surgery the animals were placed in clean home cages and fecal pellet output and food intake were monitored for 48 h. TZP-101 or vehicle were administered as 3 i.v. bolus infusions at 0 h, 2 h and 4 h post-surgery. TZP-101 (0.03-1 mg/kg) dose-dependently decreased the time to first bowel movement and increased fecal pellet output measured at 12 h and 24 h post-surgery compared to the vehicle. The administration of TZP-101 was not associated with a significant alteration in food intake. In conclusion, this study provides the first experimental evidence that a novel ghrelin receptor agonist improves large bowel function in rats with postoperative ileus, suggesting that TZP-101 may be useful in the clinic to accelerate upper gastrointestinal transit and to shorten the time to the first bowel movement following surgery.

Topics: Abdomen; Animals; Body Weight; Colon; Defecation; Disease Models, Animal; Eating; Gastrointestinal Transit; Ileus; Macrocyclic Compounds; Male; Morphine; Postoperative Complications; Rats; Rats, Sprague-Dawley; Receptors, Ghrelin; Time Factors