azd2066 and Gastroesophageal-Reflux

The management of patients with refractory GERD (rGERD) is a major clinical challenge for gastroenterologists. In up to 30% of patients with typical GERD symptoms (heartburn and/or regurgitation), acid-suppressive therapy does not provide clinical benefit. In this Review, we discuss the current management algorithm for GERD and the features and management of patients who do not respond to treatment (such as those individuals with an incorrect diagnosis of GERD, inadequate PPI intake, persisting acid reflux and persisting weakly acidic reflux). Symptom response to existing surgical techniques, novel antireflux procedures, and the value of add-on medical therapies (including prokinetics and reflux inhibitors) for rGERD symptoms are discussed. Pharmaceutical agents targeting oesophageal sensitivity, a condition that can contribute to symptom generation in rGERD, are also discussed. Finally, on the basis of available published data and our expert opinion, we present an outline of a current, usable algorithm for management of patients with rGERD that considers the timing and diagnostic use of pH-impedance monitoring on or off PPI, additional diagnostic tests, the clinical use of baclofen and the use of add-on neuromodulators (tricyclic agents and selective serotonin reuptake inhibitors).

Topics: Alginates; Algorithms; Antacids; Baclofen; Chronic Disease; Esophagoscopy; Gastroesophageal Reflux; Gastrointestinal Agents; Gastroscopy; Humans; Isoxazoles; Muscle Relaxants, Central; Neurotransmitter Agents; Phosphinic Acids; Propylamines; Triazoles

Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans.. To assess the effect of single doses of the mGluR5 antagonist AZD2066 on TLESRs and reflux in humans.. Healthy male volunteers received AZD2066 13 mg and placebo (part A), or AZD2066 2 mg and AZD2066 6 mg and placebo (part B), in a randomised crossover study. Postprandial manometry/pH-impedance measurements were taken after each dose.. A total of 13 individuals completed part A of the study and 19 individuals completed part B. There was a significant reduction in the geometric mean number of TLESRs (27%; P = 0.02) and the geometric mean number of reflux episodes (51%; P = 0.01) in subjects receiving AZD2066 13 mg compared with placebo. Adverse events in participants receiving AZD2066 13 mg were mostly related to the nervous system [dizziness (3/13); disturbance in attention (3/13)]. Adverse events were reversible and of mild intensity. There were no serious adverse events. The effects of AZD2066 appeared dose-dependent, with smaller reductions in TLESRs and reflux episodes (relative to placebo) and fewer adverse events observed for AZD2066 2 mg and AZD2066 6 mg compared with AZD2066 13 mg.. The mGluR5-mediated inhibition of TLESRs may be a useful approach for inhibiting gastro-oesophageal reflux.

Topics: Adult; Analysis of Variance; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Esophageal Sphincter, Lower; Gastroesophageal Reflux; Gastrointestinal Agents; Humans; Hydrogen-Ion Concentration; Isoxazoles; Male; Postprandial Period; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Triazoles; Young Adult