Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017168 (gastroesophageal reflux disease)
 11,783 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastro-oesophageal reflux disease (GORD) is caused by disordered control of the gastro-oesophageal reflux barrier, comprised internally of the lower oesophageal sphincter (LOS) and externally the crural diaphragm (CD). Both relax briefly to allow bolus passage during oesophageal peristalsis. Brief relaxation also occurs prior to gastro-oesophageal reflux, known as transient LOS relaxation (TLOSR), normally allowing venting of gas. TLOSRs also account for up to 90% of acid reflux episodes. The development of GORD therefore depends upon the rate of TLOSR and the physical and chemical nature of refluxate. We established an animal model of reflux in ferrets, in which similar patterns of TLOSR are seen to humans. TLOSRs are mediated via a vago-vagal pathway initiated by tension receptors in the gastric musculature. They have central terminals in the brainstem which provide input to a central program generator. The program has 3 simultaneous outputs: 1. brief activation of vagal motor neurones to the LOS, which activate inhibitory enteric motorneurones, leading to smooth muscle relaxation: 2. suppression of oesophageal peristalsis: 3. suppression of motor output to the CD. We have investigated several aspects of the TLOSR pathway in ferrets, and determined that the optimal site for therapeutic pharmacological intervention is at gastric vagal tension receptor endings. Their responses to distension are potently inhibited by gamma-aminobutyric acid type B (GABAB) receptor agonists and metabotropic glutamate type 5 receptor (mGluR5) antagonists. These effects translate to inhibition of TLOSR and reflux in animal models and humans. Clinical studies indicate both types of drug may have potential in the treatment of GORD.
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PMID:New insights in the neural regulation of the lower oesophageal sphincter. 1892 42

Defined pharmacologically by its insensitivity to the GABA(A) antagonist bicuculline and sensitivity to the GABA analogue baclofen, the G protein-linked gamma-aminobutyric acid type B (GABA(B)) receptor couples to adenylyl cyclase, voltage-gated calcium channels, and inwardly-rectifying potassium channels. On the basis of a wealth of preclinical data in conjunction with early clinical observations that baclofen improves symptoms of gastroesophageal reflux disease (GERD), the GABA(B) receptor has been proposed as a therapeutic target for a number of diseases including GERD. Subsequently, there has been a significant effort to develop a peripherally-restricted GABA(B) agonist that is devoid of the central nervous system side effects that are observed with baclofen. In this article we review the in vitro and in vivo pharmacology of the peripherally-restricted GABA(B) receptor agonists and the preclinical and clinical development of lesogaberan (AZD3355, (R)-(3-amino-2-fluoropropyl) phosphinic acid), a potent and predominately peripherally-restricted GABA(B) receptor agonist with a preclinical therapeutic window superior to baclofen.
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PMID:GABAB receptor agonism as a novel therapeutic modality in the treatment of gastroesophageal reflux disease. 2065 87