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)

Understanding the innervation of the esophagus is a prerequisite for successful treatment of a variety of disorders, e.g., dysphagia, achalasia, gastroesophageal reflux disease (GERD) and non-cardiac chest pain. Although, at first glance, functions of the esophagus are relatively simple, their neuronal control is considerably complex. Vagal motor neurons of the nucleus ambiguus and preganglionic neurons of the dorsal motor nucleus innervate striated and smooth muscle, respectively. Myenteric neurons represent the interface between the dorsal motor nucleus and smooth muscle but they are also involved in striated muscle innervation. Intraganglionic laminar endings (IGLEs) represent mechanosensory vagal afferent terminals. They also establish intricate connections with enteric neurons. Afferent information is implemented by the swallowing central pattern generator in the brainstem, which generates and coordinates deglutitive activity in both striated and smooth esophageal muscle and orchestrates esophageal sphincters as well as gastric adaptive relaxation. Disturbed excitation/inhibition balance in the lower esophageal sphincter results in motility disorders, e.g., achalasia and GERD. Loss of mechanosensory afferents disrupts adaptation of deglutitive motor programs to bolus variables, eventually leading to megaesophagus. Both spinal and vagal afferents appear to contribute to painful sensations, e.g., non-cardiac chest pain. Extrinsic and intrinsic neurons may be involved in intramural reflexes using acetylcholine, nitric oxide, substance P, CGRP and glutamate as main transmitters. In addition, other molecules, e.g., ATP, GABA and probably also inflammatory cytokines, may modulate these neuronal functions.
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PMID:Innervation of the mammalian esophagus. 1657 41

The past 20 years have seen notable advances in our understanding of the physiology and pharmacology of the emetic reflex leading to the identification of the anti-emetic effects of 5-hydroxytryptamine(3) (5-HT(3)) and neurokinin(1) receptor (NK(1)) antagonists. The introduction of 5-HT(3) and NK(1) receptor antagonists into the clinic has had a major impact in alleviating the nausea and vomiting associated with the treatment of cancer and the sequelae to anaesthesia and surgery (post-operative nausea and vomiting, PONV). Despite these advances there are major gaps in our understanding. Interestingly, one of these is the relatively poor ability to treat nausea. Additional gaps in our knowledge are highlighted to provide a framework within which directions for research can be proposed. Particular attention is drawn to: lacunae in knowledge of some currently used anti-emetics such as the source of dopamine required to initiate emesis; the theoretical assumptions and mechanisms underlying the concept of a "universal anti-emetic"; the variety of receptors at which agonists act to have anti-emetic effects (GABA (B), CB(1), 5-HT(1A), ghrelin, opioid); issues of translation from animals to humans and the relationship between the pathways involved in emesis and certain gastrointestinal disorders such as dyspepsia and gastroesophageal reflux, with the latter being of particular interest as some agents affecting reflux are also anti-emetic. Together, the unmet clinical need to adequately control nausea, possibly by new drugs acting within the brainstem, and the significant gaps in understanding key aspects of the emetic reflex, suggest an important need to focus and re-direct research into the distressing and sometimes life-threatening symptoms of nausea and vomiting.
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PMID:Treatment of nausea and vomiting: gaps in our knowledge. 1693 36

We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.
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PMID:Synthesis and pharmacological evaluation of novel gamma-aminobutyric acid type B (GABAB) receptor agonists as gastroesophageal reflux inhibitors. 1857 71

A significant proportion of patients on proton pump inhibitors (PPI) reports insufficient control of symptoms, most probably resulting from ongoing reflux of non-acid and acid material. As reflux mainly occurs during transient lower esophageal sphincter relaxations (TLESRs), drugs targeting this motor pattern may be of great interest to further reduce symptoms. Baclofen, a GABA(B) receptor agonist, is the prototype of reflux inhibitors, reducing the number of TLESRs, reflux, and symptoms, but the central side effects are significant. Peripheral acting GABA(B) agonists hopefully devoid of these side effects are currently under study. Alternatively, antagonists to the metabotropic glutamate receptor 5 (mGluR5) reported to reduce TLESRs and reflux may be of interest. Upcoming clinical trials with these reflux inhibitors will hopefully answer the question whether reflux inhibitors are indeed a new approach to treat GERD.
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PMID:Reflux inhibitors: a new approach for GERD? 1877 51

Antisecretory therapies that raise intragastric pH provide the best healing of the esophageal mucosal damage that occurs in gastroesophageal reflux disease. Continuous maintenance therapy is also effective to reduce the likelihood of recurrence of esophagitis and control symptoms in the long term. Proton pump inhibitor (PPI) therapy is an effective approach for healing esophagitis and controlling symptoms. Endoscopic and surgical treatments may provide an option for patients who are refractory to PPIs in whom reflux has been clearly demonstrated. Long-term antireflux medication is often needed after surgical treatment because of persisting or recurrent pathologic reflux and symptoms. An alternative approach to controlling transient lower esophageal sphincter relaxations, such as the GABA-B agonists, deserves further study.
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PMID:Medical management of gastroesophageal reflux disease. 1902 23

Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition of transient lower esophageal sphincter relaxation (TLESR) with a proposed peripherally acting GABA(B) receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABA(B) receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABA(B) receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABA(B) receptor antagonist and absent in GABA(B)-/- mice). AZD3355 and baclofen differed markedly in their distribution in rat brain; AZD3355, but not baclofen, was concentrated in circumventricular organs as a result of active uptake (shown by avid intracellular sequestration) and related to binding of AZD3355 to native GABA transporters in rat cerebrocortical membranes. AZD3355 was also shown to be transported by all four recombinant human GABA transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate of AZD3355) inhibited the response of ferret mechanoreceptors to gastric distension, further supporting its peripheral site of action on TLESR. In summary, AZD3355 probably inhibits TLESR through stimulation of peripheral GABA(B) receptors and may offer a potential new approach to treatment of GERD.
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PMID:(R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABAB receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action. 1964 70

Lesogaberan, under development by AstraZeneca plc, is a GABA(B) agonist for the potential treatment of gastroesophageal reflux disease (GERD). In vitro, lesogaberan was an efficient GABA(B) agonist and was taken up by GABA(B) receptors, thereby maintaining low extracellular levels of lesogaberan in the CNS and avoiding the serious CNS side-effect profile of the GABA(B) agonist baclofen. In phase I and IIa clinical trials, lesogaberan treatment was well tolerated, and resulted in a substantial reduction in reflux episodes by decreasing the frequency of transient lower esophageal sphincter relaxations. At the time of publication, a phase IIa trial was ongoing in patients with GERD that was partially refractive to standard proton pump inhibitor (PPI) therapy. Lesogaberan may have potential to be used as an add-on therapy to PPIs. However, the safety, efficacy and advantages of lesogaberan compared with existing therapies remain to be established in phase IIb and III trials.
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PMID:Lesogaberan, a GABA(B) agonist for the potential treatment of gastroesophageal reflux disease. 1969 77

Baclofen, a GABA(B)-receptor (GABA(B)R) agonist has been proposed to be useful as therapeutic agent for the management of gastro-esophageal reflux disease, but whether the compound acts directly at the lower esophageal sphincter (LES) remains to be elucidated. We performed the present study to assess the presence of GABA(B)R in human LES. Western blot analysis showed that both proteins of GABA(B1(a))/GABA(B1(b)) and GABA(B2) subunits were present in the muscle layer of LES. Immunohistochemical findings showed that both GABA(B1)- and GABA(B2)-subunit proteins were located on the neurons within the myenteric plexus, and furthermore, both proteins were observed in the same neurons. Reverse transcriptase-polymerase chain reaction analysis also revealed the presence of mRNAs for both subunits of GABA(B)R and also mRNAs for 6 isoforms of GABA(B1) subunits, from GABA(B1(a)) to GABA(B1(g)), except GABA(B1(d)), in human LES. Thus, the functional GABA(B)R-forming heterodimers with subunits of GABA(B1) and GABA(B2) are located on the myenteric neurons in human LES, suggesting that GABA(B)R agonists and antagonists act at least, at the level of the peripheral nervous system.
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PMID:Presence of GABA(B) receptors forming heterodimers with GABA(B1) and GABA(B2) subunits in human lower esophageal sphincter. 1989 76

Proton pump inhibitors are highly successful in treating gastroesophageal reflux disease, but a significant proportion of patients have persistent symptoms from weakly or nonacidic reflux. Transient lower esophageal sphincter relaxation (TLESR) represents the dominant mechanism of gastroesophageal reflux and has therefore become the most intensely investigated therapeutic target. The triggering of TLESR involve the vagal pathways and the gamma-aminobutyric type B (GABA(B)) and metabotropic glutamate type 5 (mGluR5) receptors. Baclofen is a GABA(B) receptor agonist that is effective in inhibiting TLESR and reducing the number of reflux episodes, but is associated with significant central nervous system (CNS) side effects. The newer GABA(B) agonists, such as AZD9343 and AZD3355, and mGluR5 antagonists, such as 2-methyl-6-(phenylethynyl)-pyridine (MPEP), have been shown in small, randomized, controlled trials to have comparable efficacy to baclofen, but possibly a more favorable CNS side effect profile. Cannibinoid agonists, such as Delta(9)-THC, have also been demonstrated to reduce TLESRs and reflux events respectively. Macrolide antibiotics (eg, erythromycin) show early promise in a select group of patients with possible reflux associated post-lung transplant problems.
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PMID:Beyond acid suppression: new pharmacologic approaches for treatment of GERD. 2042 77

This chapter forms an introduction to the subsequent chapters in this volume which highlight the significance and potential therapeutic application of GABA(B) receptors. It is now 30 years since the GABA(B) site was first described in mammalian tissue. Since then much has emerged about its physiological role in the mammalian nervous system and its relationship to other neurotransmitter receptors. It appears to function at pre- and postsynaptic locations as both an auto- and a hetero-receptor where its activation modulates the membrane conductance of Ca(2+) and K(+). The receptor is G-protein coupled and was the first to be shown to exist, possibly in multiple forms, as a heterodimer. The primary agonist for the receptor is baclofen and this continues to be used therapeutically as a centrally active muscle relaxant. Other potential applications for agonists are suggested and positive allosteric modulators may provide an alternative and more effective approach. One application of an agonist, for which there are strong positive clinical data, is in gastroesophageal reflux disease where the receptor target is outside the brain. Antagonists of the GABA(B) receptor may also have therapeutic applications such as in cognitive deficits, affective disorders, and absence seizures but robust clinical evidence remains to be demonstrated. Each of these applications is also discussed in the chapters that follow.
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PMID:Historical perspective and emergence of the GABAB receptor. 2065 76


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