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)

Transient lower esophageal sphincter relaxation is the major mechanism for gastroesophageal reflux. The present study was initiated to investigate the potential effect of the metabotropic glutamate 5 (mGlu5) receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), on transient lower esophageal sphincter relaxations in the conscious dog. MPEP (1.4-8.7 micromol/kg i.v.) produced a dose-dependent inhibition of transient lower esophageal sphincter relaxations (59+/-11% inhibition at 8.7 micromol/kg). In addition, there was a reduction of the number of reflux episodes and an increase in latency time to the occurrence of the first transient lower esophageal sphincter relaxation. No effect was seen on basal lower esophageal sphincter pressure or on swallowing. It is concluded that the mGlu5 receptor antagonist MPEP potently inhibits transient lower esophageal sphincter relaxations and that the mGlu5 receptor is a potential target for treatment of gastroesophageal reflux disease.
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PMID:Transient lower esophageal sphincter relaxations in dogs are inhibited by a metabotropic glutamate receptor 5 antagonist. 1610 47

Metabotropic glutamate receptors (mGluR) are classified into group I, II, and III mGluR. Group I (mGluR1, mGluR5) are excitatory, whereas group II and III are inhibitory. mGluR5 antagonism potently reduces triggering of transient lower esophageal sphincter relaxations and gastroesophageal reflux. Transient lower esophageal sphincter relaxations are mediated via a vagal pathway and initiated by distension of the proximal stomach. Here, we determined the site of action of mGluR5 in gastric vagal pathways by investigating peripheral responses of ferret gastroesophageal vagal afferents to graded mechanical stimuli in vitro and central responses of nucleus tractus solitarius (NTS) neurons with gastric input in vivo in the presence or absence of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP). mGluR5 were also identified immunohistochemically in the nodose ganglia and NTS after extrinsic vagal inputs had been traced from the proximal stomach. Gastroesophageal vagal afferents were classified as mucosal, tension, or tension-mucosal (TM) receptors. MPEP (1-10 microM) inhibited responses to circumferential tension of tension and TM receptors. Responses to mucosal stroking of mucosal and TM receptors were unaffected. MPEP (0.001-10 nmol icv) had no major effect on the majority of NTS neurons excited by gastric distension or on NTS neurons inhibited by distension. mGluR5 labeling was abundant in gastric vagal afferent neurons and sparse in fibers within NTS vagal subnuclei. We conclude that mGluR5 play a prominent role at gastroesophageal vagal afferent endings but a minor role in central gastric vagal pathways. Peripheral mGluR5 may prove a suitable target for reducing mechanosensory input from the periphery, for therapeutic benefit.
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PMID:Peripheral versus central modulation of gastric vagal pathways by metabotropic glutamate receptor 5. 1705 58

Gastric acid secretion is a complex phenomenon under nervous and hormonal influence. The stimulation of proton pump (H(+), K(+)-ATPase) in the parietal cell represents the final step of acid secretion and this knowledge has led to the development of a class of drugs, the proton pump inhibitors (PPIs), which are targeted at blocking this enzyme. Chemically, all the available PPIs consist of a benzimidazole ring and a pyridine ring, but vary in the specific side ring substitution. As a class, they are the most potent inhibitors of gastric acid secretion available. Although there are differences among PPIs concerning their pharmacokinetics, pharmacodynamics, influence by food and antacids as well as potential for drug interactions, it is not always evident whether these often subtle differences are clinically relevant. A careful evaluation of the available studies reveals that rabeprazole and esomeprazole achieve more rapid acid inhibition than other PPIs. Also, the effect of rabeprazole is less dependent upon genetic make-up than all other PPIs, giving rise to less inter-subject variability and leading to a more predictable effect. Esomeprazole, by inhibiting its own catabolism, makes all patients slow metabolizers, but could expose them to potential drug interactions. PPIs are the mainstay of medical treatment of gastro-oesophageal reflux disease (GORD), in that they are able to provide 80-85% healing rate of oesophageal lesions, including ulcers, and to reduce the incidence of complications like strictures as well as dysplasia and adenocarcinoma in Barrett's oesophagus (BO). Also relief of symptoms can be achieved in about 80% of cases, even though this benefit is reduced by a factor of approximately 20% in patients with non-erosive reflux disease (NERD). Their effect on Barrett's oesophagus and the extra-oesophageal manifestations of GORD is much less consistent. In general, the tolerability profile of PPIs is good in both short- and long-term clinical trials. This safety profile is similar across the various PPIs used in clinical practice and is extended to children and pregnant women, where they do not present any major teratogenic risk.
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PMID:Proton pump inhibitors in GORD An overview of their pharmacology, efficacy and safety. 1897 44

Inhibition of H(+),K(+)-ATPase is accepted as the most effective way of controlling gastric acid secretion. However, current acid suppressant therapy for gastroesophageal reflux disease, using histamine H(2) receptor antagonists and proton pump inhibitors, does not fully meet the needs of all patients because of their mechanism of action. This study sought to characterize the in vitro and in vivo pharmacology of a novel acid pump antagonist, N-(2-Hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), and to compare it with other acid suppressants. Porcine, canine, and human recombinant gastric H(+),K(+)-ATPase activities were measured by ion-leaky and ion-tight assay. The affinities for a range of receptors, ion channels, and enzymes were determined to analyze selectivity profile. Acid secretion in Ghosh-Schild rats and Heidenhain pouch dogs were measured by titrating perfusate and gastric juice samples. PF-03716556 demonstrated 3-fold greater inhibitory activity than 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinoline-2-yl)pyrimidine (revaprazan), the only acid pump antagonist that has been available on the market, in ion-tight assay. The compound did not display any species differences, exhibiting highly selective profile including the canine kidney Na(+),K(+)-ATPase. Kinetics experiments revealed that PF-03716556 has a competitive and reversible mode of action. More rapid onset of action than 5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-sulfinyl}-benzimidazole (omeprazole) and 3-fold greater potency than revaprazan were observed in Ghosh-Schild rats and Heidenhain pouch dogs. PF-03716556, a novel acid pump antagonist, could improve upon or even replace current pharmacological treatment for gastroesophageal reflux disease.
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PMID:N-(2-hydroxyethyl)-N,2-dimethyl-8-{[(4R)-5-methyl-3,4-dihydro-2H-chromen-4-yl]amino}imidazo[1,2-a]pyridine-6-carboxamide (PF-03716556), a novel, potent, and selective acid pump antagonist for the treatment of gastroesophageal reflux disease. 1898 Dec 88

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