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 (LES) relaxation is the major mechanism of gastroesophageal reflux. This study uses an established ferret model to evaluate GABA(B) receptor agonists' ability to reduce triggering of transient LES relaxations. One hundred sixty manometric/pH studies were performed on 18 conscious ferrets. In untreated animals, intragastric infusion of 25 ml glucose (pH 3.5) led to 2.0 +/- 0.6 reflux episodes over the first 30 min. Twenty-nine of forty-seven reflux episodes occurred during transient LES relaxation, and 18 occurred after downward drifts (<1 mmHg/s) in basal LES pressure. The GABA(B) receptor agonists baclofen (7 micromol/kg ip), CGP-44532, and SKF-97541 (both ED(50) <0.3 micromol/kg) reduced reflux episodes and transient LES relaxations. The putative peripherally selective GABA(B) receptor agonist 3-aminopropylphosphinic acid (80-240 micromol/kg) was ineffective, as was the GABA(A) receptor agonist muscimol (5 micromol/kg). Baclofen's inhibition of transient LES relaxations and reflux was unaffected by low-affinity GABA(B) receptor antagonists CGP-35348 and CGP-36742 at 100 micromol/kg but was reversed by higher-affinity CGP-54626 and CGP-62349 (0.7 micromol/kg) or by CGP-36742 at 200 micromol/kg. Therefore, GABA(B) receptor inhibition of reflux shows complex pharmacology. Our and other data indicate the therapeutic potential for these drugs.
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PMID:Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists. 1051 54

Activation of gastric vagal mechanoreceptors by distention is thought to be the trigger for transient lower esophageal sphincter relaxations (TLESR), which lead to gastroesophageal reflux. The contribution of higher-threshold gastric splanchnic mechanoreceptors is uninvestigated. GABA(B) receptor agonists, including baclofen, potently reduce triggering of TLESR by low-level gastric distention. We aimed to determine first whether this effect of baclofen is maintained at high-level distention and second the role of splanchnic pathways in triggering TLESR. Micromanometric/pH studies in conscious ferrets showed that intragastric glucose infusion (25 ml) increased triggering of TLESR and reflux. Both were significantly reduced by baclofen (7 micromol/kg ip) (P < 0.05). When 40 ml of air was added to the glucose infusion, more TLESR occurred than with glucose alone (P < 0.01). These were also reduced by baclofen (P < 0.001). TLESR after glucose/air infusion were assessed before and after splanchnectomy (2-4, 9-11, and 23-25 days), which revealed no change. Baclofen inhibits TLESR after both low- and high-level gastric distention. Splanchnic pathways do not contribute to increased triggering of TLESR by high-level gastric distention.
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PMID:Triggering of transient LES relaxations in ferrets: role of sympathetic pathways and effects of baclofen. 1089 58

The metabotropic gamma-aminobutyric acid (GABA) receptor (GABA(B) receptor) agonist baclofen inhibits transient lower esophageal sphincter relaxation in dogs, ferrets, and humans. Since transient lower esophageal sphincter relaxations are the major cause of gastroesophageal reflux, GABA(B) receptor agonists may have a therapeutic value in the treatment of gastroesophageal reflux disease. However, repeated stimulation of the GABA(B) receptor may induce receptor desensitization which, depending on the magnitude, would limit the therapeutic effect. The aim of the present study was to follow the effects of baclofen on transient lower esophageal sphincter relaxation in the dog after repeated administration. The effect of 7 micromol/kg baclofen b.i.d. (given intragastrically) on transient lower esophageal sphincter relaxation and related parameters was determined in four dogs. Transient lower esophageal sphincter relaxations stimulated by infusion of liquid nutrient and insufflation of air were quantified after placebo and then after the 1st, 13th, and 27th dose. Baclofen reduced the number of transient lower esophageal sphincter relaxations without affecting their duration, and the latency to the first transient lower esophageal sphincter relaxation was prolonged. Basal sphincter pressure was unaffected by baclofen, and the number of reflux episodes and esophageal acid exposure decreased. There was a statistically insignificant numerical decrease (approximately 30%) in the effect of baclofen on transient lower esophageal sphincter relaxation after the seventh dose but this was not further accentuated after the 27th dose. The effect on latency was also reduced with repeated dosing, but again, the effects after the 1st, 13th, and 27th doses were not statistically significant. The attenuation of acid exposure and reflux episodes was unaltered after repeated dosing. Three of the dogs greatly reduced their food intake within the first 2-3 days but this side effect was resolved subsequently. It is concluded that repeated dosing of baclofen leads to mild tolerance development in terms of the effects on transient lower esophageal sphincter relaxation, but that the tolerance is much less pronounced than that previously reported in other animal models.
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PMID:Effects of repeated administration of baclofen on transient lower esophageal sphincter relaxation in the dog. 1096 58

The effect of the GABA(B) receptor agonist baclofen, a potential treatment for gastroesophageal reflux, on gastric emptying has not been determined. The effect of 1-4 mg/kg baclofen on liquid and solid gastric emptying in mice was evaluated by noninvasive [13C] breath tests. Baclofen accelerated gastric emptying of solids but delayed emptying of liquid, suggesting that it may have differential effects on proximal and distal stomach emptying.
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PMID:The effect of the GABAB receptor agonist baclofen on liquid and solid gastric emptying in mice. 1278 36

Transient lower esophageal sphincter relaxations (TLESRs) are rapid and prolonged relaxations of the lower esophageal sphincter (LES) that are not associated with swallowing. They are the mechanism by which most gastroesophageal reflux episodes occur in normal people and in patients with esophagitis. Transient LES relaxations appear to be mediated by a vagovagal reflex initiated by gastric distention. Baclofen is a g-aminobutyric acid (GABA) derivative that inhibits the production of TLESRs by acting as a GABA(B) receptor agonist at one or more loci along the vagovagal reflex arc. Animal and human studies suggest that baclofen decreases the number of reflux events and amount of esophageal acid exposure. Baclofen or another GABA(B) receptor agonist may be clinically useful in treatment of gastroesophageal reflux disease.
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PMID:Gastroesophageal reflux disease and baclofen: is there a light at the end of the tunnel? 1512 88

GABA(B) receptors inhibit mechanosensitivity of visceral afferents. This is associated with reduced triggering of events that lead to gastro-esophageal reflux, with important therapeutic consequences. In other neuronal systems, GABA(B) receptor activation may be linked via G-proteins to reduced N-type Ca(2+) channel opening, increased inward rectifier K(+) channel opening, plus effects on a number of intracellular messengers. Here we aimed to determine the role of Ca(2+) and K(+) channels in the inhibition of vagal afferent mechanoreceptor function by the GABA(B) receptor agonist baclofen. The responses of three types of ferret gastro-esophageal vagal afferents (mucosal, tension and tension mucosal receptors) to graded mechanical stimuli were investigated in vitro. The effects of baclofen (200 microM) alone on these responses were quantified, and the effects of baclofen in the presence of the G-protein-coupled inward rectifier potassium channel blocker Rb(+) (4.7 mM) and/or the N-type calcium channel blocker omega-conotoxin GVIA (0.1 microM). Baclofen inhibition of mucosal receptor mechanosensitivity was abolished by both blockers. Its inhibitory effect on tension mucosal receptors was partly reduced by both. The inhibitory effect of baclofen on tension receptors was unaffected. The data indicate that the inhibitory action of GABA(B) receptors is mediated via different pathways in mucosal, tension and tension mucosal receptors via mechanisms involving both N-type Ca(2+) channels and inwardly rectifying K(+) channels and others.
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PMID:Inhibition of mechanosensitivity in visceral primary afferents by GABAB receptors involves calcium and potassium channels. 1628 39

Although proton pump inhibitors have become the mainstay of treatment in gastro-oesophageal reflux disease (GORD), there are still unmet needs in the management of this very common disorder. For example, all current proton pump inhibitors have a relatively slow onset of action and their activity is limited mainly to the post-prandial period with far less effective inhibition of nocturnal acid secretion. In order to achieve more potent, rapid and sustained acid inhibition several compounds are currently under development, such as new proton pump inhibitors with a prolonged plasma half-life, potassium competitive ATPase blockers (PCABs), histamine H3 agonists, and gastrin antagonists. Acid suppression does not, however, cure the disease and relapses are frequently observed after discontinuation of proton pump inhibitor therapy. Among the different abnormalities involved in the pathophysiology of this multifactorial disease, transient lower oesophageal sphincter relaxations represent the major mechanism responsible for episodes of reflux. Baclofen, the prototype GABA(B) receptor agonist, is one of the most potent inhibitors of transient lower oesophageal sphincter relaxations identified. To date the transfer of these relaxation-controlling pharmacological agents into clinical practice has however been hampered by the occurrence of unacceptable side effects. Beside "anti-relaxation therapy", the potential of novel prokinetics such as motilin agonists has been explored, especially since the motilin receptor has been cloned. Thus far the broad therapeutic value of prokinetics in GORD does, however, seem very limited in terms of efficacy with respect to oesophageal motility and acid exposure. Lastly, further research is necessary to better understand the complex mechanisms involved in oesophageal sensitivity and mucosal defence.
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PMID:Pharmacological targets in gastro-oesophageal reflux disease. 1636 47

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

Up to 50% of patients with gastroesophageal reflux disease (GERD) still suffer from GERD symptoms despite proton pump inhibitor (PPI) therapy, indicating a need for new treatments. The lower esophageal sphincter (LES) plays a crucial role in maintaining the mechanical barrier necessary for prevention of gastric reflux. Transient LES relaxation (TLESR) is an important factor behind the occurrence of reflux, and preclinical studies have identified a number of targets for pharmacologic modification of TLESR. However, only gamma-aminobutyric acid (GABA) type B receptor (GABA(B)) agonists and metabotropic glutamate receptor 5 (mGluR5) modulators have shown positive proof of concept in the clinical setting. The mGluR5 negative allosteric modulator ADX10059 improved symptoms in GERD patients, but was associated with central side effects such as dizziness. Baclofen, a GABA(B) receptor agonist, reduces the incidence of TLESR and improves GERD symptoms in both adult and pediatric GERD patients. However, the utility of baclofen is similarly limited by poor tolerability and recent research has focused on the development of GABA(B) receptor agonists with improved tolerability. XP19986, a prodrug of R-baclofen, reduced the number of reflux episodes in a dose-ranging study and was similarly tolerated to placebo. AZD3355 and AZD9343 are GABA(B) receptor agonists with limited central nervous system activity that have been shown in preclinical studies to reduce the incidence of TLESR and decrease esophageal acid exposure; data from clinical studies of these agents in GERD patients are awaited with interest. Agents that target TLESR activity may therefore offer a promising new add-on treatment for patients who suffer from GERD symptoms despite PPI therapy.
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PMID:Novel treatments of GERD: focus on the lower esophageal sphincter. 1892 49

For many years, acid-suppressive therapy has been at the forefront of treating gastroesophageal reflux disease (GERD), yet despite the advent of the proton pump inhibitors (PPIs) some patients continue to experience persistent GERD symptoms. Therapeutic (non-surgical) options for such patients are currently limited. To tackle this clinical issue, research efforts have begun to focus on 'reflux inhibition' as a potential therapeutic target - i.e. inhibition of transient lower esophageal relaxations (TLESRs), the predominant mechanism of gastroesophageal reflux. Preclinical research has identified a number of drug targets through which TLESRs can be modulated, and the gamma-aminobutyric acid (GABA) type B (GABA(B)) receptor has emerged as one of the most promising. Studies with baclofen, a well-known agonist of this receptor, have demonstrated that reflux inhibition is a valid concept in the clinical setting in that reducing the incidence of TLESRs improves GERD symptoms. But baclofen is associated with significant central nervous system (CNS) side effects, rendering it undesirable for use as a treatment for GERD. Further development work has yielded a number of novel GABA(B) receptor agonists with reduced CNS side effect profiles, and clinical trials are currently being performed with several agents. Compounds that target TLESRs may therefore present a new add-on treatment for patients with persistent GERD symptoms despite PPI therapy.
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PMID:GABAB receptors as drug targets to treat gastroesophageal reflux disease. 1930


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