Effect of acute and chronic administration of the GABAB agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease

Ciccaglione, Antonio Francesco

doi:10.1136/gut.52.4.464

Cited by 151 publications

(108 citation statements)

References 28 publications

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“…Inhibitors of TLESR may therefore afford symptomatic relief in this population. Baclofen, for example, the prototypical GABA B receptor agonist, has been demonstrated to inhibit TLESR and acid reflux in those with GERD (van Herwaarden et al, 2002;Zhang et al, 2002); in turn, GERD symptoms are mitigated (Ciccaglione and Marzio, 2003;Koek et al, 2003;Vela et al, 2003). Another beneficial effect of baclofen is its enhancing effect on basal LES pressure (Zhang et al, 2002;Lee et al, 2003), which may be therapeutically relevant in some patients.…”

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confidence: 99%

(R)-(3-Amino-2-fluoropropyl) Phosphinic Acid (AZD3355), a Novel GABA_B Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxation through a Peripheral Mode of Action

Lehmann¹,

Antonsson²,

Holmberg³

et al. 2009

J Pharmacol Exp Ther

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Gastroesophageal reflux disease (GERD) affects Ͼ10% 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 Ϫ/Ϫ 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.The GABA B receptor was originally defined pharmacologically by virtue of its insensitivity to the GABA A receptor antagonist bicuculline and its sensitivity to the GABA analog baclofen (Bowery et al., 1980). The GABA B receptor, a member of family C of the G protein-coupled receptors, is characterized by its large, ligand-binding extracellular N-terminal domain. It couples negatively to adenylyl cyclase and to voltage-gated calcium channels and positively to inwardly rectifying potassium channels (Bettler et al., 2004).Based on a wealth of preclinical data, the GABA B receptor has been proposed as a therapeutic target for several dis-

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confidence: 99%

(R)-(3-Amino-2-fluoropropyl) Phosphinic Acid (AZD3355), a Novel GABA_B Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxation through a Peripheral Mode of Action

Lehmann¹,

Antonsson²,

Holmberg³

et al. 2009

J Pharmacol Exp Ther

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“…Therefore, acid parameters intuitively drive symptom outcome from medical management, and it follows that the predictive value of testing subjects off antisecretory therapy would be higher compared with those on therapy, as the diagnostic yield is much higher off therapy. In recent years, baclofen, a gamma amino butyric acid B receptor agonist, has been implemented as an adjunct to reduce the frequency of reflux events to complement anti-secretory therapy (43)(44)(45). This agent could potentially augment medical management of reflux and improve symptomatic outcomes by reducing reflux events; however, baclofen was not utilized for medical management in our study cohort.…”

Section: Discussionmentioning

confidence: 99%

816 Acid-Based Parameters on pH-Impedance Testing Predict Symptom Improvement With Medical Management Better Than Impedance Parameters

Patel¹,

Sayuk²,

Gyawali³

2013

Gastroenterology

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“…The first is based on the fact that baclofen has been proposed as an effective drug for the treatment of gastroesophageal reflux disease (GERD) by its ability to inhibit the intermittent relaxation of the LES. This is the main physiopathological mechanism that determines this dysfunction, thus reducing, with the therapeutic use of baclofen, the reflux of stomach content to the esophagus in humans (11,22,23,26,48) . There is no information about the effect of baclofen on the pylorus.…”

Section: Discussionmentioning

confidence: 99%

Effect of baclofen on liquid and solid gastric emptying in rats

Collares

Vinagre

2010

Arq. Gastroenterol.

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-Context -Gamma-aminobutyric acid (GABA) is a potent inhibitory neurotransmitter. There is evidence that GABA B receptors located in the dorsal complex and in afferent fibers of the vagus nerve participate in the control of gastrointestinal motility. Objectives -To assess the intracerebroventricularly (ICV) and intravenously (IV) effect of baclofen, a GABA B receptor agonist, on liquid and solid gastric emptying in rats. Methods -Adult male Wistar rats weighing 250-300 g (n = 6-8 animals) were used. Gastric emptying of liquid test meals labeled with phenol red was evaluated by the determination of percent gastric retention (%GR) 10 and 15 min after orogastric administration of saline and 10% glucose meals, respectively. Baclofen was injected ICV (1 and 2 mg/animal) through a tube implanted into the lateral ventricle of the brain and was injected IV (1 and 2 mg/kg) into a tail vein. The gastric emptying of liquid was determined 10 or 30 min after ICV and IV baclofen administration, respectively. The gastric emptying of the solid meal was assessed by the determination of percent gastric retention 2 h after the beginning of the ingestion of the habitual ratio by the animal, consumed over a period of 30 min. Baclofen was administered ICV (1 and 2 mg/animal) or IV (1 and 2 mg/kg) immediately after the end of the ingestion of the solid meal. The control groups received vehicle (sterile saline solution) ICV or IV.Results -The group of animals receiving baclofen ICV (2 mg/animal) presented a significantly lower (P<0.05, Tukey test) %GR (mean ± SEM) of the saline (18.1 ± 2.5%) compared to control (33.2 ± 2.2%). In the group receiving the drug IV, the gastric retention of the same test meal did not differ from control. ICV and IV administration of baclofen had no effect on the gastric emptying of the 10% glucose solution compared to control. ICV administration of 1 or 2 mg baclofen/animal significantly increased the gastric retention of the solid test meal (57.9 ± 6.5% and 66.6 ± 6.3%, respectively) compared to control (35.1 ± 4.4%). The same phenomenon was observed only with the IV dose of 2 mg/kg (71.9 ± 2.6%) compared to control (52.7 ± 2.8%). Conclusions -Baclofen administered: 1. ICV (2 mg/animal), but not IV, increased gastric emptying of a non-caloric isotonic liquid test meal (saline); 2. when administered ICV or IV, it had no effect of gastric emptying of a 10% glucose solution; 3) when administered ICV (1 and 2 mg/animal) and IV (2 mg/kg) it delayed the gastric emptying of the solid meal. HEADINGS -Gastric emptying. Baclofen. Rats.

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Effect of acute and chronic administration of the GABAB agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease

Cited by 151 publications

References 28 publications

(R)-(3-Amino-2-fluoropropyl) Phosphinic Acid (AZD3355), a Novel GABA_B Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxation through a Peripheral Mode of Action

(R)-(3-Amino-2-fluoropropyl) Phosphinic Acid (AZD3355), a Novel GABA_B Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxation through a Peripheral Mode of Action

816 Acid-Based Parameters on pH-Impedance Testing Predict Symptom Improvement With Medical Management Better Than Impedance Parameters

Effect of baclofen on liquid and solid gastric emptying in rats

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Effect of acute and chronic administration of the GABAB agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease

Cited by 151 publications

References 28 publications

(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

(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

816 Acid-Based Parameters on pH-Impedance Testing Predict Symptom Improvement With Medical Management Better Than Impedance Parameters

Effect of baclofen on liquid and solid gastric emptying in rats

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(R)-(3-Amino-2-fluoropropyl) Phosphinic Acid (AZD3355), a Novel GABA_B Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxation through a Peripheral Mode of Action

(R)-(3-Amino-2-fluoropropyl) Phosphinic Acid (AZD3355), a Novel GABA_B Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxation through a Peripheral Mode of Action