376 AZD3355, a Novel GABAB Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxations in the Dog

Lehmann, Anders; Brändén, Lena; Carlsson, Anita; Jensen, Jörgen; Mattsson, Jan P.; Nilsson, Karolina; Uvebrant, Anna; Unge, Sverker von

doi:10.1016/s0016-5085(08)60239-5

Cited by 7 publications

(3 citation statements)

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“…Transient lower oesophageal sphincter relaxations is the predominant mechanism underlying reflux in GERD 13, 14 and use of pharmacological agents to reduce the number of TLESRs has been shown also to reduce the occurrence of reflux episodes in healthy subjects and patients with GERD 25, 26 . In dogs, lesogaberan has been shown to inhibit TLESRs in a dose‐dependent manner 21 . In the current study in healthy male subjects, a single oral dose of lesogaberan 0.8 mg/kg reduced the number of TLESRs by approximately 36% compared with placebo.…”

Section: Discussionmentioning

confidence: 99%

“…Lesogaberan (AZD3355) is a competitive, selective GABA B ‐receptor agonist that dose‐dependently inhibits TLESRs and reduces the number of reflux episodes and oesophageal acid exposure in dogs 21, 22 . Lesogaberan has been shown to reduce the activation of ferret gastric vagal mechanoreceptors, 23 indicating that it has a peripheral site of action.…”

Section: Introductionmentioning

confidence: 99%

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Effect of lesogaberan, a novel GABA_B‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects

Boeckxstaens¹,

Rydholm²,

Lei³

et al. 2010

Aliment Pharmacol Ther

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of lesogaberan, a novel GABA_B‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects

Boeckxstaens¹,

Rydholm²,

Lei³

et al. 2010

Aliment Pharmacol Ther

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“…Side effects of baclofen include sedation, confusion and memory impairment, as well as the potential for seizures following withdrawal which may limit its use 19. A novel GABA B receptor peripheral agonist, AZD3355, has been shown to inhibit TLOSRs in dogs resulting in a decrease of acid reflux episodes by half, and also a decrease in overall acid exposure time 21 22. Similar results have been found with AZD9343 23.…”

Section: Potential Therapeutic Agentsmentioning

confidence: 57%

The relevance of transient lower oesophageal sphincter relaxations in the pathophysiology and treatment of GORD

Sharma

Anderson

2013

Frontline Gastroenterol

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Gastro-oesophageal reflux disease (GORD) is associated with the passage of gastric contents into the oesophagus resulting in potential oesophageal damage and impaired quality of life. GORD is a frequently encountered problem in today's population, with 25% of people in western populations reporting such symptoms at least once a month. Proton pump inhibitors (PPI) are the drug of choice, with surgery being employed in refractory cases. Although acid suppression is often effective, some patients remain symptomatic despite maximal PPI therapy. By delving into the mechanisms of the disease, it is clear that transient lower oesophageal sphincter relaxations are a key component of its pathophysiology. Research has demonstrated various therapeutic targets for reducing the frequency of such relaxations through GABA and glutamate modulation, for instance. This review highlights such modulations and hopes to explore these mechanisms and therapeutic targets in an area that will no doubt see a change in its pharmacological management in the near future.TRANSIENT LOWER OESOPHAGEAL SPHINCTER RELAXATIONS-MECHANISMS Transient lower oesophageal sphincter relaxations (TLOSR) account for 65% of reflux episodes. 1 2 They are vagally mediated by stretch receptor activation following stomach distension.3 Evidence for this has been provided, courtesy of the 5-hydroxytryptamine 1 agonist sumatriptan, which results in a higher frequency of TLOSRs and reduced gastric emptying. 4 During such relaxations, diaphragmatic crural contraction inhibition hinders the crural diaphragm pinch-cock effect around the sphincter. 5A variety of dietary factors increase the rate of TLOSRs, including chocolate, fats, alcohol and peppermint. 6 A study by Piche et al 7 analysed the effect of carbohydrates on colonic fermentation, and demonstrated an increase in the rate of postprandial TLOSRs most likely due to excess release of glucagon-like peptide 1. Obesity is also implicated in the pathogenesis of reflux disease and TLOSRs. Schneider et al 8 concluded that obese individuals have two-thirds more TLOSRs per hour than non-obese patients with diffuse oesophageal spasm, with the majority of TLOSRs being complete and isolated in nature. Kahrilas et al 9 demonstrated that the presence of a hiatus hernia is also associated with TLOSRs with frequency being directly proportional to the size of hernia. Posture might also play a role with the right recumbent position increasing the frequency of TLOSRs. 10The relevance of TLOSRs has long been underestimated. Kawahara et al 11 showed that in children if swallow induced lower oesophageal sphincter (LOS) relaxation-associated reflux was reclassified as, in fact, due to TLOSR, the number of reflux episodes attributed to TLOSR would rise from 58% to 81%.The basal LOS pressure is also relevant. TLOSRs can occur even at low LOS pressures (less than 5 mm Hg) and certainly some reflux episodes in this setting are due to TLOSR rather than a low basal pressure. 12Studies have also shown that the refluxate associat...

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Reflux inhibitors: a new approach for GERD?

Boeckxstaens¹

2008

Current Opinion in Pharmacology

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376 AZD3355, a Novel GABAB Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxations in the Dog

Cited by 7 publications

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Effect of lesogaberan, a novel GABA_B‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects

Effect of lesogaberan, a novel GABA_B‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects

The relevance of transient lower oesophageal sphincter relaxations in the pathophysiology and treatment of GORD

Reflux inhibitors: a new approach for GERD?

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376 AZD3355, a Novel GABAB Receptor Agonist, Inhibits Transient Lower Esophageal Sphincter Relaxations in the Dog

Cited by 7 publications

References 0 publications

Effect of lesogaberan, a novel GABAB‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects

Effect of lesogaberan, a novel GABAB‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects

The relevance of transient lower oesophageal sphincter relaxations in the pathophysiology and treatment of GORD

Reflux inhibitors: a new approach for GERD?

Contact Info

Product

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Effect of lesogaberan, a novel GABA_B‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects

Effect of lesogaberan, a novel GABA_B‐receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects