Novel Therapeutics for Gastroesophageal Reflux Symptoms

Abstract and Introduction

Abstract

Approximately 20–30% of patients with gastro–esophageal reflux symptoms report inadequate symptom relief while on proton-pump inhibitor therapy. The mechanisms involved are failure of the antireflux barrier (transient lower esophageal sphincter relaxations), high proximal extent of the refluxate, esophageal hypersensitivity and impaired mucosal integrity. Persisting acid or nonacid reflux can be demonstrated in 40–50% of cases, suggesting that there is room for antireflux therapy in these patients. New antireflux compounds have been shown to decrease the occurrence of transient lower esophageal sphincter relaxations. The most promising classes of compounds are GABA type B agonists and metabotropic glutamate receptor 5 antagonists, which can reduce both reflux episodes and symptoms, but the development of these compounds has been abandoned for either safety issues or lack of efficacy. Esophageal hypersensitivity and impaired mucosal integrity may prove to be relevant therapeutic targets in the future.

Introduction

Gastro–esophageal reflux disease (GERD) is a common disorder caused by the reflux of gastric contents into the esophagus. According to a recent global definition, GERD can cause esophageal and extra-esophageal syndromes, which can be associated or not in the same individual.^[1] The diagnosis of GERD can rely on typical symptoms such as heartburn and regurgitation as well as the presence of esophageal mucosal breaks at endoscopy. GERD management is primarily based on empiric therapy, with lifestyle modifications and medication, especially in general practice. Experimental and pH studies have demonstrated the major role of the acidic component of the refluxate in the pathogenesis of symptoms and mucosal damage.^[2] This is confirmed by the remarkable efficacy of proton-pump inhibitors (PPIs) for mucosal healing and symptom relief.^[3] However, although there is no consensus on the definition of failure, 30–40% of patients with reflux symptoms do not achieve adequate symptom relief after a 4-week course of a single dose of PPI.^[4] Most of these patients belong to the so-called nonerosive reflux disease (NERD) subgroup.^[5,6]

Although failure of PPIs is one of the most common indications for antireflux surgery, it is generally considered by experts that antireflux surgery in these patients has a less favorable clinical outcome compared with that obtained in patients with adequate PPI symptom control.^[4,7] Indeed, many patients with refractory symptoms do not have GERD, but suffer from functional heartburn or dyspepsia; however, studies with 24-h esophageal pH-impedance monitoring showed that 40–50% of patients have symptoms that are associated with persisting acid or nonacid reflux events.^[8,9] These results demonstrate that, in a substantial group of patients with GERD, there is room for therapies that can restore an efficient antireflux barrier. Nevertheless, it is crucial to consider that an impaired antireflux barrier is far from being the only mechanism involved in the pathophysiology of refractory GERD. The other potential targets are an improved control of gastric acid secretion, limitation of proximal extent of the refluxate, modulation of esophageal hypersensitivity and restoration of esophageal mucosal integrity.

Table 1. Pharmacological control of transient lower esophageal sphincter relaxations.
Target	Compound	Agonist/antagonist	Human/animal use
Nitric oxide synthase	L-NAME and L-NMMA	Inhibitor	Dog and human
CCK₁ receptor	Loxiglumide and devazepide	Antagonist	Dog and human
Muscarinic receptor	Atropine	Antagonist	Human
µ opioid receptor	Morphine	Agonist	Human
CB1 receptor	WIN55, 212-2, Δ-9-tetrahydrocannabinol	Agonist	Dog, ferret and human
mGluR5 receptor	MTEP and MPEP ADX10059 and AZD2066	Antagonist	Dog, ferret and human
GABA_B receptor	Baclofen Lesogaberan (AZD3355) Arbaclofen placarbil	Agonist	Dog, ferret, cat and human

GABA_B: GABA type B; L-NAME: L-NG-nitroarginine methyl ester; L-NMMA: L-NG-monomethylarginine; mGluR5: Metabotropic glutamate receptor 5; MPEP: 2-methyl-6-(phenylethynyl)-pyridine; MTEP: 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine.