Beyond Acid Suppression: New Pharmacologic Approaches for Treatment of GERD

Abstract

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.

Lack of direct effects of acyl ghrelin, des-acyl ghrelin, and obestatin on rat lower esophageal sphincter motility in vitro

“…27 Many receptors have been cloned from LES, such as gamma-aminobutyric type B and metabotropic glutamate type 5 receptors. 28 Both the new gamma-aminobutyric type B receptor agonist, AZ3355, and the metabotropic glutamate type 5 receptor agonist, 2-methyl-6-(phenylethynyl)-pyridine, have been shown to be effective in inhibiting transient LES relaxation and reducing the number of reflux episodes. 29 These two new drugs have been developed for the treatment of GERD.…”

Cough: an unmet clinical need

“…Transient lower oesophageal sphincter relaxation (TLESR) promotes the occurrence of gastro‐oesophageal reflux. The GABA‐B agonist baclofen has been shown to inhibit TLESR, and reduces the number of reflux episodes in subjects with GERD, reduces GERD symptoms in one study of chronic administration and increases basal lower oesophageal sphincter pressure in healthy volunteers and subjects with GERD (Kuo and Holloway, 2010). In addition, baclofen has been shown to be an anti‐tussive agent independent of its effect on reflux by inhibiting capsaicin‐induced cough in healthy volunteers (Dicpinigaitis and Dobkin, 1997).…”

“…Despite such compelling evidence, baclofen has not gained widespread use because of undesirable side effects including sedation, dizziness, headache and confusion. Hence, newer GABA‐B agonists with more specific peripheral activity and less central effects are currently the subject of active research (Kuo and Holloway, 2010).…”

Different in vitro and in vivo profiles of substituted 3‐aminopropylphosphinate and 3‐aminopropyl(methyl)phosphinate GABAB receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation

“…The major drawback of baclofen is its central side effects, and this, together with the lack of receptor subtype selective compounds, has encouraged the discovery of new GABAB receptor agonists. The present report suggests that group II GABAB agonists may have a therapeutic utility in GORD (Kuo and Holloway, 2010). The finding that 3-aminopropylphosphinic acids generally have high oral availability and favourable plasma halflife makes these compounds highly interesting from a drug discovery and development point of view.…”