JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2017, 68, 6, 797-805 www.jpp.krakow.pl Review article H. ZATORSKI 1, P. MOSINSKA 1, M. STORR 2, J. FICHNA 1 RELAMORELIN AND OTHER GHRELIN RECEPTOR AGONISTS - FUTURE OPTIONS FOR GASTROPARESIS, FUNCTIONAL DYSPEPSIA AND PROTON PUMP INHIBITORS-RESISTANT NON-EROSIVE REFLUX DISEASE 1Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland; 2Center of Endoscopy, Starnberg, Germany There is an unmet need for effective pharmacological therapies for the treatment of gastroparesis and other upper gastrointestinal (GI) motility disorders, which reduce patients’ quality of life and are a burden to the healthcare system. Ghrelin is an endogenous growth hormone secretagogue receptor ligand and has been shown to exert prokinetic effects on GI motility. Nevertheless, considering the short half-life of ghrelin its use in clinical practice is limited. Thus, ghrelin receptor agonists with enhanced pharmacokinetics were developed; they accelerate gastric emptying and improve symptoms of gastroparesis in animal models and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other analogs which are in preclinical or clinical development stages for the management of upper GI disorders. Key words: gastroparesis, gastrointestinal motility, ghrelin, functional dyspepsia, non-erosive reflux disease, relamorelin INTRODUCTION (scleroderma) disorders. Currently, treatment in gastroparesis focuses on the management of an underlying cause, if identified, Upper gastrointestinal (GI) disorders are amongst others such as optimization of glucose levels in diabetics as well as characterized by inadequate and uncoordinated GI muscular stimulation of gastric emptying and dietary therapy with motility. These disorders may be caused by endogenous or restoration of fluid and electrolytes (4). exogenous factors, but there is usually no evidence of a structural etiology (1). The most common upper GI disorders with the evidence of abnormal motility pattern include gastroparesis, FUNCTIONAL DYSPEPSIA functional dyspepsia (FD) and gastroesophageal reflux (GERD). Patients suffering from upper GI disorders typically present with FD is an upper GI disorder defined as bothersome various symptoms such as early satiety, postprandial fullness, postprandial fullness, early satiation, epigastric pain and/or bloating, nausea, vomiting and epigastric pain (1). epigastric burning in the absence of any known organic, systemic This review summarizes the current knowledge on ghrelin or metabolic disease that has been present for the last three receptor (GHSR) agonists ( Fig . 1), with the relamorelin in the months with onset more than 6 months prior to the diagnosis (5). forefront, which are in preclinical or clinical stages of FD has been further sub-classified into the postprandial distress development in improving delayed gastric emptying and syndrome (PDS) characterized by bothersome postprandial symptoms associated with impaired upper GI motility. fullness or early satiation at least 3 days per week and the Furthermore, the potential new applications of GHSR agonists epigastric pain syndrome (EPS) characterized by bothersome are discussed. epigastric pain or burning at least 1 day per week. The cause of FD remains to be established, but recent data suggest that infections, brain-gut disturbances, duodenal perturbations and GASTROPARESIS food may play a crucial role in pathophysiology of FD (6). Gastroparesis is defined as a delayed gastric emptying with no sign of mechanical obstruction of the stomach. Recent modeling PROTON PUMP INHIBITORS-RESISTANT study estimated that delayed gastric emptying affects 1.8% of the NON-EROSIVE REFLUX DISEASE population (2). Its prevalence is estimated as 9.6/100,000 persons for men and 37.8/100,000 persons for women (2, 3). The most Reflux of gastric acid plays a major role in the common causes of gastroparesis are diabetes, postsurgical and pathophysiology of GERD (7). Thus, conventional therapeutic idiopathic; less common causes include iatrogenic, extrinsic strategy for GERD involves the use of proton pomp inhibitors neuronal (parkinsonism or paraneoplastic disease) and infiltrative (PPI) to inhibit acid secretion (8). However, in clinical practice, 798 troublesome GERD symptoms persist in 20 – 30% of patients be responsible for the decreased food intake after gastric ischemia despite daily treatment with a proton pomp inhibitor (PPI). The PPI and reperfusion, which significantly contributes to the gastric resistance rate (40 – 50%) in patients without erosion of the mucosal injuries caused by stress, Helicobacter pylori infection esophageal mucosa (non-erosive reflux disease, NERD) is higher and other factors (21). Moreover, ghrelin is known to interact with when compared to patients with reflux esophagitis (RE). the reproductive, cardiovascular and immune system (22) as well Therefore, the underlying mechanism of development of NERD is as oxidative stress defense mechanisms (23). indisputably different from that of RE (9, 10). It is widely known Ghrelin expression is highest in the stomach and relatively low that the persistent GERD symptoms e.g. resulting from PPI in the small and large intestines. Recent research showed altered resistance worsen the quality of life in patients with PPI-refractory levels of ghrelin in inflammatory diseases of stomach, such as NERD. However, such resistance in these patients may be caused peptic ulcer disease, and its complications, e.g. gastric outlet by several other factors, including esophageal mucosal obstruction (24, 25). The plasma ghrelin levels are significantly hypersensivity, bile acid reflux, abnormal esophageal motility, higher in the duodenal ulcer rat model induced by oral gastric motility disorders and rather than from acid reflux (10). administration of cysteamine. Importantly, the study performed by Consequently, some combinations of prokinetic drugs and PPIs Fukuhara et al . showed that an increase in plasma ghrelin levels have been tested to alleviate symptoms of disorders associated with precedes the formation of duodenal ulcers in rats (24). In another gastric emptying and esophageal clearance, which play an study, performed by Suzuki et al . expression of preproghrelin important role in the pathophysiology of GERD (11). However, mRNA and total ghrelin levels were significantly decreased after such therapeutic regiments have not been, proven useful for every H. pylori colonization in Mongolian gerbils, suggesting that peptic type of GERD (8). Thus, a suitable and multi-selective therapeutic ulcer development caused by H. pylori infection may be modulated strategy is needed as soon as possible for such cases. by ghrelin (26). Interestingly, ghrelin production and secretion in the gastric mucosa is increased in mice lacking H 2 receptor, suggesting that ghrelin may stimulate acid secretion independently GHRELIN from histamine-dependent pathway (27). Suzuki et al . showed that plasma ghrelin levels were significantly higher in patients with Currently, conventional treatment options used to improve duodenal and gastric ulcer than in those without ulcers, which functional GI diseases symptoms are of limited efficacy and confirmed findings from the animal model. Nevertheless, elevated usually judged as unsatisfactory. Furthermore, the use of plasma levels of ghrelin did not change significantly after the ulcers medications such as metoclopramide is restricted due to its adverse were healed (28). In a rat model of gastric outlet obstruction effects, such as gynecomastia, changes in the affect and mimicking pyloric stricture, seen in clinical settings in conditions involuntary movements to name only a few (12). Taking into like duodenal ulcers or advanced gastric cancer, fasting plasma consideration their increasing prevalence, difficulties in diagnosis, levels were increased in comparison to control group suggesting and patients’ low quality of life, upper GI disorders have become that dysregulation of gastric motility may alter ghrelin levels (25). an emerging problem in gastroenterology. Thus, there is an unmet Interestingly, plasma ghrelin levels may also be altered by need to introduce new therapeutics in the treatment of upper GI emotional stress and thus in upper GI functional diseases (29). For disorders. instance, in a study performed by Nishizawa et al . on 97 patients Since the discovery in 1999 ghrelin has been seen as a the plasma ghrelin levels were significantly higher in patients with potential therapeutic option in medicine (13). Recent studies functional dyspepsia, particularly in those with dysmotility-like suggest that ghrelin may play an important role in the FD, in comparison to healthy individuals (30). pathogenesis of upper GI functional diseases. Indisputably, ghrelin enhances gastric emptying and induces Ghrelin, a 28-amino acid peptide, is the endogenous ligand of contractile activity in the GI tract. Nevertheless, the short half- the growth hormone secretagogue receptor (GHSR), later renamed life and plasma instability of ghrelin impairs its usefulness (22). as the ghrelin receptor. In humans it is mainly produced in the Thus, small molecule GHSR agonists with prolonged receptor P/D1-like cells of the oxyntic mucosa of the stomach and accounts activity currently represent an attractive therapeutic option for for approximately 20% of the endocrine cell population in the the management of upper GI tract motility disorders. In this stomach (14). Ghrelin