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 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 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 , 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 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 , 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 is also produced in smaller amounts in other review, we summarize the latest preclinical and clinical studies tissues, such as the pituitary, hypothalamus, pancreas, heart and evaluating the potential of relamorelin and other GHSR agonist liver (15). GHSR is a G protein-coupled receptor appearing in two (Fig . 1) in improving delayed gastric emptying and symptoms alternative splicing variants. The GHR-S1a form is an active 7- associated with impaired upper GI motility. transmembrane domain receptor, whereas GHR-S1b form is a truncated 5-transmembrane domain receptor, with no evident psychological function. The activation of GHSR modulates several GHRELIN RECEPTOR AGONISTS intracellular signaling pathways and exhibits different endocrine and non-endocrine effects (16). Ghrelin administered either Delayed gastric emptying is considered to play a role in peripherally or centrally stimulates food intake. Peripheral ghrelin pathogenesis of upper GI motility disorders symptoms and, thus, is thought to increase food intake via the GHSR in vagal afferents constitutes a major therapeutic target. Small-molecules, such as or being transported in the bloodstream to act on centers in relamorelin, , , EX-1314, and the brain (17, 18). Pirnik et al . showed that subcutaneous GHRP-6 stimulate gastric emptying in animals. Only a small administration of a GHSR agonist, Dpr-(N-octanyl)-3-ghrelin, number of preclinical animal studies have been performed so far stimulated food intake via Fos expression and activation of tyrosine (Table 1 ). hydroxylase neurons in hypothalamic arcuate nucleus (19). Furthermore, i.p. injection of the ghrelin-O-acyltransferase (GOAT) inhibitor, which blocks a specific enzyme that modifies RELAMORELIN ghrelin with a medium-chain fatty acid resulted in the reduction of food intake in Sprague-Dawley rats. This anorexigenic effect was Relamorelin is a pentapeptide GHSR agonist with improved mainly due to reduction of meal frequency, whereas meal size was stability and longer plasma circulating half-life (31) compared to not altered when compared to vehicle (20). Mogami et al . ghrelin. Relamorelin activates GHSR with approximately 6-fold demonstrated that significantly reduced plasma ghrelin levels may greater potency than natural ghrelin. 799

Fig . 1. Ghrelin and GHSR agonists structures available at www. pubchem.ncbi.nlm.nih.gov .

Table 1 . GHSR agonists under investigation in preclinical animal studies. Route Animal Reference Generic name Effect of admin. Model No Stimulation of gastric emptying, POI and morphine- Relamorelin s.c. GI transit in the proximal and (32) induced ileus middle part of small intestine Ulimorelin Normalization of delayed gastric s.c. POI (38) (TZP-101) emptying TZP-102 in a dose-dependent Rat model of gastric TZP-102 NP manner increased gastric (43) emptying emptying Capromorelin i.p. Increase in gastric emptying Healthy animals (47) Increase in gastric emptying, EX-1314 i.p., p.o. improvement in small intestinal POI (44) transit, fecal output Ipamorelin i.p. Acceleration of gastric emptying POI (45) GHRP-6 i.p. Acceleration of gastric emptying POI (67)

NP, not provided; i. p., i ntraperitoneal; s.c., subcutaneo us; p .o, per os ; POI , pos toperati v e ile us; GHSR, gro wth hormone secretagogue receptor, ghrelin

Animal studies In another phase I study (ClinicalTrials.gov Identifier: NCT01394055) relamorelin in a single-day treatment with a Animal studies showed that relamorelin due to higher dose of 100 µg s.c. significantly accelerated gastric emptying of potency to GHSR may become a useful therapeutic in upper GI solids and reduced upper GI symptoms such as nausea, motility disorders (32). Relamorelin exhibited approximately vomiting, fullness and pain in patients with type 1 diabetes (35). 100-fold more potency than ghrelin and reversed delayed gastric Interestingly, in patients with type 2 diabetes and documented emptying in morphine-induced model of gastroparesis in delayed-gastric emptying relamorelin greatly accelerated the Spraque-Dawley rats. Additionally, oral administration of gastric emptying of solids but failed to improve Gastrointestinal relamorelin enhanced GI transit in the proximal and middle part Cardinal Symptom Index (GCSI) such as nausea, bloating, early of the small intestine (32). satiety and pain (35). Interestingly, relamorelin may possess anti-inflammatory Results of the latest double-blinded trial of 204 patients with properties as it reduces signs of macroscopic colonic diabetic gastroparesis with moderate to severe symptoms and inflammation, reverses weight loss and improves survival in rat delayed gastric emptying published by Lembo et al . (36) model of TNBS-induced colonic inflammation (32). Moreover, successfully demonstrated that relamorelin may be useful relamorelin exhibits anti-inflammatory properties in cachexia therapeutic option for GI motility disorders. Relamorelin in dose models by reducing elevated levels of interleukin-1, interleukin- 10 µg s.c. administered twice daily significantly accelerated 6, interleukin-12, as well as TNF- , compared to controls (33). gastric emptying. Of note, relamorelin significantly reduced vomiting frequency and severity in comparison to the placebo Human studies group. Nevertheless, relamorelin did not improve other GI symptoms such as abdominal pain and satiety. Importantly, Translated into humans, in a randomized, double-blinded, patients with baseline vomiting benefited the most from placebo-controlled study of 16 healthy volunteers relamorelin in prokinetic actions of relamorelin (36) (ClinicalTrials.gov a dose 30 µg s.c. significantly increased frequency of distal Identifier: NCT01571297) . antral motility contractions without significant effect on their Very recently, results of a phase IIB study (ClinicalTrials.gov amplitude (ClinicalTrials.gov Identifier: NCT02466711) (34). Identifier: NCT02357420) were published in patients with 800 diabetic gastroparesis who received twice daily an injection of end of the study there was a statistically significant improvement relamorelin in a dose 10, 30 or 100 µg s.c. (37). Patients who in severity of GCSI Loss of Appetite and Vomiting Scores for were given relamorelin had a 75% reduction in vomiting that dose group. Moreover, in patients group receiving a dose of frequency compared to baseline, but this difference did not reach TZP-101 80 ug/kg meal related Gastroparesis Symptoms the statistical significance. Administration of relamorelin over the Assessment (GSA) scores for postprandial fullness were 12-week study significantly reduced all 4 symptoms of diabetic significantly improved compared to placebo group (41). gastroparesis (nausea abdominal pain, postprandial fullness and In two phase III studies (ClinicalTrials.gov Identifier: bloating). Moreover, relamorelin significantly accelerated gastric NCT01285570 and NCT01296620) involving patients emptying from baseline compared to placebo. Nevertheless, undergoing partial bowel resection, ulimorelin failed to adverse effects of relamorelin administration were also noted. demonstrate its effectiveness. There were no differences Relamorelin was responsible for glycemic control worsening in between groups receiving ulimorelin and placebo in the study 14.5% of patients in a dose-dependent manner. Some patients endpoints, which included postsurgical time to first bowel needed insulin or other diabetic drug dosage modifications (37). movement, tolerance of solid food and discharge eligibility (42). Yet, there are no clinical trials evaluating the effect of this ghrelin agonist in patients with upper GI motility disorders. TZP-101 (ULIMORELIN)

TZP-101 is a macrocyclic peptidomimetic GHSR agonist TZP-102 widely investigated in the management of GI motility. TZP-102 is an oral low molecular weight synthetic Animal studies macrocyclic compound with a substantially longer half-life, thereby allowing more sustained action as a potent GHSR In the study by Venkova et al . (38) systemic administration agonist compared to parenteral ghrelin agonists (16). of TZP-101 (0.03 – 1.0 mg/kg i.v.) in Sprague-Dawley rats was equally effective against the delayed GI transit induced by Animal studies surgery, morphine or both interventions simultaneously. Importantly, the promotility action of TZP-101 was more Prokinetic activity of TZP-102 was evaluated in a rat model pronounced in the stomach compared to the small intestine. of gastric emptying, in which TZP-102 in a dose-dependent In detail, TZP-101 significantly increased gastric emptying manner increased gastric emptying up to 51% in comparison to in a dose-dependent manner up to 96.9% of the values in naïve vehicle. Of note, TZP produced promotility effect comparable to animals in postoperative (POI) model induced by surgery. metoclopramide, which administered p.o. in a dose 30 mg/kg Additionally, TZP-101 administration accelerated gastric increased gastric emptying in 35 – 57% (43). emptying, increased the geometric center and the distance reached by the meal in a model of morphine-induced delay in GI Human studies transit (38). In a multicenter, randomized, double-blinded, placebo Human studies controlled phase II study (ClinicalTrials.gov Identifier: NCT00889486) oral administration of TZP-102 once daily for In Phase I study Lasseter et al . (39) evaluated safety, 28-days demonstrated significant improvements in the most pharmacokinetics and pharmacodynamic of TZP-101 in healthy prevalent symptoms of gastroparesis in diabetic patients (43). volunteers. Overall, administration of TZP-101 in a single dose Nevertheless, no significant change in gastric emptying after ranging from 20 to 600 ug/kg by a 30-minute intravenous administration of TZP-102 was observed in this study. The infusion was well tolerated. A few adverse effects such as average improvement in GCSI total score was greater than in dizziness, headache, lower abdominal pain and diarrhea were placebo group (43). reported. Nevertheless, at the highest dose 2 subjects In another phase II study the primary outcome was to experienced bradycardia. Moreover, at higher doses, mean investigate the effect of TZP-102 in a dose 10 mg on symptoms arterial blood pressure and heart rate decreased form baseline associated with diabetic gastroparesis. Nevertheless, the study approximately 45 to 60 minutes after the start of the infusion was terminated due to insufficient efficacy in planned interim (39). This study suggested that TZP-101 possesses promising futility analysis (ClinicalTrials.gov Identifier: NCT01664637). pharmacokinetic, pharmacodynamic and safety profiles for use in GI motility disorders. In another study ten patients with diabetes, 7 with type 1 and ELIXIR (EX-1314) AND EX-1315 3 with type 2, with moderate to severe gastroparesis symptoms were enrolled. TZP-101 improved solid-meal gastric half- Animal studies emptying and solid- as well as liquid meal latency time in diabetes patients with gastroparesis compared to placebo. Intraperitoneal administration of 500 ug/kg of the small- Nevertheless, due to the small number of patients in each dose molecule GHSR agonists, EX-1314 and EX-1315 resulted in a group, authors could not make any meaningful conclusion significant increase in gastric emptying compared to vehicle- regarding dose-effect. Importantly, TZP-101 infusion improved treated mice. Furthermore, rats treated with EX-1314 either gastric emptying in a similar magnitude to those observed in intraperitoneally or by oral gavage had a significant increase in diabetes patients with gastroparesis following ghrelin infusion. gastric emptying relative to the vehicle group. After However, reductions in overall postmeal symptom intensity and intraperitoneal injection, gastric emptying was significantly postprandial fullness following TZP-101 infusion were not increased in rats given EX-1314 at 5-, 10- and 20-min time statistically significant (40). points, whereas oral gavage of GHSR agonist produced a In another double-blinded, randomized, placebo-controlled significant difference only at the 5-min time point. In addition, study (ClinicalTrials.gov Identifier: NCT 00612014) the TZP- administration of EX-1314 improved small intestinal transit, 101 dose of 80 ug/kg was identified as the most effective. At the fecal output as well as stimulated food intake (44). 801

To our knowledge, this compound had never been tested on Human studies humans and currently there is no research concerning usefulness of this drug in therapy of GI tract motility disorders. To date, pharmacokinetics and safety of capromorelin as a drug with potential to treat constipation were investigated in Phase I study enrolling patients with spinal cord injury (47). IPAMORELIN Currently there is not enough available data to support a possible clinical application of capromorelin in the management of There is limited data available on possible role of ipamorelin gastroparesis or other upper GI motility disorders. To our in upper GI motility disorders. Recent studies focused on knowledge, there are no ongoing studies registered in constipation-related disorders, however those studies are out of ClinicalTrials.gov, thereby suggesting that its development is no scope of this review. More detailed information can be found in longer pursued. Mosinska et al . (22).

Animal studies DIRECTIONS FOR FUTURE RESEARCH OF GHRELIN RECEPTOR AGONIST In rats undergoing laparotomy and intestinal manipulation AND POTENTIAL THERAPY LIMITATIONS: intravenous administration of ipamorelin in a dose ranging from 0.014 to 0.14 µmol/kg resulted in significant acceleration of gastric emptying compared to vehicle-treated Potential use of relamorelin and other agonists in FD and NERD animals. In the tissue isolated from the gastric fundus, refractory to PPI ipamorelin normalized the contractile response to cholinergic neural stimulation. These results suggest that ipamorelin Indisputably, the majority of studies presented in this paper improves delayed gastric emptying by stimulating gastric support the notion that the small molecule ghrelin and GRLR-R contractility via a GHSR receptor mediated mechanism agonists may offer a well-integrated therapeutic option for the located on cholinergic neurons (45). management of various hypomotility disorders, especially gastroparesis ( Table 2 ). Human studies Several consistent results from both animal studies and clinical trials, provide strong evidence for great and sustainable Currently, results of one study concerning prokinetic effect effects of relamorelin in improving gastroparesis-related of ipamorelin for the management of postoperative ileus in symptoms and gastric emptying without causing severe adverse bowel resection patients are available (ClinicalTrials.gov effects. Nevertheless, despite holding a great promise, further Identifier: NCT00672074) (44). Administration of ipamorelin in studies are still needed to establish the chronic effect of a dose 0.03 mg/kg twice daily did not shorten time to first relamorelin on gastric motility. tolerated meal compared to control (44). Gastroparesis, FD and NERD have some similarities and some degree of clinical overlap between those disorders would appear inevitable. In a cohort of 198 gastroparesis patients Parkman et al . GHRP-6 studied the presence of PDS symptoms. Importantly, severe or very severe early satiety and postprandial fullness symptoms were Animal studies presented in more than 50% of patients. Furthermore, increasing severity of aforementioned was associated with slower gastric GHRP-6 is a peptide GHSR agonist tested for potential emptying, higher scores for other symptoms as well as greater usefulness in the treatment of motility disorders associated impairment of quality of life (48). Of note, acyl-ghrelin levels have with delayed gastric emptying (46, 47). In a study performed been associated with gastric emptying (49, 50) and delayed gastric by Kitazawa et al . (47) GHRP-6 improved gastric emptying of emptying has been associated with postprandial fullness and severe solids. In another study GHRP-6 stimulated gastric emptying early satiety in patients with FD (51). Recent research and small intestinal transit, but not colonic transit in vivo . In demonstrated that ghrelin and acyl-ghrelin levels are changed in both studies atropine blocked the effect of GHRP-6 on gastric patients with FD, however results are conflicting (6). Nevertheless, emptying, thereby suggesting that these effects may be in a study performed by Akamizu et al . repeated i.v. infusions of mediated through potentiation of peripheral cholinergic acyl-ghrelin in dose 3 µg/kg twice daily to patients with FD for 2 pathways (46, 47). weeks tended to increase daily intake and hunger sensation (52). To our knowledge, this compound had never been tested on It is widely recognized that patients with PPI-resistant humans and currently there is no research concerning usefulness NERD have lower quality of life due to persistent symptoms of this drug in therapy of GI tract motility disorders. resulting from PPI resistance. This resistance may be caused by several factors, with gastric motility disorders among others (bile acid reflux, esophageal mucosal hypersensitivity, abnormal CAPROMORELIN esophageal motility). Although the symptoms experienced by NERD patients are not as severe as those experienced by patients Animal studies with GERD, one cannot classify NERD as a milder form of GERD. Moreover, recent studies showed that the pathogenesis In one study capromorelin, a non-peptide GHSR agonist, of NERD may differ from that of erosive GERD or Barrett’s accelerated gastric emptying in mice in an equipotent manner esophagus (49). In their study Shindo et al . demonstrated that with ghrelin. Moreover Kitazawa et al . demonstrated that not 33% of NERD patients exhibited delayed gastric emptying (49). only ghrelin but also capromorelin can increase electrically Furthermore, plasma acylated ghrelin levels in FD patients, induced cholinergic contractions, masked by nitrergic nerves, especially patients with PDS, and NERD were significantly without affecting smooth muscle tonus. This suggests the lower than in healthy volunteers (49). These results involvement of nitrergic and cholinergic pathways in demonstrated that ghrelin analogs, especially relamorelin, have acceleration of gastric emptying caused by capromorelin (47). great therapeutic potential in the treatment of FD and NERD. 802

Another piece of evidence supporting a potential use of treatment with ghrelin enhancer for 4 weeks significantly ghrelin analogs in the treatment of GI motility disorders other than improved mental component summary scores in a short-form gastroparesis, is Rikkunshito, a representative of Kampo health survey-8 (SF-8) in patients with low BMI values (under 22) medicines in Japan, with promising results in the treatment of FD as well as acid-related dysmotility symptoms in females and the and NERD. Rikkunshito, known as a ghrelin enhancer, is prepared elderly assessed by the Frequency Scale for the Symptoms of from eight crude medications: Atractylodis Lanceae Rhizoma , GERD (57). In another multicenter, randomized, double-blind, Ginseng Radix , Pinelliae Tuber , Poria , Zizyphi Fructus , Aurantii placebo-controlled, parallel-group conducted by Nobilis Pericarpium , Glycyrrhizae Radix , and Zingiberis Rhizoma Suzuki et al . on the effect of Rikkunshito on 247 patients, the 8- (53). It has been reported that Rikkunshito elicits a continuously week administraton of ghrelin enhancer reduced dyspepsia. In increased acylated ghrelin signal in GHS-R-expressing cells and a addition, epigastric pain was significantly alleviated and decreased afferent activity of the gastric vagus nerve (54). postprandial fullness tended to improve (58). Togawa et al . in a Furthermore, Rikkunshito suppressed cisplatin-induced decrease post-hoc analysis of a randomized placebo-controlled trial on the in plasma acylated-ghrelin and food intake in an anorexia model efficiency and safety of rikkunshito for the treatment of FD in rats through 5-HT 2 receptor antagonism (55). Flavonoids found focused on the differences between responders and non- in Rikkunshito, such as heptamethoxyflavone, hesperidin and responders to rikkunshito. Interestingly, a low baseline level of isoliquiritigenin were responsible for the 5-HT 2 antagonistic effect plasma des-acyl ghrelin was associated with an increased of this herbal (55). In a randomized trial of treatment efficacy of rikkunshito among FD patients, especially in gastroprokinetic agents for 27 patients, conducted by Arai et al ., H. pylori -negative population (59). Rikkunshito was effective in ameliorating upper GI symptoms, Taking into consideration promising effects of ghrelin agonists assessed by their scores on the Gastrointestinal Symptoms Rating in alleviating gastroparesis-related symptoms as well as the effect Scale Questionnaire (56). Furthermore, Tominaga et al . in a of acyl-ghrelin and Rikkunshito on FD and NERD symptoms, new randomized, placebo-controlled, double-blind trial of Rikkunshito clinical trials should be designed to evaluate potential therapeutic for 242 patients with NERD refractory to PPI showed that efficacy of relamorelin in FD and NERD-refractory to PPI.

T able 2 . GHSR agonists under investigation on different phases of clinical trials. Phase of Route Dosage Generic clinical ClinicalTrial.gov Reference Company Indication of used in Primary outcome Secondary outcomes Enrolment name trial/approval Identifier No. admin. the study status Effect of relamorelin Motus Gastric on gastric emptying, Phase I s.c 30 µg - 16 NCT02466711 (34) Therapeutics motility satiety and gastric motility Safety and tolerability of Motus Diabetic Effect of relamorelin relamorelin Phase I s.c 100 µg/kg 20 NCT01394055 (35, 68) Therapeutics gastroparesis on gastric emptying Pharmacokinetics of relamorelin Relamorelin Effect of relamorelin on key 10, 30, 100 µg Motus Diabetic Effect of relamorelin symptoms of gastroparesis Phase IIB s.c. bid for 393 NCT02357420 (37) Therapeutics gastroparesis on vomiting episodes Effect of relamorelin on 12 weeks gastric emptying 10 µg Motus Diabetic once daily; Effect of relamorelin Effect of relamorelin on Phase II s.c 204 NCT01571297 (36) Therapeutics gastroparesis bid for 35 on gastric emptying symptoms of gastroparesis days 160 µg/kg, Diabetic Effect of ulimorelin Effect of ulimorelin on Tranzyme Phase I i.v. 320 µg/kg, 10 NCT00639808 NP gastroparesis on 12-lead ECG data gastric emptying 600 µg/kg 40, 80, Diabetic Effect of ulimorelin Effect of ulimorelin on Tranzyme Phase II i.v 160, 320, 76 NCT00612014 (41) gastroparesis on mean GCSI score cumulative GSA score 600 µg/kg Ulimorelin Post- Effect of ulimorelin Tranzyme, 160 µg/kg, Effect of ulimorelin on Phase III operative GI i.v. on recovery of GI 332 NCT01285570 (42) Norgine 480 µg/kg ancillary GI functions dysmotility function Post- Effect of ulimorelin Tranzyme, 160 µg/kg, Effect of ulimorelin on Phase III operative GI i.v. on recovery of GI 330 NCT01296620 (42) Norgine 480 µg/kg ancillary GI functions dysmotility function Effect of TZP-102 on Effect of TZP-102 on Health-related quality of Diabetic 10 mg, symptoms associated life, adverse effects, Tranzyme Phase II p.o. 201 NCT01452815 (69) gastroparesis 20 mg with diabetic Cardiovascular Parameters, gastroparesis Clinical chemistry and haematology parameters 10 mg, Effect of TZP-102 Effect of TZP-102 on Diabetic Tranzyme Phase II p.o. 20 mg, on gastric half- gastroparesis symptoms and 92 NCT00889486 (43) TZP-102 gastroparesis 40 mg emptying time health-related quality of life Phase II, terminated Effect of TZP-102 on (insufficient Effect of TZP-102 on Diabetic symptoms associated Tranzyme efficacy in p.o. 10 mg health-related quality of life 120 NCT01664637 NP gastroparesis with diabetic planned Adverse effects gastroparesis interim futility analysis Effect of ipamorelin on Post- 0.03, 0.06 Effect of ipamorelin Helsinn ancillary GI functions Phase II operative i.v. mg/kg bid, on recovery of GI 320 NCT01290344 NP Therapeutics Measurement of safety and ileus 0.06 mg/kg tid functions tolerability Ipamorelin Partial Effect of ipamorelin Helsinn small/large Phase II i.v. 0.03 mg/kg on recovery of GI - 117 NCT00672074 (70) Therapeutics bowel function resection

NP, not provided; i.v., intravenous; s.c., subcutaneous; p.o, per os ; GCSI, Gastrointestinal Cardinal Symptom Index; GSA, Gastroparesis Symptoms Assessment; GHSR, Growth Hormone secretagogue receptor, ghrelin receptor. 803

Advantages of therapy with relamorelin functional dyspepsia; GCSI, Gastrointestinal Cardinal Symptom Index; GSA, Gastroparesis Symptoms Assessment; GERD, While there are very limited treatment options in gastroesophageal reflux; GHSR, growth hormone secretagogue gastroparesis, relamorelin shows promising efficacy of this receptor, ghrelin receptor; GI, gastrointestinal; GOAT, ghrelin- condition with a significant reduction in core symptoms and the O-acyltransferase; i.p., intraperitoneally; i.v., intravenously; overall composite score of Diabetic Gastroparesis Symptom NERD, non-erosive reflux disease; POI, postoperative ileus; Severity Diary (DGSSD) as well as acceleration of gastric PDS, postprandial distress syndrome; PPI, proton pump emptying. Nevertheless, there was no meaningful association inhibitors; RE, reflux esophagitis; s.c., subcutaneously between improvement of gastric emptying and symptoms of gastroparesis in the phase IIA and IIB studies (60). This is a Author’s contributions : Hubert Zatorski, Paula Mosinska, common observation in studies concerning prokinetic treatment Martin Storr, and Jakub Fichna provided the overall concept and in gastroparesis (60). Thus, it is possible that beneficial effects framework of the manuscript; Hubert Zatorski researched and of relamorelin result from activation of GHSRs in vagal afferent identified appropriate articles, and wrote the manuscript; Paula pathways, with reduction of vagal tone and therefore, reduced Mosinska, Hubert Zatorski, Martin Storr, and Jakub Fichna sensations expressed as symptoms (61). revised the manuscript; and all authors approved the final Patients with gastroparesis are at risk of lost weight or version of the manuscript. nutritional deficiencies (62). Thus, administration of relamorelin, which may increase appetite and reverses weight Acknowledgements: The study was supported by the loss, may be beneficial for these patients. On the other hand, the Medical University of Lodz (502-03/1-156-04/502-14-339 to administration of ghrelin agonist may result in weight gain HZ, 503/1-156-04/503-11-001 to JF and 502-03/1-156-04/502- which may be a potential concern in patients with gastroparesis 14-343 to PM ) and National Science Center due to diabetes, who may become more overweight or obese (2016/21/N/NZ5/01932 to PM). Hubert Zatorski is the recipient (60). Since data from an available clinical trial did not show of Diamentowy Grant Program of the Polish Ministry of Science significant changes in weight, future studies should focus on the and Higher Education (No. 0202/DIA/2015/44). effect of relamorelin on weight changes in patients with diabetic gastroparesis (36). Conflict of interests: None declared. Another advantage of relamorelin is that compared to presently available therapies for gastroparesis, relamorelin was efficacious and well tolerated (63). 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