Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

Mosińska, Paula; Zatorski, Hubert; Storr, Martin; Fichna, Jakub

doi:10.5056/jnm16183

Cited by 17 publications

(12 citation statements)

References 54 publications

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“…Studies indicated that the synthetic ghrelin agonist relamorelin may be effective in increasing stool frequency and accelerating colonic transit. 76 However, so far marketing authorization for relamorelin in constipation has not been granted. Recently, the Parkinson study group could not detect significant clinical benefits for relamorelin in PD-associated constipation which may, however, be attributed to the failure of meeting the recruitment target.…”

Section: Discussionmentioning

confidence: 99%

Management of constipation in patients with Parkinson’s disease

Carrasco

Timmermann

Pedrosa

2018

npj Parkinson's Disease

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A considerable body of research has recently emerged around nonmotor symptoms in Parkinson’s disease (PD) and their substantial impact on patients’ well-being. A prominent example is constipation which occurs in up to two thirds of all PD-patients thereby effecting psychological and social distress and consequently reducing quality of life. Despite the significant clinical relevance of constipation, unfortunately little knowledge exists on effective treatments. Therefore this systematic review aims at providing a synopsis on clinical effects and safety of available treatment options for constipation in PD. For this purpose, three electronic databases (MEDLINE, EMBASE, PsycINFO) were searched for experimental and quasi-experimental studies investigating the efficacy/effectiveness of interventions in the management of PD-associated constipation. Besides, adverse events were analyzed as secondary outcome. In total, 18 publications were identified involving 15 different interventions, of which none can be attributed sufficient evidence to derive strong recommendations. Nevertheless, some evidence indicates that dietetic interventions with probiotics and prebiotics may reduce symptom burden while providing a very favorable side-effects profile. Furthermore, the use of lubiprostone, macrogol and in the specific case of isolated or prominent outlet obstruction constipation injections of botulinum neurotoxin A into the puborectal muscles may as well be moderately supported. In summary, too little attention has been paid to treatment options for constipation in PD leaving abundant room for further research addressing this topic.

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Section: Discussionmentioning

confidence: 99%

Management of constipation in patients with Parkinson’s disease

Carrasco

Timmermann

Pedrosa

2018

npj Parkinson's Disease

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“…The finding that ghrelin agonists, with an ability to cross the blood-brain barrier, stimulate colonic prokinetic activity points to the potential usefulness of centrally acting ghrelin agonists for the treatment of patients with chronic constipation (Shimizu et al, 2006;Shafton et al, 2009;Avau et al, 2013;Pustovit et al, 2014;Acosta et al, 2015;Mosi nska et al, 2017). Thus, we investigated whether a novel ghrelin agonist with the ability to penetrate the blood-brain barrier (HM01) had any effect on delayed GI motility.…”

Section: Discussionmentioning

confidence: 99%

“…The GI prokinetic effects of ghrelin occur through two mechanisms: a direct peripheral effect on ghrelin receptors within the myenteric plexus or via ghrelin receptors on the vagus and pelvic nerves activating a centrally mediated mechanism. The upper GI prokinetic effects are thought to activate peripheral ghrelin receptors in the enteric nervous system, whereas the accelerated colonic transit induced by ghrelin itself or ghrelin mimetics likely occurs through a central site of action via vagal and pelvic nerves (Binn et al, 2006;Pustovit et al, 2014;Mosi nska et al, 2017). However, a study in guinea pigs suggested that the contribution of peripheral enteric ghrelin receptors in the stimulation of upper GI transit is modest, and that the gastrostimulatory action of ghrelin can occur through activation of capsaicinsensitive extrinsic vago-vagal reflex pathways (Nakamura et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

A Comparison of the Central versus Peripheral Gastrointestinal Prokinetic Activity of Two Novel Ghrelin Mimetics

Mohammadi

Pietra

Giuliano

et al. 2018

J Pharmacol Exp Ther

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The gastrointestinal (GI) prokinetic effects of ghrelin occur through direct peripheral effects on ghrelin receptors within the enteric nervous system and via the ghrelin receptor on the vagus nerve, which activate a centrally mediated mechanism. However, the relative contribution of peripheral versus central effects to the overall prokinetic effect of ghrelin agonists requires further investigation. Here, we investigated the central versus peripheral prokinetic effect of ghrelin by using two novel ghrelin agonists:, a more peripherally acting ghrelin agonist. The pharmacokinetic profiles of both ghrelin agonists were evaluated after intravenous and oral administration in rats. The efficacy of HM01 and HM02 was assessed in a rat model of postoperative ileus (POI) induced by abdominal surgery and in a rodent defecation assay. Pharmacokinetic results in our models confirmed that HM01, but not HM02, was a brain-penetrant ghrelin agonist. Administration of either HM01 or HM02 reversed the delayed upper and lower gastrointestinal transit induced by abdominal surgery to levels resembling the non-POI controls. In the defecation test, HM01, but not HM02, significantly increased the weight of fecal pellets. Our findings suggest that, in a rodent model of POI, synthetic ghrelin agonists stimulate GI transit through a peripheral site of action. However, in the defecation assay, our data suggest that a ghrelin-mediated mechanism is located at a central site. Taken together, a ghrelin agonist with both central and peripheral prokinetic activity may show therapeutic potential to treat delayed GI transit disorders.

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“…However, in patients undergoing intestinal resection, ipamorelin does not shorten the time for the first meal intake compared to placebo [30]. The Phase II clinical trial below showed no significant difference in measurable colonic functions between ipamorelin and placebo [31]. Due to these disappointing results, its development was halted.…”

Section: Ipamorelinmentioning

confidence: 98%

State-of-the-Art Clinical Results of Growth Hormone Secretagogues, SARM and Antagonists

Zotarelli-Filho¹

2020

Preprint

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Introduction: The term growth hormone secretagogues (GHS) encompasses compounds that were developed to increase growth release of growth hormone (GH). GHSs include growth hormone receptor secretagogue agonists (GHS-R), whose natural ligand is ghrelin, and growth hormone releasing hormone (GHRH) agonists, to which GHRH binds as a native ligand. In the context of selective androgen receptor modulators (SARM), the presence of a Toll-IL-1 receptor domain (TIR) predicts a role for SARMs in innate immunity. SARMs are an emerging class of therapies aimed at cachexia, sarcopenia and hypogonadism or treatment of stress urinary incontinence, osteoporosis, breast cancer and Duchenne muscular dystrophy. Objective: To present the state-of-the-art scientific evidence in humans on the use of growth hormone secretagogues, SARM and antagonists. Methods: Experimental and clinical studies were included (case reports, retrospective, prospective, randomized studies and systematic review) with qualitative and/or quantitative analysis. For further specifications, the description "Clinical Trail" for refinement was added during the research, following the rules of the systematic review-PRISMA. Of 384 articles, a total of 80 articles were evaluated in full and 58 were included and discussed in this study. Results and conclusion: Several clinical trials have been conducted and completed to assess the safety and efficacy of GHS for the diagnosis and / or treatment of GH deficiency. Over the past two decades, scientists' efforts have focused on the discovery and biological characterization of new tissue-specific SARM to promote the beneficial effects of androgens with greatly reduced undesirable side effects. In this regard, numerous studies with SARM of different structures have been reported. Despite evidenced clinical and preclinical studies, no SARM has yet received full clinical approval.

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Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

Cited by 17 publications

References 54 publications

Management of constipation in patients with Parkinson’s disease

Management of constipation in patients with Parkinson’s disease

A Comparison of the Central versus Peripheral Gastrointestinal Prokinetic Activity of Two Novel Ghrelin Mimetics

State-of-the-Art Clinical Results of Growth Hormone Secretagogues, SARM and Antagonists

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