The mechanism of enhanced defecation caused by the ghrelin receptor agonist, ulimorelin

Pustovit, Ruslan V; Callaghan, Brid; Kosari, Sam; Rivera, Leni R.; Thomas, Helmut; Brock, James A.; Furness, John B.

doi:10.1111/nmo.12259

Cited by 32 publications

(63 citation statements)

References 40 publications

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“…These are centrally penetrant ghrelin receptor agonists that stimulate neurons in the spinal defecation centres. 6,7 As the majority of spinal cord injuries are at levels rostral to the defecation centres at L5-S4, these compounds have the potential to be used to treat constipation in SCI and thus decrease the chances of incontinence.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers

et al. 2014

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Study design: Single centre, single ascending dose study. Objectives: To compare the pharmacokinetics and assess the safety of capromorelin, a compound that has potential to treat constipation following spinal cord injury (SCI), in groups of able-bodied and SCI volunteers. Setting: Local population from Victoria, Australia. Methods: Following initial screening and baseline blood collections, participants received ascending oral doses (20, 50 and then 100 mg at least 1-week apart) of capromorelin after pre-dose blood collection, followed by blood collections over the following 12 h for pharmacokinetic analysis and 1-week and 4-week follow-up blood collections for safety evaluations. Blood pressure and heart rate were monitored. Results: No serious adverse events were recorded following any dose in either the able-bodied group or the SCI group. There were no abnormal blood pressure or heart rate changes. Minor adverse events resolved quickly without the need for treatment. Pharmacokinetic behaviour was broadly similar between groups, with both exhibiting dose-dependent increases in C max and AUC 0-∞ . The SCI participants showed greater variance in pharmacokinetic parameters and had a slightly delayed T max and half-life. Conclusion: Capromorelin at the doses tested was safe and well tolerated in both SCI and able-bodied participants and also showed similar pharmacokinetics with dose-dependent increases in concentration and drug exposure.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers

et al. 2014

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“…Because the pharmacological potential of ghrelin is hampered by its short half‐life, GHSs with enhanced pharmacokinetics were developed. Centrally penetrant GHSs stimulate defaecation and improve impaired bowel functions in animals and humans …”

Section: Pharmacologymentioning

confidence: 99%

Growth hormone secretagogues: history, mechanism of action, and clinical development

Ishida

Saitoh

Ebner

et al. 2020

JCSM Rapid Communications

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Growth hormone secretagogues (GHSs) are a generic term to describe compounds that increase growth hormone (GH) release. GHSs include agonists of the growth hormone secretagogue receptor (GHS‐R), whose natural ligand is ghrelin, and agonists of the growth hormone‐releasing hormone (GHRH) receptor, to which the GHRH binds as a native ligand. Several GHSs have been developed with a view to treating or diagnosing of GH deficiency, which causes growth retardation, gastrointestinal dysfunction, and altered body composition, in parallel with extensive research to identify GHRH, GHS‐R, and ghrelin. This review will focus on the research history and the pharmacology of each GHS, which reached randomized clinical trials. Furthermore, we will highlight the publicly disclosed clinical trials regarding GHSs.

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“…Evidence of increased defecation in humans caused by Lumbosacral Defecation Center (LDC)-mediated effects, induced by ghrelin receptor agonists, has been shown whereas direct evidence using intrathecal injections have been reported in animal models (Shimizu et al, 2006). Indeed, defecation induced pharmacologically was prevented by cutting the nerve pathways that connect the lumbosacral spinal cord and the colorectum, but not by severing the thoracic spinal cord (Ferens et al, 2011; Pustovit et al, 2014). Unfortunately, Ghrelin or its known agonists (e.g., ulimorelin) do not elicit defecation when administered orally and may increase blood pressure when delivered i.t.…”

Section: Characteristics Of Other Cpgsmentioning

confidence: 99%

Preclinical evidence supporting the clinical development of central pattern generator-modulating therapies for chronic spinal cord-injured patients

Guertin

2014

Front. Hum. Neurosci.

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Ambulation or walking is one of the main gaits of locomotion. In terrestrial animals, it may be defined as a series of rhythmic and bilaterally coordinated movement of the limbs which creates a forward movement of the body. This applies regardless of the number of limbs—from arthropods with six or more limbs to bipedal primates. These fundamental similarities among species may explain why comparable neural systems and cellular properties have been found, thus far, to control in similar ways locomotor rhythm generation in most animal models. The aim of this article is to provide a comprehensive review of the known structural and functional features associated with central nervous system (CNS) networks that are involved in the control of ambulation and other stereotyped motor patterns—specifically Central Pattern Generators (CPGs) that produce basic rhythmic patterned outputs for locomotion, micturition, ejaculation, and defecation. Although there is compelling evidence of their existence in humans, CPGs have been most studied in reduced models including in vitro isolated preparations, genetically-engineered mice and spinal cord-transected animals. Compared with other structures of the CNS, the spinal cord is generally considered as being well-preserved phylogenetically. As such, most animal models of spinal cord-injured (SCI) should be considered as valuable tools for the development of novel pharmacological strategies aimed at modulating spinal activity and restoring corresponding functions in chronic SCI patients.

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The mechanism of enhanced defecation caused by the ghrelin receptor agonist, ulimorelin

Abstract: Ulimorelin is a potent prokinetic that causes propulsive contractions of the colorectum by activating ghrelin receptors of the lumbosacral defecation centers. Its effects are long-lasting, in contrast with other colokinetics that target ghrelin receptors.

Cited by 32 publications

References 40 publications

Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers

Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers

Growth hormone secretagogues: history, mechanism of action, and clinical development

Preclinical evidence supporting the clinical development of central pattern generator-modulating therapies for chronic spinal cord-injured patients

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