Treatment Of Gastrointestinal Motility Disorders Research Articles

Capsules for the Diagnosis and Treatment of Gastrointestinal Motility Disorders- A Game Changer.

Over the last few decades, there have been remarkable strides in endoscopy and radiological imaging that have advanced gastroenterology. However, the management of neurogastroenterological disorders has lagged behind, in part handicapped by the use of catheter-based manometry that is both non-physiological and uncomfortable. The advent of capsule technology has been a game changer for both diagnostic and therapeutic applications. Here, we discuss several capsule devices that are available or under investigation. There are three technologies that are FDA approved. Wireless motility capsule measures pH and pressure and provides clinically impactful information regarding gastric, small intestine and colonic transit, without radiation that has been demonstrated to guide management of gastroparesis, dyspepsia and constipation. Wireless ambulatory pH monitoring capsule is currently the gold standard for assessing gastroesophageal acid reflux. In the therapeutics arena, an orally ingested vibrating capsule has been recently FDA approved for the treatment of chronic constipation, supported by a robust phase 3 clinical trial which showed significant improvement in constipation symptoms and quality of life. There are several capsules currently under investigation. Smart capsule bacterial detection system and Capscan® are capsules that can sample fluid in the small or large bowel and provide microbiome analysis for detection of small intestinal bacterial (SIBO) or fungal overgrowth (SIFO). Another investigational gas sensing capsule analyzing hydrogen, CO2, volatile fatty acids and capsule orientation, can measure regional gut transit time and luminal gas concentrations and assess gastroparesis, constipation or SIBO. Therapeutically, other vibrating capsules are in development. Innovations in capsule technology are poised to transform our ability to investigate gut function physiologically, and non-invasively deliver targeted treatment(s), thereby providing both accurate diagnostic information and luminally-directed, safe therapy.

Common Pathophysiological Mechanisms and Treatment of Diabetic Gastroparesis.

Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus, marked by gastrointestinal motility disorder, a delayed gastric emptying present in the absence of mechanical obstruction. Clinical manifestations include postprandial fullness and epigastric discomfort, bloating, nausea, and vomiting. DGP may significantly affect the quality of life and productivity of patients. Research on the relationship between gastrointestinal dynamics and DGP has received much attention because of the increasing prevalence of DGP. Gastrointestinal motility disorders are closely related to a variety of factors including the absence and destruction of interstitial cells of Cajal, abnormalities in the neuro-endocrine system and hormone levels. Therefore, this study will review recent literature on the mechanisms of DGP and gastrointestinal motility disorders as well as the development of prokinetic treatment of gastrointestinal motility disorders in order to give future research directions and identify treatment strategies for DGP.

Drugs in focus: Domperidone.

Domperidone is a peripheral dopamine D2 receptor antagonist with prokinetic and antiemetic properties. Its prokinetic effects are mainly manifest in the upper gastrointestinal (GI) tract. Currently its use is restricted to relief of nausea and vomiting in children older than 12 years for a short period of time. However, among (paediatric) gastroenterologists, domperidone is also used outside its authorised indication ("off label") for treatment of symptoms associated with gastro-oesophageal reflux disease, dyspepsia and gastroparesis. Little is known about its efficacy in the treatment of GI motility disorders in children and controversial data have emerged in the paediatric literature. As its use is off label, appropriate knowledge of its efficacy is helpful to support an "off label/on evidence" prescription. Based on this, the purpose of this review is to summarise all evidence on the efficacy of domperidone for the treatment of GI disorders in infants and children and to report an overview of its pharmacological properties and safety profile.

Structural basis for motilin and erythromycin recognition by motilin receptor

Motilin is an endogenous peptide hormone almost exclusively expressed in the human gastrointestinal (GI) tract. It activates the motilin receptor (MTLR), a class A G protein-coupled receptor (GPCR), and stimulates GI motility. To our knowledge, MTLR is the first GPCR reported to be activated by macrolide antibiotics, such as erythromycin. It has attracted extensive attention as a potential drug target for GI disorders. We report two structures of Gq-coupled human MTLR bound to motilin and erythromycin. Our structures reveal the recognition mechanism of both ligands and explain the specificity of motilin and ghrelin, a related gut peptide hormone, for their respective receptors. These structures also provide the basis for understanding the different recognition modes of erythromycin by MTLR and ribosome. These findings provide a framework for understanding the physiological regulation of MTLR and guiding drug design targeting MTLR for the treatment of GI motility disorders.

Therapeutic potential of allosteric modulators for the treatment of gastrointestinal motility disorders.

Gastrointestinal motility is tightly regulated by the enteric nervous system (ENS). Disruption of coordinated enteric nervous system activity can result in dysmotility. Pharmacological treatment options for dysmotility include targeting of G protein-coupled receptors (GPCRs) expressed by neurons of the enteric nervous system. Current GPCR-targeting drugs for motility disorders bind to the highly conserved endogenous ligand-binding site and promote indiscriminate activation or inhibition of the target receptor throughout the body. This can be associated with significant side-effect liability and a loss of physiological tone. Allosteric modulators of GPCRs bind to a distinct site from the endogenous ligand, which is typically less conserved across multiple receptor subtypes and can modulate endogenous ligand signalling. Allosteric modulation of GPCRs that are important for enteric nervous system function may provide effective relief from motility disorders while limiting side-effects. This review will focus on how allosteric modulators of GPCRs may influence gastrointestinal motility, using 5-hydroxytryptamine (5-HT), acetylcholine (ACh) and opioid receptors as examples. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.

The Key Ingredient Acacetin in Weishu Decoction Alleviates Gastrointestinal Motility Disorder Based on Network Pharmacology Analysis

Background Gastrointestinal motility disorder is a common gastrointestinal disease, which seriously affects life quality. Traditional Chinese medicine (TCM) has been widely used as an alternative therapy for gastrointestinal motility disorder. Acacetin is a natural flavonoid compound that has antioxidant and anti-inflammatory, antidepressant, and anticancer properties. However, the efficacy of Acacetin in the treatment of gastrointestinal motility disorders has not been studied. Our aim was to investigate the mechanism of Acacetin-alleviated gastrointestinal motility disorder and its efficacy based on network pharmacology. Methods We performed network pharmacology to predict the active components, match Weishu decoction (WSD) targets in gastrointestinal motility disorders, and investigate its potential pharmacological mechanisms. We performed the GO and KEGG enrichment analysis. In vivo, we investigated the effects of Acacetin in the gastrointestinal motility disorder model. Results Based on network pharmacological method, the key active ingredient of WSD was identified as Acacetin, and the enrichment signaling pathway was the PI3K-AKT signaling pathway. Acacetin and Mosapride accelerated gastric emptying time, reduced gastric remnant rate, and increased small intestinal propulsion rate. The levels of GAS and MTL were increased after using Acacetin. These results indicated that Acacetin could improve gastrointestinal motility disorders. Among them, high-dose Acacetin showed a better effect. Acacetin could regulate protein and lipid metabolism in mice with gastrointestinal motility disorder. Furthermore, Acacetin could modulate gastrointestinal inflammation and apoptosis. The detection of the PI3K-AKT signaling pathway-related proteins showed that Acacetin improved gastrointestinal motility disorder by inhibiting the activation of the PI3K-AKT signaling pathway. Conclusion The key ingredient Acacetin in WSD could alleviate gastrointestinal motility disorder by inhibiting the activation of the PI3K-AKT signaling pathway based on network pharmacology analysis. The efficacy and safety of Acacetin treatment provide strong experimental support for the clinical treatment of gastrointestinal motility disorder.

In Vivo Evaluation of Fractal Microelectrodes Towards a More Targeted and Energy‐Efficient Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is a moderately effective treatment option for intractable epilepsy, depression, and pain, with promising applications in the treatment of gastrointestinal motility disorders like gastroparesis. The wide-ranging potential indications of VNS suggest an opportunity for a better understanding of underlying neural circuits that can be targeted using microscale electrodes. However, microscale Platinum (Pt) electrodes often have limited charge injection capacity due to their high impedance. Recently, we experimentally demonstrated that microscale Pt electrodes with Vicsek fractal geometry can facilitate electrochemical charge transfer more efficiently with 57% higher cathodic charge storage capacity than conventional circular microelectrodes. Here we are investigating whether the fractal electrode may be more effective in eliciting small fibers in the vagus nerve with less energy consumption due to its enhanced charge injection capability. To evaluate the in vivo performance of these novel microelectrode designs and to determine whether these electrodes are capable of stimulating small, unmyelinated C fibers that supply the stomach, we designed a cuff electrode with an array with four pairs of fractal and circular microelectrode to explore the possibility of radial selective stimulation of vagus nerve. We determined the dimension of the cuff to be 760 μm in diameter to wrap around a rat's vagus nerve so that it can withstand the swelling of the nerve from chronic implantation. We patterned fractal microelectrode to have a geometrical surface area equivalent to that of a circle with 100 μm of diameter. Using a rat model, we have stimulated the right cervical vagus nerve with fractal/circular electrode and recorded the compound action potential (CAP) distal from the stimulation site with 5-7 mm of conduction distance or the dorsal trunk of the abdominal vagus (conduction distance: 70 mm). We used an autonomous neural control (ANC) system, which can stimulate and record from the nerve with randomized stimulus parameter combinations (pulse amplitude: 0-0.4 mA, pulse width: 0.02-1 ms). We adapted a cathode-first, alternating monophasic stimulation for the reliable suppression of stimulus artifact (pulse repetition frequency: 5 Hz). Results from right cervical VNS experiments in anesthetized rats showed that both the fractal and the circular electrodes can recruit small, myelinated Ad and B fibers to a similar degree (pulse amplitude: 0-0.4 mA, pulse width: 0.1 ms) (Figure 1.), but fractal electrodes produce a more uniform and consistent fiber recruitment profile (Figure 2.). We observed volleys within the slow conduction velocity range (< 3 m/s), which we suspect to be signals from the C-fibers. Our next plan is to obtain more experimental data to statistically identify the efficiency of various electrode designs in stimulating small fibers and to investigate the electrical potential profile of these electrodes in a biophysical model.

Protein kinase A facilitates relaxation of mouse ileum via phosphorylation of neuronal nitric oxide synthase.

The enteric neurotransmitter nitric oxide (NO) regulates gastrointestinal motility by relaxing smooth muscle. Pharmacological cAMP induction also relaxes gastrointestinal smooth muscle, but it is uncertain whether cAMP augments or suppresses enteric NO signalling. In other organ systems, cAMP can increase neuronal NO production by stimulating protein kinase A (PKA) to phosphorylate neuronal NOS (nNOS) Serine-1412 (S1412). We hypothesized that cAMP also increases nNOS S1412 phosphorylation by PKA in enteric neurons to augment nitrergic relaxation of mouse ileum. We measured contractile force and nNOS S1412 phosphorylation in ileal rings suspended in an organ bath. We used forskolin to induce cAMP-dependent relaxation of wild type, nNOSS1412A knock-in and nNOSα-null ileal rings in the presence or absence of PKA, protein kinase B (Akt) and NOS inhibitors. Forskolin stimulated phosphorylation of nNOS S1412 in mouse ileum. Forskolin relaxed nNOSα-null and nNOSS1412A ileal rings less than wild-type ileal rings. PKA inhibition blocked forskolin-induced nNOS phosphorylation and attenuated relaxation of wild type but not nNOSS1412A ileum. Akt inhibition did not alter nNOS phosphorylation with forskolin but did attenuate relaxation of wild type and nNOSS1412A . NOS inhibition with L-NAME eliminated the effects of PKA and Akt inhibitors on relaxation. PKA phosphorylation of nNOS S1412 augments forskolin-induced nitrergic ileal relaxation. The relationship between cAMP/PKA and NO is therefore synergistic in enteric nitrergic neurons. Because NO regulates gut motility, selective modulation of enteric neuronal cAMP synthesis may be useful for the treatment of gastrointestinal motility disorders.

Effect of Chaihu Shugan Powder-Contained Serum on Glutamate-Induced Autophagy of Interstitial Cells of Cajal in the Rat Gastric Antrum.

Gastrointestinal (GI) motility disorder is caused by excessive autophagy of the interstitial cells of Cajal (ICC). Chaihu Shugan Powder (CSP) is a traditional Chinese medicine with therapeutic benefits in GI motility disorders; however, the underlying mechanism of its therapeutic effect in GI disorders, especially autophagy of ICC, remains unclear. Thus, this study investigated the effects of CSP-contained serum on glutamate-induced autophagy in rat gastric ICC, exploring its underlying mechanism. In vitro cultured rat stomach ICC were identified by fluorescence microscopy and then stimulated with glutamate (5 mmol/L) for 3 h to establish the autophagy model. These cells were then treated with 10% CSP-containing serum or the autophagy inhibitor 3-methyladenine (3-MA; 5 mmol/L) for 24 h. The control group was cultured with only 10% serum containing physiological saline. The viability of ICC was measured by the CCK-8 assay. The ultrastructure and autophagosomes of ICC were observed using transmission electron microscopy. LC3 expression was detected by immunofluorescence, and LC3, Beclin1, Bcl2, and PI3KC3 expression was detected by western blot analysis. Transmission electron microscopy showed abundant endoplasmic reticulum, mitochondria, and other organelles in the control group, whereas the cells in the autophagy model control group had clear autophagic vacuoles, which were not apparent in both CSP and 3-MA groups. ICC viability was significantly increased by CSP and 3-MA interventions (P < 0.01), accompanied by a decrease in LC3 fluorescence (P < 0.01). Moreover, the expression levels of LC3II/I, Beclin1, and PI3KC3 were significantly decreased (all P < 0.01) with CSP and 3-MA treatment, while Bcl2 expression level was higher than that of the model group (P < 0.01). Thus, CSP can reduce autophagic damage by enhancing Bcl2 expression and downregulating the expression of LC3, Beclin1, and PI3KC3 to protect ICC. These results highlight the potential of CSP in the treatment of GI motility disorders.

Pathophysiology and Treatment of Gastrointestinal Motility Disorders in the Acutely Ill.

Gastrointestinal dysmotility causes delayed gastric emptying, enteral feed intolerance, and functional obstruction of the small and large intestine, the latter functional obstructions being frequently termed ileus and Ogilvie syndrome, respectively. In addition to meticulous supportive care, drug therapy may be appropriate in certain situations. There is, however, considerable variation among individuals regarding what gastric residual volume identifies gastric dysmotility and would encourage use of a promotility drug. While the administration of either metoclopramide or erythromycin is supported by evidence it appears that, dual-drug therapy (erythromycin and metoclopramide) reduces the rate of treatment failure. There is a lack of evidence to guide drug therapy of ileus, but neither erythromycin nor metoclopramide appear to have a role. Several drugs, including ghrelin agonists, highly selective 5-hydroxytryptamine receptor agonists, and opiate antagonists are being studied in clinical trials. Neostigmine, when infused at a relatively slow rate in patients receiving continuous hemodynamic monitoring, may alleviate the need for endoscopic decompression in some patients.

Formulation and in vitro evaluation of a thermoreversible mucoadhesive nasal gel of itopride hydrochloride

Itopride hydrochloride (ITO HCl) is a prokinetic agent, used in the treatment of gastrointestinal motility disorders. The aim of the study was to develop stable mucoadhesive thermoreversible nasal gel to avoid first pass effect. ITO HCl was incorporated into the blends of thermoreversible polymers like poloxamer 407 and various mucoadhesive polymers in different concentrations to increase the contact of the formulations with nasal mucosa. The compatibility between the drug and the suggested polymers was studied by Fourier transform infrared and differential scanning calorimetry (DSC). The formulations were evaluated for clarity, pH, gelation temperature, mucoadhesive strength, gel strength, viscosity, and drug content. In addition, the in vitro drug release and the dissolution efficiency (DE)% were measured. The optimized formulations that showed the highest dissolution efficiency% (DE%) in saline phosphate buffer of pH 6.4 at 35 ± 0.5 °C were chosen for stability testing at temperatures of 4 ± 2 and 25 ± 2 °C/60 ± 5% RH. It was found that F1 and F17 that contain 18% w/v poloxamer 407 and 0.5% w/v of hydroxypropylmethyl cellulose K4M or methyl cellulose (MC), respectively, showed higher stability results as indicated by their higher t90 values (days).

Quantitative Analysis and Chromatographic Fingerprinting of WeiChangShu Tablet Using High-Performance Liquid Chromatography Combined with Chemometric Methods

WeiChangShu tablet is used for the treatment of gastrointestinal motility disorders for more than 10 years. However, no quality control method for this formulation has been established. Hence, it is important to establish a simple and effective method for chromatographic fingerprinting and quantitative analysis to assess the quality of WeiChangShu tablet. In this study, a high-performance liquid chromatography method was developed to obtain a fingerprint chromatogram, and to simultaneously determine 11 indexes including hydroxypaeoniflorin, albiflorin, peoniflorin, benzoylpaeoniflorin, rhein, aloeemodin, physcion, emodin, chrysophanol, liquiritin, and glycyrrhizinic acid. After the methodology validation, the chromatographic fingerprints and the contents of 11 compounds in 10 samples were obtained successfully to evaluate the uniformity of the quality of WeiChangShu tablet. Three chemometric methods including similarity analysis, principal component analysis and hierarchical cluster analysis were applied to classify and differentiate the different samples, and to evaluate the consistency of 10 samples of WeiChangShu tablet. A similar division was observed for 10 samples, and they were divided into three groups: group 1 (S1, S2), group 2 (S6–S9), and group 3 (S3–S5, S10). These results demonstrated that the developed method was suitable for the quality evaluation of WeiChangShu tablet.

Relamorelin for the treatment of gastrointestinal motility disorders

ABSTRACTIntroduction: Current treatments for gastroparesis are limited. Chronic idiopathic constipation (CIC) has more treatment options, but none are efficacious for severe cases.Areas covered: Molecular targets to accelerate GI motility are being identified, and relamorelin, a synthetic ghrelin analog, has been promising. In humans, relamorelin increases growth hormone levels and accelerates gastric emptying. Relamorelin was superior to placebo for symptom relief in phase IIA studies for diabetic gastroparesis (DG) and CIC. In phase IIB studies in DG, relamorelin did not significantly reduce vomiting frequency when compared to placebo, but it reduced four symptoms of DG (nausea, fullness, bloating and abdominal pain) and accelerated gastric emptying. To date, relamorelin has been well tolerated and safe in humans without cardiac or neurologic adverse effects. It is still in clinical trial stages and not yet approved by the Food and Drug Administration. Phase III studies are underway.Expert opinion: Relamorelin shows promise in treating DG, with a reduction in core symptoms. Relative to available treatments, it appears to be efficacious and well tolerated. The absence of neurological or cardiovascular adverse effects places it at an advantage over other available therapies. Once approved, it will likely become the drug of first choice for DG.

Comparative pharmacokinetics of (S)-MP3950, a novel 5-HT4 receptor agonist, in normal and atropine-induced gastrointestinal motility disorders rats

1. (S)-MP3950 is the (S)-enantiomer of active metabolite of mosapride, which exhibits higher 5-HT4 receptor agonistic effect than mosapride. It shows promise to become a novel drug candidate for the treatment of gastrointestinal motility disorders (GMDs). However, the pharmacokinetic behavior of (S)-MP3950 in the pathological state of GMDs remains unclear. Herein, we investigated the comparative pharmacokinetics of (S)-MP3950 in normal and GMDs rats.2. The comparative pharmacokinetics of (S)-MP3950 in normal and atropine-induced GMD rats were studied by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The validated UPLC-MS/MS method was successfully applied to investigate the pharmacokinetic profiles of (S)-MP3950 in normal and atropine-induced GMDs rats. Results showed that comparing to normal rats, Cmax reduced by 73.8%, AUC0-t decreased by 57.6% and AUC0-∞ declined by 56.8% in model rats. Additionally, the elimination half-life (t1/2) and Tmax were prolonged slightly.3. The pharmacokinetic results demonstrated that the atropine-induced GMDs reduced the absorption of (S)-MP3950. The pharmacokinetics research in the pathological state might provide more useful information for further study of novel gastric motility candidates.

Surgical treatment of gastrointestinal motility disorders

Surgical treatment of gastrointestinal motility disorders

In vitro and non-invasive invivo effects of the cannabinoid-1 receptor agonist AM841 on gastrointestinal motor function in the rat.

Cannabinoids have been traditionally used for the treatment of gastrointestinal (GI) symptoms, but the associated central effects, through cannabinoid-1 receptors (CB1R), constitute an important drawback. Our aims were to characterize the effects of the recently developed highly potent long-acting megagonist AM841 on GI motor function and to determine its central effects in rats. Male Wistar rats were used for invitro and invivo studies. The effect of AM841 was tested on electrically induced twitch contractions of GI preparations (invitro) and on GI motility measured radiographically after contrast administration (invivo). Central effects of AM841 were evaluated using the cannabinoid tetrad. The non-selective cannabinoid agonist WIN 55,212-2 (WIN) was used for comparison. The CB1R (AM251) and CB2R (AM630) antagonists were used to characterize cannabinoid receptor-mediated effects of AM841. AM841 dose-dependently reduced invitro contractile activity of rat GI preparations via CB1R, but not CB2R or opioid receptors. In vivo, AM841 acutely and potently reduced gastric emptying and intestinal transit in a dose-dependent and AM251-sensitive manner. The invivo GI effects of AM841 at 0.1mg/kg were comparable to those induced by WIN at 5mg/kg. However, at this dose, AM841 did not induce any sign of the cannabinoid tetrad, whereas WIN induced significant central effects. The CB1R megagonist AM841 may potently depress GI motor function in the absence of central effects. This effect may be mediated peripherally and may be useful in the treatment of GI motility disorders.

Identification of Glycyrrhiza as the rikkunshito constituent with the highest antagonistic potential on heterologously expressed 5-HT3A receptors due to the action of flavonoids.

The traditional Japanese phytomedicine rikkunshito is traditionally used for the treatment of gastrointestinal motility disorders, cachexia and nausea. These effects indicate 5-HT3 receptor antagonism, due to the involvement of these receptors in such pathophysiological processes. E.g., setrons, specific 5-HT3 receptor antagonists are the strongest antiemetics, developed so far. Therefore, the antagonistic effects of the eight rikkunshito constituents at heterologously expressed 5-HT3Areceptors were analyzed using the two-electrode voltage-clamp technique. The results indicate that tinctures from Aurantii, Ginseng, Zingiberis, Atractylodis and Glycyrrhiza inhibited the 5-HT3A receptor response, whereas the tinctures of Poria cocos, Jujubae and Pinellia exhibited no effect. Surprisingly, the strongest antagonism was found for Glycyrrhiza, whereas the Zingiberis tincture, which is considered to be primarily responsible for the effect of rikkunshito, exhibited the weakest antagonism of 5-HT3A receptors. Rikkunshito contains various vanilloids, ginsenosides and flavonoids, a portion of which show an antagonistic effect on 5-HT3 receptors. A screening of the established ingredients of the active rikkunshito constituents and related substances lead to the identification of new antagonists within the class of flavonoids. The flavonoids (-)-liquiritigenin, glabridin and licochalcone A from Glycyrrhiza species were found to be the most effective inhibitors of the 5-HT-induced currents in the screening. The flavonoids (-)-liquiritigenin and hesperetin from Aurantii inhibited the receptor response in a non-competitive manner, whereas glabridin and licochalcone A exhibited a potential competitive antagonism. Furthermore, licochalcone A acts as a partial antagonist of 5-HT3A receptors. Thus, this study reveals new 5-HT3A receptor antagonists with the aid of increasing the comprehension of the complex effects of rikkunshito.

Capsaicin alleviates abnormal intestinal motility through regulation of enteric motor neurons and MLCK activity: Relevance to intestinal motility disorders.

Capsaicin is an active component of chili peppers, having diverse effects. However, the effects of capsaicin on intestinal motility are still controversial. The present study aimed to investigate the effects of capsaicin on intestinal motility disorder and uncover related mechanisms. A rat model with intestinal motility disorder was established in vitro through adding different stimuli into tissue bath; in vivo using constipation and diarrhea model, respectively. Capsaicin exerted dual effects on intestinal motility, i.e. the relaxation and contraction of jejunum induced by corresponding stimulus were, respectively, regulated to be normal contraction by capsaicin. The mechanisms underlined capsaicin-induced dual effects were investigated using Western blotting, qRT-PCR, and whole-cell patch clamp, respectively. Results showed that cholinergic excitatory nerves, adrenergic nerves, and neurons containing nitric oxide synthase, which are the main muscle motor neurons in enteric nervous system (ENS), are involved in capsaicin-induced dual effects. The competition for regulation of Ca(2+) influx by capsaicin induced the interaction with components of the ENS. Capsaicin significantly increased myosin light chain kinase (MLCK) expression and myosin phosphorylation extent in jejunal segments of constipation-prominent rats and significantly decreased MLCK expression and myosin phosphorylation extent in jejunal segments of diarrhea-prominent rats. In summary, capsaicin alleviates abnormal intestinal motility through regulating enteric motor neurons and MLCK activity, which is beneficial for the treatment of gastrointestinal motility disorders.

Emerging treatments in Neurogastroenterology: relamorelin: a novel gastrocolokinetic synthetic ghrelin agonist.

Synthetic ghrelin agonists, predominantly small molecules, are being developed as prokinetic agents that may prove useful in the treatment of gastrointestinal motility disorders. Relamorelin (RM-131) is a pentapeptide synthetic ghrelin analog that activates the growth hormone secretagogue (GHS)-1a (also called the ghrelin) receptor with approximately sixfold greater potency than natural ghrelin. The ability of relamorelin to stimulate growth hormone (GH) release is comparable to that of native ghrelin. Relamorelin has enhanced efficacy and plasma stability compared to native ghrelin. In this review, we discuss the pharmacokinetics, pharmacodynamics and potential indications for relamorelin. Relamorelin is administered subcutaneously, dosed daily or twice daily. Relamorelin is being studied for the treatment of patients with gastrointestinal motility disorders. Phase IIA pharmacodynamic studies have demonstrated acceleration of gastric emptying in patients with type 1 diabetes mellitus (T1DM) and type 2 DM (T2DM) and upper gastrointestinal symptoms. In a phase IIA study in patients with diabetic gastroparesis, relamorelin accelerated gastric emptying and significantly improved vomiting frequency compared to placebo and improved other symptoms of gastroparesis in a prespecified subgroup of patients with vomiting at baseline. In patients with chronic idiopathic constipation with defined transit profile at baseline, relamorelin relieved constipation and accelerated colonic transit compared to placebo. These characteristics suggest that this new ghrelin analog shows great promise to relieve patients with upper or lower gastrointestinal motility disorders.

5-HT4 Receptor Agonists in the Treatment of Gastrointestinal Motility Disorders: Current Status and Perspective

Background: 5-HT4 receptor plays important roles regulating gastrointestinal motility, enteric neuronal signaling and visceral pain in the gastrointestinal tract. Over the past decade, the 5-HT4 receptor has been highlighted as an attractive drug target for the treatment of gastrointestinal motility disorders such as irritable bowel syndrome, chronic constipation, functional dyspepsia, gastroparesis and so on. Objectives: This article aims to provide an overview of serotonin receptors related to the gastrointestinal motility disorders, and to address the characteristics of past, current and future 5-HT4 receptor agonists for treatment of functional gastrointestinal disorders, focusing on the pharmacology, efficacy and safety profile.