Real-world safety and effectiveness of Pistacia lentiscus (mastic gum) in patients with diabetic gastroparesis: 24-week interim analysis postintervention.

INTRODUCTION: Gastrointestinal neuropathies are frequently found in diabetic patients. AIM: The aim of this study was to find out the safety, adverse reactions, and long-term effectiveness of Pistacia lentiscus plant extract (mastic gum) in diabetic gastroparesis (DG) with respect to sustainable improvement in gastroparesis symptoms (Gastrointestinal Cardinal Symptom Index [GCSI] score) by observational follow-up study of a single-centric double-blind noninferiority randomized control trial. MATERIALS AND METHODS: Thirty-eight individuals were recruited and equally randomized in two study groups based on GCSI score and TC99 radionuclide gastric emptying scintigraphy (GES), i.e. the mastic gum group and the levosulpiride group. After 24 weeks, the GCSI score was recalculated in both the groups, and patients were evaluated for the safety, adverse reactions, and long-term effectiveness of mastic gum and the standard drug levosulpiride. RESULTS: In the extended study, mean GCSI score changes at 24 weeks were statistically significant (P < 0.001) (t-test) between the two groups. In the mastic gum arm, the change in mean GCSI score at 24 weeks was statistically nonsignificant mean ± (standard deviation [SD]) 16.7± (3.81) compared to the GCSI score at 2-month postintervention mean (SD) 16.35± (2.27) (intragroup P = 0.89) (repeated measures ANOVA). It strongly indicates that mastic gum provided a sustainable improvement in DG symptoms in comparison to levosulpiride, with excellent subjective well-being postintervention, without any obvious significant adverse effects. CONCLUSION: Six-month (24-week) interim analysis of patients suggests that mastic gum gives a sustainable improvement in DG symptoms without any obvious adverse effects as compared to levosulpiride.

Glucagonlike Peptide-1 Receptor Agonists: The Good, the Bad, and the Ugly-Benefits for Glucose Control and Weight Loss with Side Effects of Delaying Gastric Emptying.

Glucagonlike peptide-1 (GLP-1) receptor agonists (RAs) are being increasingly used for glycemic control in patients with diabetes and for weight loss and weight management in obese subjects. There has been recent public awareness of the potential of GLP-1 RAs to delay gastric emptying and cause gastroparesis. By delaying gastric emptying, these agents can complicate the clinical evaluation of patients on these drugs by affecting diagnostic testing for gastroparesis. This article discusses GLP-1 RAs and their effects on gastric emptying, gastric food retention, and gastroparesis. This article highlights how physicians should be attuned to the gastric side effects of these popular therapeutic agents for blood glucose control in people with diabetes and for weight loss and weight management in obese patients.

A. officinarum Hance - P. cablin (Blanco) Benth drug pair improves oxidative stress, intracellular Ca2+ concentrations and apoptosis by inhibiting the AGE/RAGE axis to ameliorate diabetic gastroparesis: In vitro and in vivo studies.

ETHNOPHARMACOLOGICAL RELEVANCE: Alpinia officinarum Hance is a perennial natural medicine herbivorous plant, has been used in the management of treat stomach pain and diabetes, it is abundantly cultivated in Qiongzhong, Baisha and other places. P. cablin (Blanco) Benth, one of the most important traditional Chinese plants, which plays functions in antioxidant and gastrointestinal regulation, has been extensively planted in Hainan, Guangdong and other regions. AIM OF THE STUDY: In this study, we investigated the role and underlying molecular mechanism of AP on diabetic gastroparesis (DGP) in vitro and in vivo. MATERIALS AND METHODS: In this study, using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) to identify active compounds in A. officinarum Hance-P. cablin (Blanco) Benth drug pair (AP). Molecular docking were utilized to explore the potential mechanism of AP treatment of DGP. In in vitro assays, gastric smooth muscle cells (GSMCs) were treated with 35 mM glucose to promote apoptosis and construct the DGP model, which was treated with different concentrations of AP. Furthermore, transfection technology was used to overexpress RAGE in GSMCs and elucidate the underlying mechanisms of alleviation of DGP by AP. RESULTS: Using UPLC-MS/MS analysis, nine components of AP were identified. We found that AP effectively blocked the increase in apoptosis, oxidative stress, and intracellular Ca2+ concentrations. For in vivo experiments, mice were fed with a high-fat irregular diet to construct DGP model, and AP was co-administered via oral gavage daily to prevent the development of DGP. Compared with DGP mice, AP significantly decreased fasting blood glucose levels and increased gastric emptying levels. Consistent with in vitro experiments, AP also considerably decreased the increase in oxidative stress in DGP mice. Mechanistically, AP alleviates apoptosis and DGP by decreasing oxidative stress and intracellular Ca2+ concentrations via the inhibition of the AGE/RAGE axis. CONCLUSIONS: Collectively, this study has established that AP can improve DGP, and the mechanism may be related to the inhibition the AGE/RAGE axis to mitigate apoptosis and DGP. To summarize, this study provides a novel supplementary strategy for DGP treatment.

Alpinia officinarum Hance extract ameliorates diabetic gastroparesis by regulating SCF/c-kit signaling pathway and rebalancing gut microbiota.

Diabetic gastroparesis (DGP) is a common complication of type 2 diabetes mellitus (T2DM). Alpinia officinarum Hance (AOH) is one of the most commonly used both as a food and folk medicines, which is rich in diarylheptanoids and flavonoids. The gastroprotection and hypoglycemic effect make AOH has great potential in developing of anti-DGP complementary medicine. However, the molecular mechanisms of AOH that act against DGP are yet to be elucidated. In this study, we evaluated the therapeutic effects, the potential molecular mechanism, and the changes of gut microbiota of AOH in DGP. The 5 components of the AOH were analyzed, and the potential signaling pathway of AOH improving DGP was predicted by molecular docking. Subsequently, DGP rat model was constructed using high-fat-irregular-diet, AOH intervention significantly reduced blood glucose levels, increased gastrointestinal propulsion rate, and improved gastric histological morphology in DGP rats. Meanwhile, AOH has been shown to regulate the SCF/c-kit signaling pathway and rebalance the gut microbiota, which may be closely related to its role in improving DGP. Taken together, AOH may play a protective role on DGP through multiple mechanisms, which might pave the road for development and utilization of AOH.

Gastric peroral endoscopic myotomy versus botulinum toxin injection for the treatment of refractory gastroparesis: results of a double-blind randomized controlled study.

INTRODUCTION: Gastric peroral endoscopic myotomy (G-POEM) is a promising technique for treating refractory gastroparesis. We present the first double-blind randomized study comparing the clinical efficacy of G-POEM versus pyloric botulinum toxin injection (BTI). METHODS: This randomized study, conducted in two expert centers, enrolled patients with refractory gastroparesis, medically managed for >6 months and confirmed by gastric emptying scintigraphy (GES), into two groups, G-POEM versus BTI, with follow-up of 1 year. The primary end point was the 3-month clinical efficacy, defined as a >1-point decrease in the mean Gastroparesis Cardinal Symptom Index (GCSI) score. Secondary end points were: 1-year efficacy, GES evolution, adverse events, and quality of life. RESULTS: 40 patients (22 women; mean age 48.1 [SD 17.4]), with mean symptom duration of 5.8 (SD 5.7) years, were randomized. Etiologies included idiopathic (n=18), diabetes (n=11), postoperative (n=6), and mixed (n=4). G-POEM showed a higher 3-month clinical success than BTI (65% vs. 40%, respectively; P=0.10), along with non-significantly higher 1-year clinical success (60% vs. 40%, respectively) on intention-to-treat analysis. The GCSI decreased in both groups at 3 months and 1 year. Only three minor adverse events occurred in the G-POEM group. The GES improvement rate was 72% in the G-POEM group versus 50% in the BTI group (non-significant). CONCLUSION: G-POEM seems to have a higher clinically relevant success rate than BTI, but this was not statistically demonstrated. This study confirms the interest in treatments targeting the pylorus, either mechanically or chemically, for managing refractory gastroparesis.

Droperidol undermining gastroparesis symptoms (DRUGS) in the emergency department.

BACKGROUND/PURPOSE: Gastroparesis is a syndrome of delayed gastric emptying without obstruction. There are high rates of Emergency Department (ED) visits due to gastroparesis, and this chronic disease is difficult to treat which often leads to hospital admissions. This study aimed to evaluate the impact droperidol administration has on opioid therapy, symptom relief, co-administration of antiemetic and prokinetic medications, disposition, cost, and length of stay (LOS) of patients presenting to the ED. RESULTS: A total of 431 patients were identified and 233 met the inclusion criteria. Droperidol administration reduced the number of patients requiring opioid therapy (108/233 [46%] vs 139/233 [60%], P-value 0.0040), reduced patient-reported pain scales by 4 points, and reduced antiemetic therapy requirement (140/233 [60%] vs 169/233 [73%], P-value 0.0045). No differences were found in terms of ED LOS (Median 6 h [IQR 4-8] vs 5 h [IQR 4-9], P-value 0.3638), hospital LOS (Median 6 h [IQR 4-30 vs 7 h [IQR 4-40], P-value 0.8888), hospital admission rates (67/233 [29%] vs 71/233 [31%], P-value 0.6101), ED cost to the facility (Median $1462 [IQR $1114 - $1986] vs $1481 [IQR $1034 - $2235], P-value 0.0943), or hospital cost (Median $4412 [IQR $2359 - $9826] vs $4672 [IQR $2075 - $9911], P-value 0.3136). CONCLUSION: In patients with gastroparesis presenting to the ED, droperidol reduced opioid use, improved pain control, and decreased antiemetic use without any differences in MME per dose, length of stay, hospital admission rate, or cost.

Botulinum Toxin Treatment for Cancer-Related Disorders: A Systematic Review.

This systematic review investigates the effect of botulinum neurotoxin (BoNT) therapy on cancer-related disorders. A major bulk of the literature is focused on BoNT's effect on pain at the site of surgery or radiation. All 13 published studies on this issue indicated reduction or cessation of pain at these sites after local injection of BoNTs. Twelve studies addressed the effect of BoNT injection into the pylorus (sphincter between the stomach and the first part of the gut) for the prevention of gastroparesis after local resection of esophageal cancer. In eight studies, BoNT injection was superior to no intervention; three studies found no difference between the two approaches. One study compared the result of intra-pyloric BoNT injection with preventive pyloromyotomy (resection of pyloric muscle fibers). Both approaches reduced gastroparesis, but the surgical approach had more serious side effects. BoNT injection was superior to saline injection in the prevention of esophageal stricture after surgery (34% versus 6%, respectively, p = 0.02) and produced better results (30% versus 40% stricture) compared to steroid (triamcinolone) injection close to the surgical region. All 12 reported studies on the effect of BoNT injection into the parotid region for the reduction in facial sweating during eating (gustatory hyperhidrosis) found that BoNT injections stopped or significantly reduced facial sweating that developed after parotid gland surgery. Six studies showed that BoNT injection into the parotid region prevented the development of or healed the fistulas that developed after parotid gland resection-parotidectomy gustatory hyperhidrosis (Frey syndrome), post-surgical parotid fistula, and sialocele. Eight studies suggested that BoNT injection into masseter muscle reduced or stopped severe jaw pain after the first bite (first bite syndrome) that may develop as a complication of parotidectomy.

Intrapyloric Botulinum Toxin Injection for Refractory Nausea and Vomiting in Pediatric Patients.

OBJECTIVES: Chronic nausea and vomiting may be associated with gastroparesis or other conditions. Poor mechanistic understanding of symptoms often precludes targeted therapy. Numerous case series suggest that intrapyloric botulinum toxin injection (IPBI) may be beneficial in treating gastroparesis and dyspepsia in children. We hypothesized that nausea, vomiting, and other symptoms, independent of gastroparesis, may improve with IPBI. We sought to identify gastric emptying (GE) and manometric patterns in IPBI responders versus nonresponders. METHODS: Electronic records of 25 pediatric patients who received IPBI for refractory nausea, vomiting, or both were retrospectively reviewed. We assessed symptom improvement post-IPBI and compared symptoms, GE, and antroduodenal manometry (ADM) findings between IPBI responders and nonresponders. RESULTS: At least one major symptom improved in 19 patients (76%) after IPBI. Of 22 patients completing a GE study, 14 had delayed GE with no significant difference between IPBI responders and nonresponders. Of 22 patients who underwent ADM, 18 had normal fasting peristalsis, 5 had postprandial antral hypomotility, 4 had neuropathic findings, and 19 had pylorospasm. IPBI responders, compared to nonresponders, demonstrated higher antral pressures with feeding ( P < 0.0001) and shorter duration of pylorospasm ( P = 0.0036). Antral pressures did not differ significantly with fasting or following motilin agonists. CONCLUSIONS: Our findings suggest that IPBI may have therapeutic benefit in pediatric patients with chronic nausea and/or vomiting, independent of gastroparesis. ADM findings of intact antral peristalsis and elevated antral pressures, in conjunction with efficacy of IPBI, support pyloric non-relaxation as a potential contributor to nausea and/or vomiting in pediatric patients.

Exploring the Underlying Mechanism of Alpinia officinarum Hance Ameliorating Diabetic Gastroparesis through Combining Network Pharmacology, Molecular Docking, and in Vivo Experimental Verification.

BACKGROUND: Alpinia officinarum Hance (AOH) has a long history in China as a Chinese medicine and exerts the pharmacological effects of antidiabetic and gastrointestinal protection. In traditional Chinese medicine theory, AOH is often combined with other Chinese medicines for the treatment of diabetic gastroparesis (DGP). However, the molecular mechanisms, potential targets, and bioactive ingredients of AOH that act against DGP are yet to be elucidated. In this study, network pharmacology, molecular docking, and experimental study were used to predict the therapeutic effects and the potential molecular mechanism of AOH in DGP. METHODS: Network pharmacology analysis was performed to acquire information on the active chemical ingredients, DGP-related target proteins in AOH, and potential signaling pathway. In addition, molecular docking approach was used to simulate the binding of drugs and targets. Finally, DGP-mice model was used for experimental verification in vivo. Results: Through the network pharmacological research, AKT1 was found to be the core protein in AOH for the treatment of DGP and was mainly involved in the PI3K-AKT signaling pathway. Additionally, the interactions between bioactive compounds and target proteins (PIK3CA and AKT1) were analyzed using molecular docking, which verified the results of network pharmacology. Further in vivo studies indicated that AOH could reduce fasting blood glucose levels, improve gastric emptying rate, and ameliorate biochemical indicators in DGP mice. Moreover, AOH could increase the expressions and phosphorylation levels of PI3K and AKT in the stomach to regulate oxidative stress. CONCLUSIONS: The study has shown that AOH may play a protective role on DGP through mediation of the PI3K-AKT signaling pathway to regulate oxidative stress.

Pharmacologic treatment of gastroparesis: What is (still) on the horizon?

Gastroparesis is a neuromuscular disorder of the upper gastrointestinal tract. Patients typically complain about early satiety, postprandial fullness, nausea and vomiting. Etiology is multifactorial. Treatment strategies include nutritional support, pharmacologic agents or surgery for refractory cases. Metoclopramide is the first and only FDA approved pharmacologic agent for (diabetic) Gastroparesis. A couple of compounds are currently in clinical testing. Some beacons of hope have failed recently, however. Here we present an update on possible future treatment options.

Impact of anesthetics on pyloric characteristics measured using the EndoFLIP® system in patients with gastroparesis.

BACKGROUND: Pyloric distensibility has been reported as a predictive measure in gastroparesis. Measures can be obtained either during endoscopy under anesthesia or in unsedated patients. However, the impact of anesthetic drugs on the results of pyloric characteristics remains unknown. The objective of the present study was to determine the impact of anesthetics on pyloric characteristics measured using EndoFLIP® in patients with gastroparesis. METHODS: Consecutive patients with gastroparesis from three French tertiary centers were retrospectively analyzed. Patients with a previous history of pyloric intervention were not considered for analysis. Medical records were reviewed for the potential use of anesthetic drugs during EndoFLIP® measurement. KEY RESULTS: One hundred twenty-five patients were included in the present study [median age: 55.0 years (43.0-66.0)]. Thirty-four patients (27.2%) had pyloric assessment without general anesthesia and 91 patients (72.8%) with general anesthesia. Pyloric pressure at 40 mL of distension was higher in patients with general anesthesia in comparison with patients without general anesthesia [18.7 (13.0-25.6) mmHg vs. 15.4 (11.9-20.7) mmHg; p = 0.044)]. In multivariate analysis, suxamethonium chloride administration was associated with decreased pyloric distensibility (OR: 3.9; 95% CI: 1.3-11.4; p = 0.013) while ephedrine was rather associated with increased pyloric distensibility (OR: 0.3; 95% CI: 0.1-0.9; p = 0.036). CONCLUSIONS AND INFERENCES: This study is the first to have found an impact of general anesthesia on pyloric measurement using the EndoFLIP®. Therefore, further studies are needed to confirm these findings, if possible, prospective studies.

Gastric per-oral endoscopic myotomy versus pyloric injection of botulinum toxin for the treatment of gastroparesis: our institutional experience and a systematic review of the literature.

INTRODUCTION: Gastric Per-Oral Endoscopic Myotomy (GPOEM) has been developed as an effective treatment option for patients with medically refractory gastroparesis. Other endoscopic options, such as pyloric injection of botulinum toxin (Botox), is often performed with limited efficacy. The purpose of this study was to evaluate GPOEM for the treatment of gastroparesis and compare its efficacy to Botox injection results reported in the literature. METHODS: A retrospective review was conducted to identify all patients who underwent a GPOEM for the treatment of gastroparesis between September 2018 and June 2022. Changes in Gastric Emptying Scintigraphy (GES) studies and Gastroparesis Cardinal Symptom (GCSI) scores from the preoperative to postoperative period were analyzed. In addition, a systematic review was conducted to identify all publications reporting the outcomes of Botox injections for the treatment of gastroparesis. RESULTS: A total of 65 patients (51 female, 14 male) underwent a GPOEM during the study period. Twenty-eight patients (22 female, 6 male) had both preoperative and postoperative GES studies in addition to GCSI scores. The etiologies of gastroparesis were diabetic (n = 4), idiopathic (n = 18), and postsurgical (n = 6). Fifty percent of these patients had undergone previous failed interventions including Botox injections (n = 6), gastric stimulator placement (n = 2), and endoscopic pyloric dilation (n = 6). Outcomes showed a significant decrease in GES percentages (mean difference = - 23.5%, p < 0.001) and GCSI scores (mean difference = - 9.6, p = 0.02) postoperatively. In the systematic review for Botox, transient mean improvements in postoperative GES percentages and GCSI scores were reported at 10.1% and 4.0, respectively. CONCLUSION: GPOEM leads to significant improvement in GES percentages and GCSI scores postoperatively and is superior to Botox injection results reported in the literature.

A Randomized, Controlled Trial of Efficacy and Safety of Cannabidiol in Idiopathic and Diabetic Gastroparesis.

BACKGROUND & AIMS: Cannabis (delta-9-tetrahydrocannabinol), a nonselective cannabinoid-receptor agonist, relieves nausea and pain. Cannabidiol (CBD), a cannabinoid receptor 2 inverse agonist with central effects, also reduces gut sensation and inflammation. We compared the effects of 4 weeks of treatment with pharmaceutical CBD vs placebo in patients with idiopathic or diabetic (diabetes mellitus) gastroparesis. METHODS: We performed a randomized, double-blinded, placebo-controlled study of CBD twice daily (Epidiolex escalated to 20 mg/kg/d; Jazz Pharmaceuticals, Dublin, Ireland) in patients with nonsurgical gastroparesis with delayed gastric emptying of solids (GES). Symptoms were assessed by the Gastroparesis Cardinal Symptom Index Daily Diary. After 4 weeks of treatment, we measured GES, gastric volumes, and Ensure (Abbott Laboratories, Abbott Park, IL) satiation test (1 kcal/mL, 30 mL/min) to assess volume to comfortable fullness and maximum tolerance. Patients underwent specific FAAH and CNR1 genotyping. Statistical analysis compared 2 treatments using analysis of variance including baseline measurements and body mass index as covariates. RESULTS: Among 44 patients (32 idiopathic, 6 diabetes mellitus type 1, and 6 diabetes mellitus type 2), 5 patients did not tolerate full-dose escalation; 3 withdrew before completing 4 weeks of treatment (2 placebo, 1 CBD); 95% completed 4 weeks of treatment and diaries. Compared with placebo, CBD reduced the total Gastroparesis Cardinal Symptom Index score (P = .008), inability to finish a normal-sized meal (P = .029), number of vomiting episodes/24 hours (P = .006), and overall symptom severity (P = .034). Patients treated with CBD had a higher volume to comfortable fullness and maximum tolerance and slower GES. FAAH rs34420 genotype significantly impacted nutrient drink ingestion. The most common adverse events reported were diarrhea (14 patients), fatigue (8 patients), headache (8 patients), and nausea (7 patients). CONCLUSIONS: CBD provides symptom relief in patients with gastroparesis and improves the tolerance of liquid nutrient intake, despite slowing of GES. CLINICALTRIALS: gov NCT #03941288.

Buspirone for early satiety and symptoms of gastroparesis: A multi-centre, randomised, placebo-controlled, double-masked trial (BESST).

BACKGROUND: Patients with gastroparesis and related disorders have symptoms including early satiety, postprandial fullness and bloating. Buspirone, a 5-HT1 receptor agonist, may improve fundic accommodation. AIM: To determine if buspirone treatment improves early satiety and postprandial fullness in patients with symptoms of gastroparesis. METHODS: This 4-week multi-centre clinical trial randomised patients with symptoms of gastroparesis and moderate-to-severe symptoms of fullness (Gastroparesis Cardinal Symptom Index [GCSI] early satiety/postprandial fullness subscore [ES/PPF]) to buspirone (10 mg orally) or placebo three times per day. The primary outcome was a change in the ES/PPF from baseline to 4 weeks. The primary analysis was per protocol intention-to-treat ANCOVA of between-group baseline vs. 4-week differences (DoD) in ES/PPF adjusted for baseline ES/PPF. Results are reported using both nominal and Bonferroni (BF) p values. RESULTS AND CONCLUSIONS: Ninety-six patients (47 buspirone, 49 placeboes; 92% female, 50% delayed gastric emptying, 39% diabetic) were enrolled. There was no between-groups difference in the 4-week ES/PPF primary outcome: -1.16 ± 1.25 (SD) on buspirone vs -1.03 ± 1.29 (SD) on placebo (mean DoD: -0.11 [95% CI: -0.68, 0.45]; p = 0.69). Buspirone performed better than placebo in patients with severe-to-very severe bloating at baseline compared to patients with none to moderate: (ES/PPF DoD = -0.65 vs. 1.58, pTX*GROUP  = 0.003; pBF  = 0.07). Among individual GCSI symptoms, only bloating appeared to improve with buspirone vs. placebo. CONCLUSIONS: Patients with moderate-to-severe early satiety/postprandial fullness and other symptoms of gastroparesis did not benefit from buspirone treatment to improve the ES/PPF primary outcome compared with placebo. There was a suggestion of the benefit of buspirone in patients with more severe bloating. TRIAL REGISTRATION: ClinicalTrials.gov NCT0358714285.

Review article: An analysis of the pharmacological rationale for selecting drugs to inhibit vomiting or increase gastric emptying during treatment of gastroparesis.

BACKGROUND: Drugs which can inhibit nausea/vomiting and/or increase gastric emptying are used to treat gastroparesis, mostly 'off-label'. Within each category, they act at different targets and modulate different physiological mechanisms. AIMS: Address the questions: In gastroparesis, why should blocking one pathway causing vomiting, be more appropriate than another? Why might increasing gastric emptying via one mechanism be more appropriate than another? METHODS: Drugs used clinically were identified via consensus opinions and reviews, excluding the poorly characterised. Their pharmacology was defined, mapped to mechanisms influencing vomiting and gastric emptying, and rationale developed for therapeutic use. RESULTS: Vomiting: Rationale for 5-HT3 , D2 , H1 or muscarinic antagonists, and mirtazapine, amitriptyline, nortriptyline, are poor. Arguments for inhibiting central consequences of vagal afferent transmission by NK1 antagonism are complicated by doubts over effects on nausea. Gastric emptying: Confusion emerges because of side-effects of drugs increasing gastric emptying: Metoclopramide (5-HT4 agonist, D2 and 5-HT3 antagonist; also blocks some emetic stimuli and causes tardive dyskinesia) and Erythromycin (high-efficacy motilin agonist, requiring low doses to minimise side-effects). Limited trials with selective 5-HT4 agonists indicate variable efficacy. CONCLUSIONS: Several drug classes inhibiting vomiting have no scientific rationale. NK1 antagonism has rationale but complicated by limited efficacy against nausea. Studies must resolve variable efficacy of selective 5-HT4 agonists and apparent superiority over motilin agonists. Overall, lack of robust activity indicates a need for novel approaches targeting nausea (e.g., modulating gastric pacemaker or vagal activity, use of receptor agonists or new targets such as GDF15) and objective assessments of nausea.

Gastroparesis syndromes: emerging drug targets and potential therapeutic opportunities.

INTRODUCTION: Gastroparesis (Gp) and related disorders such as chronic unexplained nausea and vomiting and functional dyspepsia, known as gastropareis syndromes (GpS), have large unmet needs. Mainstays of GpS treatments are diet and drugs. AREAS COVERED: The purpose of this review is to explore potential new medications and other therapies for gastroparesis. Before discussing possible new drugs, the currently used drugs are discussed. These include dopamine receptor antagonists, 5-hydroxytryptamine receptor agonists and antagonists, neurokinin-1 receptor antagonists and other anti-emetics. The article also considers future drugs that may be used for Gp, based on currently known pathophysiology. EXPERT OPINION: Gaps in knowledge about the pathophysiology of gastroparesis and related syndromes are critical to developing therapeutic agents that will be successful. Recent major developments in the gastroparesis arena are related to microscopic anatomy, cellular function, and pathophysiology. The major challenges moving forward will be to develop the genetic and biochemical correlates of these major developments in gastroparesis research.

The role of mosapride and levosulpiride in gut function and glycemic control in diabetic rats.

BACKGROUND AND STUDY AIMS: Gastroparesis is a well-known consequence of long-standing diabetes that presents with gastric dysmotility in the absence of gastric outlet obstruction. This study aimed to evaluate the therapeutic effects of mosapride and levosulpiride on improving gastric emptying in type 2 diabetes mellitus (T2DM) while regulating glycemic levels. MATERIAL AND METHODS: Rats were divided into the normal control, untreated diabetic, metformin-treated (100 mg/kg/day), mosapride-treated (3 mg/kg/day), levosulpiride-treated (5 mg/kg/day), metformin (100 mg/kg/day) + mosapride (3 mg/kg/day)-treated, and metformin (100 mg/kg/day) + levosulpiride (5 mg/kg/day)-treated diabetic groups. T2DM was induced by a streptozotocin-nicotinamide model. Fourweeks from diabetes onset, the treatment was started orally daily for 2 weeks. Serum glucose, insulin, and glucagon-like peptide 1 (GLP-1) levels were measured. Gastric motility study was performed using isolated rat fundus and pylorus strip preparations. Moreover, the intestinal transit rate was measured. RESULTS: Mosapride and levosulpiride administration showed a significant decrease in serum glucose levels with improvement of gastric motility and intestinal transit rate. Mosapride showed a significant increase in serum insulin and GLP-1 levels. Metformin with mosapride and levosulpiride co-administration showed better glycemic control and gastric emptying than either drug administered alone. CONCLUSION: Mosapride and levosulpiride showed comparable prokinetic effects. Metformin administration with mosapride and levosulpiride showed better glycemic control and prokinetic effects. Mosapride provided better glycemic control than levosulpiride. Metformin + mosapride combination provided superior glycemic control and prokinetic effects.

Risk of Adverse Events Associated with Domperidone and Metoclopramide in Gastroparesis: Systematic Review and Meta-analysis.

BACKGROUND: Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis. METHODS: We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI). RESULTS: We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs. CONCLUSIONS: The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions. REGISTRATION: PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).