Prokinetic Research Articles

Adding Acotiamide to Gastric Acid Inhibitors Is Effective for Treating Refractory Symptoms in Patients with Non-erosive Reflux Disease

BackgroundApproximately 30% of patients who are treated with proton pump inhibitors (PPIs) for gastroesophageal reflux disease (GERD) experience persistent symptoms. No prokinetic agent regiments are useful for symptom relief.AimsThis study was conducted to examine the effect of adding acotiamide to PPI or vonoprazan refractory GERD.MethodsThis was a randomized, prospective, double-blind, placebo-controlled trial. Seventy-one patients were enrolled. Patients underwent upper endoscopy before initial therapy [15 reflux esophagitis and 55 non-erosive reflux disease (NERD)]. Patients with persistent reflux symptoms were administered 300 mg/day acotiamide or placebo for 2 weeks. The primary endpoint was overall treatment effect (OTE), and gastrointestinal symptoms were evaluated. High-resolution manometry (HRM) and 24-h multiple intraluminal impedance-pH (MII-pH) monitoring were conducted before and after treatment when possible.ResultsSeventy patients were randomized (35 acotiamide and 35 placebo). Sixteen and 10 patients in the acotiamide and placebo groups, respectively, completed MII-pH and HRM. The OTE improvement rates were 28.6% and 14.3% in patients administered acotiamide and placebo, respectively (p = 0.145). In patients with NERD, however, the OTE improvement rate and responder rate for regurgitation in the acotiamide group was significantly higher than those in the placebo group (29.6 vs. 7.1%; p = 0.030, 37.0 vs. 10.7%; p = 0.021, respectively). Acotiamide significantly reduced the total reflux episodes (p = 0.001), acid (p = 0.020), proximal reflux (p = 0.007), and liquid reflux (p = 0.013) episodes.ConclusionAdding acotiamide to gastric acid inhibitors can improve symptoms in patients with refractory NERD.

Evaluation of the Additive Effect of Domperidone on Patients with Refractory Gastroesophageal Reflux Disease; A Randomized Double Blind Clinical Trial.

BACKGROUND Gastroesophageal reflux disease (GERD) is a common problem with annoying symptoms. It is associated with negative impact on quality of life. Prokinetic agents may be used in combination with acid suppression agents as an adjunctive in patients with GERD refractory to proton pump inhibitors (PPI) therapy, rather than as sole treatment. This study aimed to evaluate the efficacy of combination of PPI with domperidone (a prokinetic agent) compared with PPI alone in the treatment of patients with refractory GERD. METHODS This study was a double blind clinical trial on 29 patients with GERD refractory to PPI during the period of one month. By randomization, the patients were divided into two groups. Group A was treated by pantoprazole 40 mg twice daily and domperidone three times a day for a month, while group B was treated by pantoprazole 40 mg twice daily and placebo three times a day. In this study endoscopy was performed to evaluate the prevalence of erosive esophagitis, non-erosive reflux, and hiatal hernia. Manometry was conducted to study the prevalence of dysmotility. GERD symptom questionnaires including the Gastrointestinal Symptom Rating Scale (GSRS), Carlson Dennett, and the Medical Outcomes Study Short Form-36 health survey (SF36) were used before and after treatment for screening GERD and assessing treatment response. RESULTS There were 17 (58.62%) women and 12 (41.37%) men. The prevalence of erosive esophagitis and non-erosive reflux, was 10.34% and 89.66%, respectively. There was a significant difference comparing reflux symptoms before and after treatment between the two groups according to reflux and Carlson Dennett questionnaires. At the end of the study, symptoms of reflux significantly improved by treatment. Although, the quality of life questionnaire scores improved by treatment, there was no statistically significant difference in response to treatment between the two groups. CONCLUSION In this research, we showed that adding domperidone to PPI could not make any improvement in patients with refractory reflux regarding the quality of life and improving the symptoms.

Real-World, Non-Interventional, Observational Study to Evaluate Effectiveness and Tolerability of Acotiamide Hydrochloride Hydrate in Treatment of Functional Dyspepsia.

Functional dyspepsia (FD) is a highly prevalent condition which reduces patients' quality of life (QoL) and imparts a significant economic burden on the healthcare system. Acotiamide is a novel prokinetic agent useful in treatment of FD, and this study evaluated the effectiveness of acotiamide hydrochloride hydrate in management of FD over a 4-week period in a real-world setting. This study was a prospective, observational, real-world data collection of 132 patients (85 male, 47 female) over 18years of age diagnosed with FD as per Rome III criteria and treated with acotiamide for 4weeks at a gastroenterology unit of a medical school in India. Those receiving prokinetics and cholinergic drugs, having any structural lesion on endoscopy, with coexisting irritable bowel syndrome and having heartburn in the past 12weeks were excluded. Primary outcome was responders based on overall treatment efficacy (OTE) recorded on a seven-point Likert scale for postprandial distress syndrome (PDS; postprandial fullness, early satiety and upper abdominal bloating), epigastric pain syndrome (EPS; upper abdominal pain and upper abdominal discomfort) and associated symptoms (nausea, vomiting and excessive belching) at the end of 2 and 4weeks. Secondary outcomes were elimination of symptoms of PDS, QoL assessed on the Short-Form Nepean Dyspepsia Index (SFNDI) questionnaire and clinical safety after 2 and 4weeks. The responder rates with acotiamide at 2 and 4weeks were 51.5% and 65.9%, respectively, for PDS. Similarly, the responder rates for EPS were 31.8% and 41.7%, respectively, at 2weeks and 4weeks. The responder rates for associated symptoms of nausea, vomiting and excessive belching were respectively 18.2%, 17.4% and 16.7% at 2weeks and 18.2%, 17.4% and 18.2% at 4weeks. Symptom elimination rates were 9.8% and 18.9% for postprandial fullness, 12.9% and 22.0% for early satiety, and 18.9% and 24.2% for abdominal bloating at 2 and 4weeks, respectively. Significant improvement (p < 0.0001) in the SFNDI total scores from 25.91 (5.00) at 2weeks to 23.76 (4.84) at 4weeks were found at 4weeks compared to 2weeks. A total of 7 (5.30%) patients reported mild adverse events which were dizziness (4), headache (3) and nausea (1). The current study demonstrates that treatment with acotiamide improves symptoms, QoL and is well tolerated in Indian patients with FD. Clinical Trial Registry of India, CTRI/2017/11/010421. Dr. Reddy's Laboratories, India.

The effects of three different prokinetic drugs on the motility hormones level in lambs with postoperative ileus

The aim of this study was to evaluate the effects of the three different prokinetic agents, namely erythromycin, lidocaine, and metoclopramide in lambs with postoperative ileus (POI) using motilin and ghrelin, which are known as motility markers. Twenty lambs were allocated to 4 groups of 5 lambs each. An enterotomy was performed on the ileum of each lamb. Erythromycin (8.8 mg/kg), metoclopramide (0.2 mg/kg), and saline (2 mL) were administered as single dose IM before surgery in the ERT, MET, and CNTR groups, respectively. Lidocaine was administered to the LID group, both as a bolus before (1.3 mg/kg IV) and as a continuous rate infusion during surgery (0.05 mg/kg/h IV). Serum motilin and ghrelin concentrations as motility hormones were measured with ELISA. The serum motilin concentration was significantly higher at 0, 1, 3, 5, 10, 24, and 48 h in the ERT group and at 1 and 10 h in the LID group. The serum ghrelin concentration was significantly higher at 0, 1, and 48 h in the ERT group and at 3, 5, 10, 24, and 48 h in the LID group. As a result, erythromycin and lidocaine was thought to be useful in lambs with POI according to the stimulatory effects on the motility hormones.

Intranasal Surface-Modified Mosapride Citrate-Loaded Nanostructured Lipid Carriers (MOS-SMNLCs) for Treatment of Reflux Diseases: In vitro Optimization, Pharmacodynamics, and Pharmacokinetic Studies.

Gastroesophageal reflux disease (GERD) is an esophageal injury occurred when the stomach contents reflux abnormally into the esophagus. GERD complications include esophageal adenocarcinoma. Mosapride (MOS) is a safe prokinetic agent potentially used to treat GERD. Yet, its low solubility and bioavailability due to extensive first-pass metabolism limits its applications. This study aimed to formulate MOS nanostructured lipid carriers (MOS-NLCs) via the intranasal route to improve its bioavailability. Melt-emulsification low temperature-solidification technique using 23 full factorial design was adopted to formulate MOS-NLCs. Eight formulae were prepared and assessed in terms of entrapment efficiency (%EE), particle size, and in vitro release. Glycerol addition significantly reduced the particle sizes and improved %EE and %drug released. Surface modification using chitosan was applied. The optimized MOS surface-modified nanostructured lipid carriers (MOS-SMNLCs-F7)(stearic acid, 4% glycerol, 0.5% LuterolF127, 0.5% chitosan) showed low particle size 413.8nm ± 11.46nm and high %EE 90.19% ± 0.06% and a threefold increase in permeation of MOS with respect to the drug suspension. MOS-SMNLCs (F7) was also evaluated for its bioavailability compared with drug suspension and commercial product. Statistical analysis revealed a significant increase in gastric emptying rate to be 21.54 ± 1.88 contractions/min compared with10.02 ± 0.62 contractions/min and 8.9 ± 0.72 contractions/min for drug suspension and oral marketed product respectively. Pharmacokinetic studies showed 2.44-fold rise in bioavailability as compared to MOS suspension and 4.54-fold as compared to the oral marketed product. In vitro/in vivo studies proven to level A correlation between in vitro permeation through sheep nasal mucosa and in vivo absorption. Therefore, MOS-SMNLCs could be considered a step forward towards enhancing the clinical efficacy of Mosapride.

Comparing Longitudinal Overall and Individual Symptom Outcomes on Neuromodulator versus Prokinetic Drugs in Patients With Symptoms Suspicious for Gastroparesis but With Non—Delayed Gastric Emptying

Introduction: Most patients with suspected gastroparesis do not have delayed gastric emptying. These patients are often treated with prokinetic agents but neuromodulator drugs are also given to reduce symptoms. Relative benefits of each drug class are unknown. In a multicenter study, we hypothesized that patients with suspected gastroparesis with non—delayed gastric emptying on scintigraphy (GES) or wireless motility capsules (WMC) show differential symptom benefits after prescribing neuromodulator vs. prokinetic medications. Methods: Management plans were devised for 150 patients with suspected gastroparesis. Investigators reviewed concurrent GES and WMC results and recommended therapy changes for those patients with non—delayed gastric emptying by GES (<10% 4 hr retention) or WMC (emptying <5 hr). Symptom (GCSI/PAGI—SYM) scores at baseline and 6 months were related to neuromodulator and prokinetic recommendations.1201_A Figure 1. Overall GCSI Reductions on Neuromodulators and Prokinetics in Patients with Non—Delayed Gastric Emptying1201_B Figure 2. Improvements in Individual Symptoms on Neuromodulators and Prokinetics in Patients with Non—Delayed Gastric EmptyingResults: 76% and 65% of patients had non—delayed gastric emptying by GES and WMC. 64 were prescribed neuromodulators including antidepressants—42 (mirtazapine/tricyclics—35), gabapentin—10, buspirone—9, and other—5. 49 received prokinetics including dopamine receptor antagonists (DRAs) (metoclopramide/domperidone—34) and pure prokinetics (macrolides, pyridostigmine, botulinum toxin—22). At 6 months, neuromodulators and prokinetics reduced overall GCSI scores similarly (Table). DRAs but not pure prokinetics reduced overall scores. Of neuromodulators, antidepressants and buspirone but not gabapentin reduced overall GCSIs. Individual symptoms improved with both drug classes; N/V improved less than other symptoms on neuromodulators but not prokinetics (Figure). DRAs but not pure prokinetics reduced all individual symptoms (P<0.05). Antidepressants but not gabapentin reduced all individual symptoms with GES vs. fullness and pain with WMC (P<0.05). Buspirone lowered fullness and bloating (P<0.05). Conclusion: Neuromodulator and prokinetic drugs are associated with differential benefits in patients with suspected gastroparesis with non—delayed gastric emptying on GES and WMC testing. Both drug classes are associated with improved symptoms, but lower N/V responses on neuromodulators suggest they are less effective antiemetics than prokinetics. Dopamine antagonists are associated with better responses than pure prokinetics. Antidepressants and buspirone relate to better responses than gabapentin. Our results offer unique insight into treating this large, distinct patient group.

Do You Eat Healthy? You May Need a Diet Coke! A Case Report of Successful Non-Surgical Phytobezoar Treatment

Cola drinks have become increasingly targeted as dangerous beverages that only increase the risk of diabetes, heart disease, and obesity. However, for certain types of abdominal pain caused by gastric phytobezoars, it is exactly the therapy we need. Phytobezoars are composed of accumulated vegetable material, but there are bezoars composed of hair and medications as well. Risk factors include gastric dysmotility due to previous vagotomy or pyloroplasty, use of opiates and anticholinergics, or prior gastric outlet obstruction. While most remain asymptomatic, they can cause complications such as abdominal pain, obstruction, and anorexia. Surgery can provide definitive treatment for severe cases, however we present an instance where chemical dissolution proved to be a successful alternative. A 62 year old male with a history of Billroth-II bypass surgery 25 years ago and multiple episodes of small bowel obstruction presented with severe left upper quadrant abdominal pain, vomiting, and nausea after eating pizza an hour earlier. An abdominal CT revealed copious amounts of material in a severely dilated stomach. Afterwards, an EGD showed 50% of the stomach obscured by a large gastric bezoar which was unable to be suctioned or passed via endoscopic water jet. The patient was treated with 500 cc of diet cola via gastric lavage BID for seven days for bezoar dissolution. Afterwards, the patient's symptoms resolved and he was discharged after tolerating a full diet without complications.Therapy for bezoars vary depending on their composition, and interestingly for phytobezoars the high sodium bicarbonate content in cola drinks is believed to create carbon dioxide bubbles that dissolve gastric contents. Dosages may vary from 500 cc to 3 L per day for several weeks with or without a combination of other prokinetic agents. Other options include cellulase tablets, papain meat tenderizer, or acetylcysteine via nasogastric tube. To prevent recurrence, patients should be advised to avoid high fiber diets, chew their food carefully, and stay well hydrated. This case represents an important reminder that clinicians should expand their differentials to include gastric bezoars when evaluating for possible causes of acute upper abdominal pain, especially in patients with prior gastric surgery. Although unusual, the existence of cola drinks as a cost-effective and available therapy should be stressed to clinicians to prevent unnecessary endoscopic or surgical treatment.2706_A Figure 1. CT Abdomen showing faecalized gastric contents causing severe gastric dilatation2706_B Figure 2. Large Bezoar occupying 50% of the stomach pouch

Effect of moxibustion combined with acupuncture intervention on the success rate of bedside naso intestinal catheterization in critically ill patients

Objective To investigate the effect of moxibustion or acupuncture combined with prokinetic drugs (metoclopramide injection) on the success rate of placing the nasal and intestinal tubes in critically ill patients at bedside. Methods A total of 107 patients underwent enteral nutrition from January 2015 to August 2017 in the Intensive Care Unit (ICU) of Wenzhou Central Hospital in Zhejiang Province were recruited and given bedside manual placement of spiral nasointestinal tube. According to whether the acupuncture or moxibustion combined with the use of the prokinetic drugs in the process of placing the tube, the cases can be divided into three groups: simple prokinetic drugs group (n=23) , moxibustion combined with prokinetic drugs group (n=22) , acupuncture and moxibustion combined with prokinetic drugs group (n=62) . The success rate of catheterization in three groups was analyzed and compared statistically. Results After 72 hours of catheterization, bedside X-ray abdominal radiography showed that the end of the catheter was located behind the pylorus in 81 cases out of the 107 patients. The success rate of catheterization was 75.70%. The unsuccessful patients were given gastroscopy guided nasointestinal tube. The success rate of catheterization was 30.43% in simple prokinetic drugs group, 63.64% in moxibustion combined with prokinetic drugs group, and 96.77% in acupuncture and moxibustion combined with prokinetic drugs group. Comparing the success rate of the catheterization, the difference was statistically significant (χ2=49.75, P<0.01) . Conclusions The combination of moxibustion and acupuncture can significantly increasing the success rate of placing the spiral nasointestinal tube, and provide practical benefits for the critically ill patients. This method should be popularized in clinic. Key words: Intensive Care Units; Nasointestinal tube; Moxibustion; Acupuncture; Prokinetic drugs

RA01.08: LAPAROSCOPIC ROUX-EN-Y GASTROJEJUNOSTOMY FOR GASTRIC CONDUIT OUTLET OBSTRUCTION FOLLOWING ESOPHAGECTOMY FOR CANCER

Abstract Description After Ivor Lewis esophagectomy, gastric outlet obstruction refractory to prokinetic therapy and/or endoscopic pyloric dilatation is a challenging clinical problem. Thoracoscopic implant of a gastric neurostimulator has been reported to be effective, but long-term results are lacking. The patient, a 57-year-old woman, underwent a Ivor Lewis esophagectomy for T1N0 adenocarcinoma in 2007. Postoperatively, the patient complained of persistent dysphagia, regurgitation, and 29-kg weight loss. A mechanical obstruction was ruled out by barium swallow study and upper gastrointestinal endoscopy. Several conservative attempts with prokinetic agents and endoscopic dilatations failed, and the patient was exclusively fed through jejunostomy until the thoracoscopic implant of a gastric neurostimulator in October 2015. The postoperative course was uneventful. At six-months follow-up, the patient was able to assume a soft diet and reported a weight gain of 3 kg, with a significant improvement of the total symptom score and gastric emptying scintigraphy. Nevertheless, this encouraging clinical benefit gradually disappeared after the first year of follow-up. At the beginning of 2017, the patient experienced persistent episodes of vomiting and returned to jejunostomy feeding. The video shows the technique of laparoscopic Roux-en-Y gastrojejunostomy. After adhesiolysis and transhiatal mobilization of the distal gastric conduit, a 50 cm long Roux-en-Y alimentary limb was fashioned and anastomosed to the antrum. Post-operative course was uneventful and a gastrographin swallow study showed a satisfactory emptying of the conduit. At the 3-month follow-up the patient was able to resume a soft oral diet. Laparoscopic Roux-en-Y gastrojejunostomy appears to be safe and effective in treating refractory gastric outlet obstruction following Ivor-Lewis esophagectomy. Disclosure All authors have declared no conflicts of interest.

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).

Effects of Gamisoyo-San Decoction, a Traditional Chinese Medicine, on Gastrointestinal Motility

Background: Gamisoyo-San decoction (GSS), a traditional Chinese medicine, has been used to treat various gastrointestinal (GI) symptoms and diseases such as functional dyspepsia. The purpose of this study was to investigate the effect of GSS on GI motility functions in mice. Methods: Percent intestinal transit rate (ITR%) and gastric emptying (GE) values were measured using Evans Blue and phenol red, respectively, in normal mice and in mice with experimentally induced GI motility dysfunction (GMD). Results: In normal mice, GSS (0.01–1 g/kg) induced higher GE values than non-treated controls. Also, GSS could increase GE in loperamide-induced and cisplatin-induced GE delay models. In addition, GSS increased ITR% in a dose-dependent manner. Loperamide decreased ITR% and GSS recovered this loperamide-induced decrease in ITR%. To examine the effect of GSS on GMD, we used acetic acid (AA)-induced and streptozotocin (STZ)-induced mouse GMD models. The AA mouse model showed a significant decrease in ITR%. However, intragastric treatment with GSS significantly recovered this inhibition. Furthermore, STZ-induced diabetic mice showed a significant reduction in ITR%, which was also significantly inhibited by GSS. Conclusion: These results demonstrate that GSS can modulate bowel activity and that it could be used as a gastroprokinetic agent in the treatment of GI motility diseases.

Erythromycin as a Prokinetic Agent

Erythromycin as a Prokinetic Agent

Use of prokinetic agents or antibiotics is associated with the occurrence of spontaneous bacterial peritonitis in cirrhotic patients

BackgroundProkinetics have been shown to improve intestinal bacterial overgrowth and dysmotility in cirrhotic patients. Antibiotics are suggested for high risk patients for prophylaxis of spontaneous bacterial peritonitis (SBP). However, limited studies have investigated the association of SBP and these medications. We examined the association of prokinetics or antibiotics use and the first episode of SBP development in patients with cirrhosis. MethodsWe conducted a case-crossover study using the Taiwanese National Health Insurance Research Database from 2001 to 2010. A total of 129 cirrhotic patients with SBP were identified (defined as International Classification of Disease-Ninth Revision-CM codes: 571.xx for cirrhosis; 567.2, 567.8, and 567.9 for ascites; 789.5 for SBP). We investigated the short term (defined as 14-day period) effect of prokinetic agents or antibiotics use on SBP development using conditional logistic regressions with the adjustment of potential confounders. ResultsThe results suggested that prokinetic agents or antibiotics use during the 14 days before SBP were associated with an increased risk of SBP [adjusted odds ratio (OR) = 3.2, 95% confidence interval (CI): 1.02–10.04 for prokinetic agents; and adjusted OR = 2.95, 95% CI: 1.05–5.23 for antibiotics]. In dose analysis, the use of prokinetic agents more than 0.5 defined daily dose was more commonly found in the case period without a statistical difference (adjusted OR = 3.637; 95% CI: 0.69–19.13). ConclusionThe results demonstrated an increased risk of primary SBP development among cirrhotic patients with prokinetic agents or antibiotics use. It is important to closely monitor those patients for the occurrence of SBP.

Corticotrophin-releasing factor-mediated effects of DA-9701 in Postoperative Ileus Guinea Pig Model.

Postoperative ileus (POI) is abdominal surgery-induced impaired gastrointestinal (GI) motility. We aimed to investigate the effects of DA-9701, a prokinetic agent formulated from Pharbitis Semen and Corydalis tuber, likely mediated via corticotrophin-releasing factor (CRF) pathways, in a POI model. A laparotomy with cecal manipulation was performed to induce POI in guinea pigs. GI transit was measured based on charcoal migration after intragastric administration of DA-9701 1, 3, and 10mgkg-1 . CRF1 receptor antagonist, CP-154526 (subcutaneous) or agonist, human/rat (h/r) CRF (intraperitoneal) was injected. Then, plasma adrenocorticotropic hormone (ACTH) levels were measured, and the average intensity of the CRF expression was analyzed in the proximal colon and hypothalamus, and c-Fos in the hypothalamus. DA-9701 significantly increased delayed GI transit in POI in a dose-dependent manner and decreased plasma ACTH levels at 10mgkg-1 . CP-154526 significantly decreased plasma ACTH levels but was not as effective on GI transit as DA-9701 was. h/r CRF did not significantly affect GI transit and plasma ACTH levels. No significant difference was observed in GI transit and plasma ACTH levels in both groups administered DA-9701 with h/r CRF and h/r CRF alone. CRF expression in the proximal colon decreased after DA-9701 administration, but not significantly, compared with levels in POI alone. However, CRF expression in the hypothalamus was significantly lower in the DA-9701-pretreated POI than in the untreated POI. The DA-9701-induced improvement in GI transit and inhibition of plasma ACTH levels was mediated by the central CRF pathway.

Trimebutine Promotes Glioma Cell Apoptosis as a Potential Anti-tumor Agent.

Gliomas are the most common primary brain tumors with a usually fatal malignancy. They are associated with a poor prognosis although multiple therapeutic options have been available. Trimebutine is one of the prokinetic agents and it has been mainly used for treatment of disorders of the gastrointestinal (GI) tract such as irritable bowel syndrome. However, its effects on glioma cells remain unknown. Here, we used various concentrations of trimebutine to treat SHG44, U251, and U-87 MG human glioma/glioblastoma cells. And combined experiments of MTT, colony formation assay, and wound healing assay, as well as western blot and immunofluorescence staining were used to evaluate the effects of trimebutine on glioma cells. The results demonstrated that trimebutine significantly inhibited cell viability and colony formation. A significant inhibition of glioma cell migration was also indicated by wound healing assay. In addition, trimebutine promoted cell apoptosis and induced Bcl-2 downregulation, accompanied with Bax upregulation. Both immunofluorescence staining and western blot results showed that trimebutine increased the level of active Caspase-3. Moreover, trimebutine reduced the activation of both AKT and ERK signaling pathways. In subcutaneous U-87 MG cell xenograft tumors in nude mice, trimebutine significantly inhibited tumor growth. More TUNEL-positive apoptotic cells in tumor sections were observed in trimebutine-treated mice when compared to the vehicle control. Reduced Bcl-2 and upregulated Bax, as well as perturbed p-AKT and p-ERK signaling pathways were also observed in trimebutine-treated xenograft tissues. Our combined data indicated that trimebutine may be potentially applied for the clinical management of glioma/glioblastoma.

Interventions for preventing distal intestinal obstruction syndrome (DIOS) in cystic fibrosis.

Cystic fibrosis (CF) is the most common, life-limiting, genetically inherited disease. It affects multiple organs, particularly the respiratory system. However, gastrointestinal problems such as constipation and distal intestinal obstruction syndrome (DIOS) are also important and well-recognised complications in CF. They share similar symptoms e.g. bloating, abdominal pain, but are distinct conditions. Constipation occurs when there is gradual faecal impaction of the colon, but DIOS occurs when there is an accumulation of faeces and sticky mucus, forming a mass in the distal part of the small intestine. The mass may partially block the intestine (incomplete DIOS) or completely block the intestine (complete DIOS). Symptoms of DIOS can affect quality of life and other aspects of CF health, such as airway clearance, exercise, sleep and nutritional status. Treatment of constipation and prevention of complete bowel obstruction are required for gastrointestinal management in CF. However, many different strategies are used in clinical practice and there is a lack of consensus. The importance of this topic was highlighted in a recent research priority setting exercise by the James Lind Alliance. To evaluate the effectiveness and safety of laxative agents of differing types for preventing DIOS (complete and incomplete) in children and adults with CF. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of search: 22 May 2018.We also searched online trial registries. Date of last search: 10 June 2018. Randomised and quasi-randomised controlled parallel trials comparing laxative therapy for preventing DIOS (including osmotic agents, stimulants, mucolytics and substances with more than one action) at any dose to placebo, no treatment or an alternative laxative therapy, in people of any age with pancreatic sufficient or insufficient CF and any stage of lung disease. Randomised cross-over trials were judged on an individual basis. Two authors independently assessed trials for inclusion, extracted outcome data and performed a risk of bias assessment for the included data. We judged the quality of the evidence using GRADE criteria. We included one cross-over trial (17 participants) with a duration of 12 months, in which participants were randomly allocated to either cisapride (a gastro-prokinetic agent) or placebo for six months each. The trial had an unclear risk of bias for most domains but had a high risk of reporting bias.Radiograph scores revealed no difference in occurrence of DIOS between cisapride and placebo (narrative report, no data provided). There were no adverse effects. Symptom scores were the only secondary outcome within the review that were reported. Total gastrointestinal symptom scores favoured cisapride with a statistically significant mean difference (MD) of -7.60 (95% confidence interval (CI) -14.73 to -0.47). There was no significant difference at six months between cisapride and placebo for abdominal distension, MD -0.90 (95% CI -2.39 to 0.59) or abdominal pain, MD -0.4 (95% CI -2.05 to 1.25). The global symptom scores (whether individuals felt better or worse) were reported in the paper to favour cisapride and be statistically significant (P < 0.05).We assessed the available data to be very low quality. There was a great deal of missing data from the included trial and the investigators failed to report numerical data for many outcomes. The overall risk of bias of the trial was unclear and it had a high risk for reporting bias. There was also indirectness; the trial drug (cisapride) has since been removed from the market in several countries due to adverse effects, thus it has no current applicability for preventing DIOS. The included trial also had very few participants, which downgraded the quality a further level for precision. There is an absence of evidence for interventions for the prevention of DIOS. As there was only one included trial, we could not perform a meta-analysis of the data. Furthermore, the included trial compared a prokinetic agent (cisapride) that is no longer licensed for use in a number of countries due to the risk of serious cardiac events, a finding that came to light after the trial was conducted. Therefore, the limited findings from the trial are not applicable in current clinical practice.Overall, a great deal more research needs to be undertaken on gastrointestinal complications in CF, as this is a very poorly studied area compared to respiratory complications in CF.

An Efficient and Improved Process for the Synthesis of Itopride Hydrochloride and Trimethobenzamide Hydrochloride

Aim and Objective: Itopride is a prokinetic agent used for treating conditions like non-ulcer dyspepsia. Itopride is administered as its hydrochloride salt. Trimethobenzamide is used for treating nausea and vomiting and administered as its hydrochloride salt. The aim is to develop a novel and environmental friendly method for large-scale production of itopride and trimethobenzamide. Materials and Methods: Itopride and trimethobenzamide can be prepared from a common intermediate 4- (dimethylaminoethoxy) benzyl amine. The intermediate is prepared from one pot synthesis using Phyrdroxybenzaldehye and zinc dust and further reaction of the intermediate with substituted methoxy benzoic acid along with boric acid and PEG gives itopride and trimethobenzamide. Results: The intermediate 4-(dimethylaminoethoxy) benzylamine is prepared by treating p-hydroxybenzaldehyde and 2-dimethylaminoethyl chloride. The aldehyde formed is treated with hydroxylamine hydrochloride. The intermediate is confirmed by NMR and the purity is analysed by HPLC. Conclusion: Both itopride and trimethobenzamide were successfully synthesized by this method. The developed method is environmental friendly, economical for large-scale production with good yield and purity.

Design, Formulation and In Vitro Evaluation of Sustained-release Tablet Formulations of Levosulpiride.

Levosulpiride is a widely used gastroprokinetic agent in the treatment of various gastric disorders; however, its short half-life and increased dosage frequency leads to non-compliance and possible adverse effects. The prime objective of the current study was to develop a sustained-release formulation of Levosulpiride incorporating bioresorbable cellulose derivatives. Sustained-release formulations of Levosulpiride were prepared through direct compression using various cellulose derivatives such as CMC sodium, HPC, and HPMC in different polymer-to-drug weight ratios as release-modifying polymers. The powder blends and compressed tablets were then subjected to pre-compressional and post-compressional evaluation, as well as FTIR analysis. In vitro release studies were performed for all formulations of the model drug in buffer solution of pH 6.8 at a wave length of 214 nm by a UV-visible light spectrophotometer. The FTIR results confirmed that the interaction between components was physical, and from the different kinetic models data, the release profile was best expressed by the Higuchi model because the results showed high linearity. The results also showed formulation F9 to be the ideal one among the developed formulations, exhibiting sustained- release behavior. Levosulpiride sustained-release matrices were prepared successfully using CMC sodium, HPC, and HPMC as the release-retarding polymer/carrier.

Multicentre observational study of gastrointestinal recovery after elective colorectal surgery.

Postoperative ileus (POI) is characterised by delayed gastrointestinal recovery and is common after colorectal surgery. Numerous strategies to optimise POI have been proposed but its management remains an unmet clinical need. This study aimed to characterise the duration and management of gastrointestinal recovery in patients undergoing elective colorectal surgery. A snapshot, prospective, observational study was undertaken between November 2016 and January 2017 at 10 regional hospitals in the United Kingdom. Adult patients undergoing elective colorectal surgery with resection of bowel or reversal of stoma were included. Outcomes included time until return of gastrointestinal function, timing of nasogastric tube (NGT) insertion, uptake of targeted interventions and clinical outcomes. Data were validated for accuracy by independent investigators. 204 patients met the eligibility criteria. The median time for gastrointestinal recovery was 3days (IQR 2-4); right-sided resections were associated with longer gastrointestinal recovery than left sided (4days (2.75-5.25) vs 3days (2-4); P=0.002). The rate of NGT insertion was 22.5% at a median time of 4 (4-4.75)days. NGT insertion after vomiting was associated with a higher incidence of bronchopneumonia compared to early placement (13.3% vs 29.0%). Targeted interventions, such as chewing gum (4.4%), selective mu-receptor antagonists (1.0%) and pro-kinetic agents (13.7%) were infrequently used. The average time to gastrointestinal recovery after elective colorectal surgery was three days. Late NGT insertion was associated with an increased incidence of bronchopneumonia. The clinical uptake of targeted interventions to improve gastrointestinal recovery was poor.

Noninvasive Magnetogastrography Detects Erythromycin-Induced Effects on the Gastric Slow Wave

The prokinetic action of erythromycin is clinically useful under conditions associated with gastrointestinal hypomotility. Although erythromycin is known to affect the electrogastrogram, no studies have examined the effects that erythromycin has on gastric slow wave magnetic fields. In this study, gastric slow wave activity was assessed simultaneously using noninvasive magnetogastrogram (MGG), electrogastrogram, and mucosal electromyogram recordings. Recordings were obtained for 30 min prior to and 60 min after intravenous administration of erythromycin at dosages of 3 and 6 mg/kg. MGG recordings showed significant changes in the percentage power distribution of gastric signal after infusion of both 3 and 6 mg/kg erythromycin at t = 1-5 min that persisted for t = 30-40 min after infusion. These changes agree with the changes observed in the electromyogram. We did not observe any statistically significant difference in MGG amplitude before or after injection of either 3 or 6 mg/kg erythromycin. Both 3 and 6 mg/kg erythromycin infusion showed retrograde propagation with a statistically significant decrease in slow wave propagation velocity 11-20 min after infusion. Propagation velocity started returning toward baseline values after approximately 21-30 min for the 3 mg/kg dosage and after 31-40 min for a dosage of 6 mg/kg. Our results showed that the magnetic signatures were sensitive to disruptions in normal slow wave activity induced by pharmacological and prokinetic agents such as erythromycin. This study shows that repeatable noninvasive bio-electro-magnetic techniques can objectively characterize gastric dysrhythmias and may quantify treatment efficacy in patients with functional gastric disorders.