Can mosapride citrate reduce the volume of lavage solution for colonoscopy preparation?

AIM:To evaluate the possibility of reducing the volume of polyethylene glycol(PEG)-electrolyte solution using adjunctive mosapride citrate for colonoscopy preparation. METHODS:This was a single-center,prospective, randomized,investigator-blinded,non-inferiority study involving 252 patients of both sexes,aged from 20 to 80 years,scheduled for screening or diagnostic colonoscopy in our department.A total of 126 patients was randomized to receive 1.5 L PEG-electrolyte solution plus 15 mg of mosapride(1.5 L group),and 126 received 2 L PEG-electrolyte solution plus 15 mg of mosapride(2 L group).Patients completed a questionnaire on the acceptability and tolerability of the bowel preparation process.The efficacy of bowel preparation was assessed using a 5-point scale based on the Aronchick scale.The primary end point was adequate bowel preparation rates(score of excellent/good/fair) vs(poor/inadequate).Acceptability and tolerability,as well as disease detection,were secondary end points. RESULTS:A total of 244 patients was included in the analysis.There were no significant differences between the 2 L and 1.5 L groups in age,sex,body mass index, number of previous colonoscopies,and the preparation method used previously.The adequate bowel preparation rates were 88.5%in the 2 L group and 82.8%in the 1.5 L group[95%lower confidence limit(LCL)for the difference=-14.5%,non-inferiority P=0.019]in the right colon.In the left colon,the adequate bowel preparation rates were 89.3%in the 2 L group and 81.1%in the 1.5 L group(95%LCL=-17.0%,non-inferiority P=0.066).Compliance,defined as complete (100%)intake of the PEG solution,was significantly higher in the 1.5 L group than in the 2 L group(96.8% vs 85.7%,P=0.002).The proportion of abdominal distension(none/mild/moderate/severe)was significantly lower in the 1.5 L group than in the 2 L group (36/65/22/3 vs 58/48/18/2,P=0.040).Within the subgroup who had undergone colonoscopy previously, a significantly higher number of patients in the 1.5 L group than in the 2 L group felt that the current preparation was easier than the previous one(54.1%vs 28.0%,P=0.001).The disease detection rate was not significantly different between the two groups. CONCLUSION:Although the 1.5 L group had better acceptability and tolerability,15 mg of mosapride may be insufficient to compensate for a 0.5-L reduction of PEG solution.

Implications of small-bowel transit time in the detection rate of capsule endoscopy: A multivariable multicenter study of patients with obscure gastrointestinal bleeding

AIM To define the role of small-bowel transit time in the detection rate of significant small-bowel lesions.METHODS Small-bowel capsule endoscopy records, prospectively collected from 30 participating centers in the Lombardy Registry from October 2011 to December 2013, were included in the study if the clinical indication was obscure gastrointestinal bleeding and the capsule reached the cecum. Based on capsule findings, we created two groups: P2(significant findings) and P0-1(normal/negligible findings). Groups were compared for age, gender, small-bowel transit time, type of instrument, modality of capsule performance(outpatients vs inpatients), bowel cleanliness, and center volume.RESULTS We retrieved and scrutinized 1,433 out of 2,295 capsule endoscopy records(62.4%) fulfilling the inclusion criteria. Patients were 67 ± 15 years old, and 815(57%) were males. In comparison with patients in the P0-1 group, those in the P2 group(n = 776, 54%) were older(P < 0.0001), had a longer small-bowel transit time(P = 0.0015), and were more frequently examined in low-volume centers(P < 0.001). Age and smallbowel transit time were correlated(P < 0.001), with age as the sole independent predictor on multivariable analysis. Findings of the P2 group were artero-venous malformations(54.5%), inflammatory(23.6%) and protruding(10.4%) lesions, and luminal blood(11.5%).CONCLUSION In this selected, prospectively collected cohort of small-bowel capsule endoscopy performed for obscure gastrointestinal bleeding, a longer small-bowel transit time was associated with a higher detection rate of significant lesions, along with age and a low center volume, with age serving as an independent predictor.

Gastroparesis:New insights into an old disease

Gastroparesis(Gp)is a chronic disease characterized by a delayed gastric emptying in the absence of mechanical obstruction.Although this condition has been reported in the literature since the mid-1900s,only recently has there been renewed clinical and scientific interest in this disease,which has a potentially great impact on the quality of life.The aim of this review is to explore the pathophysiological,diagnostic and therapeutical aspects of Gp according to the most recent evidence.A comprehensive online search for Gp was carried out using MEDLINE and EMBASE.Gp is the result of neuromuscular abnormalities of the gastric motor function.There is evidence that patients with idiopathic and diabetic Gp may display a reduction in nitrergic inhibitory neurons and in interstitial cells of Cajal and/or telocytes.As regards diagnostic approach,99-Technetium scintigraphy is currently considered to be the gold standard for Gp.Its limits are a lack of standardization and a mild risk of radiation exposure.The C13 breath testing is a valid and safe alternative method.13C acid octanoic and the 13C Spirulina platensis recently approved by the Food and Drug Administration are the most commonly used diagnostic kits.The wireless motility capsule is a promising technique,but its use is limited by costs and scarce availability in many countries.Finally,therapeutic strategies are related to the clinical severity of Gp.In mild and moderate Gp,dietary modification and prokinetic agents are generally sufficient.Metoclopramide is the only drug approved by the Food and Drug Administration for Gp.However,other older and new prokinetics and antiemetics can be considered.As a second-line therapy,tricyclic antidepressants and cannabinoids have been proposed.In severe cases the normal nutritional approach can be compromised and artificial nutrition may be needed.In drug-unresponsive Gp patients some alternative strategies(endoscopic,electric stimulation or surgery)are available.

Personalized medicine in functional gastrointestinal disorders:Understanding pathogenesis to increase diagnostic and treatment efficacy

There is overwhelming evidence that functional gastrointestinal disorders(FGIDs) are associated with specific mechanisms that constitute important targets for personalized treatment. There are specific mechanisms in patients presenting with functional upper gastrointestinal symptoms(UGI Sx). Among patients with UGI Sx, approximately equal proportions(25%) of patients have delayed gastric emptying(GE), reduced gastric accommodation(GA), both impaired GE and GA,or neither, presumably due to increased gastric or duodenal sensitivity.Treatments targeted to the underlying pathophysiology utilize prokinetics,gastric relaxants, or central neuromodulators. Similarly, specific mechanisms in patients presenting with functional lower gastrointestinal symptoms, especially with diarrhea or constipation, are recognized, including at least 30% of patients with functional constipation pelvic floor dyssynergia and 5% has colonic inertia(with neural or interstitial cells of Cajal loss in myenteric plexus); 25% of patients with diarrhea-predominant irritable bowel syndrome(IBSD) has evidence of bile acid diarrhea; and, depending on ethnicity, a varying proportion of patients has disaccharidase deficiency, and less often sucrose-isomaltase deficiency. Among patients with predominant pain or bloating, the role of fermentable oligosaccharides, disaccharides, monosaccharides and polyols should be considered. Personalization is applied through pharmacogenomics related to drug pharmacokinetics, specifically the role of CYP2 D6, 2 C19 and 3 A4 in the use of drugs for treatment of patients with FGIDs. Single mutations or multiple genetic variants are relatively rare, with limited impact to date on the understanding or treatment of FGIDs. The role of mucosal gene expression in FGIDs, particularly in IBS-D, is the subject of ongoing research. In summary, the time for personalization of FGIDs, based on deep phenotyping, is here;pharmacogenomics is relevant in the use of central neuromodulators. There is still unclear impact of the role of genetics in the management of FGIDs.

Gastric electrical stimulation: An emerging therapy for children with intractable gastroparesis

Management of gastroparesis remains challenging,particularly in pediatric patients.Supportive care and pharmacological therapies for symptoms remain the mainstay treatment.Although they are effective for mild and some moderately severe cases,often time they do not work for severe gastroparesis.There are a few prokinetics available,yet the use of these drugs is limited by a lack of persistent efficacy and/or safety concerns.Currently,the only modality for adult patients with severe intractable gastroparesis is surgery,e.g.,pyloroplasty and partial gastrectomy,however,this option is generally considered too radical for a growing child.Novel therapeutic approaches,particularly those which are less invasive,are needed.This article explores gastric electrical stimulation(GES),a new therapy for gastroparesis.Unlike others,it neither needs medications nor gastrectomy;rather,it treats through the use of microelectrodes to deliver high-frequency low energy electric stimulation to the pacemaker area of the stomach.Thus,it is tolerated and safe in children.Like in adult patients,GES appears to work in releasing symptoms,improving nutrition,and enhancing the quality of life;it also helps wean off medications and eliminate many needs for hospitalization.Considering the transient nature of gastroparesis in children in many occasions,GES is considered a“bridging”therapy after failed medical interventions and before surgery.

Finding the solution for incomplete small bowel capsule endoscopy

AIM:To evaluate whether the use of real time viewer(RTV)and administration of domperidone to patients with delayed gastric passage of the capsule could reduce the rate of incomplete examinations(IE)and improve the diagnostic yield of small bowel capsule endoscopy(SBCE).METHODS:Prospective single center interventional study,from June 2012 to February 2013.Capsule location was systematically checked one hour after ingestion using RTV.If it remained in the stomach,the patient received 10 mg domperidone per os and the location of the capsule was rechecked after 30 min.If the capsule remained in the stomach a second dose of10 mg of domperidone was administered orally.After another 30 min the position was rechecked and if the capsule remained in the stomach,it was passed into the duodenum by upper gastrointestinal(GI)endoscopy.The rate of IE and diagnostic yield of SBCE were compared with those of examinations performed before the use of RTV or domperidone in our Department(control group,January 2009-May 2012).RESULTS:Both groups were similar regarding age,sex,indication,inpatient status and surgical history.The control group included 307 patients,with 48(15.6%)IE.The RTV group included 82 patients,with3(3.7%)IE,P=0.003.In the control group,average gastric time was significantly longer in patients with IE than in patients with complete examination of the small bowel(77 min vs 26 min,P=0.003).In the RTV group,the capsule remained in the stomach one hour after ingestion in 14/82 patients(17.0%)vs 48/307(15.6%)in the control group,P=0.736.Domperidone did not significantly affect small bowel transit time(260min vs 297 min,P=0.229).The capsule detected positive findings in 39%of patients in the control group and 49%in the RTV group(P=0.081).CONCLUSION:The use of RTV and selective administration of domperidone to patients with delayed gastric passage of the capsule significantly reduces incomplete examinations,with no effect on small bowel transit time or diagnostic yield.

Pharmacological therapy of feed intolerance in the critically ills

Feed intolerance in the setting of critical illness is associated with higher morbidity and mortality,and thusrequires promptly and effective treatment. Prokineticagents are currently considered as the first-line therapygiven issues relating to parenteral nutrition and post-pyloric placement. Currently,the agents of choice areerythromycin and metoclopramide,either alone or incombination,which are highly effective with relativelylow incidence of cardiac,hemodynamic or neurologicaladverse effects. Diarrhea,however,can occur in up to 49% of patients who are treated with the dual prokinetic therapy,which is not associated with Clostridiumdifficile infection and settled soon after the cessation ofthe drugs. Hence,the use of prokinetic therapy over along period or for prophylactic purpose must be avoided,and the indication for ongoing use of the drug(s)must be reviewed frequently. Second line therapy,suchas total parenteral nutrition and post-pyloric feeding,must be considered once adverse effects relating theprokinetic therapy develop.

Effect of DA-9701 on gastric emptying in a mouse model: Assessment by ^(13)C-octanoic acid breath test

AIM:To evaluate the effects of DA-9701 on the gastric emptying of a solid meal using the 13C-octanoic acid breath test in a mouse model. METHODS:Male C57BL/6 mice aged > 8 wk and with body weights of 20-25 g were used in this study. The solid test meal consisted of 200 mg of egg yolk labeled with 1.5 L/g 13C-octanoic acid. The mice were placed in a 130 mL chamber flushed with air at a flow speed of 200 mL/min. Breath samples were collected for 6 h. The half-emptying time and lag phase were calculated using a modified power exponential model. To assess the reproducibility of the 13C-octanoic acid breath test, the breath test was performed two times at intervals of one week in ten mice without drug treatment. To assess the gastrokinetic effects of DA-9701, the breath test was performed three times in another twelve mice, with a randomized crossover sequence of three drug treatments:DA-9701 3 mg/kg, erythromycin 6 mg/kg, or saline. Each breath test was performed at an interval of one week. RESULTS:Repeatedly measured half gastric emptying time of ten mice without drug treatment showed 0.856 of the intraclass correlation coefficient for the half gastric emptying time (P = 0.004). The mean cumulative excretion curve for the 13C-octanoic acid breath test showed accelerated gastric emptying after DA-9701 treatment compared with the saline control (P = 0.028). The median half gastric emptying time after the DA-9701 treatment was significantly shorter than after the saline treatment [122.4 min (109.0-137.9 min) vs 134.5 min (128.4-167.0 min), respectively; P = 0.028] and similar to that after the erythromycin treatment [123.3 min (112.9-138.2 min)]. The lag phase, which was defined as the period taken to empty 15% of a meal, was significantly shorter after the DA-9701 treatment than after the saline treatment [48.1 min (44.6-57.1 min) vs 52.6 min (49.45-57.4 min), respectively; P = 0.049]. CONCLUSION:The novel prokinetic agent DA-9701 accelerated gastric emptying, assessed with repeated measurements in the same mouse using the 13Coctanoic acid breath test. Our findings suggest that DA-9701 has therapeutic potential for the treatment of functional dyspepsia.

Interaction of insulin with prokinetic drugs in STZ-induced diabetic mice

AIM:To study the possible interactions of metoclopramide,domperidone and erythromycin in streptozotocin-induced diabetic mice treated with insulin by various parameters.METHODS:Effects of the individual as well as combined drugs were studied in diabetic mice via estimation of the blood glucose and serum insulin levels,small intestinal transit(SIT),gastric emptying(GE),xylose absorption and glucose tolerance tests.Groups were given insulin 2 IU/kg s.c.,metoclopramide 20 mg/kg p.o.,domperidone 20 mg/kg p.o.and erythromycin 6 mg/kg p.o.individually and in combination.There were also normal and diabetic control groups.The first set of experiments was carried out to investigate the subchronic effect on blood glucose and serum insulin levels in diabetic mice of one week of daily dose administration of the tested drugs individually as well as the combination of insulin with each prokinetic drug.The other five sets of experiments were carried out to investigate the acute effect of a single dose of each drug individually and in combination on blood glucose and serum insulin levels,SIT,GE,oral xylose absorption and glucose tolerance tests.RESULTS:The study included the prokinetic drugs metoclopramide(20 mg/kg),domperidone(20 mg/kg) and erythromycin(6 mg/kg),as well as insulin(2 IU/kg),which was individually effective in decreasing SIT,enhancing GE and increasing xylose absorption significantly in diabetic mice.Erythromycin tended to decrease blood glucose level and increase serum insulin level after 1 wk of daily administration in diabetic mice.Erythromycin potentiated the effect of insulin on blood glucose level and serum insulin level whereas other prokinetic agents failed to do so after repeated dose administration in diabetic mice.Metoclopramide or erythromycin in combination with insulin significantly decreased SIT,in diabetic mice,to lower levels than with insulin alone.Administration of prokinetic drugs along with insulin antagonized the action of insulin on xylose absorption.These combinations also increased the rate of glucose absorption from the gut.CONCLUSION:The present study suggests that prokinetic drugs could potentially improve glycemic control in diabetic gastroparesis by allowing a more predictable absorption of nutrients,matched to the action of exogenous insulin.The use of prokinetics,such as erythromycin,may be interesting in the clinic in decreasing the need for insulin in diabetic patients.The dose of insulin may be safely decreased with erythromycin in chronic treatments.

Fixed Dose Combination of Magaldrate Plus Domperidone Is More Effective than Domperidone Alone in the Treatment of Patients with Gastroesophageal Reflux Symptoms: A Randomized Double-Blind Study

Gastroeophageal reflux is a condition in which the acidified liquid content of the stomach backs up into the esophagus. The antiacid magaldrate and prokinetic domperidone are two drugs clinically used for the treatment of gastroesophageal reflux symptoms. However, the evidence of a superior effectiveness of this combination in comparison with individual drugs is lacking. A double-blind, randomized and comparative clinical trial study was designed to characterize the efficacy and safety of a fixed dose combination of magaldrate (800 mg)/domperidone (10 mg) against domperidone alone (10 mg), in patients with gastroesophageal reflux symptoms. One hundred patients with gastroesophageal reflux diagnosed by Carlsson scale were randomized to receive a chewable tablet of a fixed dose of magaldrate/domperidone combination or domperidone alone four times each day during a month. Magaldrate/domperidone combination showed a superior efficacy to decrease global esophageal (pyrosis, regurgitation, dysphagia, hiccup, gastroparesis, sialorrhea, globus pharyngeus and nausea) and extraesophageal (chronic cough, hoarseness, asthmatiform syndrome, laryngitis, pharyngitis, halitosis and chest pain) reflux symptoms than domperidone alone. In addition, magaldrate/domperidone combination improved in a statistically manner the quality of life of patients with gastroesophageal reflux respect to monotherapy, and more patients perceived the combination as a better treatment. Both treatments were well tolerated. Data suggest that oral magaldrate/domperidone mixture could be a better option in the treatment of gastroesophageal reflux symptoms than only domperidone.

Current developments in pharmacological therapeutics for chronic constipation

Chronic constipation is a common gastrointestinal disease severely affecting the patient's quality of life. The traditional treatment of constipation is the use of laxatives. Recently, several new drugs including lubiprostone, linaclotide and prucalopride have been approved for treatment of chronic constipation. However, a significant unmet medical need still remains, particularly among those patients achieving poor results by current therapies. The 5-HT4 receptor modulators velusetrag and naronapride,the guanylate cyclase C agonist plecanatide and the ileal bile acid transporter inhibitor elobixibat are recognized as the most promising drugs under investigation. Herein, we give a comprehensive review on the pharmacological therapeutics for the treatment of chronic constipation, with the purpose of reflecting the drug development trends in this field.