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Objective: The aim of this study was to investigate and evaluate the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus (T2DM) induced by glucagon-like peptide 1 receptor agonist (GLP-1 RA) hypoglycemic drugs., Materials and Methods: We searched papers in PubMed, Web of Science, Cochrane Library, Google Scholar, CNKI, Wanfang, Embase, and VIP databases, and the retrieval time limit was set from the establishment of the database to May 2023. Randomized Controlled Trials (RCTs) were collected in which the subjects were T2DM patients, the intervention was GLP-1RA compared with placebo or traditional hypoglycemic drugs, and the outcome indicators included dyspepsia and anorexia. A meta-analysis and a network meta-analysis were performed., Results: The results of the traditional meta-analysis showed that the risk of dyspepsia and anorexia of total GLP-1 RA was 3.01 and 2.56 times that of placebo, respectively. All types of GLP-1RA were compared with placebo and the results also showed a trend towards increased risk of digestive system adverse events (DSAEs). Among all interventions included, liraglutide was the one with the highest risk of dyspepsia in patients with T2DM, and dulaglutide was the one with the highest risk of anorexia., Conclusions: The results of the two meta-analyses are consistent, and both clearly show that GLP-1RA can increase the risk of dyspepsia and anorexia in T2DM patients.

Context: Rebound acid hypersecretion after cessation of proton pump inhibitors (PPIs) can provoke dyspeptic symptoms. The search for alternatives to minimize the dyspeptic rebound symptoms after PPI discontinuation is warranted. Spirulina platensis, a dietary supplement made from blue-green algae, might be an alternative., Objective: The study intended to assess whether Spirulina platensis, through its anti-inflammatory and analgesic properties, can minimize rebound symptoms after PPI withdrawal., Design: The research team performed a randomized, phase 2, double-blinded, placebo-controlled clinical trial., Setting: The study took place at São Vicente de Paulo Hospital (trial registry number NCT04988347) in Passo Fundo, Brazil., Participants: Participants were 45 Brazilian patients in the clinical practice of two of the research team's member between November 2010 and February 2012, who were using PPIs regularly., Interventions: Participants underwent clinical and endoscopic evaluations after a 28-day run-in phase of 40 mg/day of pantoprazole. In the absence of a large hiatal hernia, peptic ulcer, or severe reflux esophagitis, participants stopped using PPIs, and the research team randomly assigned them to receive either 1.6g/day of spirulina or of a placebo for two months, followed by clinical and endoscopic reevaluations., Outcome Measures: Using an intention-to-treat analysis, the primary outcomes postintervention were dyspepsia and typical reflux symptoms, either the appearance or maintenance of symptoms of >50% from baseline., Results: The median time of continuous PPI use was 32 months. The research team excluded two participants due to large hiatal hernias. Among the remaining 43 participants, 18 received spirulina (42%), and 25 used a placebo (58%). Two months later, 12 participants who had received spirulina (67%) and 18 who had received the placebo (72%) completed the study (P = .968). Rebound dyspepsia occurred in 10 out of 18 patients treated with spirulina (55.56%) and in 22 out of 25 patients treated with placebo (88%), with relative risk=0.63, CI95% (0.41-0.98), and P = .039. Reflux symptoms postintervention occurred in 72% and 76%, with the relative risk=0.95, CI95% (0.66-1.36), and P > .05, respectively. No significant side effects occurred in either group. The findings from endoscopy and gastric histology didn't differ between groups., Conclusions: A two-month course of Spirulina platensis was able to attenuate rebound dyspepsia but not reflux symptoms after PPI discontinuation. Considering its good safety profile, spirulina might be useful to relieve dyspeptic symptoms after PPI discontinuation.

Background: Assessing the potential effects of a low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) diet on functional gastrointestinal symptoms, particularly upper gastrointestinal symptoms, is not clearly understood. The current study aimed to explore the association of a diet low in FODMAPs with uninvestigated chronic dyspepsia (UCD) and functional dyspeptic symptoms in a large population of Iranian adults., Methods: This cross-sectional study was conducted on 2987 adults. Dietary FODMAPs intake estimated using a validated food-frequency questionnaire. UCD, early satiation, postprandial fullness and gastric pain were determined using a modified and validated version of the Rome III Questionnaire., Results: After controlling for various confounders, consumption of a diet low in FODMAPs was associated with increased risk of UCD in the whole population (OR=1.85; 95% CI: 1.23-2.78; P=0.009) and women (OR=2.41; 95% CI: 1.46-3.95; P=0.004), but not in men. Higher consumption of a low-FODMAPs diet was related to increased risk of postprandial fullness (OR=1.38; 95% CI: 1.08-1.78; P=0.046). The inverse association between FODMAPs and epigastric pain tended to be significant after controlling for eating behaviors (OR=1.31; 95% CI: 0.98-1.76; P=0.084). No significant association was observed for early satiation., Conclusions: Our data suggest that consumption of a low-FODMAPs diet may increase the risk of UCD and postprandial fullness; however, well-planned randomized controlled trials and prospective cohorts are required to ascertain the effect of FODMAPs on upper gastrointestinal symptoms.

Background and Objectives : Dyspepsia is a common adverse event associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with lumbar spinal stenosis. Although proton pump and cyclooxygenase-2 inhibitors are potential treatment options, the optimal strategy remains unclear. This study aimed to compare the efficacy and safety of combination therapy with aceclofenac and ilaprazole versus celecoxib monotherapy for the treatment of dyspepsia caused by NSAID use in patients with lumbar spinal stenosis. Materials and Methods : This prospective, double-blind, randomized, actively controlled study was conducted at Seoul National University Bundang Hospital in South Korea from July 2020 to September 2021. The participants were randomized into one of two treatment groups: celecoxib monotherapy (control group) and combination therapy with aceclofenac and ilaprazole (test group). The primary efficacy endpoint was the mean change in the Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ) scores from baseline to treatment week 8. The secondary efficacy endpoint was the mean change in Short-Form-12 (SF-12) scores from baseline (week 0) to treatment week 8. Results : The study enrolled 140 patients who were randomly assigned to receive combination therapy with aceclofenac and, ilaprazole or celecoxib. In the per protocol set, the mean change in SF-LDQ scores from week 0 to week 8 was -0.51 ± 4.78 and 1.85 ± 6.70 in the combination therapy and celecoxib group, respectively ( p = 0.054). SF-12 scores did not differ significantly between the two groups. Adverse events were reported in both groups, but there was no significant difference in incidence. Conclusions : Combination therapy with aceclofenac and ilaprazole can be a treatment option for NSAID-induced dyspepsia in some situations.

Objectives: To examine the potential therapeutic effects of ursodeoxycholic acid (UDCA) on diseases of the esophagus, stomach, and duodenum., Methods: A search was conducted using EBSCO, Medline, PubMed, Google Scholar and Web of Science as well as international guidelines using MESH terms for treatment of UDCA for diseases of the upper gastrointestinal disorders in adult humans without regard to publication language or date restrictions., Results: A total of 256 articles and 22 guidelines were initially identified, and 221 were excluded. Final revision of 13 articles and 22 guidelines confirmed that UDCA is found to have a cytoprotective role in Barret's esophagus within esophageal disorders, improves abdominal pain in functional dyspepsia, and does not alter Helicobacter pylori colonization or inflammation. Conflicting results are noted regarding the role of UDCA in the duodenum as chemopreventive treatment for familial adenomatous polyposis, with polyps regressing and their growth characteristics improving with low doses (10-25 mg/kg/day). On the contrary, no positive effect was noted upon the combination with Celecoxib and with doses of 1000-2000 mg or 20-30 mg/kg/d. Gastrointestinal side effects were predominantly reported. No side effects necessitated hospitalization or ICU admission., Conclusion: Ursodeoxycholic acid has a limited therapeutic role in functional dyspepsia. There is promising evidence that it may serve as a chemopreventive for Familial adenomatous polyposis and Barret's esophagus, although further research is needed to confirm these findings. PROSPERO No.: CRD 42021267689 ., (Copyright: © Saudi Medical Journal.)

Background and Study Aim: The study was designed to detect novel Adverse Events (AEs) of pantoprazole by disproportionality analysis in the FDA (Food and Drug Administration) database of Adverse Event Reporting System (FAERS) using Data Mining Algorithms (DMAs). Pantoprazole, the most commonly over-utilized Over The Counter (OTC) medication, was selected to assess any short-term or long-term AEs. The study aimed to analyze the novel adverse events of pantoprazole using the FAERS database., Materials and Methods: A retrospective case/non-case disproportionality analysis was performed in the FAERS database. This study was based on AEs reported to FAERS from 2006Q1-2021Q3. Openvigil 2.1 was used for data extraction. Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), and Information Component (IC) were applied to measure the disproportionality in reporting. A value of ROR-1.96SE > 1, PRR ≥ 2, and IC-2SD > 0 were considered as the threshold for a positive signal., Results: A total of 1050 reports of dyspepsia, 7248 reports of hypocalcemia and 995 reports of hyponatremia were identified. A potential positive signal for dyspepsia (ROR-1.96SE = 2.231, PRR = 2.359, IC-2SD = 1.13), hypocalcemia (4.961, 5.45, 2.23) and hyponatremia (3.948, 4.179, 1.92) were identified for pantoprazole., Conclusion: Data mining in the FAERS database produced three potential signals associated with pantoprazole. As a result, further clinical surveillance is needed to quantify and validate potential hazards associated with pantoprazole-related adverse events., Competing Interests: Declaration of competinginterests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Emerging evidence suggests that a high-fat diet (HFD) can influence endoplasmic reticulum (ER) stress and gut microbiota. Crataegi Fructus is a traditional Chinese herb widely used in formulas for dyspepsia, with Dashanzha Pill composed of raw Crataegi Fructus (DR) being a representative drug. Processing products of Crataegi Fructus, however, have a stronger pro-digestive effect, and we hypothesized that Dashanzha Pill composed of charred Crataegi Fructus (DC) is more effective. We found that the contents of glucose 1-phosphate and luteolin in DR and DC were substantially different via ultra-high performance liquid chromatography-hybrid quadrupole-Orbitrap high-resolution mass spectrometry. DC outperformed DR in improving histopathological changes, increasing gastrin and motilin, and decreasing vasoactive intestinal peptides in rats with HFD induced dyspepsia. Fecal microbiota analysis revealed that DC could restore the disturbed intestinal microbiota composition, including that of Bacteroides, Akkermansia, and Intestinimonas to normal levels. Furthermore, DC significantly reduced the mRNA and protein levels of glucose-regulated protein 78, protein kinase R-like ER kinase, and eukaryotic initiation factor 2α. Taken together, DC outperformed DR in relieving dyspepsia by regulating gut microbiota and alleviating ER stress., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

This study assessed the effects of glucose-fructose co-ingestion during recovery from high-intensity rugby training on subsequent performance. Nine professional, senior academy Rugby Union players performed two trials in a double-blind, randomized, crossover design. Identical rugby training sessions were separated by a 3-hour recovery period, during which participants ingested protein (0.3 g×kg BM×h -1 ) and carbohydrate-containing (0.8 g×kg BM×h -1 ) recovery drinks, comprised of glucose polymers (GLUCOSE ONLY) or a glucose-fructose mixture (GLUCOSE+FRUCTOSE). Performance outcomes were determined from global positioning systems combined with accelerometry and heart rate monitoring. Mean speed during sessions 1 (am) and 2 (pm) of GLUCOSE ONLY was (mean±SD) 118±6 and 117±4 m×min -1 , respectively. During GLUCOSE+FRUCTOSE, mean speed during session 1 and 2 was 117±4 and 116±5 m×min -1 , respectively (time x trial interaction,  p  = 0.61). Blood lactate concentrations were higher throughout recovery in GLUCOSE+FRUCTOSE (mean ±SD: 1-h 3.2 ±2.0 mmol×L -1 ; 3-h 2.1 ±1.2 mmol×L -1 ) compared to GLUCOSE ONLY (1-h 2.0 ±1.0 mmol×L -1 ; 3-h 1.4 ±1.0 mmol×L -1 ; trial effect  p  = 0.05). Gastrointestinal discomfort low in both conditions. These data suggest glucose-fructose mixtures consumed as protein-carbohydrate recovery drinks following rugby training do not enhance subsequent performance compared to glucose-based recovery drinks.

Background: In recent years, the prevalence of proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD) has been increasing, posing a clinical obstacle to improving the management of GERD patients. The ability of known predictive factors to explain therapeutic response to PPI remains insufficient. Therefore, we examined whether the addition of early therapeutic response to PPI as an explanatory variable may increase the predictive power for PPI-refractory GERD., Methods: The severity and therapeutic response of GERD symptoms to PPI were evaluated using the GastroEsophageal Reflux and Dyspepsia Therapeutic Efficacy and Satisfaction Test (GERD-TEST) questionnaire at baseline and at 2 and 4 weeks after treatment. The relevance of the therapeutic effect of PPI at 2 weeks compared to that at 4 weeks was examined in 301 patients with GERD. Independent predictive factors for refractory GERD at 4 weeks of PPI therapy were examined in 182 patients. The effect of various clinical factors, including the early response to PPI, was assessed using multiple regression analysis., Results: The number of PPI-therapy responders increased significantly with the duration of treatment (p < 0.0001). The response to PPI therapy at 2 weeks was significantly correlated with that at 4 weeks (p < 0.0001). Multiple regression analysis revealed that the therapeutic response to PPI at 2 weeks was by far the strongest predictor of the therapeutic effect at 4 weeks among all clinical factors., Conclusions: Medication change for PPI-refractory GERD at 2 weeks may be an efficacious therapeutic strategy to improve patients' quality of life.

Introduction: Paeoniflorin is a main active component in traditional Chinese medicine. Paeoniae alba radix is widely used as a spasmolytic and pain-relieving agent for abdominal spasmodic pain. Functional dyspepsia (FD) is characterized by pain or burning in the epigastrium, fullness, bloating and nausea. However, limited information is available about the effect of paeoniflorin on FD., Materials and Methods: In this study, iodoacetamide or clonidine-induced FD rat models were established to investigate the impacts of paeoniflorin on FD induced by different pathophysiologic disturbances., Results: We found the therapeutic effect of paeoniflorin through assessing the gastric emptying, gastric accommodation and visceral hypersensitivity. This function of paeoniflorin was related to the release of acetylcholine (ACh), which was accompanied by reduced acetylcholinesterase (AchE) activity in stomach and hypothalamus. Paeoniflorin administration inhibited the cyclo-oxygenase-2 (COX-2) expression and increased the level of ghrelin in the stomach. Besides, the levels of occludin and ZO-1 were elevated in the duodenum from paeoniflorin-treated rats, suggesting the impaired duodenal barrier was ameliorated., Discussion: These results indicate that paeoniflorin possesses the ability to alleviate functional dyspepsia., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Zou et al.)

Since July 2017, different generic imatinib formulations have been introduced in Italy for the treatment of patients with chronic myeloid leukemia (CML). We analyzed 168 chronic phase CML patients treated with branded imatinib for a median of 12 years (range 1-16) at a single institution who switched to a single generic formulation in order to assess the safety and impact on molecular response. The Sokal risk was low/intermediate/high in 63%, 33%, and 4% of patients, respectively. The median duration of generic imatinib treatment was 19 months (range 4-22). Twenty-seven percent of patients were in MMR and 73% were in deep molecular responses (MR4-4.5) at the time of the switch. After 12 months of treatment with generic imatinib, 140 patients were evaluable for response: 23.6% and 76.4% were respectively in MMR and in deep molecular response. When the degree of response was compared with the best molecular response observed with branded imatinib, it was found that 84% of patients maintained the response previously achieved, 6% improved it, and 10% of patients had a molecular fluctuation from the previous deep molecular response to MMR. Only 1 patient lost the MMR and no patient switched to another TKI for inefficacy. In terms of safety, 20% of patients reported new or worsening side effects, but only 2 patients returned to branded imatinib for toxicity. Our data show that the switch to generic imatinib in patients who have been previously treated with branded imatinib appears to maintain efficacy, although a proportion of patients experience new or worsening side effects.

Objective: Electroacupuncture (EA) is effective in treating visceral pain associated with functional dyspepsia (FD). The aim of this study was to explore the effect of chronic EA (CEA) on gastric hypersensitivity and the involvement of sympathetic nervous system in a rodent model of FD., Materials and Methods: Gastric hypersensitivity in adulthood was induced by iodoacetamide (IA) in neonatal rats. The IA-treated rats were randomized to receive no treatment (control), sham-CEA, CEA, or adrenergic antagonists, for one week. Gastric sensitivity to graded gastric distensions was then assessed by electromyogram (EMG) analysis. Autonomic functions were assessed from the spectral analysis of heart rate variability (HRV) to derive the low-frequency (LF, sympathetic activity) and high-frequency (HF, mainly vagal activity) components expressed as percentage of total spectral power. Blood was collected for the measurement of corticosterone (CORT) and norepinephrine (NE)., Results: 1) CEA, but not sham-CEA, reduced the EMG response to graded gastric distension in IA-treated control rats at 40 mmHg (128 ± 6% vs. 171 ± 15%, p = 0.009), 60 mmHg (204 ± 14% vs. 271 ± 24%, p = 0.010) and 80 mmHg (269 ± 19% vs. 364 ± 33%, p = 0.025), respectively. 2) CEA, but not sham CEA, increased HF component (0.61 ± 0.02 vs. 0.46 ± 0.04 in IA-treated rats, p = 0.003) and decreased LF component (0.39 ± 0.02 vs. 0.54 ± 0.04, p = 0.003). 3) Adrenergic antagonists reduced the EMG response to graded gastric distension. 4) CEA significantly reduced plasma CORT and NE in IA-treated rats., Conclusions: EA ameliorates gastric hypersensitivity in IA-treated rats and the effect may be related to the improved sympathovagal balance and the decrease of stress hormones., (© 2020 International Neuromodulation Society.)

Background: Cisplatin is a widely used antineoplastic drug. However, cisplatin-induced dyspepsia syndromes, including delayed gastric emptying, gastric distension, early satiety, nausea, and vomiting, often force patients to take doses lower than those prescribed or even refuse treatment. D-methionine has an appetite-enhancing effect and alleviates weight loss during cisplatin treatment., Methods: This work established a model of anorexia and dyspepsia symptoms with intraperitoneal injection of cisplatin (5 mg/kg) once a week for three cycles. Presupplementation with or without D-methionine (300 mg/kg) was performed. Orexigenic and anorexigenic hormones (ghrelin, leptin, and glucagon-like peptide-1), tryptophan hydroxylase 1 (TPH1), 5-hydroxytryptamine receptors (5-HT 2C and 5-HT 3 ), and hypothalamic feeding-related peptides were measured by immunohistochemistry staining, enzyme-linked immunosorbent assay, and real-time PCR assay., Key Results: Cisplatin administration caused marked decrease in appetite and body weight, promoted adipose and fat tissue atrophy, and delayed gastric emptying and gastric distension, and D-methionine preadministration prior to cisplatin administration significantly ameliorated these side effects. Besides, cisplatin induced an evident increase in serum ghrelin level, TPH1 activity, and 5-HT 3 receptor expression in the intestine and decreased plasma leptin levels and gastric ghrelin mRNA gene expression levels. D-methionine supplementation recovered these changes. The expression of orexigenic neuropeptide Y/agouti-related peptide and anorexigenic cocaine- and amphetamine-regulated transcript proopiomelanocortin neurons were altered by D-methionine supplementation in cisplatin-induced anorexia rats., Conclusions and Inferences: D-methionine supplementation prevents cisplatin-induced anorexia and dyspepsia syndrome possibly by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration. Therefore, D-methionine can be used as an adjuvant therapy for treating cisplatin-induced adverse effects., (© 2020 John Wiley & Sons Ltd.)

Introduction: Dyspepsia accounts for a significant burden of worldwide disease, but there is a relative paucity of data from the sub-Saharan African setting. We undertook to describe the burden, risk factors and severity of dyspepsia across Rwanda., Methods: We performed a population-based clustered cross-sectional survey between November 2015 and January 2016, nationwide in Rwanda, using the Short Form Leeds Dyspepsia Questionnaire to describe the presence and severity of dyspepsia, and the Short Form Nepean Dyspepsia Index to describe the concomitant quality of life effects. Univariate and multivariate logistic regression models were constructed to correlate measured sociodemographic factors with dyspepsia., Results: The prevalence of clinically significant dyspepsia in the general Rwandan population was 14.2% (283/2000). The univariate factors that significantly predicted severity were gender, profession, socioeconomic status, and non-steroidal anti-inflammatory drug, aspirin and alcohol use, with gender, current smoking, aspirin use both in the past and currently, and alcohol use in the past remaining significant on multivariate modelling. Dyspeptics had a significantly lower gastrointestinal-related quality of life, though the sociodemographic factors measured did not modify the observed quality of life., Conclusion: Dyspepsia is prevalent in the Rwandan setting and is associated with a significant burden on quality of life. More work is required to determine the pathological entities involved, and the optimal approach to mitigating this burden., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aim: Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major cause of gastric mucosal lesions. In China, teprenone is frequently prescribed as a mucoprotective agent, but the literature regarding their efficacy is limited. Our purpose was to address the effects of teprenone on long-term NSAID-associated gastric mucosal lesions., Methods: This study examined 369 patients taking NSAIDs for at least 12 weeks. Patients without gastroduodenal ulcer and without Helicobacter pylori infection on endoscopy at baseline were randomized to receive either NSAID plus teprenone (150 mg/day) or NSAID only for 12 weeks. Lanza scores were examined using endoscopy before and after treatment, and dyspeptic symptom scores are also analyzed., Results: A total of 158 patients were randomized to the teprenone group (n = 74) or the control group (n = 84) for 12 weeks. Seventy-one of patients in the teprenone group and 79 of patients in the control group were analyzed finally. After treatment, the Lanza scores and dyspeptic symptom scores decreased significantly in the teprenone group while increased in the control group (P < 0.05). The changes of Lanza scores and dyspeptic symptom scores were higher in the teprenone group than in the control group (P < 0.05). For subgroup analysis, the change in Lanza scores and dyspeptic symptom scores improved significantly in the teprenone group receiving long-term low-dose aspirin treatment, as well as in the teprenone group receiving other NSAIDs treatment (P < 0.05)., Conclusions: Teprenone may be an effective treatment choice of gastric mucosal injuries and dyspepsia symptoms in patients who used NSAIDs chronically without H. pylori infection or history of gastroduodenal ulcer., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Ethnopharmacological Relevance: Banha-sasim-tang (BST; Hange-shashin-to in Kampo medicine; Banxia xiexin tang in traditional Chinese medicine) is a traditional Chinese harbal medicine that has been commonly used for gastrointestinal disorders., Aim of the Study: To investigate the pharmacological effects of BST, a standardized herbal drug, on main symptoms of functional dyspepsia including delayed gastric emptying, and underlying mechanisms of action in mouse model., Methods and Materials: Balb/C mice were pretreated with BST (25, 50, 100 mg/kg, po) or mosapride (3 mg/kg, po) for 3 days, and then treated with loperamide (10 mg/kg, ip) after 19 h fasting. A solution of 0.05% phenol red (500 μL) or 5% charcoal diet (200 μL) was orally administered, followed by scarifying and assessment of gastric emptying or gastro-intestinal motility. C-kit (immunofluorescence), nNOS (western blot) and gastric contraction-related gene expression were examined in stomach tissue., Results: The loperamide injection substantially delayed gastric emptying, while the BST pretreatment significantly attenuated this peristaltic dysfunction, as evidenced by the quantity of stomach-retained phenol red (p < 0.05 or 0.01) and stomach weight (p < 0.05 or 0.01). The BST pretreatment significantly tempered the loperamide-induced inactivation of c-kit and nNOS (p < 0.05 or 0.01) as well as the contraction-related gene expression, such as the 5HT 4 receptor (5HT 4 R), anoctamin-1 (ANO1), ryanodine receptor 3 (RYR3) and smooth muscle myosin light chain kinase (smMLCK). The BST pretreatment also significantly attenuated the alterations in gastro-intestinal motility (p < 0.01)., Conclusion: Our results are the first evidence of the prokinetic agent effects of Banha-sasim-tang in a loperamide-induced FD animal model. The underlying mechanisms of action may involve the modulation of peristalsis via activation of the interstitial cells of Cajal and the smooth muscle cells in the stomach., (Copyright © 2019. Published by Elsevier B.V.)

Background: Irritable bowel syndrome (IBS) is a highly prevalent condition. It is diagnosed on the basis of chronic symptoms after the clinical and/or investigative exclusion of organic diseases that can cause similar symptoms. There is no reproducible non-invasive test for the diagnosis of IBS, and this raises diagnostic uncertainty among physicians and hinders acceptance of the diagnosis by patients. Functional gastrointestinal (GI) syndromes often present with overlapping upper and lower GI tract symptoms, now believed to be generated by visceral hypersensitivity. This study examines the possibility that, in IBS, a nutrient drink test (NDT) provokes GI symptoms that allow a positive differentiation of these patients from healthy subjects., Aim: To evaluate the NDT for the diagnosis of IBS., Methods: This prospective case-control study compared the effect of two different nutrient drinks on GI symptoms in 10 IBS patients (patients) and 10 healthy controls (controls). The 500 kcal high nutrient drink and the low nutrient 250 kcal drink were given in randomized order on separate days. Symptoms were assessed just before and at several time points after drink ingestion. Global dyspepsia and abdominal scores were derived from individual symptom data recorded by two questionnaires designed by our group, the upper and the general GI symptom questionnaires, respectively. Psycho-social morbidity and quality of life were also formally assessed. The scores of patients and controls were compared using single factor analysis of variance test., Results: At baseline, IBS patients compared to controls had significantly higher levels of GI symptoms such as gastro-esophageal reflux ( P = 0.05), abdominal pain ( P = 0.001), dyspepsia ( P = 0.001), diarrhea ( P = 0.001), and constipation ( P = 0.001) as well as higher psycho-social morbidity and lower quality of life. The very low incidence of GI symptoms reported by control subjects did not differ significantly for the two test drinks. Compared with the low nutrient drink, IBS patients with the high nutrient drink had significantly more dyspeptic symptoms at 30 ( P = 0.014), 45 ( P = 0.002), 60 ( P = 0.001), and 120 min ( P = 0.011). Dyspeptic symptoms triggered by the high nutrient drink during the first 120 min gave the best differentiation between healthy controls and patients (area under receiver operating curve of 0.915 at 45 min for the dyspepsia score). Continued symptom monitoring for 24 h did not enhance separation of patients from controls., Conclusion: A high NDT merits further evaluation as a diagnostic tool for IBS., Competing Interests: Conflict-of-interest statement: None of the authors have conflicts of interest to be declared.

Background: Chemotherapy-associated dyspepsia syndrome (CADS) is among the most intensive side effects and critical concerns for patients with cancer. To investigate the effects and mechanisms of chronic electroacupuncture (EA) at ST36 on chemotherapy-associated dyspeptic symptoms (CADS) in rats., Methods: Cisplatin (8 mg/kg, ip) was given once to establish CADS model. EA or sham-EA treatment was then performed one hour daily for 21 days., Key Results: (a) EA treatment decreased kaolin intake within 24 hours (1.67 ± 0.23 g vs 2.36 ± 0.37 g in sham-EA, P < 0.05); EA increased food intake (9.43 ± 2.28 vs 4.32 ± 1.26 in sham-EA, P < 0.05) and cisplatin-induced reduction of body weight (426.38 ± 13.25 vs 407.92 ± 13.26 in sham-EA, P = 0.05). (b) The incidence of normal behavioral satiety sequence (53%) in EA group was greater than that in sham-EA (32%) group (X 2  = 17.68, P < 0.01). (c) EA increased the percentage of normal gastric slow waves (82.6 ± 5.98 vs 22.8 ± 1.90 in sham-EA, P < 0.05). (d) EA normalized cisplatin delayed gastric emptying (71.3% ± 6.8% vs 44.6% ± 11.2% in control, P < 0.05). (e) EA decreased ratio of heart rate variability (0.30 ± 0.03 vs 0.56 ± 0.05 in sham-EA, P < 0.05). (f) EA decreased fasting ghrelin, glucagon-like peptide-1 and peptide YY (P < 0.01 vs sham-EA for all)., Conclusions and Inferences: Chronic EA ameliorates dyspepsia symptom and improves gastric dysmotility induced by Cisplatin, mediated via the vagal and gastrointestinal hormonal mechanisms., (© 2018 John Wiley & Sons Ltd.)

Background: High-fat meals are associated with dyspeptic symptoms in functional dyspepsia (FD) patients. It is still unclear how fat is processed, or how FD symptoms and neuronal activities are modulated by psychological factors., Objective: We investigated brain activity by functional magnetic resonance imaging (fMRI) after the ingestion of high- and low-fat foods with correct/incorrect fat information., Design: We compared 12 FD patients and 14 healthy controls (HCs). We recorded resting-state fMRI on four different days before and after ingestion of four yogurts (200 mL, 10% or 0.1% fat, "low fat" or "high fat" label)., Results: FD patients showed more pronounced dyspeptic symptoms than did HCs, and symptoms were relieved less after consuming high fat-labeled yogurt than low fat-labeled yogurt, irrespective of the actual fat content. This is indicative of either a placebo effect of low-fat information or a nocebo effect of high-fat information on symptom expression. FD patients showed greater activity than did HCs in occipital areas before and after ingestion regardless of fat content and label, as well as greater activity in the middle frontal gyrus before ingestion. In addition, functional connectivity (FC) from the insula to the occipital cortex (I-O) increased after high fat ingestion and decreased after low fat ingestion in FD patients. FC from the insula to the precuneus (I-P) was higher in FD patients than in HCs after ingestion of low fat-labeled yogurt. In FD patients, I-O FC negatively correlated with nausea and I-P FC with FD symptom intensity, food craving, and depression., Conclusions: Our results endorse the importance of psychological perception of food on the incidence of dyspeptic symptoms and on the altered brain activities. These findings show the importance of cognitive components in perceptions of fat, food craving, depression, and brain functions in pathophysiologic mechanisms of FD. This trial was registered at clinicaltrials.gov as NCT02618070.

Adverse drug reactions (ADRs) are very common with anticancer drugs. The objectives of the survey are to evaluate ADRs of AC (Adriamycin (Doxorubicin) and Cyclophosphamide) combination therapy with special reference to GIT (Gastrointestinal system). It was a prospective, descriptive, observational study which included 90 female patients receiving AC combination therapy for their treatment through a purposive sampling and from 01-01-2016 to 31-12-2016 at Cancer Hospital Jamshoro Pakistan. Patients were interviewed during follow up session with a consultant, their response was recorded in a questionnaire and verified through British National formulary (BNF), Hartwig & Siegel scale (ADR severity assessment scale). The survey results shows that AC anticancer combination therapy can result in various disturbances in gastrointestinal tract among which nausea, vomiting decreased appetite and hyperacidity were most common. These must be taken into account and managed with supportive treatment in order to maintain better quality of life during the cancer treatment.

Objective: To evaluate regular non-steroidal anti-inflammatory drug (NSAID) users for dyspepsia, as well as to assess the effect of preventive measures, and the reasons for non-adherence to gastroprotective agents (GPA) from a real-world perspective., Methods: A prospective longitudinal study was conducted among outpatients with regular NSAID usage. The presence of dyspepsia was assessed by locally validated versions of the Leeds dyspepsia questionnaire (LDQ), GPA and the participants' adherence to the drugs were assessed at recruitment and 2 weeks later. GPA was defined as the use of antisecretory medications or cyclooxygenase-2 inhibitors., Results: Initially, 409 participants (mean age 52.3 ± 14.6 years, 60.6% females, 48.4% treated for musculoskeletal pain) were recruited. At recruitment, 50.9% of the participants had at least one upper gastrointestinal symptom. Complete data for follow-up analysis were collected from 158 participants who were naive NSAID users, had no prior gastrointestinal medication and who could be contacted. At 2-week follow-up there was no significant difference in the LDQ score change between NSAID users treated with GPA and those did not. However, there was a greater reduction in abdominal pain/discomfort (8.8% vs 5.0%, P < 0.001) and burping (8.8% vs 4.0%, P < 0.001) among participants using GPA compared with those who were not. Adherence to GPA was poor, with study participants citing the absence of gastrointestinal symptoms as their main reason for non-adherence., Conclusions: The use of GPA in patients on regular NSAIDs does not improve their overall dyspepsia, but it reduces abdominal pain and burping. Poor adherence to GPA may be a contributing factor., (© 2018 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Stress is considered an independent factor causing and aggravating gastrointestinal symptoms, including visceral pain. The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on stress-induced gastric hypersensitivity in rats treated with neonatal iodoacetamide mimicking human functional dyspepsia (FD)., Methods: Neonatal rats were treated with gavage of 0.2 mL of 0.1% iodoacetamide in 2% sucrose daily for six days starting on tenth day after birth. The control group was given 0.2 mL of 2% sucrose. When the rats were eight weeks old, acute restraint stress was performed on them for 90 min. EA at ST36 (ZuSanLi) was performed during the acute stress or 30 min after the stress. Adrenoceptor blocking drugs (propranolol and phentolamine) were injected intraperitoneally 30 min before acute restraint stress to explore possible sympathetic mechanisms. Visceral-motor responses to gastric distention were assessed by electromyogram (EMG)., Results: 1) Stress-induced gastric hypersensitivity was significantly more severe in the FD rats, compared to the control rats. It was blocked by the adrenoceptor antagonists. 2) EA inhibited stress-induced gastric hypersensitivity; the preventive effect of EA (given during stress) was more remarkable than the curative effect (given after stress). Stress resulted in a higher sympathovagal ratio and this was suppressed by EA., Conclusions: Rats treated with neonatal iodoacetamide mimicking FD are more vulnerable to stress. Stress-induced gastric hypersensitivity can be prevented or suppressed by EA at ST36 via the restoration of sympathovagal balance., (© 2017 International Neuromodulation Society.)

Background: Persistence to treatment affects clinical outcomes in patients with chronic disease such as atrial fibrillation (AF)., Methods: This prospective cohort study included consecutive non-valvular AF patients prescribed with non-vitamin K oral anticoagulants (NOACs) and investigated for any permanent discontinuation at 1-year of this therapy, as well as any reasons for discontinuation., Results: Overall, 1305 patients were prescribed with dabigatran (N=473), rivaroxaban (N=425) or apixaban (N=407). Of these, 201 patients (15.4%) discontinued NOACs during the first year of treatment. More than 60% of these discontinuations occurred during the first 6months. Reasons for discontinuation included: dyspepsia or abdominal pain in 38 patients (2.9%) and bleeding in 59 (4.5%). Discontinuation for the former occurred earlier (50% within 2months) compared to the latter (66% after the first 4months). The prescription of reduced NOAC doses resulted being an independent predictor of discontinuation (OR 1.74, 95% CI 1.23-2.45, p=0.002). Regarding the use of dabigatran, rivaroxaban and apixaban, the following were observed: discontinuers were 22.0% (95% CI 18.5-25.9), 14.4% (95% CI 11.3-18.0) and 8.8% (95% CI 6.5-12.0), the risk of discontinuation associated with bleeding was 20.2%, 44.3% and 30.6% and dyspepsia or abdominal pain was 35.6%, 1.6% and 0%, respectively., Conclusion: Discontinuation of NOACs in AF patients was relatively common and more than often occurred in the first six months after prescription. Patients treated with reduced doses of NOACs had a higher probability to discontinue compared to those who were prescribed conventional doses., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Early initiation of combination therapy using antihyperglycemic agents is recommended for treating type 2 diabetes (T2D). The present multicenter double-blind randomized parallel-group study examined the efficacy and safety of a sitagliptin and metformin fixed-dose combination (Sita/Met) compared with glimepiride in T2D patients as initial treatment., Methods: Type 2 diabetes patients (aged ≥18 years) were randomized to Sita/Met or glimepiride for 30 weeks after a wash-off run-in period. The primary endpoint was change from baseline (CFB) in HbA1c. Secondary endpoints included the proportion of patients achieving target goal (HbA1c < 7.0 % [53 mmol/mol]) and CFB in fasting plasma glucose (FPG). Safety assessments comprised weight gain from baseline and the incidence of adverse events (AEs)., Results: In total, 292 patients were randomized to Sita/Met (n = 147) or glimepiride (n = 145). After 30 weeks, Sita/Met demonstrated superiority over glimepiride in reducing HbA1c (-1.49 % vs -0.71 %, respectively; between-group difference - 0.78 %; P < 0.001). A significantly higher proportion of patients achieved the target goal with Sita/Met (81.2 %) than with glimepiride (40.1 %; P < 0.001). Greater reduction in FPG occurred with Sita/Met than with glimepiride (least-squares mean difference - 23.5 mg/dL; P < 0.001). Both drugs were generally well tolerated. Hypoglycemia events and weight gain were significantly lower in patients with Sita/Met than with glimepiride (5.5 % vs 20.1 % and -0.83 vs +0.90 kg, respectively; both P < 0.001). No serious drug-related AEs or deaths were reported., Conclusions: Compared with glimepiride, Sita/Met as an initial treatment led to significantly greater improvements in glycemic control and body weight changes, with a lower incidence of hypoglycemia, over 30 weeks., (© 2016 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.)

Constipation and dyspepsia are disturbing gastrointestinal symptoms that are often ignored in research on physical comorbidities of schizophrenia. The aim was to assess dyspepsia and constipation in a sample of outpatients with schizophrenia spectrum psychoses. A general practitioner performed a thorough physical health check for 275 outpatients and diagnosed constipation and dyspepsia. This study assessed the possible contribution of several sociodemographic, lifestyle, and clinical variables to constipation and dyspepsia using logistic regression analysis. This study also assessed whether these symptoms were associated with abnormal laboratory findings. The prevalence of constipation was 31.3%, and of dyspepsia 23.6%. Paracetamol (OR =3.07, 95% CI =1.34-7.02) and clozapine use (OR =5.48, 95% CI =2.75-10.90), older age (OR =1.04, 95% CI =1.01-1.06), and living in sheltered housing (OR =2.49, 95% CI =1.16-5.33) were risk factors for constipation. For dyspepsia the risk factors were female sex (OR =2.10, 95% CI =1.15-3.83), non-steroidal anti-inflammatory drugs (OR =2.47, 95% CI =1.13-5.39), and diabetes medication (OR =2.42, 95% CI =1.12-5.25). Patients with dyspepsia had lower haemoglobin and haematocrit and higher glucose values than those without dyspepsia. Patients with constipation had lower thrombocyte values than patients without constipation. However, these findings were explained by factors pre-disposing to constipation and dyspepsia. Clozapine use markedly increases the risk of constipation and may lead to life-threatening complications. In addition, analgesics and diabetes medication were related to gastrointestinal symptoms. These medications and their association to gastrointestinal symptoms should be kept in mind when treating patients with schizophrenia.

Venous thromboembolism (VTE) incidence is increasing among children owing to many factors, including improved diagnosis of VTE. There is a need for alternative treatment options. Our objective was to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran etexilate in adolescents with VTE. Adolescents aged 12 to <18 years (n = 9) who successfully completed planned treatment for primary VTE were administered dabigatran etexilate twice daily for three days; initially 1.71 (± 10 %) mg/kg (80 % of a 150 mg/70 kg twice daily adult dose), followed by 2.14 (± 10 %) mg/kg (target adult dose adjusted for patient's weight), if there were no safety concerns. No bleeding events, deaths or drug-related serious adverse events (AEs) were reported; three treatment-emergent AEs, all gastrointestinal-related, occurred in two patients. In these adolescent patients with normal renal function, presumed steady-state trough plasma concentrations of dabigatran were low (geometric mean dose-normalised total dabigatran plasma concentration: 0.493 ng/ml/mg at 72 hours). Total dabigatran concentrations were well predicted by the RE-LY® population PK model (94 % of trough concentrations were within the 80 % prediction interval). The relationship between total dabigatran plasma concentration, diluted thrombin time and ecarin clotting time (ECT) was linear; the relationship with activated partial thromboplastin time (aPTT) was non-linear. Adult population PK/PD models predicted the adolescent concentration-ECT and -aPTT relationships well. In conclusion, dabigatran etexilate was generally well tolerated, except for occurrence of dyspepsia in two patients, over the three-day treatment period. The dabigatran PK/PD relationship observed in adolescent patients was similar to that in adult patients.

Osteoarthritis (OA) is the most common form of arthritis in older individuals and is among the most prevalent and disabling chronic conditions worldwide.We conducted a meta-analysis to determine the efficacy and safety of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor in the treatment of osteoarthritis. Studies were pooled, and mean difference (MD), relative risk (RR), and its corresponding 95% confidence interval (CI) were calculated. Fifteen relevant articles were included for this meta-analysis study.We observed that osteoarthritis total score (MD = -4.41, 95% CI -7.27 to -1.55), pain subscale score (MD = -0.86, 95% CI -1.10 to -0.62), and function subscale score (MD = -2.90, 95% CI -5.12 to -0.67) in OA patients treatment with celecoxib was significantly improved than that with placebo. There was no significant difference in the incidence of adverse events (AEs), SAEs, and discontinuations due to AEs; however, the incidence of gastrointestinal AEs in OA patients treatment with celecoxib is significantly higher than that with placebo. For AE, the incidence of abdominal pain in OA patients with celecoxib was significantly higher than that with placebo (RR = 2.24, 95% CI: 1.40-3.58; P = 0.839, I = 0%). There was no significant difference in diarrhea, dyspepsia, headache, and nausea.This meta-analysis indicated that celecoxib treatment (200 mg orally once daily) led to significant improvement in the pain and function of osteoarthritis. However, compared with placebo control, celecoxib resulted in greater gastrointestinal AEs, especially abdominal pain after approximately 10 to 13 weeks of treatment. The current study, therefore, provides valuable information to help physicians make treatment decisions for their patients with OA.

Background: The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin., Objectives: The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets., Methods: Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into "low-dose" (≤ 100 mg) and "high-dose" (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists., Results: Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group., Conclusions: Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ≥6 yr., Objective: To analyze long-term safety with sunitinib in mRCC patients., Design, Setting, and Participants: Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g., cytokine refractory or treatment-naïve)., Outcome Measurements and Statistical Analysis: Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment., Results and Limitations: Among long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients., Conclusions: Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative., Patient Summary: More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Dabigatran is a novel target specific oral anticoagulant for stroke prevention in non valvular atrial fibrillation. Little is still known about its real-world effectiveness and safety in the italian population. Aim of our study was to evaluate the efficacy and safety of dabigatran in a large single-center cohort of "real-life" italian population with non-valvular AF and to compare the results with those obtained from the RE-LY trial and the Medicare study., Patients and Methods: We studied a prospective cohort of 2108 patients (1119 male; mean age 69.4 ± 9.4 years) who started the oral anticoagulant treatment with dabigatran 110 mg twice-daily (DAB 110; N = 1075; 51%) or 150 mg twice-daily (DAB 150; N = 1033; 49%). Follow-up data were obtained trough outpatients visits each 3-6 months for assessing the clinical status, adherence to treatment, occurrence of side effects and major cardiovascular complications., Results: In DAB 150 group the mean age was 64.9 ± 8.8 years, 56.8% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 94.3% and HAS-BLED was ≥ 3 in 59.7%. In DAB 110 group (N = 1075) the mean age was 73.9 ± 7.5 years; 49.5% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 73.4% and HAS-BLED was ≥ 3 in 87.4% of DAB 110 patients. One patient taking Dabigatran 110 mg bid had ischemic stroke without significantly neurological sequelae. In both groups, no patient experienced hemorrhagic stroke during the follow-up period. 147 patients (6.9%) of MonaldiCare population reported adverse effects from treatment with dabigatran, of whom 121 patients (5.7%) discontinued therapy. We reported one case of subarachnoid hemorrhage (0.05%) in a patient with high thrombo-embolic and high hemorrhagic risk score who was taking dabigatran 150 mg bid and one case (0.05%) of bladder bleeding in a patient who was taking dabigatran 110 mg bid. No major gastrointestinal bleeding was observed in the MonaldiCare population., Conclusions: MonaldiCare registry showed a safety profile of both dosages of dabigatran regarding major of fatal bleeding in a "real life" single center italian population at high thromboembolic and hemorrhagic risk. The majority of MonaldiCare patients tolerated dabigatran treatment without significant side effects. The efficacy of dabigatran was demonstrated by very low prevalence of ictus/TIA, also when patients underwent electrical AF cardioversion independently of the transesophageal examination.

Gastrointestinal symptoms are among the most common side effects of drugs. There is a broad spectrum of symptoms. Patients often report upper abdominal pain, an early sense of satiety, epigastric discomfort or pain in the upper abdomen or behind the breastbone, flatulence, diarrhoea or constipation. Some of these symptoms are attributed to the stomach or upper abdomen by the patient and/or the physician. "Stomach pain", pain in the epigastric region, occurs in most cases in combination with other symptoms such as a feeling of pressure in the upper abdomen or bloating, early satiety, nausea or vomiting--a combination called dyspepsia. Given the high frequency of these symptoms in the general population and the large number of medications many patients are taking, it can be very difficult in a given patient to differentiate between drug-induced side effects and spontaneously occurring symptoms., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Data concerning rates of gastrointestinal (GI) events in non-steroidal anti-inflammatory drug (NSAID) users derive mainly from clinical trials. The EVIDENCE study quantified the incidence of symptomatic uncomplicated and/or complicated GI events in at-risk European patients treated with NSAIDs in real-life practice., Methods: This non-interventional study assessed 4144 adults with at least one GI risk factor who recently initiated NSAID therapy for osteoarthritis (85%), rheumatoid arthritis (11%), ankylosing spondylitis (3%) or a combination (1%). Patient characteristics and medical history were collected from medical records. GI events (upper and lower) were recorded at in-clinic visits during 6 months' follow-up., Results: Mean time on index NSAID at enrolment was 33 days. The incidence (per 100 person-years) was 18.5 per 100 person-years for uncomplicated GI events and 0.7 per 100 person-years for complicated GI events. Upper GI events were far more common (12%) than lower GI events (1%) during study follow-up (median 182 days (range 61-320)). Other reported rates for cardiovascular, anaemia or non-GI events were much less frequent. A minority (28%) of patients had ongoing proton pump inhibitor use at enrolment, with strong variation by practice and country., Conclusions: EVIDENCE is the largest prospective study of the real-life management of European patients treated with NSAIDs for rheumatic diseases and at increased GI risk. It shows that GI events from the upper GI tract are far more common than those from the lower GI tract. It also shows adherence to guidelines for gastroprotection is generally low., Clinicaltrialsgov Identifier: NCT01176682., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: This Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder., Methods: Patients were randomized to 3 weeks of double-blind treatment with cariprazine 3-12mg/day (n=158) or placebo (n=154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score., Results: Mean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3-12mg/day versus placebo (P=0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, P<0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (≥50% improvement: cariprazine, 58.9%; placebo, 44.1%; P=0.0097) and remission (YMRS total score≤12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025) and mean change in CGI-S (P=0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P=0.0035) total score. The most common cariprazine-related (≥10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups., Limitations: Lack of active comparator arm; short duration of study., Conclusion: In this study, cariprazine 3-12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the long-term safety of the single-tablet combination of ibuprofen 800 mg and famotidine 26.6 mg., Research Design and Methods: A phase 3b open-label study (NCT00984815) was conducted in 86 adults requiring daily non-steroidal anti-inflammatory drug (NSAID) administration for ≥12 months. The combination tablet of ibuprofen/famotidine was self-administered orally three times daily for up to 54 consecutive weeks. Adverse events (AEs) were collected beginning at the first dose and continued through completion (54 weeks). The Severity of Dyspepsia Assessment (SODA) questionnaire was completed by patients to assess tolerability., Results: Most patients (65%) finished the trial, with 76% contributing data at 6 months, and 21% withdrew due to adverse effects. Overall and gastrointestinal AE discontinuation rates (21% and 13%, respectively) were lower than that previously reported with ibuprofen 2400 mg given alone. Each of the SODA subscale scores demonstrated improvement by week 6 and improved statistically significantly at week 24 and week 54. Of the cardiovascular AEs, hypertension was reported most frequently (9/86, 9.3%), with 3.5% determined to be drug related. Twelve serious AEs were reported by 9 of 86 (10%) patients; two were considered possibly related to the study medication (unstable angina and gastric ulcer). There were no reports of serious gastrointestinal or CV complications. Most AEs were mild or moderate in severity and not considered drug related., Conclusions: These data, together with previously reported findings of a significant decrease in upper gastrointestinal endoscopic ulcer rate at 6 months, support the overall safety, compliance, and tolerability of this single-tablet formulation.

Objective: To evaluate the safety of the fixed combination of ibuprofen and famotidine compared with ibuprofen alone from two 24-week, multicenter, double-blind trials designed to evaluate the comparative incidence of endoscopically documented upper gastrointestinal ulcers and a 28-week double-blind extension study., Research Design and Methods: Safety was analyzed by pooling data from the two double-blind trials and the follow-on study. Safety was assessed by monitoring the incidence, causality, and severity of adverse events (AEs)., Results: In the pivotal efficacy and safety trials, discontinuation rates due to any cause and dyspepsia were significantly lower for the ibuprofen/famotidine combination versus ibuprofen alone. Other than dyspepsia, gastrointestinal and cardiovascular AEs of special interest were similar. Events judged to be treatment related were significantly lower with the ibuprofen/famotidine combination (20.6% vs. 25%). In the safety extension population, there were no differences in the discontinuation rates and the reporting of AEs or serious AEs (SAEs) between the two groups. Gastrointestinal-related events were similar between the groups. Incidence of cardiovascular-related AEs of special interest were 11% (ibuprofen/famotidine) and 2% (ibuprofen) (p=0.06), possibly due to a higher number of rheumatoid arthritis patients in the combination group. Of these, 80% were reports of hypertension (8% ibuprofen/famotidine vs. 2% ibuprofen). Three cases of hypertension in the ibuprofen/famotidine group were considered treatment related. The probability of a cardiovascular event decreased during days 112-167 of treatment and remained low with continued treatment., Conclusions: One-year safety data from two pivotal trials and a long-term extension study indicate that the ibuprofen/famotidine combination demonstrates a favorable gastrointestinal safety profile and more patients continued on therapy compared to ibuprofen alone. No new safety signals have been identified. These data offer additional evidence supporting a new therapeutic option to improve gastrointestinal safety and adherence for patients who require long-term ibuprofen.

Non-valvular atrial fibrillation is the most common cardiac source of emboli and cardioembolic stroke. Anticoagulants are recommended for preventing stroke in patients with non-valvular atrial fibrillation. Warfarin reduces the risk of stroke in patients with AF by approximately two-thirds. Several novel anticoagulants that can overcome the limitations of warfarin have been introduced in the market or are under development. The NOACs are at least as effective as warfarin for stroke prevention in AF. Bleeding complications, including gastrointestinal bleeding, are common complication of anticoagulant treatment. The NOACs therapy are associated with an increased risk of major gastrointestinal bleeding compared with warfarin, and dabigatran is associated with an increased risk of non-bleeding upper GI symptoms such as dyspepsia and heartburn. This review provides information on the safety and risks of using NOACs, methods of treatment of gastrointestinal complications events in patients with non-valvular atrial fibrillation.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed group of drugs in the world. They are used primarily for pain relief in chronic inflammatory joint disease and act by inhibiting enzymes COX1 and COX2 and ultimately preventing the production of active prostanoids which are required for the innate inflammatory pathway. The use of NSAIDs have been associated with the development of gastrointestinal (GI) symptoms ranging from simple dyspepsia to life threatening GI bleeds and perforations. The definition of dyspepsia has evolved over the years and this has hampered accurate studies on the prevalence of dyspepsia as different studies used varying criteria to define dyspepsia. It is now known that NSAIDs significantly increase the risk of dyspepsia.The risk of developing peptic ulcer disease vary with specific NSAIDs and dosages but there is no correlation between the symptoms of dyspepsia and underlying peptic ulcers. The pathogenesis of dyspepsia with NSAIDs is not completely understood. Peptic ulceration alone is not able to account for the majority of dyspepsia symptoms encountered by NSAIDs users. Erosive oesophagitis secondary to NSAIDs may be contributing factor to the prevalence of dyspepsia in NSAIDs users. Altered gut permeability and changes in gastric mechanosensory function due to NSAIDs may also be a contributory factor. Management of NSAID induced dyspepsia is involves a multipronged approach. Drug avoidance if possible would be ideal. Other options include using the lowest effective dose, changing to an NSAIDs with a safer GI risk profile, avoiding concurrent use with other NSAIDs or if the patient has a previous history of peptic ulcer disease, and co-prescribing with anti-secretory medications such as proton pump inhibitors. Eradication of Helicobacter pylori has a protective role against developing peptic ulcers and may also improve symptoms of NSAIDs induced dyspepsia.

It has been reported that sevelamer hydrochloride, which is often used as a polymer phosphorus (P) binder for managing serum P concentration in dialysis patients, causes gastrointestinal adverse effects such as constipation, etc. The reason for this is thought to be that sevelamer hydrochloride has high water absorption, causing it to absorb water and swell in the gastrointestinal tract. In June 2012, the new polymer P binder bixalomer was launched in Japan. Since bixalomer has low swelling due to water absorption, it can be expected to alleviate adverse effects in the gastrointestinal system. In our study, for 21 cases of maintenance hemodialysis patients undergoing treatment with sevelamer hydrochloride at our hospital, the P binder was switched from sevelamer hydrochloride to the same dosage of bixalomer, and the concentrations of serum P, corrected calcium (Ca) and whole parathyroid hormone (PTH) before and one month after the switch were compared. In addition, gastrointestinal symptoms (acid reflux, abdominal pain, indigestion, diarrhea and constipation) were evaluated before and after the switch using a questionnaire based on the Japanese version of the Gastrointestinal Symptom Rating Scale (GSRS). By switching to bixalomer, serum P concentration was significantly reduced (P=0.024), but there were no significant changes observed for serum corrected Ca and whole PTH. Furthermore, there were no significant changes observed for all five of the evaluation items of the GSRS, before and after the switch. These results suggest that although bixalomer can more potently reduce the serum P concentration than sevelamer hydrochloride, there were no significant differences in the effects of both P binders on the gastrointestinal symptoms., (© 2014 The Authors. Therapeutic Apheresis and Dialysis © 2014 International Society for Apheresis.)

Enteric-coated aspirin has been developed in order to decrease the risk of gastrointestinal side effects. When reviewing the existing literature on the effects of the coating on the incidence of gastrointestinal side effects we find that enteric-coated aspirin causes significantly less minor gastrointestinal lesions compared to plain aspirin evaluated by endoscopy after short-term treatment, but there seems to be no effect of enteric-coating on the incidence of dyspepsia or gastrointestinal bleeding of clinical relevance. In conclusion enteric-coated aspirin is not superior to plain aspirin.

Background/aims: Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium (EC-MPS) given to treat GI mucosal lesions., Methods: Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by EC-MPS. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE., Results: Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms., Conclusion: Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to EC-MPS for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found., (© 2014 S. Karger AG, Basel.)

Background: The mean follow-up in the clinical trials of antiplatelet drugs in the secondary prevention of ischemic atherothrombotic stroke ranges from 1 to 5.5 years. Thus, the safety and efficacy of these drugs in the very long term is not totally documented. We have assessed the safety and effectiveness of triflusal and aspirin for a very long-term period in the secondary prevention of patients with ischemic atherothrombotic stroke., Methods: Patients with atherothrombotic ischemic stroke, including TIA, who participated in randomized clinical trials of triflusal versus aspirin were included in the study. The period of recruitment was between 1983 and 1999. After finishing their participation in the clinical trials, patients were followed up in the Neurology Department of our hospital. All patients were treated with aspirin or triflusal during a mean period of 17.2 years. Groups were comparable with respect to sex, age, risk factor and etiology of the stroke. Adverse events and vascular events (including stroke recurrence, ischemic heart disease and vascular death) that appeared throughout the study were registered. Statistical analysis was performed using the statistical package SPSS 15.0 for Windows. Kaplan-Meier curves and the log-rank test were used to compare treatments., Results: A total of 441 patients (305 men) with a mean age (±SD) of 51.1±12.4 years were included in the study; 288 patients (65.3%) were treated with triflusal and 153 with aspirin. There were no statistically significant differences between aspirin and triflusal concerning new vascular events (72.5 vs. 60.4%; p=0.28), stroke recurrence (49.7 vs. 46.5%; p=0.53), ischemic heart events (54.9 vs. 55.6%; p=0.90), vascular death (25.5 vs. 24%; p=0.73) and global mortality (42.5 vs. 42%; p=0.92). The incidence of serious bleeding (upper digestive tract hemorrhage and cerebral hemorrhage) was 18.3% in aspirin-treated patients and 5.5% in triflusal-treated patients (p<0.001). In reference to other adverse events, no significant differences were found between aspirin and triflusal., Conclusions: In the secondary prevention of ischemic stroke, very long-term treatment with triflusal or aspirin seems to have a similar efficacy, but triflusal is safer with a lower hemorrhagic risk. Triflusal may be an alternative therapy, particularly in patients who present aspirin resistance., (© 2014 S. Karger AG, Basel.)

Background: Effects of palm olein (POL) on calcium and fat metabolic balance and gastrointestinal (GI) tolerance have been clinically evaluated but its use in combination with palm kernel oil (PKO), and canola oil has not been similarly assessed in infants., Methods: Calcium and fat balance and GI tolerance were evaluated in 33 healthy term infants (age = 68-159 d) in a randomized, double-blinded, 14 d crossover trial at a day care center in Salvador, Brazil; followed by a 4d hospital ward metabolic balance study in 17 of the male subjects. The study compared two commercially available milk-based powdered formulas in Brazil; one containing POL (44% of total fat), PKO (21.7%) and canola oil (18.5%) as predominant fats (PALM), and the other containing none (NoPALM). Occasional human milk (HM) supplementation was allowed at home., Results: Formula and HM intakes, and growth were not different (p > 0.05). Calcium absorption (%) for infants fed NoPALM (58.8 ± 16.7%; means ± SD) was higher (p = 0.023) than those fed PALM (42.1 ± 19.2%), but was not significant (p = 0.104) when calcium intake was used as a covariate. Calcium intake was higher (p < 0.001) in NoPALM versus PALM fed infants. However, calcium retention (%) was higher in infants fed NoPALM compared to PALM with (p = 0.024) or without (p = 0.015) calcium intake as a covariate. Fat absorption (%) for NoPALM was greater than PALM fed infants (NoPALM = 96.9 ± 1.2 > PALM = 95.1 ± 1.5; p = 0.020 in Study Period I). Mean rank stool consistency was softer in infants fed NoPALM versus PALM (p < 0.001; metabolic period). Adverse events, spit-up/vomit, fussiness and gassiness were not different (p > 0.05). Formula acceptability was high and comparable for both formula feedings, regardless of HM supplementation., Conclusions: Term infants fed PALM based formula (containing palm olein, palm kernel and canola oils) demonstrated lower calcium retention and fat absorption, and less softer stool consistency versus infants fed NoPALM based formula. Study suggested formula fat differences may affect GI function in infants.

Aim: The association of motilin, ghrelin, leptin, gastrin, pepsinogen (PG) I and II with cancer chemotherapy-associated dyspepsia syndrome (CADS) was investigated in 35 patients with breast cancer receiving first cycle of 5-fluorouracil, cyclophosphamide, epirubicin (FEC60) chemotherapy., Patients and Methods: The onset of dyspeptic symptoms on days 3 and 10 after chemotherapy identified patients with and without CADS. Gastrointestinal symptoms were scored with the Gastrointestinal Symptom Scoring Rate (GSRS) questionnaire. Gastrointestinal peptides were evaluated by enzyme-linked immunosorbent assay., Results: Twenty-one patients (60%) had CADS. The area under the curve (AUC) of ghrelin was higher, whereas that of PGI, PGII and motilin were lower in patients with CADS compared to those without. In patients with CADS, the AUC of PGI and PGII negatively correlated with the GSRS indigestion cluster., Conclusion: Impairment of gastrointestinal motility suggested by low motilin concentrations and mucosal damage mirrored by an increase of ghrelin seem to be involved in the onset of CADS in patients during chemotherapy for breast cancer.

Background: The purpose of the study was to compare the safety of artemether-lumefantrine (AL) with other artemisinin-based combinations in children., Methods: A search of EMBASE (from 1974 to April 2013), MEDLINE (from 1946 to April 2013) and the Cochrane library of registered controlled trials for randomized controlled trials (RCTs) which compared AL with other artemisinin-based combinations was done. Only studies involving children ≤ 17 years old in which safety of AL was an outcome measure were included., Results: Four thousand, seven hundred and twenty six adverse events (AEs) were recorded in 6,000 patients receiving AL. Common AEs (≥ 1/100 and <1/10) included: coryza, vomiting, anaemia, diarrhoea, vomiting and abdominal pain; while cough was the only very commonly reported AE (≥ 1/10). AL-treated children have a higher risk of body weakness (64.9%) than those on artesunate-mefloquine (58.2%) (p = 0.004, RR: 1.12 95% CI: 1.04-1.21). The risk of vomiting was significantly lower in patients on AL (8.8%) than artesunate-amodiaquine (10.6%) (p = 0.002, RR: 0.76, 95% CI: 0.63-0.90). Similarly, children on AL had a lower risk of vomiting (1.2%) than chlorproguanil-dapsone-artesunate (ACD) treated children (5.2%) (p = 0.002, RR: 0.63, 95% CI: 0.47-0.85). The risk of serious adverse events was significantly lower for AL (1.3%) than ACD (5.2%) (p = 0.002, RR: 0.45, 95% CI: 0.27-0.74)., Conclusion: Artemether-lumefantrine combination is as safe as ASAQ and DP for use in children. Common adverse events are cough and gastrointestinal symptoms. More studies comparing AL with artesunate-mefloquine and artesunate-azithromycin are needed to determine the comparative safety of these drugs.

Objective: To assess the efficacy and safety of tadalafil, a phosphodiesterase 5 (PDE5) inhibitor efficacious for erectile dysfunction and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH), in population subgroups, using pooled data from 4 international, randomized, placebo-controlled studies in men with LUTS/BPH., Methods: The safety database included 1500 men randomized to tadalafil 5 mg once daily or placebo for 12 weeks. Changes in total International Prostate Symptom Score (IPSS), IPSS-quality of life index, and BPH impact index were examined overall, and changes in IPSS or adverse events (AEs) were examined across subgroups of interest. Treatment-group differences were assessed using analysis of covariance., Results: Results of pooled data confirmed that tadalafil (N = 752) resulted in significant improvements from baseline vs placebo (N = 746) in IPSS (mean difference -2.3; P <.001), and also in BPH impact index and IPSS-quality of life index (both P <.001). Subgroup analyses demonstrated that IPSS improvements were significant regardless of baseline LUTS severity (IPSS <20/≥20), age (≤65/>65 years), recent previous use of α-blockers or PDE5 inhibitors, total testosterone level (<300/≥300 ng/dL), or prostate-specific antigen predicted prostate volume (<40/≥40 mL). [corrected] Rates of treatment emergent AEs were comparable between subgroups of baseline age (≤65/>65 years), previous PDE5 inhibitor use, and the presence or absence of pre-existing diabetes, hypertension, or cardiovascular disease (including hypertension), but somewhat higher for recent previous α-blocker use., Conclusion: In these pooled data analyses, tadalafil 5 mg improved LUTS/BPH across subgroups of age, LUTS severity, testosterone levels, and prostate volume. Rates of AEs were similar across the subgroups assessed., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: In clinical trials, adherence to a prescribed regimen with dabigatran was enhanced by frequent follow-up visits and pill counts., Objectives: To describe the experience of dabigatran treatment in clinical practice, focusing on adherence., Patients/methods: In a cross-sectional cohort study, we interviewed 103 patients treated for at least 3 months with dabigatran and followed by our anticoagulant clinic. We obtained information on the number of capsules of dabigatran dispensed by the pharmacy of each patient covering the entire treatment period and calculated the adherence. In addition, information on the frequency of missed capsules, bleeding, thromboembolic events and other adverse events, specifically dyspepsia, was captured from the interviews and medical records., Results: The mean age was 75.5 (± 8.5) years, 46% were females, and the mean CHADS2 score was 2.5. Dispensation data were obtained for 99 patients and adherence was 99.7% (median; interquartile range 94.6%-100%) with 11 patients showing < 80% adherence. During their interview, 31 patients (30%) acknowledged that they sometimes had missed taking the medication, ranging from 'twice in 6 years' to 'every day'. One additional patient with adherence < 80% was identified. Twenty-one patients (20%) reported bleeding complications, two of which were major; one patient had an ischemic stroke and 34 (33%) reported some degree of dyspepsia. There were no significant differences in the results between RE-LY study-experienced and study-naïve patients., Conclusion: In our clinical practice adherence to the twice-daily dabigatran regimen was generally good, although 12% of the patients had an inadequate adherence. Routine feedback from the pharmacies could inform the physician to improve the anticoagulant management., (© 2013 International Society on Thrombosis and Haemostasis.)

Atrial fibrillation (AF) is associated with an increased risk of thromboembolism, and is the most prevalent factor for cardioembolic stroke. Vitamin K antagonists (VKAs) have been the standard of care for stroke prevention in patients with AF since the early 1990s. They are very effective for the prevention of cardioembolic stroke, but are limited by factors such as drug-drug interactions, food interactions, slow onset and offset of action, haemorrhage and need for routine anticoagulation monitoring to maintain a therapeutic international normalised ratio (INR). Multiple new oral anticoagulants have been developed as potential replacements for VKAs for stroke prevention in AF. Most are small synthetic molecules that target thrombin (e.g. dabigatran etexilate) or factor Xa (e.g. rivaroxaban, apixaban, edoxaban, betrixaban, YM150). These drugs have predictable pharmacokinetics that allow fixed dosing without routine laboratory monitoring. Dabigatran etexilate, the first of these new oral anticoagulants to be approved by the United States Food and Drug Administration and the European Medicines Agency for stroke prevention in patients with non-valvular AF, represents an effective and safe alternative to VKAs. Under the auspices of the Regional Anticoagulation Working Group, a multidisciplinary group of experts in thrombosis and haemostasis from Central and Eastern Europe, an expert panel with expertise in AF convened to discuss practical, clinically important issues related to the long-term use of dabigatran for stroke prevention in non-valvular AF. The practical information reviewed in this article will help clinicians make appropriate use of this new therapeutic option in daily clinical practice., (© 2013 John Wiley & Sons Ltd.)

Background: A randomised, double-blind, placebo-controlled study evaluated lipid- and glucose-lowering effects of colesevelam in patients with prediabetes and primary hyperlipidaemia. We report the effect of colesevelam on lipoprotein particle concentration and particle size (determined by nuclear magnetic resonance spectroscopy) in these patients., Methods: Adults with prediabetes (World Health Organization criteria), low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥2.6 mmol/L) and triglycerides < 500 mg/dL (<5.6 mmol/L) were randomised to colesevelam 3.75 g/day or placebo for 16 weeks. The intent-to-treat population comprised 103 colesevelam and 106 placebo recipients., Results: At the end of the study, mean reduction from baseline in total LDL particle concentration was significantly greater with colesevelam versus placebo (mean treatment difference: -113 nmol/L; p = 0.02). Increases in total very low-density lipoprotein particle concentration (VLDL-P) and high-density lipoprotein particle concentration (HDL-P) did not differ significantly between the groups; however, with colesevelam versus placebo, there were significantly (p < 0.05) greater increases in large and medium VLDL-P and large HDL-P and reductions in small VLDL-P. Mean size increases were significantly greater with colesevelam for VLDL (mean treatment difference: 5.3 nm; p < 0.0001) and HDL (0.1 nm; p = 0.002)., Conclusions: Colesevelam improved the overall atherogenic lipoprotein profile in adults with prediabetes and primary hyperlipidaemia, despite potentially less favourable changes in VLDL particles.