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Background Tenapanor, a small molecule with minimal systemic availability, is a first-in-class sodium/hydrogen exchanger 3 (NHE3) inhibitor that acts in the gut. Here, we evaluate the pharmacodynamics and safety of tenapanor in healthy adults. Methods Two phase I, single-center, randomized, double-blind, placebo-controlled studies were performed. The first study assessed single-ascending oral tenapanor doses of 10, 50, 150, 450, and 900 mg ( n  = 8 per group; six tenapanor, two placebo) and multiple ascending doses over 7 days of 3, 10, 30, and 100 mg q.d. ( n  = 10 per group; eight tenapanor, two placebo). In the second study, different tenapanor regimens were evaluated over 7 days ( n  = 15 per group; 12 tenapanor, three placebo): 15 mg twice daily (b.i.d.), 30 mg once daily (q.d.), 30 mg b.i.d., 30 mg three times daily (t.i.d.), 60 mg b.i.d., escalating b.i.d. dose (daily total 30–90 mg), 30 mg b.i.d. with psyllium. Results Tenapanor produced generally dose-dependent increases in stool sodium excretion and decreases in urinary sodium excretion versus placebo; in addition, twice-daily dosing appeared to have a greater effect on sodium absorption than once-daily dosing with an equivalent daily dose. Tenapanor softened stool consistency and increased stool frequency and weight from baseline versus placebo. Tenapanor concentrations were below the quantification limit (0.5 ng/ml) in 98.5% of 895 plasma samples. Adverse events were mild or moderate in severity, and were typically gastrointestinal in nature. There were no clinically relevant changes in serum electrolytes. Conclusions Tenapanor was well tolerated and resulted in reduced intestinal sodium absorption and softer stool consistency versus placebo. Systemic exposure to tenapanor was minimal. These results support potential use of tenapanor in patients who could benefit from modification of gastrointestinal sodium balance. ClinicalTrials.gov identifiers NCT02819687, NCT02796131.

In two 12-week trials, linaclotide, a minimally absorbed peptide agonist of the guanylate cyclase-C receptor, increased the frequency of spontaneous bowel movements and improved symptoms in patients with chronic constipation. Longer-term studies are needed. Chronic constipation affects between 12 and 19% of the U.S. population. 1 , 2 The symptoms of chronic constipation, including infrequent bowel movements, hard stools, straining during defecation, bloating, abdominal discomfort, and a sense of incomplete evacuation, 3 adversely affect quality of life 4 , 5 and are associated with substantial costs. 6 , 7 Few currently available therapies for chronic constipation have been shown to be effective and safe in well-controlled, long-term trials, 8 and many persons with this disorder are not completely satisfied with their current treatment options. 4 Linaclotide is a 14-amino-acid synthetic peptide that is structurally related to the endogenous guanylin peptide family. It binds . . .

This study investigated the safety and efficacy of subcutaneous methylnaltrexone, a μ-opioid–receptor antagonist, for treating opioid-induced constipation in patients with advanced illness. Methylnaltrexone rapidly induced laxation without affecting central analgesia or precipitating withdrawal. This study investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness. Methylnaltrexone rapidly induced laxation without affecting central analgesia or precipitating withdrawal. Clinicians often use opioids to treat moderate-to-severe pain; however, opioids frequently induce or aggravate constipation. Empirically, laxative therapy may be burdensome and ineffective and result in temporally unpredictable responses. In addition, severe opioid-induced constipation may limit opioid therapy, worsening analgesia. These drawbacks can substantially compromise the quality of life, especially in patients with advanced illness. Opioid-induced constipation is predominantly mediated by gastrointestinal μ-opioid receptors. 1 , 2 Selective blockade of these peripheral receptors might relieve constipation without compromising centrally mediated effects of opioid analgesia or precipitating withdrawal. N-methylation of the uncharged systemic opioid antagonist, naltrexone, 3 results in a charged derivative, methylnaltrexone, which . . .

Background Constipation is prevalent after bariatric surgery and glucagon-like-peptide 1 (GLP-1) analogues. Increasing fat content in the distal small intestine and colon can enhance colonic peristalsis, potentially alleviating symptoms of constipation. Aim We investigated whether oleic acid can ameliorate constipation in patients undergoing bariatric surgery or receiving GLP-1 analogues. Methodology Fourteen adults with chronic constipation according to Rome IV criteria following bariatric surgery or GLP-1 analogues were on stable treatment for constipation for more than 4 weeks. This randomized double-blind crossover trial compared microcapsules containing 21.25 g of oleic acid delivered in the distal small intestine or the stomach. The primary outcome was changed in the number of bowel motions over 24 h. Exploratory endpoints included alterations in straining, diarrhoea, faecal leakage over 24 h and hunger, fullness, nausea and calorie intake for the 3 h after ingesting the microcapsules. Findings Receiving oleic acid into the distal small intestine increased number of bowel movements per day (2.5 vs 1.1, p  = 0.009) and caused softer stool consistency ( p  = 0.03). 9/14 of the control group passed motions and 13/14 of the intervention group passed motions in 24 h ( p  = 0.059). No significant differences were observed in straining ( p  = 0.65), rapid bowel movements ( p  = 0.08), accidental leakage ( p  = 0.32), hunger, fullness, nausea or food intake between the groups (all p  > 0.05). There were no disparities in safety profile between groups. Conclusion Microcapsules containing oleic acid delivered to the distal small intestine appear to be a safe and effective relief from chronic constipation in patients undergoing bariatric surgery and/or receiving GLP-1 analogues. Graphical Abstract

Painful defecation, the passage of hard stools, unpleasant or irregular bowel deviation/movements from regular rate, and/or the feeling of not enough elimination of stool are common symptoms of functional constipation. The goals in treating constipation are to produce soft, painless stools and to prevent the re-accumulation of feces. This study looked at how the telerehabilitation home program (TRP) affected the symptoms of FC and the children who were constipated in terms of their quality of life. A randomized controlled trial included 400 children aging 4–18 years with functional constipation distributed in two groups: control group consisted of 200 children receiving pharmaceutical treatment and the intervention group consisted of 200 children receiving the telerehabilitation home program in addition to pharmaceutical treatment. Both groups received the interventions for 6 months. The outcomes in terms of functional constipation symptoms and quality of life are measured and compared pre- and post-interventions. Adding the telerehabilitation home program to pharmaceutical treatment of functional constipation in children results in prominent improvement in the condition; there is a significant difference between the intervention and control group in all Rome criteria which assess symptoms of functional constipation except rush to the bath-room to poop which showed non-significant difference; there is also a significant difference between the intervention and control group in all domains of the SF-36 questionnaire which assess quality of life except the mental health domain which showed non-significant difference. Conclusion : Adding the telerehabilitation home program to pharmaceutical treatment of functional constipation in children results in prominent improvement in symptoms of functional constipation and quality of life. Trial registration : Our study was registered retrospectively with Clinicaltrials.gov under the identifier NCT06207721 on 5 January 2024. What Is Known: • Painful defecation, passage of hard stools, unpleasant or irregular bowel movements, feeling of incomplete stool elimination are common symptoms of functional constipation. • Goals in treating constipation include producing soft, painless stools and preventing re-accumulation of feces. What Is New: • Adding telerehabilitation home program to pharmaceutical treatment resulted in significant improvement in functional constipation symptoms and quality of life. • Significant differences between intervention group (200 children receiving telerehabilitation home program in addition to pharmaceutical treatment) and control group (200 children receiving pharmaceutical treatment) were observed in all Rome criteria except for rush to the bathroom to poop, and in all domains of SF36 questionnaire except for the mental health domain.

In this 12-week randomized trial, prucalopride, a selective 5-HT 4 receptor agonist, substantially relieved constipation. Because of cardiac adverse events seen with other 5-HT 4 receptor agonists, electrocardiograms were monitored; there was no prolongation of the corrected QT interval. Diarrhea and headache were more common in the prucalopride groups than in the placebo group. This study was not large or long enough to rule out cardiovascular events or other uncommon adverse events. Prucalopride, a selective 5-HT 4 receptor agonist, substantially relieved constipation. Because of cardiac adverse events seen with other 5-HT 4 receptor agonists, electrocardiograms were monitored; there was no prolongation of the corrected QT interval. Constipation affects 14.7% of the U.S. population, 1 specifically 16% of children 2 and 15 to 50% of the elderly, 3 and it is more common in women than in men. 4 Patients associate constipation with several symptoms: infrequent bowel movements, hard or lumpy stools, straining, bloating, the feeling of incomplete evacuation after a bowel movement, and abdominal discomfort. 5 Health-related quality of life is negatively affected by the presence of chronic constipation 6 and by its severity. 7 , 8 Reduced colonic motility is one of the pathophysiological mechanisms in severe chronic constipation. 5 There is insufficient evidence from randomized, controlled trials to assess the long-term effectiveness and . . .

Rhubarb, a traditional herb, has been used in clinical practice for hundreds of years to cure constipation, but its mechanism is still not clear enough. Currently, growing evidence suggests that intestinal flora might be a potential target for the treatment of constipation. Thus, the aim of this study was to clarify the laxative effect of rhubarb via systematically analyzing the metagenome and metabolome of the gut microbiota. In this study, the laxative effects of rhubarb were investigated by loperamide-induced constipation in rats. The gut microbiota was determined by high-throughput sequencing of 16S rRNA gene. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used for fecal metabolomics analysis. The data showed that rhubarb could significantly shorten gastrointestinal transit time, increase fecal water content and defecation frequency, improve gastrointestinal hormone disruption, and protect the colon mucus layer. Analysis of 16S rRNA gene sequencing indicated that rhubarb could improve the disorder of intestinal microbiota in constipated rats. For example, beneficial bacteria such as Ligilactobacillus , Limosilalactobacillus , and Prevotellaceae UCG-001 were remarkably increased, and pathogens such as Escherichia-Shigella were significantly decreased after rhubarb treatment. Additionally, the fecal metabolic profiles of constipated rats were improved by rhubarb. After rhubarb treatment, metabolites such as chenodeoxycholic acid, cholic acid, prostaglandin F2α, and α-linolenic acid were markedly increased in constipation rats; in contrast, the metabolites such as lithocholic acid, calcidiol, and 10-hydroxystearic acid were notably reduced in constipation rats. Moreover, correlation analysis indicated a close relationship between intestinal flora, fecal metabolites, and biochemical indices associated with constipation. In conclusion, the amelioration of rhubarb in constipation might modulate the intestinal microflora and its metabolism. Moreover, the application of fecal metabolomics could provide a new strategy to uncover the mechanism of herbal medicines. Key points • Rhubarb could significantly improve gut microbiota disorder in constipation rats. • Rhubarb could markedly modulate the fecal metabolite profile of constipated rats.

Stimulant laxatives are well established as first- or second-line treatments for constipation and although they have a reliable therapeutic effect, alleged safety concerns still exist, particularly with long-term use. The potential harmful effects on the gastrointestinal system (including carcinogenicity) of the long-term use of diphenylmethane [bisacodyl, sodium picosulfate (SPS)] and senna stimulant laxatives were assessed in a comprehensive review of the publications identified in literature searches performed in PubMed and Embase up to and including June 2023. We identified and reviewed 43 publications of interest. While stimulant laxatives at supratherapeutic doses have been shown to cause structural alterations to surface absorptive cells in animals and humans, these effects are reversible and not considered clinically relevant. No formal long-term studies have demonstrated morphological changes in enteric neural elements or intestinal smooth muscle with bisacodyl or SPS in humans. Furthermore, there is no convincing evidence that stimulant laxatives are associated with the development of colon cancer, and in fact, chronic constipation itself has been reported to potentially increase the risk of colon cancer, therefore, the use of stimulant laxatives might reduce this risk. Many studies suggesting a possible harmful effect from laxatives were limited by their failure to consider confounding factors such as concomitant neurological disease, metabolic disorders, and age. These findings highlight the lack of evidence for the harmful effects of laxatives on the colon, and thus, the benefits of treatment with stimulant laxatives, even in the long-term, should be reconsidered for the management of patients with constipation. Plain language summary Do stimulant laxatives damage the gut? Stimulant laxatives are widely used treatments for constipation that work by causing the muscles in the gut to contract and so move stool more effectively. Examples of these treatments include senna, bisacodyl and sodium picosulfate. Treatments such as these are typically available without a doctor’s prescription and have a long history of helping people relieve their constipation. However, some concerns have been expressed about the safety of these treatments, particularly when they are used for a long time. We did a critical review of published studies of the safety of stimulant laxatives to try to find out whether there is any strong evidence for harm being caused by these treatments. We found 43 papers with information on the gut safety of stimulant laxatives. These studies looked at whether the treatments are associated with changes to gut structure or function and at whether there might be a link between these treatments and bowel cancer. Unfortunately, many of the studies were of poor quality. For instance, they did not look for things, in addition to the laxatives, that could have affected the results, such as the age of the patients, other medications they were taking or whether they had other health conditions that might have affected the bowel. Also, the populations in which the studies were done differed a lot, so they were hard to compare with one another. However, we did not find any strong evidence suggesting that stimulant laxatives damage the gut or cause cancer. We therefore concluded that the harms associated with stimulant laxatives are likely to have been overstated, and that patients should not be denied the benefits of stimulant laxatives for constipation, especially as they have been on the market for a very long time with no serious problems emerging.