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Mayo Clinic Proceedings Nov 2019Constipation is a common symptom that may be primary (idiopathic or functional) or associated with a number of disorders or medications. Although most constipation is... (Review)
Review
Constipation is a common symptom that may be primary (idiopathic or functional) or associated with a number of disorders or medications. Although most constipation is self-managed by patients, 22% seek health care, mostly to primary care physicians (>50%) and gastroenterologists (14%), resulting in large expenditures for diagnostic testing and treatments. There is strong evidence that stimulant and osmotic laxatives, intestinal secretagogues, and peripherally restricted μ-opiate antagonists are effective and safe; the lattermost drugs are a major advance for managing opioid-induced constipation. Constipation that is refractory to available laxatives should be evaluated for defecatory disorders and slow-transit constipation using studies of anorectal function and colonic transit. Defecatory disorders are often responsive to biofeedback therapies, whereas slow-transit constipation may require surgical intervention in selected patients. Both efficacy and cost should guide the choice of treatment for functional constipation and opiate-induced constipation. Currently, no studies have compared inexpensive laxatives with newer drugs that work by other mechanisms.
Topics: Analgesics, Opioid; Chronic Disease; Constipation; Gastrointestinal Agents; Humans; Laxatives; Risk Factors
PubMed: 31054770
DOI: 10.1016/j.mayocp.2019.01.031 -
Current Drug Metabolism 2016Digestive enzymes are able to break down proteins and carbohydrates and lipids, and their supplementation may play a role in the management of digestive disorders, from... (Review)
Review
BACKGROUND
Digestive enzymes are able to break down proteins and carbohydrates and lipids, and their supplementation may play a role in the management of digestive disorders, from lactose intolerance to cystic fibrosis. To date, several formulations of digestive enzymes are available on the market, being different each other in terms of enzyme type, source and origin, and dosage.
METHODS
This review, performed through a non-systematic search of the available literature, will provide an overview of the current knowledge of digestive enzyme supplementation in gastrointestinal disorders, discussion of the use of pancreatic enzymes, lactase (β-galactosidase) and conjugated bile acids, and also exploring the future perspective of digestive enzyme supplementation.
RESULTS
Currently, the animal-derived enzymes represent an established standard of care, however the growing study of plant-based and microbe-derived enzymes offers great promise in the advancement of digestive enzyme therapy.
CONCLUSION
New frontiers of enzyme replacement are being evaluated also in the treatment of diseases not specifically related to enzyme deficiency, whereas the combination of different enzymes might constitute an intriguing therapeutic option in the future.
Topics: Animals; Bile Acids and Salts; Dietary Supplements; Gastrointestinal Agents; Gastrointestinal Diseases; Humans; beta-Galactosidase
PubMed: 26806042
DOI: 10.2174/138920021702160114150137 -
The New England Journal of Medicine Sep 2023Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established.
METHODS
In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed.
RESULTS
Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea.
CONCLUSIONS
In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).
Topics: Humans; Biopsy; Double-Blind Method; Fibroblast Growth Factors; Fibrosis; Gastrointestinal Agents; Injections, Subcutaneous; Non-alcoholic Fatty Liver Disease; Treatment Outcome
PubMed: 37356033
DOI: 10.1056/NEJMoa2304286 -
The American Journal of Gastroenterology Jun 2021Constipation is commonly treated with over-the-counter (OTC) products whose efficacy and safety remain unclear. We performed a systematic review of OTC therapies for...
INTRODUCTION
Constipation is commonly treated with over-the-counter (OTC) products whose efficacy and safety remain unclear. We performed a systematic review of OTC therapies for chronic constipation and provide evidence-based recommendations.
METHODS
We searched PubMed and Embase for randomized controlled trials of ≥4-week duration that evaluated OTC preparations between 2004 and 2020. Studies were scored using the US Preventive Services Task Force criteria (0-5 scale) including randomization, blinding, and withdrawals. The strengths of evidence were adjudicated within each therapeutic category, and recommendations were graded (A, B, C, D, and I) based on the level of evidence (level I, good; II, fair; or III, poor).
RESULTS
Of 1,297 studies identified, 41 met the inclusion criteria. There was good evidence (grade A recommendation) for the use of the osmotic laxative polyethylene glycol (PEG) and the stimulant senna; moderate evidence (grade B) for psyllium, SupraFiber, magnesium salts, stimulants (bisacodyl and sodium picosulfate), fruit-based laxatives (kiwi, mango, prunes, and ficus), and yogurt with galacto-oligosaccharide/prunes/linseed oil; and insufficient evidence (grade I) for polydextrose, inulin, and fructo-oligosaccharide. Diarrhea, nausea, bloating, and abdominal pain were common adverse events, but no serious adverse events were reported.
DISCUSSION
The spectrum of OTC products has increased and quality of evidence has improved, but methodological issues including variability in study design, primary outcome measures, trial duration, and small sample sizes remain. We found good evidence to recommend polyethylene glycol or senna as first-line laxatives and moderate evidence supporting fiber supplements, fruits, stimulant laxatives, and magnesium-based products. For others, further validation with more rigorously designed studies is warranted.
Topics: Bisacodyl; Cathartics; Chronic Disease; Citrates; Constipation; Defecation; Fruit; Gastrointestinal Agents; Glucans; Humans; Inulin; Laxatives; Magnesium; Nonprescription Drugs; Oligosaccharides; Organometallic Compounds; Picolines; Polyethylene Glycols; Psyllium; Senna Extract; Yogurt
PubMed: 33767108
DOI: 10.14309/ajg.0000000000001222 -
Gut Jan 2022Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are... (Review)
Review
Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.
Topics: Cholestasis; Gastrointestinal Agents; Humans; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear
PubMed: 34615727
DOI: 10.1136/gutjnl-2021-324305 -
Gastroenterology Feb 2020Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective αβ integrin, is administered intravenously. Some patients might prefer a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective αβ integrin, is administered intravenously. Some patients might prefer a subcutaneous formulation of vedolizumab for maintenance treatment. Subcutaneous vedolizumab was investigated as maintenance treatment in patients with moderately to severely active ulcerative colitis.
METHODS
We performed a phase 3, double-blind, double-dummy trial at 141 sites in 29 countries from December 18, 2015 through August 21, 2018. Patients with moderately to severely active ulcerative colitis received open-label treatment with intravenous vedolizumab 300 mg at weeks 0 and 2. At week 6, patients with clinical response were randomly assigned maintenance treatment with subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo. The primary end point was clinical remission at week 52, which was defined as a total Mayo score of ≤2 and no subscore >1.
RESULTS
Among the randomized 216 patients, clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively (subcutaneous vedolizumab vs placebo: Δ32.3%; 95% confidence interval, 19.7%-45.0%; P < .001). The subcutaneous vedolizumab group also had greater endoscopic improvement and durable clinical response at week 52 compared with placebo (both P < .001). The incidence of injection-site reactions was more frequent in patients given subcutaneous vedolizumab (10.4%) than intravenous vedolizumab (1.9%) or placebo (0%); these were not treatment limiting, most were mild, and none resulted in discontinuation. Subcutaneous and intravenous vedolizumab safety profiles were otherwise similar.
CONCLUSIONS
Subcutaneous vedolizumab is effective as maintenance therapy in patients with moderately to severely active ulcerative colitis who had a clinical response to intravenous vedolizumab induction therapy. It has a favorable safety and tolerability profile. ClinicalTrials.gov ID: NCT02611830; EudraCT 2015-000480-14.
Topics: Administration, Intravenous; Adult; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Colonoscopy; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Infections; Injection Site Reaction; Injections, Subcutaneous; Maintenance Chemotherapy; Male; Middle Aged; Remission Induction
PubMed: 31470005
DOI: 10.1053/j.gastro.2019.08.027 -
Gastroenterology Jun 2020We evaluated the efficacy and safety of upadacitinib, an oral selective inhibitor of Janus kinase 1, as induction therapy for ulcerative colitis (UC). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
We evaluated the efficacy and safety of upadacitinib, an oral selective inhibitor of Janus kinase 1, as induction therapy for ulcerative colitis (UC).
METHODS
We performed a multicenter, double-blind, phase 2b study of 250 adults with moderately to severely active UC and an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomly assigned to groups that received placebo or induction therapy with upadacitinib (7.5 mg, 15 mg, 30 mg, or 45 mg, extended release), once daily for 8 weeks. The primary endpoint was the proportion of participants who achieve clinical remission according to the adapted Mayo score at week 8. No multiplicity adjustments were applied.
RESULTS
At week 8, 8.5%, 14.3%, 13.5%, and 19.6% of patients receiving 7.5 mg, 15 mg, 30 mg, or 45 mg upadacitinib, respectively, achieved clinical remission compared with none of the patients receiving placebo (P = .052, P = .013, P = .011, and P = .002 compared with placebo, respectively). Endoscopic improvement at week 8, defined as endoscopic subscore of ≤ 1, was achieved in 14.9%, 30.6%, 26.9%, and 35.7% of patients receiving upadacitinib 7.5 mg, 15 mg, 30 mg, or 45 mg, respectively, compared with 2.2% receiving placebo (P = .033, P < .001, P < .001, and P < .001 compared with placebo, respectively). One event of herpes zoster and 1 participant with pulmonary embolism and deep venous thrombosis (diagnosed 26 days after treatment discontinuation) were reported in the group that received upadacitinib 45 mg once daily. Increases in serum lipid levels and creatine phosphokinase with upadacitinib were observed.
CONCLUSION
In a phase 2b trial, 8 weeks of treatment with upadacitinib was more effective than placebo for inducing remission in patients with moderately to severely active UC. (ClinicalTrials.gov, Number: NCT02819635).
Topics: Adolescent; Adult; Aged; Colitis, Ulcerative; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Remission Induction; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult
PubMed: 32092309
DOI: 10.1053/j.gastro.2020.02.030 -
Clinical Interventions in Aging 2015Constipation is a common functional gastrointestinal disorder, with prevalence in the general population of approximately 20%. In the elderly population the incidence of... (Review)
Review
Constipation is a common functional gastrointestinal disorder, with prevalence in the general population of approximately 20%. In the elderly population the incidence of constipation is higher compared to the younger population, with elderly females suffering more often from severe constipation. Treatment options for chronic constipation (CC) include stool softeners, fiber supplements, osmotic and stimulant laxatives, and the secretagogues lubiprostone and linaclotide. Understanding the underlying etiology of CC is necessary to determine the most appropriate therapeutic option. Therefore, it is important to distinguish from pelvic floor dysfunction (PFD), slow and normal transit constipation. Evaluation of a patient with CC includes basic blood work, rectal examination, and appropriate testing to evaluate for PFD and slow transit constipation when indicated. Pelvic floor rehabilitation or biofeedback is the treatment of choice for PFD, and its efficacy has been proven in clinical trials. Surgery is rarely indicated in CC and can only be considered in cases of slow transit constipation when PFD has been properly excluded. Other treatment options such as sacral nerve stimulation seem to be helpful in patients with urinary dysfunction. Botulinum toxin injection for PFD cannot be recommended at this time with the available evidence. CC in the elderly is common, and it has a significant impact on quality of life and the use of health care resources. In the elderly, it is imperative to identify the etiology of CC, and treatment should be based on the patient's overall clinical status and capabilities.
Topics: Aged; Aging; Cathartics; Chronic Disease; Constipation; Digestive System Surgical Procedures; Gastrointestinal Agents; Gastrointestinal Transit; Humans; Laxatives; Pelvic Floor Disorders; Physical Examination; Physical Therapy Modalities; Quality of Life; Severity of Illness Index; Sex Factors
PubMed: 26082622
DOI: 10.2147/CIA.S54304 -
BMJ (Clinical Research Ed.) Jan 2007
Review
Topics: Acute Disease; Child; Diet; Fluid Therapy; Gastroenteritis; Gastrointestinal Agents; Humans
PubMed: 17204802
DOI: 10.1136/bmj.39036.406169.80 -
European Journal of Gastroenterology &... Apr 2019A consolidated overview of evidence for the effectiveness and safety/tolerability of hepatic encephalopathy (HE) treatment over the long term is currently lacking. We... (Review)
Review
A consolidated overview of evidence for the effectiveness and safety/tolerability of hepatic encephalopathy (HE) treatment over the long term is currently lacking. We identified and assessed published evidence for the long-term (≥6 months) pharmacological management of HE with lactulose and/or rifaximin. A literature search was conducted in PubMed (cutoff date 05 March 2018) using the search terms 'hepatic encephalopathy+rifaximin' and 'hepatic encephalopathy+lactulose'. All articles containing primary clinical data were manually assessed to identify studies in which long-term (≥6 months) effectiveness and/or safety/tolerability end points were reported for lactulose and/or rifaximin. Long-term effectiveness outcomes were reported in eight articles for treatment with lactulose alone and 19 articles for treatment with rifaximin, alone or in combination with lactulose. Long-term safety/tolerability outcomes were reported in six articles for treatment with lactulose alone and nine articles for treatment with rifaximin, alone or in combination with lactulose. These studies showed that lactulose is effective for the prevention of overt HE recurrence over the long term and that the addition of rifaximin to lactulose significantly reduces the risk of overt HE recurrence and HE-related hospitalization, compared with lactulose therapy alone, without compromising tolerability. Current evidence therefore supports recommendations for the use of lactulose therapy for the prevention of overt HE recurrence over the long term, and for the additional benefit of adding rifaximin to lactulose therapy. Addition of rifaximin to standard lactulose therapy may result in substantial reductions in healthcare resource utilization over the long term, by reducing overt HE recurrence and associated rehospitalization.
Topics: Drug Therapy, Combination; Evidence-Based Medicine; Gastrointestinal Agents; Hepatic Encephalopathy; Humans; Lactulose; Recurrence; Rifaximin; Secondary Prevention
PubMed: 30444745
DOI: 10.1097/MEG.0000000000001311