Linaclotide

Progressive up-regulation of β-catenin signaling is very common in the transformation of colorectal epithelium to colorectal cancer (CRC). Practical measures for opposing such signaling hence have potential for preventing or slowing such transformation. cAMP/PKA activity in colon epithelium, as stimulated by COX-2-generated prostaglandins and β2-adrenergic signaling, boosts β-catenin activity, whereas cGMP/PKG signaling has the opposite effect. Bacterial generation of short-chain fatty acids (as supported by unrefined high-carbohydrate diets, berberine, and probiotics), dietary calcium, daily aspirin, antioxidants opposing cox-2 induction, and nicotine avoidance, can suppress cAMP production in colonic epithelium, whereas cGMP can be boosted via linaclotides, PDE5 inhibitors such as sildenafil or icariin, and likely high-dose biotin...

Chronic constipation is one of the most common digestive diseases encountered in clinical practice. Constipation manifests as a variety of symptoms, such as infrequent bowel movements, hard stools, feeling of incomplete evacuation, straining at defecation, a sense of anorectal blockage during defecation, and use of digital maneuvers to assist defecation. During the diagnosis of chronic constipation, the Bristol Stool Form Scale, colonoscopy, and a digital rectal examination are useful for objective symptom evaluation and differential diagnosis of secondary constipation...

The regioselective synthesis of multiple disulfide bonds in peptides has been a significant challenge in synthetic peptide chemistry. In this work, two disulfide bonds in peptides were regioselectively synthesized via an approach of MetSeO oxidation and deprotection reaction (SeODR), in which the first disulfide bond was constructed through oxidation of dithiol by MetSeO in a neutral buffer, and the second disulfide bond was then directly constructed through the deprotection of two Acm groups or one Acm group and one Thz group by MetSeO in acidic media...

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride)...

Duodenal bicarbonate secretion is critical to epithelial protection, nutrient digestion/absorption and is impaired in cystic fibrosis (CF). We examined if linaclotide, typically used to treat constipation, may also alter duodenal bicarbonate secretion. Bicarbonate secretion was measured in vivo and in vitro using mouse and human duodenum. Ion transporter localization was identified with confocal microscopy and de novo analysis of human duodenal single cell RNA sequencing (sc-RNAseq) was performed. Linaclotide increased bicarbonate secretion in mouse and human duodenum in the absence of CFTR expression or function...

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults. METHODS: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride)...

No abstract text is available yet for this article.

Article Title: Linaclotide Reduced Response Time for Irritable Bowel Syndrome with Constipation Symptoms: Analysis of Four Randomized Controlled Trials.

Linaclotide is a 14-amino acid residue peptide approved by the FDA for the treatment of irritable bowel syndrome with constipation (IBS-C), which activates guanylate cyclase C to accelerate intestinal transit. Here we show a new method for the synthesis of linaclotide through the completely selective formation of three disulfide bonds in satisfactory overall yields via mild oxidation reactions of the solid phase and liquid phase, using 4-methoxytrityl (Mmt), diphenylmethyl (Dpm) and 2-nitrobenzyl (O-NBn) protecting groups of cysteine as substrate, respectively...

Peptides are steadily gaining importance as pharmaceutical targets, and efficient, green methods for their preparation are critically needed. A key deficiency in the synthetic toolbox is the lack of an industrially viable peptide desulfurization method. Without this tool, the powerful native chemical ligation reaction typically used to assemble polypeptides and proteins remains out of reach for industrial preparation of drug targets. Current desulfurization methods require very large excesses of phosphine reagents and thiol additives or low-abundance metal catalysts...

BACKGROUND AND AIMS: The single dose of 2 L polyethylene glycol (PEG) has shown high cleaning efficacy and tolerability in low-risk patients. However, the dosage of this regimen is still challenging for many patients. We investigated the efficacy and tolerability of a novel ultra-low-volume regimen using 1 L PEG and linaclotide (1 L PEG+L) versus a single dose of 2 L PEG in low-risk patients. METHODS: In this prospective, randomized, observer-blinded, multicenter study, low-risk adult patients scheduled for colonoscopy were enrolled and randomized (1:1) to receive the 1 L PEG+L regimen or the 2 L PEG regimen...

No abstract text is available yet for this article.

INTRODUCTION: With the growing rate of aging and the incidence of cancer and chronic diseases, there has been an upsurge in opioid prescription and abuse worldwide. This has been associated with increased reports of opioid-related adverse events, particularly opioid-induced bowel dysfunction (OIBD), calling for a rational clinical management strategy. AREAS COVERED: Through searching PubMed, Scopus, Cochrane Library, and Web of Science, exciting English literature was gathered as of January 1, 2017...

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we reveal that intestinal GUCY2C is selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans...

Opioid-induced constipation (OIC) is a common condition in older adults who may not be responsive to traditional laxative therapy. OIC is defined as new or worsening constipation symptoms that occur with initiation of or altering the dose of opioid analgesia. For adult patients with OIC and noncancer pain, we recommend considering nonpharmacologic interventions (eg, dietary measures, increased physical activity, and biofeedback training) and over-the-counter laxatives, followed by prescription opioid receptor antagonists (methylnaltrexone, naloxegol, and naldemedine) if traditional over-the-counter laxatives fail...

INTRODUCTION: Chronic idiopathic constipation is a common gastrointestinal disorder whose treatment is still far from being satisfactory for patients. Osmotic laxatives, in particular polyethylene glycol, are the first-line approach, but new emerging pharmacological agents may be useful in refractory patients. AREAS COVERED: Published articles regarding the development and clinical efficacy of new agents in treating chronic idiopathic constipation were reviewed...

BACKGROUND: Chronic constipation leads to poor quality of life, and treatment remains unsatisfactory for patients. In Japan, magnesium oxide has been commonly used as the first choice of treatment for constipation; however, there are some cases of low satisfaction with magnesium oxide treatment. Linaclotide has recently been used to treat chronic constipation. In this study, we will examine whether linaclotide improves symptoms and quality of life in patients showing insufficient response to magnesium oxide...

BACKGROUND: MD-7246, a delayed-release formulation of linaclotide, is designed to target the ileocaecal junction and caecum with the aim of relieving abdominal pain independently of bowel function. AIMS: To evaluate the efficacy, safety and dose-response of MD-7246 in patients with irritable bowel syndrome with diarrhoea (IBS-D). METHODS: A randomised, double-blind, phase 2 clinical trial enrolled adult patients with IBS-D (Rome IV criteria)...

INTRODUCTION: These post hoc analyses provide clinically relevant data concerning time to response for individual irritable bowel syndrome with constipation (IBS-C) symptoms after linaclotide use. METHODS: Time-to-response data were pooled from 4 randomized controlled trials. Response time for abdominal symptoms (pain, discomfort, and bloating) and complete spontaneous bowel movements (CSBMs) were analyzed using the Kaplan-Meier method; patients were categorized as early responders (≤4 weeks), late responders (>4-12 weeks), or nonresponders...

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, and ALS patients may experience disturbed gastrointestinal motility often resulting in acute colonic pseudo-obstruction (ACPO). There is currently a paucity in the literature to guide the treatment of patients with both ALS and ACPO. CASE PRESENTATION: Here we describe a 39-year-old male patient with advanced ALS who developed ACPO. His condition was refractory to both medical and procedural managements including polyethylene glycol, senna, and docusate suppository, metoclopramide, linaclotide, erythromycin, prucalopride, neostigmine, and repeated colonoscopies...