Influence of Demographic Factors on Clinical Outcomes in Adults With Chronic Idiopathic Constipation Treated With Plecanatide.

Introduction: Chronic idiopathic constipation (CIC) is a common condition that affects some patient groups more often. Demographic/clinical characteristics can differ in presentation and therapeutic response. The impact of these characteristics on plecanatide efficacy/safety was examined.

Plecanatide for the treatment of constipation-predominant irritable bowel syndrome.

: As an analogue of uroguanylin plecanatide binds to the Guanylate Cyclase-C receptor activating fluid and ion secretion in the small intestine with the same pH-dependent binding kinetics as the natural ligand. Plecanatide has been FDA approved as safe and effective for the indications of Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C).: All clinical trial results supporting approval of plecanatide in IBS-C are reported, evaluated and interpreted in the context of the complex pathophysiology of functional diseases and the barriers that must be overcome for appropriate protocol design and conduct.

Benefit-Risk Assessment of Plecanatide in the Treatment of Chronic Idiopathic Constipation.

Plecanatide, a uroguanylin analog, activates the guanylate cyclase C receptors in the epithelial lining of the gastrointestinal tract in a pH-dependent fashion initiating (1) the conversion of intracellular guanosine triphosphate to cyclic guanosine monophosphate, which increases the activity of the cystic fibrosis transmembrane conductance regulator to increase chloride and bicarbonate secretion into the intestinal lumen and (2) a decrease in activity of the sodium-hydrogen ion exchanger. The resulting ionic shifts cause an increase in lumenal fluid to facilitate digestion. Plecanatide has been approved by the FDA for use in chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation.

Pilot, Randomized, Blinded, Placebo-Controlled Trial Investigating the Correlation Between Acid Control and Heartburn Relief with 14 Days of Esomeprazole Treatment.

Introduction: Reflux symptoms are frequently associated with esophageal acid exposure. However, other potential causes unrelated to acid secretion are possible, and the relationship between acid control and symptomatic improvement remains unclear. This study investigated the correlation between individual intragastric pH control and heartburn relief among subjects with frequent heartburn who are likely to self-treat with over-the-counter (OTC) medications.

Elobixibat, the first-in-class Ileal Bile Acid Transporter inhibitor, for the treatment of Chronic Idiopathic Constipation.

Elobixibat is the first in class ileal bile acid transporter (IBAT) inhibitor. IBAT inhibitors block ileal absorption of bile acids by: (1) interrupting the enterohepatic circulation of bile resulting in a fall in serum cholesterol and (2) increasing the delivery of bile acids into the colon. Increasing colonic bile acids causes mucosal fluid secretion and enhances colonic motor activity.

Efficacy and safety of plecanatide in treating constipation predominant irritable bowel syndrome.

Uroguanylin interacting with intestinal Guanylate Cyclase C (GC-C) receptors plays an important role in gastrointestinal fluid and electrolyte homeostasis. Plecanatide is the first uroguanylin analog that stimulates GC-C receptors on gastrointestinal mucosa with pH-sensitive receptor binding. Binding to the GC-C receptor activates intracellular conversion of GTP to cGMP resulting in the stimulation of intestinal fluid secretion.

Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies.

Background: A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells.

A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation.

Objectives: This study assessed the efficacy and safety of plecanatide, a guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog approved for the treatment of chronic idiopathic constipation (CIC).

Methods: This phase III, multicenter, double-blind, placebo-controlled study randomized 1,394 patients with CIC. Patients received either plecanatide (3 or 6 mg) or placebo, orally, once daily, for 12 weeks.

New pharmacological treatment options for irritable bowel syndrome with constipation.

Introduction: Constipation predominant irritable bowel syndrome (IBS-C) is a common disorder and accounts for a large number of ambulatory visits. Sensory abnormalities, that is, presence of abdominal pain and discomfort, distinguish IBS-C from chronic idiopathic constipation.

Area Covered: This review focuses on the pharmacology, efficacy, safety, and future of prucalopride, YKP-10811, DSP-6952, dexloxiglumide, linaclotide, plecanatide, tenapanor, and elobixibat.

Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study.

Background: The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders.

Methods: In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan.

Exploring the physiologic role of human gastroesophageal reflux by analyzing time-series data from 24-h gastric and esophageal pH recordings.

Our previous finding of a fractal pattern for gastric pH and esophageal pH plus the statistical association of sequential pH values for up to 2 h led to our hypothesis that the fractal pattern encodes information regarding gastric acidity and that depending on the value of gastric acidity, the esophagus can signal the stomach to alter gastric acidity by influencing gastric secretion of acid or bicarbonate. Under our hypothesis values of gastric pH should provide information regarding values of esophageal pH and vice versa. We used vector autoregression, a theory-free set of inter-related linear regressions used to measure relationships that can change over time, to analyze data from 24-h recordings of gastric pH and esophageal pH.

Evaluation of esophageal sensation.

Dramatic progress has been made over the past decade in the sophistication and availability of equipment to test esophageal motility and sensation. High-resolution esophageal manometry and impedance have moved from the research clinic into clinical practice. Some of the testing is costly and time consuming, and requires extensive experience to perform the testing and properly interpret the results.

Histamine2-receptor antagonists: Rapid development of tachyphylaxis with repeat dosing.

Histamine2-receptor antagonists (H2RAs) are available over-the-counter (OTC) for the treatment and prevention of heartburn, but more than occasional, single-dose use can lead to rapid development of tachyphylaxis. The aim of this review is to assess the published evidence regarding the development of tachyphylaxis with repeat usage of H2RAs. PubMed and SCOPUS were searched across all years to identify clinical studies that examined the development of tachyphylaxis with repeated dosing of H2RAs.

Evidence-based treatment of frequent heartburn: the benefits and limitations of over-the-counter medications.

Purpose: This review summarizes the pharmacological effects of over-the-counter (OTC) heartburn drugs, and the implications for treating frequent heartburn.

Data Sources: PubMed and SCOPUS were searched across all years to identify well-controlled, randomized clinical studies that assessed mechanism of action and efficacy.

Conclusions: Antacids can transiently neutralize acid in the esophagus, but do not significantly affect gastric pH or prevent subsequent heartburn episodes.

Determination of serum antibodies to Clostridium difficile toxin B in patients with inflammatory bowel disease.

Clostridium difficile infection has increased in prevalence among patients with inflammatory bowel disease (IBD). Serum antibodies against C. difficile toxins have been detected in susceptible populations and may be protective; however, such antibodies have not been previously characterized in IBD patients.

Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation.

Background: Lubiprostone helps relieve constipation in short-term 4-week studies. There are limited data on long-term pharmacological treatment with lubiprostone for chronic idiopathic constipation.

Aims: To examine the long-term safety and effectiveness of lubiprostone in patients with chronic idiopathic constipation.

Safety aspects and rational use of a naproxen + esomeprazole combination in the treatment of rheumatoid disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for reduction of pain and inflammation, particularly in the setting of rheumatologic disorders. While effective, they are associated with risks, including nephrotoxicity, gastrointestinal inflammation, peptic ulcer disease, and worsened cardiovascular outcomes. After development of cyclo-oxygenase 2 inhibitors to minimize gastrointestinal complications, early use revealed increased cardiovascular event rate risk, and retrospective analysis of traditional NSAIDs revealed similar concerns, with the exception of naproxen.

Antisense inhibition of ICAM-1 expression as therapy provides insight into basic inflammatory pathways through early experiences in IBD.

Background: Alicaforsen (ISIS 2302), an antisense to intercellular adhesion molecule-1 (ICAM-1) (CD54), was designed to inhibit ICAM-1 expression. ICAM-1 seems to play a role in cell-mediated inflammation, specifically cell trafficking. For this reason, it may be useful in a variety of immune-mediated diseases, including inflammatory bowel disease.

New developments in gastroesophageal reflux disease diagnosis and therapy.

Purpose Of Review: Gastroesophageal reflux disease is a highly prevalent chronic condition in Western populations. It has a profound effect on our society in terms of economic cost and quality of life. There have been major advances in understanding of disease pathogenesis over the last few years which are summarized in this article.

Tegaserod in patients with mechanical sensitivity and overlapping symptoms of functional heartburn and functional dyspepsia.

Background: While functional heartburn (FH) and functional dyspepsia (FD) are recognized clinical entities, symptoms often overlap across both disorders. Despite their frequency, little is known of the underlying pathophysiology of overlapping symptoms. This study evaluated the effect of the 5-HT(4) agonist, tegaserod, on visceral sensitivity and symptom improvement in patients with overlapping symptoms of FH and FD.

Time esophageal pH < 4 overestimates the prevalence of pathologic esophageal reflux in subjects with gastroesophageal reflux disease treated with proton pump inhibitors.

Background: A Stanford University study reported that in asymptomatic GERD patients who were being treated with a proton pump inhibitor (PPI), 50% had pathologic esophageal acid exposure.

Aim: We considered the possibility that the high prevalence of pathologic esophageal reflux might simply have resulted from calculating acidity as time pH < 4.

Methods: We calculated integrated acidity and time pH < 4 from the 49 recordings of 24-hour gastric and esophageal pH from the Stanford study as well as from another study of 57 GERD subjects, 26 of whom were treated for 8 days with 20 mg omeprazole or 20 mg rabeprazole in a 2-way crossover fashion.

Effect of esophageal acid and prophylactic rabeprazole on performance in runners.

Introduction: Acid reflux occurs during exercise. The effects of esophageal acid and prophylactic antisecretory treatment on exercise performance are unknown.

Aims: To determine 1) the effect of esophageal acid perfusion during exercise on pulmonary function and exercise performance, and 2) whether acid suppression with rabeprazole (RAB) 20 mg x d(-1) increases exercise performance during esophageal acid infusion.