FAAH inhibitor URB597 shows anti-hyperalgesic action and increases brain and intestinal tissues fatty acid amides in a model of CRF agonist mediated visceral hypersensitivity in male rats.

Background And Aims: The endocannabinoid (eCB) system includes ligands (anandamide and 2-arachidonoyl glycerol, 2-AG), receptors and catabolizing enzymes (fatty acid amide hydrolase, FAAH and monoacylglycerol lipase) expressed in both the brain and gut. We investigated whether the FAAH inhibitor, URB597, influenced visceral pain to colorectal distension (CRD) in an acute stress-related model of visceral hypersensitivity induced by the selective corticotropin-releasing factor receptor subtype 1 (CRF) agonist, cortagine.

Methods: Male Sprague-Dawley rats were injected subcutaneously (SC) with URB597 (3 mg/kg) or vehicle and 2 h later, intraperitoneally with cortagine (10 μg/kg) or vehicle.

The CNS-penetrant soluble guanylate cyclase stimulator CYR119 attenuates markers of inflammation in the central nervous system.

Background: Inflammation in the central nervous system (CNS) is observed in many neurological disorders. Nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling plays an essential role in modulating neuroinflammation. CYR119 is a CNS-penetrant sGC stimulator that amplifies endogenous NO-sGC-cGMP signaling.

The CNS-Penetrant Soluble Guanylate Cyclase Stimulator CY6463 Reveals its Therapeutic Potential in Neurodegenerative Diseases.

Effective treatments for neurodegenerative diseases remain elusive and are critically needed since the burden of these diseases increases across an aging global population. Nitric oxide (NO) is a gasotransmitter that binds to soluble guanylate cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP). Impairment of this pathway has been demonstrated in neurodegenerative diseases.

Differential Bile Acid Detection in Refractory GERD Patient Saliva Using a Simple and Sensitive Liquid Chromatography Tandem Mass Spectrometry Approach.

Goals: The aim was to measure bile acids in human saliva using a sensitive ultraperformance liquid chromatography tandem mass spectrometry analysis method to distinguish quantitative differences in refractory gastroesophageal reflux disease (GERD) patients as compared with proton pump inhibitor (PPI) controlled GERD patients and healthy volunteers.

Study: Human saliva samples were analyzed from 2 separate studies. The first a meal-controlled pilot, in which premeal and postmeal saliva samples were analyzed from 20 healthy subjects and 20 patients with GERD symptoms controlled by PPIs.

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease: A Randomized Placebo-Controlled Clinical Trial.

Background And Objectives: Impaired nitric oxide signaling through soluble guanylate cyclase has been implicated in the pathophysiology of diabetic kidney disease. Praliciguat, a soluble guanylate cyclase stimulator that amplifies nitric oxide signaling, inhibited kidney inflammation and fibrosis in animal models.

Design, Setting, Participants, & Measurements: In a phase 2 trial, 156 adults with type 2 diabetes, eGFR 30-75 ml/min per 1.

Praliciguat inhibits progression of diabetic nephropathy in ZSF1 rats and suppresses inflammation and apoptosis in human renal proximal tubular cells.

Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In the present study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy.

An impaired natriuretic peptide hormone system may play a role in COVID-19 severity in vulnerable populations.

Advanced age, underlying cardiovascular disease (including hypertension), and obesity are associated with a higher risk of progression to severe hypoxemia, acute respiratory distress syndrome (ARDS), and death in COVID-19-infected patients. African Americans have a higher degree of COVID-19 mortality. The incidence of salt-sensitive hypertension is higher in older individuals and African Americans.

Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease.

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5' GMP (cGMP) signaling plays a central role in regulation of diverse processes including smooth muscle relaxation, inflammation, and fibrosis. sGC is activated by the short-lived physiologic mediator NO. sGC stimulators are small-molecule compounds that directly bind to sGC to enhance NO-mediated cGMP signaling.

Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of praliciguat, a clinical-stage soluble guanylate cyclase stimulator in rats.

The pharmacokinetics (PK), metabolism, excretion, mass balance, and tissue distribution of [ C]praliciguat were evaluated following oral administration of a 3-mg/kg dose in Sprague-Dawley rats and in a quantitative whole-body autoradiography (QWBA) study conducted in male Long-Evans rats. Plasma T was 1 hour and the t of total plasma radioactivity was 23.7 hours.

An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension.

Aims/hypothesis: Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension.

Methods: This Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose- and BP-lowering therapies.

Soluble guanylate cyclase stimulator praliciguat attenuates inflammation, fibrosis, and end-organ damage in the Dahl model of cardiorenal failure.

Reduced nitric oxide (NO) and a decrease in cGMP signaling mediated by soluble guanylate cyclase (sGC) has been linked to the development of several cardiorenal diseases. Stimulation of sGC is a potential means for enhancing cGMP production in conditions of reduced NO bioavailability. The purpose of our studies was to determine the effects of praliciguat, a clinical-stage sGC stimulator, in a model of cardiorenal failure.

sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH.

Endothelial dysfunction and reduced nitric oxide (NO) signaling are a key element of the pathophysiology of nonalcoholic steatohepatitis (NASH). Stimulators of soluble guanylate cyclase (sGC) enhance NO signaling; have been shown preclinically to reduce inflammation, fibrosis, and steatosis; and thus have been proposed as potential therapies for NASH and fibrotic liver diseases. Praliciguat, an oral sGC stimulator with extensive distribution to the liver, was used to explore the role of this signaling pathway in NASH.

Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis.

Background: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population.

Methods: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12-26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks.

A Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Soluble Guanylate Cyclase Stimulator Praliciguat in Healthy Subjects.

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling is central to the regulation of several physiological processes, including blood flow and inflammation. Deficient NO signaling is implicated in multiple diseases. sGC stimulators are small molecules that enhance sGC activity, particularly in combination with NO.

Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease.

Soluble guanylate cyclase (sGC), a key signal-transduction enzyme, increases the conversion of guanosine-5'-triphosphate to cGMP upon binding of nitric oxide (NO). Endothelial dysfunction and/or reduced NO signaling have been implicated in cardiovascular disease pathogenesis and complications of diabetes and have been associated with other disease states and aging. Soluble guanylate cyclase (sGC) stimulators are small-molecule drugs that bind sGC and enhance NO-mediated cGMP signaling.

Linaclotide in irritable bowel syndrome with constipation: A Phase 3 randomized trial in China and other regions.

Background And Aim: Linaclotide is a guanylate cyclase-C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS-C). China has unmet need for well-tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS-C. This trial evaluated linaclotide's efficacy and safety in IBS-C patients in China and other regions.

Low-Dose Linaclotide (72 μg) for Chronic Idiopathic Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial.

Objectives: Linaclotide is a guanylate cyclase-C agonist approved in the United States, Canada, and Mexico at a once-daily 145-μg dose for the treatment of chronic idiopathic constipation (CIC); a once-daily 72-μg dose for CIC recently received FDA approval. The trial objective was to evaluate the efficacy and safety of a 72-μg linaclotide dose in CIC patients.

Methods: This double-blind, placebo-controlled trial randomized patients with CIC (Rome III criteria) to once-daily linaclotide 72 μg or 145 μg, or placebo for 12 weeks.

Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans.

In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.

Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial.

Background: Abdominal bloating is a common and bothersome symptom of chronic idiopathic constipation. The objective of this trial was to evaluate the efficacy and safety of linaclotide in patients with chronic idiopathic constipation and concomitant moderate-to-severe abdominal bloating.

Methods: This Phase 3b, randomized, double-blind, placebo-controlled clinical trial randomized patients to oral linaclotide (145 or 290 μg) or placebo once daily for 12 weeks.

MRP4 Modulation of the Guanylate Cyclase-C/cGMP Pathway: Effects on Linaclotide-Induced Electrolyte Secretion and cGMP Efflux.

MRP4 mediates the efflux of cGMP and cAMP and acts as an important regulator of these secondary messengers, thereby affecting signaling events mediated by cGMP and cAMP. Immunofluorescence staining showed high MRP4 expression localized predominantly in the apical membrane of rat colonic epithelium. In vitro studies were performed using a rat colonic mucosal layer mounted in an Ussing chamber.