Cardiovascular Effects of Stimulators of Soluble Guanylate Cyclase Administration: A Meta-analysis of Randomized Controlled Trials.

PURPOSE OF REVIEW: Heart failure (HF) is one of the main causes of cardiovascular mortality in the western world. Despite great advances in treatment, recurrence and mortality rates remain high. Soluble guanylate cyclase is an enzyme which, by producing cGMP, is responsible for the effects of vasodilation, reduction of cardiac pre- and after-load and, therefore, the improvement of myocardial performance. Thus, a new therapeutic strategy is represented by the stimulators of soluble guanylate cyclase (sGCs). The aim of this meta-analysis was to analyze the effects deriving from the administration of sGCs, in subjects affected by HF. A systematic literature search of Medline, SCOPUS, and Google Scholar was conducted up to December 2022 to identify RCTs assessing the cardiovascular effects, as NT-pro-BNP values and ejection fraction (EF), and all-cause mortality, of the sGCs. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RECENT FINDINGS: The results obtained documented a statistically significant improvement in NT-proBNP values (SMD: - 0.258; 95% CI: - 0.398, - 0.118; p < 0.001) and EF (WMD: 0.948; 95% CI: 0.485, 1.411; p < 0.001) in subjects treated with sGCs; however, no significant change was found in the all-cause mortality rate (RR 0.96; 95% CI 0.868 to 1.072; I2, p = 0). The sGCs represent a valid therapeutic option in subjects suffering from HF, leading to an improvement in cardiac performance.

Randomized controlled trial of linaclotide in children aged 6-17 years with functional constipation.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for treatment of children 6-17 years old with functional constipation (FC). This study evaluated the safety and efficacy of several linaclotide doses in children 6-17 years old with FC. METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase 2 study, 173 children with FC (based on Rome III criteria) were randomized to once-daily linaclotide (A: 9 or 18 µg, B: 18 or 36 µg, or C: 36 or 72 µg) or placebo in a 1:1:1:1 ratio for 6- to 11-year-olds (dosage determined by weight: 18 to <35 or ≥35 kg) and linaclotide (18, 36, 72, or 145 µg) or placebo in a 1:1:1:1:1 ratio for 12- to 17-year-olds. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency throughout the 4-week treatment period. Adverse events (AE), clinical laboratory values, and electrocardiograms were monitored. RESULTS: Efficacy and safety were assessed in 173 patients (52.0% aged 6-11 years; 48.0% aged 12-17 years); 162 (93.6%) completed the treatment period. A numerical improvement in mean SBM frequency was observed with increasing linaclotide doses (1.90 in 6- to 11-year-olds [36 or 72 µg] and 2.86 in 12- to 17-year-olds [72 µg]). The most reported treatment-emergent AE was diarrhea, with most cases being mild; none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population, with a trend toward efficacy in the higher doses, warranting further evaluation.

Mechanisms of Action of Current Pharmacologic Options for the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

Multiple therapeutic agents are currently available for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. A better understanding of the mechanism of action of each treatment provides important insights into expected responses and is key to optimizing treatment outcomes. Some constipation treatments, such as stimulant laxatives, may increase bowel movement frequency but are ineffective at relieving, and may even exacerbate, abdominal symptoms. On the contrary, prescription treatments, such as the guanylyl cyclase-C agonists, for example, may improve bowel symptoms and reduce visceral hypersensitivity. This review summarizes the mechanisms of action of commonly used over-the-counter and prescription therapies for chronic idiopathic constipation and irritable bowel syndrome with constipation, outlining how these mechanisms contribute to the efficacy and safety of each treatment option.

Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3',5'-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics.

Efficacy of Linaclotide in Reducing Abdominal Symptoms of Bloating, Discomfort, and Pain: A Phase 3B Trial Using a Novel Abdominal Scoring System.

INTRODUCTION: Linaclotide improves abdominal pain and constipation in patients with constipation-predominant irritable bowel syndrome (IBS-C). Patients report additional bothersome abdominal symptoms of bloating and discomfort. The intention of this study was to evaluate linaclotide's efficacy in relieving IBS-C-related abdominal symptoms (bloating, discomfort, and pain) using a novel multi-item Abdominal Score (AS). METHODS: Patients with IBS-C with abdominal pain ≥3 (0-10 scale) were randomized to linaclotide 290 µg or placebo daily for 12 weeks. The AS, derived from the Diary for IBS Symptoms-Constipation, is the average of abdominal bloating, discomfort, and pain at their worst (0 = none, 10 = worst possible). The primary end point was overall change from baseline (CFB) in AS. Secondary end points included CFB in 12-week AS evaluated using cumulative distribution function and 6-week/12-week AS responder (AS improvement ≥2 points for ≥6-week/12-week). RESULTS: Overall, 614 patients (mean age 46.7 years; 81% female) were randomized. All prespecified end points showed significant benefit of linaclotide vs placebo. The mean overall CFB AS reduction for linaclotide was -1.9 vs -1.2 for placebo (P < 0.0001); the 6-week/12-week AS responder rate was 40.5% for linaclotide vs 23.4% for placebo (odds ratio = 2.2 [95% confidence interval, 1.55-3.12; P < 0.0001]). Diarrhea was the most common treatment-emergent adverse event (linaclotide = 4.6%, placebo = 1.6%). DISCUSSION: Linaclotide significantly reduced multiple abdominal symptoms important to patients with IBS-C (bloating, discomfort, and pain) compared with placebo, as measured by a novel multi-item AS. The AS, derived from the Diary for IBS Symptoms-Constipation, should be considered for use in future IBS-C clinical studies to measure clinically meaningful improvements beyond traditional end points.

Improving the Gastrointestinal Stability of Linaclotide.

High susceptibility to proteolytic degradation in the gastrointestinal tract limits the therapeutic application of peptide drugs in gastrointestinal disorders. Linaclotide is an orally administered peptide drug for the treatment of irritable bowel syndrome with constipation (IBS-C) and abdominal pain. Linaclotide is however degraded in the intestinal environment within 1 h, and improvements in gastrointestinal stability might enhance its therapeutic application. We therefore designed and synthesized a series of linaclotide analogues employing a variety of strategic modifications and evaluated their gastrointestinal stability and pharmacological activity at its target receptor guanylate cyclase-C. All analogues had substantial improvements in gastrointestinal half-lives (>8 h vs linaclotide 48 min), and most remained active at low nanomolar concentrations. This work highlights strategic approaches for the development of gut-stable peptides toward the next generation of orally administered peptide drugs for the treatment of gastrointestinal disorders.

The Use of Linaclotide in Children with Functional Constipation or Irritable Bowel Syndrome: A Retrospective Chart Review.

BACKGROUND: Linaclotide is a well-tolerated and effective agent for adults with functional constipation (FC) or irritable bowel syndrome with constipation (IBS-C). However, data in children are lacking. The aim of this study is to examine the efficacy and safety of linaclotide in children. METHODS: We performed a retrospective review of children < 18 years old who started linaclotide at our institution (Nationwide Children's Hospital, Columbus, Ohio). We excluded children already using linaclotide or whom had an organic cause of constipation or abdominal pain. We recorded information on patient characteristics, medical and surgical history, symptoms, clinical response, course of treatment, and adverse events at baseline, first follow-up, and after 1 year of linaclotide use. A positive clinical response was based on the physician's global assessment of symptoms at the time of the visit as documented. RESULTS: We included 93 children treated with linaclotide for FC (n = 60) or IBS-C (n = 33); 60% were female; median age was 14.7 years (IQR 13.2-16.6). Forty-five percent of patients with FC and 42% with IBS-C had a positive clinical response at first follow-up a median of 2.5 and 2.4 months after starting linaclotide, respectively. Approximately a third of patients experienced adverse events and eventually 27% stopped using linaclotide due to adverse events. The most common adverse events were diarrhea, abdominal pain, nausea, and bloating. CONCLUSION: Nearly half of children with FC or IBS-C benefited from linaclotide, but adverse events were relatively common. Further prospective, controlled studies are needed to confirm these findings and to identify which patients are most likely to benefit from linaclotide.

Soluble guanylate cyclase stimulators and their potential use: a patent review.

Introduction: In 2013, riociguat a potent and specific stimulator of the soluble guanylyl cyclase (sGC) was approved as first in class sGC stimulator which reflected a first culmination of intense research and development efforts starting in the mid 1990ies. In the meantime, it turned out that triggering cGMP production by sGC stimulators could have a broad treatment potential. In consequence, various pharmaceutical companies are still very active in identifying novel chemistry for sGC stimulators. After the first generation of sGC stimulators like riociguat or lificiguat, new compound classes with different physicochemical and kinetic profiles were identified, like the sGC stimulators vericiguat or praliciguat.Area covered: Patent literature on sGC stimulators with a focus on recent compounds of the years 2014-2019 as on claimed use and formulations of these compounds. The information was collected from publicly available data sources only (MedLine, EmBase, Chemical Abstracts, Orbit, Dolphin).Expert Opinion: With the recent advancements reported in the patent literature, sGC stimulators might be differentiated due to tissue selectivity or route of application although exhibiting the same molecular mode of action. The indication space of these compounds is potentially very broad and multiple indications in cardiovascular diseases and beyond are under investigation.

Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation.

INTRODUCTION: Immediate-release (IR) formulation of linaclotide 290 µg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects. METHODS: This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 µg; MD-7246 30, 100, or 300 µg; or IR 290 µg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. RESULTS: Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. DISCUSSION: Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.

Peripheral Guanylate Cyclase-C modulation of corticolimbic activation and corticotropin-releasing factor signaling in a rat model of stress-induced colonic hypersensitivity.

BACKGROUND: Psychological stress is a risk factor for irritable bowel syndrome, a functional gastrointestinal pain disorder featuring abnormal brain-gut connectivity. The guanylate cyclase-C (GC-C) agonist linaclotide has been shown to relieve abdominal pain in IBS-C and exhibits antinociceptive effects in rodent models of post-inflammatory visceral hypersensitivity. However, the role GC-C signaling plays in psychological stress-induced visceral hypersensitivity is unknown. Here, we test the hypothesis that GC-C agonism reverses stress-induced colonic hypersensitivity via inhibition of nociceptive afferent signaling resulting in normalization of stress-altered corticotropin-releasing factor (CRF) expression in brain regions involved in pain perception and modulation. METHODS: Adult female rats were exposed to water avoidance stress or sham stress for 10 days, and the effects of linaclotide on stress-induced changes in colonic sensitivity, corticolimbic phospho-extracellular signal-regulated kinase (pERK), and CRF expression were measured using a combination of behavioral assessments, immunohistochemistry, and qRT-PCR. KEY RESULTS: Stressed rats exhibited colonic hypersensitivity and elevated corticolimbic pERK on day 11, which was inhibited by linaclotide. qRT-PCR analysis revealed dysregulated CRF expression in the medial prefrontal cortex, paraventricular nucleus of the hypothalamus, and central nucleus of the amygdala on day 28. Dysregulated CRF expression was not affected by linaclotide treatment. CONCLUSIONS AND INFERENCES: Our results demonstrate that exposure to repeated stress induces chronic colonic hypersensitivity in conjunction with altered corticolimbic activation and CRF expression. GC-C agonism attenuated stress-induced colonic hypersensitivity and ERK phosphorylation, but had no effect on CRF expression, suggesting the analgesic effects of linaclotide occur independent of stress-driven CRF gene expression in corticolimbic circuitry.

ACG Clinical Guideline: Management of Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a highly prevalent, chronic disorder that significantly reduces patients' quality of life. Advances in diagnostic testing and in therapeutic options for patients with IBS led to the development of this first-ever American College of Gastroenterology clinical guideline for the management of IBS using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Twenty-five clinically important questions were assessed after a comprehensive literature search; 9 questions focused on diagnostic testing; 16 questions focused on therapeutic options. Consensus was obtained using a modified Delphi approach, and based on GRADE methodology, we endorse the following: We suggest that a positive diagnostic strategy as compared to a diagnostic strategy of exclusion be used to improve time to initiating appropriate therapy. We suggest that serologic testing be performed to rule out celiac disease in patients with IBS and diarrhea symptoms. We suggest that fecal calprotectin be checked in patients with suspected IBS and diarrhea symptoms to rule out inflammatory bowel disease. We recommend a limited trial of a low fermentable oligosaccharides, disacchardies, monosaccharides, polyols (FODMAP) diet in patients with IBS to improve global symptoms. We recommend the use of chloride channel activators and guanylate cyclase activators to treat global IBS with constipation symptoms. We recommend the use of rifaximin to treat global IBS with diarrhea symptoms. We suggest that gut-directed psychotherapy be used to treat global IBS symptoms. Additional statements and information regarding diagnostic strategies, specific drugs, doses, and duration of therapy can be found in the guideline.

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 1.73 m2, and urine albumin-creatinine ratio 200-5000 mg/g treated with renin-angiotensin system inhibitors were randomly allocated 1:1:1 to placebo, 20 mg praliciguat, or 40 mg praliciguat daily for 12 weeks. The primary efficacy and safety outcomes were change from baseline to weeks 8 and 12 in urine albumin-creatinine ratio and treatment-emergent adverse events, respectively. Other outcomes assessed were 24-hour ambulatory BP and metabolic parameters. RESULTS: Of 156 participants randomized, 140 (90%) completed the study. The primary efficacy analysis demonstrated a mean change from baseline in urine albumin-creatinine ratio of -28% (90% confidence interval, -36 to -18) in the pooled praliciguat group and -15% (-28 to 0.4) in the placebo group (difference -15%; -31 to 4; P=0.17). Between-group decreases from baseline to week 12 for praliciguat versus placebo were seen in mean 24-hour systolic BP (-4 mm Hg; -8 to -1), hemoglobin A1c (-0.3%; -0.5 to -0.03), and serum cholesterol (-10 mg/dl; -19 to -1). The incidence of treatment-emergent adverse events was similar in the pooled praliciguat and placebo groups (42% and 44%, respectively). Serious adverse events, events leading to study drug discontinuation, and events potentially related to BP lowering were reported at higher frequency in the 40-mg group but were similar in 20-mg and placebo groups. CONCLUSIONS: Praliciguat treatment for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. Nonetheless, the observed changes in urine albumin-creatinine ratio, BP, and metabolic variables may support further investigation of praliciguat in diabetic kidney disease. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: A Study to Evaluate the Soluble Guanylate Cyclase (sGC) Stimulator IW-1973 in Diabetic Nephropathy/Diabetic Kidney Disease as Measured by Albuminuria, NCT03217591.

An update on guanylyl cyclase C in the diagnosis, chemoprevention, and treatment of colorectal cancer.

Introduction: Colorectal cancer remains the second leading cause of cancer death in the United States, underscoring the need for novel therapies. Despite the successes of new targeted agents for other cancers, colorectal cancer suffers from a relative scarcity of actionable biomarkers. In this context, the intestinal receptor, guanylyl cyclase C (GUCY2C), has emerged as a promising target.Areas covered: GUCY2C regulates a tumor-suppressive signaling axis that is silenced through loss of its endogenous ligands at the earliest stages of tumorigenesis. A body of literature supports a cancer chemoprevention strategy involving reactivation of GUCY2C through FDA-approved cGMP-elevating agents such as linaclotide, plecanatide, and sildenafil. Its limited expression in extra-intestinal tissues, and retention on the surface of cancer cells, also positions GUCY2C as a target for immunotherapies to treat metastatic disease, including vaccines, chimeric antigen receptor T-cells, and antibody-drug conjugates. Likewise, GUCY2C mRNA identifies metastatic cells, enhancing colorectal cancer detection, and staging. Pre-clinical and clinical programs exploring these GUCY2C-targeting strategies will be reviewed.Expert opinion: Recent mechanistic insights characterizing GUCY2C ligand loss early in tumorigenesis, coupled with results from the first clinical trials testing GUCY2C-targeting strategies, continue to elevate GUCY2C as an ideal target for prevention, detection, and therapy.

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. Praliciguat monotherapy did not affect hemodynamics. In contrast, enalapril monotherapy lowered blood pressure but did not attenuate proteinuria. Renal expression of genes in pathways involved in inflammation, fibrosis, oxidative stress, and kidney injury was lower in praliciguat-treated obese ZSF1 rats than in obese control rats; fasting glucose and cholesterol were also lower with praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacological effects on the kidneys, we studied the effects of praliciguat on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTCs). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein-1 in tumor necrosis factor-α-challenged RPTCs. Praliciguat treatment also attenuated transforming growth factor-ß-mediated apoptosis, changes to a mesenchyme-like cellular phenotype, and phosphorylation of SMAD3 in RPTCs. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of diabetic nephropathy, and its actions in human RPTCs suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.

Pharmacologic Treatments for Irritable Bowel Syndrome: an Umbrella Systematic Review.

BACKGROUND AND AIMS: Multiple pharmacologic treatments are available for the management of irritable bowel syndrome (IBS), and a large body of evidence has been presented. However, the strength and credibility of the evidence have not been comprehensively evaluated. We aimed to review the systematic reviews and meta- analyses of pharmacologic treatments for IBS and evaluate the credibility of the findings. METHODS: We searched MEDLINE, Embase, and Cochrane library from inception to September 2019 for systematic reviews evaluating the effectiveness of pharmacologic treatments for IBS. We summarized relative ratios (RR), evaluated the credibility of the evidence and classified the evidence into convincing, highly suggestive, suggestive, and weak. RESULTS: We included 11 systematic reviews with 40 meta-analyses (330 randomized controlled trials and 86,459 participants) assessing 10 treatment categories and 2 drugs. Most of the pharmacologic treatments were significantly superior over placebo as reported by the included meta-analyses. The evidence for 5-hydroxytryptamine (5-HT)3 antagonists (RR=1.56, 95%CI: 1.43-1.71), antispasmodics (RR=1.19, 95%CI: 1.02-1.39), and alosetron (RR=1.46, 95%CI: 1.26-1.71) were highly suggestive for relieving global IBS symptoms. 5-HT4 agonists (RR= 1.26, 95%CI: 1.19-1.34) and guanylate cyclase-C (GCC) agonists (RR=1.73, 95%CI: 1.54-1.95) were found to give convincing evidence for the improvement of the responder rate. 5-HT3 antagonists (RR=1.32, 95%CI: 1.26-1.38) offered convincing evidence for relieving abdominal pain. CONCLUSIONS: Evidence for 5-HT3 antagonists, 5-HT4 agonists and GCC agonists, antispasmodics, and alosetron were suggestive for the treatment of IBS. However, owing to the risk of bias in randomization methods, the results for GCC should be interpreted with caution.

Deciphering ion transporters, kinases and PDZ-adaptor molecules that mediate guanylate cyclase C agonist-dependent intestinal fluid loss in vivo.

BACKGROUND: The molecular basis for heat-stable Escherichia coli enterotoxin (STa) action and its synthetic analogue linaclotide is well understood at the enterocyte level. Pharmacologic strategies to prevent STa-induced intestinal fluid loss by inhibiting its effector molecules, however, have achieved insufficient inhibition in vivo. AIMS AND EXPERIMENTAL APPROACH: To investigate whether the currently discussed effector molecules and signaling mechanisms of STa/linaclotide-induced diarrhea have similar relevance in vivo than at the enterocyte level, we studied the effect of 10-7M of the STa analogue linaclotide on short circuit current (Isc) of chambered isolated jejunal mucosa, and on the in vivo action on fluid transport in a perfused segment of proximal jejunum of anesthetized mice. The selected mice were deficient of transport (NHE3, CFTR, Slc26a3/a6), adaptor (NHERF1-3), or signal transduction molecules [cGMP-dependent kinase II (GKII)] considered to be downstream effectors after STa/linaclotide binding to guanylate cyclase C (GCC). Selective NHE3 inhibition by tenapanor was also employed. KEY RESULTS, CONCLUSIONS AND IMPLICATIONS: The comparison allowed the separation of effectors for stimulation of electrogenic anion secretion and for inhibition of electrolyte/fluid absorption in response to STa/linaclotide. The cGKII-NHERF1-CFTR and cGKII-NHERF2-NHE3 interactions are indeed major effectors of small intestinal fluid loss downstream of GCC activation in vitro and in vivo, but 50% of the linaclotide-induced fluid loss in vivo, while dependent on CFTR activation and NHE3 inhibition, does not involve cGKII, and 30% does not depend on NHERF1 or NHERF2. A combined NHERF1 and NHERF2 inhibition appears nevertheless a good pharmacological strategy against STa-mediated fluid loss.

Chronic Constipation in the United States: Results From a Population-Based Survey Assessing Healthcare Seeking and Use of Pharmacotherapy.

OBJECTIVES: Chronic idiopathic constipation (CIC) is characterized by unsatisfactory defecation and difficult or infrequent stools. CIC affects 9%-20% of adults in the United States, and although prevalent, gaps in knowledge remain regarding CIC healthcare seeking and medication use in the community. We recruited a population-based sample to determine the prevalence and predictors of (i) individuals having discussed their constipation symptoms with a healthcare provider and (ii) the use of constipation therapies. METHODS: We recruited a representative sample of Americans aged 18 years or older who had experienced constipation. Those who met the Rome IV criteria for irritable bowel syndrome and opioid-induced constipation were excluded. The survey included questions on constipation severity, healthcare seeking, and the use of constipation medications. We used multivariable regression methods to adjust for confounders. RESULTS: Overall, 4,702 participants had experienced constipation (24.0% met the Rome IV CIC criteria). Among all respondents with previous constipation, 37.6% discussed their symptoms with a clinician (primary care provider 87.6%, gastroenterologist 26.0%, and urgent care/emergency room physician 7.7%). Age, sex, race/ethnicity, marital status, employment status, having a source of usual care, insurance status, comorbidities, locus of control, and constipation severity were associated with seeking care (P < 0.05). Overall, 47.8% of respondents were taking medication to manage their constipation: over-the-counter medication(s) only, 93.5%; prescription medication(s) only, 1.3%; and both over-the-counter medication(s) and prescription medication(s), 5.2%. DISCUSSION: We found that 3 of 5 Americans with constipation have never discussed their symptoms with a healthcare provider. Furthermore, the use of prescription medications for managing constipation symptoms is low because individuals mainly rely on over-the-counter therapies.

Rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved ejection fraction (CAPACITY HFpEF).

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality worldwide. Exercise intolerance is the main symptom of HFpEF and is associated with a poor quality of life and increased mortality. Currently, there are no approved medications for the treatment of HFpEF. Praliciguat (IW-1973), a novel soluble guanylate cyclase stimulator that may help restore deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine 3',5'-monophosphate signaling, is being investigated for the treatment of patients with HFpEF. METHODS: CAPACITY HFpEF is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacy of praliciguat over 12 weeks in approximately 184 patients with HFpEF. Eligible patients must have evidence supporting clinical HFpEF and at least 2 of the following 4 conditions associated with NO deficiency: diabetes/prediabetes, hypertension, obesity, and age >70 years. The primary efficacy end point is the change from baseline in peak VO2 by cardiopulmonary exercise test (CPET). Secondary end points include the change from baseline in 6-minute walk test distance and the change in ventilatory efficiency on CPET, as well as number of CPET responders. Other exploratory end points include changes in echocardiographic parameters, New York Heart Association functional classification, cardiac events, blood and urine biomarkers pathophysiologically relevant to heart failure, and patient-reported outcomes including Kansas City Cardiomyopathy Questionnaire. CONCLUSIONS: The CAPACITY HFpEF trial will provide data on short-term safety and efficacy of praliciguat on peak exercise capacity, as well as multiple secondary end points of submaximal functional capacity, patient-reported outcomes, and biomarkers.

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

Introduction: 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).Areas covered: 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.Expert opinion: The Expert Opinion section discusses safety and efficacy of plecanatide for IBS-C. Broader consideration of some of the inherent challenges in understanding and treating functional gastrointestinal disorders includes: 1. the difficulty of understanding diseases with complex pathophysiology that clinically present with a few simple symptoms, 2. exploring the pathophysiology of functional diseases using pharmacophysiology, 3. value of 'Set Theory' in the evaluation of complex clinical data and 4. physiologic and pathophysiologic insight gained by evaluation 'physiologic redundancy' and 'conservation of function'.

Oral Pharmacological Activation of Hypothalamic Guanylate Cyclase 2C Receptor Stimulates Brown Fat Thermogenesis to Reduce Body Weight.

Linaclotide is a synthetic peptide approved by the FDA for the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. Linaclotide binds and activates the transmembrane receptor guanylate cyclase 2C (Gucy2c). Uroguanylin (UGN) is a 16 amino acid peptide that is mainly secreted by enterochromaffin cells in the duodenum and proximal small intestine. UGN is the endogenous ligand of Gucy2c and decreases body weight in diet-induced obese (DIO) mice via the activation of the thermogenic program in brown adipose tissue. Therefore, we wanted to evaluate whether oral linaclotide could also improve DIO mice metabolic phenotype. In this study, we have demonstrated that DIO mice orally treated with linaclotide exhibited a significant reduction of body weight without modifying food intake. Linaclotide exerts its actions through the central nervous system, and more specifically, via Gucy2c receptors located in the mediobasal hypothalamus, leading to the activation of the sympathetic nervous system to trigger the thermogenic activity of brown fat stimulating energy expenditure. These findings indicate for first time that, in addition to its effects at intestinal level to treat irritable bowel syndrome with constipation and chronic constipation, linaclotide also exerts a beneficial effect in whole body metabolism.