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Abo Elnaga AA, Serag I, Alsaied MA, Khalefa BB, Rajput J, Ramadan S, Elettreby AM. Efficacy and safety of tenapanor vs placebo in treating CKD patients on dialysis and with hyperphosphatemia: a systematic review and meta-analysis of 2251 patients. Int Urol Nephrol 2025; 57:1835-1850. [PMID: 39702842 DOI: 10.1007/s11255-024-04316-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/26/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND Hyperphosphatemia is common in chronic kidney disease (CKD) patients, especially patients on hemodialysis. Tenapanor is a novel drug with fewer side effects and high compliance compared to traditional phosphate binders. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of tenapanor. METHODS A comprehensive search was conducted on PubMed, Scopus, Web of Science, and Cochrane Library, from inception to June 25, 2024. Nine randomized controlled trials (RCTs) and three single-arm studies comparing tenapanor to placebo were included. By adopting a random-effect empirical Bayes model, STATA and RevMan were used to pool dichotomous and continuous data. The primary outcome assessed was serum phosphate. Secondary outcomes included intact parathyroid hormone (iPTH), serum calcium, potassium, and sodium, bowel movement frequency, stool consistency using BSFS score and safety outcomes. RESULTS Twelve studies with a total of 2,251 patients were included. Tenapanor was superior to placebo in reducing phosphate at all assessed end points, week 1 (MD = -1.28 mg/dL, P < 0.001), week 2 (MD = -1.07 mg/dL, P < 0.001), week 3 (MD = -1.22 mg/dL, P < 0.001), and week 4 (MD = -0.91 mg/dL, P < 0.001). In addition, iPTH was almost statistically significantly lower in the tenapanor group (MD = -36.53 ng/L, P = 0.07). Moreover, it led to a statistically significant reduction in sodium level (MD = -0.7 mmol/L, P = 0.0003). On the contrary, tenapanor had no statistically significant effect on calcium or potassium levels. Bowel movement frequency and stool consistency were significantly higher in the tenapanor group at all assessed end points. Regarding safety analysis, diarrhea and nausea were statistically significantly higher in the tenapanor group, (RR = 3.71, P < 0.001) and (RR = 1.97, P < 0.001), respectively. There were no significant differences in other adverse events. CONCLUSION Based on our meta-analysis, tenapanor can effectively reduce serum phosphate, iPTH, and sodium. Additionally, it improves bowel movement frequency and stool consistency. However, it is associated with a higher risk of GIT symptoms that should be considered and managed during treatment. We recommend conducting further RCTs to perform head-to-head comparisons against other active comparators such as phosphate binders.
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Affiliation(s)
| | - Ibrahim Serag
- Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | | | | | - Jaisingh Rajput
- Vaughn Clinic, Department of Family Medicine, Baptist Family Medicine Residency Program, Montgomery Alabama, USA
| | - Shrouk Ramadan
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Copur S, Burlacu A, Kanbay M. Novel approaches in antihypertensive pharmacotherapeutics. Curr Opin Nephrol Hypertens 2025:00041552-990000000-00228. [PMID: 40265521 DOI: 10.1097/mnh.0000000000001081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
PURPOSE OF REVIEW The management of hypertension remains suboptimal despite the widespread use of multiple antihypertensive medication groups. We hereby aim to evaluate the novel therapeutic approaches for the management of hypertension. RECENT FINDINGS As the decline in SBP and/or DBP is associated with a significant decline in major adverse cardiovascular events and all-cause mortality, the optimal management of hypertension is at most importance. The high prevalence of resistant hypertension, approximately 10% of hypertensive population, remains a major concern associated with high morbidity and mortality. Recently, multiple novel pharmacotherapeutic approaches have been implicated in the management of hypertension on various pathophysiological mechanisms, including aldosterone synthetase inhibitors, RNA-based therapies such as antisense oligonucleotides and small-interfering RNA, atrial natriuretic peptide analogs, dual endothelin antagonists, intestinal sodium-hydrogen exchanger-3 inhibitors, compound 17b and nonsteroidal mineralocorticoid receptor antagonists. SUMMARY Pharmacotherapeutic management options for hypertension is a growing field of research with potential clinical implications for multiple agents in upcoming years. Such novel approaches have the potential to improve clinical outcomes of hypertension management.
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Affiliation(s)
- Sidar Copur
- Department of Internal Medicine, Division of Internal Medicine, Koç University School of Medicine, Istanbul, Turkey
| | - Alexandru Burlacu
- Faculty of Medicine, University of Medicine and Pharmacy "Grigore T Popa,"
- Institute of Cardiovascular Diseases "Prof. Dr George I.M. Georgescu," Iasi, Romania
| | - Mehmet Kanbay
- Department of Internal Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
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Akizawa T, Urano N, Ikejiri K, Nakanishi K, Fukagawa M. Tenapanor: A novel therapeutic agent for dialysis patients with hyperphosphatemia. Ther Apher Dial 2025; 29:157-169. [PMID: 39829064 PMCID: PMC11879479 DOI: 10.1111/1744-9987.14241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/27/2024] [Accepted: 12/08/2024] [Indexed: 01/22/2025]
Abstract
Patients on dialysis often develop hyperphosphatemia, contributing to an increased risk of cardiovascular events and mortality. Currently, several types of phosphate binders (PBs) exist for the treatment of hyperphosphatemia, but they are sometimes associated with drug-specific side effects and high pill burden, making it difficult to control serum phosphorus appropriately. Tenapanor, which has a novel mechanism to reduce serum phosphorus via selective sodium/proton exchange transporter 3 inhibition, was approved for hyperphosphatemia in Japan in 2023. Four phase 3 studies of tenapanor have been performed in Japan and have demonstrated its efficacy and safety as a single-agent drug, add-on effects to PBs for patients with refractory hyperphosphatemia that cannot be improved with PBs alone, and reduction of the pill burden associated with PBs. This review provides an overview of the characteristics and previous clinical studies of tenapanor and describes the clinical benefits of tenapanor over current therapy in patients on dialysis.
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Affiliation(s)
- Tadao Akizawa
- Division of Nephrology, Department of MedicineShowa University School of MedicineTokyoJapan
| | | | | | | | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology, and Metabolism, Department of Internal MedicineTokai University School of MedicineIseharaKanagawaJapan
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Salera D, Bellasi A, Del Vecchio L, Locatelli F. Update on current and emerging treatment paradigms for hyperphosphatemia in chronic kidney disease. Expert Opin Pharmacother 2025; 26:85-100. [PMID: 39676576 DOI: 10.1080/14656566.2024.2441328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 12/09/2024] [Indexed: 12/17/2024]
Abstract
INTRODUCTION Hyperphosphatemia in advanced CKD often accompanies high PTH and FGF23 levels, impaired bone mineralization, ectopic calcifications, and increased cardiovascular risks. Novel treatments are now available to lower serum phosphorus effectively. However, safety, tolerability, and patient adherence must be evaluated to determine the best therapeutic option for hyperphosphatemia. AREAS COVERED This review examines available treatment strategies for hyperphosphatemia in CKD patients and new emerging treatments, emphasizing the latest inhibitors of active phosphate absorption. EXPERT OPINION Despite the numerous compounds available, managing hyperphosphatemia in CKD remains challenging. While many phosphate binders exist, they often have limitations and side effects. Aluminum carries significant toxicity risks. Calcium-based binders are effective but can cause hypercalcemia and vascular calcification. Lanthanum is absorbed in the gut, but its long-term tissue deposition appears clinically irrelevant. Sevelamer reduces vascular calcification but has inconclusive data and gastrointestinal side effects. Iron-based binders are effective but may cause gastrointestinal discomfort and lack long-term outcome data. New inhibitors of intestinal phosphate absorption show promise with low pill burden but need more clinical validation. Although these newer compounds might eventually improve phosphate management in CKD patients, enhancing adherence and reducing pill burden, future studies are required to elucidate the best treatment for hyperphosphatemia.
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Affiliation(s)
- Davide Salera
- Service of Nephrology, Ospedale Regionale di Lugano, Ospedale Civico, Ente Ospedaliero Cantonale, Lugano, Switzerland
| | - Antonio Bellasi
- Service of Nephrology, Ospedale Regionale di Lugano, Ospedale Civico, Ente Ospedaliero Cantonale, Lugano, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera italiana (USi), Lugano, Switzerland
| | - Lucia Del Vecchio
- Department of Nephrology and Dialysis, Sant'Anna Hospital, ASST Lariana, Como, Italy
| | - Francesco Locatelli
- Department of Nephrology and Dialysis, Past Director, Alessandro Manzoni Hospital, ASST Lecco, Lecco, Italy
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Sawant A, Kanji N, DiMare M, Matusow D, Edelstein S, Menakuru SR. A randomized pilot study to evaluate the stability, taste, and palatability of a novel liquid formulation of tenapanor. Drug Dev Ind Pharm 2025; 51:29-37. [PMID: 39686557 DOI: 10.1080/03639045.2024.2441880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 12/18/2024]
Abstract
OBJECTIVE This pilot study aimed to develop a liquid formulation of tenapanor and evaluate taste and palatability with different sweetener and flavor combinations. SIGNIFICANCE Tenapanor is a first-in-class, minimally absorbed, small molecule inhibitor of intestinal sodium/hydrogen exchanger 3, indicated (as tablets) to treat adults with constipation-predominant irritable bowel syndrome. It is also approved as add-on therapy to reduce serum phosphorus in adults with chronic kidney disease on dialysis who are intolerant of, or unacceptably responsive to, any dose of phosphate binder therapy. Since many patients have difficulty swallowing pills and pediatric studies are underway, a liquid formulation was developed, and taste profiles were evaluated for overall acceptability. METHODS Formulation of liquid tenapanor targeted a concentration of 5 mg/mL, for a dosing range of 1-50 mg twice daily. Improvements in solubility and stability of tenapanor in water were investigated with the use of buffers, cosolvents, and preservatives. Seven liquid formulations with different sweetener/flavor combinations were assessed for taste and palatability by healthy adult participants using the sip-and-spit method in a randomized design. RESULTS An aqueous solution of tenapanor (5 mg/mL), pH 3.4, with 0.05 % (w/v) benzoic acid, was stable at 2-8 °C for 12 months. The formulation with sucralose and raspberry flavor had the greatest improvement in overall acceptability and taste when compared to the reference solution without sweeteners or flavors. CONCLUSIONS A suitable liquid formulation was identified for progression to patient studies.
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Hill Gallant KM, Sprague SM, Rosenbaum DP, Spiegel DM, Kozuka K, Edelstein S, Chertow GM. Tenapanor: A Phosphate Absorption Inhibitor for the Management of Hyperphosphatemia in Patients With Kidney Failure. J Ren Nutr 2025; 35:25-34. [PMID: 38992521 DOI: 10.1053/j.jrn.2024.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 07/01/2024] [Indexed: 07/13/2024] Open
Abstract
Because of increased risks of cardiovascular disease and death, patients with hyperphosphatemia receiving maintenance dialysis are advised to limit phosphorus consumption and are prescribed phosphate binders in an effort to better control serum phosphate concentrations. Because of large pill size, pill burden, and tolerability issues, phosphate binder adherence is relatively poor. On ingestion, phosphate is absorbed from the intestine via transcellular or paracellular transport. Data show that inhibiting sodium-hydrogen exchanger 3 modulates paracellular phosphate absorption (the predominant pathway in humans). Tenapanor is a first-in-class, minimally absorbed, phosphate absorption inhibitor that selectively inhibits sodium-hydrogen exchanger 3, with a mechanism distinct from, and complementary to, that of phosphate binders. In phase 3 and postregistrational studies, tenapanor conferred statistically significant and clinically meaningful reductions in serum phosphate in patients receiving maintenance dialysis with hyperphosphatemia. Here, we review the available preclinical and clinical data on the effects of tenapanor on controlling intestinal phosphate absorption.
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Affiliation(s)
- Kathleen M Hill Gallant
- Associate Professor, Department of Food Science and Nutrition, University of Minnesota, Saint Paul, Minnesota.
| | - Stuart M Sprague
- Clinical Professor of Medicine, Endeavor Health, University of Chicago, Evanston, Illinois
| | | | - David M Spiegel
- Vice President, Nephrology, Ardelyx, Inc., Waltham, Massachusetts
| | - Kenji Kozuka
- Director, Preclinical Research and Nonclinical Development, Ardelyx, Inc., Fremont, California
| | - Susan Edelstein
- Senior Vice President, Clinical Research, Ardelyx, Inc., Waltham, Massachusetts
| | - Glenn M Chertow
- Professor of Medicine - Nephrology, Departments of Medicine and Epidemiology and Population Health, Stanford University, Palo Alto, California
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Brenner DM, Sayuk GS, Cash BD, Harris LA, Ahuja NK, Deutsch JK, Yang Y, Zhao S, Rosenbaum DP, Lembo AJ. Tenapanor Improves Abdominal Symptoms Irrespective of Changes in Complete Spontaneous Bowel Movement Frequency in Adults with Irritable Bowel Syndrome with Constipation. Dig Dis 2024; 43:146-157. [PMID: 39701047 PMCID: PMC11965839 DOI: 10.1159/000543166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 12/12/2024] [Indexed: 12/21/2024]
Abstract
INTRODUCTION Tenapanor is a first-in-class, minimally absorbed intestinal sodium/hydrogen exchanger isoform 3 inhibitor approved by the US Food and Drug Administration for adults with irritable bowel syndrome with constipation (IBS-C). Pooled data from the phase 2b (NCT01923428) and phase 3 T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) studies examined the effects of tenapanor on abdominal symptoms independent of tenapanor's effect on complete spontaneous bowel movement (CSBM) frequency in adults with IBS-C. METHODS This post hoc analysis was performed for patients with no CSBMs in ≥6 of the first 12 weeks of treatment (no-CSBM subgroup). The three-item abdominal score (AS3; the average of weekly abdominal pain, bloating, and discomfort scores) measured abdominal symptom response in tenapanor versus placebo. The overall change from baseline and response rate (improvement of ≥2 points or a reduction of ≥30%) in AS3 and individual abdominal scores during the 12 weeks were assessed. RESULTS In the pooled safety analysis set (N = 1,382), 641 patients were classified as no-CSBM patients and 640 were included in the efficacy analysis. Among the no-CSBM subgroup, tenapanor-treated patients experienced a greater improvement in AS3 in week 12 versus placebo-treated patients (least squares mean change, -1.74 vs. -1.29; p = 0.007), and the AS3 responder rate was higher for tenapanor (40.2% vs. 29.6%; p = 0.008). Similar improvements were displayed across individual abdominal symptom scores. Diarrhea was the most common adverse event in tenapanor-treated patients. CONCLUSION Tenapanor was observed to improve abdominal symptoms independent of its effect on bowel symptoms in adults with IBS-C. INTRODUCTION Tenapanor is a first-in-class, minimally absorbed intestinal sodium/hydrogen exchanger isoform 3 inhibitor approved by the US Food and Drug Administration for adults with irritable bowel syndrome with constipation (IBS-C). Pooled data from the phase 2b (NCT01923428) and phase 3 T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) studies examined the effects of tenapanor on abdominal symptoms independent of tenapanor's effect on complete spontaneous bowel movement (CSBM) frequency in adults with IBS-C. METHODS This post hoc analysis was performed for patients with no CSBMs in ≥6 of the first 12 weeks of treatment (no-CSBM subgroup). The three-item abdominal score (AS3; the average of weekly abdominal pain, bloating, and discomfort scores) measured abdominal symptom response in tenapanor versus placebo. The overall change from baseline and response rate (improvement of ≥2 points or a reduction of ≥30%) in AS3 and individual abdominal scores during the 12 weeks were assessed. RESULTS In the pooled safety analysis set (N = 1,382), 641 patients were classified as no-CSBM patients and 640 were included in the efficacy analysis. Among the no-CSBM subgroup, tenapanor-treated patients experienced a greater improvement in AS3 in week 12 versus placebo-treated patients (least squares mean change, -1.74 vs. -1.29; p = 0.007), and the AS3 responder rate was higher for tenapanor (40.2% vs. 29.6%; p = 0.008). Similar improvements were displayed across individual abdominal symptom scores. Diarrhea was the most common adverse event in tenapanor-treated patients. CONCLUSION Tenapanor was observed to improve abdominal symptoms independent of its effect on bowel symptoms in adults with IBS-C.
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Affiliation(s)
- Darren M. Brenner
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Gregory S. Sayuk
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - Brooks D. Cash
- Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health Science Center, Houston, TX, USA
| | - Lucinda A. Harris
- Mayo Clinic, Alix School of Medicine, Division of Gastroenterology and Hepatology, Scottsdale, AZ, USA
| | - Nitin K. Ahuja
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA
| | - Jill K. Deutsch
- Section of Digestive Diseases, Department of Internal Medicine, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, USA
| | | | | | | | - Anthony J. Lembo
- Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
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Popa IP, Clim A, Pînzariu AC, Lazăr CI, Popa Ș, Tudorancea IM, Moscalu M, Șerban DN, Șerban IL, Costache-Enache II, Tudorancea I. Arterial Hypertension: Novel Pharmacological Targets and Future Perspectives. J Clin Med 2024; 13:5927. [PMID: 39407987 PMCID: PMC11478071 DOI: 10.3390/jcm13195927] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 09/29/2024] [Accepted: 10/02/2024] [Indexed: 10/20/2024] Open
Abstract
Arterial hypertension (HTN) is one of the major global contributors to cardiovascular diseases and premature mortality, particularly due to its impact on vital organs and the coexistence of various comorbidities such as chronic renal disease, diabetes, cerebrovascular diseases, and obesity. Regardless of the accessibility of several well-established pharmacological treatments, the percentage of patients achieving adequate blood pressure (BP) control is still significantly lower than recommended levels. Therefore, the pharmacological and non-pharmacological management of HTN is currently the major focus of healthcare systems. Various strategies are being applied, such as the development of new pharmacological agents that target different underlying physiopathological mechanisms or associated comorbidities. Additionally, a novel group of interventional techniques has emerged in recent years, specifically for situations when blood pressure is not properly controlled despite the use of multiple antihypertensives in maximum doses or when patients are unable to tolerate or desire not to receive antihypertensive medications. Nonetheless, reducing the focus on antihypertensive medication development by the pharmaceutical industry and increasing recognition of ineffective HTN control due to poor drug adherence demands ongoing research into alternative approaches to treatment. The aim of this review is to summarize the potential novel pharmacological targets for the treatment of arterial hypertension as well as the future perspectives of the treatment strategy.
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Affiliation(s)
- Irene Paula Popa
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Andreea Clim
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Alin Constantin Pînzariu
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Cristina Iuliana Lazăr
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Ștefan Popa
- 2nd Department of Surgery–Pediatric Surgery and Orthopedics, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Ivona Maria Tudorancea
- Advanced Research and Development Center for Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universității Street, 700115 Iași, Romania
| | - Mihaela Moscalu
- Department of Preventive Medicine and Interdisciplinarity, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
| | - Dragomir N. Șerban
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Ionela Lăcrămioara Șerban
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
| | - Irina-Iuliana Costache-Enache
- Department of Internal Medicine I, Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
- Cardiology Clinic, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
| | - Ionuț Tudorancea
- Department of Morpho-Functional Sciences II, Discipline of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania (D.N.Ș.)
- Cardiology Clinic, “St. Spiridon” County Clinical Emergency Hospital, 700111 Iași, Romania
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Sendzischew Shane MA, Ruddy J, Cline M, Rosenbaum DP, Edelstein S, Moshiree B. Review of the Patient Burden and Therapeutic Landscape of Irritable Bowel Syndrome with Constipation in the United States. Clin Exp Gastroenterol 2024; 17:227-253. [PMID: 39114809 PMCID: PMC11303673 DOI: 10.2147/ceg.s464375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/25/2024] [Indexed: 08/10/2024] Open
Abstract
Irritable bowel syndrome (IBS) is a common disorder of the gut-brain axis. IBS with constipation (IBS-C) accounts for approximately one-third of IBS cases and is associated with substantial burden of illness and decreased quality of life. This narrative review provides an overview of the current and upcoming treatment options and disease management for IBS-C from a US perspective and discusses the importance of the relationship between patient and health care provider in diagnosis and treatment. A positive diagnostic strategy for IBS-C is recommended, based on clinical history, physical examination, and minimal laboratory tests. An effective communication strategy between patients and health care professionals is essential to ensure early diagnosis and reduce both health care costs and overall disease burden. Treatment typically begins with lifestyle interventions and nonpharmacologic options, such as dietary interventions, fiber supplements, and osmotic laxatives. In patients with inadequate response to these therapies, 4 currently available therapies (lubiprostone, linaclotide, plecanatide, and tenapanor) approved by the US Food and Drug Administration may relieve IBS-C symptoms. These agents are generally well tolerated and efficacious in improving IBS-C symptoms, including constipation and abdominal pain. In patients with persistent abdominal pain and/or psychological symptoms, brain-gut behavioral therapy or neuromodulator therapy may be beneficial.
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Affiliation(s)
| | | | - Michael Cline
- Department of Gastroenterology, Cleveland Clinic, Cleveland, OH, USA
| | | | | | - Baharak Moshiree
- Division of Gastroenterology, Advocate Health Wake Forest Medical University, Charlotte, NC, USA
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Taclob JA, Kalas MA, McCallum RW. Examining linaclotide for the treatment of chronic idiopathic constipation. Expert Opin Pharmacother 2024; 25:1281-1290. [PMID: 39058326 DOI: 10.1080/14656566.2024.2386160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/18/2024] [Accepted: 07/25/2024] [Indexed: 07/28/2024]
Abstract
INTRODUCTION Chronic idiopathic constipation (CIC) is characterized by infrequent bowel movements and hard stools lasting for at least three months or longer. This disease affects 8-12% of the US population and 10-17% of the world population. Treatment and management involve identifying the primary cause, changing dietary habits, and adequate physical activity. Linaclotide is a guanylate cyclase-agonist acting locally in the luminal surface of the intestinal enterocyte leading to a signal transduction cascade, activation of the cystic fibrosis transmembrane conductance regulator (CFTR), thus increasing secretion of chloride and bicarbonate into the intestinal lumen with eventual increased intestinal fluid and faster transit time. AREAS COVERED We reviewed multiple studies and did a thorough literature review on CIC including its pathophysiology. Through this literature review, we were able to discuss and give the context and rationale for drug regimens indicated for CIC. EXPERT OPINION The era we live in right now is akin to nutrient-rich and fertilized soil as knowledge and resources are abundant. The opportunities and potential are endless. Constipation being more extensively studied, our understanding of medications and diseases broadens, leading to novel medications being discovered. Linaclotide is a pioneer in this aspect and can pave the way for future generations.
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Affiliation(s)
- Jeff Angelo Taclob
- Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - M Ammar Kalas
- Division of Gastroenterology, Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Richard W McCallum
- Division of Gastroenterology, Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
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Wolfson S, Saps M. Recent advances in treating constipation in children. Expert Rev Gastroenterol Hepatol 2024; 18:325-338. [PMID: 39034812 DOI: 10.1080/17474124.2024.2383636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 07/19/2024] [Indexed: 07/23/2024]
Abstract
INTRODUCTION Functional constipation (FC) is a common childhood condition, diagnosed via the Rome IV criteria. Standard therapy includes lifestyle and dietary modification followed by initiation of osmotic laxative therapy. About 30% of children continue to experience symptoms related to FC despite appropriate management. New pharmacologic, surgical, and neuromodulatory therapies for FC are now available for use in adult and pediatric populations. In 2023, the first pharmacologic agent, linaclotide, obtained FDA approval for treatment of FC in children 6-17 years old. AREAS COVERED This article reviews current and emerging pharmacologic, surgical, and neuromodulation therapies for the management of FC in pediatric patients. Efficacy and safety data regarding each of these modalities was reviewed and discussed. EXPERT OPINION Advancements in therapeutics available for the management of FC necessitate further investigation on safety and efficacy in pediatric populations. Careful consideration should be taken in choosing an available treatment with limited pediatric evidence as adult and pediatric FC have different underlying pathophysiology and require a different therapeutic approach. Standardization of methodology and pediatric endpoints are needed to optimize ability to compare efficacy of different treatments. We predict the future of pediatric FC management will include a personalized approach to care, resulting in improved outcomes.
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Affiliation(s)
- Sharon Wolfson
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Miguel Saps
- Division of Pediatric Gastroenterology,Hepatology and Nutrition, University of Miami, Miami, FL, USA
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12
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Chrysant SG. The Interaction of Kidneys and Gut in Development of Salt-Sensitive Hypertension. Cardiol Rev 2024; 32:356-361. [PMID: 37273192 DOI: 10.1097/crd.0000000000000518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
The incidence of salt-sensitive hypertension is quite common and varies between 30-60% in hypertensive patients. Regarding the causal role of high salt intake in the development of salt-sensitive hypertension, recent evidence has demonstrated that the gut through its microbiota plays a significant role in its genesis. Besides the gut, the kidneys also play important role in salt-sensitive hypertension and there is clinical and experimental evidence of an interrelationship between the gut and the kidneys in the development of salt-sensitive hypertension through the so-called "gastro-renal axis." The gut besides being an absorptive organ, it is also a hormonal secretory organ involving the secretion of gastrin, dopamine, norepinephrine, angiotensin, and aldosterone which through their action with the kidneys are involved in the development of salt-sensitive hypertension. In addition, the kidneys exert a protective role against the development of hypertension through the secretion of prostaglandins and their vasodilatory action. To assess the current evidence on the role of high salt intake and the interplay of the gut and kidneys in its development, a Medline search of the English literature was contacted between 2012 and 2022, and 46 pertinent papers were selected. These papers together with collateral literature will be discussed in this review.
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Affiliation(s)
- Steven G Chrysant
- From the University of Oklahoma Health Sciences Center, Oklahoma City, OK
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Lembo AJ, Chey WD, Harris LA, Frazier R, Brenner DM, Chang L, Lacy BE, Edelstein S, Yang Y, Zhao S, Rosenbaum DP. Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis. Am J Gastroenterol 2024; 119:937-945. [PMID: 38294158 PMCID: PMC11062617 DOI: 10.14309/ajg.0000000000002685] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/20/2023] [Indexed: 02/01/2024]
Abstract
INTRODUCTION This post hoc analysis evaluated the efficacy of tenapanor on abdominal symptoms in patients with irritable bowel syndrome with constipation. Abdominal symptoms assessed included pain, discomfort, bloating, cramping, and fullness. METHODS The abdominal symptom data were pooled from 3 randomized controlled trials (NCT01923428, T3MPO-1 [NCT02621892], and T3MPO-2 [NCT02686138]). Weekly scores were calculated for each abdominal symptom, and the Abdominal Score (AS) was derived as the average of weekly scores for abdominal pain, discomfort, and bloating. The overall change from baseline during the 12 weeks was assessed for each symptom weekly score and the AS. The AS 6/12-week and 9/12-week response rates (AS improvement of ≥2 points for ≥6/12- or ≥9/12-week) were also evaluated. The association of weekly AS response status (reduction of ≥30%) with weekly complete spontaneous bowel movement (CSBM) status (=0 and >0) was assessed. RESULTS Among 1,372 patients (684 tenapanor [50 mg twice a day] and 688 placebo), the least squares mean change from baseline in AS was -2.66 for tenapanor vs -2.09 for placebo ( P < 0.0001). The 6/12-week AS response rate was 44.4% for tenapanor vs 32.4% for placebo ( P < 0.0001), and for 9/12-week AS, 30.6% for tenapanor vs 20.5% for placebo ( P < 0.0001). A significant association between weekly CSBM status and weekly AS response status was observed each week ( P < 0.0001), with a greater proportion achieving an AS reduction in patients with >0 CSBMs in a week. DISCUSSION Tenapanor significantly reduced abdominal symptoms in patients with irritable bowel syndrome with constipation, particularly pain, discomfort, and bloating measured by AS, compared with placebo.
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Affiliation(s)
- Anthony J. Lembo
- Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - William D. Chey
- Division of Gastroenterology, Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Lucinda A. Harris
- Division of Gastroenterology & Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Rosita Frazier
- Division of Gastroenterology & Hepatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Darren M. Brenner
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
| | - Brian E. Lacy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | | | - Yang Yang
- Ardelyx, Waltham, Massachusetts, USA
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King AJ, Chang L, Li Q, Liu L, Zhu Y, Pasricha PJ, Wang J, Siegel M, Caldwell JS, Edelstein S, Rosenbaum DP, Kozuka K. NHE3 inhibitor tenapanor maintains intestinal barrier function, decreases visceral hypersensitivity, and attenuates TRPV1 signaling in colonic sensory neurons. Am J Physiol Gastrointest Liver Physiol 2024; 326:G543-G554. [PMID: 38252683 PMCID: PMC11376972 DOI: 10.1152/ajpgi.00233.2023] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 01/04/2024] [Accepted: 01/17/2024] [Indexed: 01/24/2024]
Abstract
The pathogenesis of irritable bowel syndrome (IBS) is multifactorial, characterized in part by increased intestinal permeability, and visceral hypersensitivity. Increased permeability is associated with IBS severity and abdominal pain. Tenapanor is FDA-approved for the treatment of IBS with constipation (IBS-C) and has demonstrated improvements in bowel motility and a reduction in IBS-related pain; however, the mechanism by which tenapanor mediates these functions remains unclear. Here, the effects of tenapanor on colonic pain signaling and intestinal permeability were assessed through behavioral, electrophysiological, and cell culture experiments. Intestinal motility studies in rats and humans demonstrated that tenapanor increased luminal sodium and water retention and gastrointestinal transit versus placebo. A significantly reduced visceral motor reflex (VMR) to colonic distension was observed with tenapanor treatment versus vehicle in two rat models of visceral hypersensitivity (neonatal acetic acid sensitization and partial restraint stress; both P < 0.05), returning VMR responses to that of nonsensitized controls. Whole cell voltage patch-clamp recordings of retrogradely labeled colonic dorsal root ganglia (DRG) neurons from sensitized rats found that tenapanor significantly reduced DRG neuron hyperexcitability to capsaicin versus vehicle (P < 0.05), an effect not mediated by epithelial cell secretions. Tenapanor also attenuated increases in intestinal permeability in human colon monolayer cultures caused by incubation with proinflammatory cytokines (P < 0.001) or fecal supernatants from patients with IBS-C (P < 0.005). These results support a model in which tenapanor reduces IBS-related pain by strengthening the intestinal barrier, thereby decreasing permeability to macromolecules and antigens and reducing DRG-mediated pain signaling.NEW & NOTEWORTHY A series of nonclinical experiments support the theory that tenapanor inhibits IBS-C-related pain by strengthening the intestinal barrier. Tenapanor treatment reduced visceral motor responses to nonsensitized levels in two rat models of hypersensitivity and reduced responses to capsaicin in sensitized colonic nociceptive dorsal root ganglia neurons. Intestinal permeability experiments in human colon monolayer cultures found that tenapanor attenuates increases in permeability induced by either inflammatory cytokines or fecal supernatants from patients with IBS-C.
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Affiliation(s)
- Andrew J King
- Ardelyx, Inc., Waltham, Massachusetts, United States
| | - Lin Chang
- Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States
| | - Qian Li
- Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Liansheng Liu
- Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Yaohui Zhu
- Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Pankaj J Pasricha
- Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Ji Wang
- Ardelyx, Inc., Waltham, Massachusetts, United States
| | | | | | | | | | - Kenji Kozuka
- Ardelyx, Inc., Waltham, Massachusetts, United States
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Sprague SM, Weiner DE, Tietjen DP, Pergola PE, Fishbane S, Block GA, Silva AL, Fadem SZ, Lynn RI, Fadda G, Pagliaro L, Zhao S, Edelstein S, Spiegel DM, Rosenbaum DP. Tenapanor as Therapy for Hyperphosphatemia in Maintenance Dialysis Patients: Results from the OPTIMIZE Study. KIDNEY360 2024; 5:732-742. [PMID: 38323855 PMCID: PMC11146652 DOI: 10.34067/kid.0000000000000387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 02/01/2024] [Indexed: 02/08/2024]
Abstract
Key Points Tenapanor, a first-in-class local inhibitor of sodium/hydrogen exchanger isoform 3, acts as a phosphate absorption inhibitor by decreasing paracellular phosphate absorption. Tenapanor alone or with phosphate binders achieved P ≤ 5.5 mg/dl over 10 weeks in 34%–38% of patients taking phosphate binders at baseline. Tenapanor can help adults with CKD on maintenance dialysis achieve normal serum phosphate concentrations. Background OPTIMIZE was a randomized, open-label study evaluating different tenapanor initiation methods. OPTIMIZE evaluated tenapanor alone and in combination with phosphate binders (PBs) to achieve target serum phosphate (P) ≤5.5 mg/dl. Methods Patients with inadequately controlled P receiving maintenance dialysis from 42 US locations who were taking PBs with baseline P > 5.5 mg/dl and ≤ 10.0 mg/dl, or were PB-naive with baseline P > 4.5 mg/dl and ≤ 10.0 mg/dl, were included in OPTIMIZE. Participants taking PBs at baseline were randomized to switch from PBs to tenapanor (Straight Switch ; n =151) or reduce PB dosage by ≥50% and add tenapanor (Binder Reduction ; n =152); PB-naive patients started tenapanor alone (Binder-Naive ; n =30). Participants received tenapanor 30 mg twice a day for 10 weeks (part A), followed by an elective, 16-week open-label extension (part B). Outcomes included changes from baseline in P, intact fibroblast growth factor 23, parathyroid hormone, serum calcium, and medication burden; patient-reported outcomes; and safety. Results By part A end point, 34.4% (Straight Switch ), 38.2% (Binder Reduction ), and 63.3% (Binder-Naive ) of patients achieved P ≤ 5.5 mg/dl. Mean P reduction and median pill burden reduction from baseline to part A end point were 0.91±1.7 mg/dl and 4 pills/d for the Straight Switch and 0.99±1.8 mg/dl and 1 pill/d for the Binder Reduction group. The mean P reduction for Binder-Naive patients was 0.87±1.5 mg/dl. Among Straight Switch and Binder Reduction patients who completed patient experience questionnaires, 205 of 243 (84.4%) reported an improved phosphate management routine. Diarrhea was the most common adverse event (133 of 333 [39.9%]). Conclusions Tenapanor as monotherapy or in combination with PBs effectively lowered P toward the target range in patients who were PB-naive or who were not at goal despite PB use. Clinical Trial registration number NCT04549597 .
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Affiliation(s)
- Stuart M. Sprague
- NorthShore University Health System, Evanston, Illinois
- University of Chicago Pritzker School of Medicine, Chicago, Illinois
| | | | | | | | - Steven Fishbane
- Zucker School of Medicine at Hofstra & Northwell Health, Great Neck, New York
| | | | | | - Stephen Z. Fadem
- Kidney Associates, PLLC and Baylor College of Medicine, Houston, Texas
| | | | - George Fadda
- Balboa Nephrology Medical Group, La Mesa, California
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Singh P, Sayuk GS, Rosenbaum DP, Edelstein S, Kozuka K, Chang L. An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation. Clin Exp Gastroenterol 2024; 17:87-96. [PMID: 38617992 PMCID: PMC11016248 DOI: 10.2147/ceg.s454526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 03/22/2024] [Indexed: 04/16/2024] Open
Abstract
Background Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults. Aim This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain. Findings Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling. Conclusion By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.
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Affiliation(s)
- Prashant Singh
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Gregory S Sayuk
- Department of Medicine, Washington University School of Medicine, St Louis, MO, USA
| | | | | | | | - Lin Chang
- Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
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Mahenthiran A, Wilcox J, Tang WHW. Heart Failure: a Punch from the Gut. Curr Heart Fail Rep 2024; 21:73-80. [PMID: 38300390 PMCID: PMC10924029 DOI: 10.1007/s11897-024-00648-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/10/2024] [Indexed: 02/02/2024]
Abstract
PURPOSE OF REVIEW This article seeks to elucidate the mechanisms underlying the bidirectional relationship between the gut and the heart, focusing on the pathophysiology of heart failure. We have previously demonstrated that Heart failure (HF) has significant effects on splanchnic vasculature and leads to key alterations in the gut microbiome, portending greater comorbidity with HF. RECENT FINDINGS A growing field of research is focused on the effects of a "leaky gut" in the development of disease across organ systems. The leaky gut hypothesis centers on intestinal epithelial barrier dysfunction causing increased permeability of the gut and subsequent alterations to gut composition by endotoxins and microbial metabolites. Changes in the quantities of metabolites including short-chain fatty acids, trimethylamine N-oxide and other amino acid metabolites, and various bile acid species have been shown to result in gut dysbiosis and worsening HF. The gut plays a highly significant role in HF prognosis and requires greater attention for future therapeutic interventions. Treatments targeting gut composition could have very beneficial effects on HF prognosis.
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Affiliation(s)
| | - Jennifer Wilcox
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - W H Wilson Tang
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH, 44195, USA.
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Nakayama M, Kobayashi S, Kusakabe M, Ohara M, Nakanishi K, Akizawa T, Fukagawa M. Tenapanor for peritoneal dialysis patients with hyperphosphatemia: a phase 3 trial. Clin Exp Nephrol 2024; 28:153-164. [PMID: 37910313 PMCID: PMC10808471 DOI: 10.1007/s10157-023-02406-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/10/2023] [Indexed: 11/03/2023]
Abstract
BACKGROUND Tenapanor is a novel selective inhibitor of intestinal sodium/hydrogen exchanger 3 transporter. This is the first trial to assess the efficacy and safety of tenapanor in Japanese patients with hyperphosphatemia who are undergoing peritoneal dialysis. METHODS This phase 3, open-label, multicenter, single-arm clinical trial targeted patients whose serum phosphorus was within 3.5-7.0 mg/dL with phosphate binders at screening. After phosphate binder washout, tenapanor was orally administered twice-daily, stepwise from 5 to 30 mg/dose for 16 weeks. The primary endpoint, mean change in serum phosphorus level, was evaluated at week 8. The 16-week treatment period was completed with tenapanor alone, and only one phosphate binder type was allowed for combined use after the primary endpoint. RESULTS Of the 54 patients enrolled, 34 completed the study. At week 8, the primary endpoint, mean change in serum phosphorus level (last observation carried forward), was - 1.18 mg/dL (95% confidence interval: - 1.54, - 0.81 mg/dL) with tenapanor. From a baseline value of 7.65 mg/dL, serum phosphorus decreased to 6.14 and 5.44 mg/dL at weeks 8 and 16, respectively, and 46.3% and 76.5% of patients achieved serum phosphorus within 3.5-6.0 mg/dL at week 8 and week 16, respectively. The most common adverse event, diarrhea, occurred in 74.1% of patients; the severity of diarrhea was mild or moderate. Thus, the discontinuation percentage due to diarrhea was low at 5.6%. CONCLUSIONS Administration of tenapanor resulted in a sufficient reduction in serum phosphorus level at week 8 and was considered safe and tolerable. TRIAL REGISTRATION NCT04766385.
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Affiliation(s)
- Masaaki Nakayama
- Kidney Center, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan.
| | | | | | - Meiko Ohara
- R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | | | - Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology, and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan
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Fatima N, Ashique S, Upadhyay A, Kumar S, Kumar H, Kumar N, Kumar P. Current Landscape of Therapeutics for the Management of Hypertension - A Review. Curr Drug Deliv 2024; 21:662-682. [PMID: 37357524 DOI: 10.2174/1567201820666230623121433] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 03/16/2023] [Accepted: 03/22/2023] [Indexed: 06/27/2023]
Abstract
Hypertension is a critical health problem. It is also the primary reason for coronary heart disease, stroke, and renal vascular disease. The use of herbal drugs in the management of any disease is increasing. They are considered the best immune booster to fight against several types of diseases. To date, the demand for herbal drugs has been increasing because of their excellent properties. This review highlights antihypertensive drugs, polyphenols, and synbiotics for managing hypertension. Evidence is mounting in favour of more aggressive blood pressure control with reduced adverse effects, especially for specific patient populations. This review aimed to present contemporary viewpoints and novel treatment options, including cutting-edge technological applications and emerging interventional and pharmaceutical therapies, as well as key concerns arising from several years of research and epidemiological observations related to the management of hypertension.
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Affiliation(s)
- Neda Fatima
- Department of Pharmacology, Amity University, Lucknow Campus, Lucknow, Uttar Pradesh 226010, India
| | - Sumel Ashique
- Department of Pharmaceutics, Pandaveswar School of Pharmacy, Pandaveswar, West Bengal 713378, India
| | - Aakash Upadhyay
- Department of Pharmaceutics, Bharat Institute of Technology (BIT), School of Pharmacy, Meerut, Uttar Pradesh, 250103, India
| | - Shubneesh Kumar
- Department of Pharmaceutics, Bharat Institute of Technology (BIT), School of Pharmacy, Meerut, Uttar Pradesh, 250103, India
| | - Himanshu Kumar
- Department of Pharmaceutics, Bharat Institute of Technology (BIT), School of Pharmacy, Meerut, Uttar Pradesh, 250103, India
| | - Nitish Kumar
- SRM Modinagar College of Pharmacy, SRM Institute of Science and Technology (Deemed to be University), Delhi-NCR Campus, Modinagar, Ghaziabad, Uttar Pradesh, 201204, India
| | - Prashant Kumar
- College of Pharmacy, Teerthanker Mahaveer University, Moradabad-244001, UP, India
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Stamatopoulos K, Mistry N, Fotaki N, Turner DB, Swift B. Physiologically Based Biopharmaceutics Model (PBBM) of Minimally Absorbed Locally Acting Drugs in the Gastrointestinal Tract-Case Study: Tenapanor. Pharmaceutics 2023; 15:2726. [PMID: 38140067 PMCID: PMC10747343 DOI: 10.3390/pharmaceutics15122726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/23/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023] Open
Abstract
A physiologically based biopharmaceutics model (PBBM) was developed to predict stool and urine sodium content in response to tenapanor administration in healthy subjects. Tenapanor is a minimally absorbed small molecule that inhibits the sodium/hydrogen isoform 3 exchanger (NHE3). It is used to treat irritable bowel syndrome with constipation (IBS-C). Its mode of action in the gastrointestinal tract reduces the uptake of sodium, resulting in an increase in water secretion in the intestinal lumen and accelerating intestinal transit time. The strategy employed was to perform drug-drug interaction (DDI) modelling between sodium and tenapanor, with sodium as the "victim" administered as part of daily food intake and tenapanor as the "perpetrator" altering sodium absorption. Food effect was modelled, including meal-induced NHE3 activity using sodium as an inducer by normalising the induction kinetics of butyrate to sodium equivalents. The presented model successfully predicted both urine and stool sodium content in response to tenapanor dosed in healthy subjects (within 1.25-fold error) and provided insight into the clinical observations of tenapanor dosing time relative to meal ingestion. The PBBM model was applied retrospectively to assess the impact of different forms of tenapanor (free base vs. HCl salt) on its pharmacodynamic (PD) effect. The developed modelling strategy can be effectively adopted to increase confidence in using PBBM models for the prediction of the in vivo behaviour of minimally absorbed, locally acting drugs in the gastrointestinal tract, when other approaches (e.g., biomarkers or PD data) are not available.
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Affiliation(s)
| | - Nena Mistry
- Biopharmaceutics, DPD, MDS, GSK, Ware SG12 0DP, UK;
| | - Nikoletta Fotaki
- Centre for Therapeutic Innovation, Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, UK;
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Currò D, Ianiro G, Gasbarrini A. A pharmacokinetic evaluation of tenapanor for the treatment of irritable bowel syndrome with constipation: an update of the literature. Expert Opin Drug Metab Toxicol 2023; 19:889-894. [PMID: 38108081 DOI: 10.1080/17425255.2023.2294937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
INTRODUCTION Tenapanor is the latest addition to the second-line pharmacotherapeutic options for the treatment of irritable bowel syndrome with constipation. It is a first-in-class inhibitor of type 3 sodium/hydrogen exchanger (NHE3), characterized by very low oral absorption. Its pharmacological properties are discussed here based on the latest literature. AREAS COVERED A general description of tenapanor is provided, highlighting those pharmacokinetic and pharmacodynamic characteristics of the drug which may be of major importance for tolerability and safety. This description is associated with a summary and analysis of currently available toxicological data. EXPERT OPINION Plasma concentrations of free tenapanor after oral administration are well below the half maximal inhibitory concentration for NHE3, so that systemic effects of the drug are minimal. Therefore, the action of tenapanor is limited to NHE3 located on the apical membrane of enterocytes. The consequent reduction in intestinal sodium absorption increases the intraluminal content by osmosis, which in turn enhances the propulsive activity of the colon. Diarrhea is the most frequent adverse effect of tenapanor. Increased fecal sodium and water excretion do not appear to expose patients to short- and long-term hydro-electrolyte imbalances.
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Affiliation(s)
- Diego Currò
- Pharmacology Section, Department of Health Care Surveillance and Bioethics, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gianluca Ianiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
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Lembo AJ, Friedenberg KA, Fogel RP, Edelstein S, Zhao S, Yang Y, Rosenbaum DP, Chey WD. Long-term safety of tenapanor in patients with irritable bowel syndrome with constipation in the T3MPO-3 study. Neurogastroenterol Motil 2023; 35:e14658. [PMID: 37668173 DOI: 10.1111/nmo.14658] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 06/26/2023] [Accepted: 07/31/2023] [Indexed: 09/06/2023]
Abstract
BACKGROUND Tenapanor, a first-in-class, minimally systemic inhibitor of intestinal sodium/hydrogen exchanger isoform 3 (NHE3), is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults based on two randomized, placebo-controlled, phase III studies (T3MPO-1 [NCT02621892], T3MPO-2 [NCT02686138]). The open-label T3MPO-3 extension study (NCT02727751) enrolled patients who completed these studies to investigate long-term safety and tolerability of tenapanor. METHODS Patients who completed T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) were eligible for enrollment in T3MPO-3. Patients in T3MPO-3 received open-label tenapanor 50 mg twice a day for up to an additional 39 (T3MPO-1) or 26 (T3MPO-2) weeks. Treatment-emergent adverse events (TEAEs) were evaluated in the entire T3MPO-3 safety population and in patients who received a total of ≥52 weeks of tenapanor. KEY RESULTS A total of 312 patients were enrolled in T3MPO-3; 90 received ≥52 weeks of tenapanor. TEAEs were reported in 117 (37.5%) patients in the safety population and in 52 (57.8%) patients who received ≥52 weeks of tenapanor. Diarrhea was the most common TEAE, occurring in 10.6% of the safety population and in 11.1% of patients who received ≥52 weeks of tenapanor. Most cases were mild or moderate in severity, with only two severe cases reported in the safety population. No deaths occurred during the T3MPO-3 study. CONCLUSIONS Tenapanor was tolerable over ≥52 weeks of treatment and showed similar safety to that seen in shorter studies. Combined results of the T3MPO studies indicate that tenapanor is a valuable new treatment option for patients with IBS-C.
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Affiliation(s)
- Anthony J Lembo
- Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | | | - Ronald P Fogel
- Digestive Health Center of Michigan, Chesterfield, Michigan, USA
| | | | | | - Yang Yang
- Ardelyx, Inc., Waltham, Massachusetts, USA
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Silva AL, Chertow GM, Hernandez GT, Lynn RI, Tietjen DP, Rosenbaum DP, Yang Y, Edelstein S. Tenapanor Improves Long-Term Control of Hyperphosphatemia in Patients Receiving Maintenance Dialysis: the NORMALIZE Study. KIDNEY360 2023; 4:1580-1589. [PMID: 37853560 PMCID: PMC10695649 DOI: 10.34067/kid.0000000000000280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/11/2023] [Indexed: 10/20/2023]
Abstract
Key Points Tenapanor is a first-in-class, minimally systemic sodium–hydrogen exchanger 3 inhibitor with a mechanism of action distinct from phosphate binders. Tenapanor alone or with phosphate binders led to 35%–49% of patients achieving serum phosphate ≤4.5 mg/dl over an 18-month period versus 22% at baseline. Tenapanor alone or with phosphate binders may help adults with CKD on maintenance dialysis achieve normal serum phosphate concentrations. Background Most patients with ESKD and hyperphosphatemia have difficulty controlling serum phosphate (sP) concentrations despite maintenance dialysis, dietary restriction, and phosphate binder treatment. NORMALIZE evaluated the efficacy and safety of tenapanor 30 mg twice daily alone or in combination with phosphate binders to achieve sP within the adult population reference range (2.5–4.5 mg/dl). Methods Patients who completed the Phase 3 PHREEDOM study could enroll in NORMALIZE. Patients enrolled in NORMALIZE who had received tenapanor during the PHREEDOM study (n =111) added sevelamer carbonate if sP was >4.5 mg/dl. Patients who had received sevelamer carbonate during the PHREEDOM study (n =61) added tenapanor and decreased sevelamer carbonate if sP was ≤4.5 mg/dl, per protocol titration schedule. Patients were followed in NORMALIZE for up to 18 months. We assessed efficacy in the full analysis set, defined as patients who received ≥1 dose of study drug and had ≥1 post-treatment sP measurement (n =171). We assessed safety in all patients who received ≥1 dose of study drug (n =172). Results At the end point visit, 57 of 171 patients (33%) in the full analysis set achieved sP between 2.5 and 4.5 mg/dl. Eight of 23 patients (35%) who were on tenapanor alone at the end point visit achieved sP between 2.5 and 4.5 mg/dl. The mean reduction from PHREEDOM baseline to end of NORMALIZE in sP was 2.0 mg/dl. Serum intact fibroblast growth factor-23 was significantly reduced; serum intact parathyroid hormone was significantly reduced among patients with intact parathyroid hormone ≥300 pg/ml at PHREEDOM baseline. The most commonly reported treatment-emergent adverse event was diarrhea in 38 of 172 patients (22%), which led to tenapanor discontinuation in four patients (2%). Conclusions Tenapanor alone or in combination with phosphate binders helped adult patients on maintenance dialysis achieve normal sP concentrations. Safety was consistent with previous studies of tenapanor. Clinical trial registry name and registration number A Long-Term Study to Evaluate the Ability of Tenapanor Alone or in Combination With Sevelamer to Treat to Goal Serum Phosphorus in Patients With ESKD on Dialysis (NORMALIZE), NCT03988920 .
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Affiliation(s)
| | - Glenn M. Chertow
- Departments of Medicine and Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California
| | | | | | | | | | - Yang Yang
- Ardelyx, Inc., Waltham, Massachusetts
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Fukagawa M, Urano N, Ikejiri K, Kinoshita J, Nakanishi K, Akizawa T. Tenapanor for the Treatment of Hyperphosphatemia in Japanese Hemodialysis Patients: A Randomized Phase 3 Monotherapy Study With an Up-titration Regimen. Am J Kidney Dis 2023; 82:635-637. [PMID: 37330134 DOI: 10.1053/j.ajkd.2023.03.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 03/28/2023] [Indexed: 06/19/2023]
Affiliation(s)
- Masafumi Fukagawa
- Division of Nephrology, Endocrinology, and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan.
| | | | | | | | | | - Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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25
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Nitta K, Itoyama S, Ikejiri K, Kinoshita J, Nakanishi K, Fukagawa M, Akizawa T. Randomized Study of Tenapanor Added to Phosphate Binders for Patients With Refractory Hyperphosphatemia. Kidney Int Rep 2023; 8:2243-2253. [PMID: 38025211 PMCID: PMC10658421 DOI: 10.1016/j.ekir.2023.08.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/26/2023] [Accepted: 08/07/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Serum phosphorus management is important for patients with chronic kidney disease on dialysis to reduce the risk of hyperparathyroidism and ectopic vascular calcification. Phosphate binders (PBs) control serum phosphorus levels; however, some patients do not achieve adequate control with existing PBs. The similar mechanisms of action of each PB may limit their ability to lower serum phosphorus levels. Therefore, drugs with novel mechanisms of action that can be added to existing PBs to further lower serum phosphorus levels are desired. Tenapanor, a novel selective inhibitor of intestinal sodium/hydrogen exchanger 3 transporters, decreases passive phosphate absorption in the intestine, thereby decreasing serum phosphorus levels. Methods This study evaluated the efficacy and safety of tenapanor treatment with up-titration when added to PBs among Japanese hemodialysis patients with hyperphosphatemia poorly controlled by PBs alone. In total, 169 patients taking PBs whose serum phosphorus level was ≥6.1 and <10.0 mg/dl initiated the 8-week treatment (placebo + PB, n = 85; tenapanor + PB, n = 84). Results The least squares mean change from baseline to week 8 in serum phosphorus level was -0.24 and -2.00 mg/dl in the placebo and tenapanor groups, respectively, with a statistically significant difference between groups (-1.76 mg/dl; P < 0.0001). Diarrhea as a treatment-emergent adverse event (TEAE) occurred in 14.1% and 63.1% of patients in the placebo and tenapanor groups, respectively. All diarrhea events were mild or moderate. Conclusion Tenapanor added to PBs improved serum phosphorus levels that could not previously be controlled by PBs alone, and no new safety concerns were raised.
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Affiliation(s)
- Kosaku Nitta
- Department of Nephrology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Saki Itoyama
- Research and Development Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Kazuaki Ikejiri
- Research and Development Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Jun Kinoshita
- Research and Development Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Kaoru Nakanishi
- Research and Development Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology, and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan
| | - Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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26
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Zachos NC, Vaughan H, Sarker R, Est-Witte S, Chakraborty M, Baetz NW, Yu H, Yarov-Yarovoy V, McNamara G, Green JJ, Tse CM, Donowitz M. A Novel Peptide Prevents Enterotoxin- and Inflammation-Induced Intestinal Fluid Secretion by Stimulating Sodium-Hydrogen Exchanger 3 Activity. Gastroenterology 2023; 165:986-998.e11. [PMID: 37429363 PMCID: PMC11283679 DOI: 10.1053/j.gastro.2023.06.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/05/2023] [Accepted: 06/09/2023] [Indexed: 07/12/2023]
Abstract
BACKGROUND & AIMS Acute diarrheal diseases are the second most common cause of infant mortality in developing countries. This is contributed to by lack of effective drug therapy that shortens the duration or lessens the volume of diarrhea. The epithelial brush border sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) accounts for a major component of intestinal Na+ absorption and is inhibited in most diarrheas. Because increased intestinal Na+ absorption can rehydrate patients with diarrhea, NHE3 has been suggested as a potential druggable target for drug therapy for diarrhea. METHODS A peptide (sodium-hydrogen exchanger 3 stimulatory peptide [N3SP]) was synthesized to mimic the part of the NHE3 C-terminus that forms a multiprotein complex that inhibits NHE3 activity. The effect of N3SP on NHE3 activity was evaluated in NHE3-transfected fibroblasts null for other plasma membrane NHEs, a human colon cancer cell line that models intestinal absorptive enterocytes (Caco-2/BBe), human enteroids, and mouse intestine in vitro and in vivo. N3SP was delivered into cells via a hydrophobic fluorescent maleimide or nanoparticles. RESULTS N3SP uptake stimulated NHE3 activity at nmol/L concentrations under basal conditions and partially reversed the reduced NHE3 activity caused by elevated adenosine 3',5'-cyclic monophosphate, guanosine 3',5'-cyclic monophosphate, and Ca2+ in cell lines and in in vitro mouse intestine. N3SP also stimulated intestinal fluid absorption in the mouse small intestine in vivo and prevented cholera toxin-, Escherichia coli heat-stable enterotoxin-, and cluster of differentiation 3 inflammation-induced fluid secretion in a live mouse intestinal loop model. CONCLUSIONS These findings suggest pharmacologic stimulation of NHE3 activity as an efficacious approach for the treatment of moderate/severe diarrheal diseases.
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Affiliation(s)
- Nicholas C Zachos
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Hannah Vaughan
- Translational Tissue Engineering Center, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Rafiquel Sarker
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Savannah Est-Witte
- Translational Tissue Engineering Center, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Molee Chakraborty
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nicholas W Baetz
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Hongzhe Yu
- Translational Tissue Engineering Center, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Vladimir Yarov-Yarovoy
- Department of Physiology and Membrane Biology, University of California Davis, Davis, California; Department of Anesthesiology and Pain Medicine, University of California Davis, Davis, California
| | - George McNamara
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jordan J Green
- Translational Tissue Engineering Center, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Chung-Ming Tse
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mark Donowitz
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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27
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Kanbay M, Copur S, Tanriover C, Ucku D, Laffin L. Future treatments in hypertension: Can we meet the unmet needs of patients? Eur J Intern Med 2023; 115:18-28. [PMID: 37330317 DOI: 10.1016/j.ejim.2023.06.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/17/2023] [Accepted: 06/12/2023] [Indexed: 06/19/2023]
Abstract
The prevalence of arterial hypertension is approximately 47% in the United States and 55% in Europe. Multiple different medical therapies are used to treat hypertension including diuretics, beta blockers, calcium channel blockers, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, alpha blockers, central acting alpha receptor agonists, neprilysin inhibitors and vasodilators. However, despite the numerous number of medications, the prevalence of hypertension is on the rise, a considerable proportion of the hypertensive population is resistant to these therapeutic modalities and a definitive cure is not possible with the current treatment approaches. Therefore, there is a need for novel therapeutic strategies to provide better treatment and control of hypertension. In this review, our aim is to describe the latest developments in the treatment of hypertension including novel medication classes, gene therapies and RNA-based modalities.
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Affiliation(s)
- Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey.
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Cem Tanriover
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Duygu Ucku
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Luke Laffin
- Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA
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28
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Cernaro V, Longhitano E, Calabrese V, Casuscelli C, Di Carlo S, Spinella C, Gembillo G, Santoro D. Progress in pharmacotherapy for the treatment of hyperphosphatemia in renal failure. Expert Opin Pharmacother 2023; 24:1737-1746. [PMID: 37527180 DOI: 10.1080/14656566.2023.2243817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/03/2023]
Abstract
INTRODUCTION Among the clinical and metabolic complications of progressive chronic kidney disease (CKD), CKD-mineral bone disorder (CKD-MBD) significantly contributes to morbidity and mortality. While overt and persistent hyperphosphatemia is typical of advanced CKD and requires treatment, other abnormalities of calcium/phosphate metabolism begin to occur since the early stages of the disease. AREAS COVERED We searched on the PubMed database, without restrictions for language or time range, for randomized clinical trials and meta-analyses investigating phosphate-lowering therapies. The various phosphate binders show different safety profiles and diverse effects on calcium/phosphate metabolism and vascular calcification. The in-depth knowledge of the characteristics of these drugs is crucial to ensure adequate treatment to CKD patients. EXPERT OPINION A proper control of serum phosphate can be achieved using phosphate binders. These medications may induce side effects. Moreover, data on their impact on clinical outcomes are partly controversial or scarce, especially for the new generation drugs. Hyperphosphatemia favors cardiovascular disease and increases the risk for CKD progression. These effects are partially mediated by fibroblast growth factor 23 (FGF23), a phosphaturic hormone that raises to maintain normal serum phosphate. Since there are no data supporting the use of phosphate-lowering agents when phosphataemia is normal, a key role is played by reducing dietary phosphate intake with the aim to control serum phosphate and the compensatory FGF23 and parathyroid hormone (PTH) increase.
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Affiliation(s)
- Valeria Cernaro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Elisa Longhitano
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Vincenzo Calabrese
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Chiara Casuscelli
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Silvia Di Carlo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Claudia Spinella
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
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29
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Herekar A, Shimoga D, Jehangir A, Shahsavari D, Yan Y, Karunaratne TB, Sharma A. Tenapanor in the Treatment of Irritable Bowel Syndrome with Constipation: Discovery, Efficacy, and Role in Management. Clin Exp Gastroenterol 2023; 16:79-85. [PMID: 37309470 PMCID: PMC10257918 DOI: 10.2147/ceg.s384251] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 05/29/2023] [Indexed: 06/14/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction (DGBI). IBS significantly impacts the quality of life of patients. Since its pathogenesis is unclear and can be multifactorial, it highlights the need for new and improved pharmaceutical drugs that not only improve bowel symptoms, but also address global IBS symptoms, such as abdominal pain. Tenapanor, a recently Food & Drug Administration (FDA)-approved medication for IBS with constipation (IBS-C), is a small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) that inhibits the absorption of sodium and phosphate in the gastrointestinal tract, resulting in fluid retention and softer stool. Furthermore, tenapanor reduces intestinal permeability to improve visceral hypersensitivity and abdominal pain. Due to its recent approval, tenapanor was not included in the recent IBS guidelines, however, it may be considered for IBS-C patients failing first-line treatment of soluble fiber. In this review article, we aim to provide in-depth information to the reader regarding the design of tenapanor, its development through Phase I, II and III randomized clinical trials, and its role in the treatment of IBS-C.
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Affiliation(s)
- Anam Herekar
- Department of Medicine, Augusta University, Augusta, GA, USA
| | - Dhanush Shimoga
- Department of Medicine, Augusta University, Augusta, GA, USA
| | - Asad Jehangir
- Department of Medicine, Augusta University, Augusta, GA, USA
| | | | - Yun Yan
- Department of Medicine, Augusta University, Augusta, GA, USA
| | | | - Amol Sharma
- Department of Medicine, Augusta University, Augusta, GA, USA
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30
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Mutengo KH, Masenga SK, Mweemba A, Mutale W, Kirabo A. Gut microbiota dependant trimethylamine N-oxide and hypertension. Front Physiol 2023; 14:1075641. [PMID: 37089429 PMCID: PMC10118022 DOI: 10.3389/fphys.2023.1075641] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 03/31/2023] [Indexed: 04/25/2023] Open
Abstract
The human gut microbiota environment is constantly changing and some specific changes influence the host's metabolic, immune, and neuroendocrine functions. Emerging evidence of the gut microbiota's role in the development of cardiovascular disease (CVD) including hypertension is remarkable. There is evidence showing that alterations in the gut microbiota and especially the gut-dependant metabolite trimethylamine N-oxide is associated with hypertension. However, there is a scarcity of literature addressing the role of trimethylamine N-oxide in hypertension pathogenesis. In this review, we discuss the impact of the gut microbiota and gut microbiota dependant trimethylamine N-oxide in the pathogenesis of hypertension. We present evidence from both human and animal studies and further discuss new insights relating to potential therapies for managing hypertension by altering the gut microbiota.
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Affiliation(s)
- Katongo H. Mutengo
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone, Zambia
- Schools of Public Health and Medicine, University of Zambia, Lusaka, Zambia
| | - Sepiso K. Masenga
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone, Zambia
- Schools of Public Health and Medicine, University of Zambia, Lusaka, Zambia
| | - Aggrey Mweemba
- Department of Medicine, Levy Mwanawasa Medical University, Lusaka, Zambia
| | - Wilbroad Mutale
- School of Public Health, University of Zambia, Lusaka, Zambia
| | - Annet Kirabo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
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31
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Gunata M, Parlakpinar H. Experimental heart failure models in small animals. Heart Fail Rev 2023; 28:533-554. [PMID: 36504404 DOI: 10.1007/s10741-022-10286-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/08/2022] [Indexed: 12/14/2022]
Abstract
Heart failure (HF) is one of the most critical health and economic burdens worldwide, and its prevalence is continuously increasing. HF is a disease that occurs due to a pathological change arising from the function or structure of the heart tissue and usually progresses. Numerous experimental HF models have been created to elucidate the pathophysiological mechanisms that cause HF. An understanding of the pathophysiology of HF is essential for the development of novel efficient therapies. During the past few decades, animal models have provided new insights into the complex pathogenesis of HF. Success in the pathophysiology and treatment of HF has been achieved by using animal models of HF. The development of new in vivo models is critical for evaluating treatments such as gene therapy, mechanical devices, and new surgical approaches. However, each animal model has advantages and limitations, and none of these models is suitable for studying all aspects of HF. Therefore, the researchers have to choose an appropriate experimental model that will fully reflect HF. Despite some limitations, these animal models provided a significant advance in the etiology and pathogenesis of HF. Also, experimental HF models have led to the development of new treatments. In this review, we discussed widely used experimental HF models that continue to provide critical information for HF patients and facilitate the development of new treatment strategies.
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Affiliation(s)
- Mehmet Gunata
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, 44280, Türkiye
| | - Hakan Parlakpinar
- Department of Medical Pharmacology, Faculty of Medicine, Inonu University, Malatya, 44280, Türkiye.
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32
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Niranjan PK, Bahadur S. Recent Developments in Drug Targets and Combination Therapy for the Clinical Management of Hypertension. Cardiovasc Hematol Disord Drug Targets 2023; 23:226-245. [PMID: 38038000 DOI: 10.2174/011871529x278907231120053559] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 10/30/2023] [Accepted: 11/03/2023] [Indexed: 12/02/2023]
Abstract
Raised blood pressure is the most common complication worldwide that may lead to atherosclerosis and ischemic heart disease. Unhealthy lifestyles, smoking, alcohol consumption, junk food, and genetic disorders are some of the causes of hypertension. To treat this condition, numerous antihypertensive medications are available, either alone or in combination, that work via various mechanisms of action. Combinational therapy provides a certain advantage over monotherapy in the sense that it acts in multi mechanism mode and minimal drug amount is required to elicit the desired therapeutic effect. Such therapy is given to patients with systolic blood pressure greater than 20 mmHg and/or diastolic blood pressure exceeding 10 mmHg beyond the normal range, as well as those suffering from severe cardiovascular disease. The selection of antihypertensive medications, such as calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and low-dose diuretics, hinges on their ability to manage blood pressure effectively and reduce cardiovascular disease risks. This review provides insights into the diverse monotherapy and combination therapy approaches used for elevated blood pressure management. In addition, it offers an analysis of combination therapy versus monotherapy and discusses the current status of these therapies, from researchbased findings to clinical trials.
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Affiliation(s)
| | - Shiv Bahadur
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India
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33
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Pergola PE. Phosphate Frustration: Treatment Options to Complement Current Therapies. Int J Nephrol 2022; 2022:9457440. [PMID: 36045900 PMCID: PMC9424003 DOI: 10.1155/2022/9457440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/16/2022] [Indexed: 11/18/2022] Open
Abstract
Hyperphosphatemia eventually develops in almost all patients with advanced chronic kidney disease and is associated with negative clinical outcomes. Thus, guidelines recommend targeting treatment to normal phosphate levels in patients with chronic kidney disease. Despite low phosphorus diets, clearance by dialysis, and phosphate binder use, many patients with chronic kidney disease on dialysis are unable to consistently achieve and maintain serum phosphate concentrations <5.5 mg/dL. A chart audit of patients on dialysis receiving phosphate binders showed that 74 to 86% were unable to consistently achieve serum phosphate ≤5.5 mg/dL over 6 months. Furthermore, although there is evidence that serum phosphate concentrations <4.5 mg/dL are associated with improved survival and cardiovascular outcomes, real-world phosphate control data suggest achieving and maintaining this goal for most patients would be extremely challenging, if not near impossible, using current therapies. As phosphate binders can only remove approximately 300 mg of the 2,500 mg or more daily dietary phosphate intake, therapeutic innovations are necessary to improve phosphate management. We present treatment options to complement current therapies including tenapanor, a novel sodium/hydrogen exchanger isoform 3 inhibitor that blocks the dominant paracellular phosphate absorption pathway and has been shown to reduce phosphate levels in several clinical trials.
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Jiang X, Liu Y, Zhang XY, Liu X, Liu X, Wu X, Jose PA, Duan S, Xu FJ, Yang Z. Intestinal Gastrin/CCKBR (Cholecystokinin B Receptor) Ameliorates Salt-Sensitive Hypertension by Inhibiting Intestinal Na +/H + Exchanger 3 Activity Through a PKC (Protein Kinase C)-Mediated NHERF1 and NHERF2 Pathway. Hypertension 2022; 79:1668-1679. [PMID: 35674015 PMCID: PMC9278716 DOI: 10.1161/hypertensionaha.121.18791] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background: The present study directly tested the crucial role of intestinal gastrin/CCKBR (cholecystokinin B receptor) in the treatment of salt-sensitive hypertension. Methods: Adult intestine-specific Cckbr-knockout mice (Cckbrfl/flvillin-Cre) and Dahl salt-sensitive rats were studied on the effect of high salt intake (8% NaCl, 6–7 weeks) on intestinal Na+/H+ exchanger 3 expression, urine sodium concentration, and blood pressure. High-salt diet increased urine sodium concentration and systolic blood pressure to a greater extent in Cckbrfl/flvillin-Cre mice and Dahl salt-sensitive rats than their respective controls, Cckbrfl/flvillin mice and SS13BN rats. We constructed gastrin-SiO2 microspheres to enable gastrin to stimulate specifically and selectively intestinal CCKBR without its absorption into the circulation. Results: Gastrin-SiO2 microspheres treatment prevented the high salt-induced hypertension and increase in urine Na concentration by inhibiting intestinal Na+/H+ exchanger 3 trafficking and activity, increasing stool sodium without inducing diarrhea. Gastrin-mediated inhibition of intestinal Na+/H+ exchanger 3 activity, related to a PKC (protein kinase C)-mediated activation of NHERF1 and NHERF2. Conclusions: These results support a crucial role of intestinal gastrin/CCKBR in decreasing intestinal sodium absorption and keeping the blood pressure in the normal range. The gastrointestinal administration of gastrin-SiO2 microspheres is a promising and safe strategy to treat salt-sensitive hypertension without side effects.
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Affiliation(s)
- Xiaoliang Jiang
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.)
| | - Yunpeng Liu
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.)
| | - Xin-Yang Zhang
- Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, P.R. China (X.-Y.Z., S.D., F.-J.X.)
| | - Xue Liu
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.)
| | - Xing Liu
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.)
| | - Xianxian Wu
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.)
| | - Pedro A Jose
- Department of Pharmacology and Physiology (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC.,Division of Kidney Diseases and Hypertension, Department of Medicine (P.A.J.), The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Shun Duan
- Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, P.R. China (X.-Y.Z., S.D., F.-J.X.)
| | - Fu-Jian Xu
- Key Lab of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, P.R. China (X.-Y.Z., S.D., F.-J.X.)
| | - Zhiwei Yang
- NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS&PUMC), National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, P.R. China (X.J., Y.L., Xue Liu, Xing Liu, X.W., Z.Y.)
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Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation. Gastroenterology 2022; 163:118-136. [PMID: 35738724 DOI: 10.1053/j.gastro.2022.04.016] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction associated with significant disease burden. This American Gastroenterological Association guideline is intended to support practitioners in decisions about the use of medications for the pharmacological management of IBS-C and is an update of a prior technical review and guideline. METHODS The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The technical review panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of the following agents: tenapanor, plecanatide, linaclotide, tegaserod, lubiprostone, polyethylene glycol laxatives, tricyclic antidepressants, selective serotonin reuptake inhibitors, and antispasmodics. The Guideline Panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. CONCLUSIONS The panel agreed on 9 recommendations for the management of patients with IBS-C. The panel made a strong recommendation for linaclotide (high certainty) and conditional recommendations for tenapanor, plecanatide, tegaserod, and lubiprostone (moderate certainty), polyethylene glycol laxatives, tricyclic antidepressants, and antispasmodics (low certainty). The panel made a conditional recommendation against the use of selective serotonin reuptake inhibitors (low certainty).
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Affiliation(s)
- Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
| | - Shahnaz Sultan
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota; Veterans Affairs Healthcare System, Minneapolis, Minnesota
| | - Anthony Lembo
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - G Nicholas Verne
- Department of Medicine, University of Tennessee College of Medicine, Memphis, Tennessee
| | - Walter Smalley
- Department of Medicine, Division of Gastroenterology, Vanderbilt University, Nashville, Tennessee
| | - Joel J Heidelbaugh
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
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Patil CN, Ritter ML, Wackman KK, Oliveira V, Balapattabi K, Grobe CC, Brozoski DT, Reho JJ, Nakagawa P, Mouradian GC, Kriegel AJ, Kwitek AE, Hodges MR, Segar JL, Sigmund CD, Grobe JL. Cardiometabolic effects of DOCA-salt in male C57BL/6J mice are variably dependent on sodium and nonsodium components of diet. Am J Physiol Regul Integr Comp Physiol 2022; 322:R467-R485. [PMID: 35348007 PMCID: PMC9054347 DOI: 10.1152/ajpregu.00017.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/14/2022] [Accepted: 03/23/2022] [Indexed: 01/22/2023]
Abstract
Hypertension characterized by low circulating renin activity accounts for roughly 25%-30% of primary hypertension in humans and can be modeled experimentally via deoxycorticosterone acetate (DOCA)-salt treatment. In this model, phenotypes develop in progressive phases, although the timelines and relative contributions of various mechanisms to phenotype development can be distinct between laboratories. To explore interactions among environmental influences such as diet formulation and dietary sodium (Na) content on phenotype development in the DOCA-salt paradigm, we examined an array of cardiometabolic endpoints in young adult male C57BL/6J mice during sham or DOCA-salt treatments when mice were maintained on several common, commercially available laboratory rodent "chow" diets including PicoLab 5L0D (0.39% Na), Envigo 7913 (0.31% Na), Envigo 2920x (0.15% Na), or a customized version of Envigo 2920x (0.4% Na). Energy balance (weight gain, food intake, digestive efficiency, and energy efficiency), fluid and electrolyte homeostasis (fluid intake, Na intake, fecal Na content, hydration, and fluid compartmentalization), renal functions (urine production rate, glomerular filtration rate, urine Na excretion, renal expression of renin, vasopressin receptors, aquaporin-2 and relationships among markers of vasopressin release, aquaporin-2 shedding, and urine osmolality), and blood pressure, all exhibited changes that were subject to interactions between diet and DOCA-salt. Interestingly, some of these phenotypes, including blood pressure and hydration, were dependent on nonsodium dietary components, as Na-matched diets resulted in distinct phenotype development. These findings provide a broad and robust illustration of an environment × treatment interaction that impacts the use and interpretation of a common rodent model of low-renin hypertension.
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Affiliation(s)
- Chetan N Patil
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - McKenzie L Ritter
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Kelsey K Wackman
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Vanessa Oliveira
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Connie C Grobe
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Daniel T Brozoski
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - John J Reho
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Pablo Nakagawa
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Gary C Mouradian
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Alison J Kriegel
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Anne E Kwitek
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Matthew R Hodges
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jeffrey L Segar
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Curt D Sigmund
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
- Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Justin L Grobe
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
- Comprehensive Rodent Metabolic Phenotyping Core, Medical College of Wisconsin, Milwaukee, Wisconsin
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
- Center of Systems Molecular Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
- Biomedical Engineering, Medical College of Wisconsin, Milwaukee, Wisconsin
- Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin
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Nikolovska K, Seidler UE, Stock C. The Role of Plasma Membrane Sodium/Hydrogen Exchangers in Gastrointestinal Functions: Proliferation and Differentiation, Fluid/Electrolyte Transport and Barrier Integrity. Front Physiol 2022; 13:899286. [PMID: 35665228 PMCID: PMC9159811 DOI: 10.3389/fphys.2022.899286] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/19/2022] [Indexed: 12/11/2022] Open
Abstract
The five plasma membrane Na+/H+ exchanger (NHE) isoforms in the gastrointestinal tract are characterized by distinct cellular localization, tissue distribution, inhibitor sensitivities, and physiological regulation. NHE1 (Slc9a1) is ubiquitously expressed along the gastrointestinal tract in the basolateral membrane of enterocytes, but so far, an exclusive role for NHE1 in enterocyte physiology has remained elusive. NHE2 (Slc9a2) and NHE8 (Slc9a8) are apically expressed isoforms with ubiquitous distribution along the colonic crypt axis. They are involved in pHi regulation of intestinal epithelial cells. Combined use of a knockout mouse model, intestinal organoid technology, and specific inhibitors revealed previously unrecognized actions of NHE2 and NHE8 in enterocyte proliferation and differentiation. NHE3 (Slc9a3), expressed in the apical membrane of differentiated intestinal epithelial cells, functions as the predominant nutrient-independent Na+ absorptive mechanism in the gut. The new selective NHE3 inhibitor (Tenapanor) allowed discovery of novel pathophysiological and drug-targetable NHE3 functions in cystic-fibrosis associated intestinal obstructions. NHE4, expressed in the basolateral membrane of parietal cells, is essential for parietal cell integrity and acid secretory function, through its role in cell volume regulation. This review focuses on the expression, regulation and activity of the five plasma membrane Na+/H+ exchangers in the gastrointestinal tract, emphasizing their role in maintaining intestinal homeostasis, or their impact on disease pathogenesis. We point to major open questions in identifying NHE interacting partners in central cellular pathways and processes and the necessity of determining their physiological role in a system where their endogenous expression/activity is maintained, such as organoids derived from different parts of the gastrointestinal tract.
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Nwia SM, Li XC, Leite APDO, Hassan R, Zhuo JL. The Na +/H + Exchanger 3 in the Intestines and the Proximal Tubule of the Kidney: Localization, Physiological Function, and Key Roles in Angiotensin II-Induced Hypertension. Front Physiol 2022; 13:861659. [PMID: 35514347 PMCID: PMC9062697 DOI: 10.3389/fphys.2022.861659] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/25/2022] [Indexed: 01/29/2023] Open
Abstract
The sodium (Na+)/hydrogen (H+) exchanger 3 (NHE3) is one of the most important Na+/H+ antiporters in the small intestines of the gastrointestinal tract and the proximal tubules of the kidney. The roles of NHE3 in the regulation of intracellular pH and acid-base balance have been well established in cellular physiology using in vitro techniques. Localized primarily on the apical membranes in small intestines and proximal tubules, the key action of NHE3 is to facilitate the entry of luminal Na+ and the extrusion of intracellular H+ from intestinal and proximal tubule tubular epithelial cells. NHE3 is, directly and indirectly, responsible for absorbing the majority of ingested Na+ from small and large intestines and reabsorbing >50% of filtered Na+ in the proximal tubules of the kidney. However, the roles of NHE3 in the regulation of proximal tubular Na+ transport in the integrative physiological settings and its contributions to the basal blood pressure regulation and angiotensin II (Ang II)-induced hypertension have not been well studied previously due to the lack of suitable animal models. Recently, novel genetically modified mouse models with whole-body, kidney-specific, or proximal tubule-specific deletion of NHE3 have been generated by us and others to determine the critical roles and underlying mechanisms of NHE3 in maintaining basal body salt and fluid balance, blood pressure homeostasis, and the development of Ang II-induced hypertension at the whole-body, kidney, or proximal tubule levels. The objective of this invited article is to review, update, and discuss recent findings on the critical roles of intestinal and proximal tubule NHE3 in maintaining basal blood pressure homeostasis and their potential therapeutic implications in the development of angiotensin II (Ang II)-dependent hypertension.
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Affiliation(s)
- Sarah M. Nwia
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Xiao Chun Li
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Ana Paula de Oliveira Leite
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Rumana Hassan
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Jia Long Zhuo
- Tulane Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States,Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States,*Correspondence: Jia Long Zhuo,
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Nikolovska K, Cao L, Hensel I, Di Stefano G, Seidler A, Zhou K, Qian J, Singh AK, Riederer B, Seidler U. Sodium/hydrogen-exchanger-2 modulates colonocyte lineage differentiation. Acta Physiol (Oxf) 2022; 234:e13774. [PMID: 34985202 DOI: 10.1111/apha.13774] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/12/2021] [Accepted: 01/01/2022] [Indexed: 12/11/2022]
Abstract
AIM The sodium/hydrogen exchanger 2 (NHE2) is an intestinal acid extruder with crypt-predominant localization and unresolved physiological significance. Our aim was to decipher its role in colonic epithelial cell proliferation, differentiation and electrolyte transport. METHODS Alterations induced by NHE2-deficiency were addressed in murine nhe2-/- and nhe2+/+ colonic crypts and colonoids, and NHE2-knockdown and control Caco2Bbe cells using pH-fluorometry, gene expression analysis and immunofluorescence. RESULTS pHi -measurements along the colonic cryptal axis revealed significantly decreased intracellular pH (pHi ) in the middle segment of nhe2-/- compared to nhe2+/+ crypts. Increased Nhe2 mRNA expression was detected in murine colonoids in the transiently amplifying/progenitor cell stage (TA/PE). Lack of Nhe2 altered the differentiation programme of colonic epithelial cells with reduced expression of absorptive lineage markers alkaline phosphatase (iAlp), Slc26a3 and transcription factor hairy and enhancer-of-split 1 (Hes1), but increased expression of secretory lineage markers Mucin 2, trefoil factor 3 (Tff3), enteroendocrine marker chromogranin A and murine atonal homolog 1 (Math1). Enterocyte differentiation was found to be pHi dependent with acidic pHi reducing, and alkaline pHi stimulating the expression of enterocyte differentiation markers in Caco2Bbe cells. A thicker mucus layer, longer crypts and an expanded brush border membrane zone of sodium/hydrogen exchanger 3 (NHE3) abundance may explain the lack of inflammation and the normal fluid absorptive rate in nhe2-/- colon. CONCLUSIONS The results suggest that NHE2 expression is activated when colonocytes emerge from the stem cell niche. Its activity increases progenitor cell pHi and thereby supports absorptive enterocyte differentiation.
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Affiliation(s)
- Katerina Nikolovska
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
| | - Li Cao
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
- Department of Gastroenterology Tongji Hospital Huazhong University Wuhan China
| | - Inga Hensel
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
| | - Gabriella Di Stefano
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
| | - Anna Elisabeth Seidler
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
| | - Kunyan Zhou
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
| | - Jiajie Qian
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
- Department of Transplantation and Hepatobiliary Surgery First Affiliated Hospital of Zheijang University Hangzhou China
| | - Anurag Kumar Singh
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
- Department of Physiological Chemistry University of Halle Halle (Saale) Germany
| | - Brigitte Riederer
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
| | - Ursula Seidler
- Department of Gastroenterology, Hepatology and Endocrinology Hannover Medical School Hannover Germany
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Xue J, Thomas L, Murali SK, Levi M, Fenton RA, Dominguez Rieg JA, Rieg T. Enhanced phosphate absorption in intestinal epithelial cell-specific NHE3 knockout mice. Acta Physiol (Oxf) 2022; 234:e13756. [PMID: 34978760 PMCID: PMC9286053 DOI: 10.1111/apha.13756] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 11/16/2021] [Accepted: 01/01/2022] [Indexed: 12/11/2022]
Abstract
Aims The kidneys play a major role in maintaining Pi homeostasis. Patients in later stages of CKD develop hyperphosphatemia. One novel treatment option is tenapanor, an intestinal‐specific NHE3 inhibitor. To gain mechanistic insight into the role of intestinal NHE3 in Pi homeostasis, we studied tamoxifen‐inducible intestinal epithelial cell‐specific NHE3 knockout (NHE3IEC‐KO) mice. Methods Mice underwent dietary Pi challenges, and hormones as well as urinary/plasma Pi were determined. Intestinal 33P uptake studies were conducted in vivo to compare the effects of tenapanor and NHE3IEC‐KO. Ex vivo Pi transport was measured in everted gut sacs and brush border membrane vesicles. Intestinal and renal protein expression of Pi transporters were determined. Results On the control diet, NHE3IEC‐KO mice had similar Pi homeostasis, but a ~25% reduction in FGF23 compared with control mice. Everted gut sacs and brush border membrane vesicles showed enhanced Pi uptake associated with increased Npt2b expression in NHE3IEC‐KO mice. Acute oral Pi loading resulted in higher plasma Pi in NHE3IEC‐KO mice. Tenapanor inhibited intestinal 33P uptake acutely but then led to hyper‐absorption at later time points compared to vehicle. In response to high dietary Pi, plasma Pi and FGF23 increased to higher levels in NHE3IEC‐KO mice which was associated with greater Npt2b expression. Reduced renal Npt2c and a trend for reduced Npt2a expression were unable to correct for higher plasma Pi. Conclusion Intestinal NHE3 has a significant contribution to Pi homeostasis. In contrast to effects described for tenapanor on Pi homeostasis, NHE3IEC‐KO mice show enhanced, rather than reduced, intestinal Pi uptake.
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Affiliation(s)
- Jianxiang Xue
- Department of Molecular Pharmacology and Physiology Morsani College of Medicine University of South Florida Tampa Florida USA
| | - Linto Thomas
- Department of Molecular Pharmacology and Physiology Morsani College of Medicine University of South Florida Tampa Florida USA
| | | | - Moshe Levi
- Department of Biochemistry and Molecular & Cellular Biology Georgetown University Washington District of Columbia USA
| | | | - Jessica A. Dominguez Rieg
- Department of Molecular Pharmacology and Physiology Morsani College of Medicine University of South Florida Tampa Florida USA
- James A. Haley Veterans' Hospital Tampa Florida USA
| | - Timo Rieg
- Department of Molecular Pharmacology and Physiology Morsani College of Medicine University of South Florida Tampa Florida USA
- James A. Haley Veterans' Hospital Tampa Florida USA
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Leifheit-Nestler M, Vogt I, Haffner D, Richter B. Phosphate Is a Cardiovascular Toxin. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1362:107-134. [DOI: 10.1007/978-3-030-91623-7_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Layer P, Andresen V, Allescher H, Bischoff SC, Claßen M, Elsenbruch S, Freitag M, Frieling T, Gebhard M, Goebel-Stengel M, Häuser W, Holtmann G, Keller J, Kreis ME, Kruis W, Langhorst J, Jansen PL, Madisch A, Mönnikes H, Müller-Lissner S, Niesler B, Pehl C, Pohl D, Raithel M, Röhrig-Herzog G, Schemann M, Schmiedel S, Schwille-Kiuntke J, Storr M, Preiß JC, Andus T, Buderus S, Ehlert U, Engel M, Enninger A, Fischbach W, Gillessen A, Gschossmann J, Gundling F, Haag S, Helwig U, Hollerbach S, Karaus M, Katschinski M, Krammer H, Kuhlbusch-Zicklam R, Matthes H, Menge D, Miehlke S, Posovszky MC, Schaefert R, Schmidt-Choudhury A, Schwandner O, Schweinlin A, Seidl H, Stengel A, Tesarz J, van der Voort I, Voderholzer W, von Boyen G, von Schönfeld J, Wedel T. Update S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM) – Juni 2021 – AWMF-Registriernummer: 021/016. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:1323-1415. [PMID: 34891206 DOI: 10.1055/a-1591-4794] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- P Layer
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - V Andresen
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - H Allescher
- Zentrum für Innere Medizin, Gastroent., Hepatologie u. Stoffwechsel, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Deutschland
| | - S C Bischoff
- Institut für Ernährungsmedizin, Universität Hohenheim, Stuttgart, Deutschland
| | - M Claßen
- Klinik für Kinder- und Jugendmedizin, Klinikum Links der Weser, Bremen, Deutschland
| | - S Elsenbruch
- Klinik für Neurologie, Translational Pain Research Unit, Universitätsklinikum Essen, Essen, Deutschland.,Abteilung für Medizinische Psychologie und Medizinische Soziologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - M Freitag
- Abteilung Allgemeinmedizin Department für Versorgungsforschung, Universität Oldenburg, Oldenburg, Deutschland
| | - T Frieling
- Medizinische Klinik II, Helios Klinikum Krefeld, Krefeld, Deutschland
| | - M Gebhard
- Gemeinschaftspraxis Pathologie-Hamburg, Hamburg, Deutschland
| | - M Goebel-Stengel
- Innere Medizin II, Helios Klinik Rottweil, Rottweil, und Innere Medizin VI, Psychosomat. Medizin u. Psychotherapie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - W Häuser
- Innere Medizin I mit Schwerpunkt Gastroenterologie, Klinikum Saarbrücken, Saarbrücken, Deutschland
| | - G Holtmann
- Faculty of Medicine & Faculty of Health & Behavioural Sciences, Princess Alexandra Hospital, Brisbane, Australien
| | - J Keller
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - M E Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| | | | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Deutschland
| | - P Lynen Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, Berlin, Deutschland
| | - A Madisch
- Klinik für Gastroenterologie, interventionelle Endoskopie und Diabetologie, Klinikum Siloah, Klinikum Region Hannover, Hannover, Deutschland
| | - H Mönnikes
- Klinik für Innere Medizin, Martin-Luther-Krankenhaus, Berlin, Deutschland
| | | | - B Niesler
- Abteilung Molekulare Humangenetik Institut für Humangenetik, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - C Pehl
- Medizinische Klinik, Krankenhaus Vilsbiburg, Vilsbiburg, Deutschland
| | - D Pohl
- Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Schweiz
| | - M Raithel
- Medizinische Klinik II m.S. Gastroenterologie und Onkologie, Waldkrankenhaus St. Marien, Erlangen, Deutschland
| | | | - M Schemann
- Lehrstuhl für Humanbiologie, TU München, Deutschland
| | - S Schmiedel
- I. Medizinische Klinik und Poliklinik Gastroenterologie, Universitätsklinikum Hamburg-Eppendorf, Deutschland
| | - J Schwille-Kiuntke
- Abteilung für Psychosomatische Medizin und Psychotherapie, Medizinische Universitätsklinik Tübingen, Tübingen, Deutschland.,Institut für Arbeitsmedizin, Sozialmedizin und Versorgungsforschung, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - M Storr
- Zentrum für Endoskopie, Gesundheitszentrum Starnberger See, Starnberg, Deutschland
| | - J C Preiß
- Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Hepatologie, Vivantes Klinikum Neukölln, Berlin, Deutschland
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Kovesdy CP, Adebiyi A, Rosenbaum D, Jacobs JW, Quarles LD. Novel Treatments from Inhibition of the Intestinal Sodium-Hydrogen Exchanger 3. Int J Nephrol Renovasc Dis 2021; 14:411-420. [PMID: 34880650 PMCID: PMC8646223 DOI: 10.2147/ijnrd.s334024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/11/2021] [Indexed: 12/31/2022] Open
Abstract
Plasma membrane sodium–hydrogen exchangers (NHE) transport Na+ into cells in exchange for H+. While there are nine isoforms of NHE in humans, this review focuses on the NHE3 isoform, which is abundantly expressed in the gastrointestinal tract, where it plays a key role in acid–base balance and water homeostasis. NHE3 inhibition in the small intestine results in luminal sodium and water retention, leading to a general decrease in paracellular water flux and diffusional driving force, reduced intestinal sodium absorption, and increased stool sodium excretion. The resulting softer and more frequent stools are the rationale for the development of tenapanor as a novel, first-in-class NHE3 inhibitor to treat irritable bowel syndrome with constipation. NHE3 also has additional therapeutic implications in nephrology. Inhibition of intestinal NHE3 also lowers blood pressure by reducing intestinal sodium absorption. Perhaps, the most novel effect is its ability to decrease intestinal phosphate absorption by inhibiting the paracellular phosphate absorption pathway. Therefore, selective pharmacological inhibition of NHE3 could be a potential therapeutic strategy to treat not only heart failure and hypertension but also hyperphosphatemia. This review presents an overview of the molecular and physiological functions of NHE3 and discusses how these functions translate to potential clinical applications in nephrology.
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Affiliation(s)
- Csaba P Kovesdy
- Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Adebowale Adebiyi
- Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | | | | | - L Darryl Quarles
- Division of Nephrology, University of Tennessee Health Science Center, Memphis, TN, USA
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Inaba M, Une Y, Ikejiri K, Kanda H, Fukagawa M, Akizawa T. Dose-Response of Tenapanor in Patients With Hyperphosphatemia Undergoing Hemodialysis in Japan—a Phase 2 Randomized Trial. Kidney Int Rep 2021; 7:177-188. [PMID: 35155857 PMCID: PMC8820999 DOI: 10.1016/j.ekir.2021.11.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 11/03/2021] [Accepted: 11/08/2021] [Indexed: 12/18/2022] Open
Abstract
Introduction Simplified, but effective, hyperphosphatemia treatments with novel mechanisms of action, tolerable safety profiles, and low pill burden are needed for patients undergoing hemodialysis. Tenapanor is a calcium (Ca)-free, nonmetal, nonpolymeric drug that reduces phosphate absorption by selectively inhibiting intestinal sodium-hydrogen exchanger 3. As the serum phosphorus (P) level-lowering effect of tenapanor has not been evaluated in Japanese patients with hyperphosphatemia undergoing hemodialysis, we evaluated its efficacy and safety in this population. Methods This was a multicenter, phase 2, double-blind, placebo-controlled, parallel-group, dose-finding study. Change in serum P level from baseline at week 6 was the primary end point. Results Overall, 207 patients were randomized to 5 groups (placebo [n = 41] and tenapanor 5-mg taken twice daily [BID] [n = 42], 10-mg BID [n = 41], 30-mg BID [n = 42], and 30-mg BID dose-titration [n = 41]) and treated for 6 weeks. Mean changes from baseline at week 6 in serum P level were 0.64, −0.93, −1.36, −1.92, and −1.99 mg/dl in the placebo and tenapanor groups, respectively. Serum P level was significantly decreased from baseline in all tenapanor groups compared with placebo (P < 0.001, for each dose). Diarrhea was the most frequent drug-related adverse event (AE) with an incidence of 9.8%, 50.0%, 65.9%, 76.2%, and 65.9% in the respective placebo and tenapanor groups. Conclusion In Japanese patients undergoing hemodialysis, tenapanor was found to have a dose-responsive, serum P level-lowering effect. Diarrhea was the most frequent drug-related AE; most cases were mild and generally tolerable. Tenapanor may become a first-in-class therapeutic agent for patients with hyperphosphatemia.
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Block GA, Bleyer AJ, Silva AL, Weiner DE, Lynn RI, Yang Y, Rosenbaum DP, Chertow GM. Safety and Efficacy of Tenapanor for Long-term Serum Phosphate Control in Maintenance Dialysis: A 52-Week Randomized Phase 3 Trial (PHREEDOM). KIDNEY360 2021; 2:1600-1610. [PMID: 35372979 PMCID: PMC8785778 DOI: 10.34067/kid.0002002021] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 08/25/2021] [Indexed: 12/17/2022]
Abstract
Background Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia. Methods In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphate 6.0-10.0 mg/dl) and a 1.5 mg/dl increase after phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks of treatment with tenapanor were rerandomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period), and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy end point was the difference in the change in serum phosphate from the end of the randomized treatment period to the end of the randomized withdrawal period, among participants who achieved ≥1.2 mg/dl decrease in serum phosphate during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set. Results Of 564 eligible participants randomized to receive tenapanor (n=423) or sevelamer carbonate (n=141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were rerandomized to tenapanor (n=128) or placebo (n=127) during the randomized withdrawal period. In the efficacy analysis set (n=131), the difference in estimated mean change in serum phosphate level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was -1.4 mg/dl (P<0.0001); in the ITT analysis set (n=243), the estimated mean difference was -0.7 mg/dl (P=0.002). Loosened stools were the most frequently reported adverse event (53% during the randomized treatment period). Serious adverse events were reported more frequently for participants treated with sevelamer carbonate (16%-23% across the three study periods) compared with tenapanor (11%-17%). Conclusions Tenapanor reduced serum phosphate concentrations and maintained control of serum phosphate in participants receiving maintenance dialysis, with an acceptable safety and tolerability profile.
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Affiliation(s)
- Geoffrey A Block
- Clinical Research and Medical Affairs, US Renal Care, Inc., Plano, Texas
| | - Anthony J Bleyer
- Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Arnold L Silva
- Boise Kidney and Hypertension Institute, Meridian, Idaho
| | - Daniel E Weiner
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Robert I Lynn
- Department of Medicine, Albert Einstein College of Medicine, New York, New York.,Kidney Medical Associates, New York, New York
| | - Yang Yang
- Biometrics, Ardelyx, Inc., Fremont, California
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Zhou K, Amiri M, Salari A, Yu Y, Xu H, Seidler U, Nikolovska K. Functional characterization of the sodium/hydrogen exchanger 8 and its role in proliferation of colonic epithelial cells. Am J Physiol Cell Physiol 2021; 321:C471-C488. [PMID: 34288721 DOI: 10.1152/ajpcell.00582.2020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Intestinal NaCl, HCO3-, and fluid absorption are strongly dependent on apical Na+/H+ exchange. The intestine expresses three presumably apical sodium-hydrogen exchanger (NHE) isoforms: NHE2, NHE3, and NHE8. We addressed the role of NHE8 [solute carrier 9A8 (SLC9A8)] and its interplay with NHE2 (SLC9A2) in luminal proton extrusion during acute and chronic enterocyte acidosis and studied the differential effects of NHE8 and NHE2 on enterocyte proliferation. In contrast to NHE3, which was upregulated in differentiated versus undifferentiated colonoids, the expression of NHE2 and NHE8 remained constant during differentiation of colonoids and Caco2Bbe cells. Heterogeneously expressed Flag-tagged rat (r)Nhe8 and human (h)NHE8 translocated to the apical membrane of Caco2Bbe cells. rNhe8 and hNHE8, when expressed in NHE-deficient PS120 fibroblasts showed higher sensitivity to HOE642 compared to NHE2. Lentiviral shRNA knockdown of endogenous NHE2 in Caco2Bbe cells (C2Bbe/shNHE2) resulted in a decreased steady-state intracellular pH (pHi), an increased NHE8 mRNA expression, and augmented NHE8-mediated apical NHE activity. Lentiviral shRNA knockdown of endogenous NHE8 in Caco2Bbe cells (C2Bbe/shNHE8) resulted in a decreased steady-state pHi as well, accompanied by decreased NHE2 mRNA expression and activity, which together contributed to reduced apical NHE activity in the NHE8-knockdown cells. Chronic acidosis increased NHE8 but not NHE2 mRNA expression. Alterations in NHE2 and NHE8 expression/activity affected proliferation, with C2Bbe/shNHE2 cells having lower and C2Bbe/shNHE8 having higher proliferative capacity, accompanied by amplified ERK1/2 signaling pathway and increased EGFR expression in the latter cell line. Thus, both Na+/H+ exchangers have distinct functions during cellular homeostasis by triggering different signaling pathways to regulate cellular proliferation and pHi control.
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Affiliation(s)
- Kunyan Zhou
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Mahdi Amiri
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Azam Salari
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Yan Yu
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Hua Xu
- Department of Pediatrics, University of Arizona Health Science Center, Tucson, Arizona
| | - Ursula Seidler
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katerina Nikolovska
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Nelson AD, Black CJ, Houghton LA, Lugo-Fagundo NS, Lacy BE, Ford AC. Systematic review and network meta-analysis: efficacy of licensed drugs for abdominal bloating in irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2021; 54:98-108. [PMID: 34114657 DOI: 10.1111/apt.16437] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/24/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Although bloating is a highly prevalent and troublesome symptom in irritable bowel syndrome with constipation (IBS-C), treatment is empirical with no specific guidelines for its management. AIM To conduct a pairwise and network meta-analysis, using a frequentist approach, of Food and Drug Administration-licensed drugs for IBS-C comparing their efficacy for abdominal bloating as a specific endpoint. METHODS We searched the medical literature through December 2020 to identify randomised controlled trials (RCTs) in IBS-C, with abdominal bloating reported as a dichotomous assessment. Efficacy of each drug was reported as a pooled relative risk (RR) with 95% confidence intervals (CIs) to summarise effect of each comparison tested. Treatments were ranked according to their P-score. RESULTS We identified 13 eligible RCTs, containing 10 091 patients. Linaclotide 290 µg o.d., lubiprostone 8 µg b.d., tenapanor 50 mg b.d. and tegaserod 6 mg b.d. were all superior to placebo for abdominal bloating in patients with IBS-C, in both pairwise and the network meta-analyses. Linaclotide demonstrated the greatest improvement in abdominal bloating in both pairwise and network meta-analysis (RR of failure to achieve an improvement in abdominal bloating = 0.78; 95% CI 0.74-0.83, number needed to treat = 7, P-score 0.97). Indirect comparison revealed no significant differences between individual drugs. CONCLUSIONS We found all licensed drugs for IBS-C to be superior to placebo for abdominal bloating. Linaclotide appeared to be the most efficacious at relieving abdominal bloating. Further research is needed to assess long-term efficacy of these agents and to better understand the precise mechanism of improving bloating.
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Affiliation(s)
- Alfred D Nelson
- Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Christopher J Black
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Lesley A Houghton
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | | | - Brian E Lacy
- Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
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Efficacy of Tenapanor in Treating Patients With Irritable Bowel Syndrome With Constipation: A 26-Week, Placebo-Controlled Phase 3 Trial (T3MPO-2). Am J Gastroenterol 2021; 116:1294-1303. [PMID: 33337659 PMCID: PMC8183489 DOI: 10.14309/ajg.0000000000001056] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Tenapanor is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger isoform 3. This phase 3 trial assessed the long-term efficacy and safety of tenapanor 50 mg b.i.d. for the treatment of patients with irritable bowel syndrome with constipation (IBS-C). METHODS In this randomized double-blind study (ClinicalTrials.gov identifier: NCT02686138), patients with IBS-C received tenapanor 50 mg b.i.d. or placebo b.i.d. for 26 weeks. The primary endpoint was the proportion of patients who had a reduction of ≥30.0% in average weekly worst abdominal pain and an increase of ≥1 weekly complete spontaneous bowel movement from baseline, both in the same week, for ≥6 of the first 12 treatment weeks (6/12-week combined responder). RESULTS Of the 620 randomized patients with IBS-C, 593 (95.6%) were included in the intention-to-treat analysis set (tenapanor: n = 293; placebo: n = 300) and 481 patients (77.6%) completed the 26-week treatment period. In the intention-to-treat analysis set (mean age: 45.4 years; 82.1% women), a significantly greater proportion of patients treated with tenapanor were 6/12-week combined responders than those treated with placebo (36.5% vs 23.7%; P < 0.001). Abdominal symptoms and global symptoms of IBS were significantly improved with tenapanor compared with placebo. Diarrhea, the most common adverse event, was typically transient and mild to moderate in severity. Diarrhea led to study drug discontinuation for 19 (6.5%) and 2 patients (0.7%) receiving tenapanor and placebo, respectively. DISCUSSION Tenapanor 50 mg b.i.d. improved IBS-C symptoms over 26 weeks and was generally well tolerated, offering a potential new long-term treatment option for patients with IBS-C (see Visual abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B797).
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Jung EY, Lee SY, Lee DY, Kim OY, Park Y, Hur SJ. Effect of encapsulated edible halophyte with different biopolymers on the inhibition of sodium absorption in mouse. Food Sci Nutr 2021; 9:1972-1979. [PMID: 33841815 PMCID: PMC8020925 DOI: 10.1002/fsn3.2163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 11/10/2022] Open
Abstract
The purpose of this study was to investigate the effects of edible halophyte Salicornia herbacea encapsulated with biopolymers on inhibition of sodium absorption in mouse. Salicornia herbacea encapsulated with four biopolymers (pectin, chitosan, cellulose and dextrin) were fed to mice for 48 hr, and inhibiting sodium absorption was measured. In primary in vitro condition, fresh Salicornia herbacea encapsulated with 1% cellulose had 40% binding rate. Juice residue Salicornia herbacea encapsulated with 1% chitosan had the highest sodium binding rate by 50%. In mouse model, fresh, juice, and juice residue of Salicornia herbacea encapsulated with 4% chitosan had the highest sodium absorption inhibitory rate by 19%. These results indicate that biopolymer-encapsulated Salicornia herbacea could be combined with sodium under in vitro condition, and Salicornia herbacea encapsulated with biopolymers reduced sodium absorption in a mouse model. Chitosan and cellulose had the highest sodium absorption inhibitory effects compared with the other biopolymers.
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Affiliation(s)
- Eun Young Jung
- Department of Animal Science and TechnologyChung‐Ang UniversityAnseong‐siKorea
| | - Seung Yun Lee
- Department of Animal Science and TechnologyChung‐Ang UniversityAnseong‐siKorea
| | - Da Young Lee
- Department of Animal Science and TechnologyChung‐Ang UniversityAnseong‐siKorea
| | - On You Kim
- Department of Animal Science and TechnologyChung‐Ang UniversityAnseong‐siKorea
| | - Yeonhwa Park
- Department of Food ScienceUniversity of Massachusetts AmherstAmherstMAUSA
| | - Sun Jin Hur
- Department of Animal Science and TechnologyChung‐Ang UniversityAnseong‐siKorea
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Impaired Intestinal Sodium Transport in Inflammatory Bowel Disease: From the Passenger to the Driver's Seat. Cell Mol Gastroenterol Hepatol 2021; 12:277-292. [PMID: 33744482 PMCID: PMC8165433 DOI: 10.1016/j.jcmgh.2021.03.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 03/09/2021] [Accepted: 03/09/2021] [Indexed: 12/22/2022]
Abstract
Although impaired intestinal sodium transport has been described for decades as a ubiquitous feature of inflammatory bowel disease (IBD), whether and how it plays a pivotal role in the ailment has remained uncertain. Our identification of dominant mutations in receptor guanylyl cyclase 2C as a cause of IBD-associated familial diarrhea syndrome brought a shift in the way we envision impaired sodium transport. Is this just a passive collateral effect resulting from intestinal inflammation, or is it a crucial regulator of IBD pathogenesis? This review summarizes the mutational spectrum and underlying mechanisms of monogenic IBD associated with congenital sodium diarrhea. We constructed a model proposing that impaired sodium transport is an upstream pathogenic factor in IBD. The review also synthesized emerging insights from microbiome and animal studies to suggest how sodium malabsorption can serve as a unifying mediator of downstream pathophysiology. Further investigations into the mechanisms underlying salt and water transport in the intestine will provide newer approaches for understanding the ion-microbiome-immune cross-talk that serves as a driver of IBD. Model systems, such as patient-derived enteroids or induced pluripotent stem cell models, are warranted to unravel the role of individual genes regulating sodium transport and to develop more effective epithelial rescue and repair therapies.
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