Sa1600 - Tenapanor Attenuates Increased Macromolecule Permeability in Human Colon Monolayer Cultures Induced by Inflammatory Cytokines and Human Fecal Supernatants

Wang, Ji; Larauche, Muriel; Siegel, Matthew; King, Andrew J.; Mayer, Emeran A.; Tillisch, Kirsten; Labus, Jennifer S.; Chang, Lin; Caldwell, Jeremy S.

doi:10.1016/s0016-5085(18)31424-0

Cited by 6 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These basic science studies provide the rationale for the application of a small-molecule inhibitor of the gastrointestinal NHE3, such as tenapanor, to reverse (sodium and water) absorption in the intestine and therefore relieve constipation in lower FGIDs. Tenapanor also reduced permeability (FITC-dextran flux) of primary human monolayer colonic cell cultures exposed to fecal supernatants (obtained from 9 patients with Rome III-positive IBS-C and 10 healthy controls and prepared by diluting 1 g stool in 0.3 mL Krebs-Ringer buffer, homogenizing, and filtering with 100-m-pore size filters), suggesting additional mucosal effects that were speculated to reduce visceral pain by reducing access of potentially injurious molecules to the subepithelial layers (86).…”

Section: Nhe3 Inhibitor: Tenapanormentioning

confidence: 99%

What’s in the pipeline for lower functional gastrointestinal disorders in the next 5 years?

Camilleri

2019

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

The overall objectives of this review are to summarize actionable biomarkers for organic etiology of lower functional gastrointestinal disorders (FGIDs) that lead to individualized treatment for their FGIDs and to assess the pipeline for novel approaches to the management of constipation, diarrhea, and chronic abdominal pain in lower FGIDs. The new approaches to therapy include ion exchangers/transporters for functional constipation (sodium-glucose cotransporter 1, Na+/H+ exchanger 3, and solute carrier family 26 member 3 inhibitors), bile acid modulators for constipation such as ileal bile acid transporter inhibitors and fibroblast growth factor 19 analog for functional constipation, and bile acid sequestrants or farnesoid X receptor agonists for functional diarrhea. Treatment for chronic abdominal pain remains an unmet need in patients with lower FGIDs, and promising novel approaches include delayed-release linaclotide, nonclassical opioid visceral analgesics, and selective cannabinoid receptor agonists. The role of probiotics, fecal microbial transplantation, and possible future microbiome therapies is discussed.

show abstract

Section: Nhe3 Inhibitor: Tenapanormentioning

confidence: 99%

What’s in the pipeline for lower functional gastrointestinal disorders in the next 5 years?

Camilleri

2019

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…Inhibition of NHE3 on the apical surface of the small intestine and colon leads to retention of luminal water, thereby softening stool consistency and normalizing bowel movement frequency 16,17 . Nonclinical studies have shown that tenapanor modulates tight junctions, decreasing permeability to luminal macromolecules, although the relevance of experimental models to humans is not known 18,19 . By reducing colonic permeability to luminal macromolecules, tenapanor may also reduce the hyperexcitability of sensory neurons and, therefore, have a beneficial effect on abdominal pain 19 …”

Section: Introductionmentioning

confidence: 99%

“…Nonclinical studies have shown that tenapanor modulates tight junctions, decreasing permeability to luminal macromolecules, although the relevance of experimental models to humans is not known 18,19 . By reducing colonic permeability to luminal macromolecules, tenapanor may also reduce the hyperexcitability of sensory neurons and, therefore, have a beneficial effect on abdominal pain 19 …”

Section: Introductionmentioning

confidence: 99%

“…16,17 Nonclinical studies have shown that tenapanor modulates tight junctions, decreasing permeability to luminal macromolecules, although the relevance of experimental models to humans is not known. 18,19 By reducing colonic permeability to luminal macromolecules, tenapanor may also reduce the hyperexcitability of sensory neurons and, therefore, have a beneficial effect on abdominal pain. 19 Based on the randomized, double-blind, placebo-controlled, phase III T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) studies, tenapanor was approved by the US Food and Drug Administration (FDA) for the treatment of IBS-C in adults.…”

mentioning

confidence: 99%

“…18,19 By reducing colonic permeability to luminal macromolecules, tenapanor may also reduce the hyperexcitability of sensory neurons and, therefore, have a beneficial effect on abdominal pain. 19 Based on the randomized, double-blind, placebo-controlled, phase III T3MPO-1 (NCT02621892) and T3MPO-2 (NCT02686138) studies, tenapanor was approved by the US Food and Drug Administration (FDA) for the treatment of IBS-C in adults. 20,21 In these studies, a significantly greater percentage of patients receiving tenapanor compared with those receiving placebo met the FDA responder criteria, defined as achieving a ≥30.0% reduction in average weekly worst abdominal pain from baseline and a ≥1 per week increase in complete spontaneous bowel movements (CSBMs), both in the same week for ≥6 weeks of a 12-week treatment period.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Long‐term safety of tenapanor in patients with irritable bowel syndrome with constipation in the T3MPO‐3 study

Lembo,

Friedenberg,

Fogel

et al. 2023

Neurogastroenterology Motil

View full text Add to dashboard Cite

BackgroundTenapanor, 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.MethodsPatients 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 ResultsA 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.ConclusionsTenapanor 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.

show abstract

Pharmacological Treatments for Constipation and Opioid-Induced Constipation

Camilleri

2022

Comprehensive Pharmacology

View full text Add to dashboard Cite

Sa1600 - Tenapanor Attenuates Increased Macromolecule Permeability in Human Colon Monolayer Cultures Induced by Inflammatory Cytokines and Human Fecal Supernatants

Cited by 6 publications

References 0 publications

What’s in the pipeline for lower functional gastrointestinal disorders in the next 5 years?

What’s in the pipeline for lower functional gastrointestinal disorders in the next 5 years?

Long‐term safety of tenapanor in patients with irritable bowel syndrome with constipation in the T3MPO‐3 study

Pharmacological Treatments for Constipation and Opioid-Induced Constipation

Contact Info

Product

Resources

About