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Linaclotide

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https://www.readbyqxmd.com/read/29319191/linaclotide-in-irritable-bowel-syndrome-with-constipation-a-phase-3-randomized-trial-in-china-and-other-regions
#1
Yunsheng Yang, Jingyuan Fang, Xiaozhong Guo, Ning Dai, Xizhong Shen, Youlin Yang, Jing Sun, Bal Raj Bhandari, David S Reasner, Jacquelyn A Cronin, Mark G Currie, Jeffrey M Johnston, Peter Zeng, Niwat Montreewasuwat, George Zhijian Chen, Sam Lim
BACKGROUND AND AIM: Linaclotide is a guanylate cyclase-C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS-C). China has unmet need for well-tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS-C. This trial evaluated linaclotide's efficacy and safety in IBS-C patients in China and other regions. METHODS: This Phase 3, double-blind trial randomized IBS-C patients to once-daily oral 290-μg linaclotide or placebo at centers in China, North America, and Oceania...
January 10, 2018: Journal of Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29301746/cyclic-gmp-elevating-agents-suppress-polyposis-in-apc-min-mice-by-targeting-the-preneoplastic-epithelium
#2
Sarah K Sharman, Bianca N Islam, Yali Hou, Nagendra Singh, Franklin G Berger, Subbaramiah Sridhar, Wonsuk Yoo, Darren D Browning
The cGMP signaling axis has been implicated in the suppression of intestinal cancers but the inhibitory mechanism and the extent to which this pathway can be targeted remains poorly understood. The present study has tested the effect of cGMP-elevating agents on tumorigenesis in the ApcMin/+ mouse model of intestinal cancer. Treatment of ApcMin/+ mice with the receptor guanylyl-cyclase C (GCC) agonist linaclotide, or the phosphodiesterase-5 (PDE5) inhibitor sildenafil, significantly reduced the number of polyps per mouse (67% and 50% respectively)...
January 4, 2018: Cancer Prevention Research
https://www.readbyqxmd.com/read/29278278/determining-an-optimal-dose-of-linaclotide-for-use-in-japanese-patients-with-irritable-bowel-syndrome-with-constipation-a-phase-ii-randomized-double-blind-placebo-controlled-study
#3
S Fukudo, A Nakajima, Y Fujiyama, M Kosako, A Nakagawa, H Akiho, Y Nakashima, J M Johnston, H Miwa
BACKGROUND: Clinical testing to determine a suitable dose of linaclotide for Japanese patients with irritable bowel syndrome with constipation (IBS-C) was needed. METHODS: This was a randomized, double-blind, placebo-controlled, dose-finding trial. Japanese patients with IBS-C diagnosed using Rome III criteria (n = 559, men/women: 49/510) were randomly assigned to 1 of 4 linaclotide doses (0.0625, 0.125, 0.25, or 0.5 mg) or placebo for the 12-week treatment period...
December 26, 2017: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
https://www.readbyqxmd.com/read/29210639/guanylate-cyclase-c-a-current-hot-target-from-physiology-to-pathology
#4
Jose Antonio Uranga, Marta Castro, Raquel Abalo
Guanylate cyclase C (GC-C) receptor is a transmembrane receptor, predominantly expressed in intestinal epithelial cells, that plays a main role in homeostasis and function of the digestive tract. The endogenous ligands for this receptor are the paracrine hormones uroguanylin and guanylin. The heat-stable enterotoxin, produced by enterotoxigenic bacteria, is also a natural ligand of this receptor. Upon ligand binding, GC-C receptors increase the second messenger cyclic guanosine monophosphate (cGMP) levels, regulating a variety of key cell-type specific processes such as chloride and bicarbonate secretion (which increases luminal fluid and intestinal motility), epithelial cell growth, regulation of intestinal barrier integrity and visceral sensitivity...
December 5, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29184433/diagnosis-and-treatment-of-irritable-bowel-syndrome-with-predominant-constipation-in-the-primary-care-setting-focus-on-linaclotide
#5
REVIEW
Apoorva Krishna Chandar
Irritable bowel syndrome (IBS) is a complex functional gastrointestinal disorder that is exceedingly common in clinical practice. IBS with predominant constipation (IBS-C) is a subtype of IBS that accounts for more than a third of the IBS diagnosed. Diagnosis of IBS requires a careful personalized approach, a comprehensive clinical history, limited but relevant investigations, and continued follow-up. Major IBS societies and guidelines recommend offering a positive diagnosis of IBS based on presenting symptomatology...
2017: International Journal of General Medicine
https://www.readbyqxmd.com/read/29095765/new-therapies-in-irritable-bowel-syndrome-what-works-and-when
#6
Orla Craig
PURPOSE OF REVIEW: The purpose of this review is to examine the evidence supporting the use of recently developed pharmacological treatments for IBS together with new evidence supporting more traditional therapies in order to understand where the new agents are best used in the treatment pathway. RECENT FINDINGS: There is evidence to support the use of traditional treatments such as antispasmodics, antidepressants and dietary alteration in IBS. New therapeutic agents such as Linaclotide, Lubiprostone, Plecanatide, Rifaxamin and Eluxadoline are all more effective than placebo in treating symptoms of IBS with Tenapanor being a promising new agent...
January 2018: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/29091082/low-dose-linaclotide-72%C3%A2-%C3%AE-g-for-chronic-idiopathic-constipation-a-12-week-randomized-double-blind-placebo-controlled-trial
#7
Philip Schoenfeld, Brian E Lacy, William D Chey, Anthony J Lembo, Caroline B Kurtz, David S Reasner, Wieslaw Bochenek, Kenneth Tripp, Mark G Currie, Susan M Fox, Rick E Blakesley, Christopher R O'Dea, Nicholas D Omniewski, Michael L Hall
OBJECTIVES: Linaclotide is a guanylate cyclase-C agonist approved in the United States, Canada, and Mexico at a once-daily 145-μg dose for the treatment of chronic idiopathic constipation (CIC); a once-daily 72-μg dose for CIC recently received FDA approval. The trial objective was to evaluate the efficacy and safety of a 72-μg linaclotide dose in CIC patients. METHODS: This double-blind, placebo-controlled trial randomized patients with CIC (Rome III criteria) to once-daily linaclotide 72 μg or 145 μg, or placebo for 12 weeks...
August 22, 2017: American Journal of Gastroenterology
https://www.readbyqxmd.com/read/28970722/pharmacological-evaluation-of-nsaid-induced-gastropathy-as-a-translatable-model-of-referred-visceral-hypersensitivity
#8
Michele Hummel, Terri Knappenberger, Meghan Reilly, Garth T Whiteside
AIM: To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity. METHODS: Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice (n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated...
September 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28830131/-pharmacotherapy-in-patients-with-chronic-constipation
#9
REVIEW
Sang Jin Kim, Kyung Sik Park
Chronic constipation is one of the most common digestive diseases frequently observed in a clinical setting. It has been known to cause considerable damage to the quality of life of patients. Despite recent developments, there are considerable limitations in the use of constipation-modulating agents in Korea. Chloride channel inhibitors, such as lubiprostone and linaclotide, have not been introduced in Korea yet, and prucalopride and several kinds of polyethylene glycol are not covered under medical insurance...
August 25, 2017: Korean Journal of Gastroenterology, Taehan Sohwagi Hakhoe Chi
https://www.readbyqxmd.com/read/28711731/insulin-chains-as-efficient-fusion-tags-for-prokaryotic-expression-of-short-peptides
#10
Ligang Deng, Xiaoying Xue, Cangjie Shen, Xiaohan Song, Chunyang Wang, Nan Wang
Insulin chains are usually expressed in Escherichia coli as fusion proteins with different tags, including various low molecular weight peptide tags. The objective of this study was to determine if insulin chains could facilitate the recombinant expression of other target proteins, with an emphasis on low molecular weight peptides. A series of short peptides were fused to mini-proinsulin, chain B or chain A, and induced for expression in Escherichia coli. All the tested peptides including glucagon-like peptide 1 (GLP-1), a C-terminal extended GLP-1, oxyntomodulin, enfuvirtide, linaclotide, and an unstructured artificial peptide were expressed with reasonable yields, identified by Tricine-SDS-PAGE and immunoblotting...
October 2017: Protein Expression and Purification
https://www.readbyqxmd.com/read/28592587/linaclotide-activates-guanylate-cyclase-c-cgmp-protein-kinase-ii-dependent-trafficking-of-cftr-in-the-intestine
#11
Md Kaimul Ahsan, Boris Tchernychev, Marco M Kessler, Robert M Solinga, David Arthur, Cristina I Linde, Inmaculada Silos-Santiago, Gerhard Hannig, Nadia A Ameen
The transmembrane receptor guanylyl cyclase-C (GC-C), expressed on enterocytes along the intestine, is the molecular target of the GC-C agonist peptide linaclotide, an FDA-approved drug for treatment of adult patients with Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation. Polarized human colonic intestinal cells (T84, CaCo-2BBe) rat and human intestinal tissues were employed to examine cellular signaling and cystic fibrosis transmembrane conductance regulator (CFTR)-trafficking pathways activated by linaclotide using confocal microscopy, in vivo surface biotinylation, and protein kinase-II (PKG-II) activity assays...
June 2017: Physiological Reports
https://www.readbyqxmd.com/read/28448580/sildenafil-normalizes-bowel-transit-in-preclinical-models-of-constipation
#12
Sarah K Sharman, Bianca N Islam, Yali Hou, Margaux Usry, Allison Bridges, Nagendra Singh, Subbaramiah Sridhar, Satish Rao, Darren D Browning
Guanylyl cyclase-C (GC-C) agonists increase cGMP levels in the intestinal epithelium to promote secretion. This process underlies the utility of exogenous GC-C agonists such as linaclotide for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Because GC-C agonists have limited use in pediatric patients, there is a need for alternative cGMP-elevating agents that are effective in the intestine. The present study aimed to determine whether the PDE-5 inhibitor sildenafil has similar effects as linaclotide on preclinical models of constipation...
2017: PloS One
https://www.readbyqxmd.com/read/28423917/management-of-opioid-induced-constipation-in-hospice-patients
#13
Leah Sera, Mary Lynn McPherson
BACKGROUND: Constipation is a common symptom in patients with advanced disease taking opioids. Opioid-induced constipation (OIC) is commonly treated with laxatives and stool softeners. Recently, newer agents have come to market which broaden options for patients in whom first-line therapies are not effective. OBJECTIVE: To determine what pharmacologic regimens are currently used in hospice programs to prevent and treat OIC, whether those regimens have changed with the introduction of newer agents and evidence discouraging the use of docusate, and whether hospice programs are standardizing the management of OIC...
January 1, 2017: American Journal of Hospice & Palliative Care
https://www.readbyqxmd.com/read/28396341/bioactivity-of-oral-linaclotide-in-human-colorectum-for-cancer-chemoprevention
#14
David S Weinberg, Jieru E Lin, Nathan R Foster, Gary Della'Zanna, Asad Umar, Drew Seisler, Walter K Kraft, David M Kastenberg, Leo C Katz, Paul J Limburg, Scott A Waldman
Guanylate cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA-approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined...
June 2017: Cancer Prevention Research
https://www.readbyqxmd.com/read/28357122/therapeutically-targeting-guanylate-cyclase-c-computational-modeling-of-plecanatide-a-uroguanylin-analog
#15
Andrea Brancale, Kunwar Shailubhai, Salvatore Ferla, Antonio Ricci, Marcella Bassetto, Gary S Jacob
Plecanatide is a recently developed guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog designed to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). GC-C receptors are found across the length of the intestines and are thought to play a key role in fluid regulation and electrolyte balance. Ligands of the GC-C receptor include endogenous agonists, uroguanylin and guanylin, as well as diarrheagenic, Escherichia coli heat-stable enterotoxins (ST)...
April 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28238460/-irritable-bowel-syndrome-with-constipation-and-functional-constipation-in-adults-treatment-part-2-of-2
#16
F Mearin, C Ciriza, M Mínguez, E Rey, J J Mascort, E Peña, P Cañones, J Júdez
In this Clinical practice guide we examine the diagnostic and therapeutic management of adult patients with constipation and abdominal discomfort, at the confluence of the spectrum of irritable bowel syndrome and functional constipation. Both fall within the framework of functional intestinal disorders and have major personal, health and social impact, altering the quality of life of the patients affected. The former is a subtype of irritable bowel syndrome in which constipation and altered bowel habit predominate, often along with recurring abdominal pain, bloating and abdominal distension...
March 2017: Atencion Primaria
https://www.readbyqxmd.com/read/28236087/gastrointestinal-pharmacology
#17
REVIEW
Miguel Saps, Adrian Miranda
There is little evidence for most of the medications currently used to treat functional abdominal pain disorders (FAPDs) in children. Not only are there very few clinical trials, but also most have significant variability in the methods used and outcomes measured. Thus, the decision on the most appropriate pharmacological treatment is frequently based on adult studies or empirical data. In children, peppermint oil, trimebutine, and drotaverine have shown significant benefit compared with placebo, each of them in a single randomized clinical trial...
2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28162021/guanylate-cyclase-c-as-a-target-for-prevention-detection-and-therapy-in-colorectal-cancer
#18
REVIEW
Allison A Aka, Jeff A Rappaport, Amanda M Pattison, Takami Sato, Adam E Snook, Scott A Waldman
Colorectal cancer remains the second leading cause of cancer death in the United States, and new strategies to prevent, detect, and treat the disease are needed. The receptor, guanylate cyclase C (GUCY2C), a tumor suppressor expressed by the intestinal epithelium, has emerged as a promising target. Areas covered: This review outlines the role of GUCY2C in tumorigenesis, and steps to translate GUCY2C-targeting schemes to the clinic. Endogenous GUCY2C-activating ligands disappear early in tumorigenesis, silencing its signaling axis and enabling transformation...
May 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28116777/pharmacological-treatment-for-antipsychotic-related-constipation
#19
REVIEW
Susanna Every-Palmer, Giles Newton-Howes, Mike J Clarke
BACKGROUND: Antipsychotic-related constipation is a common and serious adverse effect, especially for people taking clozapine. Clozapine has been shown to impede gastrointestinal motility, leading to constipation, and has been reported in up to 60% of patients receiving clozapine. In rare cases, complications can be fatal. Appropriate laxatives should be prescribed to treat constipation in people taking antipsychotics, but there is a lack of guidance on the comparative effectiveness and harms of different agents in this population...
January 24, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28116695/update-on-the-management-of-chronic-constipation
#20
REVIEW
Jenna Koliani-Pace, Brian E Lacy
Chronic constipation (CC) is a highly prevalent disorder encountered by health care providers of all specialties. The diagnosis can be confidently made by taking a careful history, evaluating for warning signs and symptoms, performing an examination, including a digital rectal exam, and using the Rome IV criteria. Treatment should begin at the first visit; most patients require few diagnostic tests to make, or confirm, the diagnosis of CC. Assuming that the patient has persistent symptoms of constipation, despite using traditional therapy (fiber, osmotic agents), then patients should be offered one of the newer treatments, rather than repeating prior treatments, which is a common practice...
March 2017: Current Treatment Options in Gastroenterology
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