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Severe functional constipation: Surgery and gastroenterologic collaboration
Published in Alejandra Vilanova-Sánchez, Marc A. Levitt, Pediatric Colorectal and Pelvic Reconstructive Surgery, 2020
Peter L. Lu, Desalegn Yacob, Carlo Di Lorenzo
Traditional pharmacological treatment for children with constipation has included osmotic laxatives, stimulant laxatives, and lubricants [17]. However, newer pharmacological treatments used in adults with constipation and IBS with constipation show promise for children with similar conditions, particularly when abdominal pain limits stimulant laxative use. Lubiprostone is a prostaglandin E1 derivative that promotes intestinal fluid secretion, softening stool and promoting intestinal motility through luminal distention [18]. Several randomized-controlled studies have demonstrated the efficacy and safety of lubiprostone in adults with constipation [19–21]. An open-label study of lubiprostone in children with functional constipation found it to be well tolerated and effective in improving bowel movement frequency, but improvements in abdominal pain were not significant [22]. Linaclotide is a peptide agonist of the intestinal guanylate cyclase-C receptor, which also promotes intestinal fluid secretion. Linaclotide not only softens stool and accelerates intestinal transit, but can also decrease visceral sensitivity in animal models [18,23]. Several randomized-controlled studies in adults have demonstrated improvements in constipation symptoms and abdominal pain [23–25]. Although research is ongoing, no studies have been published yet on the use of linaclotide for children with constipation-predominant IBS, and its use is contraindicated in children younger than 6 years of age because of the risk of severe dehydration.
Constipation
Published in Linda Cardozo, Staskin David, Textbook of Female Urology and Urogynecology - Two-Volume Set, 2017
Kaori Futaba, Yvette Perston, Tony Mak, Simon Radley
1–12 rAnged from 19.5% to 28.9%, compAred with 9.6% to 13.0% for plAcebo (All p 0.001) [62–64]. HeAdAche, nAuseA, And diArrheA were more common side effects with prucAlopride compAred to plAcebo [55]. A smAller study compAring efficAcy of prucAlopride on pAtients with different subtypes of constipAtion showed thAt All cAtegories of constipAtion mAy respond to prucAlopride [65]. Colonic SecretAgogues Lubiprostone is A member of A new clAss of medicAtion cAlled prostones, which ActivAte type 2 chloride chAnnels (CIC-2) on enterocytes, And promote the secretion of chloride-rich intestinAl fluid without Altering the serum concentrAtion of sodium or potAssium. It is thought thAt by increAsing the intestinAl secretions, smAll bowel motility is increAsed, thereby increAsing the pAssAge of stool [66–68]. Three rCts compAring lubiprostone 24 g twice dAily with plAcebo in 610 pAtients showed thAt lubiprostone significAntly enhAnced bowel movement frequency And relieved other constipAtionrelAted symptoms [68–70]. The most commonly reported side effects include nAuseA And diArrheA [55]. It is currently licensed for treAtment of chronic idiopAthic constipAtion. There Are limited but supportive dAtA on sAfety And efficAcy of use of lubiprostone in the elderly populAtion [71], constipAted pAtients with PArkinson's diseAse [72], And treAtment of opioid-induced constipAtion [73]. TreAtment of IrritAble Bowel Syndrome with ConstipAtion It is importAnt to identify symptoms thAt Are Affecting the individuAl pAtient And tAilor the treAtment Accordingly [10,49]. to treAt their constipAtion, bulk-forming lAxAtive, such As soluble fiber (ispAghulA husk or oAts), or osmotic lAxAtives (mAcrogol) Are recommended. AntispAsmodics or low-dose tricyclic AntidepressAnts mAy eAse AbdominAl pAin AssociAted with Ibs. LinAclotide is currently licensed for the treAtment of moderAte to severe Ibs AssociAted with constipAtion. It is A first-in-clAss, orAl guAnylAte cyclAse-C receptor Agonist of
Targeted Radiolabeled Receptor-Avid Peptides
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Guanylin/guanylate cyclase C (GC-C) receptors have been shown to be expressed on virtually all of the histologically confirmed primary and metastatic colorectal cancer tumors removed from human patients (166,167). Thus, development of radiolabeled peptides that target GC-C receptors may provide new imaging radiopharmaceuticals and/or TRT agents for treatment of this disease. The GC-C receptors are single transmembrane–spanning G protein–coupled receptors (47,168,169). The amount of work directed to development of new GC-C receptor–targeting radiopharmaceuticals has been limited. Several guanylin homologues that bind GC-C receptors have been reported (168,169), however, the heat stable (ST) bacterial peptide conjugates have been identified as a class of peptides that bind to these receptors with the highest affinity (3). The E. coli human ST (STh) peptide is metabolically stable and binds with nanomolar affinities in an agonist manner and undergoes receptor-mediated endocytosis (166,168). The primary structure of one of the N-terminal DOTA-conjugated E. coli STh analogues reported is shown in Figure 6B. The only difference between the Phe19STh(1–19)-binding moiety shown in Figure 6 and the native STh(1–19) is replacement of the Tyr19 residue by Phe19 (Fig. 6A). In the biologically active form, disulfide bridges between Cys6 and Cys11, Cys7 and Cys15, and Cys10 and Cys18 are formed (169,170). Methods to produce and purify the unique biologically active conformer have been developed (34,171,172). Several radiolabeled STh derivatives labeled with either 99mTc or 111In have been synthesized that exhibit high GC-C receptor–binding affinities and demonstrate selective in vivo targeting of human colon cancer xenografts for imaging tumors in rodent animal models (173–175). These radiolabeled STh conjugates are cleared rapidly from the blood stream, almost exclusively via the kidney, with minimal uptake in the liver (173–175). The lack of significant liver deposition provides evidence that visualization of these radiolabeled tracers localized on colorectal metastatic tumors in liver will be feasible.
Fabry disease – a multisystemic disease with gastrointestinal manifestations
Published in Gut Microbes, 2022
Some major GI symptoms in patients with FD can be treated with various concomitant drugs that are symptomatically effective. Patients with acute diarrhea can be treated with classical anti-diarrhea medication such as loperamid. By contrast, patients suffering from gastroparesis can benefit from treatments with pro-motility agents, such as metoclopramide, which increase the contractile force and accelerate intraluminal transit.68 Patients suffering from upper GI symptoms may benefit from proton pump inhibitors (e.g. omeprazole) or ondansetron if nausea is present.34 Medication against bloating and flatulence may include the administration of simethicone, which eliminates and prevents foam formation.69,70 Furthermore, linaclotide, which is an oligo-peptide agonist of guanylate cyclase 2C is used to treat IBS with constipation and chronic constipation with unknown cause.71,72 The antispasmodic dicyclomine, which blocks the action of acetylcholine on cholinergic receptors in smooth muscles in the GI tract, is used to treat spasms of the intestine in IBS,73 and might also be of relevance, although it should be used with caution, especially in patients with any unstable cardiac condition.
Genetic and transcriptional analysis of inflammatory bowel disease-associated pathways in patients with GUCY2C-linked familial diarrhea
Published in Scandinavian Journal of Gastroenterology, 2018
Rune R. Tronstad, Tatiana Polushina, Hans-Richard Brattbakk, Christine Stansberg, Hilde Løland von Volkmann, Kurt Hanevik, Eva Ellinghaus, Silje Fjellgård Jørgensen, Kari Merete Ersland, Khanh D.-C. Pham, Odd Helge Gilja, Nils Hovdenak, Trygve Hausken, Morten H. Vatn, Andre Franke, Per Morten Knappskog, Stephanie Le Hellard, Tom Hemming Karlsen, Torunn Fiskerstrand
Diarrhea is a common symptom in inflammatory bowel disease (IBD) and can be attributed to various disturbances of intestinal ion transport [1]. We have previously reported Familial GUCY2C diarrhea syndrome (FGDS), characterized by the early onset diarrhea and high prevalence of IBD [2]. In this disorder diarrhea results from autosomal dominant activating mutations in the GUCY2C gene, which encodes the intestinal receptor guanylate cyclase C (GC-C). GC-C regulates intestinal secretion of sodium chloride and water, through downstream activation of the cystic fibrosis transmembrane conductance regulator (CFTR) and inhibition of the sodium-hydrogen exchanger 3 (NHE3) [3]. Binding of the endogenous ligands uroguanylin and guanylin to GC-C, as well as bacterial toxins and a novel class of drugs [3,4], elicit cellular formation of the second messenger cyclic guanosine monophosphate (cGMP). This activates CFTR via protein kinase GII. Pharmacological GC-C activation is employed therapeutically to hydrate the gut and relieve constipation, [4] but vigorous GC-C activation results in diarrhea [2,3,5].
Drugs under development for the treatment of functional dyspepsia and related disorders
Published in Expert Opinion on Investigational Drugs, 2019
Jan Tack, Imke Masuy, Karen Van Den Houte, Lucas Wauters, Jolien Schol, Tim Vanuytsel, Alain Vandenberghe, Florencia Carbone
Guanylate cyclase agonists, such as linaclotide, are used for the treatment of IBS-C and chronic constipation, because of their effects on intestinal fluid secretion and on visceral hypersensitivity [8]. IW-9179, an investigational guanylate cyclase-C (GC-C) agonist designed to target the upper gastrointestinal tract [54] was evaluated in a small pilot study in FD patients not suffering from overlapping conditions, including IBS. Although underpowered, there was a suggestion of decreased symptom intensity with the active agent over placebo. The main side effect was diarrhea [55]. Subsequently, the drug was studied in diabetic gastroparesis but development was halted for lack of robust efficacy [57].