Clinical utility of plecanatide in the treatment of chronic idiopathic constipation

International Journal of General Medicine Dovepress open access to scientific and medical research REVIEW International Journal of General Medicine downloaded from https://www.dovepress.com/ by 37.59.46.207 on 21-Dec-2018 For personal use only. Open Access Full Text Article Clinical utility of plecanatide in the treatment of chronic idiopathic constipation This article was published in the following Dove Press journal: International Journal of General Medicine Bianca N Islam Sarah K Sharman Darren D Browning Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA Introduction Chronic constipation is one of the most common gastrointestinal complaints in the United States, affecting about 30% of Americans per year.1 While not a life-threatening condition, chronic constipation can have a profound negative effect on quality of life. Constipation is characterized by a variety of symptoms including lumpy or hard stools, infrequent bowel movements, abdominal cramping and bloating, excessive straining, and the sensation of incomplete defecation.2 Chronic constipation is often due to dietary factors (ie, poor fiber intake), lifestyle factors (ie, reduced activity and mobility), or disorders in colonic propulsion or rectal emptying. Secondary causes of chronic constipation are mediated by medications (ie, opioids, antihypertensives, tricyclic antidepressants, etc) or result from organic disease processes (ie, diabetes, colorectal cancer, polyps, strictures, etc).2 Correspondence: Darren D Browning Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, CN1164, 1410 Laney Walker Blvd, Augusta, GA 30912-2100, USA Tel +1 706 721 9526 Fax +1 706 721 6608 Email Constipation disorders: chronic idiopathic constipation (CIC), irritable bowel syndrome with constipation (IBS-C), and opioid-induced constipation (OIC) Functional bowel disorders (FBDs) are distinguished from other gastrointestinal illnesses based on symptom duration (>6 months), symptoms at current presentation 323 submit your manuscript | www.dovepress.com International Journal of General Medicine 2018:11 323–330 Dovepress © 2018 Islam et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/IJGM.S125051 Powered by TCPDF (www.tcpdf.org) Abstract: Constipation is an important health burden that reduces the quality of life for countless millions of people. Symptom-centric therapeutics are often used to treat constipation due to unknown etiology, but in many cases, these drugs are either inadequate or have significant side effects. More recently, synthetic peptide agonists for epithelial guanylyl cyclase C (GC-C) have been developed which are effective at treating constipation in a sub-population of adult constipation patients. The first to market was linaclotide that is structurally related to the diarrheagenic enterotoxin, but this was followed by plecanatide, which more closely resembles endogenous uroguanylin. Both the drugs exhibit almost identical clinical efficacy in about 20% of patients, with diarrhea being a common side effect. Despite the potential for reduced side effects with plecanatide, detailed analysis suggests that clinically, they are very similar. Ongoing clinical and preclinical studies with these drugs suggest that treating constipation might be the tip of the iceberg in terms of clinical utility. The expression of cGMP signaling components could be diagnostic for functional bowel disorders, and increasing cGMP using GC-C agonists or phosphodiesterase inhibitors has huge potential for treating enteric pain, ulcerative colitis, and for the chemoprevention of colorectal cancer. Keywords: linaclotide, irritable bowel syndrome, guanylyl cyclase, phosphodiesterase, cGMP, diarrhea Dovepress International Journal of General Medicine downloaded from https://www.dovepress.com/ by 37.59.46.207 on 21-Dec-2018 For personal use only. Islam et al (at least 3 months), and frequency (symptoms on average, at least 1 day/week). Constipation is associated with three of the six FBDs highlighted in the 2016 Rome IV guidelines: IBS (C1), functional constipation/CIC (C2), and OIC (C6).3 The largest group of chronic constipation sufferers largely fall under functional constipation where no identifiable structural or biochemical etiology is known to be the cause. As defined in the Rome IV guidelines, the diagnosis of functional constipation (CIC) is made when the patient’s symptomatology does not meet the criteria for IBS. In the new guidelines, bloating and pain are not considered predominant symptoms of functional constipation and may not be present. The diagnosis is made when patients experience two of the following symptoms in the past 3 months: fewer than three bowel movements in a week, straining, lumpy or hard stool, abdominal symptoms such as bloating and abdominal discomfort, and sensation of incomplete defecation.4,5 The diagnosis of IBS is made when a patient experiences recurrent abdominal pain, on average, at least 1 day/week in the last 3 months, and is associated with two or more of the following criteria related to defecation, associated with a change in frequency of stool, and lastly associated with a change in form (appearance) of stool. Furthermore, to classify the IBS-C subtype, more than 25% of bowel movements are with Bristol stool form type 1 or 2 and less than 25% of bowel movements are with Bristol stool form type 6 or 7.3 OIC was recently added to the Rome IV guidelines under the FBDs category, but it is uniquely distinct in that the etiology is known. It is widely accepted that OIC shares similar characteristics of functional constipation, and in recent years, it has become more prevalent with the rapidly growing health problem of opioid abuse in the United States. Stimulation of opioid receptors throughout the enteric neuronal system affects gastrointestinal function by delaying colonic transit, stimulating non-propulsive motility, and increasing intestinal absorption, thus causing constipation. Non-prescription treatment options for constipation Since the underlying cause of CIC and IBS-C is not fully understood, the treatment strategies often focus on controlling disease symptoms. The first line of treatment for constipation includes recommendations for lifestyle modification, with a (...truncated)