Clinical utility of plecanatide in the treatment of chronic idiopathic constipation

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.

The endogenous ligand for guanylate cyclase-C activation reliefs intestinal inflammation in the DSS colitis model

“…In accordance with these findings, Boulete and others (Boulete et al, 2018) indicated that activation of GC-C signaling may be an attractive therapeutic approach to treat functional constipation disorders and inflammatory gastrointestinal conditions (Boulete et al, 2018). Recent studies reported that GC-C agonists plecanatide and linaclotide can be used in the treatment of chronic idiopathic constipation (Lembo et al, 2011;Islam et al, 2018). As we know, diarrhea is the most common manifestation of UC.…”

Diagnosing Constipation Spectrum Disorders in a Primary Care Setting

“…Chronic idiopathic constipation is the most commonly diagnosed subtype of chronic constipation [ 9 , 10 ] and can be divided into normal-transit constipation, slow-transit constipation (STC), and DDs [ 4 ]. CIC is diagnosed when there are no identifiable physiological or biochemical etiologies of the symptom complex [ 10 ].…”

“…Chronic constipation may or may not have an identifiable cause; causes may be primary (related to intrinsic gastrointestinal structure and function) or secondary (related to systemic disease or medication) [ 1 , 9 ]. An identifiable cause of constipation is unknown in the largest subset of chronic constipation sufferers [ 10 ]. Primary constipation can be caused by functional colonic abnormalities or by defects in the process of defecation itself [ 9 ].…”

Ingestible Contrast Agents for Gastrointestinal Imaging

“…Other causes of constipation include opioid use, which can result in the delay of colonic transit and reduction in intestinal motility and absorption, eventually resulting in constipation. Also, for chronic idiopathic constipation, the relatively unbalanced expression of cyclic guanosine monophosphate (cGMP) signaling components can potentially cause constipation; moreover, overexpression of PDE5 can also cause refractory constipation; it cannot be treated with linaclotide or plecanatide, but PDE5 inhibitors can provide treatment for this type of constipation …”

“…Therefore, InFroMs represent a novel nanoplatform that can be used for multimodal imaging of the intestine . Beyond that, other novel imaging strategies are adding new possibilities to the field of theranostics and molecular imaging …”