Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models

Boulete, Illona-Marie; Thadi, Anusha; Beaufrand, Catherine; Patwa, Viren; Joshi, Apoorva; Foss, John A.; Eddy, Evangeline P.; Eutamène, Hélène; Palejwala, Vaseem A.; Théodorou, Vassilia; Shailubhai, Kunwar

doi:10.3748/wjg.v24.i17.1888

Cited by 23 publications

(22 citation statements)

References 42 publications

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“…These patients reported a median satisfaction score for treatment of 4.0 (quite satisfied) and were “quite likely” to continue the medication. Animal models suggest that plecanatide, similar to linaclotide, also reduces visceral sensitivity 101 , and phase 3 trials in patients with IBS-C have demonstrated a significant improvement in bowel motion frequency, stool consistency, and abdominal pain above that seen with placebo 102 . Sustained response with the 6 mg dose of plecanatide was seen in 30% of patients in the first study (placebo response 18%, p <0.001) and 24% in the second trial (14% placebo response, p <0.001) 102 .…”

Section: Development Of Novel Therapeutic Agents For the Treatment Ofmentioning

confidence: 99%

Recent advances in understanding and managing chronic constipation

Prichard

Bharucha

2018

F1000Res

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Constipation, a condition characterized by heterogeneous symptoms, is common in Western society. It is associated with reduced physical health, mental health, and social functioning. Because constipation is rarely due to a life-threatening disease (for example, colon cancer), current guidelines recommend empiric therapy. Limited surveys suggest that fewer than half of treated individuals are satisfied with treatment, perhaps because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. For example, although a substantial proportion of constipated patients have a defecatory disorder that is more appropriately treated with pelvic floor biofeedback therapy than with laxatives, virtually no pharmacological trials formally assessed for anorectal dysfunction. Recent advances in investigational tools have improved our understanding of the physiology and pathophysiology of colonic and defecatory functions. In particular, colonic and anorectal high-resolution manometry are now available. High-resolution anorectal manometry, which is increasingly used in clinical practice, at least in the United States, provides a refined assessment of anorectal pressures and may uncover structural abnormalities. Advances in our understanding of colonic molecular physiology have led to the development of new therapeutic agents (such as secretagogues, pro-kinetics, inhibitors of bile acid transporters and ion exchangers). However, because clinical trials compare these newer agents with placebo, their efficacy relative to traditional laxatives is unknown. This article reviews these physiologic, diagnostic, and therapeutic advances and focuses particularly on newer therapeutic agents.

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Section: Development Of Novel Therapeutic Agents For the Treatment Ofmentioning

confidence: 99%

Recent advances in understanding and managing chronic constipation

Prichard

Bharucha

2018

F1000Res

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“…Chang and others (Chang et al, 2017) showed that orally administered plecanatide reduced the degree of inflammation-driven colonic dysplasia in mice (Chang et al, 2017). 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).…”

Section: Introductionmentioning

confidence: 87%

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

et al. 2020

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Ulcerative colitis (UC) is a major type of inflammatory bowel disease (IBD) and significantly impacts patient quality of life. Previous research revealed that the guanylate cyclase-C (GC-C) signaling pathway is associated with the severity of UC. We aimed to investigate the effect of the GC-C agonist, guanylin (Gn), on inflammatory injury in mice with colitis. An experimental UC model was established in Balb/c mice. Mesalamine served as a positive control. The Gn overexpression vector was administered once per day for 1 week. Intestinal permeability of the mice was measured using fluorescein isothiocyanate-dextran after the treatment. Histopathologic grading was estimated to assess the inflammatory injury of the colon. The expression level of crucial mediators of the GC-C signaling pathway (Gn, Ugn and GC-C) and tight junction proteins (occludin, claudin-1 and ZO-1) was measured in the colon. Additionally, the level of pro-inflammatory cytokines (IL-8 and TNF-α) in serum was measured. After injecting the UC mice with the Gn overexpression vector, the body weight increased, and the frequency of loose stools and bloody stools was decreased. Intestinal permeability and histopathologic score were significantly reduced (P<0.05). The expression level of GC-C, Gn, Ugn, claudin-1 and ZO-1 was significantly increased (P<0.05). The level of IL-8 and TNF-α in the serum was significantly decreased (P<0.01). Therefore, the application of Gn overexpression vector can ameliorate the intestinal inflammatory injury and repair the mucosal barrier in colitis mice, which further suggests the clinical therapeutic potential of GC-C agonists in IBD.

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“…Delayed gastric emptying through sympathetic activation (36,137) Increased active ghrelin concentration (137,139,140) Hypersensitivity (134)(135)(136) Hyperpermeability through re-organization of the cytoskeleton (134) Changes in mucosal morphology and decrease of glial cells in the submucosa plexus Increased immune cells infiltration (MC Eo)…”

Section: Stress-related Models Of Fgidmentioning

confidence: 99%

“…This protocol is mostly used as an acute stressor with a 1 to 2 h period of restraint. However, this short exposure already promoted (1) colonic hypersensitivity ( 134 – 136 ), (2) an increased influx of immune cells in the mucosa, mostly consisting of mast cells and eosinophils ( 135 ), (3) an intestinal hyperpermeability through the reorganization of the cytoskeleton in epithelial cells ( 134 ), (4) a delayed gastric emptying associated with the stress-induced sympathetic activation, increased CRF ( 36 , 137 ) and associated peptides ( 138 ) as well as active ghrelin concentration ( 137 , 139 , 140 ), and (5) changes in colonic morphology and a decrease of enteric glial cells especially in the submucosa plexus ( 135 ). By using this model for 14 days, Yi et al could demonstrate the implication of the insular cortex in stress-induced visceral hypersensitivity, a region found to be abnormally activated in FGID patients ( 19 ) and more in general in patients with chronic pain ( 141 ).…”

Section: Stress-related Models Of Fgidmentioning

confidence: 99%

Animal Models for Functional Gastrointestinal Disorders

Accarie

Vanuytsel

2020

Front. Psychiatry

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Functional gastrointestinal disorders (FGID), such as functional dyspepsia (FD) and irritable bowel syndrome (IBS) are characterized by chronic abdominal symptoms in the absence of an organic, metabolic or systemic cause that readily explains these complaints. Their pathophysiology is still not fully elucidated and animal models have been of great value to improve the understanding of the complex biological mechanisms. Over the last decades, many animal models have been developed to further unravel FGID pathophysiology and test drug efficacy. In the first part of this review, we focus on stress-related models, starting with the different perinatal stress models, including the stress of the dam, followed by a discussion on neonatal stress such as the maternal separation model. We also describe the most commonly used stress models in adult animals which brought valuable insights on the brain-gut axis in stress-related disorders. In the second part, we focus more on models studying peripheral, i.e., gastrointestinal, mechanisms, either induced by an infection or another inflammatory trigger. In this section, we also introduce more recent models developed around food-related metabolic disorders or food hypersensitivity and allergy. Finally, we introduce models mimicking FGID as a secondary effect of medical interventions and spontaneous models sharing characteristics of GI and anxiety-related disorders. The latter are powerful models for brain-gut axis dysfunction and bring new insights about FGID and their comorbidities such as anxiety and depression.

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Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models

Cited by 23 publications

References 42 publications

Recent advances in understanding and managing chronic constipation

Recent advances in understanding and managing chronic constipation

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

Animal Models for Functional Gastrointestinal Disorders

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