Emerging treatments for chronic constipation

Gudsoorkar, Vineet; Quigley, Eamonn Martin

doi:10.1517/14728214.2013.831068

Cited by 11 publications

(5 citation statements)

References 59 publications

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“…[ 6 , 9 ] Few treatments have been shown to improve abdominal bloating in patients with CIC. [ 10 , 11 ] In fact, abdominal bloating may be exacerbated by some treatments aimed at improving constipation-related symptoms. [ 10 , 11 ]…”

Section: Introductionmentioning

confidence: 99%

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Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial

et al. 2015

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BackgroundAbdominal bloating is a common and bothersome symptom of chronic idiopathic constipation. The objective of this trial was to evaluate the efficacy and safety of linaclotide in patients with chronic idiopathic constipation and concomitant moderate-to-severe abdominal bloating.MethodsThis Phase 3b, randomized, double-blind, placebo-controlled clinical trial randomized patients to oral linaclotide (145 or 290 μg) or placebo once daily for 12 weeks. Eligible patients met Rome II criteria for chronic constipation upon entry with an average abdominal bloating score ≥5 (self-assessment: 0 10-point numerical rating scale) during the 14-day baseline period. Patients reported abdominal symptoms (including bloating) and bowel symptoms daily; adverse events were monitored. The primary responder endpoint required patients to have ≥3 complete spontaneous bowel movements/week with an increase of ≥1 from baseline, for ≥9 of 12 weeks. The primary endpoint compared linaclotide 145 μg vs. placebo.ResultsThe intent-to-treat population included 483 patients (mean age=47.3 years, female=91.5%, white=67.7%). The primary endpoint was met by 15.7% of linaclotide 145 μg patients vs. 7.6% of placebo patients (P<0.05). Both linaclotide doses significantly improved abdominal bloating vs. placebo (P<0.05 for all secondary endpoints, controlling for multiplicity). Approximately one-third of linaclotide patients (each group) had ≥50% mean decrease from baseline in abdominal bloating vs. 18% of placebo patients (P<0.01). Diarrhea was reported in 6% and 17% of linaclotide 145 and 290 μg patients, respectively, and 2% of placebo patients. AEs resulted in premature discontinuation of 5% and 9% of linaclotide 145 μg and 290 μg patients, respectively, and 6% of placebo patients.ConclusionsOnce-daily linaclotide (145 and 290 μg) significantly improved bowel and abdominal symptoms in chronic idiopathic constipation patients with moderate-to-severe baseline abdominal bloating; in particular, linaclotide significantly improved abdominal bloating compared to placebo, an important finding given the lack of agents available to treat abdominal bloating in chronic idiopathic constipation patients.Trial RegistrationClinicalTrials.gov NCT01642914

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Section: Introductionmentioning

confidence: 99%

“…[ 10 , 11 ] In fact, abdominal bloating may be exacerbated by some treatments aimed at improving constipation-related symptoms. [ 10 , 11 ]…”

Section: Introductionmentioning

confidence: 99%

Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial

et al. 2015

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“…In such patients, mutations in CFTR result in downregulated transepithelial Clsecretion and are associated with the clinical manifestation of constipation and intestinal obstruction (van der Doef et al 2010). Furthermore, in non-CF patients with constipation, drugs which activate CFTR (e.g., lubiprostone) have been shown to be an effective treatment (Norimatsu et al 2012, Gudsoorkar andQuigley 2013).…”

Section: Cystic Fibrosis Transmembrane Conductance Regulatormentioning

confidence: 99%

Nutraceutical targeting of the bile acid receptor, farnesoid X receptor, for intestinal disease

et al. 2022

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Introduction Bile acids classically known for their roles in dietary fat absorption are now recognized as hormones critical to regulating intestinal and metabolic function, including mucosal immune responses, epithelial proliferation/apoptosis, and transepithelial transport and barrier function. Downregulation of the nuclear bile acid receptor, farnesoid X receptor (FXR), in intestinal epithelium occurs in inflammatory bowel disease and colorectal cancer, whereas FXR activation prevents disease progression in pre‐clinical models. Thus strategies to upregulate epithelial FXR expression have been proposed to treat such conditions. Previous studies suggest that some plant‐derived phytochemicals have the capacity to modulate FXR activity. Plant sources have been reported to contain such phytochemicals, which are proposed to modulate FXR. Aim The aim of the current study was to investigate the potential for developing plant extracts, rich in FXR‐modulating phytochemicals, as a novel nutraceutical‐based approach to treat and prevent intestinal diseases. Methods T84 human colonic epithelial cells and primary cultures of murine colonic epithelial enteroids were employed to examine the effects of a common‐dietary phytochemical, denoted here as KFS1, and a KFS1‐rich plant extract on FXR expression and signaling in vitro. Ex vivo studies were carried out on human colonic tissue obtained during endoscopy with ethical approval from Beaumont Hospital. In vivo studies in C57BL/6 mice were carried out and proximal colonic tissue were examined with ethical approval from the HPRA. Expression of FXR and FGF19/15, an established marker of FXR activation, was assessed by qRT‐PCR, ELISA and immunoblotting. Data are expressed as mean ± SEM for a series of n experiments. Results KFS1 treatment (5 µM; 24hrs) increased FXR mRNA and protein expression in T84 cells by 4.2 ± 0.4 (p<0.05; n = 4) and 1.7 ± 0.1 fold (p<0.05; n = 7) respectively. KFS1 also enhanced FGF19 protein expression in response to the FXR agonist GW4064 (5 µM), by 4.1 ± 0.5 fold (p<0.001; n = 7). Similarly KFS1 upregulated FXR expression by 2.1 ± 0.4 fold in human biopsies (p<0.05; n = 6). Oral KFS1 administration to mice had a tendency to upregulate colonic epithelial FXR signaling in vivo and increased FXR expression and GW4064‐induced FGF15 by 2.3 ± 0.2 (p<0.01; n = 4) and 2.2 ± 0.1 fold (p<0.01; n = 4) in murine colonic enteroids. Finally a methanolic KFS1‐rich plant extract, denoted QE1, verified by LC/MS to contain KFS1, increased FXR protein expression in vitro by 1.8 ± 0.2 fold (p<0.05; n = 5) and enhanced GW4064‐induced FGF19 protein by 1.9 ± 0.1 fold (p<0.01; n = 9). Conclusion Our data demonstrate that KFS1‐containing plant extracts modulate expression and activity of FXR in the intestinal epithelium. Given the critical role of FXR in maintenance of gut health and metabolic function, such extracts have significant therapeutic and commercial potential to be developed as a novel first‐in‐class “FXR‐targeted nutraceutical” for treatment and prevention of common in...

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“…Elobixibat is a potent inhibitor of ileal bile acid transporters. It therefore can increase the bile acid content in the colon which in turn increases the fluid secretion and motility of the colon 45 . One randomized, double-blind, placebo-controlled trial in adult females has shown some promising results including significant acceleration of colonic transit time 46 .…”

Section: Other Drugsmentioning

confidence: 99%

Constipation in children: New developments

Rajindrajith

Devanarayana

2016

Sri Lanka J Child Health

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Functional constipation (FC) is a troublesome problem in children. It is characterized by reduced stool frequency, pain and difficulty in passing stools, stool withholding and faecal incontinence. It has been defined in many ways in the past, including the usage of a single symptom such as low bowel frequency or using symptoms complexes. However, since 1999, Rome criteria have been used to define FC in children. This Rome definition of FC is an evolving process and 2 iterations of Rome criteria have been in the field up to now 1,2. The current definition (Rome IV) of FC is given in box 1 3. Rome criteria use multiple clinical features to define FC rather than a single clinical feature such as low defaecation frequency or difficulty in passing stools.

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Emerging treatments for chronic constipation

Cited by 11 publications

References 59 publications

Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial

Linaclotide in Chronic Idiopathic Constipation Patients with Moderate to Severe Abdominal Bloating: A Randomized, Controlled Trial

Nutraceutical targeting of the bile acid receptor, farnesoid X receptor, for intestinal disease

Constipation in children: New developments

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