Linaclotide for treatment of irritable bowel syndrome—The view of European regulators

Berntgen, Michael; Enzmann, Harald; Schabel, Elmer; Yerro, Concepción Prieto; Gómez-Outes, Antonio; Salmonson, Tomas; Musaus, Joachim

doi:10.1016/j.dld.2013.03.017

Cited by 5 publications

(2 citation statements)

References 12 publications

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“…Unlike lubiprostone, linaclotide first activates GC-C receptors on the luminal surface of enterocytes to enhance intraand extracellular levels of cyclic guanosine monophosphate and in turn promote CFTR to secrete chloride and bicarbonate into gut lumen to improve defecation. Interestingly, the activation of GC-C receptors also diminishes visceral pain [23,128,129] . Clinically, linaclotide improves abdominal pain/discomfort, bloating and the defecated symptoms of straining, incomplete defecation and stool consistency of IBS-C patients.…”

Section: Receptor Targeted Drugsmentioning

confidence: 97%

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Irritable bowel syndrome: The evolution of multi-dimensional looking and multidisciplinary treatments

Chang¹

2014

WJG

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Irritable bowel syndrome (IBS) is common in the society. Among the putative pathogeneses, gut dysmotility results in pain and disturbed defecation. The latter is probably caused by the effect of abnormal gut water secretion. The interaction between abnormal gas accumulation, abdominal pain and bloating remains controversial. Visceral hypersensitivity and its modification along with the central transmission are the characteristics of IBS patients. The identification of biologic markers based on genetic polymorphisms is undetermined. Imbalanced gut microbiota may alter epithelial permeability to activate nociceptive sensory pathways which in turn lead to IBS. Certain food constituents may exacerbate bowel symptoms. The impact of adult and childhood abuses on IBS is underestimated. Using the concept of biopsychosocial dysfunction can integrate multidimensional pathogeneses. Antispasmodics plus stool consistency modifiers to treat the major symptoms and defecation are the first-line drug treatment. New drugs targeting receptors governing bowel motility, sensation and secretion can be considered, but clinicians must be aware of their potential serious side effects. Psychiatric drugs and modalities may be the final options for treating intractable subjects. Probiotics of multi-species preparations are safe and worth to be considered for the treatment. Antibiotics are promising but their long-term safety and effectiveness are unknown. Diet therapy including exclusion of certain food constituents is an economic measure. Using relatively safe complementary and alternative medicines (CAMs) may be optional to those patients who failed classical treatment. In conclusion, IBS is a heterogeneous disorder with multidimensional pathogeneses. Personalized medicines with multidisciplinary approaches using different classes of drugs, psychiatric measures, probiotics and antibiotics, dietary therapy, and finally CAMs, can be considered.

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Section: Receptor Targeted Drugsmentioning

confidence: 97%

“…The most common side effect of linaclotide has been severe diarrhea (20%), thus subjects with a tendency to water and electrolyte imbalance are not indicated. Until now, its long-term safety has not been established yet [128,129,131] .…”

Section: Receptor Targeted Drugsmentioning

confidence: 98%

Irritable bowel syndrome: The evolution of multi-dimensional looking and multidisciplinary treatments

Chang¹

2014

WJG

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Linaclotide for the treatment of chronic constipation

Bassotti

Usai-Satta

Bellini

2018

Expert Opinion on Pharmacotherapy

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Chronic constipation (CC) is a common gastrointestinal disorder with limited treatment options. Linaclotide is a potent peptide agonist of the guanylate cyclase-C receptor. This action activates intracellular conversion of guanosine 5-triphosphate to cyclic guanosine monophosphate resulting in the stimulation of intestinal fluid secretion. Linaclotide is a promising new agent for refractory constipation. Areas covered: All published articles regarding the development, clinical efficacy, and safety of linaclotide in treating CC were reviewed. Pharmacodynamics, pharmacokinetics, and metabolism of this secretagogue agent were examined. Clinical studies showed that linaclotide increases the number of spontaneous bowel movements and stool consistency scores. Overall, patients reported relief from abdominal discomfort and severity of constipation. Finally, linaclotide has a good safety profile, with diarrhea being the main side effect. Expert opinion: Linaclotide appears to be a well-tolerated and effective agent for patients with CC, and could be effectively combined with other drugs in patients with refractory constipation. However, data on the efficacy and safety of linaclotide in pediatric patients and in opioid-induced constipation are currently limited and more studies need to be undertaken.

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Linaclotide for the treatment of refractory lower bowel manifestations of systemic sclerosis

Dein

Wigley

2021

BMC Gastroenterol

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Background Lower gastrointestinal (GI) tract involvement can affect up to 50% of systemic sclerosis (SSc) patients, and may result in malabsorption, pseudo-obstruction, hospitalization, and death. We report our experience with linaclotide, a selective agonist of guanylate cyclase C (GC-C), for SSc patients with refractory lower GI disease. Methods We performed an analysis of patients seen at the Johns Hopkins Scleroderma Center and identified patients prescribed linaclotide for refractory lower GI manifestations. Patients had clinical data collected in our longitudinal database. Linaclotide responders were on medication for at least 12 months with documented effectiveness by the treating physician. Results Thirty-one patients with SSc were treated with linaclotide. At the time of linaclotide initiation, 23 of these patients (74%) were classified as having severe GI disease, as defined by recurrent pseudo-obstruction, malabsorption, and/or need for artificial nutrition (Medsger GI severity score ≥ 3). The majority of patients (90.3%; 28/31) had a treatment response, while only three patients (9.7%) reported ineffectiveness or intolerable side effects. Low-dose linaclotide (≤ 145 mcg daily) was used in 18 patients and was effective in 94%. High-dose therapy (> 145 mcg daily) was effective in 11 of 13 patients (85%). Common side effects were diarrhea, cramping, or bloating (11/31, 35%). Ineffectiveness, cost, and abdominal pain were complaints cited among those who discontinued therapy. Conclusion Linaclotide is a well-tolerated and efficacious pro-secretory and pro-motility agent that can be used to manage refractory lower GI manifestations in SSc. We found that low-dose linaclotide is an effective option and may be better tolerated, though a subset of patients may require high dose regimens.

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Linaclotide for treatment of irritable bowel syndrome—The view of European regulators

Cited by 5 publications

References 12 publications

Irritable bowel syndrome: The evolution of multi-dimensional looking and multidisciplinary treatments

Irritable bowel syndrome: The evolution of multi-dimensional looking and multidisciplinary treatments

Linaclotide for the treatment of chronic constipation

Linaclotide for the treatment of refractory lower bowel manifestations of systemic sclerosis

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