Linaclotide

McWilliams, Vanessa; Whiteside, Glenn; McKeage, Kate

doi:10.2165/11470590-000000000-00000

Cited by 19 publications

(10 citation statements)

References 12 publications

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“…Clinically, linaclotide improves abdominal pain/discomfort, bloating and the defecated symptoms of straining, incomplete defecation and stool consistency of IBS-C patients. Meta-analyses confirmed its superior efficacy over placebo to treat IBS-C and functional constipation [128,130,131] . 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.…”

Section: Receptor Targeted Drugsmentioning

confidence: 85%

“…Similarly, linaclotide was marketed in United States and Europe to treat severe constipated patients including IBS patients in 2012 [128] . It is a synthetic 14-amino-acid peptide of guanylate cyclase C (GC-C) agonist mainly to increase intestinal fluid secretion and gut transit.…”

Section: Receptor Targeted Drugsmentioning

confidence: 99%

“…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: 99%

“…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: 99%

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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: 85%

Section: Receptor Targeted Drugsmentioning

confidence: 99%

Section: Receptor Targeted Drugsmentioning

confidence: 99%

Section: Receptor Targeted Drugsmentioning

confidence: 99%

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

Chang¹

2014

WJG

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“…Targeting GUCY2C signaling would leverage an endogenous endocrine mechanism mediating energy homeostasis. Moreover, GUCY2C activation may be achievable with reformulations of existing drugs like the synthetic GUCY2C peptide agonist, linaclotide (Linzess ™ , Ironwood Pharmaceuticals, Forest Laboratories), which has already been approved by the FDA and EMA to treat disorders of gastrointestinal motility (chronic idiopathic constipation, irritable bowel syndrome with constipation) [169,170]. In clinical trials, patients with chronic constipation improved after 12 or 26 weeks of treatment with 290 μg oral linaclotide, which had no systemic exposure, was well-tolerated, and had minimal adverse effects, diarrhea being the most common [170].…”

Section: Expert Opinionmentioning

confidence: 99%

New advances in models and strategies for developing anti-obesity drugs

Kim

Lin

Blomain

2013

Expert Opinion on Drug Discovery

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Introduction Obesity is a worldwide pandemic. Obesity-related health and economic costs are staggering. Existing strategies to combat obesity through lifestyle improvements and medical intervention have had limited success. Pharmacotherapy, in combination with lifestyle modification, may play a vital role in reversing the disease burden. However, past and current weight-loss medications have had serious safety risks, notably cardiovascular and psychiatric events. Areas covered We review the strategies for designing new anti-obesity drugs by describing those currently in development. We describe their target, mechanism of action, and developmental or regulatory status. We also discuss the problem of weight regain following weight loss, and its relevance to the long-term success of anti-obesity pharmacotherapy. Expert opinion For weight management drugs to achieve the safety and efficacy required to be impactful, current studies are uncovering and characterizing new targets, including new signaling circuits and hormones regulating appetite and metabolism, and re-evaluating the role of pharmacotherapy in weight management. To avoid the safety failures of many past weight-loss drugs, the models and strategies covered in this article incorporate recent advances in knowledge and technology. We discuss the emergence of cGMP signaling as a potentially transformative target in weight management. Modulating cGMP signaling may represent an ideal goal for an anti-obesity pharmacotherapy, reflecting some of the major themes described in the present review: targeting pathways that are newly realized as relevant for weight management; promoting safety by re-purposing drugs that are safe, proven, and approved for clinical use; and having a synergistic effect on multiple, reinforcing pathways.

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A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa

Kang

Marchelletta

Penrose

et al. 2015

Pharmacology Res & Perspec

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Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation.

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Linaclotide

Cited by 19 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

New advances in models and strategies for developing anti-obesity drugs

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa

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