DOCSLIB.ORG

Tegaserod in the Treatment of Constipation-Predominant Functional Gastrointestinal Disorders

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tegaserod in the Treatment of Constipation-Predominant Functional Gastrointestinal Disorders DRUG PROFILE Tegaserod in the treatment of constipation-predominant functional gastrointestinal disorders Anurag Agrawal & Irritable bowel syndrome is a common condition for which, until recently, treatment Peter Whorwell† options have been limited. Tegaserod has selective serotonin subtype 4 receptor agonist †Author for correspondence activity and acts by increasing gastrointestinal motility, secretion and possibly reducing ERC Building, First Floor, Wythenshawe Hospital, visceral sensitivity. It has been developed to treat patients with irritable bowel syndrome Southmoor Road, who suffer from abdominal pain, constipation and bloating. Studies so far suggest that it is Manchester, M23 9LT, an effective treatment for these symptoms with an excellent safety profile. Its role in other UK Tel.: +44 161 291 5813 functional gastrointestinal disorders, such as functional dyspepsia, is still being assessed. Fax: +44 161 291 4184 This review describes the structure, pharmacokinetic and pharmacodynamic properties of tegaserod and its effect on gastrointestinal physiology, as well as its clinical utility. Irritable bowel syndrome (IBS) is the most com- drugs such as antidiarrheals, laxatives, antispas- mon condition dealt with by gastroenterolo- modics and antidepressants. Behavioral therapy gists, accounting for up to 30% of their practice is sometimes tried in patients who do not and 10% of primary care case loads [1]. It is respond to conventional treatment. characterized by abdominal pain or discomfort In addition to its costs to the patient, IBS also often related to a change in bowel habit and fre- has a significant direct and indirect economic quently exacerbated by eating. Investigation burden. The direct cost in terms of healthcare reveals no structural abnormality, although a utilization has been estimated to be between variety of gastrointestinal (GI) physiological US$1.7–10 billion/year in the USA alone. The changes have been described. Population-based indirect cost in terms of days off work and studies have suggested that the prevalence is impairment whilst at work can amount to between 10 and 15%, with some variation US$20 billion, with the common cold being the according to the population group studied or only condition that can match IBS in terms of its the diagnostic criteria used [2]. economic impact [4–6]. IBS can be classified as diarrhea-predominant Functional constipation is a very common (d-IBS), constipation-predominant (c-IBS) or condition that affects the general population. It alternating bowel habit (a-IBS) subtypes accord- is defined as a group of functional disorders that ing to the predominant bowel habit, with an present as persistent, difficult, infrequent or approximately equal prevalence between the seemingly incomplete defecation in the absence three groups. More recent studies have suggested of other features to suggest IBS (Rome II crite- that patients with alternating bowel habits tend ria). The estimates of the prevalence of constipa- to have a greater variation of their symptoms tion in North America range from 12 to 19% compared with the other subgroups, with this and up to 50% in patients above the age of 65 fluctuation tending to be greater between c-IBS years, with a female-to-male ratio of 2.2:1 [7]. In and a-IBS rather than c-IBS and d-IBS or d-IBS one cohort, 89% of patients with constipation and a-IBS. This has led to the suggestion that the still reported constipation at 14.7 months fol- term mixed IBS (m-IBS) should be used [3]. low-up. There is some evidence to suggest that The diagnosis of IBS is based on a clinical his- quality of life (QoL) is impaired in constipation; Keywords: bloating, tory and the absence of certain red flag features however, this is not conclusive [7,8]. constipation, irritable bowel such as rectal bleeding, weight loss, absence of syndrome, serotonin, family history of bowel cancer, inflammatory Treatment of IBS: unsatisfactory tegaserod bowel disease or celiac disease. Investigations solution to a common problem required to rule out other gastroenterological The ideal IBS treatment would provide rapid, conditions should generally be kept to a mini- sustained, global relief of the multiple symptoms mum and treatment includes a range of of IBS with a single, effective, well-tolerated Future Drugs Ltd approaches including dietary modification or agent. Treatments that target only single IBS 10.1586/14750708.3.4.475 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(4), 475–484 475 DRUG PROFILE – Agrawal & Whorwell symptoms are considered suboptimal forms of greatest trigger. Serotonin has a number of effects therapy by the Rome II Committee and the in the GI tract that are mediated by a variety of American College of Gastroenterology Func- receptor subtypes. Pancreatic and mucosal secre- tional Gastrointestinal Disorders Task Force tion as well as peristalsis are stimulated via the (ACG FGID) [9–11]. direct action of serotonin on enterocytes in addi- Although in some patients traditional IBS tion to its stimulatory effects on intrinsic primary treatment options are beneficial in relieving sin- afferent neurons. In addition to this effect, serot- gle symptoms (e.g., antispasmodics for abdomi- onin also activates extrinsic sensory nerves such as nal pain, laxatives for constipation, and the vagus and spinal nerves which innervate the antidiarrheal agents for diarrhea), none of these GI tract and thus has a role in the perception of drugs for IBS have been assessed in trials that ful- pain in the GI tract [13,14]. A recent study has sug- fill the recently introduced, rather strict criteria gested that IBS patients have reduced stores of set out by the European Committee for Medici- serotonin in the gut mucosa, which is independ- nal Products for Human use (CHMP). The ent of the bowel habit subtype, although EC cells CHMP recommended in 2003 that drugs which appear to be increased in the colonic mucosa of are used for short-term relief of IBS should be patients with post-infectious IBS [15,16]. There is assessed using a re-randomization design with evidence that circulating postprandial serotonin two primary outcome variables. Furthermore, levels vary between c- and d-IBS, with the former patient surveys demonstrate general dissatisfac- tending to be lower in healthy controls and the tion with most of the available agents and evi- latter higher [17]. These data, although somewhat dence-based support for their use is also lacking, conflicting, do suggest that disturbances in sero- with the ACG FGID Task Force claiming that tonergic function can lead to disturbance of GI the methodology in most clinical trials of these motility, sensation and secretion. older agents was flawed. They also concluded One of the key components of normal sero- that many studies only met the criteria for level 2 tonergic function is the rapid and effective clear- evidence (grade B recommendation), defined as ance of serotonin following release. The randomized, controlled trials with p > 0.05, less serotonin reuptake transporter (SERT) is a spe- than adequate sample sizes, poor methodology, cialized transporter protein that is responsible for or a combination of these flaws [12]. Although the the transcellular transport and intracellular bulking agents, antidiarrheals and tricyclic anti- deactivation of serotonin. SERT is inhibited depressants (TCAs) were found to relieve some therapeutically by selective serotonin reuptake of the single symptoms of IBS (constipation, inhibitors (SSRIs) and TCAs. Recent reports diarrhea and abdominal pain, respectively), these have identified differences in the genetic coding agents were not considered more effective than of IBS patients with diarrhea and constipation placebo in providing global relief of the multiple subtypes [18]. symptoms of IBS. In addition, these agents often There are at least seven different subclasses of cause adverse reactions, some of which may serotonin receptor, with at least 21 different mimic or exacerbate IBS symptoms (e.g., consti- subtypes. In the gut, serotonin receptors are pation from antidepressants and bloating from present mainly on gut neurons, smooth muscle high doses of fiber). cells and EC cells. Of the different receptor Over the last few years there has been a surge subtypes the most important are the 5-HT3 and of interest in a new class of drugs that modulate 5-HT4 subtypes. serotonin and its receptors, with the 5-HT3 There is a predominance of 5-HT3 receptors receptor antagonist alosetron and the 5-HT4 on the enteric neurons of the gut, where they receptor agonist tegaserod being the focus of have a variety of effects including the potential to much attention with respect to IBS therapy. control motility, fluid secretion and visceral sen- sitivity. Studies have also indicated that 5-HT4 Role of serotonin and its receptors in IBS receptors are located in the enteric neurons and Serotonin is distributed mainly in the enterochro- the smooth muscle with their stimulation lead- maffin (EC) cells, which are located in the epithe- ing to a prokinetic effect and enhanced fluid lium of the small intestine as well as the colon. secretion [13]. More recent work has indicated There are many triggers for serotonin release from that 5-HT4 receptors are present not only on EC cells, including mechanical distension, nutri- submucous and myenteric plexus neurons but ents, toxins, neurotransmitters and a change in also on the interstitial cells of Cajal, which may pH, with mechanical stimulation being the have a role in regulating motility [19]. 476 Therapy (2006) 3(4) Tegaserod – DRUG PROFILE Serotonin receptor modulators: The most extensively studied 5-HT4 agonists background are cisapride, prucalopride and tegaserod. Unfor- The serotonin receptors are among the most com- tunately, cisapride has the potential to provoke pelling targets for motility-modifying agents, ventricular arrhythmias and prolongation of the given the central role that serotonin plays in the QT interval and this is linked to HERG potas- initiation of the peristaltic reflex and the excita- sium channel blockade rather than 5-HT4 recep- tory action of serotonin on enteric neurons.
Load more

Recommended publications
  • The American Society of Colon and Rectal Surgeons' Clinical Practice
    CLINICAL PRACTICE GUIDELINES The American Society of Colon and Rectal Surgeons’ Clinical Practice Guideline for the Evaluation and Management of Constipation Ian M. Paquette, M.D. • Madhulika Varma, M.D. • Charles Ternent, M.D. Genevieve Melton-Meaux, M.D. • Janice F. Rafferty, M.D. • Daniel Feingold, M.D. Scott R. Steele, M.D. he American Society of Colon and Rectal Surgeons for functional constipation include at least 2 of the fol- is dedicated to assuring high-quality patient care lowing symptoms during ≥25% of defecations: straining, Tby advancing the science, prevention, and manage- lumpy or hard stools, sensation of incomplete evacuation, ment of disorders and diseases of the colon, rectum, and sensation of anorectal obstruction or blockage, relying on anus. The Clinical Practice Guidelines Committee is com- manual maneuvers to promote defecation, and having less posed of Society members who are chosen because they than 3 unassisted bowel movements per week.7,8 These cri- XXX have demonstrated expertise in the specialty of colon and teria include constipation related to the 3 common sub- rectal surgery. This committee was created to lead inter- types: colonic inertia or slow transit constipation, normal national efforts in defining quality care for conditions re- transit constipation, and pelvic floor or defecation dys- lated to the colon, rectum, and anus. This is accompanied function. However, in reality, many patients demonstrate by developing Clinical Practice Guidelines based on the symptoms attributable to more than 1 constipation sub- best available evidence. These guidelines are inclusive and type and to constipation-predominant IBS, as well. The not prescriptive.
    [Show full text]
  • Anorectal Disorders Satish S
    Gastroenterology 2016;150:1430–1442 Anorectal Disorders Satish S. C. Rao,1 Adil E. Bharucha,2 Giuseppe Chiarioni,3,4 Richelle Felt-Bersma,5 Charles Knowles,6 Allison Malcolm,7 and Arnold Wald8 1Division of Gastroenterology and Hepatology, Augusta University, Augusta, Georgia; 2Department of Gastroenterology and Hepatology, Mayo College of Medicine, Rochester, Minnesota; 3Division of Gastroenterology of the University of Verona, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy; 4Division of Gastroenterology and Hepatology and UNC Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; 5Department of Gastroenterology/Hepatology, VU Medical Center, Amsterdam, The Netherlands; 6National Centre for Bowel Research and Surgical Innovation, Blizard Institute, Queen Mary University of London, London, United Kingdom; 7Division of Gastroenterology, Royal North Shore Hospital, and University of Sydney, Sydney, Australia; 8Division of Gastroenterology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin This report defines criteria and reviews the epidemiology, questionnaires and bowel diaries are correlated,5 some pathophysiology, and management of the following com- patients may not accurately recall bowel symptoms6; hence, mon anorectal disorders: fecal incontinence (FI), func- symptom diaries may be more reliable. tional anorectal pain, and functional defecation disorders. In this report, we examine the prevalence and patho- FI is defined as the recurrent uncontrolled passage of fecal physiology of anorectal disorders, listed in Table 1,and material for at least 3 months. The clinical features of FI provide recommendations for diagnostic evaluation and are useful for guiding diagnostic testing and therapy. management. These supplement practice guidelines rec- ANORECTAL Anorectal manometry and imaging are useful for evalu- ommended by the American Gastroenterological Associa- fl ating anal and pelvic oor structure and function.
    [Show full text]
  • Linaclotide: a Novel Therapy for Chronic Constipation and Constipation- Predominant Irritable Bowel Syndrome Brian E
    Linaclotide: A Novel Therapy for Chronic Constipation and Constipation- Predominant Irritable Bowel Syndrome Brian E. Lacy, PhD, MD, John M. Levenick, MD, and Michael D. Crowell, PhD, FACG Dr. Lacy is Section Chief of Gastroenter- Abstract: Chronic constipation and irritable bowel syndrome ology and Hepatology and Dr. Levenick (IBS) are functional gastrointestinal disorders that significantly is a Gastroenterology Fellow in the affect patients’ quality of life. Chronic constipation and IBS are Division of Gastroenterology and prevalent—12% of the US population meet the diagnostic crite- Hepatology at Dartmouth-Hitchcock Medical Center in Lebanon, New ria for IBS, and 15% meet the criteria for chronic constipation— Hampshire. Dr. Crowell is a Professor and these conditions negatively impact the healthcare system of Medicine in the Division of from an economic perspective. Despite attempts at dietary Gastroenterology and Hepatology at modification, exercise, or use of over-the-counter medications, Mayo Clinic in Scottsdale, Arizona. many patients have persistent symptoms. Alternative treatment options are limited. This article describes linaclotide (Linzess, Address correspondence to: Dr. Brian E. Lacy Ironwood Pharmaceuticals/Forest Pharmaceuticals), a new, first- Division of Gastroenterology and in-class medication for the treatment of chronic constipation Hepatology, Area 4C and constipation-predominant IBS. Dartmouth-Hitchcock Medical Center 1 Medical Center Drive Lebanon, NH 03756; Tel: 603-650-5215; Fax: 603-650-5225; onstipation is
    [Show full text]
  • THE HARD TRUTH ABOUT PROKINETIC MEDICATION USE in PETS Introduction Pathophysiology/Etiology to That Observed in Dogs
    VETTALK Volume 15, Number 04 American College of Veterinary Pharmacists THE HARD TRUTH ABOUT PROKINETIC MEDICATION USE IN PETS Introduction Pathophysiology/Etiology to that observed in dogs. It can be The moving topic of this Vet Talk As with most diseases in the veteri- due to a trichobezoar, dehydration, newsletter will be prokinetic medica- nary world, the etiology and patho- obesity, old age, diabetes, immobility, tions. The availability of information physiology of constipation are varied pain from trauma to the low back, on the many prokinetic agents is var- depending on the species being dis- bladder infection, or an anal sac infec- ied at best so an overall consensus of cussed, where in their gastrointestinal tion. In cases that are more chronic, prokinetic medications will be as- tract the problem is occurring, and underlying disease such as colitis or sessed in this article, hopefully giving any accompanying comorbid condi- Irritable Bowel Syndrome (IBS) may better insight to practitioners about tions. be the culprit. On the other hand, the which agents to use in their patients. cause may be idiopathic which is Canines: In man’s best friend, consti- frustrating for both veterinarian and Prevalence pation has many origins. A dog’s patient since this form is most diffi- Chronic constipation and gastroin- digestive tract itself is complex but cult to treat. testinal stasis are highly debilitating ultimately the mass movements and conditions that not only affect human haustral contractions from the large Equines: Despite their large size, patients but our four legged patients intestine (colon), propel feces into the horses have incredibly delicate diges- as well! Though this condition is rectum stimulating the internal anal tive systems.
    [Show full text]
  • The Pharmacology of Prokinetic Agents and Their Role in the Treatment of Gastrointestinal Disorders
    The Pharmacology of ProkineticAgents IJGE Issue 4 Vol 1 2003 Review Article The Pharmacology of Prokinetic Agents and Their Role in the Treatment of Gastrointestinal Disorders George Y. Wu, M.D, Ph.D. INTRODUCTION Metoclopramide Normal peristalsis of the gut requires complex, coordinated neural and motor activity. Pharmacologic Category : Gastrointestinal Abnormalities can occur at a number of different Agent. Prokinetic levels, and can be caused by numerous etiologies. This review summarizes current as well as new Symptomatic treatment of diabetic gastric agents that show promise in the treatment of stasis gastrointestinal motility disorders. For these Gastroesophageal reflux e conditions, the most common medications used in s Facilitation of intubation of the small the US are erythromycin, metoclopramide, and U intestine neostigmine (in acute intestinal pseudo- Prevention and/or treatment of nausea and obstruction). A new prokinetic agent, tegaserod, vomiting associated with chemotherapy, has been recently approved, while other serotonin radiation therapy, or post-surgery (1) agonist agents (prucalopride, YM-31636, SK-951, n ML 10302) are currently undergoing clinical o Blocks dopamine receptors in chemoreceptor i t studies. Other prokinetics, such as domperidone, c trigger zone of the CNS (2) A are not yet approved in the US, although are used in f Enhances the response to acetylcholine of o other countries. tissue in the upper GI tract, causing enhanced m s i n motility and accelerated gastric emptying a DELAYED GASTRIC EMPTYING OR h without stimulating gastric, biliary, or c G A S T R O E S O P H A G E A L R E F L U X e pancreatic secretions.
    [Show full text]
  • Constipation
    Constipation Constipation is defined as having a bowel movement fewer than three times per week. With constipation stools are usually hard, dry, Esophagus small in size, and difficult to eliminate. Some people who are constipated find it painful to Liver Stomach have a bowel movement and often experience straining, bloating, and the sensation of a full Pancreas bowel. Large Some people think they are constipated if they intestine do not have a bowel movement every day. However, normal stool elimination may be Small three times a day or three times a week, intestine depending on the person. Rectum Constipation is a symptom, not a disease. Anus Almost everyone experiences constipation at some point in their life, and a poor diet Appendix typically is the cause. Most constipation is temporary and not serious. Understanding its The digestive tract. causes, prevention, and treatment will help most people find relief. Self-treatment of constipation with overthe- counter (OTC) laxatives is by far the most Who gets constipated? common aid. Around $725 million is spent on Constipation is one of the most common laxative products each year in America. gastrointestinal complaints in the United States. More than 4 million Americans have frequent What causes constipation? constipation, accounting for 2.5 million To understand constipation, it helps to know physician visits a year. Those reporting how the colon, or large intestine, works. As food constipation most often are women and adults moves through the colon, the colon absorbs ages 65 and older. Pregnant women may have water from the food while it forms waste constipation, and it is a common problem products, or stool.
    [Show full text]
  • Zelnorm®) for Safety Reasons
    NATIONAL PBM BULLETIN April 3, 2007 DEPARTMENT OF VETERANS AFFAIRS VETERANS HEALTH ADMINISTRATION PHARMACY BENEFITS MANAGEMENT STRATEGIC HEALTHCARE GROUP, MEDICAL ADVISORY PANEL, AND CENTER FOR MEDICATION SAFETY (VA MEDSAFE) Discontinued Marketing of Tegaserod (Zelnorm®) for Safety Reasons I. ISSUE – On March 30, 2007, Novartis suspended US marketing and sales of tegaserod in compliance with the Food and Drug Administration’s (FDA) request which was based on a retrospective analysis of pooled clinical trial data showing increased risk of serious cardiovascular adverse events associated with use of tegaserod compared to placebo. II. BACKGROUND – Novartis reported results of an analysis involving 29 short-term randomized, controlled clinical trials of tegaserod which included over 18,000 patients in the clinical trial database. Serious cardiovascular events (angina, MI, and stroke) occurred in 13 of 11,614 (0.11%) tegaserod-treated patients compared to 1 of 7,031 (0.01%) placebo-treated patients (p=0.024). All patients affected had pre-existing cardiovascular disease. III. DISCUSSION – Tegaserod was approved in July 2002 for the short-term treatment of constipation-predominant irritable bowel syndrome (IBS) in women. Subsequently, the drug was approved in August 2004 for the treatment of chronic constipation in men and women under age 65. In January 2006, VA PBM provided criteria for nonformulary use of tegaserod based on available evidence reviewed in the PBM Drug Monograph for tegaserod. A preliminary utilization evaluation was conducted by VAMedSAFE to look at variations in prescribing patterns. Although not an approved indication, patients with gastroesophageal reflux disease (GERD) appeared to be the largest users of tegaserod.
    [Show full text]
  • Zelnorm Page: 1 of 5
    Federal Employee Program® 1310 G Street, N.W. Washington, D.C. 20005 202.942.1000 Fax 202.942.1125 5.50.25 Section: Prescription Drugs Effective Date: April 1, 2020 Subsection: Gastrointestinal Agents Original Policy Date: April 26, 2019 Subject: Zelnorm Page: 1 of 5 Last Review Date: March 13, 2020 Zelnorm Description Zelnorm (tegaserod) Background Zelnorm is an agonist of serotonin type-4 (5-HT4) receptors that stimulates the peristaltic reflex and intestinal secretion, inhibits visceral sensitivity, enhances basal motor activity, and normalizes impaired motility throughout the gastrointestinal tract (1). Regulatory Status FDA-approved indication: Zelnorm is a serotonin-4 (5-HT4) receptor agonist indicated for treatment of adult women less than 65 years of age with irritable bowel syndrome with constipation (IBS-C) (1). Limitations of Use: The safety and effectiveness of Zelnorm in men with IBS-C have not been established (1). Zelnorm is contraindicated in patients with: (1) 1. A history of myocardial infarction (MI), stroke, transient ischemic attack (TIA), or angina. 2. A history of ischemic colitis or other forms of intestinal ischemia. 3. Severe renal impairment (eGFR < 15 mL/min/1.73 m2) or end-stage renal disease. 4. Moderate and severe hepatic impairment (Child-Pugh B or C). 5. A history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi Dysfunction, or abdominal adhesions. 5.50.25 Section: Prescription Drugs Effective Date: April 1, 2020 Subsection: Gastrointestinal Agents Original Policy Date: April 26, 2019 Subject: Zelnorm Page: 2 of 5 The safety and effectiveness of Zelnorm in pediatric patients less than 18 years of age have not been established (1).
    [Show full text]
  • Rifaximin (XIFAXAN)
    Rifaximin (XIFAXAN) for Irritable Bowel Syndrome with Diarrhea National Drug Monograph March 2016 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a focused drug review for making formulary decisions. Updates will be made when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. FDA Approval Information Description/Mechanism of Minimally absorbed, broad-spectrum antibacterial that inhibits bacterial RNA Action synthesis. The specific mechanism of action of rifaximin in irritable bowel syndrome (IBS) has not been determined. The most likely mechanism of rifaximin is reduction in overall bacterial load, particularly in the large bowel1; however, rifaximin also seems to modulate gut microenvironment and produce cytoprotective effects.2 Indication(s) Under Review in Treatment of IBS with diarrhea (IBS-D) in adults this Document Dosage Form(s) Under 550 mg tablet Review REMS REMS No REMS Postmarketing Requirements Pregnancy Rating No data available on pregnant women to inform any drug associated risks. Executive Summary Efficacy Rifaximin had a small, statistically significant beneficial effect relative to placebo in global IBS symptom response using pooled data: 40.7% vs. 31.7%, with a difference of 9.0 percentage points, p < 0.001; NNT = 11. Rifaximin had a small, statistically significant beneficial effect relative to placebo in terms of the response rate for adequate relief of bloating (the key secondary efficacy measure): 40.2% vs. 30.3%, difference of 9.9 percentage points, p < 0.001; NNT = 10 (pooled results).
    [Show full text]
  • Emerging Drug List — Tegaserod Hydrogen Maleate
    Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH TEGASEROD HYDROGEN MALEATE TECHNOLOGY ASSESSMENT NO. 32 MAY 2002 Generic (Trade Name): Tegaserod hydrogen maleate (Zelnorm™) Manufacturer: Novartis Pharmaceuticals Indication: For the symptomatic treatment of irritable bowel syndrome with constipation (IBS-C) in female patients whose main symptoms are constipation and abdominal pain and/or discomfort. The maximum duration of treatment should be no longer than 12 weeks and the treatment should be discontinued if there has been no response after four weeks. Current Regulatory Zelnorm™ was approved by Health Canada's Therapeutic Products Directorate on Status: March 12, 2002. Launch in Canada is impending1. Description: Tegaserod is a partial agonist of 5-HT4 receptors, a new chemical class of proki- netic medications. This subclass of receptors is found throughout the gastroin- testinal tract, and it is postulated that when activated, they minimize the percep- tion of discomfort, pain and constipation associated with IBS. Tegaserod exhibits a low absolute bioavailablity after oral dosing (11%), and the time to achieve a peak concentration ranges from one to 1.3 hours.2 It is highly protein bound (98% to α1-acid glycoprotein) and its terminal half-life is 11± 5 hours. Diarrhea, abdominal pain, headache, flatulence and fatigue are the most frequently report- ed adverse events. Compared to placebo, no differences in QTc interval prolon- gations have been reported in clinical trials, although syncope (an effect seen with cisapride) has been observed at a greater frequency in tegaserod users. The recommended dosage of Zelnorm™ is 6 mg twice daily, administered prior to a meal with water.
    [Show full text]
  • The Significance of the Gut Microbiome in Children with Functional Constipation
    Reviews The significance of the gut microbiome in children with functional constipation Monika KwiatkowskaA–F, Aneta KrogulskaA–F Department of Pediatrics, Allergology and Gastroenterology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Poland A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation; D – writing the article; E – critical revision of the article; F – final approval of the article Advances in Clinical and Experimental Medicine, ISSN 1899–5276 (print), ISSN 2451–2680 (online) Adv Clin Exp Med. 2021;30(4):471–480 Address for correspondence Abstract Monika Kwiatkowska E-mail: [email protected] Constipation is a widespread problem in pediatric practice, affecting almost 30% of pediatric population. As much as 90–95% of constipation cases have a functional basis, and although the pathogenesis of func- Funding sources None declared tional constipation remains unclear, its etiology is considered to be multifactorial. Its growing prevalence has been attributed to the occurrence of disorders in the homeostasis of gastrointestinal microbiota. In humans, Conflict of interest the best known microbiome is that of the intestines, which has been the subject of a number of studies None declared based on recognition of the 16S rRNA gene sequence. Microbiota are believed to influence the pathogenesis of functional constipation by affecting peristalsis, relationship with diet, and physical activity. The paper evaluates the role of intestinal microbiota in functional constipation and describes its contribution to the onset Received on July 28, 2020 of disease. Determining the importance of the microbiome in the pathogenesis of functional constipation Reviewed on October 12, 2020 Accepted on December 6, 2020 creates hope for the development of new prevention and treatment methods.
    [Show full text]
  • Zelnorm Fda Ac Backgrounder Errata
    ZELNORM FDA AC BACKGROUNDER ERRATA Items from the FDA Briefing Document issued for the Advisory Committee meeting held October 17, 2018. The text for correction is identified by a strikethrough, with correction following in double underline, unless otherwise specified. 1. The following paragraph appears on page 26: From a mechanistic perspective, the potential for tegaserod to cause CV ischemia is not well understood. Available 5-HT receptor affinity and functional response data for tegaserod indicate that the drug binds to 5-HT4 receptors with high affinity as an agonist, and binds with moderate to high affinities for 5-HT1 receptor subtypes, as an agonist. Tegaserod also has antagonistic activity at 5-HT2 receptor subtypes. This paragraph is revised to the following: From a mechanistic perspective, the potential for tegaserod to cause CV ischemia is not well understood. Available 5-HT receptor affinity and functional response data for tegaserod indicate that the drug binds to 5-HT4 receptors with high affinity as an agonist, and binds with moderate to high affinities for 5-HT1 and 5-HT2 receptor subtypes, as an agonist. Tegaserod also has antagonistic activity at the 5-HT1 and 5-HT2 receptor subtypes that mediate vasoconstriction [24]. Based on the Cmax of tegaserod (10 nM) at the recommended dose, it is likely that tegaserod binding to 5-HT receptors in humans will be mostly limited to the 5-HT4 and 5-HT2B subtypes (see Table 15 below). 2. The following paragraph appears on page 26: Intravenous administration of 1 mg/kg in rats (1.6 times the recommended oral human dose (6 mg/dose) based on mg/m2) produced reductions in systolic and diastolic blood pressure, with no effects observed at 0.1 mg/kg or lower.
    [Show full text]