DOCSLIB.ORG

Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea ORIGINAL CONTRIBUTIONS 1 see related editorial on page x Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea Brooks D. Cash , MD 1 , Brian E. Lacy , MD, PhD 2 , Philip S. Schoenfeld , MD 3 , Leonard S. Dove , PhD 4 and Paul S. Covington , MD 4 OBJECTIVES: Eluxadoline is a mixed μ -opioid receptor (OR) and κ -OR agonist and δ -OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies. METHODS: Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks. Safety data were pooled. Adverse events (AEs) were assessed, with special focus on opioid-related AEs, including suspected sphincter of Oddi spasm (SOS) events. RESULTS: 2,776 patients were included in the enrolled set; the safety set comprised 2,814 patients, based on FUNCTIONAL GI DISORDERS actual treatments received. The most frequent AEs in the placebo and eluxadoline 75 and 100 mg groups were constipation (2.5, 7.4, and 8.1%, respectively) and nausea (5.0, 8.1, and 7.1%, respectively); discontinuation due to constipation was uncommon (0.3, 1.1, and 1.5%, respectively). Ten SOS events (10/1,839; 0.5%) occurred in eluxadoline-treated patients, manifesting as acute abdominal pain with elevated aminotransferases or lipase, or pancreatitis; all occurred in patients without a gallbladder. Eight of these events occurred with the higher dose of eluxadoline, within 1 week of initiation of therapy, and all resolved with eluxadoline discontinuation. There were fi ve events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use. CONCLUSIONS: Eluxadoline was well tolerated in Phase 2 and 3 trials, with constipation and nausea the most common AEs. Consistent with the known adverse effects of opioid agonists, clinically apparent SOS events were observed in eluxadoline-treated patients. All occurred in patients without a gallbladder and the majority were observed in patients on the higher dose of eluxadoline, suggesting a possible association. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg Am J Gastroenterol advance online publication, 6 December 2016; doi: 10.1038/ajg.2016.542 INTRODUCTION use of health-related resources and reduced work productivity Irritable bowel syndrome (IBS) is a chronic functional gastro- ( 7–10 ). intestinal (GI) disorder characterized by recurrent abdominal Dietary and lifestyle changes oft en comprise fi rst-line manage- pain or discomfort and altered bowel movements in the absence ment strategies for patients with IBS-D ( 1 ), although the durability of structural, infl ammatory, or biochemical abnormalities ( 1 ). of these interventions remains unproven. Approved pharmaco- IBS global prevalence ranges from ~5 to 15% ( 2–4 ) and approxi- logic therapies for IBS-D include alosetron, a serotonin antagonist mately one-third of all cases meet criteria for IBS with diarrhea used for the treatment of severe IBS-D in women who have not (IBS-D) ( 3,5 ). IBS-D is associated with impaired quality of life responded to conventional therapy ( 11 ), and rifaximin, a non- ( 6 ) as well as a marked socioeconomic impact through increased systemic antibiotic ( 12 ). Both alosetron ( 13,14 ) and rifaximin ( 15 ) 1 Department of Medicine, University of South Alabama , Mobile , Alabama , USA ; 2 Dartmouth-Hitchcock Medical Center , Lebanon , New Hampshire , USA ; 3 University of Michigan School of Medicine , Ann Arbor , Michigan , USA ; 4 Furiex Pharmaceuticals, Inc., an affi liate of Allergan plc , Parsippany, New Jersey , USA . Correspondence: Brooks D. Cash, MD, Department of Medicine, University of South Alabama, 6000 University Commons, 75 University Boulevard , Mobile , Alabama 36688 , USA . E-mail: [email protected] Received 22 June 2016 ; accepted 13 October 2016 Offi cial journal of the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 2 Cash et al. have demonstrated improvement in global IBS symptoms and Phase 3 trials abdominal pain. IBS-3001 and IBS-3002 were randomized, double-blind, placebo- Loperamide, an over-the-counter μ -opioid receptor (OR) ago- controlled, parallel-group, multicenter studies conducted across nist, is an eff ective antidiarrheal agent commonly used to manage 556 centers in the US, Canada, and the UK ( 23 ). In both trials, the disturbed defecation of IBS-D, although evidence to support patients were randomized to receive eluxadoline (75 or 100 mg) its use is minimal ( 16 ). In addition, loperamide is well known to or placebo BID for 52 weeks in IBS-3001 and 26 weeks in IBS- precipitate constipation to the point that is has been used in animal 3002. Key inclusion criteria were: patients 18−80 years of age with and human models to reliably produce constipation ( 17,18 ), con- IBS-D (Rome III criteria ( 24 )), with an average worst abdominal sistent with the eff ects of unopposed agonism of the μ -OR ( 19 ). pain score of >3.0, an average BSFS score of ≥5.5, ≥5 days with a Eluxadoline is a peripherally active, mixed μ -OR and κ -OR ago- BSFS score of ≥5, and an average IBS-D global symptom score of nist and δ -OR antagonist ( 20 ) that was recently approved by the ≥2.0 (scale of 0 (no symptoms) to 4 (very severe symptoms)). Key US Food and Drug Administration for the treatment of IBS-D in exclusion criteria were: a history of infl ammatory bowel disease, adults. Enteric neurons in the GI tract express μ -, δ -, and κ -ORs, celiac disease, or alcoholism; abnormal thyroid function; pancre- which regulate GI motility and visceral sensation ( 21 ). Although atitis, sphincter of Oddi (SO) dysfunction, or post-cholecystec- there is potential for the mixed pharmacological profi le of elux- tomy biliary pain; and cholecystitis within the previous 6 months. adoline (local agonistic targeting of μ - and κ -ORs) to be associ- ated with the known class eff ects of μ -OR agonists, the likelihood Safety assessments of these eff ects may be reduced through simultaneous μ -/δ -OR Th e safety and tolerability of eluxadoline were evaluated in each of binding ( 20 ). these Phase 2 and Phase 3 studies, and safety assessments included Th e effi cacy of eluxadoline was initially evaluated in a dose- adverse event (AE) reporting, clinical laboratory results, 12-lead FUNCTIONAL GI DISORDERS ranging Phase 2 study (IBS-2001) that demonstrated that elux- electrocardiograms, vital signs, and physical examinations. Con- adoline 100 mg twice daily (BID) could simultaneously improve comitant medication use was collected throughout the study. abdominal pain and stool consistency over the full 12-week dura- Special focus was directed on AEs related to the opioid pharma- tion of the study ( 22 ). Subsequently, two large Phase 3 trials (IBS- cologic class, including constipation and SO spasm (SOS). In addi- 3001 and IBS-3002) demonstrated the effi cacy of eluxadoline in tion to traditional AE reporting, constipation was also evaluated patients with IBS-D ( 23 ). retrospectively based on patient electronic diary (interactive voice Herein we report the pooled safety and tolerability data from the response system) entries. Diary-confi rmed constipation as pro- Phase 2 and 3 clinical studies for the approved doses of eluxado- spectively defi ned in the protocol was confi rmed retrospectively line, 75 and 100 mg. using two of the electronic diary measurements: BSFS score and number of bowel movements. Constipation using the BSFS score was defi ned as an average score <2 over any study week. Constipa- METHODS tion using the number of bowel movements was defi ned as zero Th e Phase 2 (IBS-2001; ClinicalTrial.gov identifi er: NCT01130272) bowel movements for ≥4 consecutive days. and Phase 3 (IBS-3001 and IBS-3002; NCT01553591 and As the known class eff ects of μ -OR agonists on the SO can be NCT01553747, respectively) studies described herein were con- diffi cult to diagnose ( 25 ), a safety-focused adjudication committee ducted with the approval of each investigator’s institutional review comprising three independent experts (the Hepatobiliary and Pan- board or independent ethics committee, and the studies were con- creatitis Adjudication Committee) was established outside of the ducted in accordance with the principles of Good Clinical Prac- Phase 3 study protocol in order to evaluate suspected pancreatitis tice guidelines. All patients provided written informed consent. and SOS events. For all cases adjudicated, the committee reviewed a treatment-blinded dossier of primary medical records, labora- Phase 2 trial tory reports, radiology reports, and case narratives to determine IBS-2001 was a randomized, double-blind, parallel-group, pla- whether the events met pre-specifi ed case defi nitions for acute cebo-controlled study conducted at 263 primary and tertiary care pancreatitis of any etiology or an acute hepatobiliary event, and centers in the US, the design and results of which have been pre- whether SOS was the precipitating etiology based on a decision viously reported ( 22 ). Patients were randomized to receive elux- algorithm ( Supplementary Figure S1 ). adoline (5, 25, 100, or 200 mg) or placebo BID for 12 weeks. Key Th e committee used the Atlanta criteria for the diagnosis of eligibility criteria
Load more

Recommended publications
  • Eluxadoline: a Treatment for IBS with Diarrhoea in Adults
    ■ NEW PRODUCT Eluxadoline: a treatment for IBS with diarrhoea in adults STEVE CHAPLIN Eluxadoline (Truberzi) KEY POINTS is an oral mixed opioid- receptor agonist/ ■ Eluxadoline is an opioid-receptor agonist/antagonist with low systemic absorption antagonist licensed for ■ It is licensed for the treatment of irritable bowel syndrome with diarrhoea in the treatment of irritable adults and is recommended by NICE as a second-line agent bowel syndrome with ■ The recommended dosage is 75–100mg orally twice daily diarrhoea in adults. ■ In clinical trials, response rates were 27%–31% with eluxadoline and 19.5% with placebo after 26 weeks’ treatment This article examines its ■ Common adverse effects include constipation, nausea and abdominal pain properties, efficacy in ■ Pancreatitis and sphincter of Oddi spasm were uncommon adverse events clinical trials and side- ■ Treatment with eluxadoline costs £88.20 per month. effects. he initial management of irritable locally within the gastrointestinal tract, Tbowel syndrome (IBS) entails dietary slowing gastrointestinal transit, reducing and lifestyle change and treatment with urgency and improving stool consistency; antispasmodic agents.1 For people with its abuse potential is low. IBS and diarrhoea, loperamide is the anti- Eluxadoline is licensed for the treat- motility agent of first choice, adjusting the ment of IBS with diarrhoea in adults. The dose to achieve optimum stool consist- recommended dosage is 100mg twice ency. If this is unsatisfactory, treatment daily (reduced to 75mg twice daily if with a low-dose tricyclic antidepressant poorly tolerated). Treatment should be should be considered, with an SSRI a initiated at the lower dose in older people further option if this is unsuccessful.
    [Show full text]
  • FDA Warns About an Increased Risk of Serious Pancreatitis with Irritable Bowel Drug Viberzi (Eluxadoline) in Patients Without a Gallbladder
    FDA warns about an increased risk of serious pancreatitis with irritable bowel drug Viberzi (eluxadoline) in patients without a gallbladder Safety Announcement [03-15-2017] The U.S. Food and Drug Administration (FDA) is warning that Viberzi (eluxadoline), a medicine used to treat irritable bowel syndrome with diarrhea (IBS-D), should not be used in patients who do not have a gallbladder. An FDA review found these patients have an increased risk of developing serious pancreatitis that could result in hospitalization or death. Pancreatitis may be caused by spasm of a certain digestive system muscle in the small intestine. As a result, we are working with the Viberzi manufacturer, Allergan, to address these safety concerns. Patients should talk to your health care professional about how to control your symptoms of irritable bowel syndrome with diarrhea (IBS-D), particularly if you do not have a gallbladder. The gallbladder is an organ that stores bile, one of the body’s digestive juices that helps in the digestion of fat. Stop taking Viberzi right away and get emergency medical care if you develop new or worsening stomach-area or abdomen pain, or pain in the upper right side of your stomach-area or abdomen that may move to your back or shoulder. This pain may occur with nausea and vomiting. These may be symptoms of pancreatitis, an inflammation of the pancreas, an organ important in digestion; or spasm of the sphincter of Oddi, a muscular valve in the small intestine that controls the flow of digestive juices to the gut. Health care professionals should not prescribe Viberzi in patients who do not have a gallbladder and should consider alternative treatment options in these patients.
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Supplement 1: Additional Tables and Figures
    BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Global Health Supplement 1: Additional tables and figures Box S1: Substances included and excluded from the International Narcotic Control Board (INCB) data on narcotic consumption, in alphabetical order. Opioids included in the opioid consumption calculation: 1. (+)-cis-3-methylfental 35. Bezitramide 2. 3-Acetylmorphine 36. Butyrfentanyl 3. 3-Methylfentanyl 37. Carfentanil 4. 3-Methylthiofentanyl 38. Carfentanyl 5. 3-Monoacetylmorphine 39. Clonitazene 6. 4-Fluoroisobutyrfentanyl 40. Codeine 7. 6-Acetylmorphine 41. Codeine-6GLUC 8. 6-Monoacetylmorphine 42. Codeine-6-glucuronide 9. Acetorphine 43. Codeine-Methyl 10. Acetyl-alpha-methylfentanyl 44. Codeine-N-oxide 11. Acetyldihydrocodeine 45. Codoxime 12. Acetylfentanyl 46. Conc. of poppy straw (C) ACA 13. Acetylmethadol 47. Conc. of poppy straw (C) AMA 14. Acetylmorphine 48. Conc. of poppy straw (C) AOA 15. Acrylfentanyl 49. Conc. of poppy straw (C) ATA 16. AH-7921 50. Conc. of poppy straw (C) GW 17. Alfentanil 51. Conc. of poppy straw (M) ACA 18. Allylprodine 52. Conc. of poppy straw (M) AMA 19. Alphacetylmethadol 53. Conc. of poppy straw (M) AOA 20. Alphameprodine 54. Conc. of poppy straw (M) ATA 21. Alphamethadol 55. Conc. of poppy straw (M) GW 22. alpha-Methylfentanyl 56. Conc. of poppy straw (N) GW 23. alpha-Methylthiofentanyl 57. Conc. of poppy straw (O) 24. Alphaprodine 58. Conc. of poppy straw (O) ACA 25. Anileridine 59. Conc. of poppy straw (O) AMA 26. Benzethidine 60. Conc. of poppy straw (O) AOA 27.
    [Show full text]
  • Surveillance Review Proposal PDF 387 KB
    National Institute for Health and Care Excellence Surveillance programme Surveillance proposal consultation document Irritable bowel syndrome NICE guideline CG61 – 8-year surveillance review Background information Guideline issue date: February 2008 3-year review (no update)* 6-year review (yes to update) *Although the 3-year review decision was no update, the findings were subsequently used to pilot the NICE’s rapid update process. Surveillance proposal for consultation We will not update the guideline at this time. Reason for the proposal New evidence We found 105 new studies in a search for randomised controlled trials (RCTs) and systematic reviews published between 01 September 2013 and 18 July 2016. We also considered studies identified by members of the guideline committee who originally worked on this guideline. Evidence identified in previous surveillance 3 years and 6 years after publication of the guideline was also considered. This included 52 studies identified by search. From all sources, 157 studies were considered to be relevant to the guideline. Surveillance proposal consultation document for Irritable bowel syndrome (2008) NICE guideline CG61 1 of 44 This included new evidence that is consistent with current recommendations on: diagnosis of irritable bowel syndrome (IBS) dietary interventions physical activity interventions drug treatments (antispasmodics, laxatives, anti-motility agents and antidepressants) psychotherapy hypnotherapy, biofeedback and relaxation therapy acupuncture and patient information. We also identified new evidence in the following areas that was inconsistent with, or not covered by, current recommendations, but the evidence was not considered to impact on the guideline: ondansetron vitamin D supplementation herbal medicines. We did not find any new evidence on reflexology, psychosocial interventions, or self-help and support groups.
    [Show full text]
  • 2015.09 IBS Drug Class Review.Pdf
    Drug Class Review Agents Indicated in the Treatment of Irritable Bowel Syndrome 56:92 GI Drugs, Miscellaneous Alosetron (Lotronex®) Eluxadoline (Viberzi®) Linaclotide (Linzess®) Lubiprostone (Amitiza®) Tegaserod (Zelnorm®) Final Report September 2015 Review prepared by: Melissa Archer, PharmD, Clinical Pharmacist Irene Pan, PharmD Candidate 2016 Chelsey Hancock, PharmD Candidate 2016 Carin Steinvoort, PharmD, Clinical Pharmacist Gary Oderda, PharmD, MPH, Professor University of Utah College of Pharmacy Copyright © 2015 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved. 1 Table of Contents Executive Summary ......................................................................................................................... 3 Introduction .................................................................................................................................... 4 Table 1. Comparison of the Agents Indicated in the Treatment of IBS ................................. 5 Disease Overview ........................................................................................................................ 6 Table 2. Summary of IBS Treatment Options ........................................................................ 8 Table 3. IBS Disease Staging System .................................................................................... 11 Table 4. Most Current Clinical Practice Guidelines for the Treatment of IBS ..................... 13 Pharmacology ..............................................................................................................................
    [Show full text]
  • Viberzi™ (Eluxadoline) – Safety Update
    Viberzi™ (eluxadoline) – Safety update • On March 15, 2017, the FDA announced that Allergan’s Viberzi (eluxadoline) should not be used in patients who do not have a gallbladder. • Patients who do not have a gallbladder who are taking Viberzi for irritable bowel syndrome with diarrhea (IBS-D) have an increased risk of developing pancreatitis, sphincter of Oddi spasm, and death. • Symptoms of pancreatitis have occurred with just one or two doses of Viberzi at the recommended dosage for patients who do not have a gallbladder (75 mg) and who do not consume alcohol. • Viberzi is a schedule IV controlled substance indicated in adults for the treatment of IBS-D. — IBS-D affects the large intestine and causes cramping, abdominal pain, bloating, gas, and diarrhea. Viberzi works by decreasing bowel contractions, which leads to less diarrhea. • Healthcare providers should not prescribe Viberzi to patients who do not have a gallbladder and should consider alternative over-the-counter (OTC) or prescription medicines indicated to treat IBS- D and its related symptoms in these patients. — OTC examples include bismuth subsalicylate (eg, Kaopectate®, Pepto-Bismol™), Imodium® (loperamide) and Gas-X® (simethicone). Prescription Lomotil® (diphenoxylate/atropine) may be used to treat diarrhea. — Other prescription medications indicated to treat IBS-D include Lotronex® (alosetron) and Xifaxan® (rifaximin). — Refer to individual drug labels for specific indication information. • Patients should stop taking Viberzi right away and seek immediate emergency care if they experience symptoms of pancreatitis or spasm of the sphincter of Oddi, such as new or worsening abdominal pain, or pain in the upper right side of the abdomen that radiates to the back or shoulder.
    [Show full text]
  • Current Pharmacologic Treatments of Irritable Bowel Syndrome
    IFFGD International Foundation for PO Box 170864 Milwaukee, WI 53217 Functional Gastrointestinal Disorders www.iffgd.org Medications (168) © Copyright 2002-2015 by the International Foundation for Functional Gastrointestinal Disorders Updated by IFFGD, 2015 Current Pharmacologic Treatments of Irritable Bowel Syndrome By: Tony Lembo, M.D., Associate Professor, Beth Israel Deaconess Medical Center, Harvard Medical School, MA, and Rebecca Rink, M.S. [This article reviews indications, methods of action, and side small intestine and colon, thereby increasing stool bulk. effects associated with commonly available agents used to When the recommended dosage is used, it takes treat IBS. Any product taken for a therapeutic effect should approximately 1 to 2 days for osmotic laxatives to take be considered as a drug. Use medications, whether effect. The most common poorly absorbed ions used in prescription or over-the-counter, herbs, or supplements laxatives are magnesium and phosphate. carefully and in consultation with your doctor or healthcare When these laxatives enter the intestine, only a small provider.] percentage of magnesium or phosphate is actively absorbed. The remaining magnesium or phosphate in the intestine Pharmacologic treatments for IBS are aimed at improving the creates an osmotic gradient along which water enters the predominant symptoms such as diarrhea, constipation, and intestine. Phosphate is better absorbed in the intestine than abdominal pain. The most common classes of drugs currently magnesium, so it takes a substantial dose of phosphate used are laxatives, antidiarrheals, antispasmodics, and laxative to induce the osmotic effect. antidepressants. Laxatives Nonabsorbable carbohydrate laxatives (sorbitol and A laxative is a medication that increases bowel function. lactulose) are partially broken down by bacteria into There are four main classes of laxatives: fiber, osmotic compounds that cause water to accumulate in the colon, laxatives, stimulant laxatives, and emollients.
    [Show full text]
  • Replacement of Current Opioid Drugs Focusing on MOR-Related Strategies
    JPT-107519; No of Pages 17 Pharmacology & Therapeutics xxx (2020) xxx Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Replacement of current opioid drugs focusing on MOR-related strategies Jérôme Busserolles a,b, Stéphane Lolignier a,b, Nicolas Kerckhove a,b,c, Célian Bertin a,b,c, Nicolas Authier a,b,c, Alain Eschalier a,b,⁎ a Université Clermont Auvergne, INSERM, CHU, NEURO-DOL Pharmacologie Fondamentale et Clinique de la douleur, F-63000 Clermont-Ferrand, France b Institut ANALGESIA, Faculté de Médecine, F-63000 Clermont-Ferrand, France c Observatoire Français des Médicaments Antalgiques (OFMA), French monitoring centre for analgesic drugs, CHU, F-63000 Clermont-Ferrand, France article info abstract Available online xxxx The scarcity and limited risk/benefit ratio of painkillers available on the market, in addition to the opioid crisis, warrant reflection on new innovation strategies. The pharmacopoeia of analgesics is based on products that are often old and derived from clinical empiricism, with limited efficacy or spectrum of action, or resulting in Keywords: an unsatisfactory tolerability profile. Although they are reference analgesics for nociceptive pain, opioids are sub- Analgesia ject to the same criticism. The use of opium as an analgesic is historical. Morphine was synthesized at the begin- Mu opioid receptors (MORs) ning of the 19th century. The efficacy of opioids is limited in certain painful contexts and these drugs can induce Opioid adverse side effects potentially serious and fatal adverse effects. The current North American opioid crisis, with an ever-rising number Opioid abuse and misuse of deaths by opioid overdose, is a tragic illustration of this.
    [Show full text]
  • Tapi-Party-Content-1566784086.Pdf
    Product Name Tapi Tech DMF Status IP File** US EU JP KR Abaloparatide Abemaciclib Abiraterone Acetate Acyclovir Adapalene Afatinib * Alclometasone dipropionate Alendronate sodium * Allopurinol Amcinonide Amitriptyline HCl Amlodipine besylate * Anastrozole Anidulafungin Apixaban Apremilast * Aripiprazole Atenolol Atomoxetine HCl Atorvastatin calcium * Atosiban Acetate Atracurium besylate CEP Azacitidine Azithromycin dihydrate Aztreonam Beclomethasone dipropionate * Betamethasone acetate Betamethasone base Betamethasone dipropionate Betamethasone valerate * TAPI can provide several different polymorphs or processes of this product. To obtain complete DMF files of a specific product's polymorph or process, please contact your account manager. Additional DMFs or Tech Files are available upon request ** Tech File relevant only for products prior to 1st DMF All subject to the disclaimer on the last page Product Name Tapi Tech DMF Status IP File** US EU JP KR Bicalutamide Bimatoprost Bivalirudin Bleomycin sulfate Bortezomib Brexpiprazole Bromocriptine mesylate Budesonide * Buprenorphine base Buprenorphine HCl Butorphanol tartrate Cabazitaxel Cabergoline Calcipotriene * Calcitriol Candesartan Cilexetil CEP Capecitabine Carbidopa Carboplatin Carfilzomib Carvedilol base Carvedilol phosphate Caspofungin acetate Chlormadinone acetate Ciclosporin Cilostazol Cinacalcet HCl Cisatracurium besylate Cisplatin Clarithromycin * TAPI can provide several different polymorphs or processes of this product. To obtain complete DMF files of a specific product's
    [Show full text]
  • Overview of Irritable Bowel Syndrome (IBS)
    www.idosr.org Bethany ©IDOSR PUBLICATIONS International Digital Organization for Scientific Research ISSN: 2579-0730 IDOSR JOURNAL OF BIOLOGY, CHEMISTRY AND PHARMACY 4(1)15-22, 2020. Overview of Irritable Bowel Syndrome (IBS) Bethany Hoey School of Nursing, Queensland University of Technology (QUT), Australia. ABSTRACT This article is the overview of irritable bowel syndrome (IBS). Irritable bowel syndrome (IBS) is a group of symptoms including abdominal pain and changes in the pattern of bowel movements without any evidence of underlying damage. These symptoms occur over a long time, often years. Irritable bowel syndrome (IBS) affects between 6–18% of people worldwide. This condition involves changes in frequency or form of bowel movements and lower abdominal pain Diet, stress, poor sleep and changes in gut bacteria may all trigger symptoms. The precise cause of IBS isn't known. Finding ways to deal with stress may help prevent or ease symptoms of IBS. There's no test to definitively diagnose IBS. Your doctor is likely to start with a complete medical history, physical exam and tests to rule out other conditions. IBS is a chronic functional disorder of the gastrointestinal tract with symptoms of abdominal pain and altered bowel habits that include diarrhea, constipation, or both. Patients who suffer from IBS often have an impaired quality of life. IBS affects 10% to 20% of the general population, but these percentages are likely underestimated, since only a small portion of patients with IBS symptoms seek medical attention. Keywords: Overview, irritable, bowel, syndrome and IBS. INTRODUCTION Irritable bowel syndrome (IBS) is a group in the absence of worrisome features and of symptoms including abdominal pain once other potential conditions have been and changes in the pattern of bowel ruled out.
    [Show full text]
  • Pharmacologic, Pharmacokinetic, and Pharmacogenomic Aspects Of
    Gastroenterology 2016;150:1319–1331 Pharmacologic, Pharmacokinetic, and Pharmacogenomic Aspects of Functional Gastrointestinal Disorders Michael Camilleri,1 Lionel Buéno,2,† Viola Andresen,3 Fabrizio De Ponti,4 Myung-Gyu Choi,5 and Anthony Lembo6 1Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota; 2INRA, Toulouse, France; 3Israelitic Hospital, University of Hamburg, Hamburg, Germany; 4Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 5Department of Gastroenterology, The Catholic University of Korea College of Medicine Internal Medicine, Seoul, Korea; and 6GI Motility Laboratory, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts This article reviews medications commonly used for the with a balloon connected to a barostat to measure simul- treatment of patients with functional gastrointestinal disor- taneously compliance and the response to gastrointestinal ders. Specifically, we review the animal models that have been distention. Balloons can be acutely or chronically implanted validated for the study of drug effects on sensation and in the gut.1 A number of factors influence reproducibility of motility; the preclinical pharmacology, pharmacokinetics, balloon distention studies across laboratories: balloon con- and toxicology usually required for introduction of new struction and unfolding, distention protocols, and frequency drugs; the biomarkers that are validated for studies of of balloon distentions in the same animal (which can lead to sensation and motility end points with experimental medica- sensitization), and species (eg, rats vs mice) or strain dif- tions in humans; the pharmacogenomics applied to these ferences within species. PHARMACOLOGY medications and their relevance to the FGIDs; and the phar- Chemical Stimuli. In rats, infusion of glycerol into the macology of agents that are applied or have potential for the colon through an implanted catheter induces abdominal treatment of FGIDs, including psychopharmacologic drugs.
    [Show full text]