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Review Article New Pharmacological Therapies for Treatment of Gastroesophageal Reflux Disease
Journal of Pharmaceutical Research & Clinical Practice, Oct-Dec 2013; 3(4):11-21 Review Article New Pharmacological Therapies for Treatment of Gastroesophageal Reflux Disease *Rahul Saini1, Shanmukhananda M. P.2, Sunaina3 1. Department of Pharmacology, PGIMS, Rohtak, India. 2. Novartis, Hyderabad, India. 3. Department of Radiology, PGIMS, Rohtak, India. ABSTRACT Gastroesophageal reflux disease (GERD) is a chronic, relapsing disorder characterized by recurrent symptoms of acid reflux with esophageal injury. It rarely resolves spontaneously, and it is associated with frequent recurrences. It has adverse impact on quality of life. A variety of medications have been used in GERD treatment, and acid suppression therapy is the mainstay of treatment for GERD. Although proton pump inhibitor is the most potent acid suppressant and provides good efficacy in esophagitis healing and symptom relief, about one-third of patients with GERD still have persistent symptoms with poor response to standard dose proton pump inhibitors (PPI). These are generally well tolerated but there are associated with minor side effects such as headache, diarrhea, and abdominal pain. Newer formulations of PPI which have faster and longer duration of action and potassium-competitive acid blocker, a newer acid suppressant, are also in developing stages. Transient lower oesophageal sphincter relaxation (TLESR) is an important factor behind the occurrence of reflux, and preclinical studies have identified gamma aminobutyric acid (GABA) type B receptor (GABAB) agonists and metabotropic glutamate receptor 5 (mG1uR5) modulators as candidate drugs for modifying TLESR. Another novel therapeutic agent has focused on the underlying mechanisms of GERD, such as motility disorder, mucosal protection, and esophageal hypersensitivity are also under clinical trials. -
Proton Pump Inhibitors Act with Unprecedented Potencies
DOI: 10.1002/alz.12113 RESEARCH ARTICLE Proton pump inhibitors act with unprecedented potencies as inhibitors of the acetylcholine biosynthesizing enzyme—A plausible missing link for their association with incidence of dementia Rajnish Kumar1 Amit Kumar1 Agneta Nordberg1 Bengt Långström2 Taher Darreh-Shori1 1Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Abstract Neurobiology, Care Sciences and Society, Introduction: Several pharmacoepidemiological studies indicate that proton pump Karolinska Institutet, Stockholm, Sweden inhibitors (PPIs) significantly increase the risk of dementia. Yet, the underlying mecha- 2Department of Chemistry, Uppsala University, Uppsala, Sweden nism is not known. Here, we report the discovery of an unprecedented mode of action of PPIs that explains how PPIs may increase the risk of dementia. Correspondence TaherDarreh-Shori, Division of Clinical Geri- Methods: Advanced in silico docking analyses and detailed enzymological assess- atrics, Center for Alzheimer Research, Depart- ments were performed on PPIs against the core-cholinergic enzyme, choline- ment of Neurobiology, Care Sciences and Society, Karolinska Institutet, NEO, 7th Floor, 141 52 acetyltransferase (ChAT), responsible for biosynthesis of acetylcholine (ACh). Stockholm, Sweden. Results: This report shows compelling evidence that PPIs act as inhibitors of ChAT, with Email: [email protected] high selectivity and unprecedented potencies that lie far below their in vivo plasma and Funding information brain concentrations. the international Alzheimer Association, USA, Grant/Award Number: 2016-NIRG-391599; Discussion: Given that accumulating evidence points at cholinergic dysfunction as a Swedish Research Council, Grant/Award Num- driving force of major dementia disorders, our findings mechanistically explain how ber: project no 2016-01806 prolonged use of PPIs may increase incidence of dementia. -
4 Supplementary File
Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation. -
A Systematic Review of Proton Pump Inhibitors for the Treatment of Adult Patients with Symptomatic Gastroesophageal Reflux Disease Or Peptic Ulcer Disease
Title A systematic review of proton pump inhibitors for the treatment of adult patients with symptomatic gastroesophageal reflux disease or peptic ulcer disease. Review Question(s) Requested Requested by PSD 1. What is the comparative effectiveness of different proton pump inhibitors in patients with symptoms of gastroesophageal reflux disease? 2. What is the comparative effectiveness of different proton pump inhibitors in treating peptic (duodenal and gastric) ulcer? 3. What are the comparative safety and adverse events of different proton pump inhibitors in patients being treated for symptoms of gastroesophageal reflux disease and peptic ulcer? 4. Are there subgroups of patients based on demographics, other medications, or comorbidities (including nasogastric tubes and inability to swallow solid oral medication) for which a particular proton pump inhibitor or preparation is more effective or associated with fewer adverse effects? Drug The following five proton pump inhibitors (PPI) drugs will be reviewed 1. Esomeprazole (Nexium® and its generic equivalent) 2. Lansoprazole (Prevacid® and its generic equivalent) 3. Omeprazole* (Losec® and its generic equivalent) 4. Pantoprazole* sodium and magnesium (Pantoloc®, Panto IV and their generic equivalent and Tecta® 5. Rabeprazole* (Pariet® and its generic equivalent) Note: *Omeprazole, Pantoprazole and Rabeprazole have been identified as reference drugs by PSD. Esomeprazole and Lansoprazole will be compared to these three reference drugs. TABLE OF CONTENTS TABLE OF CONTENTS ..........................................................................................................................2 -
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 . -
(12) Patent Application Publication (10) Pub. No.: US 2012/0122919 A1 Schutze Et Al
US 2012O122919A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0122919 A1 Schutze et al. (43) Pub. Date: May 17, 2012 (54) PHARMACEUTICAL COMPOSITION (30) Foreign Application Priority Data COMBINING TENATOPRAZOLE AND A HISTAMINE H2-RECEPTOR ANTAGONST Oct. 21, 2002 (FR) ...................................... 02/13114 (75) Inventors: Francois Schutze, Saint-Nom-La-Breteche (FR); Suzy Publication Classification Charbit, Creteil (FR); Hervé (51) Int. Cl. Ficheux, Nogent-sur-Marne (FR): A63L/437 (2006.01) Michel Homerin, Courcouronnes A6IPL/04 (2006.01) (FR); Alain Taccoen, Le Chesnay (FR); Nathalie Taccoen, legal representative, La Chesnay (FR); (52) U.S. Cl. ........................................................ S14/303 Yoshio Inaba, Tokyo (JP) (73) Assignees: MTSUBISH PHARMA CORPORATION, Tokyo (JP); (57) ABSTRACT SIDEM PHARMA, Luxembourg (LU) The invention relates to a novel pharmaceutical combination. The inventive pharmaceutical composition, which is intended (21) Appl. No.: 13/297,122 for the treatment of pathologies linked to gastric hyperacidity, (22) Filed: Nov. 15, 2011 comprises a combination of tenatoprazole and one or more O O histamine H2-receptor antagonists preferably selected from Related U.S. Application Data cimetidine, ranitidine, famotidine and nizatidine. The inven (63) Continuation of application No. 10/532,114, filed on tion is particularly suitable for the treatment of duodenal and Jun. 23, 2006, now abandoned, filed as application No. gastric ulcers and the symptoms of, and lesions caused by, PCT/FR2003/003124 on Oct. 21, 2003. gastroesophageal reflux. US 2012/O 122919 A1 May 17, 2012 PHARMACEUTICAL COMPOSITION nist Such as famotidine, with at least two standard antacids COMBINING TENATOPRAZOLE ANDA Such as Sodium bicarbonate and magnesium hydroxide, HISTAMINE H2-RECEPTOR ANTAGONST which display a strong neutralisation potential, and an alu minium hydroxide gel which exhibits weak neutralisation RELATED APPLICATIONS potential. -
Comparative Efficacy of Various Anti-Ulcer Medications After Gastric Endoscopic Submucosal Dissection: a Systematic Review and Network Meta-Analysis
Surgical Endoscopy (2019) 33:1271–1283 and Other Interventional Techniques https://doi.org/10.1007/s00464-018-6409-4 Comparative efficacy of various anti-ulcer medications after gastric endoscopic submucosal dissection: a systematic review and network meta-analysis Eun Hye Kim1 · Se Woo Park2 · Eunwoo Nam3 · Jae Gon Lee4 · Chan Hyuk Park4 Received: 4 May 2018 / Accepted: 24 August 2018 / Published online: 30 August 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Background The comparative efficacy of various anti-ulcer medications after gastric endoscopic submucosal dissection (ESD) has not been fully evaluated. Recently, vonoprazan, a novel potassium-competitive acid blocker, has also been used in ulcer treatment after ESD. Methods We searched for all relevant randomized controlled trials examining the efficacy of anti-ulcer medications after gastric ESD, published through October 2017. Healing of iatrogenic ulcers was investigated at 4–8 weeks after ESD. A network meta-analysis was performed to calculate the network estimates. Results Twenty-one studies with 2005 patients were included. Concerning the comparative efficacy for ulcer healing at 4 weeks after ESD, no network inconsistency was identified (Cochran’s Q-test, df = 10, P = 0.13; I2 = 34%). A combination therapy of proton-pump inhibitor (PPI) and muco-protective agent was superior to PPI alone [risk ratio (RR) (95% confi- dence interval, CI) 1.69 (1.20–2.39)]. The combination therapy of PPI and muco-protective agents tended to be superior to vonoprazan [RR (95% CI) 1.98 (0.99–3.94)]. There was no difference of ulcer healing effect between PPI and vonoprazan [RR (95% CI) PPI vs. -
Bismuth Salts for Gastrointestinal Issues: a Review of the Clinical Effectiveness and Guidelines DATE
TITLE: Bismuth Salts for Gastrointestinal Issues: A Review of the Clinical Effectiveness and Guidelines DATE: 24 November 2015 CONTEXT AND POLICY ISSUES Oral bismuth formulations have been used effectively for prophylaxis and treatment of both diarrhea and for treatment of Helicobacter pylori (H. pylori) infection.1,2 Bismuth formulations available without a prescription have been commonly used to treat episodic diarrhea for over a century. Bismuth has also been used to treat ulcers prior to the appreciation of its antimicrobial activity against the then unknown causative micro-organism, H. pylori.1 Episodes of diarrhea are especially common in travelers to resource-poor countries. It is estimated that 30% to 70% of international travelers will develop diarrhea during travels or upon return. Typically diarrhea is self-diagnosed and the causal infectious agent remains unknown. While the condition is frequently self-limiting, treatment can reduce the duration, severity, and inconvenience of diarrhea while travelling. Commonly used treatments include antibiotics, antimotility agents, oral rehydration solutions, and bismuth subsalicylate.2 H. pylori infection is a substantial public health concern as it plays a causative role in the pathogenesis of many gastrointestinal conditions such as gastritis, peptic ulcers, and gastric cancer.3 Current treatment regimens designed to eradicate infection utilize more than one antibiotic simultaneously in a standard triple therapy (STT) consisting of a proton-pump inhibitor (PPI), and two antibiotics. -
Proton Pump Inhibitors in Veterinary Medicine
American Journal of Animal and Veterinary Sciences Review Proton Pump Inhibitors in Veterinary Medicine 1Oguzhan Yavuz and 2Handan Hilal Arslan 1Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey 2Department of Internal Medicine, Faculty of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey Article history Abstract: Inhibition of gastric acid secretion is necessary to treat many Received: 01-04-2017 gastrointestinal diseases. Proton Pump Inhibitors (PPIs) are very effective Revised: 02-06-2017 drugs, used for gastric acid inhibition and therapy of important erosive and Accepted: 23-06-2017 non-erosive gastrointestinal disorders in animals as well as humans. In this review, general properties of PPIs, their mode of action, pharmacokinetics, Corresponding Author: OguzhanYavuz efficacy, adverse effects, drug interactions and clinical and alternative uses Department of Pharmacology in veterinary medicine were evaluated. and Toxicology, Faculty of Veterinary Medicine, Keywords: Gastrointestinal Disorders, Proton Pump Inhibitors, Veterinary OndokuzMayis University, Medicine Samsun, Turkey Tel: 00903623121919/2830 Fax: 00903624576922 E-mail: [email protected] Introduction All clinically used PPIs contain a pyridyl methylsulfinyl benzimidazole group and differ only type Gastric acid is the secretion of parietal cells of of substituents on the pyridine and benzimidazole rings stomach and it is controlled by paracrine, endocrine and + + (Kosma et al ., 2016). Some important physicochemical neuronal systems. An important enzyme, H /K ATPase, properties of PPIs are shown in Table 1. is the main actor to pump hydrogen ions into the + + stomach lumen (H /K proton pump) (Shin and Sachs, Mode of Action 2008; Hori et al ., 2011; Garcia-Mazcorro et al ., 2012). -
Refractory Gastroesophageal Reflux Disease: Pathophysiology, Diagnosis, and Management
Refractory Gastroesophageal Reflux Disease: Pathophysiology, Diagnosis, and Management My Editor’s Pick for this edition is Nabi et al.’s review on the topic of refractory gastroesophageal reflux disease in the context of its pathophysiology, diagnosis, and treatment. The authors explore these elements in great detail, offering a timely and helpful update on this common gastrointestinal complaint. Authors: *Zaheer Nabi, Arun Karyampudi, and D. Nageshwar Reddy Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India *Correspondence to [email protected] Disclosure: The authors have declared no conflicts of interest. Received: 10.05.19 Accepted: 02.07.19 Keywords: Antireflux surgery, endoscopy, gastroesophageal reflux, proton pump inhibitors (PPI). Citation: EMJ Gastroenterol. 2019;8[1]:62-71. Abstract Gastroesophageal reflux disease (GERD) is one of the most commonly encountered gastrointestinal diseases in clinical practice. Proton pump inhibitors (PPI) remain the cornerstone of the treatment of GERD. Up to one-third of patients do not respond to optimal doses of PPI and fall into the category of refractory GERD. Moreover, the long-term use of PPI is not risk-free, as previously thought. The pathophysiology of refractory GERD is multifactorial and includes reflux related and unrelated factors. It is therefore paramount to address refractory GERD as per the aetiology of the disease for optimal outcomes. The management options for PPI refractory GERD include optimisation of PPI, lifestyle modifications, and the addition of alginates and histamine-2 receptor blockers. Neuromodulators, such as selective serotonin reuptake inhibitors or tricyclic antidepressants, may be beneficial in those with functional heartburn and reflux hypersensitivity. Laparoscopic antireflux surgeries, including Nissen’s fundoplication and magnetic sphincter augmentation, are useful in patients with objective evidence of GERD on pH impedance studies with or without a hiatal hernia. -
Superior Control of Nocturnal Gastric-Acid Secretion by the Novel
RESEARCH HIGHLIGHTS www.nature.com/clinicalpractice/gasthep GLOSSARY Superior control of nocturnal Gastrointestinal Endoscopy has pub- ENDOSCOPIC gastric-acid secretion by the lished guidelines on the use of endoscopic RETROGRADE ultrasonography (EUS) and ENDOSCOPIC CHOLANGIO- novel proton-pump inhibitor, PANCREATOGRAPHY tenatoprazole RETROGRADE CHOLANGIOPANCREATOGRAPHY (ERCP) (ERCP) in the diagnosis and treatment of pancreatic Endoscopic technique of injecting contrast dye into Proton-pump inhibitors (PPIs) effectively prevent cystic lesions and fluid collections. Cystic pan- the ampulla of Vater for gastric-acid secretion and are used to control the creatic lesions encompass a number of benign radiologic visualization of the pancreatic and biliary symptoms of various acid-related gastrointestinal and malignant masses. Pancreatic fluid collec- ducts diseases. These compounds have a short plasma tions (PFCs) develop secondary to pancreati- half-life, however, which limits the efficacy of a tis and pancreatic trauma and typically resolve single dose. The novel PPI tenatoprazole, an without intervention. imidazopyridine derivative, benefits from an The guidelines state that although EUS is not extended plasma half-life and could negate the a reliable basis for treatment decision making, requirement for repeated dosing. Galmiche et al. it can help to differentiate between types of have recently compared the effects of tenatopra- pancreatic cystic lesions and to guide fine- zole with esomeprazole, a benzimidazole-derived needle aspiration of lesions. Levels of enzymes PPI, on intragastric pH in healthy subjects. and tumor markers in pancreatic cysts are not The randomized, two-period crossover study specific enough to identify malignancy or to recruited 24 healthy, male volunteers from a distinguish a particular type of lesion; however, French academic institution. -
New and Future Drug Development for Gastroesophageal Reflux Disease
J Neurogastroenterol Motil, Vol. 20 No. 1 January, 2014 pISSN: 2093-0879 eISSN: 2093-0887 http://dx.doi.org/10.5056/jnm.2014.20.1.6 JNM Journal of Neurogastroenterology and Motility Review New and Future Drug Development for Gastroesophageal Reflux Disease Carla Maradey-Romero and Ronnie Fass* The Esophageal and Swallowing Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA Medical therapy remains the most popular treatment for gastroesophageal reflux disease (GERD). Whilst interest in drug devel- opment for GERD has declined over the last few years primarily due to the conversion of most proton pump inhibitor (PPI)’s to generic and over the counter compounds, there are still numerous areas of unmet needs in GERD. Drug development has been focused on potent histamine type 2 receptor antagonist’s, extended release PPI’s, PPI combination, potassium-competitive acid blockers, transient lower esophageal sphincter relaxation reducers, prokinetics, mucosal protectants and esophageal pain modulators. It is likely that the aforementioned compounds will be niched for specific areas of unmet need in GERD, rather than compete with the presently available anti-reflux therapies. (J Neurogastroenterol Motil 2014;20:6-16) Key Words Erosive esophagitis; Gastroesophageal reflux; Heartburn; Proton pump inhibitors Most patients with GERD fall into 1 of 3 categories: non- erosive reflux disease (NERD), erosive esophagitis (EE), and Introduction Barrett’s esophagus (BE). The 2 main phenotypes of GERD, Gastroesophageal reflux disease (GERD) is a common con- NERD and EE, appear to have different pathophysiological and dition that develops when reflux of stomach contents cause trou- clinical characteristics.