DOCSLIB.ORG

UCLA Previously Published Works

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
UCLA Previously Published Works UCLA UCLA Previously Published Works Title Novel Approaches to Inhibition of Gastric Acid Secretion Permalink https://escholarship.org/uc/item/6319s54m Journal Current Gastroenterology Reports, 12(6) ISSN 1534-312X Authors Sachs, George Shin, Jai Moo Hunt, Richard Publication Date 2010-12-01 DOI 10.1007/s11894-010-0149-5 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Curr Gastroenterol Rep (2010) 12:437–447 DOI 10.1007/s11894-010-0149-5 Novel Approaches to Inhibition of Gastric Acid Secretion George Sachs & Jai Moo Shin & Richard Hunt Published online: 6 October 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract The gastric H,K-adenosine triphosphatase and the requirement for acid activation impair their efficacy (ATPase) is the primary target for treatment of acid- in acid suppression, particularly at night. All PPIs give related diseases. Proton pump inhibitors (PPIs) are weak excellent healing of peptic ulcer and produce good, but less bases composed of two moieties, a substituted pyridine than satisfactory, results in reflux esophagitis. PPIs combined with a primary pKa of about 4.0 that allows selective with antibiotics eradicate Helicobacter pylori, but success has accumulation in the secretory canaliculus of the parietal fallen to less than 80%. Longer dwell-time PPIs promise to cell, and a benzimidazole with a second pKa of about 1.0. improve acid suppression and hence clinical outcome. Protonation of this benzimidazole activates these prodrugs, Potassium-competitive acid blockers (P-CABs) are another converting them to sulfenic acids and/or sulfenamides that class of ATPase inhibitors, and at least one is in develop- react covalently with one or more cysteines accessible from ment. The P-CAB under development has a long duration of the luminal surface of the ATPase. The maximal pharma- action even though its binding is not covalent. PPIs with a codynamic effect of PPIs as a group relies on cyclic longer dwell time or P-CABs with long duration promise to adenosine monophosphate–driven H,K-ATPase transloca- address unmet clinical needs arising from an inability to tion from the cytoplasm to the canalicular membrane of the inhibit nighttime acid secretion, with continued symptoms, parietal cell. At present, this effect can only be achieved delayed healing, and growth suppression of H. pylori with protein meal stimulation. Because of covalent binding, reducing susceptibility to clarithromycin and amoxicillin. inhibitory effects last much longer than their plasma half- Thus, novel and more effective suppression of acid secretion life. However, the short dwell-time of the drug in the blood would benefit those who suffer from acid-related morbidity, continuing esophageal damage and pain, nonsteroidal anti- inflammatory drug–induced ulcers, and nonresponders to H. pylori eradication. G. Sachs (*) : J. M. Shin Department of Physiology and Medicine, David Geffen School Keywords Proton pump inhibitor . Gastric H,K-ATPase . of Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Ulcer . Gastroesophageal reflux disease Room 324, Building 113, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA e-mail: [email protected] Introduction J. M. Shin e-mail: [email protected] The two major types of acid-related disorders are peptic R. Hunt ulcer disease (PUD) and gastroesophageal reflux disease Farncombe Family Digestive Disease Research Institute, (GERD), although other extra-esophageal disorders are Division of Gastroenterology, McMaster University Health ascribed to gastric acid reflux (eg, reflux laryngitis). The Sciences Centre, target for treatment was and still is reduction of gastric 1200 Main Street West, Room 4W8A, Hamilton, ON L8N 3Z5, Canada acidity. However, despite clinical and commercial success, e-mail: [email protected] histamine-2 receptor antagonists (H2-RAs) have several 438 Curr Gastroenterol Rep (2010) 12:437–447 pharmacologic limitations that are increasingly apparent in Ranitidine, 300 mg, at 8 PM the clinical setting. The H -RAs are less effective for the Median intragastric pH profiles 2 7 management of GERD and gastrointestinal (GI) bleeding Control Day 1 6 than for healing of PUD, and the rapid development of Day 7 tachyphylaxis limits their usefulness for long-term maintenance Day 28 5 treatment or high-dose intravenous use. The H2-RAs have been largely supplanted by the proton pump inhibitors (PPIs) because 4 of greater efficacy and lack of pharmacologic tolerance. The pH 3 PPIs were found to be very effective for the management of patients with erosive esophagitis, and a meta-analysis in 1997 2 confirmed their superiority to H2-RAs for the treatment of 1 GERD, particularly erosive esophagitis [1]. ← ← ← Dinner Breakfast Lunch PPIs have also found a place in treatment of a wide 0 range of acid-related disorders, including nonerosive reflux 8 PM Midnight 4 AM 8 AM 12 Noon 4 PM disease (NERD) and PUD, especially as treatment or Time of day prophylaxis of GI injury caused by nonsteroidal anti- inflammatory drugs (NSAID). PPIs have became established Fig. 1 The effect of nighttime administration of ranitidine, 300 mg, as combination antisecretory treatment, together with antibiotic on intragastric pH therapy, for the eradication of Helicobacter pylori infection. Furthermore, PPIs have become the standard of care in improved GERD symptoms, because the tolerization to patients with nonvariceal upper GI bleeding or for the ranitidine shown in Figure 1 is shared by all H2-RAs. prevention of stress-related mucosalbleedinginintensive The discovery that PUD was largely the result of care units. infection with H. pylori revolutionized the treatment of PUD, namely eradication of the infection either with triple or quadruple therapy. Hence, H2-RAs are used to treat H2-Histamine Receptor Antagonists and PPIs symptomatic GERD, but are not used alone for PUD. NSAID-induced PUD requires better acid inhibition for The launch in 1979 of cimetidine (Tagamet; GlaxoSmithKline, treatment, and hence H2-RAs are not indicated with Philadelphia, PA) revolutionized medical treatment of PUD and concomitant NSAID use. GERD, for the first time providing relatively long-lasting The synthesis of a novel secretory inhibitor, omeprazole reduction of gastric acid secretion with healing of both gastric (Prilosec; AstraZeneca, Wilmington, DE), in 1978 and its and duodenal ulcers and some remission of the symptoms of launch in 1989 in the United States further revolutionized GERD. Cimetidine was followed by ranitidine (Zantac; treatment of acid-related diseases. Omeprazole was the first Boehringer Ingelheim, Ingelheim, Germany), famotidine drug of the PPI class. Four more such PPIs are now on the (Pepcid; Johnson & Johnson, New Brunswick, NJ), and market: lansoprazole (Prevacid; Takeda Pharmaceuticals, nizatidine (Axid; Eli Lilly Indianapolis, IN)—all of which Osaka, Japan), pantoprazole (Protonix; Wyeth-Ayerst have an identical mechanism of action, namely reversible Laboratories, Madison, NJ), rabeprazole (Aciphex; Eisai, inhibition of the histamine (H2) receptor on the acid-secreting Tokyo, Japan), and esomeprazole (Nexium; AstraZeneca, parietal cell of the stomach. These drugs have very similar Wilmington, DE). Their mechanism of action is unique mechanisms of action. Famotidine is the most potent and their target is the active gastric proton pump, the H, commonly prescribed H2-RA, with about a 20-fold increase K-ATPase. They are weak-base prodrugs and accumulate in potency. H2-RAs result in short-lived inhibition of acid in the unique, highly acidic canalicular space of the secretion; the onset of inhibition occurs after about 4 h and active parietal cell, where the pH is less than 2.0. At this maximal inhibition after about 8 h, with return of acid pH, they are converted to the active form of the drug, secretion after about 12 h, therefore requiring at least twice- which then covalently binds to one or more cysteines daily administration. Moreover, all these drugs exhibit that are accessed from the luminal surface of the pump. tolerance such that they lose about 50% of their efficacy over Thus the inhibition is long-lasting and no tolerance has a 7-day period (Fig. 1). been observed with this class of drug. However, they Figure 1 shows the effect of ranitidine given at night to require the presence of acid secretion for accumulation reduce nighttime GERD symptoms on days 1, 7, and 28; and activation, hence their action is meal-dependent. intragastric pH is raised to greater than 5.0 by nighttime of Moreover, they have a relatively short plasma half-life of day 1, but reaches a level between 2.0 and 3.0 by day 28 about 2 h. Given this mechanism of action, the effect on [2]. Hence, this class of drug offers little likelihood of acid secretion is cumulative, increasing to steady state Curr Gastroenterol Rep (2010) 12:437–447 439 after 3 to 5 days of administration, because pumps that Level and duration of intragastric pH elevation are nonsecreting will not be inhibited whereas inhibited achieved for optimal treatment of: pumps will stay inhibited. A typical intragastric pH 24 profile is shown for pantoprazole in Fig. 2. Untreated BID H2 antagonist OD acid pump inhibitor The ability to progressively increase intragastric pH with Duodenal ulcer Reflux disease H2-RAs and PPIs resulted in a comprehensive meta- analysis of the relationship between intragastric pH, healing h/d 16 P of duodenal and gastric ulcers, and treatment of GERD P immediately after the launch of omeprazole. This analysis R predicted that a pH greater than 4.0 for 16 h per day was 8 optimum for healing of GERD and a pH greater than 3.0 pH > 3, 4, or 5, R was optimum for healing of duodenal ulcers (Fig. 3). C C The gastric H,K-ATPase has a half-life of 50 h, hence 0 about 25% of pumps are synthesized per day, at a rate of pH > 3 pH > 4 about 1% per hour [3].
Load more

Recommended publications
  • Zolpidem Tartrate) Orally Disintegrating Tablets CIV
    NDA 21-412 FDA Approved Labeling Text dated April 25, 2007 Page 1 TOVALT™ ODT (zolpidem tartrate) Orally Disintegrating Tablets CIV Rx Only LB Rev. 04/07 DESCRIPTION TOVALT™ ODT (zolpidem tartrate) Orally Disintegrating Tablets is a non- benzodiazepine hypnotic of the imidazopyridine class and is available in 5 mg and 10 mg tablet strengths for oral administration. Chemically, zolpidem is N,N,6-trimethyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-acetamide L-( + )-tartrate (2:1). It has the following structure: Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88. Each TOVALT ODT includes the following inactive ingredients: Acesulfame Potassium, Glyceryl Monostearate, Hypromellose, Stearoyl Macrogolglycerides Polyacrylate Dispersion (30%), Talc, Mannitol, Microcrystalline Cellulose, Low Substituted Hydroxypropyl Cellulose, Crospovidone, Sodium Stearyl Fumarate, Silicon Dioxide, Monoammonium Glycyrrhizinate, Natural Intense Peppermint Flavour, FD&C Blue #2 (for 10mg only). CLINICAL PHARMACOLOGY Pharmacodynamics Subunit modulation of the GABAA receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant NDA 21-412 FDA Approved Labeling Text dated April 25, 2007 Page 2 drug properties. The major modulatory site of the GABAA receptor complex is located on its alpha (α) subunit and is referred to as the benzodiazepine (BZ) or omega (ω) receptor. At least three subtypes of the (ω) receptor have been identified. While zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Original Research Article
    Original Research Article IN SILICO LIGAND-BASED 2D PHARMACOPHORE GENERATION FOR H+/K+ ATPASE INHIBITORS ABSTRACT Objectives: At the beginning of the 20th century, Peptic Ulcer became the most prevalent disease as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) proved ineffective. Researches proved proton pump inhibitors as most successful drugs for the treatment of peptic ulcer. Hence, a ligand based pharmacophore was generated on LigandScout based on fifteen selected H+/K+ ATPase inhibitors. Methods: A pharmacophore model with three Hydrogen bond acceptors, one Hydrogen bond donor and one Hydrophobic Domain was developed. The distance between these features was estimated on Visual Molecular Dynamics (VMD) software. Results: The range between HBA-HBD was found to be 1.89-2.96A. The range between HBD-HP was 4.00-5.46A and range between HP-HBA was 1.89-2.96A. Conclusion: This research study will thus help in designing new and effective drugs for the treatment of peptic ulcer disease. Key words: Peptic Ulcer, NSAIDs, ligand, pharmacophore, Visual Molecular Dynamics INTRODUCTION Gastric H+/K+ ATPase pump is located in the parietal cells [1] and plays a crucial role in the formation of ulcers in the stomach. H pylori transmission occurs in 50% of the people worldwide [2]. A peptic ulcer is caused by Helicobacter pylori (H. pylori) infection in the gastric mucosal lining. This bacterium causes inflammation in the lining of the stomach. In response to this, gastrin hormone stimulates the gastric acid production. High levels of gastrin cause the enhance release of acid through H+/K+ ATPase pump and lead to the formation of the ulcer.
    [Show full text]
  • Herbal Remedies and Their Possible Effect on the Gabaergic System and Sleep
    nutrients Review Herbal Remedies and Their Possible Effect on the GABAergic System and Sleep Oliviero Bruni 1,* , Luigi Ferini-Strambi 2,3, Elena Giacomoni 4 and Paolo Pellegrino 4 1 Department of Developmental and Social Psychology, Sapienza University, 00185 Rome, Italy 2 Department of Neurology, Ospedale San Raffaele Turro, 20127 Milan, Italy; [email protected] 3 Sleep Disorders Center, Vita-Salute San Raffaele University, 20132 Milan, Italy 4 Department of Medical Affairs, Sanofi Consumer HealthCare, 20158 Milan, Italy; Elena.Giacomoni@sanofi.com (E.G.); Paolo.Pellegrino@sanofi.com (P.P.) * Correspondence: [email protected]; Tel.: +39-33-5607-8964; Fax: +39-06-3377-5941 Abstract: Sleep is an essential component of physical and emotional well-being, and lack, or dis- ruption, of sleep due to insomnia is a highly prevalent problem. The interest in complementary and alternative medicines for treating or preventing insomnia has increased recently. Centuries-old herbal treatments, popular for their safety and effectiveness, include valerian, passionflower, lemon balm, lavender, and Californian poppy. These herbal medicines have been shown to reduce sleep latency and increase subjective and objective measures of sleep quality. Research into their molecular components revealed that their sedative and sleep-promoting properties rely on interactions with various neurotransmitter systems in the brain. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter that plays a major role in controlling different vigilance states. GABA receptors are the targets of many pharmacological treatments for insomnia, such as benzodiazepines. Here, we perform a systematic analysis of studies assessing the mechanisms of action of various herbal medicines on different subtypes of GABA receptors in the context of sleep control.
    [Show full text]
  • Drug Points BMJ: First Published As 10.1136/Bmj.318.7192.1179 on 1 May 1999
    Papers Drug points BMJ: first published as 10.1136/bmj.318.7192.1179 on 1 May 1999. Downloaded from Hepatotoxicity associated with zolpidem respectively. Retrograde endoscopic cholangiography had treatment shown no abnormality. David Karsenti, Pascal Blanc, Yannick Bacq, Etienne-Henry Metman, Six months later, in April 1997, she had had another Service d’Hépato-Gastroentérologie, Centre Hospitalier Universitaire episode of abdominal pain. Eleven days later alanine Trousseau, and Service de Pharmacologie Clinique, Centre aminotransferase and ã-glutamyl transpeptidase activities Hospitalier Universitaire Bretonneau, F-37044 Tours Cedex, France had been 50 IU/l and 89 IU/l respectively. Zolpidem is a hypnotic drug of the imidazopyridine In June 1997 ultrasound examination of the biliary group. Another imidazopyridine, alpidem, has been with- tract gave normal results. On questioning she remem- 12 drawn from the market because of its hepatotoxicity. bered that zolpidem had been reintroduced because her Hepatoxicity has been suspected in association with zolpi- insomnia had recurred (she had taken 20 mg two days dem, but it has not been clearly established because of before the last acute episode). Viral hepatitis and concur- 34 concomitant drug treatment. We report a case of acute rent infections with Epstein-Barr virus and cytomegalovi- hepatitis mimicking biliary lithiasis after treatment with rus were excluded. No antibodies against smooth muscle, zolpidem alone at a therapeutic dose, with reappearance liver and kidney microsomes, or liver cytosol or mitochon- of the hepatoxicity after the drug was reintroduced. dria were detected in serum. Five months later the results A 53 year old woman was admitted in June 1997 for of liver function tests remained within normal limits and investigation of recurrent abdominal pain.
    [Show full text]
  • HS 172 R5/13 Briefly Review the Objectives, Content and Activities of This Session
    HS 172 R5/13 Briefly review the objectives, content and activities of this session. Upon successfully completing this session the participant will be able to: • Explain a brief history of the CNS Depressant category of drugs. • Identify common drug names and terms associated with this category. • Identify common methods of administration for this category. • Describe the symptoms, observable signs and other effects associated with this category. CONTENT SEGMENTS LEARNING ACTIVITIES A. Overview of the Category Instructor-Led Presentations B. Possible Effects Instructor Led Demonstrations C. OtdDtifEfftOnset and Duration of Effects RdiAiReading Assignmen ts D. Overdose Signs and Symptoms Video Presentations E. Expected Results of the Evaluation Slide Presentations F. Classification Exemplar HS 172 R5/13 9-2 • Explain the typical time parameters, i.e. onset and duration of effects, associated with this category. • List the clues that are likely to emerge when the drug influence evaluation is conducted for a person under the influence of this category of drugs. • Correctly answer the “topics for study” questions at the end of this session. HS 172 R5/13 9-3 A. Overview of the Category CNS Depressants Central Nervous System Depressants slow down the operations of the brain. Point out that other common names for CNS Depressants are “downers” and “sedative-hypnotics.” • Depressants first affect those arareaseas of the brain that control a person’ s conscious, voluntary actions. • Judgment, inhibitions and reaction time are some of the things that CNS Depressants affect first. • As the dose is increased, depressants begin to affect the parts of the brain that control the body’s automatic processes, heartbeat, respiration, etc.
    [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]
  • (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.
    [Show full text]
  • Pharmacological Aspects
    Pharmacological aspects Psychopharmacology of anxiety disorders Giovanni B. Cassano, MD; Nicolò Baldini Rossi, MD; Stefano Pini, MD A nxiety disorders are the most common and among the most disabling of mental disorders in adults and adolescents.1 Although many are highly circum- scribed fears of mild-to-moderate severity, it has been estimated by the Epidemiological Catchment Area (ECA) study2 that approximately one quarter of people will experience severe symptoms, disability, and handicap as a consequence of anxiety disorders at some time dur- ing their lifetime.These disorders are associated with sig- nificant morbidity3 and increased mortality, probably as a consequence of increased suicide rates among suffer- Exposure of the general population to a 1:4 lifetime risk of ers.The direct and indirect costs to the health service and disabling anxiety has inspired generations of fundamental economy are considerable.Although persons who suffer and clinical psychopharmacologists, from the era of the from anxiety disorders are high consumers of all types of earliest benzodiazepines (BZ) to that of the selective sero- health services, only a minority receive specific help.4 tonin reuptake inhibitors (SSRIs) and related compounds, The spectrum of anxiety disorders includes generalized eg, the serotonin and norepinephrine reuptake inhibitors anxiety disorder (GAD), panic disorder (PD) and ago- (SNRIs). This comprehensive practical review summarizes raphobia, obsessive-compulsive disorder (OCD), phobic current therapeutic research across the spectrum of indi- disorder (including social phobia), and posttraumatic vidual disorders: generalized anxiety disorder (GAD), panic stress disorder (PTSD). With the discovery of new psy- disorder (PD) and agoraphobia (social anxiety disorder), chotropic medications, specific diagnosis within this spec- compulsive disorder (OCD), phobic disorder (including trum is essential because each of these disorders social phobia), and posttraumatic stress disorder (PTSD).
    [Show full text]
  • 25 Years of Proton Pump Inhibitors: a Comprehensive Review
    Gut and Liver, Vol. 11, No. 1, January 2017, pp. 27-37 Review 25 Years of Proton Pump Inhibitors: A Comprehensive Review Daniel S. Strand1, Daejin Kim2, and David A. Peura1 1Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, VA, USA, and 2Division of Gastroenterology, Daegu Fatima Hospital, Daegu, Korea Proton pump inhibitors (PPIs) were clinically introduced more the modern gastroenterologist. For most, this class of drugs rep- than 25 years ago and have since proven to be invaluable, resents the first choice for treatment of esophagitis, nonerosive safe, and effective agents for the management of a variety of reflux disease (NERD), peptic ulcer disease (PUD), prevention of acid-related disorders. Although all members in this class act nonsteroidal anti-inflammatory drugs (NSAID) associated ulcers, in a similar fashion, inhibiting active parietal cell acid secre- Zollinger-Ellison syndrome (ZES), and functional dyspepsia.4-6 tion, there are slight differences among PPIs relating to their In combination with antibiotics, PPIs are also an integral part of pharmacokinetic properties, metabolism, and Food and Drug eradication therapy for Helicobacter pylori.7 Administration (FDA)-approved clinical indications. Neverthe- Despite an excellent safety profile throughout their first two less, each is effective in managing gastroesophageal reflux decades of use, the nearly universal popularity of PPIs has disease and uncomplicated or complicated peptic ulcer dis- prompted several concerns about both their short- and long- ease. Despite their overall efficacy, PPIs do have some limita- term effects.8,9 This review will examine the pharmacokinetics tions related to their short plasma half-lives and requirement and pharmacodynamics of these drugs and provide an update for meal-associated dosing, which can lead to breakthrough on both the clinical use of and remaining challenges with PPIs.
    [Show full text]