DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 8,188,101 B2 Forsblom Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 8,188,101 B2 Forsblom Et Al USOO81881 01B2 (12) United States Patent (10) Patent No.: US 8,188,101 B2 Forsblom et al. (45) Date of Patent: May 29, 2012 (54) DIHYDROPYRIDOPYRIMIDINES FOR THE WO 2005054193 A1 6, 2005 TREATMENT OF AB-RELATED WO 2005115990 A1 12/2005 WO 200703.5873 A1 3, 2007 PATHOLOGES WO 2007042.299 A1 4/2007 WO 2007044698 A1 4/2007 (75) Inventors: Rickard Forsblom, Södertälje (SE): WO 2007 114771 A1 10, 2007 Kim Paulsen, Södertälje (SE); Didier WO 2007125364 A1 11, 2007 Rotticci, Södertälje (SE); Ellen W 392. A. 58. Santangelo, Södertälje (SE); Magnus WO 2007 149033 A1 12/2007 Waldman, Södertälje (SE) WO 2008006103 A2 1/2008 WO 2008097538 A1 8, 2008 (73) Assignee: AstraZeneca AB, Sodertalje (SE) WO 200809921.0 A1 8, 2008 WO 2008100412 A1 8, 2008 (*) Notice: Subject to any disclaimer, the term of this W. SESS A. 3. patent is extended or adjusted under 35 WO 2009032277 A1 3, 2009 U.S.C. 154(b) by 217 days. WO 2009073777 A1 6, 2009 WO 2009073779 A1 6, 2009 (21) Appl. No.: 12/613,935 WO 2009076337 A1 6, 2009 WO 2009087127 A1 T 2009 (22) Filed: Nov. 6, 2009 WO 2009 103652 A1 8, 2009 9 WO 2010070008 A1 6, 2010 O O WO 2010O752O4 A2 T 2010 (65) Prior Publication Data WO 2010O83141 A1 T 2010 WO 2010O892.92 A1 8, 2010 US 2010/O13O495 A1 May 27, 2010 WO 2010O94647 A1 8, 2010 Related U.S. Application Data WO 2010.132015 A1 11, 2010 (60) Provisional application No. 61/111,786, filed on Nov. OTHER PUBLICATIONS 6, 2008, provisional application No. 61/179,088, filed Aharony etal, J Pharmacol Exp. Ther 1995, 274(3), 1216-1221. on May 18, 2009, provisional application No. Beher, Curr top Med Chem 2008, 8(1), 34-37. 61/179,459, filed on May 19, 2009. Maggietal, J Pharmacol Exp Ther 1994, 271(3), 1489-1500. Weggen et al. Nature 2001, 414(6860), 212-216. (51) Int. Cl. A 6LX3/59 (2006.01) Primary Examiner — James O Wilson (52) U.S. Cl. ..................................... 514/264.1; 544/279 Assistant Examiner — Brian McDowell (58) Field of Classification Search ................... 544/279 (74) Attorney, Agent, or Firm — Kenneth F. Mitchell See application file for complete search history. (57) ABSTRACT (56) References Cited Dihydropyridopyrimidine compounds of formula (Ia) U.S. PATENT DOCUMENTS 2005/O197361 A1 9/2005 Jirgensons et al. (Ia) 2006, OOO4013 A1 1/2006 Kimura et al. 2008.0171771 A1 7/2008 Arnold et al. 2008/0280948 A1 11/2008 Baumann et al. 2009.0099.195 A1 4/2009 Bayrakdarian et al. 2009.00992.17 A1 4/2009 Berg et al. 2009/02O3697 A1 8, 2009 Kimura et al. 2010, O105904 A1 4/2010 Kimura et al. 2010/0292210 A1 11/2010 LO-Alfredsson et al. FOREIGN PATENT DOCUMENTS and therapeutically acceptable salts thereof, wherein R', R EP 1352659 A1 10, 2003 and Zare as defined in the specification; processes for making EP 1348707 B1 8, 2010 WO 2004O73705 A1 9, 2004 them and methods for using them in the treatment of AB WO 2004.110350 A2 12/2004 related pathologies. WO 2005O12304 A2 2, 2005 WO 2005O13985 A1 2, 2005 5 Claims, No Drawings US 8,188,101 B2 1. 2 DHYDROPYRIDOPYRIMIDNES FOR THE erates the N terminus of AB, is catalyzed by the transmem TREATMENT OF AB-RELATED brane aspartyl protease BACE1. The y-cleavage, generating PATHOLOGES the ABC termini and subsequent release of the peptide, is effected by a multi-subunit aspartyl protease named Y-secre This application claims the benefit of US Provisional Patent Applications Numbered 61/111,786 filed 6 Nov. 2008, tase. Both BACE1 and Y-secretase processes APP at different 61/179,088 filed 18 May 2009 and 61/179,459 filed 19May sites, resulting in AB peptides of different lengths and heter 2009. ologous N- and C-termini. The invention described herein covers all N-terminal variants of AB. Therefore, for the sake TECHNICAL FIELD OF THE INVENTION 10 of simplicity, all N-terminal variants will be covered by the denotation AB. The present invention relates to novel compounds and The activity of y-secretase causes the liberation of many AB pharmaceutically acceptable salt thereof. Furthermore, the peptides, such as AB37, AB38, AB39, AB40, A342 and AB43, present invention also relates to pharmaceutical compositions of which AB40 is the most common These peptides show a comprising said compounds, processes for making said com 15 different propensity to aggregate, and in particular AB42 is pounds and their use as medicaments for treatment and or prone to form oligomers and fibrillar deposits. Intriguingly, prevention of various diseases. In particular, the present human genetics strongly Support a key role for AB42 as a key invention relates to compounds, which interfer with Y-secre mediator of Alzheimer pathogenesis. Indeed, more than 150 tase and or its substrate and hence modulate the formation of different mutations causing familial Alzheimer's disease AB peptides. These compounds are used for treatment and or either result in an increase in the ratio of AB 42/40 peptides prevention of AB-related pathologies, such as Alzheimer's produced or affect the intrinsic aggregation behaviour of AB. disease, Downs syndrome and B-amyloid angiopathy, such as Based on this knowledge, A?42 has become a prime target for but not limited to cerebral amyloid angiopathy, hereditary therapeutic intervention in AD (Beher D. Curr Top Med Chem cerebral hemorrhage, disorders associated with cognitive 25 2008; 8(1):34-7). Targeting AB42 at the level of Y-secretase impairment, such as but not limited to MCI (“mild cognitive activity must however be conducted with caution since impairment'), Alzheimer's disease, memory loss, attention Y-secretase catalyses proteolysis of many proteins, which deficit symptoms associated with Alzheimer's disease, neu have important physiological functions. Among its many Sub rodegeneration associated with diseases such as Alzheimer's 30 strates is the Notch receptor family, which signaling is essen disease or dementia including dementia of mixed vascular tial for many different cell fate determination processes e.g. and degenerative origin, pre-senile dementia, senile dementia during embryogenesis and in the adult. As such, A?42 low and dementia associated with Parkinson's disease, progres ering strategies at the level of Y-secretase must be compatible sive Supranuclear palsy or cortical basal degeneration. with maintained Notch signaling. 35 Encouragingly, an enormous Scientific effort and progress BACKGROUND OF THE INVENTION have suggested that it is indeed possible to combine Y-secre tase interference and lowered AB42 production without The prime neuropathological event distinguishing Alzhe obtaining toxic side effects due to impaired Notch signaling imer's disease (AD) is deposition of the amyloid B-peptide 40 There have for instance been reports, which postulate that (AB) in brain parenchyma and cerebral vessels. A large body allosteric modulation of Y-secretase combines lowered AB42 of genetic, biochemical and in vivo data Support a pivotal role production with maintained Notch signaling (Weggen et al. for AB in the pathological cascade that eventually leads to Nature 414(6860), 212-216 (2003)). In addition, a number of AD. Patients usually present early symptoms (commonly compounds interfering with Y-secretase and AB production memory loss) in their sixth or seventh decades of life. The 45 have been suggested, in e.g. WO2005/054193, WO2005/ disease progresses with increasing dementia and elevated 001398, WO2004/073705, WO2007/135969, WO2007/ deposition of AB. In parallel, a hyperphosphorylated form of 139149, WO2005/115990, WO2008/097538, WO2008/ the microtubule-associated protein tau accumulates within 099210, WO2008/100412, WO2007/125364 and WO2009/ neurons, leading to a plethora of deleterious effects on neu 50 103652. ronal function. The prevailing working hypothesis regarding The present invention describes a new class of compounds, the temporal relationship between AB and tau pathologies said compounds will inhibit the AB40 and 42 production, states that AB deposition precedes tau aggregation in humans increase AB37 and AB38 levels and maintaining Notch sig and animal models of the disease. Within this context, it is naling. These compounds will thus be useful in the prevention worth noting that the exact molecular nature of AB, mediating 55 and/or treatment of Alzheimer's Disease (AD). this pathological function is presently an issue under intense study. Most likely, there is a continuum of toxic species DISCLOSURE OF THE INVENTION ranging from lower order AB oligomers to Supramolecular assemblies such as AB fibrils. It has been found that compounds of the Formula (I), herein The AB peptide is an integral fragment of the Type I protein 60 also referred to as the compounds of the (present) invention, APP (AB amyloid precursor protein), a protein ubiquitously are affecting the Y-secretase mediated processing of APP and expressed in human tissues. A? can be found in both plasma, thereby lowering the secretion of A?42 and AB40 peptides cerebrospinal fluid (CSF), and in the medium from cultured while causing an increase in the secreted levels of AB37 and cells, and is generated as a result of APP proteolysis. There 65 AB38 and maintaining Notch signaling. These compounds are two main cleavages of APP that results in AB production, can be used for treatment and/or prevention of AB-related the so-called B-, and Y-cleavages. The B-cleavage, which gen pathologies. US 8,188,101 B2 3 4 Hence, the present invention relates to a compound accord bocyclyl, C(O) heterocyclyl or SOC-alkyl, wherein said ing to formula (I) Calkyl, heterocyclyl, carbocyclyl or CalkylOC alkyl is optionally substituted with one to three substituents selected from halogen, cyano, hydroxy, amino, NHC R7 alkyl, N(Calkyl), NC(O)Calkyl, C(O)Calkoxy, M SOC-alkyl and heterocyclyl, Y R’ is selected from hydrogen, aryl, heteroaryl, C-alkylaryl, Calkylheteroaryl, Calkylcarbocyclyl, Calkylhet erocyclyl and carbocyclyl, wherein said aryl, heteroaryl, 10 Calkylcarbocyclyl, Calkylheterocyclyl, Calky W laryl, carbocyclyl or Calkylheteroaryl is optionally Sub stituted with one or more substituents selected from halo R2 R4 gen, cyano, hydroxy, nitro, Cigalkyl, C-galkoxy, carbocyclyl, heterocyclyl, CF.
Load more

Recommended publications
  • (12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 De Juan Et Al
    US 200601 10428A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110428A1 de Juan et al. (43) Pub. Date: May 25, 2006 (54) METHODS AND DEVICES FOR THE Publication Classification TREATMENT OF OCULAR CONDITIONS (51) Int. Cl. (76) Inventors: Eugene de Juan, LaCanada, CA (US); A6F 2/00 (2006.01) Signe E. Varner, Los Angeles, CA (52) U.S. Cl. .............................................................. 424/427 (US); Laurie R. Lawin, New Brighton, MN (US) (57) ABSTRACT Correspondence Address: Featured is a method for instilling one or more bioactive SCOTT PRIBNOW agents into ocular tissue within an eye of a patient for the Kagan Binder, PLLC treatment of an ocular condition, the method comprising Suite 200 concurrently using at least two of the following bioactive 221 Main Street North agent delivery methods (A)-(C): Stillwater, MN 55082 (US) (A) implanting a Sustained release delivery device com (21) Appl. No.: 11/175,850 prising one or more bioactive agents in a posterior region of the eye so that it delivers the one or more (22) Filed: Jul. 5, 2005 bioactive agents into the vitreous humor of the eye; (B) instilling (e.g., injecting or implanting) one or more Related U.S. Application Data bioactive agents Subretinally; and (60) Provisional application No. 60/585,236, filed on Jul. (C) instilling (e.g., injecting or delivering by ocular ion 2, 2004. Provisional application No. 60/669,701, filed tophoresis) one or more bioactive agents into the Vit on Apr. 8, 2005. reous humor of the eye. Patent Application Publication May 25, 2006 Sheet 1 of 22 US 2006/0110428A1 R 2 2 C.6 Fig.
    [Show full text]
  • Prediction of Premature Termination Codon Suppressing Compounds for Treatment of Duchenne Muscular Dystrophy Using Machine Learning
    Prediction of Premature Termination Codon Suppressing Compounds for Treatment of Duchenne Muscular Dystrophy using Machine Learning Kate Wang et al. Supplemental Table S1. Drugs selected by Pharmacophore-based, ML-based and DL- based search in the FDA-approved drugs database Pharmacophore WEKA TF 1-Palmitoyl-2-oleoyl-sn-glycero-3- 5-O-phosphono-alpha-D- (phospho-rac-(1-glycerol)) ribofuranosyl diphosphate Acarbose Amikacin Acetylcarnitine Acetarsol Arbutamine Acetylcholine Adenosine Aldehydo-N-Acetyl-D- Benserazide Acyclovir Glucosamine Bisoprolol Adefovir dipivoxil Alendronic acid Brivudine Alfentanil Alginic acid Cefamandole Alitretinoin alpha-Arbutin Cefdinir Azithromycin Amikacin Cefixime Balsalazide Amiloride Cefonicid Bethanechol Arbutin Ceforanide Bicalutamide Ascorbic acid calcium salt Cefotetan Calcium glubionate Auranofin Ceftibuten Cangrelor Azacitidine Ceftolozane Capecitabine Benserazide Cerivastatin Carbamoylcholine Besifloxacin Chlortetracycline Carisoprodol beta-L-fructofuranose Cilastatin Chlorobutanol Bictegravir Citicoline Cidofovir Bismuth subgallate Cladribine Clodronic acid Bleomycin Clarithromycin Colistimethate Bortezomib Clindamycin Cyclandelate Bromotheophylline Clofarabine Dexpanthenol Calcium threonate Cromoglicic acid Edoxudine Capecitabine Demeclocycline Elbasvir Capreomycin Diaminopropanol tetraacetic acid Erdosteine Carbidopa Diazolidinylurea Ethchlorvynol Carbocisteine Dibekacin Ethinamate Carboplatin Dinoprostone Famotidine Cefotetan Dipyridamole Fidaxomicin Chlormerodrin Doripenem Flavin adenine dinucleotide
    [Show full text]
  • The Use of Stems in the Selection of International Nonproprietary Names (INN) for Pharmaceutical Substances
    WHO/PSM/QSM/2006.3 The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances 2006 Programme on International Nonproprietary Names (INN) Quality Assurance and Safety: Medicines Medicines Policy and Standards The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • Uniform Classification Guidelines for Foreign Substances and Recommended Penalties Model Rule
    DRUG TESTING STANDARDS AND PRACTICES PROGRAM. Uniform Classification Guidelines for Foreign Substances And Recommended Penalties Model Rule. January, 2018 (V.13.4) Ó ASSOCIATION OF RACING COMMISSIONERS INTERNATIONAL – 2018. Association of Racing Commissioners International 1510 Newtown Pike, Lexington, Kentucky, United States www.arci.com Page 1 of 61 Preamble to the Uniform Classification Guidelines of Foreign Substances The Preamble to the Uniform Classification Guidelines was approved by the RCI Drug Testing and Quality Assurance Program Committee (now the Drug Testing Standards and Practices Program Committee) on August 26, 1991. Minor revisions to the Preamble were made by the Drug Classification subcommittee (now the Veterinary Pharmacologists Subcommittee) on September 3, 1991. "The Uniform Classification Guidelines printed on the following pages are intended to assist stewards, hearing officers and racing commissioners in evaluating the seriousness of alleged violations of medication and prohibited substance rules in racing jurisdictions. Practicing equine veterinarians, state veterinarians, and equine pharmacologists are available and should be consulted to explain the pharmacological effects of the drugs listed in each class prior to any decisions with respect to penalities to be imposed. The ranking of drugs is based on their pharmacology, their ability to influence the outcome of a race, whether or not they have legitimate therapeutic uses in the racing horse, or other evidence that they may be used improperly. These classes of drugs are intended only as guidelines and should be employed only to assist persons adjudicating facts and opinions in understanding the seriousness of the alleged offenses. The facts of each case are always different and there may be mitigating circumstances which should always be considered.
    [Show full text]
  • Public Use Data Tape Documentation 1992 National Ambulatory Medical Care Survey
    Public Use Data Ta~e Documentation 1992 National Ambulatory Medical Care Survey From the CENTERS FOR DISEASE CONTROL AND PREVENTION/Nutional Center for Health Stdklics -—..—=-.=-=.-.‘,.- . ----. - . .- -,-- -.-- .--.,. -’ ‘ --- - –.--.------ ,-:-.-,J ----- ---------- ---P ------.-->- — .. ..- --. : _ U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Publlc Health Service Centers for Disease Control and Prevention National Center for Health Statistics CDCcE141EmFonmEUEcoumoL WMEmmm Public Use Data Tape Documentation 1992 National Ambulatory Medical Care Survey U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Centers for Disease Control and Prevention National Center for Health .SJatistics Hyattsville, Maryland November 1994 299 2 NAMcs MICRO-DATA TAPE Docum NTATION PAGE 1 ABSTRACT This material provides documentation for users of the Micro-Data tapes of the National Ambulatory Medical Care Suney (NAMCS) conducted by the National Center for Health Statistics. Section I, “Description of the National Ambulatory Medical Care Sumey,” includes information on the scope of the amm.rey,the sample, field activities, data collection procedures, medical coding procedures, population estimates, and sampling errors. Section II provides technical detaile of the tape (number of tracks, record length, etc.), and a detailed description of the contents of each data record by location. Section III contains marginal data or estimates for each item on the data record in Section II. The appendixes contain santplingerrors, instructions and definitions for completing the Patient Record Form, and list~ of codes used in the survey. TABLE OF CONTENTS PAGE I. Description of the National Ambulatory Medical Care SuNey 2-14 Distribution of physicians (Table I) 4 Population Figures (Table II) 6 Patient Log and Patient Record Form (Figure 1) 8 References 14 II.
    [Show full text]
  • Current Methods of Sedation in Dental Patients - a Systematic Review of the Literature
    Med Oral Patol Oral Cir Bucal. 2016 Sep 1;21 (5):e579-86. Conscious sedation in dentistry Journal section: Medically compromised patients in Dentistry doi:10.4317/medoral.20981 Publication Types: Review http://dx.doi.org/doi:10.4317/medoral.20981 Current methods of sedation in dental patients - a systematic review of the literature Jose-Ramón Corcuera-Flores 1, Javier Silvestre-Rangil 2, Antonio Cutando-Soriano 3, Julián López-Jiménez 4 1 PhD, DDS, Associate Professor. Special Care in Dentistry, School of Dentistry, University of Seville, Spain 2 PhD, DDS, Associate Professor. Special Care in Dentistry, School of Dentistry, University of Valencia, Spain 3 PhD, MD, DDS, Professor. Special Care in Dentistry, School of Dentistry, University of Granada, Spain 4 PhD, MD, DDS. “Nen Deu” Private Practice Hospital, Barcelona, Spain Correspondence: School of Dentistry C/Avicena s/n Corcuera-Flores JR, Silvestre-Rangil J, Cutando-Soriano A, López-Ji- 41009 Seville, Spain ménez J. Current methods of sedation in dental patients - a systematic [email protected] review of the literature. Med Oral Patol Oral Cir Bucal. 2016 Sep 1;21 (5):e579-86. http://www.medicinaoral.com/medoralfree01/v21i5/medoralv21i5p579.pdf Received: 31/07/2015 Article Number: 20981 http://www.medicinaoral.com/ Accepted: 16/03/2016 © Medicina Oral S. L. C.I.F. B 96689336 - pISSN 1698-4447 - eISSN: 1698-6946 eMail: [email protected] Indexed in: Science Citation Index Expanded Journal Citation Reports Index Medicus, MEDLINE, PubMed Scopus, Embase and Emcare Indice Médico Español Abstract Objective: The main objective of this systematic literature review is to identify the safest and most effective seda- tive drugs so as to ensure successful sedation with as few complications as possible.
    [Show full text]
  • Report on the Investigation Results
    Pharmaceuticals and Medical Devices Agency This English version is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. Report on the Investigation Results February 28, 2017 Pharmaceuticals and Medical Devices Agency I. Overview of Product [Non-proprietary name] See Attachment 1 [Brand name] See Attachment 1 [Approval holder] See Attachment 1 [Indications] See Attachment 1 [Dosage and administration] See Attachment 1 [Investigating office] Office of Safety II 1 Pharmaceuticals and Medical Devices Agency This English version is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. II. Background of the investigation 1. Status in Japan Hypnotics and anxiolytics are prescribed by various specialties and widely used in clinical practice. In particular, benzodiazepine (BZ) receptor agonists, which act on BZ receptors, bind to gamma-aminobutyric acid (GABA)A-BZ receptor complex and enhance the function of GABAA receptors. This promotes neurotransmission of inhibitory systems and demonstrates hypnotic/sedative effects, anxiolytic effects, muscle relaxant effects, and antispasmodic effects. Since the approval of chlordiazepoxide in March 1961, many BZ receptor agonists have been approved as hypnotics and anxiolytics. Currently, hypnotics and anxiolytics are causative agents of drug-related disorders such as drug dependence in Japanese clinical practice. Hypnotics and anxiolitics that rank high in causative agents are BZ receptor agonists for which high frequencies of high doses and multidrug prescriptions have been reported (Japanese Journal of Clinical Psychopharmacology 2013; 16(6): 803-812, Modern Physician 2014; 34(6): 653-656, etc.).
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,283,192 B2 Mullen Et Al
    US009283192B2 (12) United States Patent (10) Patent No.: US 9,283,192 B2 Mullen et al. (45) Date of Patent: Mar. 15, 2016 (54) DELAYED PROLONGED DRUG DELIVERY 2009. O1553.58 A1 6/2009 Diaz et al. 2009,02976O1 A1 12/2009 Vergnault et al. 2010.0040557 A1 2/2010 Keet al. (75) Inventors: Alexander Mullen, Glasgow (GB); 2013, OO17262 A1 1/2013 Mullen et al. Howard Stevens, Glasgow (GB); Sarah 2013/0022676 A1 1/2013 Mullen et al. Eccleston, Scotstoun (GB) FOREIGN PATENT DOCUMENTS (73) Assignee: UNIVERSITY OF STRATHCLYDE, Glasgow (GB) EP O 546593 A1 6, 1993 EP 1064937 1, 2001 EP 1607 O92 A1 12/2005 (*) Notice: Subject to any disclaimer, the term of this EP 2098 250 A1 9, 2009 patent is extended or adjusted under 35 JP HO5-194188 A 8, 1993 U.S.C. 154(b) by 0 days. JP 2001-515854. A 9, 2001 JP 2001-322927 A 11, 2001 JP 2003-503340 A 1, 2003 (21) Appl. No.: 131582,926 JP 2004-300148 A 10, 2004 JP 2005-508326 A 3, 2005 (22) PCT Filed: Mar. 4, 2011 JP 2005-508327 A 3, 2005 JP 2005-508328 A 3, 2005 (86). PCT No.: PCT/GB2O11AOOO3O7 JP 2005-510477 A 4/2005 JP 2008-517970 A 5, 2008 JP 2009-514989 4/2009 S371 (c)(1), WO WO99,12524 A1 3, 1999 (2), (4) Date: Oct. 2, 2012 WO WOO1 OO181 A2 1, 2001 WO WOO3,O266.15 A2 4/2003 (87) PCT Pub. No.: WO2011/107750 WO WOO3,O26625 A1 4/2003 WO WO 03/026626 A2 4/2003 PCT Pub.
    [Show full text]
  • Therapeutic Consequences of the Drug Lag 93 X Recent Developments, 1972 to 1974 ...•
    REGULATION AND DRUG DEVELOPMENT William M. Wardell and Louis Lasagna American Enterprise Institute for Public Policy Research Washington. D. C. CONTENTS INTRODUCTION .. ................... 1 PART ONE Science. Government, and the Current State of Affairs I PRE-1962 PRACTICES: THE EVOLUTION OF CON- TROLS OVER THERAPEUTIC DRUGS 5 II POST-1962 GUIDELINES AND PRACTICES 19 III THE NATURE OF EVIDENCE 27 IV WEIGHING THE EVIDENCE 37 V ECONOMICS AND DRUG DEVELOPMENT 45 PART TWO Lessons from Other Countries VI APPROACHES TO INTERNATIONAL COMPARISONS 51 VII PATTERNS OF INTRODUCTION OF NEW DRUGS IN BRITAIN AND THE UNITED STATES 55 VIII BRITISH USAGE AND AMERICAN AWARENESS OF SOME NEW DRUGS 79 IX THERAPEUTIC CONSEQUENCES OF THE DRUG LAG 93 X RECENT DEVELOPMENTS, 1972 TO 1974 ...•....... 109 PART THREE The Wider Issues XI THE INTENT OF CONGRESS AND THE NEEDS OF PATIENTS 127 XII THE RUBRICS REEXAMINED 135 XIII SUGGESTIONS FOR IMPROVEMENT. ............. .. 143 XIV CONCLUSIONS.................................... 161 APPENDIX: Definition of "Substantial Evidence" 167 NOTES 171 INTRODUCTION In the late 1950s the Congress of the United States began holding subcommittee hearings on various matters pertaining to the pharma­ ceutical industry. Two of the most vigorous and sensational were those chaired by Congressman Blatnik and by Senator Kefauver. They were highly critical of the quality of drug advertising, theevi­ dence for effectiveness of marketed pharmaceuticals, the allegedly monopolistic nature of the drug industry, and the price of medicines. The drug industry, accustomed to respect and gratitude from physicians and the public, was suddenly confronted with hostile, sensational newspaper headlines and stories and a rising wave of angry criticism.
    [Show full text]
  • Safety and Efficacy of Oral Triclofos in the Evaluation of Young and Uncooperative Children in Pediatric Ophthalmology Clinic
    Advances in Ophthalmology & Visual System Research Article Open Access Safety and efficacy of oral triclofos in the evaluation of young and uncooperative children in pediatric ophthalmology clinic Abstract Volume 5 Issue 3 - 2016 Aim: Evaluation of safety and efficacy of oral triclofos for eye examination of children 1,2 1 1 under sedation. Mihir Kothari, Kruti Shah, Renu Singhania, Khushboo Shikhangi,1 Swati Chavan1 Subjects and methods: This interventional prospective cohort study included children 1Department of clinical outpatient pediatric ophthalmology, between 1 and 16 years of age. Children without an acute medical condition and normal Jyotirmay Eye Clinic and Ocular Motility Laboratory, India cardio respiratory status, uncooperative for the relevant ocular examination were 2Department of pediatric ophthalmology, Mahatme Eye Hospital, administered oral triclofos at a dose of 75mg/kg. The pulse oximetry, onset and duration of India sedation, post sedation neurobehaviour and cognition were recorded. Correspondence: Mihir Kothari, Jyotirmay eye clinic and Results: Thirty nine examinations under sedations (EUS) on thirty six consecutive children ocular motility laboratory, 104/105 Kaalika Tower, Opp. Pratap were performed. Of 36 children, 16 were females. The mean age was 2.9 year and the Tower, Kolbad Road, Thane west 400601, Maharashtra, India, mean weight was 11.7kg. The mean duration of the onset of sedation was 64.7 minutes Email and the mean duration was 64.4 minutes. Of The drug did not have any effect on the pulse oximetry(p=0.68, p=0.37). The correlation between the onset and duration of sedation with Received: October 27, 2016 | Published: November 28, 2016 age and weight of the children was poor (r=0, r=-0.1 respectively).
    [Show full text]
  • Chloral Hydrate: Summary Report
    Chloral Hydrate: Summary Report Item Type Report Authors Yuen, Melissa V.; Gianturco, Stephanie L.; Pavlech, Laura L.; Storm, Kathena D.; Yoon, SeJeong; Mattingly, Ashlee N. Publication Date 2020-02 Keywords Compounding; Food, Drug, and Cosmetic Act, Section 503B; Food and Drug Administration; Outsourcing facility; Drug compounding; Legislation, Drug; United States Food and Drug Administration; Chloral Hydrate Rights Attribution-NoDerivatives 4.0 International Download date 26/09/2021 09:06:16 Item License http://creativecommons.org/licenses/by-nd/4.0/ Link to Item http://hdl.handle.net/10713/12087 Summary Report Chloral Hydrate Prepared for: Food and Drug Administration Clinical use of bulk drug substances nominated for inclusion on the 503B Bulks List Grant number: 2U01FD005946 Prepared by: University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) University of Maryland School of Pharmacy February 2020 This report was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award (U01FD005946) totaling $2,342,364, with 100 percent funded by the FDA/HHS. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement by, the FDA/HHS or the U.S. Government. 1 Table of Contents REVIEW OF NOMINATION ..................................................................................................... 4 METHODOLOGY ...................................................................................................................
    [Show full text]
  • Preoperative Evaluation, Premedication, and Induction of Anesthesia ELIZABETH A
    Preoperative Evaluation, Premedication, and Induction of Anesthesia ELIZABETH A. GHAZAL, MARISSA G. VADI, LINDA J. MASON, 4 AND CHARLES J. COTÉ Preparation of Children for Anesthesia Rectal Induction Fasting Full Stomach and Rapid-Sequence Induction Piercings Special Problems Primary and Secondary Smoking The Fearful Child Psychological Preparation of Children for Surgery Autism History of Present Illness Anemia Past/Other Medical History Upper Respiratory Tract Infection Laboratory Data Obesity Pregnancy Testing Obstructive Sleep Apnea Syndrome Premedication and Induction Principles Asymptomatic Cardiac Murmurs General Principles Fever Medications Postanesthesia Apnea in Former Preterm Infants Induction of Anesthesia Hyperalimentation Preparation for Induction Diabetes Inhalation Induction Bronchopulmonary Dysplasia Intravenous Induction Seizure Disorder Intramuscular Induction Sickle Cell Disease Preparation of Children for Anesthesia clear fluids from the stomach is approximately15 minutes (Fig. 4.1); as a result, 98% of clear fluids exit the stomach in children FASTING by 1 hour. Clear liquids include water, fruit juices without pulp, Infants and children are fasted before sedation and anesthesia to carbonated beverages, clear tea, and black coffee. Although fasting minimize the risk of pulmonary aspiration of gastric contents. In for 2 hours after clear fluids ensures nearly complete emptying a fasted child, only the basal secretions of gastric juice should be of the residual volume, extending the fasting interval to 3 hours present
    [Show full text]