DOCSLIB.ORG

Strategies for Organic Drug Synthesis and Design

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

STRATEGIES FOR ORGANIC DRUG SYNTHESIS AND DESIGN Second Edition DANIEL LEDNICER STRATEGIES FOR ORGANIC DRUG SYNTHESIS AND DESIGN STRATEGIES FOR ORGANIC DRUG SYNTHESIS AND DESIGN Second Edition DANIEL LEDNICER Copyright # 2009 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Sections 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or com- pleteness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in variety of electronic formats. Some content that appears in print may not be available in electronic format. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data is available. ISBN 978-0-470-19039-5 Printed in the United States of America 10987654321 To the memory of now-defunct laboratories where once I practiced my craft: Building H at G.D. Searle in Skokie, Upjohn’s Building 25 in Kalamazoo and the diminutive Chemistry Annex at the Adria Laboratories just outside Dublin, Ohio. CONTENTS PREFACE xv 1 PROSTAGLANDINS, PEPTIDOMIMETIC COMPOUNDS, AND RETINOIDS 1 1.1 Prostaglandins / 1 1.2 Peptidomimetic Compounds / 19 1.2.1 Protease Inhibitors / 19 1.2.1.1 Introduction / 19 1.2.1.2 Renin Inhibitors / 20 1.2.1.3 Antiviral Compounds / 22 1.2.2 Fibrinogen Receptor Antagonists / 30 1.2.3 Antitumor Peptidomimetic / 34 1.3 Retinoids / 35 1.4 A Miscellaneous Drug / 38 References / 40 2 DRUGS BASED ON A SUBSTITUTED BENZENE RING 43 2.1 Arylethanolamines / 43 2.2 Aryloxypropanolamines / 54 2.2.1 b-Blockers / 54 2.2.2 Non-Tricyclic Antidepressants (SSRIs) / 57 vii viii CONTENTS 2.3 Arylsulfonic Acid Derivatives / 61 2.3.1 Antibacterial Sulfonamides / 61 2.3.2 Diuretic Agents / 63 2.3.3 Oral Hypoglycemic Agents / 65 2.3.4 Miscellaneous Arylsulfonamides / 70 2.4 Arylacetic and Arylpropionic Acids / 71 2.4.1 Arylacetic acid “Fenacs” / 71 2.4.2 Arylpropionic Acid “Profens” / 75 2.4.3 Arylacetamide Antiarrhythmic Compounds / 78 2.5 Leukotriene Antagonists / 81 2.6 Miscellaneous Compounds / 84 References / 86 3 INDENES, NAPHTHALENES, AND OTHER POLYCYCLIC AROMATIC COMPOUNDS 89 3.1 Indenes / 90 3.2 Naphthalenes / 94 3.2.1 Antifungal Agents / 94 3.2.2 Miscellaneous Naphthalenes / 97 3.3 Partly Reduced Naphthalenes / 99 3.3.1 Bicyclic Retinoids / 99 3.3.2 Another b-Blocker / 101 3.3.3 Aminotetralin CNS Agents / 102 3.4 Tricyclic Compounds / 105 3.4.1 Dibenzocycloheptane and Dibenzocycloheptene Antidepressants / 105 3.4.2 Antidepressants Based on Dihydroanthracenes / 110 3.4.3 Anthraquinones: The “Antrone” Chemotherapy Agents / 113 References / 116 4 STEROIDS; PART 1: ESTRANES, GONANES, AND ANDROSTANES 119 4.1 Introduction / 119 4.2 Steroid Starting Materials / 120 4.2.1 From Diosgenin / 121 4.2.2 From Soybean Sterols / 121 4.3 Estranes / 123 4.3.1 Synthesis of Estranes / 123 4.3.2 Drugs Based on Estranes / 125 CONTENTS ix 4.4 Gonanes, the 19-nor Steroids / 128 4.4.1 Progestational Compounds / 128 4.4.2 Progesterone Antagonists / 137 4.4.3 Androgenic Compounds / 140 4.5 Androstanes / 142 4.5.1 Starting Materials / 142 4.5.2 Androgenic Compounds / 143 4.5.3 Antiandrogens / 150 4.5.4 Aldosterone Antagonists / 153 References / 157 5 STEROIDS; PART 2: COMPOUNDS RELATED TO PROGESTERONE, CORTISONE, AND CHOLESTEROL 161 5.1 Introduction / 161 5.2 Progestins / 161 5.3 Corticosteroids / 169 5.4 Compounds Derived from Cholesterol / 186 References / 189 6 NONSTEROIDAL SEX HORMONES AND THEIR ANTAGONISTS 191 6.1 Introduction / 191 6.2 Estrogens / 191 6.2.1 Nonsteroidal Estrogens / 191 6.2.2 Nonsteroid Estrogen Antagonists / 195 6.2.2.1 Arylethylenes / 195 6.2.2.2 Carbocyclic Ethylenes Fused to a Benzene Ring / 200 6.2.2.3 Heterocyclic Ethylenes Fused to a Benzene Ring / 203 6.2.3 Nonsteroid Androgen Antagonists / 207 6.2.4 A Nonsteroid Progestin Agonist / 209 References / 210 7 OPIOID ANALGESICS 213 7.1 Introduction / 213 7.2 Drugs Derived from Morphine / 214 7.3 Compounds Prepared from Thebaine / 216 x CONTENTS 7.4 Morphinans / 219 7.5 Benzomorphans / 223 7.6 Analgesics Based on Nonfused Piperidines / 226 7.6.1 4-Arylpiperidines: Meperidine and Its Analogues / 226 7.6.2 4-Amidopiperidines: Compounds Related to Fentanyl / 229 7.6.3 Miscellaneous Compounds / 234 7.6.3.1 1,2-Bisaminoceclohexanes / 234 7.6.3.2 Open Chain Compounds / 236 References / 237 8 DRUGS BASED ON FIVE-MEMBERED HETEROCYCLES 239 8.1 Introduction / 239 8.2 Rings that Contain One Heteroatom / 239 8.2.1 Furans / 239 8.2.2 Pyrrole and Its Derivatives / 241 8.2.2.1 NSAIDS and a “Statin” / 241 8.2.2.2 ACE Inhibitors / 246 8.2.2.3 Miscellaneous Compounds / 251 8.3 Rings that Contain Two Heteroatoms / 258 8.3.1 Cyclooxygenase 2 (COX-2) Inhibitor NSAIDs / 258 8.3.2 Oxazoles, Isoxazoles, and their Derivatives / 262 8.3.3 Imidazoles / 269 8.3.4 Imidazolines / 287 8.3.5 Modified Imidazoles / 291 8.3.6 Pyrrazolones and Pyrrazolodiones / 295 8.3.7 Thiazoles and Related Sulfur–Nitrogen-Containing Heterocycles / 298 8.4 Rings that Contain Three or More Heteroatoms / 304 8.4.1 1,2,4-Oxadiazoles / 304 8.4.2 Triazoles / 306 8.4.3 Thiadiazoles / 311 8.4.4 Tetrazoles / 313 References / 314 9 DRUGS BASED ON SIX-MEMBERED HETEROCYCLES 319 9.1 Rings that Contain One Heteroatom / 319 9.1.1 Pyrans / 319 9.1.2 Pyridines / 323 9.1.3 1,4-Dihydropyridines / 329 CONTENTS xi 9.1.4 Piperidines / 332 9.1.4.1 Psychotropic Compounds / 332 9.1.4.2 Miscellaneous Piperidines / 336 9.1.5 Pyridones and Glutarimides / 337 9.2 Rings that Contain Two Heteroatoms / 341 9.2.1 Pyridazines / 341 9.2.2 Pyrimidines / 344 9.2.2.1 Antibacterial Agents / 344 9.2.2.2 Antiviral and Antineoplastic Pyrimidines / 348 9.2.2.3 Miscellaneous Pyrimidines / 356 9.2.3 Pyrimidones / 359 9.2.4 Triketopyrimidines: The Barbiturates / 363 9.2.5 Pyrazines / 364 9.2.6 Piperazines / 366 9.3 Rings Containing Three Heteroatoms: The Triazines / 376 References / 379 10 FIVE-MEMBERED HETEROCYCLES FUSED TO A BENZENE RING 383 10.1 Compounds that Contain One Heteroatom / 383 10.1.1 Benzofurans / 383 10.1.2 Indoles / 389 10.1.3 Indolines and Isoindolines / 401 10.2 Compounds that Contain Two Heteroatoms / 407 10.2.1 Indazoles / 407 10.2.2 Benzimidazoles / 408 10.2.3 Benzoxazoles and Benzisoxazoles / 419 10.2.4 Benzothiazoles / 421 10.3 Compounds that Contain Three Heteroatoms / 423 References / 425 11 SIX-MEMBERED HETEROCYCLES FUSED TO A BENZENE RING 429 11.1 Compounds that Contain One Heteroatom / 429 11.1.1 Coumarins / 429 11.1.2 Chromones / 432 11.1.3 Benzopyrans / 435 11.1.4 Quinolines / 440 11.1.4.1 Antimalarial Compounds / 440 11.1.4.2 Other Quinolines / 444 xii CONTENTS 11.1.5 Quinolones / 454 11.1.5.1 Antibacterial Agents / 454 11.1.5.2 Miscellaneous Quinolones / 462 11.1.6 Isoquinoline and Its Derivatives / 463 11.2 Compounds that Contain Two Heteroatoms / 467 11.2.1 Benzodioxans / 467 11.2.2 Miscellaneous Fused Rings that Include Oxygen / 470 11.2.3 Cinnolines and Phthalazines / 472 11.2.4 Quinazolines / 476 11.2.5 Quinazolones / 482 11.3 Compounds that Contain Three Heteroatoms / 488 References / 490 12 SEVEN-MEMBERED HETEROCYCLIC RINGS FUSED TO BENZENE 495 12.1 Compounds with a Single Heterocyclic Atom / 495 12.2 Compounds with Two Heteroatoms / 499 12.2.1 Benzodiazepine Anxiolytic Agents / 499 12.2.2 Other Seven-Membered Heterocycles Fused to a Benzene Ring / 508 References / 513 13 HETEROCYCLES FUSED TO TWO AROMATIC RINGS 515 13.1 Compounds Containing a Single Heteroatom / 515 13.1.1 Derivatives of Dibenzopyran and Dibenzoxepin / 515 13.1.2 Dibenzo Heterocycles Containing One Ring Nitrogen Atom / 520 13.1.3 Dibenzo Heterocycles with One Sulfur Atom / 527 13.2 Compounds Containing Two Heteroatoms / 532 13.2.1 Phenothiazines / 532 13.2.2 A Dibenzoxazine / 535 13.2.3 Dibenzodiazepines, Dibenzoxazepines, and a Dibenzothiazepine / 536 13.3 Pyridine-Based Fused Tricyclic Compounds / 540 References / 543 14 BETA LACTAM ANTIBIOTICS
Recommended publications
  • (KPIC) PPO and Out-Of- Area Indemnity (OOA) Drug Formulary with Specialty Drug Tier

    (KPIC) PPO and Out-Of- Area Indemnity (OOA) Drug Formulary with Specialty Drug Tier

    Kaiser Permanente Insurance Company (KPIC) PPO and Out-of- Area Indemnity (OOA) Drug Formulary with Specialty Drug Tier This Drug Formulary was updated: September 1, 2021 NOTE: This drug formulary is updated often and is subject to change. Upon revision, all previous versions of the drug formulary are no longer in effect. This document contains information regarding the drugs that are covered when you participate in the California Nongrandfathered PPO and Out-of- Area Indemnity (OOA) Health Insurance Plans with specialty drug tier offered by Kaiser Permanente Insurance Company (KPIC) and fill your prescription at a MedImpact network pharmacy. Access to the most current version of the Formulary can be obtained by visiting kp.org/kpic-ca-rx-ppo-ngf. For help understanding your KPIC insurance plan benefits, including cost sharing for drugs under the prescription drug benefit and under the medical benefit, please call 1-800-788-0710 or 711 (TTY) Monday through Friday, 7a.m. to 7p.m. For help with this Formulary, including the processes for submitting an exception request and requesting prior authorization and step therapy exceptions, please call MedImpact 24 hours a day, 7 days a week, at 1-800-788-2949 or 711 (TTY). For cost sharing information for the outpatient prescription drug benefits in your specific plan, please visit: kp.org/kpic-ca-rx-ppo-ngf. For help in your preferred language, please see the Kaiser Permanente Insurance Company Notice of Language Assistance in this document. KPIC PPO NGF Table of Contents Informational Section................................................................................................................................2
  • Traditional Open Drug List

    Traditional Open Drug List

    Traditional Open Drug List Drug list — Four Tier Drug Plan Your prescription benefit comes with a drug list, which is also called a formulary. This list is made up of brand-name and generic prescription drugs approved by the U.S. Food & Drug Administration (FDA). Here are a few things to remember about the list: o You and your doctor can use it as a guide to choose drugs that are best for you. Drugs that aren’t on this list may not be covered by your plan and may cost you more out of pocket. o Your coverage has limitations and exclusions, which means there are certain rules about what's covered by your plan and what isn't. To find out more, view your Certificate/Evidence of Coverage or your Summary Plan Description by logging in at anthem.com and go to My Plan ->Benefits-> Plan Documents. o To help you see how the drug list works with your drug benefit, we've included some frequently asked questions (FAQ) about how the list is set up and what to do if a drug you take isn't on it. o This booklet is updated on a quarterly basis. To view the most up-to-date list of drugs for your plan - including drugs that have been added, generic drugs and more - log in at anthem.com and choose Prescription Benefits. If you have questions about your pharmacy benefits, we're here to help. Just call us at the Pharmacy Member Services number on your ID card. 05374MUMENABS Traditional Open Drug List What is a drug list? The drug list, also called a formulary, is a list of prescription medicines your plan covers.
  • Identification, Isolation, Synthesis and Characterization of Impurities of Quetiapine Fumarate

    Identification, Isolation, Synthesis and Characterization of Impurities of Quetiapine Fumarate

    ORIGINAL ARTICLES Aurobindo Pharma Ltd. Research Centre1, Bachupally, J. N. T. University2, Kukatpally, Hyderabad, India Identification, isolation, synthesis and characterization of impurities of quetiapine fumarate Ch. Bharathi1, K. J. Prabahar1, Ch. S. Prasad1, M. Srinivasa Rao1, G. N. Trinadhachary1, V. K. Handa1, R. Dandala1, A. Naidu2 Received May 28, 2007, accepted June 18, 2007 Ramesh Dandala, Senior Vice-President, A. P. L. Research centre, 313, Bachupally, Hyderabad 500072, India [email protected] Pharmazie 63: 14–19 (2008) doi: 10.1691/ph.2008.7174 In the process for the preparation of quetiapine fumarate (1), six unknown impurities and one known impurity (intermediate) were identified ranging from 0.05–0.15% by reverse-phase HPLC. These impu- rities were isolated from crude samples using reverse-phase preparative HPLC. Based on the spectral data, the impurities were characterized as 2-[4-dibenzo[b,f ][1,4]thiazepine-11-yl-1-piperazinyl]1-2-etha- nol (impurity I, desethanol quetiapine), 11-[(N-formyl)-1-piperazinyl]-dibenzo[b,f ][1,4]thiazepine (impur- ity II, N-formyl piperazinyl thiazepine), 2-(2-hydroxy ethoxy)ethyl-2-[2-[4-dibenzo[b,f ][1,4]thiazepine-11- piperazinyl-1-carboxylate (impurity III, quetiapine carboxylate), 11-[4-ethyl-1-piperazinyl]dibenzo [b,f ][1,4] thiazepine (impurity IV, ethylpiperazinyl thiazepine), 2-[2-(4-dibenzo[b,f ][1,4]thiazepin-11-yl-1-piperazi- nyl)ethoxy]1-ethyl ethanol [impurity V, ethyl quetiapine), 1,4-bis[dibenzo[b,f ][1,4]thiazepine-11-yl] piper- azine [impurity VI, bis(dibenzo)piperazine]. The known impurity was an intermediate, 11-piperazinyl- dibenzo [b,f ][1,4]thiazepine (piperazinyl thiazepine).
  • Anthem Blue Cross Prescription Formulary List

    Anthem Blue Cross Prescription Formulary List

    National Drug List Drug list — Three Tier Drug Plan Your prescription benefit comes with a drug list, which is also called a formulary. This list is made up of brand-name and generic prescription drugs approved by the U.S. Food & Drug Administration (FDA). We’re here to help. If you are a current Anthem member with questions about your pharmacy benefits, we're here to help. Just call us at the Member Services number on your ID card. The plan names to which this formulary applies are shown below. Solution PPO 1500/15/20 $5/$15/$50/$65/30% to $250 after deductible Solution PPO 2000/20/20 $5/$20/$30/$50/30% to $250 Solution PPO 2500/25/20 $5/$20/$40/$60/30% to $250 Solution PPO 3500/30/30 $5/$20/$40/$60/30% to $250 Rx ded $150 Solution PPO 4500/30/30 $5/$20/$40/$75/30% to $250 Solution PPO 5500/30/30 $5/$20/$40/$75/30% to $250 Rx ded $250 $5/$15/$25/$45/30% to $250 $5/$20/$50/$65/30% to $250 Rx ded $500 $5/$15/$30/$50/30% to $250 $5/$20/$50/$70/30% to $250 $5/$15/$40/$60/30% to $250 $5/$20/$50/$70/30% to $250 after deductible Here are a few things to remember: o You can view and search our current drug lists when you visit anthem.com/ca/pharmacyinformation. Please note: The formulary is subject to change and all previous versions of the formulary are no longer in effect.
  • Central Nervous System 5 Objectives

    Central Nervous System 5 Objectives

    B978-0-7234-3630-0.00005-4, 00005 Central nervous system 5 Objectives After reading this chapter, you will: ● Understand the functions of the central nervous system and the diseases that can occur ● Know the drug classes used to treat these conditions, their mechanisms of action and adverse effects. Parkinson’s disease is progressive, with continued BASIC CONCEPTS loss of dopaminergic neurons in the substantia nigra correlating with worsening of clinical symptoms. The The central nervous system consists of the brain and the possibility of a neurotoxic cause has been strengthe- spinal cord, which are continuous with one another. ned by the finding that 1-methyl-4-phenyl-1,2,3, The brain is composed of the cerebrum (which consists 6-tetrahydropyridine (MPTP), a chemical contaminant of the frontal, temporal, parietal and occipital lobes), of heroin, causes irreversible damage to the nigrostriatal the diencephalon (which includes the thalamus and dopaminergic pathway. Thus, this damage can lead hypothalamus), the brainstem (which consists of the mid- to the development of symptoms similar to those of brain, pons and medulla oblongata) and the cerebellum. idiopathic Parkinson’s disease. Drugs that block The brain functions to interpret sensory information dopamine receptors can also induce parkinsonism. obtained about the internal and external environments Neuroleptic drugs (p. 000) used in the treatment of TS1 and send messages to effector organs in response to a schizophrenia can produce parkinsonian symptoms as situation. Different parts of the brain are associated an adverse effect. Rare causes of parkinsonism are cere- with specific functions (Fig. 5.1). However, the brain is a bral ischaemia (progressive atherosclerosis or stroke), complex organ and is not yet completely understood.
  • Clinical Trial Protocol

    Clinical Trial Protocol

    Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) ------------------------------------------------------------------------------------------------------------------------------------------------------- - Confidential - Confidential - Confidential - Confidential - Clinical Trial Protocol Clinical Effectiveness Of The Newer Antipsychotic Compounds Olanzapine, Quetiapine And Aripiprazole In Comparison With Low Dose Conventional Antipsychotics (Haloperidol And Flupentixol) In Patients With Schizophrenia The Neuroleptic Strategy Study – NeSSy Protocol-ID.: NeSSy_200901 EudraCT Number 2009-010966-47 ---------------------------------------------------------------------------------------------------------------------------------------------------------- Protocol Authors: Prof. Dr. med. Mühlbauer, Dr. med. Bobis Seidenschwanz, Department of Pharmacology, Klinikum Bremen-Mitte; Prof. Dr. rer. nat. Dr. h.c. Timm, Competence Center for Clinical Trials Bremen, Version 04, 05 December 2012 Page 1 of 44 Clinical Trial Protocol - Clinical effectiveness of the newer antipsychotic compounds olanzapine, quetiapine and aripiprazole in comparison with low dose conventional antipsychotics (haloperidol and flupentixol) in patients with schizophrenia - NeSSy (Neuroleptic Strategy Study) -------------------------------------------------------------------------------------------------------------------------------------------------------
  • Doxepin Hydrochloride Capsule Mylan Pharmaceuticals Inc.

    Doxepin Hydrochloride Capsule Mylan Pharmaceuticals Inc.

    DOXEPIN HYDROCHLORIDE- doxepin hydrochloride capsule Mylan Pharmaceuticals Inc. ---------- Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of doxepin or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Doxepin is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients and PRECAUTIONS: Pediatric Use.) DESCRIPTION Doxepin hydrochloride is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C19H21NO • HCl having a molecular weight of 315.84. It is a white crystalline powder freely soluble in water, in ethanol (96%), and methylene chloride. It may be represented by the following structural formula: Chemically, doxepin hydrochloride is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents.
  • SINEQUAN® (Doxepin Hcl) CAPSULES ORAL CONCENTRATE

    SINEQUAN® (Doxepin Hcl) CAPSULES ORAL CONCENTRATE

    69-2135-00-1 SINEQUAN® (doxepin HCl) CAPSULES ORAL CONCENTRATE DESCRIPTION SINEQUAN® (doxepin hydrochloride) is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C19H21NO•HCl having a molecular weight of 316. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform. Inert ingredients for the capsule formulations are: hard gelatin capsules (which may contain Blue 1, Red 3, Red 40, Yellow 10, and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch. Inert ingredients for the oral concentrate formulation are: glycerin; methylparaben; peppermint oil; propylparaben; water. CHEMISTRY SINEQUAN (doxepin HCl) is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture of: 1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride. 1 ACTIONS The mechanism of action of SINEQUAN (doxepin HCl) is not definitely known. It is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented. Animal studies suggest that doxepin HCl does not appreciably antagonize the antihypertensive action of guanethidine. In animal studies anticholinergic, antiserotonin and antihistamine effects on smooth muscle have been demonstrated. At higher than usual clinical doses, norepinephrine response was potentiated in animals. This effect was not demonstrated in humans. At clinical dosages up to 150 mg per day, SINEQUAN can be given to man concomitantly with guanethidine and related compounds without blocking the antihypertensive effect.
  • NIH Public Access Author Manuscript Expert Opin Drug Saf

    NIH Public Access Author Manuscript Expert Opin Drug Saf

    NIH Public Access Author Manuscript Expert Opin Drug Saf. Author manuscript; available in PMC 2009 March 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Expert Opin Drug Saf. 2008 March ; 7(2): 181±194. Sudden cardiac death secondary to antidepressant and antipsychotic drugs Serge Sicouri, MD and Charles Antzelevitch, PhD† Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY, USA Abstract A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use. Keywords antidepressants; antipsychotics; arrhythmias; Brugada syndrome; long QT syndrome; sudden cardiac death 1. Introduction Sudden unexplained death in individuals with mental health problems was first described in 1849 and a link with antipsychotic drugs was postulated over 40 years ago [1,2]. Starting in early 1990, a clear relationship has been established between antipsychotics, prolongation of the QT interval of the electrocardiogram (ECG), an atypical polymorphic tachycardia known as Torsade de pointes (TdP), and sudden cardiac death (SCD).
  • Current Topics in Medicinal Chemistry, 2016, 16, 3385-3403 REVIEW ARTICLE

    Current Topics in Medicinal Chemistry, 2016, 16, 3385-3403 REVIEW ARTICLE

    Send Orders for Reprints to [email protected] 3385 Cur rent Topics in Medicinal Chemistry, 2016, 16, 3385-3403 REVIEW ARTICLE ISSN: 1568-0266 eISSN: 1873-5294 Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Impact Factor: 2.9 The international Present and Future journal for in-depth reviews on Current Topics in Medicinal Chemistry BENTHAM SCIENCE Peng Li*, Gretchen L. Snyder and Kimberly E. Vanover Intra-Cellular Therapies Inc, 430 East 29th Street, Suite 900, New York, NY 10016, USA Abstract: Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approxi- mately 1% of the world’s population. This disease is associated with considerable morbidity placing a major financial burden on society. Antipsychotics have been the mainstay of the pharmacological treatment of schizophrenia for decades. The traditional typical and atypical antipsychotics demon- strate clinical efficacy in treating positive symptoms, such as hallucinations and delusions, while are A R T I C L E H I S T O R Y largely ineffective and may worsen negative symptoms, such as blunted affect and social withdrawal, as well as cognitive function. The inability to treat these latter symptoms may contribute to social Received: April 07, 2016 Revised: May 20, 2016 function impairment associated with schizophrenia. The dysfunction of multiple neurotransmitter Accepted: May 23, 2016 systems in schizophrenia suggests that drugs selectively targeting one neurotransmission pathway DOI: 10.2174/1568026616666160608 are unlikely to meet all the therapeutic needs of this heterogeneous disorder. Often, however, the un- 084834 intentional engagement of multiple pharmacological targets or even the excessive engagement of in- tended pharmacological targets can lead to undesired consequences and poor tolerability.
  • Clinical Manual of Geriatric Psychopharmacology This Page Intentionally Left Blank Clinical Manual of Geriatric Psychopharmacology

    Clinical Manual of Geriatric Psychopharmacology This Page Intentionally Left Blank Clinical Manual of Geriatric Psychopharmacology

    Clinical Manual of Geriatric Psychopharmacology This page intentionally left blank Clinical Manual of Geriatric Psychopharmacology Sandra A. Jacobson, M.D. Assistant Professor, Department of Psychiatry and Human Behavior, Brown Medical School, Providence, Rhode Island Ronald W. Pies, M.D. Clinical Professor of Psychiatry, Tufts University School of Medicine, Boston, Massachusetts Ira R. Katz, M.D. Professor of Psychiatry and Director, Section of Geriatric Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania Washington, DC London, England Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Publishing, Inc., represent the views and opinions of the individual authors and do not necessarily represent the policies and opinions of APPI or the American Psychiatric Association. Copyright © 2007 American Psychiatric Publishing, Inc. ALL RIGHTS RESERVED Manufactured in the United States of America on acid-free paper 11 10 09 08 07 5 4 3 2 1 First Edition Typeset in Adobe’s Formata and AGaramond.
  • Handbook of Common Poisonings in Children. INSTITUTION Food and Drug Administration (DREW), Washington, D.C

    Handbook of Common Poisonings in Children. INSTITUTION Food and Drug Administration (DREW), Washington, D.C

    O DOCUMENT BESUME ED 144 708 PS 099 577 $ ...,, / 1.- . ,TITLE - Handbook of CommOn Poisonings in Children. INSTITUTION Food and Drug Administration (DREW), Washington, D.C. " fEPORT NO , HEW-FDA-707004 pus DATE /6, ' NOTE -114p. ,.. 1 AyAILABLEFRO!! Superintendent of Documents, U.S. Government Printing ..... Office, Washington, D.C. 20402 (Stock No. 017-C12-0024074, $1.50) . EDRS PRICE NF -$0.83 HC-$6.01. Pins Postage. DESCRtPTORS Accident Prevention;*Children;Emergency'SqUad Personnel; *Governm'ent Publications; icGuidaS; Hospital Pe onnel; Pharmacists;- Physicians;_ *Reference Bo ks IDENTtFIERS, *Poisoning ABSTRACT This handbook for physicians, emergency room. personhel and pharmacists lists- the manufacturer, descriptiOn, / toxiaity, symptoms and findings, treatment, and references.for-73 . / poison substances considered by the Subcommittee on 1Ccidental 1 Poisoning of the American-Academi% of'Pediatrics to be most significant in terms of accidental poisoning of.ehildFen.' (BF) 1 *****************************f**************,************************** * .DOcuments acquirNd by ERIC inclUde many inforMal unpublished *. * materials not available from other-sources. ERIC makes every effort * * to obtain the'best copy available. Nevertheless, items of marginal * * reproducibility are often encountered and this affects the quality * *sof the 'microfiche and hardcopy reproddctions ERIC makes available * via the ERIC Document (reproduction Service (EDRS) .EDRS is not . * * responsible for the quality bf the original document. Reproductions * . *.supplied by EDRS, are the best that can beemade from the 'original. ******************41********r****************************************** U.S. DEPARTtAENT OF HEALTH, EDUCATION, AND WELFARE Public vice/Fo©d and Drug Administration 5600Fi Rockville, Maryland 20857 HEW (FDA) 16-7004 , , , Handbook of # ,. Common Poisonings in Children 1976,. 0 r FDA 4,1 . For we by the 044rorinlyndsrot el Deoumenes.