DOCSLIB.ORG

The Efficacy of Selective Serotonin Reuptake Inhibitors for the Management of Chronic Pain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Efficacy of Selective Serotonin Reuptake Inhibitors for the Management of Chronic Pain See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/14027493 The Efficacy of Selective Serotonin Reuptake Inhibitors for the Management of Chronic Pain Article in Journal of General Internal Medicine · July 1997 DOI: 10.1007/s11606-006-5088-3 · Source: PubMed CITATIONS READS 130 26 3 authors, including: Thomas O Staiger University of Washington Seattle 22 PUBLICATIONS 1,046 CITATIONS SEE PROFILE All content following this page was uploaded by Thomas O Staiger on 12 December 2016. The user has requested enhancement of the downloaded file. The Efficacy of Selective Serotonin Reuptake Inhibitors for the Management of Chronic Pain Alan C. Jung, MD, Thomas Staiger, MD, Mark Sullivan, MD, PhD OBJECTIVE: To assess the effectiveness of selective seroto- Fluoxetine was introduced as the first selective sero- nin reuptake inhibitors (SSRIs) in the management of chronic tonin reuptake inhibitor (SSRI) in the United States in pain. 1988. Since then, SSRIs have become the most frequently METHODS: Randomized, controlled trials of SSRIs in the prescribed antidepressant medications owing to their fa- management of chronic pain were identified by searching vorable side-effect profile.4 More than half of antidepres- MEDLINE from 1966 to 1997 and by contacting the manufac- sant prescriptions written in the primary care setting are turers of SSRIs available in the United States. for conditions other than depression.5 There is consider- MAIN RESULTS: Nineteen studies were identified, including able interest in the use of SSRIs for the management of 10 on the treatment of headache, 3 on diabetic neuropathy, 3 chronic pain, although they are not currently approved by on fibromyalgia, and 3 on mixed-chronic pain. SSRIs were the Food and Drug Administration for this purpose. This consistently helpful for mixed-chronic pain. Results were review summarizes available data on the value of these conflicting for migraine headache, tension headache, dia- medications for pain control in several clinical situations. betic neuropathy, and fibromyalgia. CONCLUSIONS: SSRIs appear to be beneficial for mixed- METHODS chronic pain. It is unclear, from the available evidence, whether SSRIs are beneficial for migraine headaches, tension head- We used the National Library of Medicine search en- aches, diabetic neuropathy, or fibromyalgia. For those pa- gine to search MEDLINE from 1966 to 1997 using the tients it may be reasonable to reserve SSRIs for those who medical subject heading (MeSH) term “pain,” exploding it, fail to respond to other medications or who are intolerant of and adding the following words in all fields: pain, neurop- their side effects. athy, migraine, and fibromyalgia. We also searched using KEY WORDS: chronic pain, management of; selective seroto- the MeSH term “serotonin uptake inhibitors” and the fol- nin reuptake inhibitors. lowing words in all fields: sertraline, paroxetine, fluoxe- J GEN INTERN MED 1997;12:384–389. tine, fluvoxamine, femoxetine, zimelidine, and citalopram. We combined results of these two searches with the term “and,” and selected for review randomized double-blind, he clinical management of chronic pain remains a controlled studies published in English and performed on Tchallenge. Despite advances in pain research and humans. References from studies reviewed provided addi- clinical treatment, rates of disability due to chronic pain tional sources of information. We also requested relevant continue to climb worldwide.1 Although chronic pain is studies from the manufacturers of Prozac (fluoxetine), treated with many medications, such as tricyclic anti- Zoloft (sertraline), Luvox (fluvoxamine), and Paxil (parox- depressants, nonsteroidal anti-inflammatory drugs, anti- etine), the four SSRIs available in the United States. convulsants, and opioids, none has shown outstanding ef- ficacy. Narcotics are usually avoided because of the risk HEADACHE of developing tolerance, dependence, and functional dete- rioration.2 Tricyclic antidepressants have proven efficacy Ten studies evaluated the efficacy of SSRIs in the treat- in the treatment of chronic pain conditions such as dia- ment of chronic headache (Table 1). Saper et al. compared betic neuropathy, fibromyalgia, chronic headaches, and fluoxetine (20–40 mg/d) with placebo in a randomized, post-herpetic neuralgia.3 Their ability to relieve pain in double-blind study of 64 patients with chronic daily head- these conditions appears to be independent of their anti- ache (headache more than 16 d/mo) and 58 patients with depressant effect and may be related to their effect on migraine headache (4–12 attacks/mo).6 After 3 months, neuronal reuptake of serotonin and norepinephrine. Un- patients with chronic daily headache taking fluoxetine fortunately, side effects including dry mouth, constipa- showed a 53% mean improvement in self-rated, overall tion, orthostatic hypotension, and urinary retention often headache status compared with a 17% mean improvement limit their use. in those receiving placebo (p 5 .029). Of those patients with chronic daily headache taking fluoxetine, 47% also ex- perienced at least a 50% improvement in mood compared with 24% of those in the placebo group (p 5 .097). Pa- Received from the Department of Medicine (ACJ, TS) and the tients receiving fluoxetine had a modest decrease in head- Department of Psychiatry, Multidisciplinary Pain Center (MS), University of Washington, Seattle. ache frequency but not severity. In contrast to its effect Address correspondence and reprint requests to Dr. Jung: on chronic daily headache, fluoxetine was not effective on Department of Medicine Residency Office, P.O. Box 356421, any measure of migraine headache with the exception of a University of Washington, Seattle, WA 98195. modest mood improvement at the end of the third month. 384 JGIM Volume 12, June 1997 385 Table 1. Randomized, Double-Blind, Controlled Studies of SSRIs in Headache Headache Study Design Type N Results Saper et al.,6 1994 Fluoxetine vs Chronic daily 64 Mean improvement in treated 53% vs 17% with placebo placebo (p 5 .029). Migraine 58 Fluoxetine 5 placebo Langemark and Olesen,7 Paroxetine vs sulpiride, Chronic 50 Both groups improved (p , .05) in headache 1994 crossover for tension score and analgesic use compared to baseline. nonresponders Patients testing both drugs showed better relief from sulpiride (p 5 .03). Manna et al.,8 1994 Fluvoxamine vs Chronic 40 Both groups improved from baseline in headache mianserine tension frequency (p , .01), pain severity (p , .01), and analgesic consumption (p , .05). Bendtsen et al.,9 1996 Threeway crossover Chronic 40 Amitriptyline reduced the area under the headache of amitriptyline vs tension curve compared to placebo (p 5 .002). Citalopram 5 citalopram vs placebo placebo (p 5 .68). Andersson and Petersen,10 Femoxetine vs Migraine 49 Both groups had fewer migraine attacks and fewer 1981 propranolol headache days compared to baseline (p , .001). There was no difference between treatment groups. Zeeberg et al.,11 1981 Femoxetine vs Migraine 59 Femoxetine 5 placebo placebo Orholm et al.,12 1986 Femoxetine vs Migraine 65 Femoxetine 5 placebo placebo Kangsmaniemi et al.,13 Crossover of Migraine 29 Compared to baseline, those receiving propranolol 1983 femoxetine vs had a decrease in attack frequency, headache propranolol index, and use of attack relieving drugs (p , .05). Femoxetine showed no significant effect. Adly et al.,14 1992 Fluoxetine vs Migraine 32 Headache scores in the fluoxetine treated group placebo improved compared to placebo group (p , .05); 14 patients failed to complete study. Bánk,15 1994 Fluvoxamine vs Migraine 64 Both groups improved over baseline (p , .02). amitrityline Langemark and Olesen compared paroxetine (20–30 for 8 weeks. Treatment periods were separated by 2-week mg/d) with sulpiride (200–400 mg/d), a dopamine antag- washout periods. Amitriptyline reduced the area under onist used as a neuroleptic in Europe, in a randomized, the headache curve (the sum of the daily recordings of double-blind, crossover study of 50 nondepressed pa- headache duration 3 headache intensity) by 30% com- tients with chronic tension-type headache.7 Both treat- pared with placebo (p 5 .002), but citalopram had no sig- ment groups experienced a significant decrease in head- nificant effect (p 5 .68). ache scores and analgesic use over 8 weeks compared Andersson and Petersen compared femoxetine (400 with baseline (p , .05). Patients testing both drugs showed mg/d), an SSRI not available in the United States, with significantly better relief from sulpiride (p 5 .03). A pla- propranolol (160 mg/d) for the prophylaxis of migraine cebo arm was not included in the study. headache.10 They randomized 49 patients in a double- Manna and colleagues enrolled 40 patients in a ran- blind, crossover trial of 6 months’ duration. There was no domized, double-blind comparison of fluvoxamine (50– significant difference between propranolol and femoxetine 100 mg/d) and mianserine (30–60 mg/d), a presynaptic, in the number of headache days or the number of mi- serotonin receptor antagonist, for the treatment of chronic, graine attacks. There was, however, significant improve- tension-type headache.8 Both treatment groups showed ment in headache parameters with each drug when com- significant improvement in headache frequency (p , .01), pared with baseline (p , .001). pain severity (p , .01), and analgesic use (p , .05). Flu- Zeeberg et al. studied the prophylactic effect on mi-
Load more

Recommended publications
  • (12) Patent Application Publication (10) Pub. No.: US 2012/0190743 A1 Bain Et Al
    US 2012O190743A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0190743 A1 Bain et al. (43) Pub. Date: Jul. 26, 2012 (54) COMPOUNDS FOR TREATING DISORDERS Publication Classification OR DISEASES ASSOCATED WITH (51) Int. Cl NEUROKININ 2 RECEPTORACTIVITY A6II 3L/23 (2006.01) (75) Inventors: Jerald Bain, Toronto (CA); Joel CD7C 69/30 (2006.01) Sadavoy, Toronto (CA); Hao Chen, 39t. ii; C Columbia, MD (US); Xiaoyu Shen, ( .01) Columbia, MD (US) A6IPI/00 (2006.01) s A6IP 29/00 (2006.01) (73) Assignee: UNITED PARAGON A6IP II/00 (2006.01) ASSOCIATES INC., Guelph, ON A6IPI3/10 (2006.01) (CA) A6IP 5/00 (2006.01) A6IP 25/00 (2006.01) (21) Appl. No.: 13/394,067 A6IP 25/30 (2006.01) A6IP5/00 (2006.01) (22) PCT Filed: Sep. 7, 2010 A6IP3/00 (2006.01) CI2N 5/071 (2010.01) (86). PCT No.: PCT/US 10/48OO6 CD7C 69/33 (2006.01) S371 (c)(1) (52) U.S. Cl. .......................... 514/552; 554/227; 435/375 (2), (4) Date: Apr. 12, 2012 (57) ABSTRACT Related U.S. Application Data Compounds, pharmaceutical compositions and methods of (60) Provisional application No. 61/240,014, filed on Sep. treating a disorder or disease associated with neurokinin 2 4, 2009. (NK) receptor activity. Patent Application Publication Jul. 26, 2012 Sheet 1 of 12 US 2012/O190743 A1 LU 1750 15OO 1250 OOO 750 500 250 O O 20 3O 40 min SampleName: EM2OO617 Patent Application Publication Jul. 26, 2012 Sheet 2 of 12 US 2012/O190743 A1 kixto CFUgan <tro CFUgan FIG.2 Patent Application Publication Jul.
    [Show full text]
  • (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]
  • The Evidence Report
    Obesity Education Initiative C LINICAL GUIDELINES ON THE IDENTIFICATION, EVALUATION, AND TREATMENT OF OVERWEIGHT AND OBESITY IN ADULTS The Evidence Report NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE C LINICAL GUIDELINES ON THE IDENTIFICATION, EVALUATION, AND TREATMENT OF OVERWEIGHT AND OBESITY IN ADULTS The Evidence Report NIH PUBLICATION NO. 98-4083 SEPTEMBER 1998 NATIONAL INSTITUTES OF HEALTH National Heart, Lung, and Blood Institute in cooperation with The National Institute of Diabetes and Digestive and Kidney Diseases NHLBI Obesity Education Initiative Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults F. Xavier Pi-Sunyer, M.D., M.P.H. William H. Dietz, M.D., Ph.D. Chair of the Panel Director Chief, Endocrinology, Diabetes, and Nutrition Division of Nutrition and Physical Activity Director, Obesity Research Center National Center for Chronic Disease Prevention St. Luke's/Roosevelt Hospital Center and Health Promotion Professor of Medicine Centers for Disease Control and Prevention Columbia University College of Physicians and Atlanta, GA Surgeons New York, NY John P. Foreyt, Ph.D. Professor of Medicine and Director Diane M. Becker, Sc.D., M.P.H. Nutrition Research Clinic Director Baylor College of Medicine Center for Health Promotion Houston, TX Associate Professor Department of Medicine Robert J. Garrison, Ph.D. The Johns Hopkins University Associate Professor Baltimore, MD Department of Preventive Medicine University of Tennessee, Memphis Claude Bouchard, Ph.D. Memphis, TN Professor of Exercise Physiology Physical Activity Sciences Scott M. Grundy, M.D., Ph.D. Laboratory Director Laval University Center for Human Nutrition Sainte Foy, Quebec University of Texas CANADA Southwestern Medical Center at Dallas Dallas, TX Richard A.
    [Show full text]
  • Newer Generation Antidepressants for Depressive Disorders in Children and Adolescents (Review)
    Newer generation antidepressants for depressive disorders in children and adolescents (Review) Hetrick SE, McKenzie JE, Cox GR, Simmons MB, Merry SN This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 11 http://www.thecochranelibrary.com Newer generation antidepressants for depressive disorders in children and adolescents (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER....................................... 1 ABSTRACT ...................................... 1 PLAINLANGUAGESUMMARY . 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . ..... 3 BACKGROUND .................................... 6 OBJECTIVES ..................................... 7 METHODS ...................................... 7 RESULTS....................................... 12 Figure1. ..................................... 14 Figure2. ..................................... 21 Figure3. ..................................... 22 Figure4. ..................................... 24 Figure5. ..................................... 25 Figure6. ..................................... 26 Figure7. ..................................... 27 Figure8. ..................................... 29 DISCUSSION ..................................... 36 AUTHORS’CONCLUSIONS . 40 ACKNOWLEDGEMENTS . 41 REFERENCES ..................................... 42 CHARACTERISTICSOFSTUDIES . 52 DATAANDANALYSES. 114 ADDITIONALTABLES. 116 WHAT’SNEW....................................
    [Show full text]
  • Pharmaceutical Appendix to the Tariff Schedule 2
    Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9
    [Show full text]
  • Download Product Insert (PDF)
    PRODUCT INFORMATION Desmethylene Paroxetine (hydrochloride) Item No. 15908 CAS Registry No.: 1394861-12-1 Formal Name: 4-[[(3S,4R)-4-(4-fluorophenyl)- H 3-piperidinyl]methoxy]-1,2- N benzenediol, monohydrochloride OH MF: C18H20FNO3 • HCl FW: 353.8 ≥98% Purity: F O OH Supplied as: A crystalline solid • HCl Storage: -20°C Stability: ≥2 years Information represents the product specifications. Batch specific analytical results are provided on each certificate of analysis. Laboratory Procedures Desmethylene paroxetine (hydrochloride) is supplied as a crystalline solid. A stock solution may be made by dissolving the desmethylene paroxetine (hydrochloride) in the solvent of choice. Desmethylene paroxetine (hydrochloride) is soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide (DMF), which should be purged with an inert gas. The solubility of desmethylene paroxetine (hydrochloride) in ethanol and DMSO is approximately 20 mg/ml and approximately 30 mg/ml in DMF. Description Paroxetine (Item No. 14998) is a potent, selective serotonin reuptake inhibitor (Ki = 0.72 nM) that has been used in cases of depression and anxiety disorder.1-3 Desmethylene paroxetine is a major urinary metabolite of paroxetine.4,5 This compound may be used in urine drug testing applications involving paroxetine toxicology or forensic analysis. References 1. Mattson, R.J., Catt, J.D., Denhart, D.J., et al. Conformationally restricted homotryptamines. 2. Indole cyclopropylmethylamines as selective serotonin reuptake inhibitors. J. Med. Chem. 48(19), 6023-6034 (2005). 2. Baldwin, D., Woods, R., Lawson, R., et al. Efficacy of drug treatments for generalised anxiety disorder: Systematic review and meta-analysis. BMJ 342, d1199 (2011). 3.
    [Show full text]
  • An Inventory of Literature on the Relation Between Drug Use, Impaired Driving and Traffic Accidents
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by National Documentation Centre on Drug Use E.M.C.D.D.A. DRUGS MISUSE RESEARCH DIVISION HEALTH RESEARCH BOARD An Inventory of Literature on the Relation between Drug Use, Impaired Driving and Traffic Accidents CT.97.EP.14 Research Team: Colin Gemmell Trinity College, Dublin Rosalyn Moran Drugs Misuse Research Division, Health Research Board James Crowley Professor, Transport Policy Research Institute, University College Dublin Richeal Courtney Medical Expert, for the Health Research Board EMCDDA: Lucas Wiessing February 1999 Please use the following citation: European Monitoring Centre for Drugs and Drug Addiction. An Inventory of Literature on the Relation betweenDrug Use, Impaired Driving and Traffic Accidents. (CT.97.EP.14) Lisbon: EMCDDA, February 1999. Contact Details Drugs Misuse Research Division Health Research Board 73 Lower Baggot Street Dublin 2 Ireland European Monitoring Centre for Drugs and Drug Addiction Rua Cruz de Santa Apolónia 23/25 1100, Lisboa Portugal. Further copies of this bibliography can be obtained from the EMCDDA at the above address. CREDITS Principal Researchers Ms Rosalyn Moran, Project Leader, Health Research Board Professor James Crowley, Professor, Transport Policy Research Institute, UCD Dr Richeal Courtney, Medical Expert, on behalf of the Health Research Board Research Assistants Colin Gemmell (Synthesis and Final Reports) Sarah Heywood (Literature Search and Collaborative Network) For the EMCDDA Lucas Wiessing
    [Show full text]
  • Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DIX to the HTSUS—Continued
    20558 Federal Register / Vol. 60, No. 80 / Wednesday, April 26, 1995 / Notices DEPARMENT OF THE TREASURY Services, U.S. Customs Service, 1301 TABLE 1.ÐPHARMACEUTICAL APPEN- Constitution Avenue NW, Washington, DIX TO THE HTSUSÐContinued Customs Service D.C. 20229 at (202) 927±1060. CAS No. Pharmaceutical [T.D. 95±33] Dated: April 14, 1995. 52±78±8 ..................... NORETHANDROLONE. A. W. Tennant, 52±86±8 ..................... HALOPERIDOL. Pharmaceutical Tables 1 and 3 of the Director, Office of Laboratories and Scientific 52±88±0 ..................... ATROPINE METHONITRATE. HTSUS 52±90±4 ..................... CYSTEINE. Services. 53±03±2 ..................... PREDNISONE. 53±06±5 ..................... CORTISONE. AGENCY: Customs Service, Department TABLE 1.ÐPHARMACEUTICAL 53±10±1 ..................... HYDROXYDIONE SODIUM SUCCI- of the Treasury. NATE. APPENDIX TO THE HTSUS 53±16±7 ..................... ESTRONE. ACTION: Listing of the products found in 53±18±9 ..................... BIETASERPINE. Table 1 and Table 3 of the CAS No. Pharmaceutical 53±19±0 ..................... MITOTANE. 53±31±6 ..................... MEDIBAZINE. Pharmaceutical Appendix to the N/A ............................. ACTAGARDIN. 53±33±8 ..................... PARAMETHASONE. Harmonized Tariff Schedule of the N/A ............................. ARDACIN. 53±34±9 ..................... FLUPREDNISOLONE. N/A ............................. BICIROMAB. 53±39±4 ..................... OXANDROLONE. United States of America in Chemical N/A ............................. CELUCLORAL. 53±43±0
    [Show full text]
  • Dissertation Enantioselective Β
    DISSERTATION ENANTIOSELECTIVE β-FUNCTIONALIZATION OF ENALS VIA N-HETEROCYCLIC CARBENE CATALYSIS Submitted by Nicholas Andrew White Department of Chemistry In partial fulfillment of the requirements For the Degree of Doctor of Philosophy Colorado State University Fort Collins, Colorado Fall 2015 Doctoral Committee: Advisor: Tomislav Rovis Alan J. Kennan Eugene Y.-X. Chen Robert M. Williams Matt J. Kipper Copyright by Nicholas Andrew White 2015 All Rights Reserved ABSTRACT ENANTIOSELECTIVE β-FUNCTIONALIZATION OF ENALS VIA N-HETEROCYCLIC CARBENE CATALYSIS A series of δ-nitroesters were synthesized through the N-heterocyclic carbene catalyzed coupling of enals and nitroalkenes. The asymmetric coupling of these substrates via the homoenolate pathway afford δ-nitroesters in good yield, diastereoselectivity, and enantioselectivity. This methodology allows for the rapid synthesis of δ-lactams. Using this approach, we synthesized the pharmaceutically relevant piperidines paroxetine and femoxetine. A novel single-electron oxidation pathway for the N-heterocyclic carbene generated Breslow intermediate has been developed. Nitroarenes have been shown to transfer an oxygen from the nitro group to the β-position of an enal in an asymmetric fashion to generate β-hydroxy esters. This reaction affords desired β-hydroxy ester products in good yield and enantioselectivity and tolerates a wide range of enal substrates. A dimerization of aromatic enals to form 3,4-disubstituted cyclopentanones has been investigated. Using a single-electron oxidant, aromatic enals couple to form cyclopenanone products in good yield, good enantioselectivity, and excellent diastereoselectivity. A cross coupling has also been developed to afford non-symmetrical cyclopentanone products. ii ACKNOWLEDGEMENTS First, and foremost, I would like to thank my advisor, Professor Tomislav Rovis for his supervision and guidance over the past five years.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,158,152 B2 Palepu (45) Date of Patent: Apr
    US008158152B2 (12) United States Patent (10) Patent No.: US 8,158,152 B2 Palepu (45) Date of Patent: Apr. 17, 2012 (54) LYOPHILIZATION PROCESS AND 6,884,422 B1 4/2005 Liu et al. PRODUCTS OBTANED THEREBY 6,900, 184 B2 5/2005 Cohen et al. 2002fOO 10357 A1 1/2002 Stogniew etal. 2002/009 1270 A1 7, 2002 Wu et al. (75) Inventor: Nageswara R. Palepu. Mill Creek, WA 2002/0143038 A1 10/2002 Bandyopadhyay et al. (US) 2002fO155097 A1 10, 2002 Te 2003, OO68416 A1 4/2003 Burgess et al. 2003/0077321 A1 4/2003 Kiel et al. (73) Assignee: SciDose LLC, Amherst, MA (US) 2003, OO82236 A1 5/2003 Mathiowitz et al. 2003/0096378 A1 5/2003 Qiu et al. (*) Notice: Subject to any disclaimer, the term of this 2003/OO96797 A1 5/2003 Stogniew et al. patent is extended or adjusted under 35 2003.01.1331.6 A1 6/2003 Kaisheva et al. U.S.C. 154(b) by 1560 days. 2003. O191157 A1 10, 2003 Doen 2003/0202978 A1 10, 2003 Maa et al. 2003/0211042 A1 11/2003 Evans (21) Appl. No.: 11/282,507 2003/0229027 A1 12/2003 Eissens et al. 2004.0005351 A1 1/2004 Kwon (22) Filed: Nov. 18, 2005 2004/0042971 A1 3/2004 Truong-Le et al. 2004/0042972 A1 3/2004 Truong-Le et al. (65) Prior Publication Data 2004.0043042 A1 3/2004 Johnson et al. 2004/OO57927 A1 3/2004 Warne et al. US 2007/O116729 A1 May 24, 2007 2004, OO63792 A1 4/2004 Khera et al.
    [Show full text]
  • Page 1 FINLANDS FÖRFATTNINGSSAMLING Utgiven I Helsingfors
    FINLANDS FÖRFATTNINGSSAMLING MuuMnrovvvvBeslutom läkemedelsförteckning asia av Säkerhets- och utvecklingscentret för läkemedelsområdet Utgiven i Helsingfors den 23 mars 2016 201/2016 Beslut av Säkerhets- och utvecklingscentret för läkemedelsområdet om läkemedelsförteckning Säkerhets- och utvecklingscentret för läkemedelsområdet har med stöd av 83 § i läke- medelslagen av den 10 april 1987 (395/1987) beslutat fastställa följande läkemedelsför- teckning: 1§ Förteckningens syfte Föreliggande beslut innehåller en förteckning över ämnen och droger som används medicinskt i Finland. Läkemedelsförteckningen upprättas med beaktande av bestämmel- serna i 3 och 5 § i läkemedelslagen. Med läkemedel avses ett preparat eller ämne vars ändamål är att vid invärtes eller ut- värtes bruk bota, lindra eller förebygga sjukdomar eller sjukdomssymtom hos människor eller djur. Som läkemedel betraktas också ett sådant ämne eller en sådan kombination av ämnen för invärtes eller utvärtes bruk som kan användas för att genom farmakologisk, im- munologisk eller metabolisk verkan återställa, korrigera eller modifiera fysiologiska funk- tioner eller utröna hälsotillståndet eller sjukdomsorsaker hos människor eller djur. Läkemedelsförteckningen är inte uttömmande. Till läkemedel räknas även sådana äm- nen och droger som inte nämns i denna förteckning men som uppfyller definitionen av lä- kemedel i läkemedelslagen. Utöver fastställande av läkemedelsförteckningen beslutar Säkerhets- och utvecklings- centret för läkemedelsområdet med stöd av 6 § i läkemedelslagen vid behov om ett ämne eller ett preparat ska betraktas som ett läkemedel. Centret beslutar separat i respektive fall om ett preparat som innehåller ett ämne i förteckningen ska betraktas som ett läkemedel med beaktande av produktens framställningssätt, sammansättning, dess farmakologiska egenskaper, hur det används, dess spridning, hur känt det är hos konsumenterna och de ris- ker som kan vara förenade med dess användning.
    [Show full text]
  • Review of Existing Classification Efforts
    Project No. TREN-05-FP6TR-S07.61320-518404-DRUID DRUID Driving under the Influence of Drugs, Alcohol and Medicines Integrated Project 1.6. Sustainable Development, Global Change and Ecosystem 1.6.2: Sustainable Surface Transport 6th Framework Programme Deliverable 4.1.1 Review of existing classification efforts Due date of deliverable: (15.01.2008) Actual submission date: (07.02.2008) Start date of project: 15.10.2006 Duration: 48 months Organisation name of lead contractor for this deliverable: UGent Revision 1.0 Project co-funded by the European Commission within the Sixth Framework Programme (2002-2006) Dissemination Level PU Public X PP Restricted to other programme participants (including the Commission Services) RE Restricted to a group specified by the consortium (including the Commission Services) CO Confidential, only for members of the consortium (including the Commission Services) Task 4.1 : Review of existing classification efforts Authors: Kristof Pil, Elke Raes, Thomas Van den Neste, An-Sofie Goessaert, Jolien Veramme, Alain Verstraete (Ghent University, Belgium) Partners: - F. Javier Alvarez (work package leader), M. Trinidad Gómez-Talegón, Inmaculada Fierro (University of Valladolid, Spain) - Monica Colas, Juan Carlos Gonzalez-Luque (DGT, Spain) - Han de Gier, Sylvia Hummel, Sholeh Mobaser (University of Groningen, the Netherlands) - Martina Albrecht, Michael Heiβing (Bundesanstalt für Straßenwesen, Germany) - Michel Mallaret, Charles Mercier-Guyon (University of Grenoble, Centre Regional de Pharmacovigilance, France) - Vassilis Papakostopoulos, Villy Portouli, Andriani Mousadakou (Centre for Research and Technology Hellas, Greece) DRUID 6th Framework Programme Deliverable D.4.1.1. Revision 1.0 Review of Existing Classification Efforts Page 2 of 127 Introduction DRUID work package 4 focusses on the classification and labeling of medicinal drugs according to their influence on driving performance.
    [Show full text]