DOCSLIB.ORG

United States Patent 19 11) Patent Number: 5,387,604 Mcdonald Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
United States Patent 19 11) Patent Number: 5,387,604 Mcdonald Et Al US005387604A United States Patent 19 11) Patent Number: 5,387,604 McDonald et al. 45 Date of Patent: Feb. 7, 1995 (54) 14 BENZODIOXIN DERIVATIVES AND pp. 323-330, Role of 5HT1-like receptors in the reduc THEIR USE AS SEROTONIN 5HT tion of porcine cranial arteriovenous anastomotic shunt AGONSTS ing by Sumatriptan. 75 Inventors: Ian A. McDonald, Loveland; Ronald Saxena, et al, TiPS, May 1989, vol. 10, pp. 200-204; C. Bernotas, Cincinnati; Mark W. 5HT1-like receptor agonists and the pathophysiology Dudley, Somerville; Jeffrey S. of migraine. Sprouse, Cincinnati, all of Ohio Hamel et al., Br. J. Pharmacol, (1991), 102, pp. 227-233; Contractile 5HT1 receptors in human isolated pial arte 73) Assignee: Merrell Dow Pharmaceuticals Inc., rioles: correlation with 5-HT1D binding sites. Cincinnati, Ohio Edward E. Schwiezer, et al.; Psychopharmacology Bul 21 Appl. No.: 962,434 leting, vol. 22, No. 1, 1986, pp. 183-185; Open Trial of Buspirone in the Treatment of Major Depressive Disor 22 Filed: Oct. 16, 1992 der. Related U.S. Application Data European Journal of Pharmacology, 180 (1990) pp. 339-349, Dreteler, et al.; Comparison of the cardiovas 60 Division of Ser. No. 735,700, Jul. 30, 1991, Pat. No. cular effects of the 5-HT1A receptor agonist flexinoxan 5,189,179, which is a continuation-in-part of Ser. No. with that of 8-OH-DPAT in the rat. 574,710, Aug. 29, 1990, abandoned. European Journal of Pharmacology, 182 (1990) 63-72, 51) int. C.6 .................. C07D 319/20: A61K 31/335. Connor, et al.; Cardiovascular effects of 5HT1 receptor 52 U.S. C. ..................................... 514/456; 549/366 agonists injected into the dorsal raphe nucleus of con 58 Field of Search ......................... 549/366; 514/456 scious rats. 56 References Cited Clinical Neuropharmacology, vol. 14, No. 3, pp. 245-250, Julio Pascual, et al.; An open trial of Buspirone U.S. PATENT DOCUMENTS in Migraine Prophylaxis. Preliminary Report. (1990). 2,725,386 11/1955 Bovet et al. ...................... 260/340.3 European Journal of Pharmacology, 163, (1989) 4,614,807 9/1986 Flaugh ................................ 54.8/507 133-136, Peroutka, et al; Sumatriptan (GR 43175) inter FOREIGN PATENT DOCUMENTS acts selectively with 5-HT1B and 5-HT1D binding sites. 0025727 3/1981 European Pat. Off. Primary Examiner-David B. Springer 0054304 12/1981 European Pat. Off. Attorney, Agent, or Firm-J. Michael Dixon 0252005 6/1987 European Pat. Off. 478954A 4/1992 European Pat. Off. ............ 549/366 57 ABSTRACT OTHER PUBLICATIONS The present invention is directed to a new class of sero Derwent Abstract No. 88-16312224. tonin 5HT1A agonists. Derwent Abstract No. 86-190385/30. Marinus O. den Boer, etal, Br. J. Pharmacol (1991), 102, 39 Claims, No Drawings 5,387,604 1. 2 14 BENZODIOXIN DERIVATIVES AND THEIR USE ASSEROTONIN 5HTAGONISTS This is a divisional of application Ser. No. 5 07/735,700, filed Jul. 30, 1991, issued as U.S. Pat. No. 5,189,179, on Feb. 23, 1993, which is a continuation in Ol-Q) part of application Ser. No. 07/574,710, filed Aug. 29, 1990, now abandoned. in which R is represented by a substituent selected from The present invention is directed to a new class of 10 the group consisting of hydrogen, halogen, C14 alkyl, serotonin 5HT1A and 5HT1D agonists, their use in the C1-4 alkoxy, O-CH2-C6H5, CF3, OCF3, OH, NO2, treatment of anxiety, depression, migraine, stroke and CN, -CONR5R6, -CH2SO2NR5R6, -SO2NR5R6, hypertension as well as pharmaceutical and diagnostic -COOR7 or -OCH2COOR; R5 and R5 are each inde compositions containing them. pendently represented by H or C14 alkyl; R7 is repre In accordance with the present invention, a new class 15 sented by H, C1-4 alkyl, phenyl, substituted phenyl or an of serotonin 5HT1A and 1D agonists have been discov alkylphenyl substituent in which the phenyl ring may be ered which can be described by the following formula: optionally substituted; A is represented by H, or C14 alkyl; or a pharmaceutically acceptable salt thereof; with the proviso that when Her is an indolyl derivative, FORMULAI 20 then R1 is not a carbonyl derivative. Y The compounds encompassed by Formula I above BN-CH-AIka-D-CO-a-N may also be represented by the following subgeneric / Het X Z R formulae: in which R, A, B, Alk, D, X,Y, Z, and R1 are as defined above. Y FORMULA a B--CH-AI-D-co X Z R R A.N Y FORMULAIb O B--ch-A-D-co X Z R O R These compounds mimic the effects of serotonin at the 5HT1A and Dreceptor. They are useful in the treat 45 ment of anxiety, depression, migraine, stroke and hyper tension. As used in this application: in which B is represented by a C14 alkylene bridging a) the term "halogen' refers to a fluorine, chlorine, or group; Alk is represented by a linear alkylene bridging bromine atom; group containing from 2-8 carbon atoms which may 50 b) the terms "lower alkyl group and C1-4 alkyl” refer optionally be mono-substituted at one carbon atom with to a branched or straight chained alkyl group con a C14 alkyl, phenyl, substituted phenyl or an alkyl taining from 1-4 carbon atoms, such as methyl, phenyl substituent in which the phenyl ring may be ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc.; optionally substituted; D is represented by a bond or an c) the terms "lower alkoxy group and C1-4 alkoxy.' ethenylene bridging group; X, Y, and Z are each inde 55 refer to a straight or branched alkoxy group con pendently represented by hydrogen, C1-4 alkyl, phenyl, taining from 1-4 carbon atoms, such as methoxy, substituted phenyl or alkylphenyl in which the phenyl ethoxy, n-propoxy, isopropoxy, n-butoxy, isobu ring may be optionally substituted; R1 is represented by toxy, etc.; a substituent selected from the group consisting of hy d) the term “substituted phenyl ring” refers to a drogen, halogen, C1-4 alkyl, C1-5 alkoxy, CF3, OCF3, 60 phenyl moiety (C6H5) which is substituted with up OH, NO2, CN, -CONR2R3, -NR2R3, -COOR4, to 3 substituents, each substituent is independently -OCH2COOR4, -CH2SO2NR2R3, and -SO2NR2R3; selected from the group consisting of halogens, R2 and R3 are each independently represented by H or C1-4 alkyl, C14 alkoxy, CF3, OCF3, OH, CN, and a C14 alkyl; R4 is represented by H, C14 alkyl, phenyl, NO2. These substituents may be the same or differ substituted phenyl or an alkylphenyl substituent in 65 ent and may be located at any of the ortho, meta, or - which the phenyl ring may be optionally substituted; para positions. Het is represented by one of the following substituents: e) the term "alkylphenyl substituent' refers to the following structure, -(CH2)n-C6H5, in which m 5,387,604 3 4. is an integer from 1-3. This phenyl ring may be colic, lactic, pyruvic, malonic, succinic, glutaric, fu substituted in the manner described immediately maric, malic, tartaric, citric, ascorbic, maleic, hydrox above. ymaleic, benzoic, hydroxy-benzoic, phenylacetic, cin f) the term "pharmaceutically acceptable salt” refers namic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic to either a basic addition salt or an acid addition 5 acid, and sulfonic acids such as methanesulfonic acid salt. and 2-hydroxyethane sulfonic acid. Such salts can exist g) the phrase "C1-4 alkylene bridging group' refers to in either a hydrated or substantially anhydrous form. In a methylene, ethylene, propylene, butylene, 1 general, the acid addition salts of these compounds are methyl-ethylene, 2-methyl-ethylene, 2-methyl-pro soluble in water and various hydrophilic organic sol pylene, 2-ethyl-ethylene, 1-ethyl-ethylene, etc. 10 vents, and which in comparison to their free base forms, h) the term “ethenylene bridging group' refers to the generally demonstrate higher melting points. following substituent:-CH=CH-. The expression "pharmaceutically acceptable basic i) the term "Alk” refers to a linear alkylene group addition salts' is intended to apply to any non-toxic which may be represented by the following struc organic or inorganic basic addition salts of the com ture: -(CH2)-CHL-(CH2), in which p and s 15 are each independently represented by an integer pounds represented by Formula I or any of its interme from 0-7 and L is represented by H, C1-4 alkyl, diates. Illustrative bases which form suitable salts in phenyl, substituted phenyl or an alkylphenyl sub clude alkali metal or alkaline-earth metal hydroxides stituent in which the phenyl ring may be optionally such as sodium, potassium, calcium, magnesium, or substituted, with the proviso that the sum p and sis barium hydroxides; ammonia, and aliphatic, alicyclic, from 1-7. Representative examples of such linear or aromatic organic amines such as methylamine, di alkylene groups include ethylene, propylene, butyl methylamine, trimethylamine, and picoline. Either the ene, hexylene, 8-benzyl-pentylene, g-ethyl-hepty mono- or di-basic salts can be formed with those com lene, a-phenyl-propylene, g-benzylpentylene, a pounds. methylpentylene, a-methylbutylene, etc. For the Some of the compounds of Formula I contain one or purposes of this application, the d-carbon should 25 more asymmetric centers and will therefore exist as be considered to be the carbon atom immediately enantiomers and diastereomers. Any reference in this adjacent to the carbon atom bearing the Y-substitu application to one of the compounds represented by ent. Formula I, or any intermediate thereof, should be con j) the term “indolyl derivative' refers to a compound strued as covering a specific optical isomer, a racemic in which Het is represented by: 30 mixture or a diastereomeric mixture. The specific opti cal isomers can be synthesized or can be separated and recovered by techniques known in the art such as chro matography on chiral stationary phases, resolution via 35 chiral salt formation and subsequent separation by selec N tive crystallization, or enzymatic hydrolysis using ste reoselective esterases as is known in the art.
Load more

Recommended publications
  • Ayahuasca: Spiritual Pharmacology & Drug Interactions
    Ayahuasca: Spiritual Pharmacology & Drug Interactions BENJAMIN MALCOLM, PHARMD, MPH [email protected] MARCH 28 TH 2017 AWARE PROJECT Can Science be Spiritual? “Science is not only compatible with spirituality; it is a profound source of spirituality. When we recognize our place in an immensity of light years and in the passage of ages, when we grasp the intricacy, beauty and subtlety of life, then that soaring feeling, that sense of elation and humility combined, is surely spiritual. The notion that science and spirituality are somehow mutually exclusive does a disservice to both.” – Carl Sagan Disclosures & Disclaimers No conflicts of interest to disclose – I don’t get paid by pharma and have no potential to profit directly from ayahuasca This presentation is for information purposes only, none of the information presented should be used in replacement of medical advice or be considered medical advice This presentation is not an endorsement of illicit activity Presentation Outline & Objectives Describe what is known regarding ayahuasca’s pharmacology Outline adverse food and drug combinations with ayahuasca as well as strategies for risk management Provide an overview of spiritual pharmacology and current clinical data supporting potential of ayahuasca for treatment of mental illness Pharmacology Terms Drug ◦ Term used synonymously with substance or medicine in this presentation and in pharmacology ◦ No offense intended if I call your medicine or madre a drug! Bioavailability ◦ The amount of a drug that enters the body and is able to have an active effect ◦ Route specific: bioavailability is different between oral, intranasal, inhalation (smoked), and injected routes of administration (IV, IM, SC) Half-life (T ½) ◦ The amount of time it takes the body to metabolize/eliminate 50% of a drug ◦ E.g.
    [Show full text]
  • The Migraine Attack As a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory
    ISSN 0017-8748 Headache doi: 10.1111/head.13214 VC 2017 American Headache Society Published by Wiley Periodicals, Inc. Views and Perspectives The Migraine Attack as a Homeostatic, Neuroprotective Response to Brain Oxidative Stress: Preliminary Evidence for a Theory Jonathan M. Borkum, PhD Background.—Previous research has suggested that migraineurs show higher levels of oxidative stress (lipid peroxides) between migraine attacks and that migraine triggers may further increase brain oxidative stress. Oxidative stress is trans- duced into a neural signal by the TRPA1 ion channel on meningeal pain receptors, eliciting neurogenic inflammation, a key event in migraine. Thus, migraines may be a response to brain oxidative stress. Results.—In this article, a number of migraine components are considered: cortical spreading depression, platelet acti- vation, plasma protein extravasation, endothelial nitric oxide synthesis, and the release of serotonin, substance P, calcitonin gene-related peptide, and brain-derived neurotrophic factor. Evidence is presented from in vitro research and animal and human studies of ischemia suggesting that each component has neuroprotective functions, decreasing oxidant production, upregulating antioxidant enzymes, stimulating neurogenesis, preventing apoptosis, facilitating mitochondrial biogenesis, and/or releasing growth factors in the brain. Feedback loops between these components are described. Limitations and challenges to the model are discussed. Conclusions.—The theory is presented that migraines are an integrated
    [Show full text]
  • PMA-Sio2: Heteropolyacid Catalysis for Michael Addition-Convenient Route to Substituted-3-Indoles
    Available online at www.derpharmachemica.com ISSN 0975-413X Der Pharma Chemica, 2017, 9(13):112-117 CODEN (USA): PCHHAX (http://www.derpharmachemica.com/archive.html) PMA-SiO2: Heteropolyacid Catalysis for Michael Addition-Convenient Route to Substituted-3-Indoles Vijay Kumar Pasala* Deapartment of Chemistry, Osmania University, Hyderabad-500007, Telangana, India ABSTRACT Synthesis of 3-substituted indoles in a hassel-free, ecofriendly manner by treating indoles with α, β-unsaturated carbonyl or nitro compounds under acidic conditions to give good to excellent yields with shorter reaction durations are described. The catalyst is recyclable for three to four times without great loss in the activity. Keywords: Phosphomolybdic Acid (PMA), Substituted indoles, α, β-unsaturated carbonyl compounds, α, β-unsaturated nitro compounds, Michael addition INTRODUCTION Heterocyclic chemistry is one of the quintessential branches of organic synthesis beaconing towards new scaffolds with medicinal values, new methodologies to the existing active principles etc. One among such skeletons is indole. It is perhaps the most common heterocycles in chemistry and its derivatives are obtained from coal pitch, variety of plants or by the bacterial decay of tryptophan in the intestine [1]. Indole derivatives serve as signaling chemicals in plants and animals, as nucleus building blocks (serotonin [2] (A) a crucial neurotransmitter in the central nervous system [3]), as antibacterial [4], antiviral [5], protein kinase inhibitors [6], anticancer agents [7], entheogens (psilocybin (B) causes perceptional changes), hormones (melatonin (C) regulates sleep and wakefulness), antidepressants (roxindole (D), bufotenin (E)), sumatriptan (F) for the treatment of migraine and ondansetron (G) for the suppression of nausea and vastly found in natural products such as alkaloids (Corynanthe, Iboga, and Aspidosperma alkaloids) [8-10], indigoids etc., which originate, either fully or partly, from bio-oxidation of indoles [11].
    [Show full text]
  • Pharmacokinetics, Pharmacodynamics and Drug
    pharmaceutics Review Pharmacokinetics, Pharmacodynamics and Drug–Drug Interactions of New Anti-Migraine Drugs—Lasmiditan, Gepants, and Calcitonin-Gene-Related Peptide (CGRP) Receptor Monoclonal Antibodies Danuta Szkutnik-Fiedler Department of Clinical Pharmacy and Biopharmacy, Pozna´nUniversity of Medical Sciences, Sw.´ Marii Magdaleny 14 St., 61-861 Pozna´n,Poland; [email protected] Received: 28 October 2020; Accepted: 30 November 2020; Published: 3 December 2020 Abstract: In the last few years, there have been significant advances in migraine management and prevention. Lasmiditan, ubrogepant, rimegepant and monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) are new drugs that were launched on the US pharmaceutical market; some of them also in Europe. This publication reviews the available worldwide references on the safety of these anti-migraine drugs with a focus on the possible drug–drug (DDI) or drug–food interactions. As is known, bioavailability of a drug and, hence, its pharmacological efficacy depend on its pharmacokinetics and pharmacodynamics, which may be altered by drug interactions. This paper discusses the interactions of gepants and lasmiditan with, i.a., serotonergic drugs, CYP3A4 inhibitors, and inducers or breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) inhibitors. In the case of monoclonal antibodies, the issue of pharmacodynamic interactions related to the modulation of the immune system functions was addressed. It also focuses on the effect of monoclonal antibodies on expression of class Fc gamma receptors (FcγR). Keywords: migraine; lasmiditan; gepants; monoclonal antibodies; drug–drug interactions 1. Introduction Migraine is a chronic neurological disorder characterized by a repetitive, usually unilateral, pulsating headache with attacks typically lasting from 4 to 72 h.
    [Show full text]
  • The Serotonergic System in Migraine Andrea Rigamonti Domenico D’Amico Licia Grazzi Susanna Usai Gennaro Bussone
    J Headache Pain (2001) 2:S43–S46 © Springer-Verlag 2001 MIGRAINE AND PATHOPHYSIOLOGY Massimo Leone The serotonergic system in migraine Andrea Rigamonti Domenico D’Amico Licia Grazzi Susanna Usai Gennaro Bussone Abstract Serotonin (5-HT) and induce migraine attacks. Moreover serotonin receptors play an impor- different pharmacological preventive tant role in migraine pathophysiolo- therapies (pizotifen, cyproheptadine gy. Changes in platelet 5-HT content and methysergide) are antagonist of are not casually related, but they the same receptor class. On the other may reflect similar changes at a neu- side the activation of 5-HT1B-1D ronal level. Seven different classes receptors (triptans and ergotamines) of serotoninergic receptors are induce a vasocostriction, a block of known, nevertheless only 5-HT2B-2C neurogenic inflammation and pain M. Leone • A. Rigamonti • D. D’Amico and 5HT1B-1D are related to migraine transmission. L. Grazzi • S. Usai • G. Bussone (౧) syndrome. Pharmacological evi- C. Besta National Neurological Institute, Via Celoria 11, I-20133 Milan, Italy dences suggest that migraine is due Key words Serotonin • Migraine • e-mail: [email protected] to an hypersensitivity of 5-HT2B-2C Triptans • m-Chlorophenylpiperazine • Tel.: +39-02-2394264 receptors. m-Chlorophenylpiperazine Pathogenesis Fax: +39-02-70638067 (mCPP), a 5-HT2B-2C agonist, may The 5-HT receptor family is distinguished from all other 5- Introduction 1 HT receptors by the absence of introns in the genes; in addi- tion all are inhibitors of adenylate cyclase [1]. Serotonin (5-HT) and serotonin receptors play an important The 5-HT1A receptor has a high selective affinity for 8- role in migraine pathophysiology.
    [Show full text]
  • Triptans Step Therapy/Quantity Limit Criteria
    Triptans Step Therapy/Quantity Limit Criteria Program may be implemented with the following options 1) step therapy 2) quantity limits or 3) step therapy with quantity limits For Blue Cross and Blue Shield of Illinois Option 1 (step therapy only) will apply. Brand Generic Dosage Form Amerge® naratriptan tablets Axert® almotriptan tablets Frova® frovatriptan tablets Imitrex® sumatriptan injection*, nasal spray, tablets* Maxalt® rizatriptan tablets Maxalt-MLT® rizatriptan tablets Relpax® eletriptan tablets Treximet™ sumatriptan and naproxen tablets Zomig® zolmitriptan tablets, nasal spray Zomig-ZMT® zolmitriptan tablets * generic available and included as target agent in quantity limit edit FDA APPROVED INDICATIONS1-7 The following information is taken from individual drug prescribing information and is provided here as background information only. Not all FDA-approved indications may be considered medically necessary. All criteria are found in the section “Prior Authorization Criteria for Approval.” Amerge® Tablets1, Axert® Tablets2, Frova® Tablets3,Imitrex® injection4, Imitrex Nasal Spray5, Imitrex Tablets6, Maxalt® Tablets7, Maxalt-MLT® Tablets7, Relpax® Tablets8, Treximet™ Tablets9, Zomig® Tablets10, Zomig-ZMT® Tablets10, and Zomig® Nasal Spray11 Amerge (naratriptan), Axert (almotriptan), Frova (frovatriptan), Imitrex (sumatriptan), Maxalt (rizatriptan), Maxalt-MLT (rizatriptan orally disintegrating), Relpax (eletriptan), Treximet (sumatriptan/naproxen), Zomig (zolmitriptan), and Zomig-ZMT (zolmitriptan orally disintegrating) tablets, and Imitrex (sumatriptan) and Zomig (zolmitriptan) nasal spray are all indicated for the acute treatment of migraine attacks with or without aura in adults. They are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine. Safety and effectiveness of all of these products have not been established for cluster headache, which is present in an older, predominantly male population.
    [Show full text]
  • (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact
    pharmaceuticals Review Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact Andreia Machado Brito-da-Costa 1 , Diana Dias-da-Silva 1,2,* , Nelson G. M. Gomes 1,3 , Ricardo Jorge Dinis-Oliveira 1,2,4,* and Áurea Madureira-Carvalho 1,3 1 Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal; [email protected] (A.M.B.-d.-C.); ngomes@ff.up.pt (N.G.M.G.); [email protected] (Á.M.-C.) 2 UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal 3 LAQV-REQUIMTE, Laboratory of Pharmacognosy, Department of Chemistry, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal 4 Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal * Correspondence: [email protected] (D.D.-d.-S.); [email protected] (R.J.D.-O.); Tel.: +351-224-157-216 (R.J.D.-O.) Received: 21 September 2020; Accepted: 20 October 2020; Published: 23 October 2020 Abstract: Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids.
    [Show full text]
  • Daily Triptans for Headache
    Expert Opinion Daily Triptans for Headache Case History Submitted by Randolph W. Evans, MD Expert Opinion by Lawrence Robbins, MD Key words: headache, triptans Abbreviations: CDH chronic daily headache (Headache 2001;41:907-909) Will a triptan a day keep the headache away? I advised the patient that the increased frequency of the headaches could be rebound due to sumatriptan CLINICAL HISTORY and that the headaches might decrease by restricting This 47-year-old woman has a history of migraine the sumatriptan to no more than 2 days per week and since aged 4 years. Until 1 year ago, the headaches oc- starting another preventative such as sodium valpro- curred one to two times per week, lasted all day, re- ate. She is concerned about the possible side effects sulted in functional incapacity, and were not relieved of sodium valproate, which she has read can make you by over-the-counter medications or nonsteroidal anti- fat and bald. She also stated that the headaches were inflammatory drugs. About 10 years ago, she was tak- quite tolerable with the daily sumatriptan and she ing Fiorinal #3 but stopped when she developed could not see the difference between taking daily rebound headaches. She has been on multiple preven- sumatriptan as compared to a preventative which may tative medications including amitriptyline, ␤-blockers, or may not work and may have significant side effects. paroxetine, fluoxetine, and verapamil which were ei- Questions.—Is there evidence to support daily ther not effective or stopped due to side effects. triptan use for migraine? What would you recom- One year ago, she saw another neurologist and mend in this case? had an MRI scan of the brain with normal findings.
    [Show full text]
  • European Patent Office of Opposition to That Patent, in Accordance with the Implementing Regulations
    (19) TZZ _T (11) EP 2 666 772 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 409/04 (2006.01) C07D 209/16 (2006.01) 01.03.2017 Bulletin 2017/09 C07D 209/18 (2006.01) C07D 209/38 (2006.01) (21) Application number: 13173141.6 (22) Date of filing: 12.12.2003 (54) Synthesis of amines and intermediates for the synthesis thereof Synthese von Aminen und Zwischenverbindungen für die Synthese davon Synthèse d’amines et intermédiaires pour leur synthèse (84) Designated Contracting States: • DEMERSON C A ET AL: "ETODOLIC ACID AND AT BE BG CH CY CZ DE DK EE ES FI FR GB GR RELATED COMPOUNDS CHEMISTRY AND HU IE IT LI LU MC NL PT RO SE SI SK TR ANTIINFLAMMATORY ACTIONS OF SOME POTENT DI-AND TRISUBSTITUTED (30) Priority: 20.12.2002 EP 02406128 1,3,4,9-TETRAHYDROPYRANO not 3,4-B 3/4 INDOLE-I-ACETIC ACIDS", JOURNAL OF (43) Date of publication of application: MEDICINALCHEMISTRY, AMERICAN CHEMICAL 27.11.2013 Bulletin 2013/48 SOCIETY, vol. 19, no. 3, 1 March 1976 (1976-03-01), pages391-395, XP000940626, ISSN: (62) Document number(s) of the earlier application(s) in 0022-2623, DOI: 10.1021/JM00225A010 accordance with Art. 76 EPC: • HARUYASU ET ALL: "Possible metabolic 03799560.2 / 1 572 647 Intermediatesfrom IAA to beta-acid in Rice Bran", AGR. BIOL. CHEM., vol. 40, no. 12, 1976, pages (73) Proprietor: BASF SE 2465-2470, XP002714693, 67056 Ludwigshafen am Rhein (DE) • SOLL R M ET AL: "Multigram preparation of 1,8-diethyl-7-hydroxy-1,3,4,9-tetrahydropy (72) Inventors: rano[3,4-b]indole-1-acetic acid, a phenolic • Berens, Ulrich metabolite of the analgesic and antiinflammatory 79589 Binzen (DE) agent etodolac", THE JOURNAL OF ORGANIC • Dosenbach, Oliver CHEMISTRY, AMERICAN CHEMICAL SOCIETY 79415 Bad Bellingen (DE) [NOT]ETC.
    [Show full text]
  • Patient Information Leaflet
    Package Leaflet: Information for the user Sumatriptan 50 mg film-coated tablets Sumatriptan 100 mg film-coated tablets sumatriptan Read all of this leaflet carefully before you start using this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have any further questions, ask your doctor or pharmacist. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Sumatriptan tablet is and what it is used for 2. What you need to know before you use Sumatriptan tablet 3. How to use Sumatriptan tablet 4. Possible side effects 5. How to store Sumatriptan tablet 6. Contents of the pack and other information 1. What Sumatriptan tablet is and what it is used for Sumatriptan belongs to a group of medicines called serotonin receptor (5-HT1) agonists. Migraine headaches are thought to result from the dilatation of blood vessels. Sumatriptan constricts these blood vessels, thus relieving the migraine headache. Sumatriptan tablet is used to treat migraine attacks with or without aura (aura is a premonition usually connected with flashes of light, serrated images, stars or waves). 2. What you need to know before you use Sumatriptan tablet Do not use Sumatriptan tablet: - if you are allergic to sumatriptan or any of the other ingredients of this medicine (listed in section 6).
    [Show full text]
  • The Impact of Triptan and Doxycycline on Neuroinflammatory Biomarkers in Acute Migraine: Study Protocol of a Randomized Controlled Trial Study Protocol
    iMedPub Journals INTERNATIONAL ARCHIVES OF MEDICINE 2015 http://journals.imed.pub SECTION: NEUROLOGY Vol. 8 No. 13 ISSN: 1755-7682 doi: 10.3823/1612 The impact of triptan and doxycycline on neuroinflammatory biomarkers in acute migraine: study protocol of a randomized controlled trial STUDY PROTOCOL Shaheen E Lakhan, MD, Abstract PhD, MEd, MS1 Background: Increased inflammatory cytokines and matrix meta- 1 Neurological Institute, Cleveland Clinic, lloproteinases (MMPs) have been recently implicated in migraine. In- Euclid Ave, S100C, Cleveland OH . flammation may be a key player in the pathophysiology of migraine by altering blood-brain barrier (BBB) function. As an inflammation induced MMP, MMP-9 is involved in both BBB disruption and neuro- Contact information: pathic pain, and is largely derived by neutrophil degranulation during neutrophil-BBB interaction. The tetracycline group of antibiotics may Shaheen E Lakhan, MD, PhD, MEd, MS. Neurological Institute, Cleveland Clinic, suppress MMP production and neutrophil degranulation. 9500 Euclid Ave, S100C, Cleveland OH 44195. Methods/Design: We hypothesize that migraine is a primary neu- Tel: (216) 444-2200 roinflammatory disorder. We will address this theory by measuring serum biomarkers in healthy controls and after one of three abortive slakhan @gnif.org therapy strategies for acute migraine attacks and inter-ictally. We intend to investigate known neuroinflammatory biomarkers with a focus on BBB breakdown during acute migraine attacks and assess marker responses to conventional treatment (triptans), novel MMP targeted therapy (doxycycline), or a combination of triptan and do- xycycline. We will measure the effects of the interventions on neu- roinflammatory markers for acute migraine attacks, clinical outcomes (headache relief and recurrence) for acute migraine attacks, inter- ictal neuroinflammatory load per serum biomarkers in migraineurs versus healthy controls, and neuroinflammatory markers correlation with headache duration and peak headache intensity during acute migraine attacks.
    [Show full text]
  • CT Myelogram Drugs to Avoid Hold for 48 Hours Before and 12 Hours After Your Myelogram UVA Neuroradiology
    CT Myelogram Drugs to Avoid Hold for 48 Hours Before and 12 Hours After Your Myelogram UVA Neuroradiology Generic Name (Brand Name) Cidofovir (Vistide) Acetaminophen/butalbital (Allzital; Citalopram (Celexa) Bupap) Clomipramine (Anafranil) Acetaminophen/butalbital/caffeine Clonidine (Catapres; Kapvay) (Fioricet; Butace) Clorazepate (Tranxene-T) Acetaminophen/butalbital/caffeine/ Clozapine (Clozaril; FazaClo; Versacloz) codeine (Fioricet with codeine) Cyclizine (No Brand Name) Acetaminophen/caffeine (Excedrin) Cyclobenzaprine (Flexeril) Acetaminophen/caffeine/dihydrocodeine Desipramine (Norpramine) (Panlor; Trezix) Desvenlafaxine (Pristiq; Khedezla) Acetaminophen/tramadol (Ultracet) Dexmethylphenidate (Focalin) Aliskiren (Tekturna) Dextroamphetamine (Dexedrine; Amitriptyline (Elavil) ProCentra; Zenzedi) Amitriptyline and chlordiazepoxide Dextroamphetamine and amphetamine (Limbril) (Adderall) Amoxapine (Asendin) Diazepam (Valium; Diastat) Aripiprazole (Abilify) Diethylpropion (No Brand Name) Armodafinil (Nuvigil) Dimenhydrinate (Dramamine) Asenapine (Saphris) Donepezil (Aricept) Aspirin/caffeine (BC Powder; Goody Doripenem (Doribax) Powder) Doxapram (Dopram) Atomoxetine (Strattera) Doxepin (Silenor) Baclofen (Gablofen; Lioresal) Droperidol (No Brand Name) Benzphetamine (Didrex; Regimex) Duloxetine (Cymbalta) Benztropine (Cogentin) Entacapone (Comtan) Bismuth Ergotamine and caffeine (Cafergot; subcitrate/metronidazole/tetracycline Migergot) (Pylera) Escitalopram (Lexapro) Bismuth subsalicylate (Pepto-Bismol) Fluoxetine (Prozac; Sarafem)
    [Show full text]