DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 9,393,221 B2 W (45) Date of Patent: Jul.19, 2016

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 9,393,221 B2 W (45) Date of Patent: Jul.19, 2016 USOO9393221B2 (12) United States Patent (10) Patent No.: US 9,393,221 B2 W (45) Date of Patent: Jul.19, 2016 (54) METHODS AND COMPOUNDS FOR FOREIGN PATENT DOCUMENTS REDUCING INTRACELLULAR LIPID STORAGE WO WO2007096,251 8, 2007 OTHER PUBLICATIONS (75) Inventor: Sean Wu, Brookline, MA (US) Onyesom and Agho, Asian J. Sci. Res., Oct. 2010, vol. 4, No. 1, p. (73) Assignee: THE GENERAL, HOSPITAL 78-83. CORPORATION, Boston, MA (US) Davis et al., Br J Clin Pharmacol., 1996, vol. 4, p. 415-421.* Schweiger et al., Am J Physiol Endocrinol Metab, 2009, vol. 279, E289-E296. (*) Notice: Subject to any disclaimer, the term of this Maryam Ahmadian et al., Desnutrin/ATGL is regulated by AMPK patent is extended or adjusted under 35 and is required for a brown adipose phenotype, Cell Metabolism, vol. U.S.C. 154(b) by 748 days. 13, pp. 739-748, 2011. Mohammadreza Bozorgmanesh et al., Diabetes prediction, lipid (21) Appl. No.: 13/552,975 accumulation product, and adiposity measures; 6-year follow-up: Tehran lipid and glucose study, Lipids in Health and Disease, vol. 9, (22) Filed: Jul.19, 2012 pp. 1-9, 2010. Judith Fischer et al., The gene encoding adipose triglyceride lipase (65) Prior Publication Data (PNPLA2) is mutated in neutral lipid storage disease with myopathy, Nature Genetics, vol.39, pp. 28-30, 2007. US 2013/OO23488A1 Jan. 24, 2013 Astrid Gruber et al., The N-terminal region of comparative gene identification-58 (CGI-58) is important for lipid droplet binding and activation of adipose triglyceride lipase, vol. 285, pp. 12289-12298, Related U.S. Application Data 2010. (60) Provisional application No. 61/509,890, filed on Jul. Ken-Ichi Hirano et al., Triglyceride deposit cardiomyovasculopathy, The New England Journal of Medicine, vol. 359, pp. 2396-2398. 20, 2011. 2008. John D. Horowitz et al., Perhexiline and hypertrophic (51) Int. Cl. cardiomyopathy: A new horizon for metabolic modulation, Circula CI2N5/00 (2006.01) tion, vol. 122, pp. 1547-1549, 2010. CI2N 5/02 (2006.01) Sally Inglis et al., Metabolic therapeutics in angina pectoris: history A6 IK3I/37 (2006.01) revisited with perhexiline, European Journal of Cardiovascular Nurs A6 IK3I/25 (2006.01) ing, vol. 5, pp. 175-184, 2006. A6 IK3I/4375 (2006.01) Kunihisa Kobayashi et al., The lack of the C-terminal domain of A6 IK3I/439 (2006.01) adipose triglyceride lipase causes neutral lipid storage disease A6 IK3I/4458 (2006.01) through impaired interactions with lipid droplets, The Journal of A 6LX3L/24709 (2006.01) Clinical Endocrinology and Metabolism, vol. 93, pp. 2877-2884, 2008. A6 IK3I/706 (2006.01) Leong Lee et al., Metabolic modulation with perhexiline in chronic C4OB 30/06 (2006.01) heart failure: A randomized, controlled trial of short-term use of a GOIN33/50 (2006.01) novel treatment, Circulation, vol. 112, pp. 3280-3288, 2005. GOIN33/92 (2006.01) Krishnakant G. Soni et al., Coatomer-dependent protein delivery to (52) U.S. Cl. lipid droplets, Journal of CellScience, vol. 122, pp. 1834-1841, 2009. CPC ............. A6 IK3I/137 (2013.01); A61 K3I/215 John R. Ussher et al., Targeting malonyl CoA inhibition of (2013.01); A61 K3I/439 (2013.01); A61 K mitochondrial fatty acid uptake acid uptake,as an approach to treat 31/4375 (2013.01); A61 K3I/4458 (2013.01); cardiac ischemia reperfusion, Basic Research in Cardiology, vol. A61 K3I/4709 (2013.01); A61 K3I/706 104, pp. 203-210, 2009. (2013.01); C40B30/06 (2013.01); G0IN 33/5061 (2013.01); G0IN33/5073 (2013.01); * cited by examiner G0IN33/92 (2013.01) Primary Examiner — Kade Ariani (58) Field of Classification Search (74) Attorney, Agent, or Firm — Nixon Peabody LLP None See application file for complete search history. (57) ABSTRACT (56) References Cited Compounds and compositions for reducing intracellular lipid accumulation in a cell are described herein. These com U.S. PATENT DOCUMENTS pounds are useful for the treatment and prevention of lipid/ glycogen disorders, as well as for the treatment and preven 7,449.482 B2 11/2008 Cheng et al. tion of obesity. A high throughput screen for identifying 7,855,289 B2 12/2010 Nunes et al. 2001/0048980 A1 12/2001 Kishimoto et al. compounds that reduce intracellular lipid accumulation in 2007/0275997 A1 11, 2007 Frenneaux cells is also provided. 2009/0324682 A1 12/2009 Popowski 2011/0048980 A1 3/2011 Seman 9 Claims, 15 Drawing Sheets U.S. Patent Jul. 19, 2016 Sheet 1 of 15 US 9,393,221 B2 #################### V,±0IJI #################### agerse SSX 38 I’01), U.S. Patent Jul. 19, 2016 Sheet 2 of 15 US 9,393,221 B2 ------------ S33: E. s E. ran as R s w as rise ces gas ca a. warra a s s se s A 383d 8 ex es e e SSX 3 2. s was e R s w w c s i SSX 3 SS U.S. Patent Jul. 19, 2016 Sheet 3 of 15 US 9,393,221 B2 (Of’91)I {{#######{}{}&&############3 U.S. Patent Jul. 19, 2016 Sheet 4 of 15 US 9,393,221 B2 }} {}}} # {} age s’ acs x 8. U.S. Patent Jul. 19, 2016 Sheet 5 Of 15 US 9,393,221 B2 U.S. Patent Jul. 19, 2016 Sheet 7 Of 15 US 9,393,221 B2 . A W H F D M S K W M S K FoxA2 festi if U.S. Patent Jul. 19, 2016 Sheet 8 of 15 US 9,393,221 B2 U.S. Patent Jul. 19, 2016 Sheet 9 Of 15 US 9,393,221 B2 FE A PC A PEEE s: - E C. S. 8 - - - A CEE A PERENE s 3. e d E} FIG. 7D U.S. Patent Jul. 19, 2016 Sheet 11 of 15 US 9,393,221 B2 ####### * )(310,0${}\\ E On Molimanae O U.S. Patent US 9,393,221 B2 42,1149 !############ U.S. Patent US 9,393,221 B2 AS f U.S. Patent US 9,393,221 B2 Per met veh) va) NON FIG SE Pik i. FIG. SF U.S. Patent Jul. 19, 2016 Sheet 15 Of 15 US 9,393,221 B2 (c.595--Ga., p.a.233esis: 62} C, i 2 ?essic-l. p.289X) ES 3 8 3 US 9,393,221 B2 1. 2 METHODS AND COMPOUNDS FOR spleen must be removed to improve cardiopulmonary func REDUCING INTRACELLULAR LIPID tion. For patients with Fabry disease, the drugs phenyloin and STORAGE carbamazepine may be prescribed to help treat pain (includ ing bone pain). CROSS-REFERENCE TO RELATED Given the lack of specific therapies for lipid/glycogen stor APPLICATIONS age diseases, there is need in the art for compositions and methods for treatment of these disorders. This application claims the benefit under 35 U.S.CS119(e) of U.S. Provisional Application No. 61/509,890, filed Jul. 20, SUMMARY 2011, which is herein incorporated by reference in its entirety. 10 Embodiments of the present invention are based, in part, on SEQUENCE LISTING the establishment of a high throughput assay for the identifi cation of compounds capable of modulating intracellular The instant application contains a Sequence Listing which lipid storage. The inventors have generated both a murine and has been submitted in ASCII format via EFS-Web and is 15 human induced pluripotent stem cell (iPSC) model system of hereby incorporated by reference in its entirety. Said ASCII neutral lipid storage disease, myopathy subtype (NLSD-M), a copy, created on Jul. 25, 2012, is named 071061 US.txt and is condition characterized by aberrant lipid accumulation in 12,530 bytes in size. cardiac and skeletal muscle that results from the loss of func FIELD OF INVENTION tional adipose triglyceride lipase (ATGL). They demonstrate that differentiated ATGL-knockout (KO) iPSCs and human The invention relates to methods, compounds and compo mutant iPSCs exhibit significantly increased lipid accumula sitions for the treatment of lipid/glycogen storage disorders tion compared to differentiated control iPSCs, and using a and obesity. high throughput platform for iPSC differentiation and small 25 molecule screening have identified compounds that reduce BACKGROUND lipid accumulation within both mouse and human NLSD-M iPSCs and extended the mean life span of ATGK knock out Metabolic disorders, such as lipid storage disease and gly mice by 30% (from 13 to 17 weeks). They have also deter cogen storage disease, can have devastating effects on mined that inhibitors of intracellular lipid storage shift cellu patients. The Lipid storage diseases represent a group of 30 lar energy metabolism from fatty acid oxidation to glycolysis. disorders in which harmful amounts of lipids accumulate in Thus, compounds selected using the high throughput Screen various cells and tissues in the body. Glycogen storage dis are useful for the treatment and prevention of a variety of ease is the result of defects in the processing of glycogen lipid/glycogen storage disorders, as well are useful for the synthesis or breakdown within cells. Individuals with lipid/ treatment of obesity. glycogen storage disorders either do not produce enough of 35 Accordingly, in one aspect, the invention provides for a one of the enzymes needed to breakdown (metabolize) lipids, method of reducing intracellular lipid accumulation in a cell or glycogen, or they produce enzymes that do not work prop comprising a contacting the cell with an effective amount of erly. Over time, this excessive storage of fats and glycogen a compound selected from Table 1. In one embodiment, the can cause permanent cellular and tissue damage, for example, compound is selected from a compound listed in Table 2. In in the heart, muscle, brain, peripheral nervous system, liver, 40 one embodiment the compound is selected from a compound spleen, and bone marrow.
Load more

Recommended publications
  • Witola, Basis of Anthelmintic Resistance and Development Of
    9/8/2016 Basis of Anthelmintic Resistance and Novel Approaches to Development of New Efficacious Anthelmintic Drugs William H. Witola, BVetMed, MSc., Ph.D. Department of Pathobiology College of Veterinary Medicine University of Illinois at Urbana-Champaign E-mail: [email protected] Current Anthelmintics 3 Classes of anthelmintic drugs registered in the USA : 1.) Benzimidazoles • Fenbendazole, Safeguard, Panacur 2.) Macrocyclic Lactones • Avermectins: Ivermectin, Ivomec, Primectin, Privermectin • Eprinomectin: Eprinex • Doramectin: Dectomax • Milbimycins: Moxidectin, Cydectin, Quest 3.) Nicotinic Agonists • Imidothiazoles: Levamisole, Prohibit • Tetrahydropyrimidines: Morantel, Rumatel, Positive Goat Pellet, Goat dewormer, Pyrantel, Strongid Spiroindoles (Not registered in US) Amino-acetonitriles (Not registered in US ) How do anthelmintic drugs kill parasites? • Benzimidazoles (Valbazen, Safeguard): Bind to a parasite protein called β-tubulin leading to collapse of parasite skeleton structure. • Avermectin/Milbemycins (Ivomec, cydectin): Bind to proteins in throat (pharynx) of parasite leading to paralysis – parasite can’t eat anymore & dies of starvation! • Imidazothiazoles/Tetrahydropyrimidine (Levamisole, Pyrantel, Morantel): bind to acetylcholine receptors causing muscle paralysis. 1 9/8/2016 Status of Anthelmintics Efficacy Drug Host First 1st Report of Approved Resistance Benzimidazoles : Thiabendazole, Albendazole Sheep, 1961 1964 goat, Horse, 1962 1965 Imidothiazoles-tetrahydropyrimidines : Levamisole, Sheep 1970 1979 Pyrantel
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,498,481 B2 Rao Et Al
    USOO9498481 B2 (12) United States Patent (10) Patent No.: US 9,498,481 B2 Rao et al. (45) Date of Patent: *Nov. 22, 2016 (54) CYCLOPROPYL MODULATORS OF P2Y12 WO WO95/26325 10, 1995 RECEPTOR WO WO99/O5142 2, 1999 WO WOOO/34283 6, 2000 WO WO O1/92262 12/2001 (71) Applicant: Apharaceuticals. Inc., La WO WO O1/922.63 12/2001 olla, CA (US) WO WO 2011/O17108 2, 2011 (72) Inventors: Tadimeti Rao, San Diego, CA (US); Chengzhi Zhang, San Diego, CA (US) OTHER PUBLICATIONS Drugs of the Future 32(10), 845-853 (2007).* (73) Assignee: Auspex Pharmaceuticals, Inc., LaJolla, Tantry et al. in Expert Opin. Invest. Drugs (2007) 16(2):225-229.* CA (US) Wallentin et al. in the New England Journal of Medicine, 361 (11), 1045-1057 (2009).* (*) Notice: Subject to any disclaimer, the term of this Husted et al. in The European Heart Journal 27, 1038-1047 (2006).* patent is extended or adjusted under 35 Auspex in www.businesswire.com/news/home/20081023005201/ U.S.C. 154(b) by Od en/Auspex-Pharmaceuticals-Announces-Positive-Results-Clinical M YW- (b) by ayS. Study (published: Oct. 23, 2008).* This patent is Subject to a terminal dis- Concert In www.concertpharma. com/news/ claimer ConcertPresentsPreclinicalResultsNAMS.htm (published: Sep. 25. 2008).* Concert2 in Expert Rev. Anti Infect. Ther. 6(6), 782 (2008).* (21) Appl. No.: 14/977,056 Springthorpe et al. in Bioorganic & Medicinal Chemistry Letters 17. 6013-6018 (2007).* (22) Filed: Dec. 21, 2015 Leis et al. in Current Organic Chemistry 2, 131-144 (1998).* Angiolillo et al., Pharmacology of emerging novel platelet inhibi (65) Prior Publication Data tors, American Heart Journal, 2008, 156(2) Supp.
    [Show full text]
  • (12) United States Patent (10) Patent N0.: US 8,343,962 B2 Kisak Et Al
    US008343962B2 (12) United States Patent (10) Patent N0.: US 8,343,962 B2 Kisak et al. (45) Date of Patent: *Jan. 1, 2013 (54) TOPICAL FORMULATION (58) Field of Classi?cation Search ............. .. 514/226.5, 514/334, 420, 557, 567 (75) Inventors: Edward T. Kisak, San Diego, CA (US); See application ?le fOr Complete Search history. John M. NeWsam, La Jolla, CA (US); _ Dominic King-Smith, San Diego, CA (56) References C‘ted (US); Pankaj Karande, Troy, NY (US); Samir Mitragotri, Goleta, CA (US) US' PATENT DOCUMENTS 5,602,183 A 2/1997 Martin et al. (73) Assignee: NuvoResearchOntano (CA) Inc., Mississagua, 6,328,979 2B1 12/2001 Yamashita et a1. 7,001,592 B1 2/2006 Traynor et a1. ( * ) Notice: Subject to any disclaimer, the term of this 7,795,309 B2 9/2010 Kisak eta1~ patent is extended or adjusted under 35 2002/0064524 A1 5/2002 Cevc U.S.C. 154(b) by 212 days. FOREIGN PATENT DOCUMENTS This patent is subject to a terminal dis- W0 WO 2005/009510 2/2005 claimer- OTHER PUBLICATIONS (21) APPI' NO‘, 12/848,792 International Search Report issued on Aug. 8, 2008 in application No. PCT/lB2007/0l983 (corresponding to US 7,795,309). _ Notice ofAlloWance issued on Apr. 29, 2010 by the Examiner in US. (22) Med Aug- 2’ 2010 Appl. No. 12/281,561 (US 7,795,309). _ _ _ Of?ce Action issued on Dec. 30, 2009 by the Examiner in US. Appl. (65) Prior Publication Data No, 12/281,561 (Us 7,795,309), Us 2011/0028460 A1 Feb‘ 3’ 2011 Primary Examiner * Raymond Henley, 111 Related U 5 Application Data (74) Attorney, Agent, or Firm * Foley & Lardner LLP (63) Continuation-in-part of application No.
    [Show full text]
  • Metabolism and Pharmacokinetics in the Development of New Therapeutics for Cocaine and Opioid Abuse
    University of Mississippi eGrove Electronic Theses and Dissertations Graduate School 2012 Metabolism And Pharmacokinetics In The Development Of New Therapeutics For Cocaine And Opioid Abuse Pradeep Kumar Vuppala University of Mississippi Follow this and additional works at: https://egrove.olemiss.edu/etd Part of the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Vuppala, Pradeep Kumar, "Metabolism And Pharmacokinetics In The Development Of New Therapeutics For Cocaine And Opioid Abuse" (2012). Electronic Theses and Dissertations. 731. https://egrove.olemiss.edu/etd/731 This Dissertation is brought to you for free and open access by the Graduate School at eGrove. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of eGrove. For more information, please contact [email protected]. METABOLISM AND PHARMACOKINETICS IN THE DEVELOPMENT OF NEW THERAPEUTICS FOR COCAINE AND OPIOID ABUSE A Dissertation presented in partial fulfillment of requirements for the degree of Doctor of Philosophy in Pharmaceutical Sciences in the Department of Pharmaceutics The University of Mississippi by PRADEEP KUMAR VUPPALA April 2012 Copyright © 2012 by Pradeep Kumar Vuppala All rights reserved ABSTRACT Cocaine and opioid abuse are a major public health concern and the cause of significant morbidity and mortality worldwide. The development of effective medication for cocaine and opioid abuse is necessary to reduce the impact of this issue upon the individual and society. The pharmacologic treatment for drug abuse has been based on one of the following strategies: agonist substitution, antagonist treatment, or symptomatic treatment. This dissertation is focused on the role of metabolism and pharmacokinetics in the development of new pharmacotherapies, CM304 (sigma-1 receptor antagonist), mitragynine and 7-hydroxymitragynine (µ-opioid receptor agonists), for the treatment of drug abuse.
    [Show full text]
  • Alpha^ and Beta^Blocking Agents: Pharmacology and Properties
    CURRENT DRUG THERAPY DONALD G. VIDT, MD AND ALAN BAKST, PharmD, EDITORS Alpha^ and beta^blocking agents: pharmacology and properties PROFESSOR B.N.C. PRICHARD • Adrenergic receptors have been separated into alpha and beta groups, which have then been further subdivided. Agents have been developed that block each type of receptor with varying degrees of specificity between the sub-types, leading to differences in pharmacodynamic profile. A more recent innovation has been the development of multiple action beta-blocking drugs, ie, those not only blocking the beta receptors but also posessing a peripheral vasodilator effect that may be due to alpha blockade, beta-2 stimulation, or a vasodilator action independent of either alpha or beta receptors. • INDEX TERMS: ALPHA BLOCKERS; BETA BLOCKERS; HYPERTENSION • CLEVE CLIN ] MED 1991; 58:33 7-350 HE CONCEPT that binding of Rosenblueth suggested that a transmitter released at catecholamines to receptors leads to differ- sympathetic nerve endings produced either inhibitory ing responses was first described by Langley, or excitatory responses as a result of combination with who in 1905 noted that a cell may make sympathin I or sympathin E at the receptor.3 Tmotor or inhibitory substances or both, and that "the The current classification of alpha and beta respon- effect of a nerve impulse depends upon the proportion ses is based on the classic work of Ahlquist,4 who of the two kinds of receptive substance which is af- studied six sympathomimetic amines and found two fected by the impulse."1 In 1906, Dale reported that patterns of reactivity. One group of actions, mediated ergot blocked the excitatory but not the inhibitory ac- by what were termed "alpha receptors," were principally tions of adrenaline.2 In 1933, Cannon and excitatory.
    [Show full text]
  • Chemotherapy of Gastrointestinal Helminths
    Chemotherapy of Gastrointestinal Helminths Contributors J. H. Arundel • J. H. Boersema • C. F. A. Bruyning • J. H. Cross A. Davis • A. De Muynck • P. G. Janssens • W. S. Kammerer IF. Michel • M.H. Mirck • M.D. Rickard F. Rochette M. M. H. Sewell • H. Vanden Bossche Editors H. Vanden Bossche • D.Thienpont • P.G. Janssens UNIVERSITATS- BlfiUOTHElC Springer-Verlag Berlin Heidelberg New York Tokyo Contents CHAPTER 1 Introduction. A. DAVIS A. Pathogenic Mechanisms in Man 1 B. Modes of Transmission 2 C. Clinical Sequelae of Infection 3 D. Epidemiological Considerations 3 E. Chemotherapy 4 F. Conclusion 5 References 5 CHAPTER 2 Epidemiology of Gastrointestinal Helminths in Human Populations C. F. A. BRUYNING A. Introduction 7 B. Epidemiological or "Mathematical" Models and Control 8 C. Nematodes 11 I. Angiostrongylus costaricensis 11 II. Anisakis marina 12 III. Ascaris lumbricoides 14 IV. Capillaria philippinensis 21 V. Enterobius vermicularis 23 VI. Gnathostoma spinigerum 25 VII. Hookworms: Ancylostoma duodenale and Necator americanus . 26 VIII. Oesophagostoma spp 32 IX. Strongyloides stercoralis 33 X. Ternidens deminutus 34 XI. Trichinella spiralis 35 XII. Trichostrongylus spp 38 XIII. Trichuris trichiura 39 D. Trematodes 41 I. Echinostoma spp 41 II. Fasciolopsis buski 42 III. Gastrodiscoides hominis 44 IV. Heterophyes heterophyes 44 V. Metagonimus yokogawai 46 X Contents E. Cestodes 47 I. Diphyllobothrium latum 47 II. Dipylidium caninum 50 III. Hymenolepis diminuta 51 IV. Hymenolepis nana 52 V. Taenia saginata 54 VI. Taenia solium 57 VII. Cysticercosis cellulosae 58 References 60 CHAPTER 3 Epidemiology and Control of Gastrointestinal Helminths in Domestic Animals J. F. MICHEL. With 20 Figures A. Introduction 67 I.
    [Show full text]
  • Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation
    www.sciencemag.org/cgi/content/full/327/5963/348/DC1 Supporting Online Material for Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation Jason Rihel,* David A. Prober, Anthony Arvanites, Kelvin Lam, Steven Zimmerman, Sumin Jang, Stephen J. Haggarty, David Kokel, Lee L. Rubin, Randall T. Peterson, Alexander F. Schier* *To whom correspondence should be addressed. E-mail: [email protected] (A.F.S.); [email protected] (J.R.) Published 15 January 2010, Science 327, 348 (2010) DOI: 10.1126/science.1183090 This PDF file includes: Materials and Methods SOM Text Figs. S1 to S18 Table S1 References Supporting Online Material Table of Contents Materials and Methods, pages 2-4 Supplemental Text 1-7, pages 5-10 Text 1. Psychotropic Drug Discovery, page 5 Text 2. Dose, pages 5-6 Text 3. Therapeutic Classes of Drugs Induce Correlated Behaviors, page 6 Text 4. Polypharmacology, pages 6-7 Text 5. Pharmacological Conservation, pages 7-9 Text 6. Non-overlapping Regulation of Rest/Wake States, page 9 Text 7. High Throughput Behavioral Screening in Practice, page 10 Supplemental Figure Legends, pages 11-14 Figure S1. Expanded hierarchical clustering analysis, pages 15-18 Figure S2. Hierarchical and k-means clustering yield similar cluster architectures, page 19 Figure S3. Expanded k-means clustergram, pages 20-23 Figure S4. Behavioral fingerprints are stable across a range of doses, page 24 Figure S5. Compounds that share biological targets have highly correlated behavioral fingerprints, page 25 Figure S6. Examples of compounds that share biological targets and/or structural similarity that give similar behavioral profiles, page 26 Figure S7.
    [Show full text]
  • United States Patent (19) (11) 4,310,524 Wiech Et Al
    United States Patent (19) (11) 4,310,524 Wiech et al. 45 Jan. 12, 1982 (54) TCA COMPOSITION AND METHOD FOR McMillen et al., Fed. Proc., 38,592 (1979). RAPD ONSET ANTDEPRESSANT Sellinger et al., Fed. Proc., 38,592 (1979). THERAPY Pandey et al., Fed. Proc., 38,592 (1979). 75) Inventors: Norbert L. Wiech; Richard C. Ursillo, Primary Examiner-Stanley J. Friedman both of Cincinnati, Ohio Attorney, Agent, or Firm-Millen & White 73) Assignee: Richardson-Merrell, Inc., Wilton, Conn. (57 ABSTRACT A method is provided for treating depression in a pa (21) Appl. No.: 139,498 tient therefrom and requiring rapid symptomatic relief, (22 Filed: Apr. 11, 1980 which comprises administering to said patient concur 51) Int. Cl. .................... A61K 31/33; A61K 31/135 rently (a) an effective antidepressant amount of a tricy clic antidepressant or a pharmaceutically effective acid (52) ...... 424/244; 424/330 addition salt thereof, and (b) an amount of an a-adrener 58) Field of Search ................................ 424/244, 330 gic receptor blocking agent effective to achieve rapid (56) References Cited onset of the antidepressant action of (a), whereby the PUBLICATIONS onset of said antidepressant action is achieved within Chemical Abst., vol. 66-72828m, (1967), Kellett. from 1 to 7 days. Chemical Abst, vol. 68-94371a, (1968), Martelli et al. A pharmaceutical composition is also provided which is Chemical Abst., vol. 74-86.048j, (1971), Dixit et al. especially adapted for use with the foregoing method. Holmberg et al., Psychopharm., 2,93 (1961). Svensson, Symp. Med. Hoechst., 13, 245 (1978). 17 Claims, No Drawings 4,310,524 1.
    [Show full text]
  • NON-HAZARDOUS CHEMICALS May Be Disposed of Via Sanitary Sewer Or Solid Waste
    NON-HAZARDOUS CHEMICALS May Be Disposed Of Via Sanitary Sewer or Solid Waste (+)-A-TOCOPHEROL ACID SUCCINATE (+,-)-VERAPAMIL, HYDROCHLORIDE 1-AMINOANTHRAQUINONE 1-AMINO-1-CYCLOHEXANECARBOXYLIC ACID 1-BROMOOCTADECANE 1-CARBOXYNAPHTHALENE 1-DECENE 1-HYDROXYANTHRAQUINONE 1-METHYL-4-PHENYL-1,2,5,6-TETRAHYDROPYRIDINE HYDROCHLORIDE 1-NONENE 1-TETRADECENE 1-THIO-B-D-GLUCOSE 1-TRIDECENE 1-UNDECENE 2-ACETAMIDO-1-AZIDO-1,2-DIDEOXY-B-D-GLYCOPYRANOSE 2-ACETAMIDOACRYLIC ACID 2-AMINO-4-CHLOROBENZOTHIAZOLE 2-AMINO-2-(HYDROXY METHYL)-1,3-PROPONEDIOL 2-AMINOBENZOTHIAZOLE 2-AMINOIMIDAZOLE 2-AMINO-5-METHYLBENZENESULFONIC ACID 2-AMINOPURINE 2-ANILINOETHANOL 2-BUTENE-1,4-DIOL 2-CHLOROBENZYLALCOHOL 2-DEOXYCYTIDINE 5-MONOPHOSPHATE 2-DEOXY-D-GLUCOSE 2-DEOXY-D-RIBOSE 2'-DEOXYURIDINE 2'-DEOXYURIDINE 5'-MONOPHOSPHATE 2-HYDROETHYL ACETATE 2-HYDROXY-4-(METHYLTHIO)BUTYRIC ACID 2-METHYLFLUORENE 2-METHYL-2-THIOPSEUDOUREA SULFATE 2-MORPHOLINOETHANESULFONIC ACID 2-NAPHTHOIC ACID 2-OXYGLUTARIC ACID 2-PHENYLPROPIONIC ACID 2-PYRIDINEALDOXIME METHIODIDE 2-STEP CHEMISTRY STEP 1 PART D 2-STEP CHEMISTRY STEP 2 PART A 2-THIOLHISTIDINE 2-THIOPHENECARBOXYLIC ACID 2-THIOPHENECARBOXYLIC HYDRAZIDE 3-ACETYLINDOLE 3-AMINO-1,2,4-TRIAZINE 3-AMINO-L-TYROSINE DIHYDROCHLORIDE MONOHYDRATE 3-CARBETHOXY-2-PIPERIDONE 3-CHLOROCYCLOBUTANONE SOLUTION 3-CHLORO-2-NITROBENZOIC ACID 3-(DIETHYLAMINO)-7-[[P-(DIMETHYLAMINO)PHENYL]AZO]-5-PHENAZINIUM CHLORIDE 3-HYDROXYTROSINE 1 9/26/2005 NON-HAZARDOUS CHEMICALS May Be Disposed Of Via Sanitary Sewer or Solid Waste 3-HYDROXYTYRAMINE HYDROCHLORIDE 3-METHYL-1-PHENYL-2-PYRAZOLIN-5-ONE
    [Show full text]
  • Review Article a BRIEF REVIEW on the MODE of ACTION of ANTINEMATODAL DRUGS
    Acta Veterinaria-Beograd 2017, 67 (2), 137-152 UDK: 615.284.03 DOI: 10.1515/acve-2017-0013 Review article A BRIEF REVIEW ON THE MODE OF ACTION OF ANTINEMATODAL DRUGS ABONGWA Melanie, MARTIN Richard J., ROBERTSON Alan P.* Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011, USA (Received 01 May, Accepted 24 May 2017) Anthelmintics are some of the most widely used drugs in veterinary medicine. Here we review the mechanism of action of these compounds on nematode parasites. Included are the older classes of compounds; the benzimidazoles, cholinergic agonists and macrocyclic lactones. We also consider newer anthelmintics, including emodepside, derquantel and tribendimidine. In the absence of vaccines for most parasite species, control of nematode parasites will continue to rely on anthelmintic drugs. As a consequence, vigilance in detecting drug resistance in parasite populations is required. Since resistance development appears almost inevitable, there is a continued and pressing need to fully understand the mode of action of these compounds. It is also necessary to identify new drug targets and drugs for the continued effective control of nematode parasites. Key words: anthelmintic, parasite, benzimidazoles, avermectins, cholinergic, emodepside, derquantel INTRODUCTION Anthelmintics are drugs that are used to treat infections caused by parasitic worms (helminths) [1]. There are three major groups of helminths namely: nematodes (roundworms), trematodes (fl ukes) and cestodes (tapeworms). These groups of helminths are divided into two phyla; nematodes (roundworms) and platyhelminths (trematodes and cestodes) [2]. Anthelmintics either kill worms or cause their expulsion from the body, without causing any signifi cant damage to the host [3].
    [Show full text]
  • Microgram Journal, Vol 3, Number 2
    MICROGRAM Laboratory Operations Division Office Of Science And Drug Abuse Prevention BUREAU OF NARCOTICS & DANGEROUS DRUGS / U.S. DEPARTMENT OF JUSTICE / WASHINGTION, D.C. 20537 Vol.III, No. 2 March-April, 1970 STP (4-Methyl-2,5-dimethoxyamphetamine) hydrochloride was found coating the inside of capsules sent to BNDDfrom Germany. The capsules were clear, hard gelatin, standard shape size No. o. Average weight was 114 milligrams. Each capsule had a white crystalline coating on inner surface of capsule body. Apparently a measu~ed amount of solution had been placedin the cap·sule body, after which it was rotated to spread the solution on the inner surface. The substance contained 8. 7 milli­ grams STP (DOM)HCl per ca·psule. · These were the first STP capsules of this type seen by our laboratory. A few years ago, capsules were ob­ tained in the U.S. similarly coated with LSD. STP (Free Base) on laboratory filter paper, also from Germany, was seen for the first time in our laboratory. The STP spots, containing approxi­ mately 8 miliigrams STP base each, were 5/8 to 3/4 inch in diameter. The paper was 1\ inches square. Phencyclidine (Free Base) was recently analyzed on parsley leaves. Called "Angel DUst, 11 the phencyclidine on two samples of leaves was 2.6% and 3.6%. Approximately thirty pounds of 94% pure powder was also analyzed. (For identification of phencyclidine base, see Microgram, II, 1, p.3 (Jan 1969). IMITATIONSof well-known drug products are examined frequently in our Special Testing and Research Laboratory. Many of these are well made preparations and closely resemble the imitated product.
    [Show full text]
  • An in Silico Study of the Ligand Binding to Human Cytochrome P450 2D6
    AN IN SILICO STUDY OF THE LIGAND BINDING TO HUMAN CYTOCHROME P450 2D6 Sui-Lin Mo (Doctor of Philosophy) Discipline of Chinese Medicine School of Health Sciences RMIT University, Victoria, Australia January 2011 i Declaration I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at RMIT university or any other educational institution, except where due acknowledgment is made in the thesis. Any contribution made to the research by others, with whom I have worked at RMIT university or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project‘s design and conception or in style, presentation and linguistic expression is acknowledged. PhD Candidate: Sui-Lin Mo Date: January 2011 ii Acknowledgements I would like to take this opportunity to express my gratitude to my supervisor, Professor Shu-Feng Zhou, for his excellent supervision. I thank him for his kindness, encouragement, patience, enthusiasm, ideas, and comments and for the opportunity that he has given me. I thank my co-supervisor, A/Prof. Chun-Guang Li, for his valuable support, suggestions, comments, which have contributed towards the success of this thesis. I express my great respect to Prof. Min Huang, Dean of School of Pharmaceutical Sciences at Sun Yat-sen University in P.R.China, for his valuable support.
    [Show full text]