DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2010/0009970 A1 Johansen Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2010/0009970 A1 Johansen Et Al US 20100.009970A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0009970 A1 Johansen et al. (43) Pub. Date: Jan. 14, 2010 (54) COMPOSITIONS AND METHODS FOR Publication Classification TREATMENT OF VRAL DISEASES (51) Int. Cl. (75) Inventors: Lisa M. Johansen, Belmont, MA A63L/36 (2006.01) (US); Christopher M. Owens, A63L/404 (2006.01) Cambridge, MA (US); Christina A63L/366 (2006.01) Mawhinney, Jamaica Plain, MA A 6LX 3L/505 (2006.01) (US); Todd W. Chappell, Boston, A63/495 (2006.01) MA (US); Alexander T. Brown, CD7C 2 II/33 (2006.01) Watertown, MA (US); Michael G. C07C 21 7/56 (2006.01) Frank, Boston, MA (US); Michael A6IP 25/00 (2006.01) A. Foley, Chestnut hill, MA (US); A6II 3/445 (2006.01) Ralf Altmeyer, Singapore (SG); Yu A6II 3/55 (2006.01) Chen, Singapore (SG) A 6LX 3/5.375 (2006.01) A63/4965 (2006.01) Correspondence Address: (52) U.S. Cl. ......... 514/218: 514/647: 514/419:514/460; Gearhart Law LLC 514/275: 514/255.04:564/367: 514/603; 4 Femdale Avenue 514/655; 564/384: 514/331; 514/239.5: 514/255.03 Chatham, NJ 07928 (US) (73) Assignee: Combinatorx (Singapore) Pte. (57) ABSTRACT Ltd., Singapore (SG) The present invention features compositions, methods, and kits useful in the treatment of viral diseases. In certain (21) Appl. No.: 12/406,626 embodiments, the viral disease is caused by a single stranded RNA virus, a flaviviridae virus, or a hepatic virus. In particu (22) Filed: Mar. 18, 2009 lar embodiments, the viral disease is viral hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D. hepatitis E) Related U.S. Application Data and the agent or combination of agents includes sertraline, a (60) Provisional application No. 61/070,047, filed on Mar. Sertraline analog. UK-416244, or a UK-416244 analog. Also 19, 2008, provisional application No. 61/089,850, featured are screening methods for identification of novel filed on Aug. 18, 2008. compounds that may be used to treat a viral disease. Patent Application Publication Jan. 14, 2010 Sheet 1 of 2 US 2010/0009970 A1 80 ---- Vehicle 0.5% HPMC E. - - - Sertraline-30mg/kg/day - A - 60 Sertraline-100mg/kg/day/kg/day E. - V-- Oseltamivir-30mg/kg/day --- is a Oseltamivir-100mg/kg/day CRX-165 (Sertraline 30mg/Kg+ -0. ------- 40 Prednisolone 0.1 mg/Kg) Figure 1 Patent Application Publication Jan. 14, 2010 Sheet 2 of 2 US 2010/0009970 A1 OO 58 OO 4 O 2 O Wehicle Seitaline 10ng. Kg Sertaline 30mg Kg Sentraline 100mg Kg Figure 2 US 2010/0009970 A1 Jan. 14, 2010 COMPOSITIONS AND METHODS FOR and the currently recommended therapy, a combination of TREATMENT OF VIRAL DISEASES pegylated interferon and ribavirin, is effective in only about 50% of those infected with HCV genotype 1. Further, both CROSS-REFERENCE TO RELATED interferon and ribavirin have potentially serious side effects, APPLICATIONS which include seizures, acute heart or kidney failure, and 0001. This application claims the benefit of U.S. Provi anemia. sional Application No. 61/070,047, filed Mar. 19, 2008 and 0005 Given the lack of safe, efficacious treatments for U.S. Provisional Application No. 61/089,850, filed Aug. 18, many viral diseases, there exists a need for improved thera 2008, each of which is hereby incorporated by reference. p1es. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION 0002. The invention relates to the treatment of diseases 0006 Based on the results of our screen identifying com caused by a virus. pounds and combinations of compounds having antiviral 0003 Diseases caused by viruses are major health prob activity, the present invention features compositions, meth lems worldwide, and include many potentially fatal or dis ods, and kits for the treatment of viral disease (e.g., caused by abilitating illnesses. Viral diseases include diseases caused by the viruses described herein). In certain embodiments, the single stranded RNA viruses, flaviviridae viruses, and hepatic viral disease may be caused by a virus which is a member of viruses. In one example, viral hepatitis (e.g., hepatitis A, one or more of the following groups: single Stranded RNA hepatitis B, hepatitis C, hepatitis D, and hepatitis E) can result viruses, flaviviridae viruses (e.g., a hepacivirus Such as HCV. in chronic or acute hepatitis. While vaccines protective flavivirus, pestivirus, or hepatitis G Virus), and hepatic against hepatitis A and hepatitis B exist, no cures for many viruses. HCV, for example, is a single stranded RNA virus, a viruses, including hepatitis B, C, D, or E, are available. flaviviridae virus, and a hepatic virus. In certain embodi 0004. With regard to the hepatitis C virus (HCV), the ments, the viral disease is caused by the hepatitis C virus. Center for Disease Control estimates that 4.1 million Ameri Additional exemplary viruses are described herein. cans (1.6%) have been infected with this virus. Of those 0007 Accordingly in a first aspect, the invention features infected, 3.2 million are chronically infected, and HCV is the a composition including a first agent selected from the agents leading cause of death from liver disease in the United States. of Table 1, Table 2, and Table 3, or an analog thereof, and a Hepatitis C is a major risk factor for developing liver cirrhosis second agent selected from the agents of Table 1, Table 2, and hepatocellular carcinoma, and the World Health Organi Table 3, Table 4, and Table 5, or an analog thereof (e.g., Table zation indicates that hepatitis C is responsible for two thirds 4 and Table 5, or excluding the combinations of Table 6). In of liver transplants. Worldwide, an estimated 180 million certain embodiments, the first agent is sertraline, a sertraline people, or about 3% of the world's population, are infected analog, UK-416244, or a UK-4162244 analog (e.g., any of with HCV. No vaccine for hepatitis C is presently available, those described herein). TABLE 1 Compound IC50* Compound IC50: 1.2-Bis-(2-aminophenoxy)ethane N.N.N.N.- 14.50 Isosulfan Blue 24.86 tetreacetic acid 1,5-Isoquinolinediol 25.88 JSH-23 2.55 10-Deacetylbaccatine Ii 10.34 Levothyroxine (e.g., sodium) 3.79 2,2'-(Pentamethylenedioxy)diacetanilide 3.14 Loratadine 8.16 2-Hydroxyflavanone 2.48 Manganese gluconate 24.71 2-Methoxyestradiol 7.91 Maprotiline (e.g., hydrochloride) 7.18 3,3'-(Pentamethylenedioxy)dianiline 1.63 Mebeverine (e.g., hydrochloride) 4.88 6-Nitroquipazine 16.41 Mechlorethamine (e.g., hydrochloride) 4.15 AG-490 5.03 Meclizine 4.62 AG-494 3.45 Mecobalamin O.179 Albendazole 0.324 Melphalan 5.94 Amitraz 26.4 Mequinol 8.6S Amitrole 14.62 Mesoridazine (e.g., Besylate) 9.00 Amorolfine (e.g., hydrochloride) 1.62 Mesterolone S.18 Anisomycin 0.608 Methylglyoxal bis(guanylhydrazone) dihydrochloride O.80 hydrate Auranofin 1.07 Methyltestosterone 9.11 Azelastine 6.22 Mianserin (e.g., hydrochloride) 3.72 Bay 11-7082 15.01 Mitotane 28.1% Bay 41-2272 O.754 ML 9 4.44 Benoximate (e.g., hydrochloride) 3.02 Mofebutazone 4.6O Benzamil (e.g., HCI) 4.73 MometaSone (e.g., furoate) 1.35 Benzocaine 13.91 Monobenzone 1.59 Benztropine (e.g., mesylate) 5.70 Mosapride (e.g., citrate) O.91 Benzydamine (e.g., hydrochloride) 9.00 Narasin O.176 Beta Escin 4.27 Noscapine 5.83 Beta-Caroteine 18.50 NSC 663284 O.614 Beta-Ionol 21.00 N-Tosyl-L-phenylalanine chloromethyl ketone 6.67 Betaxolol (e.g., hydrochloride) 29.4 Octyl Methoxycinnamate 1.24 BHQ 23.28 Oxeladin 8.72 US 2010/0009970 A1 Jan. 14, 2010 TABLE 1-continued Compound C50% Compound IC50: Bifonazole 6.15 Oxfendazole 7.30 Bismuth Subsalicylate 8.09 Oxibendazole O.300 Bromhexine 4.25 Oxyphenbutazone (e.g., hydrate) 4.17 Bromocriptine (e.g., meSylate) 3.38 Paclitaxel O.O092 Budesonide S.66 Padimate O 5.44 Bufexamac 8.29 P-Aminosalicylic acid 1316 Camptothecin O.O26 Parthenolide 2.69 Capsaicin 1.72 Perospirone 3.60 Carbaryl 9.65 Phenazopyridine (e.g., hydrochloride) 7.85 CAY10433 7.88 Piceatannol 547 O449 Picotamide 28.78 6.21 PKR inhibitor 1.75 Chlorophyllin 1.30 Pramoxine (e.g., hydrochloride) 5.17% Chlorphenoxamine (e.g., hydrochloride) 6.2O Promazine (e.g., hydrochloride) 16.12 Citalopram (e.g., hydrobromide) 27.30 Propidium (e.g., iodide) 9.38 Cladribine O. 112 Quinacrine 4.17 Clomiphene (e.g., citrate) 1.19 Quinestrol 5.43 Cobamamide O.410 R(+)-Verapamil (e.g., hydrochloride) 15.67 Cyclocytidine (e.g., hydrochloride) O.183 Raloxifene (e.g., hydrochloride) 3.74 Cycloheximide O.184 Repaglinide 12.21 Cyproheptadine (e.g., hydrochloride) 17.97 Rescinnamine 7.88 Dehydroepiandrosterone 1119 Reserpine 25.29 Deptropine (e.g., citrate) 11.14 Rifabutin 17.25 Desoratadine 6.07 Rifaximin 19.36 Desoxycorticosterone (e.g., acetate) 14.65 Saponin 361.62 Dextrothyroxine (e.g., sodium) S.OO Satraplatin 4.8O Dibucaine (e.g., hydrochloride) 6.68 SB-2021.90 S.18 Dicyclomine (e.g., hydrochloride) 25.01 Sertraline (e.g., hydrochloride) 5.39 Dienestrol 16.49 Shikonin 26.4% Diethylstilbestrol 12.18 SiguaZodan 2.20 Dihydroergotamine (e.g., meSylate) 22.75 Silver sulfadiazine 2.20 Dilazep (e.g., dihydrochloride) 13.87 Sirolimus 0.005* Diphenidol (e.g., hydrochloride) 25.45 Fusidic acid (e.g., sodium fusidate) 7.72 Disulfiram 5.50 Spiperone 7.21 DNA-PK inhibitor II 6.52 Stanozolol 15.18 Donepezil (e.g., hydrochloride) 29.29 Suberohydroxamic acid 4.02 Doxepin (e.g., hydrochloride) 1488 Tamoxifen (e.g., citrate) 3.13 Dydrogesterone 2.75 Terconazole 2.55 Erbstatin 7.63 Testosterone 8.11 Ergoloid Mesylates 15.25 Thapsigargin O.O113 Evans Blue 1.94 Thiostrepton 3.84 Exemestane 29.04 Thiram 3.64 Ezetimibe 4.2O Tioxolone 6.24 Fascaplysin 0.444 Tirapazamine 1.83 Fenbendazole O419 Tiratricol 5.56 Fenretinide 2.26 Tolterodine (e.g., tartrate)
Load more

Recommended publications
  • Alzheimer's Disease, a Decade of Treatment: What Have We Learned?
    A Critical Look at Medication Dementia: Alzheimer’s Disease Management Issues in Alzheimer’s Disease R.Ron Finley, B.S. Pharm., R.Ph,CGP Lecturer (Emeritus) and Assistant Clinical Professor, UCSF School of Pharmacy Clinical Pharmacist, UCSF Memory and Aging Center- Alzheimer’s Research Center Educational Objectives Disclosures 1. Define the role for cholinesterase inhibitors in the management of Alzheimer’s disease, Lewy Body dementia, Frontal Temporal Lobe dementia. Pfizer Speakers Bureau 2. Name three common side effects of atypical antipsychotic Forest Speakers Bureau drugs. Novartis Speakers Bureau 3. Construct a pharmacological treatment plan for a 77-year-old Rx Consultant Associate Editor patient diagnosed with Alzheimer’s disease and hallucinations. WindChime Consultant 4. Describe the role for antipsychotic, antidepressant, mood HGA HealthCare Consultant stabilizers and benzodiazepines in the management of psychiatric behavior problems related to Alzheimer’s disease. Elder Care Specialist Consultant 5. Cite three potential drug or disease interactions with cholinesterase inhibitors. The Many Faces of Dementia Risk Factors Linked to AD Alzheimer’s Disease Over 65 years of age and increases Vascular: Multi-infarct with age FrontalTemporal Lobe dementia ( FTD) and female Pick’s disease Head injury Lewy Body Dementia Progressive Supranuclear Palsy Factors associated with DM, HTN, CVD Corticobasal Degeneration Genetic: family history, specific Primary Progressive Aphasia chromosome mutations Huntington’s disease
    [Show full text]
  • Aldrich FT-IR Collection Edition I Library
    Aldrich FT-IR Collection Edition I Library Library Listing – 10,505 spectra This library is the original FT-IR spectral collection from Aldrich. It includes a wide variety of pure chemical compounds found in the Aldrich Handbook of Fine Chemicals. The Aldrich Collection of FT-IR Spectra Edition I library contains spectra of 10,505 pure compounds and is a subset of the Aldrich Collection of FT-IR Spectra Edition II library. All spectra were acquired by Sigma-Aldrich Co. and were processed by Thermo Fisher Scientific. Eight smaller Aldrich Material Specific Sub-Libraries are also available. Aldrich FT-IR Collection Edition I Index Compound Name Index Compound Name 3515 ((1R)-(ENDO,ANTI))-(+)-3- 928 (+)-LIMONENE OXIDE, 97%, BROMOCAMPHOR-8- SULFONIC MIXTURE OF CIS AND TRANS ACID, AMMONIUM SALT 209 (+)-LONGIFOLENE, 98+% 1708 ((1R)-ENDO)-(+)-3- 2283 (+)-MURAMIC ACID HYDRATE, BROMOCAMPHOR, 98% 98% 3516 ((1S)-(ENDO,ANTI))-(-)-3- 2966 (+)-N,N'- BROMOCAMPHOR-8- SULFONIC DIALLYLTARTARDIAMIDE, 99+% ACID, AMMONIUM SALT 2976 (+)-N-ACETYLMURAMIC ACID, 644 ((1S)-ENDO)-(-)-BORNEOL, 99% 97% 9587 (+)-11ALPHA-HYDROXY-17ALPHA- 965 (+)-NOE-LACTOL DIMER, 99+% METHYLTESTOSTERONE 5127 (+)-P-BROMOTETRAMISOLE 9590 (+)-11ALPHA- OXALATE, 99% HYDROXYPROGESTERONE, 95% 661 (+)-P-MENTH-1-EN-9-OL, 97%, 9588 (+)-17-METHYLTESTOSTERONE, MIXTURE OF ISOMERS 99% 730 (+)-PERSEITOL 8681 (+)-2'-DEOXYURIDINE, 99+% 7913 (+)-PILOCARPINE 7591 (+)-2,3-O-ISOPROPYLIDENE-2,3- HYDROCHLORIDE, 99% DIHYDROXY- 1,4- 5844 (+)-RUTIN HYDRATE, 95% BIS(DIPHENYLPHOSPHINO)BUT 9571 (+)-STIGMASTANOL
    [Show full text]
  • Meprobamate Art 107 AR
    30 March 2012 EMA/212617/2012 Assessment report for meprobamate-containing medicinal products for oral use Procedure number: EMEA/H/A-107/1316 Procedure under Article 107 of Directive 2001/83/EC, as amended Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7051 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 3 1.1. Referral of the matter to the CHMP ......................................................................... 3 2. Scientific discussion ................................................................................ 3 2.1. Introduction......................................................................................................... 3 2.2. Discussion on safety ............................................................................................. 4 2.2.1. Non-clinical data ................................................................................................ 4 2.2.2. Clinical safety .................................................................................................... 4 2.2.2.1. Clinical studies ..............................................................................................
    [Show full text]
  • In Vivo and in Vitro Characterization of Naltrindole-Derived
    Journal of Psychopharmacology http://jop.sagepub.com/ In vivo and in vitro characterization of naltrindole-derived ligands at the κ-opioid receptor Joseph J Casal-Dominguez, Mary Clark, John R Traynor, Stephen M Husbands and Sarah J Bailey J Psychopharmacol 2013 27: 192 originally published online 31 October 2012 DOI: 10.1177/0269881112464828 The online version of this article can be found at: http://jop.sagepub.com/content/27/2/192 Published by: http://www.sagepublications.com On behalf of: British Association for Psychopharmacology Additional services and information for Journal of Psychopharmacology can be found at: Email Alerts: http://jop.sagepub.com/cgi/alerts Subscriptions: http://jop.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav >> Version of Record - Jan 23, 2013 OnlineFirst Version of Record - Oct 31, 2012 What is This? Downloaded from jop.sagepub.com at University of Bath on May 14, 2013 JOP27210.1177/0269881112464828Journal of PsychopharmacologyCasal-Dominguez et al. 4648282013 Original Paper In vivo and in vitro characterization of naltrindole-derived ligands at the κ-opioid receptor Journal of Psychopharmacology 27(2) 192 –202 © The Author(s) 2013 Reprints and permission: sagepub.co.uk/journalsPermissions.nav 1 2 2 DOI: 10.1177/0269881112464828 Joseph J Casal-Dominguez , Mary Clark , John R Traynor , jop.sagepub.com Stephen M Husbands1 and Sarah J Bailey1 Abstract Accumulating evidence supports a role for κ−opioid receptor antagonists in the treatment of mood disorders. Standard κ-antagonists have an unusual pharmacodynamic action, with a single injection blocking receptor signaling for several weeks. Here, we have characterized the κ-selective properties of two ligands, 5’-(2-aminomethyl) naltrindole (5’-AMN) and N-((Naltrindol-5-yl) methyl) pentanimidamide (5’-MABN), to identify whether modifications of the naltrindole side chain produces short-acting κ-antagonists.
    [Show full text]
  • Synthetic Drugs
    Comprehensive and Confident Identification of Narcotics, Steroids and Pharmaceuticals in Urine David E. Alonso1, Petra Gerhards2, Charles Lyle1 and Joe Binkley1 | 1LECO Corporation, St. Joseph, MI; 2LECO European LSCA Centre, Moenchengladbach, Germany Introduction Experimental Sample A (Traditional Drugs) Sample B (Synthetic Drugs) Monitoring of patients in hospitals and clinics has traditionally relied on Samples Representative Compounds Representative Compounds targeted methods of analysis. These screening methods are not Peak # Name Formula R.T. (s) Area Similarity Mass Delta (mDa) MA (ppm) 1 Creatinine ME C5H9N3O 210 1326229 800 -0.05 -0.43 • Obtained from a collaborating European hospital 3.5e6 3.0e6 Peak # Name Formula R.T. (s) Area Similarity 2 o-Ethynylaniline C8H7N 219 167436 893 0.07 0.63 1 Indole C8H7N 213 2744171 917 comprehensive and result in an incomplete picture of a patient’s 3 2-Methoxy-4-vinylphenol C H O 223 65764 805 0.11 0.73 52 patient monitoring samples 9 10 2 2 Creatinine ME C5H9N3O 216 613318 651 • 2.5e6 4 Nicotine C10H14N2 234 3249121 898 -0.21 -1.29 3 Pyridine, 2-(1-methyl-2-pyrrolidinyl)- C10H14N2 230 24869771 899 activities. Gas chromatography high resolution time-of-flight mass 3.0e6 5 Hordenin C10H15NO 274 949734 775 -0.14 -0.84 4 Parabanic acid, 1-methyl- C4H4N2O3 233 434278 764 Sample preparation 5 Cotinine C10H12N2O 336 27810908 918 • 6 Methylecgonine C10H17NO3 276 104640 835 -0.22 -1.1 spectrometry (GC-HRT) provides a fast and convenient method for 2.0e6 5 6 Caffeine C8H10N4O2 371 3753598 797 2.5e6 7 4-(3-Pyridyl-tetrahydrofuran-2-one C9H9NO2 313 93817 849 -0.11 -0.68 3,4 7 1-methyl-7H-xanthine C6H6N4O2 437 4868196 850 analysis of urine samples.
    [Show full text]
  • Guidelines for the Forensic Analysis of Drugs Facilitating Sexual Assault and Other Criminal Acts
    Vienna International Centre, PO Box 500, 1400 Vienna, Austria Tel.: (+43-1) 26060-0, Fax: (+43-1) 26060-5866, www.unodc.org Guidelines for the Forensic analysis of drugs facilitating sexual assault and other criminal acts United Nations publication Printed in Austria ST/NAR/45 *1186331*V.11-86331—December 2011 —300 Photo credits: UNODC Photo Library, iStock.com/Abel Mitja Varela Laboratory and Scientific Section UNITED NATIONS OFFICE ON DRUGS AND CRIME Vienna Guidelines for the forensic analysis of drugs facilitating sexual assault and other criminal acts UNITED NATIONS New York, 2011 ST/NAR/45 © United Nations, December 2011. All rights reserved. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. This publication has not been formally edited. Publishing production: English, Publishing and Library Section, United Nations Office at Vienna. List of abbreviations . v Acknowledgements .......................................... vii 1. Introduction............................................. 1 1.1. Background ........................................ 1 1.2. Purpose and scope of the manual ...................... 2 2. Investigative and analytical challenges ....................... 5 3 Evidence collection ...................................... 9 3.1. Evidence collection kits .............................. 9 3.2. Sample transfer and storage........................... 10 3.3. Biological samples and sampling ...................... 11 3.4. Other samples ...................................... 12 4. Analytical considerations .................................. 13 4.1. Substances encountered in DFSA and other DFC cases .... 13 4.2. Procedures and analytical strategy...................... 14 4.3. Analytical methodology .............................. 15 4.4.
    [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]
  • Transient Receptor Potential Channel Promiscuity Frustrates Constellation
    the sole sensor responsible for noxious cold responses in M+A+ LETTER neurons (1). However, TRPA1 is also activated by cooling and underlies at least part of the noxious cold responsiveness of Transient receptor potential channel AITC-sensitive neurons (3). Third, the authors used nicardipine 2+ promiscuity frustrates to selectively inhibit CaV1-type voltage-gated Ca channels (1). However, several dihydropyridines, including nicardipine, also constellation pharmacology act as TRPA1 agonists (4). These considerations led us to propose an alternative Sensory neurons from the trigeminal and dorsal root ganglia molecular interpretation of the difference between M+A− (DRG) have nerve endings in the skin and mucosa, where they and M+A+ neurons, which is in much better agreement with detect environmental stimuli and convey this information to published work. In accord with the authors, we conclude that the central nervous system. Several members of the transient M+A− neurons express TRPM8 but lack expression of receptor potential (TRP) superfamily of ion channels act as TRPA1. In contrast to the authors, we propose that M+A+ prime molecular sensors for thermal and chemical stimuli in neurons express TRPA1 as the prime cold and menthol these sensory neurons. However, it is incompletely understood sensor (2, 3). This interpretation is consistent with published how TRP channel expression and modulation affect the stimulus observations that menthol responses in M+A− but not in sensitivities of distinct neuronal subtypes. M+A+ neurons are inhibited by TRPM8 antagonists (5) In a recent article, Teichert et al. (1) described a “constellation and that TRPA1-mediated responses to cold in neurons are pharmacology approach” to identify and characterize subtypes characterized by a higher (colder) threshold (3).
    [Show full text]
  • Activity of Selected Group of Monoterpenes in Alzheimer's
    International Journal of Molecular Sciences Review Activity of Selected Group of Monoterpenes in Alzheimer’s Disease Symptoms in Experimental Model Studies—A Non-Systematic Review Karolina Wojtunik-Kulesza 1,*, Monika Rudkowska 2, Kamila Kasprzak-Drozd 1,* , Anna Oniszczuk 1 and Kinga Borowicz-Reutt 2 1 Department of Inorganic Chemistry, Medical University of Lublin, Chod´zki4a, 20-093 Lublin, Poland; [email protected] 2 Independent Experimental Neuropathophysiology Unit, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; [email protected] (M.R.); [email protected] (K.B.-R.) * Correspondence: [email protected] (K.W.-K.); [email protected] (K.K.-D.) Abstract: Alzheimer’s disease (AD) is the leading cause of dementia and cognitive function im- pairment. The multi-faced character of AD requires new drug solutions based on substances that incorporate a wide range of activities. Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes—low-molecular compounds with anti-inflammatory, antioxidant, Citation: Wojtunik-Kulesza, K.; enzyme inhibitory, analgesic, sedative, as well as other biological properties. The presented review Rudkowska, M.; Kasprzak-Drozd, K.; focuses on the pathophysiology of AD and a selected group of anti-neurodegenerative monoterpenes Oniszczuk, A.; Borowicz-Reutt, K. and monoterpenoids for which possible mechanisms of action have been explained. The main body Activity of Selected Group of of the article focuses on monoterpenes that have shown improved memory and learning, anxiolytic Monoterpenes in Alzheimer’s and sleep-regulating effects as determined by in vitro and in silico tests—followed by validation in Disease Symptoms in Experimental in vivo models.
    [Show full text]
  • The Differential Effects of Statins on the Metastatic Behaviour of Prostate Cancer
    British Journal of Cancer (2012) 106, 1689–1696 & 2012 Cancer Research UK All rights reserved 0007 – 0920/12 www.bjcancer.com The differential effects of statins on the metastatic behaviour of prostate cancer *,1 1 1 2,3 2,3 2,4 1,2,4 M Brown , C Hart , T Tawadros , V Ramani , V Sangar , M Lau and N Clarke 1 Genito Urinary Cancer Research Group, University of Manchester, Paterson Institute for Cancer Research, Manchester Academic Health Science Centre, 2 The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK; Department of Urology, The Christie NHS Foundation 3 Trust, Wilmslow Road, Manchester M20 4BX, UK; Department of Urology, University Hospital of South Manchester NHS Trust, Manchester M23 9LT, 4 UK; Department of Urology, Salford Royal NHS Foundation Trust, Stott Lane, Manchester M6 8HD, UK BACKGROUND: Although statins do not affect the incidence of prostate cancer (CaP), usage reduces the risk of clinical progression and mortality. Although statins are known to downregulate the mevalonate pathway, the mechanism by which statins reduce CaP progression is unknown. METHODS: Bone marrow stroma (BMS) was isolated with ethical approval from consenting patients undergoing surgery for non- malignant disease. PC-3 binding, invasion and colony formation within BMS was assessed by standardised in vitro co-culture assays in the presence of different statins. RESULTS: Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 mM) and rosuvastatin (5 mM), but not pravastatin, significantly reducing invasion towards BMS by an average of 66.68% (range 53.93–77.04%; Po0.05) and significantly reducing both 2 2 number (76.2±8.29 vs 122.9±2.48; P ¼ 0.0055) and size (0.2±0.0058 mm vs 0.27±0.012 mm ; P ¼ 0.0019) of colonies formed within BMS.
    [Show full text]
  • List of Union Reference Dates A
    Active substance name (INN) EU DLP BfArM / BAH DLP yearly PSUR 6-month-PSUR yearly PSUR bis DLP (List of Union PSUR Submission Reference Dates and Frequency (List of Union Frequency of Reference Dates and submission of Periodic Frequency of submission of Safety Update Reports, Periodic Safety Update 30 Nov. 2012) Reports, 30 Nov.
    [Show full text]
  • Chapter Four – TRPA1 Channels: Chemical and Temperature Sensitivity
    CHAPTER FOUR TRPA1 Channels: Chemical and Temperature Sensitivity Willem J. Laursen1,2, Sviatoslav N. Bagriantsev1,* and Elena O. Gracheva1,2,* 1Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA 2Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, USA *Corresponding author: E-mail: [email protected], [email protected] Contents 1. Introduction 90 2. Activation and Regulation of TRPA1 by Chemical Compounds 91 2.1 Chemical activation of TRPA1 by covalent modification 91 2.2 Noncovalent activation of TRPA1 97 2.3 Receptor-operated activation of TRPA1 99 3. Temperature Sensitivity of TRPA1 101 3.1 TRPA1 in mammals 101 3.2 TRPA1 in insects and worms 103 3.3 TRPA1 in fish, birds, reptiles, and amphibians 103 3.4 TRPA1: Molecular mechanism of temperature sensitivity 104 Acknowledgments 107 References 107 Abstract Transient receptor potential ankyrin 1 (TRPA1) is a polymodal excitatory ion channel found in sensory neurons of different organisms, ranging from worms to humans. Since its discovery as an uncharacterized transmembrane protein in human fibroblasts, TRPA1 has become one of the most intensively studied ion channels. Its function has been linked to regulation of heat and cold perception, mechanosensitivity, hearing, inflam- mation, pain, circadian rhythms, chemoreception, and other processes. Some of these proposed functions remain controversial, while others have gathered considerable experimental support. A truly polymodal ion channel, TRPA1 is activated by various stimuli, including electrophilic chemicals, oxygen, temperature, and mechanical force, yet the molecular mechanism of TRPA1 gating remains obscure. In this review, we discuss recent advances in the understanding of TRPA1 physiology, pharmacology, and molecular function.
    [Show full text]