DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2003/0199551A1 Dreyer (43) Pub

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2003/0199551A1 Dreyer (43) Pub US 20030199551A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0199551A1 Dreyer (43) Pub. Date: Oct. 23, 2003 (54) CALCIUM BLOCKERS TO TREAT (60) Provisional application No. 60/051,962, filed on Jun. PROLIFERATIVE WITREORETINOPATHY 30, 1997. (76) Inventor: Evan B. Dreyer, Pittsburgh, PA (US) Publication Classification Correspondence Address: (51) Int. Cl." ...................... A61K 31/445; A61K 31/455 ROBERT.J. BARAN Allergan, Inc. (T2-7H) (52) U.S. Cl. ............................................ 514/317; 514/355 2525 Dupont Drive Irvine, CA 926.12 (US) (57) ABSTRACT (21) Appl. No.: 10/436,902 Glutamate causes migration and proliferation of retinal (22) Filed: May 12, 2003 pigment epithelium and/or glial cells, and glutamate antago Related U.S. Application Data nists can prevent, treat or reduce retinal pigment epithelium and/or glial migration and the Subsequent development of (63) Continuation of application No. 10/038,215, filed on proliferative Vitreoretinopathy. Avoidance or management of Jan. 2, 2002, now Pat. No. 6,573,280, which is a continuation of application No. 09/445,832, filed on proliferative vitreoretinopathy can be achieved by adminis Dec. 13, 1999, now Pat. No. 6,380,261, filed as 371 tering to the patient a compound capable of reducing of international application No. PCT/US98/12414, glutamate-induced retinal cell migration in a concentration filed on Jun. 15, 1998. effective to reduce Such migration. US 2003/0199551A1 Oct. 23, 2003 CALCIUM BLOCKERS TO TREAT 0007. A third aspect of the invention features treating PROLIFERATIVE WITREORETINOPATHY preventing or reducing proliferative vitreoretinopathy in a patient by administering to the patient's retina an effective CROSS REFERENCE TO RELATED PATENT amount of a compound that reduces glutamate related retinal APPLICATIONS cell migration, proliferation, or both. 0001. This patent application is a continuation of U.S. 0008. The compound may be one of the so-called NMDA patent application Ser. No. 09/445,832 which was filed on antagonists-i.e., it reduces neuronal damage mediated by Dec. 13, 1999 as the U.S. National Patent Application of the NMDA receptor complex. Alternatively, the compound PCT/US98/12414, which was filed on Jun. 15, 1998 and was antagonizes neuronal damage mediated by the Voltage based on U.S. Provisional Application No. 60/051,962, dependent calcium channel. Other useful compounds are which was filed on Jun. 30, 1997 in the name of Dreyer. those which limit release of glutamate from cells or reduce BACKGROUND OF THE INVENTION the intracellular neurotoxic consequences of glutamate inter 0002 This application relates to preventing, controlling action with cell membrane glutamate receptorS. Preferably, reducing and/or treating proliferative vitreoretinopathy. Pro the compound crosses the blood-retinal barrier. liferative vitreoretinopathy (including epiretinal membrane 0009. The patient may be anyone who has experienced, formation) is a potentially devastating ophthalmic condition or is at risk for experiencing, penetrating trauma, retinal tear, that can lead to blindness. It can develop after any penetra traction detachment, Vitrectomy, or intraocular Surgery. The tion of the eye-Surgical or traumatic. Predisposing condi compound may be administered to the patient topically, tions therefore include, but are not limited to, penetrating orally, or intravitreally, as well as by other routes described trauma, retinal tears, traction detachments, vitrectomy, and below. It may be administered chronically, i.e., over an intraocular Surgery. Any ophthalmic condition that precipi extended period of a month or even six months or years. tates or permits migration of retinal pigment is epithelium or 0010) The invention preferably will be used to treat glial cells can lead to the development of proliferative patients having proliferative vitreoretinopathy or to treat vitreoretinopathy. See Machamer (1978) British J. Ophthal. patients prophylactically to avoid that condition. Preferably, 62:737; Hilton et al. (1983) Ophthalmology 90:121. the agent is administered over an extended period (e.g., at SUMMARY OF THE INVENTION least six-months and preferably at least one year). Those at 0003) 1 have discovered that glutamate causes migration risk for developing proliferative vitreoretinopathy include and proliferation of retinal pigment epithelium and/or glial patients who have experienced penetrating trauma, retinal cells. The invention features the use of glutamate antagonists tears, traction detachments, Vitrectomy, or intraocular Sur to reduce or control retinal pigment epithelium and/or glial gery. migration and the Subsequent development of proliferative 0011 Particularly preferred compounds are antagonists Vitreoretinopathy. Avoidance or management of proliferative of the NMDA receptor-channel complex. The term “NMDA Vitreoretinopathy can be achieved by administering to the receptor antagonists' includes several sub-types of NMDA patient a compound capable of reducing glutamate-induced antagonists including: a) channel blockers—i.e., antagonists retinal pigment epithelium and/or glial migration in a con that operate uncompetitively to block the NMDA receptor centration effective to reduce Such migration. channel; b) receptor antagonists-antagonists that compete 0004 While I do not wish to be bound to any specific with NMDA to act at the NMDA binding site; c) agents theory, I conclude that one or more of the Several types of acting at either the glycine co-agonist Site or any of Several calcium-permeable CNS ion channels mentioned below can modulation Sites Such as the Zinc Site, the magnesium site, be involved in controlling Such migration, including: a) the the redox modulatory site, or the polyamine site; d) agents various aspects of the NMDA (N-methyl-D-aspartate) which inhibit the downstream effects of NMDA receptor receptor channel complex; b) the voltage-dependent Ca" Stimulation, Such as agents that inhibit activation of protein channels; and c) other channels directly coupled to kinase C activation by NMDA stimulation, antioxidants, and glutamate (or excitatory amino acid) receptors. Such chan agents that decrease phosphatidylinositol metabolism. nels are reviewed in: Sommer, B. and Seeburg, P. H. 0012. Other compounds that are useful in the invention “Glutamate receptor channels: novel properties and new include Voltage-dependent calcium channel antagonists, e.g. clones'Trends Pharmacological Sciences 13:291-296 those which exert a Substantial direct effect on glutamate (1992); Nakanishi, S., “Molecular Diversity of glutamate toxicity mediated by the L-type voltage dependent Ca" receptors and implications for brain function”, Science channel in that they produce a Statistically significant result 248:597-603 (1992). in experiments measuring glutamate induced effects by the 0005 One aspect of the invention generally features a general method described in Karschian and Lipton, J. method of treating, preventing, or reducing proliferative Physiol. 418: 379-396 (1989) or by other techniques for Vitreoretinopathy in a patient by administering to the measuring antagonism of the L-type Ca" channel known to patient's retina an effective amount of a compound that those in the art. (We contrast the direct effect so measured reduces CNS neuronal damage incident to (associated with) with the secondary effects of excitoxicity mediated by other is calcium ion influx. channels, which in turn causes flow through the Voltage dependent Ca" channels.) Particular candidate compounds 0006 A second aspect of the invention features treating, include Class I Voltage dependent Ca" channel antagonists, preventing, or reducing proliferative vitreoretinopathy in a e.g., phenylalkylamines. patient by administering to the patient's retina an effective amount of at least one of the compounds listed in one or 0013 Preferably, the compounds used cross the blood more of Tables 2-5. below. retina barrier and can be administered chronically. Other US 2003/0199551A1 Oct. 23, 2003 useful agents act as antagonists of non-NMDA receptors tures antagonists having certain specific characteristics: the (glutamate receptor types other than the NMDA receptor ability to cross the blood-retina barrier; and the ability to be complex discussed above), and include agents which block administered chronically. Within those guidelines, any Suit inotropic glutamate receptorS or interact with metabotropic able antagonist of the glutamate induced excitotoxicity may glutamate receptors (Nakanishi, Supra). Still other agents act be used in accordance with the invention. AS mentioned, in to limit (reduce) release of glutamate from cells, thereby preferred embodiments, N-methyl-D-aspartate (NMDA) acting upstream from the glutamate receptors in the excita Subtype of glutamate receptor-channel complex may be used tory neurotoxicity process. Still other agents may act by to reduce or prevent proliferative vitreoretinopathy-related blocking downstream effects of glutamate receptor Stimula injury. Many antagonists of the NMDA receptor have been tion, e.g., the intracellular consequences of glutamate inter identified (Watkins et al., Trends in Pharmacological Sci. action with a cell membrane glutamate receptor, Such as 11:25, 1990, hereby incorporated by reference). There are agents (like dantrolene) that block the rise in intracellular Several recognized Sub-types of NMDA receptor including: calcium following Stimulation of membrane glutamate a) channel blockers—i.e., antagonists
Load more

Recommended publications
  • Exploring Novel Estrogen Receptors
    ExploringExploring novelnovel estrogenestrogen receptorsreceptors and How many drug targets? What are the relevant drug metabolizing enzymes? Tudor I. Oprea UNM Division of Biocomputing NMNM MLSCMLSC http://screening.health.unm.edu/ Support: New Mexico Molecular Libraries Screening Center (NIH MH074425) Strasbourg Summer School on Cheminformatics Obernai, Alsace, France, June 23 2008 The University of New Mexico ♦ Health Sciences Center Copyright © Tudor I. Oprea, 2007. All rights reserved SCHOOL OF MEDICINE MLIMLI inin NumbersNumbers NIHNIH RoadmapRoadmap InitiativeInitiative MolecularMolecular Libraries Libraries Initiative Initiative 44 Chemical Chemical Synthesis Synthesis MLSCNMLSCN (9+1) (9+1) PubChemPubChem ECCRECCR (6) (6) PredictivePredictive CentersCenters 99 centers centers (NLM)(NLM) ExploratoryExploratory ADMETADMET 11 NIH NIH intramural intramural CentersCenters (8)(8) 100100 x x 10 10 = = 1000 1000 assays assays CombiChemCombiChem ParallelParallel synthesis synthesis DOSDOS NotNot renewed renewed 44 centers centers + + DPI DPI 100k–500k100k–500k compounds compounds SAR matrix ~300,000 compounds Note: Subject http://nihroadmap.nih.gov The University of New Mexico > 1000 assays to change SCHOOL OF MEDICINE NMNM MLSCMLSC (3(3--yearyear summary)summary) U54MH074425U54MH074425 • 23 primary targets (62 assays) uploaded to PubChem • 38 targets total pipeline • ~ 2.4 million datapoints loaded into PubChem • Current throughput: 150,000 samples/week • first 6-plex (small GTP-ases) of the Roadmap • 2nd 6-plex (Bcl-2) also completed
    [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]
  • Method and Compositions for the Treatment of Tumors Comprising a Calcium Channel Blocker Compound of the Dlhydropyridlne Class and a Platinum Coordination Compound
    turopaiscnes patentamt European Patent Office © Publication number: 0 221 382 Office europeen des brevets A1 (2) EUROPEAN PATENT APPLICATION © Application number: 86113897.2 © Int. CI.4: A61K 33/24 , ~ //(A61K33/24,31:44) © Date of filing: 07.10.86 © Priority: 10.10.85 US 786321 © Applicant: THE BOARD OF GOVERNORS OF WAYNE STATE UNIVERSITY © Date of publication of application: 5050 Cass Avenue 13.05.87 Bulletin 87/20 Detroit Michigan 48202(US) © Designated Contracting States: @ Inventor: Honn, Kenneth V. AT BE CH DE ES FR GB IT LI LU NL SE 1889 Stanhope Grosse Polnte Woods, Michigan 48236(US) Inventor: Tayior, John D. 1408 Joliet Place Detroit, Michigan 48207(US) Inventor: Onoda, James M. 212 Baker Street No. 203, Royal Oak, Michigan 48067(US) © Representative: Patentanwalte GrUnecker, Kinkeidey, Stockmalr & Partner Maximllianstrasse 58 D-8000 MUnchen 22(DE) «y Method and compositions for the treatment of tumors comprising a calcium channel blocker compound of the dlhydropyridlne class and a platinum coordination compound. (jy The invention relates to compositions for the vherein R, and R2 are methyl groups, R, and R» are treatment of malignant tumors in a mammal which ilkyi or alkyloxyalkylene groups containing I to 8 comprise: :arbdn atoms and R5 and R« are hydrogen or one or (a) a calcium channel blocker compound of wo electron withdrawing substituents; and the dihydropyridine class selected from the group (b) a platinum coordination compound which ^consisting of las antitumor properties in humans wherein the veight ratio of the calcium channel blocker com- x>und to the platinum coordination compound is >etween I and 1000 and 10 to I.
    [Show full text]
  • WO 2012/044761 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date _ . 5 April 2012 (05.04.2012) WO 2012/044761 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 47/48 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US201 1/053876 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 29 September 201 1 (29.09.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, (26) Publication Langi English RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (30) Priority Data: ZM, ZW. 12/893,344 29 September 2010 (29.09.2010) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): UNI¬ kind of regional protection available): ARIPO (BW, GH, VERSITY OF NORTH CAROLINA AT WILMING¬ GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, TON [US/US]; 601 South College Road, Wilmington, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, NC 28403 (US).
    [Show full text]
  • Drug Resistance Updates 32 (2017) 23–46
    Drug Resistance Updates 32 (2017) 23–46 Contents lists available at ScienceDirect Drug Resistance Updates journal homepage: www.elsevier.com/locate/drup Not only P-glycoprotein: Amplification of the ABCB1-containing MARK chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins ⁎ ⁎ Ilaria Genovesea,1, Andrea Ilarib,1, Yehuda G. Assarafc,1, Francesco Fazid, ,1, Gianni Colottib, ,1 a Dept. Biochemical Sciences, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy b Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Dept. Biochemical Sciences, Sapienza University, P.le A. Moro 5, 00185 Rome, Italy c The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel d Dept. Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology and Medical Embryology, Sapienza University, Via A. Scarpa 14-16, 00161 Rome, Italy ARTICLE INFO ABSTRACT Keywords: The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. ABC transporters Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein P-glycoprotein (P-gp) or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for ex- Cancer ample taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of pub- Chemotherapeutic drugs lished papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hemato- Multidrug resistance logical malignancies. Upon repeated or even single dose treatment of cultured tumor cells or tumors in vivo with 7q21 amplicon Sorcin anti-tumor agents such as paclitaxel and doxorubicin, increased ABCB1 copy number has been demonstrated, resulting from chromosomal amplification events at 7q11.2-21 locus, leading to marked P-glycoprotein over- expression, and multidrug resistance (MDR).
    [Show full text]
  • And Angiotensin II- Induced Changes by Calcium Antagonists in the Peripheral Circulation Ofanaesthetized Rabbits Robert P
    Br. J. Pharmac. (1985), 85, 75-87 Modification ofvasopressin- and angiotensin II- induced changes by calcium antagonists in the peripheral circulation ofanaesthetized rabbits Robert P. Hof Cardiovascular Unit of Preclinical Research, Sandoz Ltd, CH-4002 Basel, Switzerland 1 Investigations into the site of vasodilator and antivasoconstrictor activity of calcium antagonists previously performed in cats were extended to a second species, barbiturate-anaesthetized rabbits, and a second vasoconstrictor agent, vasopressin. 2 The dihydropyridine derivative darodipine (code name PY 108-068; 10, 30 and 100 pg kg-' i.v.) showed systemic haemodynamic effects comparable to those seen in cats at half these doses. Darodipine effected regional vasodilatation (measured with tracer microspheres) in the heart, brain and skeletal muscles as in cats. Only the vessels of the adrenals (dilated in rabbits but not in cats), and the kidneys and skin (constricted in rabbits but not in cats) responded differently to darodipine. 3 Angiotensin II (A II; 0.15 and 1.5 yg kg- min ')constricted the same vascular beds in rabbits as in cats, namely the heart, kidneys, small intestine, pancreas, spleen, skin and arterio-venous shunts (inferred from microspheres reaching the lungs), the only exceptions being the vessels of the stomach and liver (constriction only in cats) and the adrenals (constriction only in rabbits). 4 Darodipine (30 and 100 yg kg-') attenuated the A II-induced vasoconstriction in the same vascular beds in rabbits as in cats including the kidneys, which were constricted after administration of the antagonist alone. 5 These results indicate surprisingly small species differences for the vasodilator effects of darodipine as well as the attenuation of the vasoconstrictor effects of A II.
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • Ovid MEDLINE(R)
    Supplementary material BMJ Open Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to September 16, 2019> # Searches Results 1 exp Hypertension/ 247434 2 hypertens*.tw,kf. 420857 3 ((high* or elevat* or greater* or control*) adj4 (blood or systolic or diastolic) adj4 68657 pressure*).tw,kf. 4 1 or 2 or 3 501365 5 Sex Characteristics/ 52287 6 Sex/ 7632 7 Sex ratio/ 9049 8 Sex Factors/ 254781 9 ((sex* or gender* or man or men or male* or woman or women or female*) adj3 336361 (difference* or different or characteristic* or ratio* or factor* or imbalanc* or issue* or specific* or disparit* or dependen* or dimorphism* or gap or gaps or influenc* or discrepan* or distribut* or composition*)).tw,kf. 10 or/5-9 559186 11 4 and 10 24653 12 exp Antihypertensive Agents/ 254343 13 (antihypertensiv* or anti-hypertensiv* or ((anti?hyperten* or anti-hyperten*) adj5 52111 (therap* or treat* or effective*))).tw,kf. 14 Calcium Channel Blockers/ 36287 15 (calcium adj2 (channel* or exogenous*) adj2 (block* or inhibitor* or 20534 antagonist*)).tw,kf. 16 (agatoxin or amlodipine or anipamil or aranidipine or atagabalin or azelnidipine or 86627 azidodiltiazem or azidopamil or azidopine or belfosdil or benidipine or bepridil or brinazarone or calciseptine or caroverine or cilnidipine or clentiazem or clevidipine or columbianadin or conotoxin or cronidipine or darodipine or deacetyl n nordiltiazem or deacetyl n o dinordiltiazem or deacetyl o nordiltiazem or deacetyldiltiazem or dealkylnorverapamil or dealkylverapamil
    [Show full text]
  • Structural Basis for Human Sterol Isomerase in Cholesterol Biosynthesis and Multidrug Recognition
    ARTICLE https://doi.org/10.1038/s41467-019-10279-w OPEN Structural basis for human sterol isomerase in cholesterol biosynthesis and multidrug recognition Tao Long 1, Abdirahman Hassan 1, Bonne M Thompson2, Jeffrey G McDonald1,2, Jiawei Wang3 & Xiaochun Li 1,4 3-β-hydroxysteroid-Δ8, Δ7-isomerase, known as Emopamil-Binding Protein (EBP), is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis, autophagy, 1234567890():,; oligodendrocyte formation. The mutation on EBP can cause Conradi-Hunermann syndrome, an inborn error. Interestingly, EBP binds an abundance of structurally diverse pharmacolo- gically active compounds, causing drug resistance. Here, we report two crystal structures of human EBP, one in complex with the anti-breast cancer drug tamoxifen and the other in complex with the cholesterol biosynthesis inhibitor U18666A. EBP adopts an unreported fold involving five transmembrane-helices (TMs) that creates a membrane cavity presenting a pharmacological binding site that accommodates multiple different ligands. The compounds exploit their positively-charged amine group to mimic the carbocationic sterol intermediate. Mutagenesis studies on specific residues abolish the isomerase activity and decrease the multidrug binding capacity. This work reveals the catalytic mechanism of EBP-mediated isomerization in cholesterol biosynthesis and how this protein may act as a multi-drug binder. 1 Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 2 Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 3 State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. 4 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
    [Show full text]
  • Drugs for Primary Prevention of Atherosclerotic Cardiovascular Disease: an Overview of Systematic Reviews
    Supplementary Online Content Karmali KN, Lloyd-Jones DM, Berendsen MA, et al. Drugs for primary prevention of atherosclerotic cardiovascular disease: an overview of systematic reviews. JAMA Cardiol. Published online April 27, 2016. doi:10.1001/jamacardio.2016.0218. eAppendix 1. Search Documentation Details eAppendix 2. Background, Methods, and Results of Systematic Review of Combination Drug Therapy to Evaluate for Potential Interaction of Effects eAppendix 3. PRISMA Flow Charts for Each Drug Class and Detailed Systematic Review Characteristics and Summary of Included Systematic Reviews and Meta-analyses eAppendix 4. List of Excluded Studies and Reasons for Exclusion This supplementary material has been provided by the authors to give readers additional information about their work. © 2016 American Medical Association. All rights reserved. 1 Downloaded From: https://jamanetwork.com/ on 09/28/2021 eAppendix 1. Search Documentation Details. Database Organizing body Purpose Pros Cons Cochrane Cochrane Library in Database of all available -Curated by the Cochrane -Content is limited to Database of the United Kingdom systematic reviews and Collaboration reviews completed Systematic (UK) protocols published by by the Cochrane Reviews the Cochrane -Only systematic reviews Collaboration Collaboration and systematic review protocols Database of National Health Collection of structured -Curated by Centre for -Only provides Abstracts of Services (NHS) abstracts and Reviews and Dissemination structured abstracts Reviews of Centre for Reviews bibliographic
    [Show full text]
  • Phase II Trial of VELCADE® (Bortezomib)
    Phase II Trial of VELCADE® (Bortezomib) in Combination with Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients with Newly-diagnosed Glioblastoma Multiforme. Protocol Version: Date of Protocol: Original January 22, 2009 Amendment 1 February 14, 2011 Amendment 2 May 31, 2012 Amendment 3 August 1, 2012 Amendment 4 January 09, 2013 Amendment 5 March 13, 2013 Amendment 6 November 19, 2013 Amendment 7 February 11, 2014 Principal Investigator Dr. Albert Lai University of California at Los Angeles VELCADE (bortezomib) for Injection UCLA STUDY PROTOCOL Protocol Number X05303 Phase II Trial of VELCADE® (Bortezomib) in Combination with Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients with Newly-diagnosed Glioblastoma Multiforme. Protocol Version: Date of Protocol: Original January 22, 2009 Amendment 1 February 14, 2011 Amendment 2 May 31, 2012 Amendment 3 August 1, 2012 Amendment 4 January 09, 2013 Amendment 5 March 13, 2013 Amendment 6 November 19, 2013 Amendment 7 February 11, 2014 Investigator &Study Center: Principal Investigator Co-Principal Investigator Sub-Investigators Sub-Site: *VELCADE is the exclusive trademark of Millennium Pharmaceuticals, Inc., registered in the United States and internationally. CONFIDENTIAL Page 1 of 86 Amendment 7 version dated February 11, 2014 VELCADE (bortezomib) for Injection UCLA Neuro-Oncology Program PROTOCOL SUMMARY Title: Phase II Trial of VELCADE* (Bortezomib) in Combination with Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients with Newly-diagnosed Glioblastoma Multiforme. Objectives: This phase II study will examine the safety and efficacy of bortezomib in combination with temozolomide/radiation followed by bortezomib and temozolomide for 2 years (24 28-day cycles) in newly-diagnosed patients with glioblastoma.
    [Show full text]
  • Marrakesh Agreement Establishing the World Trade Organization
    No. 31874 Multilateral Marrakesh Agreement establishing the World Trade Organ ization (with final act, annexes and protocol). Concluded at Marrakesh on 15 April 1994 Authentic texts: English, French and Spanish. Registered by the Director-General of the World Trade Organization, acting on behalf of the Parties, on 1 June 1995. Multilat ral Accord de Marrakech instituant l©Organisation mondiale du commerce (avec acte final, annexes et protocole). Conclu Marrakech le 15 avril 1994 Textes authentiques : anglais, français et espagnol. Enregistré par le Directeur général de l'Organisation mondiale du com merce, agissant au nom des Parties, le 1er juin 1995. Vol. 1867, 1-31874 4_________United Nations — Treaty Series • Nations Unies — Recueil des Traités 1995 Table of contents Table des matières Indice [Volume 1867] FINAL ACT EMBODYING THE RESULTS OF THE URUGUAY ROUND OF MULTILATERAL TRADE NEGOTIATIONS ACTE FINAL REPRENANT LES RESULTATS DES NEGOCIATIONS COMMERCIALES MULTILATERALES DU CYCLE D©URUGUAY ACTA FINAL EN QUE SE INCORPOR N LOS RESULTADOS DE LA RONDA URUGUAY DE NEGOCIACIONES COMERCIALES MULTILATERALES SIGNATURES - SIGNATURES - FIRMAS MINISTERIAL DECISIONS, DECLARATIONS AND UNDERSTANDING DECISIONS, DECLARATIONS ET MEMORANDUM D©ACCORD MINISTERIELS DECISIONES, DECLARACIONES Y ENTEND MIENTO MINISTERIALES MARRAKESH AGREEMENT ESTABLISHING THE WORLD TRADE ORGANIZATION ACCORD DE MARRAKECH INSTITUANT L©ORGANISATION MONDIALE DU COMMERCE ACUERDO DE MARRAKECH POR EL QUE SE ESTABLECE LA ORGANIZACI N MUND1AL DEL COMERCIO ANNEX 1 ANNEXE 1 ANEXO 1 ANNEX
    [Show full text]