DOCSLIB.ORG

The Inhaled Steroid Ciclesonide Blocks SARS-Cov-2 RNA Replication by Targeting Viral

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Inhaled Steroid Ciclesonide Blocks SARS-Cov-2 RNA Replication by Targeting Viral bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.258459; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 The inhaled steroid ciclesonide blocks SARS-CoV-2 RNA replication by targeting viral 2 replication-transcription complex in culture cells 3 4 Shutoku Matsuyamaa#, Miyuki Kawasea, Naganori Naoa, Kazuya Shiratoa, Makoto Ujikeb, Wataru 5 Kamitanic, Masayuki Shimojimad, and Shuetsu Fukushid 6 7 aDepartment of Virology III, National Institute of Infectious Diseases, Tokyo, Japan 8 bFaculty of Veterinary Medicine, Nippon Veterinary and Life Science University, Tokyo, Japan 9 cDepartment of Infectious Diseases and Host Defense, Gunma University Graduate School of 10 Medicine, Gunma, Japan 11 dDepartment of Virology I, National Institute of Infectious Diseases, Tokyo, Japan. 12 13 Running Head: Ciclesonide blocks SARS-CoV-2 replication 14 15 #Address correspondence to Shutoku Matsuyama, [email protected] 16 17 Word count: Abstract 149, Text 3,016 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.258459; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 18 Abstract 19 We screened steroid compounds to obtain a drug expected to block host inflammatory responses and 20 MERS-CoV replication. Ciclesonide, an inhaled corticosteroid, suppressed replication of MERS-CoV 21 and other coronaviruses, including SARS-CoV-2, the cause of COVID-19, in cultured cells. The 22 effective concentration (EC90) of ciclesonide for SARS-CoV-2 in differentiated human bronchial 23 tracheal epithelial cells was 0.55 μM. Ciclesonide inhibited formation of double membrane vesicles, 24 which anchor the viral replication-transcription complex in cells. Eight consecutive passages of 43 25 SARS-CoV-2 isolates in the presence of ciclesonide generated 15 resistant mutants harboring single 26 amino acid substitutions in non-structural protein 3 (nsp3) or nsp4. Of note, ciclesonide still 27 suppressed replication of all these mutants by 90% or more, suggesting that these mutants cannot 28 completely overcome ciclesonide blockade. These observations indicate that the suppressive effect of 29 ciclesonide on viral replication is specific to coronaviruses, highlighting it as a candidate drug for the 30 treatment of COVID-19 patients. 31 32 Importance 33 The outbreak of SARS-CoV-2, the cause of COVID-19, is ongoing. To identify the effective antiviral 34 agents to combat the disease is urgently needed. In the present study, we found that an inhaled 35 corticosteroid, ciclesonide suppresses replication of coronaviruses, including beta-coronaviruses 36 (MHV-2, MERS-CoV, SARS-CoV, and SARS-CoV-2) and an alpha-coronavirus (HCoV-229E) in 37 cultured cells. The inhaled ciclesonide is safe; indeed, it can be administered to infants at high 38 concentrations. Thus, ciclesonide is expected to be a broad-spectrum antiviral drug that is effective 39 against many members of the coronavirus family. It could be prescribed for the treatment of MERS, 40 and COVID-19. 41 42 Introduction 43 The COVID-19 outbreak began in December 2019 in Wuhan, China(1). The causative virus, severe 44 acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread rapidly worldwide and was declared bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.258459; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 45 a global health emergency by the World Health Organization. Thus, effective antiviral agents to 46 combat the disease are urgently needed. Several drugs are effective against SARS-CoV-2 in cultured 47 cells(2–4). Of these, Remdesivir has undergone clinical trials in COVID-19 patients, with both 48 positive and negative results (5, 6). Lopinavir/ritonavir and chloroquine/hydroxychloroquine are of no 49 benefit (7, 8). 50 The virus can have inflammatory effects; therefore, steroids are used to treat severe inflammation, 51 with beneficial effects in some cases. For example, high-dose steroids reduce symptoms in those with 52 influenza encephalopathy(9). It would be highly beneficial if a virus-specific inhibitor was identified 53 among the many steroid compounds that have been well characterized. However, systemic treatment 54 with steroids is contraindicated in cases of severe pneumonia caused by Middle East respiratory 55 syndrome coronavirus (MERS-CoV) or severe acute respiratory syndrome coronavirus (SARS-CoV); 56 this is because steroids suppress innate and adaptive immune responses(10, 11), resulting in increased 57 viral replication. In fact, for SARS (2003) and MERS (2013), systemic treatment with cortisone or 58 prednisolone is associated with increased mortality(12, 13). Therefore, if steroid compounds are to be 59 used to treat patients suffering from COVID-19, their tendency to increase virus replication must be 60 abrogated. Here, we reconsidered the use of steroids for treatment of pneumonia caused by 61 coronavirus. 62 In the preprint of this study (posted in BioRxiv)(14), we showed that a corticosteroid, ciclesonide, is a 63 potent blocker of SARS-CoV-2 replication. Based on the data in our preprint study, clinical trials of a 64 retrospective cohort study to treat COVID-19 patients were started in Japanese hospital in March 65 2020. The treatment regime involves inhalation of 400 μg ciclesonide (two or three times per day) for 66 2 weeks. Three cases of COVID-19 pneumonia treated successfully with ciclesonide have been 67 reported(15), as have several case reports(16–18). None of these studies reported significant side 68 effects. The aim of the present study is to outline the scientific rationale for conducting these clinical 69 trials. 70 71 bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.258459; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 72 Results 73 Antiviral effect of steroid compounds on MERS-CoV 74 The 92 steroid compounds chosen from the Prestwick Chemical Library were examined to assess the 75 inhibitory effects of MERS-CoV-induced cytopathic effects. Vero cells treated with steroid 76 compounds were infected with MERS-CoV at an MOI = 0.1 and then incubated for 3 days. Four 77 steroid compounds, ciclesonide, mometasone furoate, mifepristone, and algestone acetophenide, 78 conferred a > 95% cell survival rate (Fig. 1). Interestingly, a structural feature of these compounds is a 79 five- or six-membered monocycle attached to the steroid core. 80 81 Next, we assessed the ability of eight steroid compounds (denoted by arrows in Fig. 1) to suppress 82 both growth of MERS-CoV and virus-mediated cytotoxicity in Vero cells over a range of drug 83 concentrations (0.1–100 µM). Ciclesonide exhibited low cytotoxicity and potent suppression of viral 84 growth (Fig. 2a). Algestone acetophenide, mometasone, and mifepristone also suppressed viral 85 growth; however, at 10 μM, the percentage viability of cells treated with algestone acetophenide and 86 mometasone was lower than that of cells treated with ciclesonide, and the ability of mifepristone and 87 mometasone to suppress viral growth was lower than that of ciclesonide. Cortisone and prednisolone, 88 which are commonly used for systemic steroid therapy, dexamethasone, which has strong 89 immunosuppressant effects, and fluticasone, a common inhaled steroid drug, did not suppress viral 90 growth (Fig. 2a). A time-of-addition assay to compare the viral inhibition efficacies of the steroids 91 with those of E64d, a cathepsin-dependent virus entry inhibitor, and lopinavir, a viral 3CL protease 92 inhibitor, previously reported for SARS-CoV(19, 20), demonstrated that ciclesonide functions at the 93 post-virus entry stage (Supplemental Fig. S1). 94 95 The antiviral effects of mometasone and ciclesonide against various viral species were tested by 96 quantifying propagated virus in the culture medium of infected cells. Ciclesonide and mometasone 97 suppressed replication of MHV-2, MERS-CoV, SARS-CoV, HCoV-229E, and SARS-CoV-2 (all of 98 which have a positive strand RNA genome), but did not affect replication of respiratory syncytial bioRxiv preprint doi: https://doi.org/10.1101/2020.08.22.258459; this version posted August 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 99 virus (RSV) or influenza virus (which have a negative strand RNA genome) (Fig. 2b). In addition, 100 ciclesonide slightly, but significantly, inhibited replication of rubella virus (which has a positive strand 101 RNA genome) (Fig. 2b). 102 103 Target of ciclesonide during MERS-CoV replication 104 In an attempt to identify a druggable target for viral replication, we performed 11 consecutive 105 passages of MERS-CoV in the presence of 40 μM ciclesonide or 40 μM mometasone. A mutant virus 106 displaying resistance to ciclesonide (but no virus displaying resistance to mometasone) was generated. 107 Viral replication in the presence of ciclesonide was confirmed by measuring the virus titer in the 108 culture medium of infected Vero cells at 24 h post-infection (hpi) and the amount of viral RNA in 109 infected cells at 6 hpi (Fig. 3a and 3b). Next-generation sequencing revealed that an amino acid 110 substitution at A25V (C19647T in the reference sequence NC_019843.3) in non-structural protein 15 111 (NSP15), a coronavirus endoribonuclease (21–23), was predicted to cause resistance to ciclesonide. 112 Subsequently, a recombinant virus carrying the A25V amino acid substitution in nsp15 (Re-Nsp15- 113 A25V) was generated from the parental MERS-CoV/EMC strain (Re-EMC/MERS) using a bacterial 114 artificial chromosome (BAC) reverse genetics system(24).
Load more

Recommended publications
  • (12) United States Patent (10) Patent No.: US 7,871,995 B2 Bunschoten Et Al
    US00787 1995 B2 (12) United States Patent (10) Patent No.: US 7,871,995 B2 Bunschoten et al. (45) Date of Patent: *Jan. 18, 2011 (54) DRUG DELIVERY SYSTEM COMPRISINGA (52) U.S. Cl. ....................................... 514/171; 514/182 TETRAHYDROXYLATED ESTROGEN FOR (58) Field of Classification Search ................. 514/171, USE IN HORMONAL CONTRACEPTION 514f182 See application file for complete search history. (75) Inventors: Evert Johannes Bunschoten, Heesch (NL); Herman Jan Tijmen Coelingh (56) References Cited Bennink, Driebergen (NL); Christian U.S. PATENT DOCUMENTS Franz Holinka, New York, NY (US) 3,440,320 A 4, 1969 Sackler et al. O O 3,797.494. A 3, 1974 Zaffaroni (73) Assignee: Pantarhei Bioscience B.V., Al Zeist 4,460.372 A 7/1984 Campbell et al. (NL) 4,573.996 A 3/1986 Kwiatek et al. 4,624,665 A 1 1/1986 Nuwayser (*) Notice: Subject to any disclaimer, the term of this 4,722,941 A 2f1988 Eckert et al. patent is extended or adjusted under 35 4,762,717 A 8/1988 Crowley, Jr. U.S.C. 154(b) by 1233 days. 4.937,238 A 6, 1990 Lemon 5,063,507 A 1 1/1991 Lindsey et al. This patent is Subject to a terminal dis- 5,130,137 A 7/1992 Crowley, Jr. claimer. 5,211,952 A 5/1993 Spicer et al. 5,223,261 A 6/1993 Nelson et al. 5,340,584 A 8/1994 Spicer et al. (21) Appl. No.: 10/478,357 5,340,585 A 8/1994 Pike et al. 1-1. 5,340,586 A 8, 1994 Pike et al.
    [Show full text]
  • Zhejiang Xianju Pharmaceutical Co. Ltd
    No.1, Xianyao Road, Xianju, Zhejiang, China, 317300 Xianju Pharma Outline Outline I. Brief Introduction II. Quality Unit III. Production System IV. EHS System I. Brief Introduction Xianju Pharma Zhejiang Xianju Pharmaceutical Co., Ltd. A professional manufacturer of steroids and hormone products with largest scale and maximum varieties in China. A state-designated manufacturer of contraceptive drugs in China. Company Milestones Jan 1972 Foundation of company May 1997 Incorporated into Zhejiang Medicine Co., Ltd Oct. 1999 Listed in Shanghai Stock Market Jun. 2000 Reorganized into Xianju Pharmaceutical Co., Ltd Dec. 2001 Reformed to Zhejiang Xianju Pharmaceutical Co., Ltd Jan. 2010 listed in Shenzhen Stock Market Location of Xianju There are six airports around Shanghai Xianju, which makes us easily accessible for our partners. Headquarter Hangzhou Located in Xianju, Taizhou City Ningbo Yangfu Site (FPPs) Located in Yangfu, Xianju, Taizhou Yiwu City 6.8km from headquarter Duqiao Site (APIs) Located in LinHai, TaiZhou City, 82.9km from headquarter Taizhou Wenzhou Yangfu Site (APIs) Under construction, finish at 2017 Company Organization General Manager Vice G.M for Vice G.M Vice G.M for Vice G.M for Vice G.M for Quality Director Sales for Market Administration Finance Technology Finance Dept Finance Dept Application Tech Dept Endineering Construction Domestic DrugRegistrationDept. Research& Development Dept. Marketing Dept. Marketing Quality Control Quality Domestic Trading Dept International TradeDep Quality Assurance For FPP Quality Assurance For API Regulatory AffairsDept Human Resource Dept Information Technology Dept Dept Enterprise Management Dept Affairs Administrative Taizhou Xianju Quality System Quality Xianju Taizhou . t G.M. Assistant EHS Dept Production Management Dept G.M.
    [Show full text]
  • This Fact Sheet Provides Information to Patients with Eczema and Their Carers. About Topical Corticosteroids How to Apply Topic
    This fact sheet provides information to patients with eczema and their carers. About topical corticosteroids You or your child’s doctor has prescribed a topical corticosteroid for the treatment of eczema. For treating eczema, corticosteroids are usually prepared in a cream or ointment and are applied topically (directly onto the skin). Topical corticosteroids work by reducing inflammation and helping to control an over-reactive response of the immune system at the site of eczema. They also tighten blood vessels, making less blood flow to the surface of the skin. Together, these effects help to manage the symptoms of eczema. There is a range of steroids that can be used to treat eczema, each with different strengths (potencies). On the next page, the potencies of some common steroids are shown, as well as the concentration that they are usually used in cream or ointment preparations. Using a moisturiser along with a steroid cream does not reduce the effect of the steroid. There are many misconceptions about the side effects of topical corticosteroids. However these treatments are very safe and patients are encouraged to follow the treatment regimen as advised by their doctor. How to apply topical corticosteroids How often should I apply? How much should I apply? Apply 1–2 times each day to the affected area Enough cream should be used so that the of skin according to your doctor’s instructions. entire affected area is covered. The cream can then be rubbed or massaged into the Once the steroid cream has been applied, inflamed skin. moisturisers can be used straight away if needed.
    [Show full text]
  • Betamethasone
    Betamethasone Background Betamethasone is a potent, long-acting, synthetic glucocorticoid widely used in equine veterinary medicine as a steroidal anti-inflammatory.1 It is often administered intra-articularly for control of pain associated with inflammation and osteoarthritis.2 Betamethasone is a prescription medication and can only be dispensed from or upon the request of a http://en.wikipedia.org/wiki/Betamethasone#/media/File:Betamethasone veterinarian. It is commercially available .png in a variety of formulations including BetaVet™, BetaVet Soluspan Suspension® and Betasone Aqueous Suspension™.3 Betamethasone can be used intra-articularly, intramuscularly, by inhalation, and topically.4 When administered intra-articularly, it is often combined with other substances such as hyaluronan.5 Intra-articular and intramuscular dosages range widely based upon articular space, medication combination protocol, and practitioner preference. Betamethasone is a glucocorticoid receptor agonist which binds to various glucocorticoid receptors setting off a sequence of events affecting gene transcription and the synthesis of proteins. These mechanisms of action include: • Potential alteration of the G protein-coupled receptors to interfere with intracellular signal transduction pathways • Enhanced transcription in many genes, especially those involving suppression of inflammation. • Inhibition of gene transcription – including those that encode pro-inflammatory substances. The last two of these are considered genomic effects. This type of corticosteroid effect usually occurs within hours to days after administration. The genomic effects persist after the concentrations of the synthetic corticosteroid in plasma are no longer detectable, as evidenced by persistent suppression of the normal production of hydrocortisone following synthetic corticosteroid administration.6 When used judiciously, corticosteroids can be beneficial to the horse.
    [Show full text]
  • Nitrate Prodrugs Able to Release Nitric Oxide in a Controlled and Selective
    Europäisches Patentamt *EP001336602A1* (19) European Patent Office Office européen des brevets (11) EP 1 336 602 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07C 205/00, A61K 31/00 20.08.2003 Bulletin 2003/34 (21) Application number: 02425075.5 (22) Date of filing: 13.02.2002 (84) Designated Contracting States: (71) Applicant: Scaramuzzino, Giovanni AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 20052 Monza (Milano) (IT) MC NL PT SE TR Designated Extension States: (72) Inventor: Scaramuzzino, Giovanni AL LT LV MK RO SI 20052 Monza (Milano) (IT) (54) Nitrate prodrugs able to release nitric oxide in a controlled and selective way and their use for prevention and treatment of inflammatory, ischemic and proliferative diseases (57) New pharmaceutical compounds of general effects and for this reason they are useful for the prep- formula (I): F-(X)q where q is an integer from 1 to 5, pref- aration of medicines for prevention and treatment of in- erably 1; -F is chosen among drugs described in the text, flammatory, ischemic, degenerative and proliferative -X is chosen among 4 groups -M, -T, -V and -Y as de- diseases of musculoskeletal, tegumental, respiratory, scribed in the text. gastrointestinal, genito-urinary and central nervous sys- The compounds of general formula (I) are nitrate tems. prodrugs which can release nitric oxide in vivo in a con- trolled and selective way and without hypotensive side EP 1 336 602 A1 Printed by Jouve, 75001 PARIS (FR) EP 1 336 602 A1 Description [0001] The present invention relates to new nitrate prodrugs which can release nitric oxide in vivo in a controlled and selective way and without the side effects typical of nitrate vasodilators drugs.
    [Show full text]
  • The National Drugs List
    ^ ^ ^ ^ ^[ ^ The National Drugs List Of Syrian Arab Republic Sexth Edition 2006 ! " # "$ % &'() " # * +$, -. / & 0 /+12 3 4" 5 "$ . "$ 67"5,) 0 " /! !2 4? @ % 88 9 3: " # "$ ;+<=2 – G# H H2 I) – 6( – 65 : A B C "5 : , D )* . J!* HK"3 H"$ T ) 4 B K<) +$ LMA N O 3 4P<B &Q / RS ) H< C4VH /430 / 1988 V W* < C A GQ ") 4V / 1000 / C4VH /820 / 2001 V XX K<# C ,V /500 / 1992 V "!X V /946 / 2004 V Z < C V /914 / 2003 V ) < ] +$, [2 / ,) @# @ S%Q2 J"= [ &<\ @ +$ LMA 1 O \ . S X '( ^ & M_ `AB @ &' 3 4" + @ V= 4 )\ " : N " # "$ 6 ) G" 3Q + a C G /<"B d3: C K7 e , fM 4 Q b"$ " < $\ c"7: 5) G . HHH3Q J # Hg ' V"h 6< G* H5 !" # $%" & $' ,* ( )* + 2 ا اوا ادو +% 5 j 2 i1 6 B J' 6<X " 6"[ i2 "$ "< * i3 10 6 i4 11 6! ^ i5 13 6<X "!# * i6 15 7 G!, 6 - k 24"$d dl ?K V *4V h 63[46 ' i8 19 Adl 20 "( 2 i9 20 G Q) 6 i10 20 a 6 m[, 6 i11 21 ?K V $n i12 21 "% * i13 23 b+ 6 i14 23 oe C * i15 24 !, 2 6\ i16 25 C V pq * i17 26 ( S 6) 1, ++ &"r i19 3 +% 27 G 6 ""% i19 28 ^ Ks 2 i20 31 % Ks 2 i21 32 s * i22 35 " " * i23 37 "$ * i24 38 6" i25 39 V t h Gu* v!* 2 i26 39 ( 2 i27 40 B w< Ks 2 i28 40 d C &"r i29 42 "' 6 i30 42 " * i31 42 ":< * i32 5 ./ 0" -33 4 : ANAESTHETICS $ 1 2 -1 :GENERAL ANAESTHETICS AND OXYGEN 4 $1 2 2- ATRACURIUM BESYLATE DROPERIDOL ETHER FENTANYL HALOTHANE ISOFLURANE KETAMINE HCL NITROUS OXIDE OXYGEN PROPOFOL REMIFENTANIL SEVOFLURANE SUFENTANIL THIOPENTAL :LOCAL ANAESTHETICS !67$1 2 -5 AMYLEINE HCL=AMYLOCAINE ARTICAINE BENZOCAINE BUPIVACAINE CINCHOCAINE LIDOCAINE MEPIVACAINE OXETHAZAINE PRAMOXINE PRILOCAINE PREOPERATIVE MEDICATION & SEDATION FOR 9*: ;< " 2 -8 : : SHORT -TERM PROCEDURES ATROPINE DIAZEPAM INJ.
    [Show full text]
  • Fluorometholone Ophthalmic Suspension 0.1% W/V Corticosteroid Anti-Inflammatory
    PRODUCT MONOGRAPH PrFML® Fluorometholone Ophthalmic Suspension 0.1% w/v Corticosteroid Anti-Inflammatory Allergan Inc. Date of Preparation: Markham, ON October 30, 1972 L6G 0B5 Date of Revision: May 2, 2018 Submission Control No: 214474 Page 1 of 12 NAME OF DRUG Pr ® FML Fluorometholone Ophthalmic Suspension 0.1% w/v THERAPEUTIC CLASSIFICATION Topical corticosteroid ACTIONS Corticosteroids inhibit the inflammatory response to a variety of inciting agents of a mechanical, chemical and immunological nature. They inhibit edema, fibrin deposition, capillary dilation, leukocyte migration, phagocytic activity, capillary proliferation, fibroblast proliferation, deposition of collagen and scar formation associated with inflammation. Corticosteroids are thought to act by controlling the rate of synthesis of proteins. Corticosteroids and their derivatives are capable of producing a rise in intraocular pressure. INDICATIONS FML® (fluorometholone ophthalmic suspension 0.1% w/v) is indicated for the treatment of steroid- responsive inflammation of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe. CONTRAINDICATIONS FML® is contraindicated in: Superficial (or epithelial) herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, and other viral diseases of the cornea and conjunctiva. Fungal diseases of ocular structures. Mycobacterial infections of the eye (e.g., Tuberculosis of the eye). Acute untreated infections of the eye. Hypersensitivity to the constituents of this medication (for a listing of ingredients, see PHARMACEUTICAL INFORMATION), or hypersensitivity to other corticosteroids. Page 2 of 12 WARNINGS Use of topical corticosteroids may cause increased intraocular pressure (IOP) in certain individuals. It is necessary that the IOP be checked frequently in patients with a history of glaucoma. Use of corticosteroids may prolong the course and may exacerbate the severity of many viral eye infections (including herpes simplex).
    [Show full text]
  • AHFS Pharmacologic-Therapeutic Classification System
    AHFS Pharmacologic-Therapeutic Classification System Abacavir 48:24 - Mucolytic Agents - 382638 8:18.08.20 - HIV Nucleoside and Nucleotide Reverse Acitretin 84:92 - Skin and Mucous Membrane Agents, Abaloparatide 68:24.08 - Parathyroid Agents - 317036 Aclidinium Abatacept 12:08.08 - Antimuscarinics/Antispasmodics - 313022 92:36 - Disease-modifying Antirheumatic Drugs - Acrivastine 92:20 - Immunomodulatory Agents - 306003 4:08 - Second Generation Antihistamines - 394040 Abciximab 48:04.08 - Second Generation Antihistamines - 394040 20:12.18 - Platelet-aggregation Inhibitors - 395014 Acyclovir Abemaciclib 8:18.32 - Nucleosides and Nucleotides - 381045 10:00 - Antineoplastic Agents - 317058 84:04.06 - Antivirals - 381036 Abiraterone Adalimumab; -adaz 10:00 - Antineoplastic Agents - 311027 92:36 - Disease-modifying Antirheumatic Drugs - AbobotulinumtoxinA 56:92 - GI Drugs, Miscellaneous - 302046 92:20 - Immunomodulatory Agents - 302046 92:92 - Other Miscellaneous Therapeutic Agents - 12:20.92 - Skeletal Muscle Relaxants, Miscellaneous - Adapalene 84:92 - Skin and Mucous Membrane Agents, Acalabrutinib 10:00 - Antineoplastic Agents - 317059 Adefovir Acamprosate 8:18.32 - Nucleosides and Nucleotides - 302036 28:92 - Central Nervous System Agents, Adenosine 24:04.04.24 - Class IV Antiarrhythmics - 304010 Acarbose Adenovirus Vaccine Live Oral 68:20.02 - alpha-Glucosidase Inhibitors - 396015 80:12 - Vaccines - 315016 Acebutolol Ado-Trastuzumab 24:24 - beta-Adrenergic Blocking Agents - 387003 10:00 - Antineoplastic Agents - 313041 12:16.08.08 - Selective
    [Show full text]
  • Penetration of Synthetic Corticosteroids Into Human Aqueous Humour
    Eye (1990) 4, 526--530 Penetration of Synthetic Corticosteroids into Human Aqueous Humour C. N. 1. McGHEE,1.3 D. G. WATSON, 3 1. M. MIDGLEY, 3 M. 1. NOBLE, 2 G. N. DUTTON, z A. I. FERNl Glasgow Summary The penetration of prednisolone acetate (1%) and fluorometholone alcohol (0.1%) into human aqueous humour following topical application was determined using the very sensitive and specific technique of Gas Chromatography with Mass Spec­ trometry (GCMS). Prednisolone acetate afforded peak mean concentrations of 669.9 ng/ml within two hours and levels of 28.6 ng/ml in aqueous humour were detected almost 24 hours post application. The peak aqueous humour level of flu­ orometholone was S.lng/ml. The results are compared and contrasted with the absorption of dexamethasone alcohol (0.1%), betamethasone sodium phosphate (0.1 %) and prednisolone sodium phosphate (0.5%) into human aqueous humour. Topical corticosteroid preparations have been prednisolone acetate (1.0%) and fluorometh­ used widely in ophthalmology since the early alone alcohol (0.1 %) (preliminary results) 1960s and over the last 10 years the choice of into the aqueous humour of patients under­ preparations has become larger and more going elective cataract surgery. varied. Unfortunately, data on the intraocular penetration of these steroids in humans has SUbjects and Methods not paralleled the expansion in the number of Patients who were scheduled to undergo rou­ available preparations; indeed until recently, tine cataract surgery were recruited to the estimation of intraocular penetration has study and informed consent was obtained in been reliant upon extrapolation of data from all cases (n=88), Patients with corneal disease animal models (see Watson et ai., 1988, for or inflammatory ocular conditions which bibliography).
    [Show full text]
  • Summary of Product Characteristics
    Health Products Regulatory Authority Summary of Product Characteristics 1 NAME OF THE MEDICINAL PRODUCT Aldactone 50 mg Film-coated tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 50 mg of Spironolactone. For a full list of excipients, see section 6.1 3 PHARMACEUTICAL FORM Film-coated tablet (Tablets) Round, white coloured, biconvex tablet with a peppermint odour embossed ‘SEARLE over 916’ on one side and the other side plain. 4 CLINICAL PARTICULARS 4.1 Therapeutic Indications In the management of refractory oedema associated with congestive cardiac failure; hepatic cirrhosis with ascites and oedema, malignant ascites, nephrotic syndrome, diagnosis and treatment of primary aldosteronism, essential hypertension. Children should only be treated under guidance of a paediatric specialist. There is limited paediatric data available (see sections 5.1 and 5.2). 4.2 Posology and method of administration Administration of Aldactone once daily with a meal is recommended. Posology Adults Congestive heart failure: Usual dose - 100 mg/day. In difficult or severe cases the dosage may be gradually increased up to 200 mg/day. When oedema is controlled, the usual maintenance level is 75 mg/day to 200 mg/day. Severe heart failure in conjunction with standard therapy (New York Heart Association Class III-IV): Based on the Randomized Aldactone Evaluation Study (RALES), treatment in conjunction with standard therapy should be initiated at a dose of spironolactone 25 mg once daily in patients with a serum potassium ≤5.0 mEq/L and serum creatinine ≤2.5 mg/dL. Patients who tolerate 25 mg once daily may have their dose increased to 50 mg once daily as clinically indicated.
    [Show full text]
  • Superior Nuclear Receptor Selectivity and Therapeutic Index of Methylprednisolone Aceponate Versus Mometasone Furoate
    DOI:10.1111/j.1600-0625.2007.00597.x www.blackwellpublishing.com/EXD Original Article Superior nuclear receptor selectivity and therapeutic index of methylprednisolone aceponate versus mometasone furoate Parham Mirshahpanah1, Wolf-Dietrich Do¨ cke2, Udo Merbold2, Khusru Asadullah2, Lars Ro¨se2, Heike Scha¨ cke2 and Thomas M. Zollner1 1Research Business Area Dermatology, Berlex Biosciences, Richmond, CA, USA; 2Corporate Research Area Inflammation, Bayer Schering Pharma, Berlin, Germany Correspondence: Thomas M. Zollner, TRG Inflammation, Bayer Schering Pharma, Berlin, Germany, Tel.: +1 510 669 4272, e-mail: [email protected] Accepted for publication 18 June 2007 Abstract: Although introduced more than 50 years ago, topical a relevant rodent model in vivo. We demonstrate that glucocorticoids are still the first line therapy for many methylprednisolone aceponate displays higher specificity in inflammatory skin disorders such as atopic eczema, contact nuclear receptor binding compared with mometasone furoate. dermatitis and many others. Recently, significant improvements Methylprednisolone aceponate was also markedly superior in have been made to optimize the ratio of desired to unwanted terms of minimizing induction of skin atrophy or telangiectasias effects. While with early compounds such as triamcinolone, when compared with mometasone furoate. Based on these topical side effects such as skin atrophy and telangiectasias can be observations, methylprednisolone aceponate is expected to have a observed rather frequently, newer drugs such as methyl- greater therapeutic index as compared with mometasone furoate, prednisolone aceponate or mometasone furoate have a at least in the test systems used here. The degree to which this significantly improved therapeutic index. The present study observation may translate into a clinical setting requires compared these two modern topical glucocorticoids, which confirmation.
    [Show full text]
  • Pharmacy and Poisons (Third and Fourth Schedule Amendment) Order 2017
    Q UO N T FA R U T A F E BERMUDA PHARMACY AND POISONS (THIRD AND FOURTH SCHEDULE AMENDMENT) ORDER 2017 BR 111 / 2017 The Minister responsible for health, in exercise of the power conferred by section 48A(1) of the Pharmacy and Poisons Act 1979, makes the following Order: Citation 1 This Order may be cited as the Pharmacy and Poisons (Third and Fourth Schedule Amendment) Order 2017. Repeals and replaces the Third and Fourth Schedule of the Pharmacy and Poisons Act 1979 2 The Third and Fourth Schedules to the Pharmacy and Poisons Act 1979 are repealed and replaced with— “THIRD SCHEDULE (Sections 25(6); 27(1))) DRUGS OBTAINABLE ONLY ON PRESCRIPTION EXCEPT WHERE SPECIFIED IN THE FOURTH SCHEDULE (PART I AND PART II) Note: The following annotations used in this Schedule have the following meanings: md (maximum dose) i.e. the maximum quantity of the substance contained in the amount of a medicinal product which is recommended to be taken or administered at any one time. 1 PHARMACY AND POISONS (THIRD AND FOURTH SCHEDULE AMENDMENT) ORDER 2017 mdd (maximum daily dose) i.e. the maximum quantity of the substance that is contained in the amount of a medicinal product which is recommended to be taken or administered in any period of 24 hours. mg milligram ms (maximum strength) i.e. either or, if so specified, both of the following: (a) the maximum quantity of the substance by weight or volume that is contained in the dosage unit of a medicinal product; or (b) the maximum percentage of the substance contained in a medicinal product calculated in terms of w/w, w/v, v/w, or v/v, as appropriate.
    [Show full text]