DOCSLIB.ORG

All-Trans-Retinoic Acid

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
All-Trans-Retinoic Acid Handbook 1 all-trans-Retinoic acid 1. Chemical and Physical Solubility Characteristics Soluble in most organic solvents, fats and oils; sparingly soluble in water (0.21 mmol/L) (Szuts 1.1 Nomenclature & Harosi, 1991). See General Remarks, section 1.4 Spectroscopy 1 1.2 Name: all-trans-Retinoic acid UV and visible: max 350 (ethanol), E i , 1510, Chemical Abstracts Services Registry Number EM 45 300 (Frickel, 1984; Barua & Furr, 1998). 302-79-4 Nuclear magnetic resonance ) IUPAC Systematic Name 1HNMR (CDCI3, 220 MHz): ô 1.02 (1-CH3 1 1.47 ) (all-E)-9, 13-Dimethyl-7(1, 1,5-trimethylcyclohex- (2-CH2 1 1.62 (3-CH), 1.72 (5-CH3), 2.01 (9-CH), 5-en-6-yl)nona-7,9, 11, 13-tetraen-15-oic acid (see 2.02 (4-CH2), 2.37 (13-CH), 5.79 (14-H), 6.14 (8- 1.3), or (all-E)-3, 7-dimethyl-9-(2,2,6-trimethylcy- H), 6.15 (10-H), 6.29 (7-H), 6.31 (12-H), 7.03 (11- clohex-1-en-1-yl)nona-2,4,6,8-tetraen-1-oic acid H); J78 (16 Hz), J1011 (11.5 Hz), J 112 (15 Hz) (Schweiter et al., 1969; Vetter et al., 1971; Frickel, Synonyms 1984; Barua & Furr, 1998). Vitamin A acid, vitamin A1 acid, trans-retinoic acid, tretinoin; Retin-A, Aberel, Airol, Aknoten, 13C-NMR (CDCI3, 68 MHz) ô 12.9 (9-CH3), 13.9 Atra, Cordes Vas, Dermairol, Epi-Aberol, Eudyna, (13-CH3), 19.5 (3-C), 21.6 (5-CH3), 29.0 (1,1- Vesanoid. CH,), 33.3 (4-C), 34.5 (1-C), 40.0 (2-C), 118.5 (14-C), 128.7 (7-C), 129.8 (5-C, 10-C), 131.1 (11- 1.3 Structural and molecular formulae and C), 135.5 (12-C), 137.6 (8-C), 138.0 (6-C), 139.3 relative molecular mass (9-C), 153.2 (13-C), 168.6 (15-C) (Englert, 1975; Frickel, 1984; Barua & Furr, 1998). 19 20 16 17 Resonance Raman, infrared and mass spectrometly 7 15 11 COO H (Frickel, 1984; Barua & Fun, 1998). X-Ray analysis 4 18 (Stam & MacGillavry, 1963; Frickel, 1984). Composition: C20H2802 Stability Relative molecular mass: 300.45 Unstable to light, oxygen and heat, protected in solution by the presence of antioxidants, such 1.4 Physical and chemical properties as butylated hydroxytoluene and pyrogallol. A variety of factors influence the stability of Description all-trans-retinoic acid in tissue culture media. Yellow crystals from ethanol Degradation and isomerization are minimized by storing under an inert gas, e.g. argon, at -20 °C or Melting-point lower temperatures in the dark (Frickel, 1984; Barua 180-182°C (Budavari et al., 1996) & Fun, 1998). 95 IARC Handbooks of Cancer Prevention 2. Occurrence, Production, Use, most efficacious oral doses are 1-2 mg/kg bw per Human Exposure and Analysis day (Peck & DiGiovanna, 1994; Vahlquist, 1994), although such doses often induce adverse side- 2.1 Occurrence effects, as discussed in section 2.4. Daily topical The concentration of all-trans-retinoic acid in the doses of up to 0.1% all-trans-retinoic acid in creams plasma of fasting individuals is 4-14 nmol/L or gels are effective in treating acne and photoage- (Blaner & Olson, 1994). Most other tissues of the ing, but adverse side-effects are again common. body also contain all-trans-retinoic acid, at concen- Both the efficacy of all-trans-retinoic acid and the trations of 40-6000 pmol/g wet weight (Napoli, incidence of side-effects are dose-dependent. Thus, 1994; Zhuang et al., 1995). The concentration of retinoids with therapeutic efficacy but little if any all-trans-retinoic acid is < 1% that of all-trans- toxicity are being sought avidly. retinol in human plasma and < 5% that of total Some of the precancerous conditions and can- vitamin A in the tissues of healthy animals and cers treated with all-trans-retinoic acid are summa- humans, and all-trans-retinoic acid is present only rized in Table 2. Oral doses of 0.5-2 mg/kg bw per in traces in plants, if at all. Thus, all-trans-retinoic day have commonly been used, but oral doses of acid is a very minor constituent of the diet. Some 5-10 mg/day have also been given. all-trans- foods, such as dairy products, sugar and comestible Retinoic acid has been approved for use in the oils, have been fortified with vitamin A but not with treatment of acute prornyelocytic leukaemia at a all-trans-reiinoic acid, which, unlike vitamin A and dose of 45 mg/m2 per day, and patients with cervi- carotenoids, is not available as a dietary supplement. cal dysplasia were treated topically with 0.37% all- trans-retinoic acid in a sponge or gel (Hong & Itri, 2.2 Production 1994). Attempts to synthesize retinol were initiated soon after its structure was determined by von Euler and Karrer in 1931. all-trans-Retinoic acid was synthe- sized by Arens and van Dorp in 1946. The first successful industrial synthesis of all-trans-retinol was devised by Isler in 1947 with the Lindlar cata- lyst. In the 1960s, Pommer and his colleagues used Acne vuigaris the Wittig reaction involving phosphonium salts Cystic acne to devise an elegant new industrial method for the Keloids synthesis of retinol, retinoic acid and 13-carotene in Lichen planus the 1960s. In the early 1970s, Julia and Arnoud Photoaged skin devised an effective synthesis of all-trans-retinoic Psoriasis acid by using the C-15 sulfone as an intermediate a (Frickel, 1984). Other synthetic procedures have Modified from Vahlquist (1994) and from Peck & since been developed which have been used in the DiGiovanna (1994) formation of a large number of related compounds (Frickel, 1984; Dawson & Hobbs, 1994). 2.3 Use all-trans-Retinoic acid is used primarily for treating dermatological disorders (Peck & DiGiovanna, 1994; Vahlquist, 1994), but it has also been used to Actinic keratosis treat several types of human cancer (Hong & Itri, Acute promyelocytic leukemia 1994), both in experimental animals and in Basal-cell carcinoma humans, and to reduce elastase-induced emphy- Cervical dysplasia sema in rats (Massaro & Massaro, 1997). Oral leukoplakia The skin disorders that have been treated with all-trans-retinoic acid are listed in Table 1. The Cited by Hong & Itri (1994) 96 All- trans- Retinoic acid 2.4 Human exposure butylated hydroxytoluene is also added at the out- As indicated above, the amount of retinoic acids in set to minimize oxidation of the retinoids. the diet is very small, probably in the range of A large number of chromatographic systems 10-100 pg/day. Because all-trans-retinoic acid is have been devised for the separation and quantifi- rapidly metabolized in the body and is not stored cation of all-trans-retinoic acid (Frolik & Olson, in the liver or other organs, it does not accumulate 1984; Furr et al., 1992, 1994; Barua & Furr, 1998; over time (Blaner & Olson, 1994). The amount of Barua etal., 1999). all-trans-retinoic acid ingested in the diet therefore all-trans-Retinoic acid can also be separated as poses neither a benefit nor a risk. As a conse- its methyl or pentafluorobenzyl ester by gas-liquid quence, exposure to all-trans-retinoic acid is or liquid-liquid chromatography and quantified limited, for all practical purposes, to the oral or by mass spectrometry. New ionization methods topical treatment of medical disorders. As indi- and tandem mass spectrometry have further cated in section 2.3, the maximum oral dose is enhanced the sensitivity and selectivity with which approximately 2 mg/kg bw per day. The many retinoic acid can be measured (Barua et al., 1999). adverse side-effects observed at such doses (Kamm et al., 1984; Armstrong et al., 1994) are described in section 7.1. 3. Metabolism, Kinetics and Genetic Topical treatment of acne and photoaged skin Variation with creams or gels containing up to 0.1% all-trans- retinoic acid is common (Peck & DiGiovanna, Information on the metabolism, plasma transport 1994; Vahlquist, 1994). Previously, higher concen- and tissue distribution of all-trans-retinoic acid in trations (0.3-0.4%) were used. humans and animal models after administration of pharmacological doses is summarized below. More 2.5 Analysis information is given in the General Remarks on all-trans-Retinoic acid in plasma and tissues is com- the endogeneous (physiological) metabolism of monly measured by high-performance liquid chro- all-trans-retinoic acid. matography (HPLC) (Barua & Furr, 1998). The plasma is collected in heparinized tubes, and either 3.1 Humans plasma or a tissue homogenate is acidified and 3.1.1 Metabolism then extracted several times with a suitable volume Muindi et al. (1992) studied the metabolism of all- of an organic solvent, such as chloroform and trans-retinoic acid in 13 patients with acute methanol, diethyl ether, dichioromethane, ace- prornyelocytic leukaemia who were receiving the tonitrue, 2-propanol or ethyl acetate. After the drug orally at a dose of 45 Mg/M2.- The only combined extract has been dried with anhydrous metabolite of all-trans-retinoic acid measured in sodium sulfate, the solvent is evaporated to plasma before treatment was all-trans-4-oxo- dryness under yellow light (to avoid isomerization) retinoic acid, which accounted for < 10% of the cir- in nitrogen or argon. The dried powder is immedi- culating all-trans-retinoic acid. The urine of these ately dissolved in the HPLC solvent and injected patients was found to contain all-trans-4-oxo- onto the HPLC column. In some cases, a solid- retinoyl-3-glucuronide, but urinary excretion of phase extraction or elution step is introduced to this compound accounted for < 1% of the admin- remove contaminants.
Load more

Recommended publications
  • Detailed Review Paper on Retinoid Pathway Signalling
    1 1 Detailed Review Paper on Retinoid Pathway Signalling 2 December 2020 3 2 4 Foreword 5 1. Project 4.97 to develop a Detailed Review Paper (DRP) on the Retinoid System 6 was added to the Test Guidelines Programme work plan in 2015. The project was 7 originally proposed by Sweden and the European Commission later joined the project as 8 a co-lead. In 2019, the OECD Secretariat was added to coordinate input from expert 9 consultants. The initial objectives of the project were to: 10 draft a review of the biology of retinoid signalling pathway, 11 describe retinoid-mediated effects on various organ systems, 12 identify relevant retinoid in vitro and ex vivo assays that measure mechanistic 13 effects of chemicals for development, and 14 Identify in vivo endpoints that could be added to existing test guidelines to 15 identify chemical effects on retinoid pathway signalling. 16 2. This DRP is intended to expand the recommendations for the retinoid pathway 17 included in the OECD Detailed Review Paper on the State of the Science on Novel In 18 vitro and In vivo Screening and Testing Methods and Endpoints for Evaluating 19 Endocrine Disruptors (DRP No 178). The retinoid signalling pathway was one of seven 20 endocrine pathways considered to be susceptible to environmental endocrine disruption 21 and for which relevant endpoints could be measured in new or existing OECD Test 22 Guidelines for evaluating endocrine disruption. Due to the complexity of retinoid 23 signalling across multiple organ systems, this effort was foreseen as a multi-step process.
    [Show full text]
  • Liarozole Hydrochloride (BANM, USAN, Rinnm) Kinetin Hidrocloruro De Liarozol; Liarozole, Chlorhydrate De; Liarozoli 1
    Isotretinoin/Liarozole 1603 Malignant neoplasms. Retinoids such as isotretinoin have 9. Matthay KK, et al. Treatment of high-risk neuroblastoma with Profile been studied in the treatment of various neoplastic or preneoplas- intensive chemotherapy, radiotherapy, autologous bone marrow Kinetin is a plant growth hormone that has been promoted in transplantation, and 13-cis-retinoic acid. N Engl J Med 1999; tic disorders. Although oral tretinoin is used for remission induc- 341: 1165–73. products for the management of photodamaged skin and hyper- tion in acute promyelocytic leukaemia (see p.1619), other retin- 10. Kohler JA, et al. A randomized trial of 13-cis retinoic acid in pigmentation but good evidence of efficacy appears to be lack- oids do not have an established role in the treatment of cancer. children with advanced neuroblastoma after high-dose therapy. ing. There may, however, be a place for the use of retinoids in the Br J Cancer 2000; 83: 1124–7. Preparations chemoprevention of some malignancies. Skin disorders. Apart from its established role in the treatment Proprietary Preparations (details are given in Part 3) There has been particular interest in the potential for retinoids to of acne (above), isotretinoin has been tried in many other skin Arg.: Kinerase†; Braz.: Kinerase; Hong Kong: Kinerase; Malaysia: Kin- prevent the formation of skin cancers (p.672) in patients at in- disorders not responding to usual therapy.1,2 Clinical responses to erase†; Mex.: Kinerase; Singapore: Kinerase; USA: Kinerase. creased risk. Maintenance immunosuppression may increase the oral isotretinoin have been reported1 in small numbers of patients incidence of pre-malignant and malignant skin lesions in solid with anogenital warts (p.1584), rosacea (p.1583), and lichen pla- organ transplant recipients; large numbers of lesions can develop nus (p.1580).
    [Show full text]
  • Pathway Development Via Retinoid X Receptor Vitamin a Enhances In
    Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway This information is current as Charles B. Stephensen, Reuven Rasooly, Xiaowen Jiang, of September 24, 2021. Michael A. Ceddia, Casey T. Weaver, Roshantha A. S. Chandraratna and R. Patterson Bucy J Immunol 2002; 168:4495-4503; ; doi: 10.4049/jimmunol.168.9.4495 http://www.jimmunol.org/content/168/9/4495 Downloaded from References This article cites 40 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/168/9/4495.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway1 Charles B. Stephensen,2* Reuven Rasooly,* Xiaowen Jiang,* Michael A. Ceddia,3* Casey T. Weaver,† Roshantha A. S. Chandraratna,‡ and R. Patterson Bucy† Vitamin A deficiency diminishes Th2-mediated Ab responses, and high-level dietary vitamin A or treatment with the vitamin A metabolite retinoic acid (RA) enhances such responses.
    [Show full text]
  • TAZORAC® (Tazarotene) Gel 0.05% (Tazarotene) Gel 0.1%
    NDA 020600 ® TAZORAC (tazarotene) Gel 0.05% (tazarotene) Gel 0.1% FOR DERMATOLOGIC USE ONLY NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE DESCRIPTION TAZORAC® Gel is a translucent, aqueous gel and contains the compound tazarotene, a member of the acetylenic class of retinoids. It is for topical dermatologic use only. The active ingredient is represented by the following structural formula: O OCH2CH3 N S TAZAROTENE C21H21NO2S Molecular Weight: 351.46 Chemical Name: Ethyl 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate Contains: Active: Tazarotene 0.05% or 0.1% (w/w) Preservative: Benzyl alcohol 1% (w/w) Inactives: Ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, carbomer 934P, edetate disodium, hexylene glycol, poloxamer 407, polyethylene glycol 400, polysorbate 40, purified water, and tromethamine. CLINICAL PHARMACOLOGY Tazarotene is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene (AGN 190299), by rapid deesterification in animals and man. AGN 190299 (“tazarotenic acid”) binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown. Psoriasis: The mechanism of tazarotene action in psoriasis is not defined. Topical tazarotene blocks induction of mouse epidermal ornithine decarboxylase (ODC) activity, which is associated with cell proliferation and hyperplasia. In cell culture and in vitro models of skin, tazarotene suppresses expression of MRP8, a marker of inflammation present in the epidermis of psoriasis patients at high levels. In human keratinocyte cultures, it inhibits cornified envelope formation, whose build-up is an element of the psoriatic scale.
    [Show full text]
  • Oxidation of Retinol to Retinoic Acid As a Requirement for Biological Activity in Mouse Epidermis1
    [CANCER RESEARCH 48, 7038-7040, December 15, 1988] Oxidation of Retinol to Retinoic Acid as a Requirement for Biological Activity in Mouse Epidermis1 Michael J. Connor Division of Dermatology, Department of Medicine, UCLA School of Medicine, Los Angeles, California 90024 ABSTRACT of retinal, which may explain its ability to inhibit both steps in The food and fragrance additive citral (3,7-dimethyl-2,6-octadienal) retinoic acid synthesis from retinol, since as an aldehyde it can inhibits the oxidation of retino! to retinole acid in mouse epidermis on act as a substrate for both the alcohol- and aldehyde-dehydro- local application. This inhibitory property was used to test the hypothesis genases involved. that oxidation to retinole acid is rate limiting for the biological activity The ability of citral to inhibit retinol oxidation provides an of vitamin A (retinol) in epithelial tissues. Citral was tested as a modulator experimental tool for testing the paradigm that retinoic acid is of the biological activities of retinol and retinole acid using two bioassays an obligatory intermediate in at least some aspects of vitamin performed in Skh.hrI (hairless) mice: (a) the ability to induce epidermal A activity in the epithelia in vivo. Citral was proposed as a hyperplasia; (/>)the ability to inhibit the induction of epidermal ornithine vitamin A antagonist in 1956 (7). Aydelotte (8, 9) studied the decarboxylase activity by tumor promoters. Citral treatment inhibited interaction of citral and retinol in whole organ cultures of chick the ability of retinol, but not of retinoic acid, to induce epidermal epithelial tissues and concluded that citral had a competitive hyperplasia.
    [Show full text]
  • (ATRA) with Arsenic Trioxide (ATO) Induction Therapy
    NCCP Chemotherapy Regimen Tretinoin (ATRA) with Arsenic Trioxide (ATO) Induction Therapy INDICATIONS FOR USE: Regimen *Reimbursement INDICATION ICD10 Code Status Treatment of patients with newly diagnosed low to intermediate C92 00356a Hospital risk Acute Promyelocytic Leukaemia (APL) *If the reimbursement status is not defined i, the indication has yet to be assessed through the formal HSE reimbursement process. TREATMENT: The starting dose of the drugs detailed below may be adjusted downward by the prescribing clinician, using their independent medical judgement, to consider each patients individual clinical circumstances. The treatment is administered until haematological complete remission (CR) or for a maximum of 60 days. Patients who achieve haematological CR progress to Consolidation Therapy with all trans retinoic acid (ATRA) and Arsenic Trioxide (Reference NCCP Regimen 00357). CR is defined as where the bone marrow is regenerating normal haematopoietic cells and contains <5% blast cells by morphology in an aspirate sample with at least 200 nucleated cells. Day Drug Dose Route Cycle 1 until complete Tretinoin 45mg/m2 in aPO n/a Continuous until remission (ATRA) divided doses Complete Remission (CR) is achieved or up to a maximum of 60 days 1-5 inclusive Arsenic 0.3mg/kg IV 250ml of 0.9% NaCl over Week 1 only trioxide infusion 2 hoursb Twice weekly Arsenic 0.25mg/kg IV 250ml of 0.9% NaCl over Week 2 to 8 trioxide infusion 2 hoursb 1 until end of Prednisolone 0.5mg/kg/day PO induction a Tretinoin (ATRA) is available as 10mg capsules. Round dose to nearest 10mg. The capsules should be swallowed whole with water.
    [Show full text]
  • Acitretin; Adapalene; Alitretinoin; Bexarotene; Isotretinoin
    8 February 2018 EMA/254364/2018 Pharmacovigilance Risk Assessment Committee (PRAC) Assessment report Referral under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data Retinoids containing medicinal products INN: Acitretin, Adapalene, Alitretinoin, Bexarotene, Isotretinoin, Tretinoin, Tazarotene Procedure number: EMEA/H/A-31/1446 Panretin EMEA/H/A-31/1446/C/000279/0037 Targretin EMEA/H/A-31/1446/C/000326/0043 Note: Assessment report as adopted by the PRAC and considered by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ......................................................................................... 2 1. Information on the procedure ................................................................. 3 2. Scientific discussion ................................................................................ 3 2.1. Introduction......................................................................................................... 3 2.2. Clinical aspects .................................................................................................... 5 2.3. Data on efficacy ..................................................................................................
    [Show full text]
  • Aetna Formulary Exclusions Drug List
    Covered and non-covered drugs Drugs not covered – and their covered alternatives 2020 Advanced Control Plan – Aetna Formulary Exclusions Drug List 05.03.525.1B (7/20) Below is a list of medications that will not be covered without a Key prior authorization for medical necessity. If you continue using one of these drugs without prior approval, you may be required UPPERCASE Brand-name medicine to pay the full cost. Ask your doctor to choose one of the generic lowercase italics Generic medicine or brand formulary options listed below. Preferred Options For Excluded Medications1 Excluded drug name(s) Preferred option(s) ABILIFY aripiprazole, clozapine, olanzapine, quetiapine, quetiapine ext-rel, risperidone, ziprasidone, VRAYLAR ABSORICA isotretinoin ACANYA adapalene, benzoyl peroxide, clindamycin gel (except NDC^ 68682046275), clindamycin solution, clindamycin-benzoyl peroxide, erythromycin solution, erythromycin-benzoyl peroxide, tretinoin, EPIDUO, ONEXTON, TAZORAC ACIPHEX, esomeprazole, lansoprazole, omeprazole, pantoprazole, DEXILANT ACIPHEX SPRINKLE ACTICLATE doxycycline hyclate capsule, doxycycline hyclate tablet (except doxycycline hyclate tablet 50 mg [NDC^ 72143021160 only], 75 mg, 150 mg), minocycline, tetracycline ACTOS pioglitazone ACUVAIL bromfenac, diclofenac, ketorolac, PROLENSA acyclovir cream acyclovir (except acyclovir cream), valacyclovir ADCIRCA sildenafil, tadalafil ADZENYS XR-ODT amphetamine-dextroamphetamine mixed salts ext-rel†, dexmethylphenidate ext-rel, dextroamphetamine ext-rel, methylphenidate ext-rel†, MYDAYIS,
    [Show full text]
  • Progress Towards Genetic and Pharmacological Therapies for Keratin Genodermatoses: Current Perspective and Future Promise
    15 March 2005 Use of Articles in the Pachyonychia Congenita Bibliography The articles in the PC Bibliography may be restricted by copyright laws. These have been made available to you by PC Project for the exclusive use in teaching, scholar- ship or research regarding Pachyonychia Congenita. To the best of our understanding, in supplying this material to you we have followed the guidelines of Sec 107 regarding fair use of copyright materials. That section reads as follows: Sec. 107. - Limitations on exclusive rights: Fair use Notwithstanding the provisions of sections 106 and 106A, the fair use of a copyrighted work, including such use by reproduction in copies or phonorecords or by any other means specified by that section, for purposes such as criticism, comment, news reporting, teaching (including multiple copies for classroom use), scholarship, or research, is not an infringement of copyright. In determining whether the use made of a work in any particular case is a fair use the factors to be considered shall include - (1) the purpose and character of the use, including whether such use is of a commercial nature or is for nonprofit educational purposes; (2) the nature of the copyrighted work; (3) the amount and substantiality of the portion used in relation to the copyrighted work as a whole; and (4) the effect of the use upon the potential market for or value of the copyrighted work. The fact that a work is unpublished shall not itself bar a finding of fair use if such finding is made upon consideration of all the above factors.
    [Show full text]
  • Acitretin; Adapalene; Alitretinoin; Bexarotene; Isotretinoin
    21 June 2018 EMA/261767/2018 Updated measures for pregnancy prevention during retinoid use Warning on possible risk of neuropsychiatric disorders also to be included for oral retinoids On 22 March 2018, the European Medicines Agency (EMA) completed its review of retinoid medicines, and confirmed that an update of measures for pregnancy prevention is needed. In addition, a warning on the possibility that neuropsychiatric disorders (such as depression, anxiety and mood changes) may occur will be included in the prescribing information for oral retinoids (those taken by mouth). Retinoids include the active substances acitretin, adapalene, alitretinoin, bexarotene, isotretinoin, tazarotene and tretinoin. They are taken by mouth or applied as creams or gels to treat several conditions mainly affecting the skin, including severe acne and psoriasis. Some retinoids are also used to treat certain forms of cancer. The review confirmed that oral retinoids can harm the unborn child and must not be used during pregnancy. In addition, the oral retinoids acitretin, alitretinoin and isotretinoin, which are used to treat conditions mainly affecting the skin, must be used in accordance with the conditions of a new pregnancy prevention programme by women able to have children. Topical retinoids (those applied to the skin) must also not be used during pregnancy, and by women planning to have a baby. More information is available below. Regarding the risk of neuropsychiatric disorders, the limitations of the available data did not allow to clearly establish whether this risk was due to the use of retinoids. However, considering that patients with severe skin conditions may be more vulnerable to neuropsychiatric disorders due to the nature of the disease, the prescribing information for oral retinoids will be updated to include a warning about this possible risk.
    [Show full text]
  • Robert Foti to Cite This Version
    Characterization of xenobiotic substrates and inhibitors of CYP26A1, CYP26B1 and CYP26C1 using computational modeling and in vitro analyses Robert Foti To cite this version: Robert Foti. Characterization of xenobiotic substrates and inhibitors of CYP26A1, CYP26B1 and CYP26C1 using computational modeling and in vitro analyses. Agricultural sciences. Université Nice Sophia Antipolis, 2016. English. NNT : 2016NICE4033. tel-01376678 HAL Id: tel-01376678 https://tel.archives-ouvertes.fr/tel-01376678 Submitted on 5 Oct 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Université de Nice-Sophia Antipolis Thèse pour obtenir le grade de DOCTEUR DE L’UNIVERSITE NICE SOPHIA ANTIPOLIS Spécialité : Interactions Moléculaires et Cellulaires Ecole Doctorale : Sciences de la Vie et de la Santé (SVS) Caractérisation des substrats xénobiotiques et des inhibiteurs des cytochromes CYP26A1, CYP26B1 et CYP26C1 par modélisation moléculaire et études in vitro présentée et soutenue publiquement par Robert S. Foti Le 4 Juillet 2016 Membres du jury Dr. Danièle Werck-Reichhart Rapporteur Dr. Philippe Roche Rapporteur Pr. Serge Antonczak Examinateur Dr. Philippe Breton Examinateur Pr. Philippe Diaz Examinateur Dr. Dominique Douguet Directrice de thèse 1 1. Table of Contents 1. Table of Contents ..............................................................................................................................
    [Show full text]
  • For Health Professionals Who Care for Cancer Patients
    November 2014 Volume 17, Number 11 For Health Professionals Who Care For Cancer Patients Inside This Issue: . Editor’s Choice – New Programs: nab-Paclitaxel and . Provincial Systemic Therapy Program – Reformat of Gemcitabine for Pancreatic Cancer, Neoadjuvant Paclitaxel BCCA Policy on Prevention and Management of and AC for Breast Cancer, Chlorambucil plus Rituximab for Extravasation of Chemotherapy Lymphomas, Chemotherapy plus Mitotane for . Drug Update – Enzalutamide Patient Assistance Adrenocortical Cancer Program . Cancer Drug Manual – Revised: Filgrastim, Gemcitabine, . List of New and Revised Protocols, Provincial Pre- Oxaliplatin, Paclitaxel, nab-Paclitaxel, Dexamethasone Printed Orders and Patient Handouts – New: . Medication Safety – Improving Website Clarity for Protocol BRLATACG, BRLATWAC, UGIPGEMABR, GUEDPM, Selection LYCHLRR Revised: BRAVEVEX, UCNBEV, GICIRB, . Benefit Drug List – New: BRLATACG, BRLATWAC, GIFFIRB, UGIFFOXB, UGIFIRINOX, GOCXCRT, GOENDH, UGIPGEMABR, GUEDPM, LYCHLRR Revised: ULYRMTN GUPLHRH, GUSCPE, HNAVP, LYIVACR, HNLAPRT, Deleted: BRLAACTW ULKATOATRA, ULKATOP, ULKATOR, ULUAVAFAT, LYABVD, LYCHOP, LYCHOPR, LYCHOPRMTX, LYRMTN . Continuing Professional Development – Workshop on Deleted: BRLAACTW Education in Palliative and End of Life Care for Oncology . Website Resources and Contact Information EDITOR’S CHOICE NEW PROGRAMS The Provincial Systemic Therapy Program has approved the following programs effective 1 November 2014: nab-Paclitaxel (ABRAXANE®) and Gemcitabine for Locally Advanced and Metastatic Pancreatic
    [Show full text]