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Retinoic Acid Metabolism Blocking Agents (RAMBAS) in Hyperkeratotic Disorders

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Retinoic Acid Metabolism Blocking Agents (RAMBAS) in Hyperkeratotic Disorders Retinoic acid metabolism blocking agents (RAMBAS) in hyperkeratotic disorders Citation for published version (APA): Verfaille, C. J. (2007). Retinoic acid metabolism blocking agents (RAMBAS) in hyperkeratotic disorders. Datawyse / Universitaire Pers Maastricht. https://doi.org/10.26481/dis.20070427cv Document status and date: Published: 01/01/2007 DOI: 10.26481/dis.20070427cv Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 04 Oct. 2021 RETINOIC ACID METABOLISM BLOCKING AGENTS (RAMBAS) IN HYPERKERATOTIC DISORDERS Lay-out: C.J. Verfaille Cover illustration: Fiji Mermaid by Takeshi Yamada (see page 239) Printing: Datawyse / Universitaire Pers Maastricht ISBN 978 -90-5278-620-9 © Copyright C.J. Verfaille, Beerse 2007 All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or any information appropriate, without the prior written permission of the publishers of the publications. RETINOIC ACID METABOLISM BLOCKING AGENTS (RAMBAS) IN HYPERKERATOTIC DISORDERS Proefschrift ter verkrijging van de graad van doctor aan de Universiteit van Maastricht op gezag van de Rector Magnificus, Prof. Mr. G.P.M.F. Mols volgens het besluit van het College van Decanen in het openbaar te verdedigen op vrijdag 27 april 2007 om 14.00 uur door Christel Jeanne Verfaille geboren te Menen, België op 19 maart 1969 UMP UNIVERSITAIRE PERS MAASTRICHT Promotor Prof. Dr. M. Borgers Prof. Dr. F.C.S. Ramaekers Prof. Dr. P.M. Steijlen Co-promotor Dr. M.A.M. van Steensel Beoordelingscommissie Prof. Dr. J.P.M. Geraedts (voorzitter) Prof. Dr. M.J.A.P. Daemen Prof. Dr. H. Degreef (Katholieke Universiteit Leuven) Prof. Dr. A.P. Oranje (Erasmus MC, Rotterdam) Prof. Dr. H. van Loveren The work presented in this thesis as well as the printing was financially supported by Barrier Therapeutics, Geel, Belgium. Aan mijn ouders En mijn familie Family, family, center of our lifes, No one wants a broken circle Hands together Bound (The Innocent Mission) Abbreviations ACTH Adrenocorticotropic Hormone ADIV Autosomal Dominant Ichthyosis Vulgaris AD Atopic Dermatitis ADH Alcohol Dehydrogenase ALDH Retinal Dehydrogenase AE Adverse Event All-trans-RA All-trans-Retinoic Acid APL Acute Promyelocytic Leukemia ARAT Acyl-CoA:Retinol Acyltransferase AUC Area under the Curve b.i.d. Bis in diem BPE Bovine Pituitary Extract BSA Bovine Serum Albumine CBIE Congenital Bullous Ichthyosiform Erythroderma of Brocq CCA Complete Case Analysis CRABP Cellular Retinoic Acid Binding Protein CRBP Cellular Retinol Binding Protein CTCL Cutaneous T-Cell Lymphoma CYP Cytochrome P-450 DR Direct Repeat ECG Electrocardiogram EGF Epidermal Growth Factor ELI Erythrodermic Lamellar Ichthyosis ELISA Enzyme-Linked ImmunoSorbent Assay FDA U.S. Food and Drug Administration FLG Filaggrin Gene FSH Follicle-Stimulating Hormone HDFa Human Adult Dermal Fibroblasts HLA Human Leucocyte Antigen HuMVEC Human Microvascular Endothelial Cells IBS Ichthyosis Bullosa of Siemens IC50 50% Inhibitory Concentration IFN- γ Interferon γ IL-1α Interleukin-1α ITT Intent-to-Treat IU International Units i.v. Intravenous KRT Keratin Gene KSFM Keratinocyte Serum-free Medium LI Lamellar Ichthyosis LH Luteïnizing Hormone LOR Loricrin Gene LRAT Lecithin:Retinol Acyltransferase LSC Liquid Scintillation Counting LSGS Low Serum Growth Supplement MHC Major Histocompatability Complex MRP-8 Migration inhibitory factor-Related Protein MTT 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide MVGS Microvascular Growth Supplement n-CIE non-Bullous Congenital Ichthyosiform Erythroderma NELI Non-Erythrodermic Lamellar Ichthyosis NHEK Normal Human Epidermal Keratinocytes 9-cis-RA 9-cis-Retinoic Acid OD Optical Density ODC Ornithine Decarboxylase PASI Psoriasis Area Severity Index PBS Phosphate Buffered Saline p.o. Per Os PP Per Protocol PPAR Peroxisome Proliferator-activated Receptor PSORS Psoriasis Susceptibility Locus PUVA Psoralen plus UVA-irradiation RA Retinoic Acid RAL Retinal RAMBA Retinoic Acid Metabolism Blocking Agent RAR Retinoic Acid Receptor RBP Retinol Binding Protein RE Retinyl Ester RHE Reconstituted Human Epidermis ROL Retinol RXR Retinoid X Receptor SAE Serious Adverse Event s.c. Subcutaneous SDR Short-chain Dehydrogenase/Reductase STS Steroid Sulfatase 13-cis-RA 13-cis-Retinoic Acid TG-1 Transglutaminase -1 TGM-1 Transglutaminase-1 gene TPA Tetradecanoyl-phorbol-13-acetate TR Thyroid Receptor TSH Thyroid Stimulating Hormone TTR Transthyretin UGT2B7 Human Liver Glucuronyl Transferase UVA Ultraviolet A UVB Ultraviolet B VDR Vitamin D Receptor XRI X-linked Recessive Ichthyosis Contents Chapter 1 General introduction 11 Hyperkeratotic skin disorders 12 Ichthyosis 14 Psoriasis 20 Acne 22 Treatment of hyperkeratotic disorders 23 General treatments 23 Retinoids 25 Retinoic Acid Metabolism Blocking Agents 37 Aim and outline of the thesis 39 Chapter 2 In vitro comparison of 3 generations RAMBAs 55 Chapter 3 Effects of R115866 on Reconstituted Human Epidermis 69 Chapter 4 In vivo pharmacology of liarozole 85 Chapter 5 Topical liarozole in ichthyosis 103 Chapter 6 Oral liarozole in ichthyosis 119 Chapter 7 Retinoids and RAMBAs in psoriasis 139 Chapter 8 Oral R115866 in psoriasis 171 Chapter 9 Oral R115866 in acne 193 Chapter 10 General discussion 207 Summary 221 Samenvatting 225 Colour figures 229 Fiji Mermaid by Takeshi Yamada 239 Dankwoord 241 Curriculum vitae 245 List of publications 248 1 General Introduction Partly based on: Verfaille CJ 1,4, van Steensel MAM 2, van de Kerkhof PCM 3 and Steijlen PM 1. Use of liarozole in ichthyosis. Submitted 1 Departments of Dermatology and Molecular Cell Biology, GROW, Maastricht University, The Netherlands. 2 Department of Dermatology, AZM, University Hospital Maastricht, The Netherlands. 3 Department of Dermatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. 4 Barrier Therapeutics nv, Geel, Belgium 11 CHAPTER 1 Hyperkeratotic skin disorders The outer layer of the skin, called “the epidermis”, is the largest organ in the human body. It is at its thinnest on the eyelids, at .05 mm, and at its thickest on the palms and soles at 1.5 mm. As a specialized non-vascularised stratifying epithelium, consisting of successive layers (strata) of keratin producing cells (keratinocytes), the epidermis is a dynamic, continually renewing structure that functions as an essential barrier to the environment. The keratinocytes gradually migrate through the different strata up to the surface (keratinocyte maturation) and are sloughed off in a process known as desquama- tion.1-3 Keratinocyte maturation can be divided into five sequences: 1. The bottom layer of the epidermis, the stratum basale, consists of undifferentiated keratinocytes shaped like columns. These cells are attached by hemi-desmosomes to a non-cellular basement membrane that separates the epidermis from the under- lying dermis. In the basal layer, the keratinocytes divide continuously and push al- ready formed cells into higher layers. Half of these cells progress upwards and dif- ferentiate, while the other half remain behind to divide again. In addition to the dif- ferentiating keratinocytes, the stratum basale also houses other cells with stem cell- like properties, Merkel cells (with apparent sensory functions) and melanocytes (pigment producing cells that protect us against ultraviolet radiation damage). 2. In the middle inner layers, the stratum spinosum (8-10 sheets of keratinocytes with limited dividing capacity), the shape of the keratinocytes changes from columnar to polygonal. Differentiating keratinocytes synthesize keratins which aggregate to form the tonofilaments that make up the cell skeleton. Condensations of these tono- filaments insert into desmosomes which connect keratinocytes and serve to disperse structural stresses through the epidermis.
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