tretinoin and Drug-Hypersensitivity

The fields of cutaneous pharmacology and toxicology existed as long as man used topical therapy; some medicaments were helpful and others harmful. This review documents recent progress in these fields in terms of the experimental method. Emphasis has been given to conceptual and methodologic progress rather than a list of new molecules. As signs of the advent of the maturity of these fields, a graduate school course has recently been completed, one text has been published (7), and at least two are in preparation. It is likely that the next review of this topic in this series will reflect this considerable progress in terms of relevance to man.

Topics: Animals; Dermatitis, Contact; Drug Hypersensitivity; Guinea Pigs; Humans; Irritants; Methods; Perfusion; Photosensitivity Disorders; Rabbits; Skin; Skin Diseases; Skin Tests; Swine; Tretinoin

In a double-blind randomized comparative multicenter trial, consisting of 29 patients with acne vulgaris who were unable to tolerate daily applications of retinoic acid, the retinoic acid derivative Ro 11--1430 (0.1% vanishing cream) was compared in a 6--8 weeks topical treatment with vanishing cream alone (placebo). Regarding efficacy, for most criteria measured the response was always better with Ro 11--1430 than with placebo, although the differences were not always statistically significant for several reasons, one probably being the small number of patients in the trial. Regarding tolerance, both treatments were satisfactory. Ro 11---1430 and placebo did not differ significantly regarding frequency and severity of erythema, desquamation and burning. These results suggest that treatment with Ro 11--1430 should be considered in acne patients who are unable to use retinoic acid due to severe local reactions.

Topics: Acne Vulgaris; Adolescent; Adult; Child; Clinical Trials as Topic; Double-Blind Method; Drug Hypersensitivity; Female; Humans; Male; Placebos; Random Allocation; Tretinoin

Hypereosinophilic syndrome (HES) has recently been recognized as a clonal leukemic lesion, which is due to a specific oncogenic event that generates hyperactive platelet-derived growth factor receptor-alpha-derived tyrosine kinase fusion proteins. In the present work, the effect of retinoids on the leukemic hypereosinophilia-derived EoL-1 cell line and on primary HES-derived cells has been investigated. We show that all-trans-retinoic acid (ATRA) inhibits eosinophil colony formation of HES-derived bone marrow cells and is a powerful inducer of apoptosis of the EoL-1 cell line. Apoptosis was shown in the nanomolar concentration range by phosphatidylserine externalization, proapoptotic shift of the Bcl-2/Bak ratio, drop in mitochondrial membrane potential, activation of caspases, and cellular morphology. Unlike in other ATRA-sensitive myeloid leukemia models, apoptosis was rapid and was not preceded by terminal cell differentiation. Use of isoform-selective synthetic retinoids indicated that retinoic acid receptor-alpha-dependent signaling is sufficient to induce apoptosis of EoL-1 cells. Our work shows that the scope of ATRA-induced apoptosis of malignancies may be wider within the myeloid lineage than thought previously, that the EoL-1 cell line constitutes a new and unique model for the study of ATRA-induced cell death, and that ATRA may have potential for the management of clonal HES.

Topics: Apoptosis; Cell Line, Tumor; Drug Hypersensitivity; Eosinophils; HL-60 Cells; Humans; Hypereosinophilic Syndrome; mRNA Cleavage and Polyadenylation Factors; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Signal Transduction; Stem Cells; Tretinoin

Human C/EBPepsilon is a recently cloned member of the C/EBP family of transcriptional factors. Previous studies demonstrated that the expression of this gene is tightly regulated in a tissue-specific manner; it is expressed almost exclusively in myeloid cells. To understand the mechanism by which the expression of C/EBPepsilon gene is controlled, we cloned a large genomic region surrounding the C/EBPepsilon gene and performed a DNase I hypersensitivity analysis of this locus. These sites probably represent areas of binding of proteins modulating gene transcription. Hypersensitive (HS) regions in 30 kb of DNA surrounding the C/EBPepsilon gene were examined in C/EBPepsilon high-expressing (NB4, HL-60), low-expressing (Jurkat), very-low-expressing (KG-1), and non-expressing (K562) hematopoietic cells as well as in non-hematopoietic-non-expressing cells (MCF-7, DU 145, PC-3). Three HS sites were detected near the first exon of C/EBPepsilon gene. They were found only in hematopoietic cells and were especially prominent in C/EBPepsilon expressing cells, suggesting that these sites play an important role in transcribing the gene. These hypersensitive bands did not change when the cells were cultured with retinoids. Gel-shift assays using 200 bp of nucleotide sequences that encompassed the hypersensitive sites and nuclear extracts from NB4 and Jurkat cells (C/EBPepsilon expressing) as well as K562 and MCF-7 cells (non-expressing) showed different retarded bands on gel electrophoresis. A fourth HS site, located about 11 kb upstream of exon 1, was found only in cells highly expressing C/EBPepsilon. Two sites, one about 4.5 kb upstream of exon 1 and another about 8.5 kb downstream of exon 2, were positive only in non-expressing cell lines, suggesting that repressors may bind in these areas. Taken together, we have found six specific DNase I hypersensitive sites in the region of C/EBPepsilon that may be involved in regulating transcription of this gene.

Topics: Alitretinoin; Antineoplastic Agents; Binding Sites; CCAAT-Enhancer-Binding Proteins; Cloning, Molecular; Deoxyribonuclease I; Drug Hypersensitivity; Electrophoretic Mobility Shift Assay; Gene Expression Regulation; Genes, Regulator; Humans; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured

A novel mucosal adhesive ointment on the base of partly neutralized polymethacrylic acid methyl ester (Eudispert) was formulated. The flow curves of the ointment show a pseudoplastic quality without any thixotropic effect. The viscosity depended on the kind and concentration of the base. During the clinical studies the pure ointment as well as a tretinoin-preparation for a lichen planus treatment showed no local irritation, good mucosal adhesion and suitable way of application for the patients.

Topics: Acrylic Resins; Adhesiveness; Drug Hypersensitivity; Humans; Lichen Planus; Mucous Membrane; Ointments; Polymethacrylic Acids; Skin Tests; Tretinoin

A clinical trial using Airol cream (retinoic acid cream 0.05%), Panoxyl-5 and Panoxyl-10 (benzoyl-peroxide alcoholic gel 5% & 10%) in combination and alone as topical applications for 10 weeks was carried out on 150 ambulatory patients with acne vulgaris. The results based on efficacy, drug tolerance and treatment duration show that the combined use of Panoxyl and Airol is superior to the use of either drug alone and that the combination of Airol cream (0.05%) in the morning and Panoxyl gel (5%) before retiring was the most satisfactory.

Topics: Acne Vulgaris; Adolescent; Adult; Benzoyl Peroxide; Child; Dermatitis, Contact; Drug Hypersensitivity; Drug Therapy, Combination; Female; Humans; Male; Ointments; Peroxides; Tretinoin