ABSTRACT
BACKGROUND: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. RESULTS: Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARß. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0·01% applied topically is highly comedolytic and has anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0·005% cream. CONCLUSIONS: Based on its RARγ selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favourable safety profile in acne and ichthyotic disorders.
Subject(s)
Acne Vulgaris/drug therapy , Dermatologic Agents/pharmacology , Receptors, Retinoic Acid/agonists , Retinoids/pharmacology , Acne Vulgaris/pathology , Administration, Cutaneous , Animals , Biopsy , Cell Differentiation/drug effects , Cell Line , Dermatologic Agents/therapeutic use , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Stability , Gene Expression/drug effects , Gene Expression Profiling , Humans , Keratinocytes/drug effects , Keratinocytes/metabolism , Mice , Microsomes, Liver , Retinoids/therapeutic use , Skin , Skin Pigmentation/drug effects , Tissue Culture Techniques , Retinoic Acid Receptor gammaABSTRACT
BACKGROUND/PURPOSE: Following intradermal injection, hyaluronic acid (HA)-based fillers tend to spread within the reticular dermis and to distribute between the dermal fibers. This biointegration is commonly measured qualitatively using histological methods. We developed a "toolbox" consisting of a visual scoring and a semi-automatic image analysis method using internal developed algorithm to quantitate the biointegration of Restylane® in histological sections. METHODS: Restylane® was injected intradermally in the abdominal skin of 10 healthy human subjects scheduled for abdominoplasty. The injections were performed either in vivo before surgery or ex vivo on samples taken post-surgery at different time points. The samples were processed for histology by visual scoring and image analysis using algorithms developed in Definiens to assess biointegration. RESULTS: The image analysis segmentation was accurate with <5% manual changes. Furthermore, the results calculated with the semi-automatic method were consistent with the visual scores obtained on injected human skin samples by means of a 5-grade photographic scale. A modified hematoxylin-eosin staining was found adequate to visualize both, the filler and the general morphology, on the same section. An excellent correlation was observed between the integration results obtained with PAS/Alcian Blue and HE-stained slides, allowing for a single staining in future studies. CONCLUSION: We developed a modified HE staining histological method and a new histomorphometric image analysis tool to quantitate biointegration of HA-based fillers in human skin. The results obtained in this study confirmed the known intermediate biointegration properties of Restylane®, thus validating these innovative methods.
Subject(s)
Algorithms , Dermal Fillers/therapeutic use , Dermis/pathology , Hyaluronic Acid/analogs & derivatives , Adult , Cosmetic Techniques , Female , Humans , Hyaluronic Acid/therapeutic use , Image Processing, Computer-Assisted , Injections, Intradermal , Male , Middle Aged , Skin/pathologyABSTRACT
The diagnosis of left ventricular aneurysm on routine chest examination can be elusive. Six cases are presented which illustrate a radiographic sign not previously emphasized: a soft tissue border seen retrosternally or superiorly on lateral chest film produced by the wall of the aneurysm silhouetting against the midline cardiac shadow. This sign is not always present since it is dependent on the direction of projection of the aneurysm. However, when observed, it should suggest the proper diagnosis.