Investigation of the Skin Thinning Effect of Prednicarbate and Other Corticoids in Mouse Skin

Artym J., Kocięba M., Zaczyńska E., Kochanowska I., Zimecki M., Kałas W., Fiedorowicz A., Pawlak A., Strządała L., Jeleń M., Morak-Młodawska B., Pluta K., Kaleta-Kuratewicz K., Madej J.P., Kuropka P., et. al.

The therapeutic efficacy of topically applied azaphenothiazine derivatives: 9-chloro-6-acetylaminobutylquinobenzo[3,2-b][1,4]thiazine (compound 4) and 6-chloroethylureidoethyldiquino[3,2-b;2';3'-e][1,4]thiazine (compound 5) in the amelioration of inflammatory symptoms of imiquimod-induced psoriasis in mice was investigated. Clobederm®, containing clobetasol propioniate, served as a reference drug. The application of the compounds led to thinning of the epidermis and reduction of the cell layers. The suppressive actions of the compounds were even stronger with regard to pathological changes of the dermis. The compounds also exerted generalized, anti-inflammatory effects by decreasing the number of circulating leukocytes, lowering subiliac lymph node weight and partially normalizing an altered blood cell composition. The changes in the composition of main cell types in the epidermis and dermis were less affected by the compounds. In addition, both compounds inhibited to a similar degree production of tumor necrosis factor α (TNF α) in human whole blood cell culture. Whereas compound 5 strongly inhibited IL-8 and CXCL10 chemokines in human keratinocytes - KERTr cell line, transfected with poly(I:C), the suppressive action of compound 4 in this model was weak. In addition, compound 5, but not compound 4, exhibited at low doses proapoptotic properties with regard to colonic cell lines. In summary, we demonstrated the therapeutic potential of two selected azaphenotiazines in the amelioration of the skin pathology elicited in a mouse experimental model of psoriasis.

Lin T., Wei K., Wu C., Lai F., Lan C.E., Chang C., Peng A.C., Tsai J., Sheu H.

Baida G., Bhalla P., Kirsanov K., Lesovaya E., Yakubovskaya M., Yuen K., Guo S., Lavker R.M., Readhead B., Dudley J.T., Budunova I.

AbstractCutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress‐inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, which mediates cutaneous atrophy. In REDD1 knockout (KO) mice, all skin compartments (epidermis, dermis, subcutaneous fat), epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. Moreover, REDD1 knockdown resulted in similar consequences in organotypic raft cultures of primary human keratinocytes. Expression profiling revealed that gene activation by glucocorticoids was strongly altered in REDD1 KO epidermis. In contrast, the down‐regulation of genes involved in anti‐inflammatory glucocorticoid response was strikingly similar in wild‐type and REDD1 KO mice. Integrative bioinformatics analysis of our and published gene array data revealed similar changes of gene expression in epidermis and in muscle undergoing glucocorticoid‐dependent and glucocorticoid‐independent atrophy. Importantly, the lack of REDD1 did not diminish the anti‐inflammatory effects of glucocorticoids in preclinical model. Our findings suggest that combining steroids with REDD1 inhibitors may yield a novel, safer glucocorticoid‐based therapies.

Chebotaev D.V., Yemelyanov A.Y., Lavker R.M., Budunova I.V.

One of the major adverse effects of glucocorticoid therapy is cutaneous atrophy, often followed by the development of resistance to steroids. It is accepted that epithelial stem cells (SCs) located in the hair follicle bulge divide during times of epidermal proliferative need. We determined whether follicular epithelial SCs and their transit amplifying progeny were stimulated to proliferate in response to the chronic application of glucocorticoid fluocinolone acetonide (FA). After first two applications of FA, keratinocyte proliferation in the interfollicular epidermis (IFE) and hair follicles was minimal and resulted in significant epidermal hypoplasia. We observed that a 50% depletion of the interfollicular keratinocyte population triggered a proliferative response. Unexpectedly, less than 2% of the proliferating keratinocytes were located in the bulge region of the hair follicle, whereas 82% were in IFE. It is known that cell desensitization to glucocorticoids is mediated via temporary decrease of glucocorticoid receptor (GR) expression. We found that GR expression was significantly decreased in IFE keratinocytes after each FA treatment. In contrast, many bulge keratinocytes retained GR in the nucleus. Our results indicate that bulge keratinocytes, including follicular SCs, are more sensitive to the antiproliferative effect of glucocorticoids than basal keratinocytes, possibly due to the incomplete process of desensitization.

Schackert C., Korting H.C., Sch??fer-Korting M.

Corticosteroids are widely used for the treatment of inflammatory skin disorders. However, systemic and local adverse drug reactions, especially skin atrophy, are potential complications that limit their use. Several attempts have been made to increase the safety of topical corticosteroid treatment, including new application schedules, special vehicles and new agents. In particular, the group of hydrocortisone and prednisolone double esters, with prednicarbate as the first and most often prescribed representative, seem to be equipotent alternatives to the gold standard betamethasone 17-valerate with respect to anti-inflammatory activity. At the same time, these new agents induce less skin atrophy, which may result from a unique skin metabolism and a specific influence on the cytokine network in the epidermis and dermis. On the basis of these effects, a new approach to in vitro quantification of the benefit-risk ratio has been developed. As already suggested by investigations in human volunteers, the benefit-risk ratio of the new compounds appears to be increased. Therefore, recent research has focused on drugs that selectively modulate cytokine release.

Kolbe L., Stoudemayer T., Kligman A.M.

Atrophy is the most common adverse effect of topical corticosteroids. The objective of this study was to determine whether atrophogenicity of a potent steroid could be demonstrated in a 3-week period of open application using non-invasive bioengineering methods.Volar forearms were treated twice daily for 3 weeks with clobetasol propionate cream. The following methods were used: 1) B-scan ultrasound; 2) Silflo-replicas for microtopogra-phy; 3) scanning electron microscopy; 4) Cutometer for bio-mechanical assessments; 5) colorimetry for measuring skin color; 6) evaporimetry for transepidermal water loss; 7) polarized light photos; 8) sticky slides for corneocyte sizing; 9) D'Squames for estimating scaling; and 10) biopsies for histologic evaluation of atrophyAfter only 1 week, Silflo-replica showed that glyphic patterns had been partially obliterated. At the same time, ultrasound scans showed dermal thinning, which increased over the 3-week period. Extensibility by Cutometer decreased steadily during the treatment. Image analysis of ?Squames revealed an increase in scaliness. Evaporimetry showed an increase in trans-epidermal water loss. Atrophy was confirmed by histology.The use of non-invasive bioengineering techniques provides a powerful tool to monitor atrophogenicity in a short period of open applications.

Degreef H., Dooms-Goossens A.

This article discusses the systemic and local side effects and properties of the new corticosteroids. The pharmaceutical industry bears the challenge of finding more effective corticosteroids with fewer side effects and identifying the least sensitizing molecules.