Preclinical efficacy investigation of human neutrophil elastase inhibitor sivelestat in animal model of psoriasis.

Background: Psoriasis is a chronic immune-mediated inflammatory skin disease manifested by an increased rate of keratinocyte division. Currently, it has been established that the cytokines of the IL-36 family play a significant role in the initiation and regulation of the inflammatory process in psoriasis. The IL-36 cytokine found in skin is inactive and its activation requires proteolytic processing that may occur via the involvement of neutrophil serine proteases such as human neutrophil elastase (HNE). The localization of these enzymes in the upper layers of the epidermis suggests that topical application of HNE inhibitors could be efficacious in the treatment of psoriasis. Sivelestat is an HNE inhibitor developed for systemic use towards the treatment of acute respiratory failure. Aim: The present study focussed on the investigation of the effects of sivelestat formulated for topical use, in the imiquimod-induced model of psoriasis in mice. Methods: The psoriasis-like state was induced by application of imiquimod (Aldara®) 5% cream to mouse shaven skin. A group of 40 inbred mice of the BALB/c strain randomized into 4 groups of 10 was used in the experiment: Group 1 - no therapy (control), Group 2 - ointment (Vaseline) containing 1% sivelestat, Group 3 - cream (lanoline + olive oil + water in equal proportions) containing 1% sivelestat, Group 4 - 1% betamethasone dipropionate. Dermatological assessment of skin lesions was performed by means of the PASI method (mPASI), as well as histological and immunohistochemical evaluation. Results: Based on the evaluation of efficacy manifestations, it was established that the total mPASI index value decreased by 50% during therapy with sivelestat cream and by 36% during therapy with sivelestat ointment. Histological study revealed that the epidermal thickness in groups that underwent therapy was 2.4-3.6 times lower compared to the control group. Immunohistochemical study of the skin indicated that following sivelestat treatment, the quantity of CD3+cells in the skin was 1.8-2.2 times lower, and the level of proliferative activity (Ki-67+cells) was 2.3-2.9 lower compared to the non-therapy group. In contrast to topical corticosteroids where the more pronounced anti-inflammatory effect is typically seen with ointment formulations, with sivelestat we observed an opposite effect. The reasons for that reversal remain unclear. Conclusion: Based on the results obtained using the animal model of imiquimod-induced psoriasis, it was established that the HNE inhibitor sivelestat demonstrated efficacy comparable to that of a strong topical glucocorticoid steroidal drug (betamethasone dipropionate 1%). Significant resolution of skin lesions, reduction of epidermal thickness, diminishing of the skin infiltration with T-lymphocytes and normalization of the cell division rate in epidermis and dermis were evident. Thus, suppression of IL-36 mediated inflammation activity in the skin by topical application of a HNE inhibitor represents a promising new direction in the treatment of psoriasis. Certainly, HNE has other targets; thus, molecular studies could be subject of future experiments beyond the scope of the present study.

Inhibition of Neutrophil Elastase and Cathepsin G As a New Approach to the Treatment of Psoriasis: From Fundamental Biology to Development of New Target-Specific Drugs.

Psoriasis therapy remains an extremely relevant area of modern drug design, due to necessity of adverse reaction reduction, inherent for actual methods of therapy. It was established that two serine proteases-neutrophil elastase 1 (HNE1) and cathepsin G (CatG)-are the key agents in psoriasis development. The collected molecular data for the presented targets form the basis for the molecular modeling strategy for the search for and identification of new target-specific inhibitors. The result of this work is a group of high-priority small-molecule compounds with double-targeted affinity, which are able to suppress the pro-psoriatic processes induced by the considered serine proteases at the initial stage of the disease.

[Experience with fractional photothermolysis in the therapy of gra-nuloma annulare]. / Opyt primeneniia fraktsionnogo fototermoliza v terapii kol'tsevidnoi granulemy.

BACKGROUND: Granuloma annulare is a benign inflammatory dermatosis of unknown etiology, which is characterized by the development of flesh-colored or red papules often arranged in rings on the skin. Currently there are no effective treatments for granuloma annulare. Topical and intradermal applications of glucocorticosteroids produce a short-term and insufficient therapeutic effect. The method cannot be used in extensive rashes. Fractional photothermolysis is a physical method for ablative exposure of tissues to an erbium laser via their local heating with light energy in certain areas. AIM: To investigate the efficiency of fractional photothermolysis in the therapy of patients with granuloma annulare. MATERIAL AND METHODS: Twenty-eight patients diagnosed with granuloma annulare were followed up. All the patients were treated with fractional Fotona Fidelis XS erbium laser at a wavelength of 2940 nm using a FS01 maniple. The treatment cycle consisted of 5 sessions. RESULT: After the treatment, the GASI index was decreased by 50, 75, and 100% in 5 (17.9%), 15 (53.6%), and 8 (28.6%) patients, respectively. The median GASI index was decreased by a total of 2.8 times (p<0.05). CONCLUSION: The study showed the high efficiency of fractional photothermolysis in the treatment of patients with granuloma annulare. This method can be recommended for the treatment of common forms of granuloma annulare.

[Improvement of dermatovenereologic care in the Armed Forces].

Authors presented data about primary incidence of diseases of the skin and subcutaneous tissue in the Armed Forces of the Russian Federation over the past 6 years and gave information about basic peculiarities of the delivery of medical dermatovenereologic care to servicemen in peacetime. A list of dermatovenereologic diseases, which have to be treated by the medical service at the troop level. Main factors affecting the level of skin and venereal diseases among servicemen are revealed. Authors' considered typical errors occurring in the process of medical care delivery to patients suffering from dermatovenereologic diseases at the troop level. These errors are usually of organizational and methodical nature.

[The free radical oxidation and antioxidant defense systems as indicators of the activity of keratinocytic proliferation in psoriasis].

The free radical oxidation and antioxidant defense (AOD) systems in the keratinocyte cultures were studied in patients with psoriasis before and after the use of combinations of liposomal preparations. Hyperproliferation of keratinocytes was found to be attended by suppressed lipid peroxidation and high cell antioxidant activity. On the contrary, the liposomal combinations-induced suppression of cell proliferation was characterized by a drastic increase in prooxidant activity in reference to the AOD of epidermal keratinocyte cultures.

[Genetic determinants of the efficiency of medium-wavelength ultraviolet irradiation of patients with psoriasis].

Therapeutic effect of medium-wavelength ultraviolet irradiation (UV therapy) in psoriatic patients is mediated through the p53-dependent mechanisms underlying apoptosis. The p53 gene is characterized by Arg/Pro polymorphism in codon 72 whose alleles exhibit differential functional activity. The present study has revealed association between p53 polymorphic variants and clinical efficiency of UV therapy in patients presenting with psoriasis. It enabled us to develop practical recommendations for predictive genetic testing of psoriatic patients; results of such testing make it possible to choose between the available treatment modalities on a patient-by-patient basis.