Determination of the therapeutic efficacy of various concentrations of sivelestat on a laboratory model of psoriasis (Part 1)

Background. Psoriasis is a common chronic multifactorial immune-mediated inflammatory skin disease characterized by an increased rate of keratinocyte division. Recent studies have shown that interleukin-36 (IL-36) plays a significant role in the initiation and regulation of the inflammatory process in psoriasis. IL-36 is inactive in the skin, and neutrophilic serine proteases are required for its activation. These data led to scientific interest in the study of a new direction in the topical therapy of patients with psoriasis based on local inhibition of serine proteases. To test this hypothesis, we have developed a drug in a topical formulation based on serine proteases inhibitor sivelestat. Objective. Evaluation of the therapeutic efficacy of various concentrations of a topical serine protease inhibitor (sivelestat cream) on a laboratory model of psoriasis. Methods. To compare the effectiveness of various concentrations of civelestat in suppressing the inflammatory reaction in the skin, a cream (lanolin+olive oil+water in equal proportions) containing sivelestat at concentrations of 0.5, 1 and 5% was used. The study was carried out on 40 inbred BALB/c mice, randomized into 4 groups of 10 animals each. For the experiment, an experimental model of psoriasis was preliminarily formed on laboratory animals. The therapeutic efficacy of various concentrations of sivelestat was determined based on the results of clinical and histological examination. Results. On the 10th day of the study clinical changes were pronounced in group 1 (control) and 2 (0.1% sivelestat), and there was a resolution of the elements of the skin rash in group 3 (1% sivelestat) and 4 (5% sivelestat), more pronounced in the last group. By the 10th day of the study, the prominent decrease in the mPASI index was observed in group 4 (sivelestat 5%) and 3 (sivelestat 1%), which significantly differed from the indicators in group 1 and 2 (p<0.05). When comparing indicators, the mPASI index in group 4 significantly differed from group 3 (p<0.05). It was found that the epidermal thickness in animals of group 4 (sivelestat 5%) was 1-2.7 times smaller than in other groups (1, 2, 3; p<0.05). There were no significant difference in the epidermal thickness between group 1 (control), 2 (sivelestat 0.1%) and 3 (sivelestat 1%). Conclusion. Topical application of 5% sivelestat cream once a day for 5 days in a laboratory model of imiquimod-induced psoriasis has high therapeutic efficacy compared to the control group and groups of 0.1- and 1% sivelestat cream. When using 5% sivelestat cream, the severity of clinical manifestations according to mPASI was lower by 70%, and histological ones according to the epidermal thickness - by 63% than in the control group.

psoriasis, sivelestat, serine proteases, topical treatment