Evaluation of the safety and tolerability of a topical serine protease inhibitor (Part 2)

Background. The high prevalence of psoriasis, the social and psychological maladjustment of patients, as well as the widespread development of diagnostic and therapeutic methods have determined the relevance of studying this topic. The discovery of a new class of interleukin-36 made it possible to create a new concept of topical targeted therapy for patients with psoriasis. As part of the implementation of this direction, we have created a new drug that inhibits serine proteases in the skin and thus suppresses the development of interleukin-36-induced inflammation and the formation of psoriatic elements. The most important stage in the creation of a new drug is the assessment of its safety and tolerability in preclinical studies on laboratory animals. Objective. Evaluation of the safety and tolerability of topical use of sivelestat in laboratory animals. Methods. To determine the safety of the sivelestat cream, its acute toxicity was assessed, and to determine its tolerance - local irritant, skin-resorptive action and allergenic properties. The assessment of acute toxicity was carried out on 10 inbred mice of the BALB/c line, 10 outbred mice and 10 outbred rats, which were treated with the drug at a dose of 2000 mg/kg, ranged from 40 to 400 mg, depending on the type and weight of laboratory animals. The local irritant effect was determined on 10 inbred and 10 outbred mice (5% sivelestat was applied in 5 mice of each group and an indifferent cream - in other 5 mice). Assessment of the allergenic effect was carried out on 10 inbred and 10 outbred mice (5% sivelestat were applied in 5 mice of each group and an indifferent cream - in other 5 mice). Skin-resorptive action was evaluated on 10 inbred and 10 outbred mice (tails of 5 mice of each group were immersed in 5% sivelestat for 30 minutes and other 5 mice - in an indifferent cream). Results. During the assessment of acute toxicity with topical use of the sivelestat at a dose of 2000 mg/kg once a day for 10 days, there were no deaths of animals, and no signs of intoxication were noted. When determining the locally irritant effect, no changes in the general condition, behavior, or the appearance of skin rash were detected. After epicutaneous sensitization for 2 weeks, no skin reactions according to the skin test scale were found; the drug did not show allergenic properties on the animals studied. Conclusion. Based on the results of assessing acute toxicity, local irritant, skin-resorptive action and allergenic properties on laboratory animals, a favorable safety and tolerability profile of 5% sivelestat cream was established.

psoriasis, sivelestat, serine proteases, topical treatment