Skinoren Gel Mechanism of Action

Pharmacotherapeutic group: other anti-acne preparations for topical use. ATC Code: D10AX03.
Pharmacology: Pharmacodynamics: Mechanism of action: The antimicrobial action and a direct influence on follicular hyperkeratosis are assumed to be the basis for the therapeutic efficacy of Azelaic acid (Skinoren) gel in acne.
Clinically, a significant reduction of the colonization density of Propionibacterium acnes and a significant reduction of the fraction of free fatty acids in the skin surface lipids is observed.
In vitro and in vivo, azelaic acid inhibits the proliferation of keratinocytes and normalizes the disturbed terminal epidermal differentiation processes in acne. In the rabbit ear model azelaic acid accelerates the comedolysis of tetradecane-induced comedones.
While the pathophysiology of rosacea is not completely understood, there is increasing consensus that inflammation involving the elevation of several pro-inflammatory effector molecules such as kallikrein-5 and cathelicidin as well as reactive oxygen species (ROS), is a central process of this disease.
Azelaic acid has been demonstrated to modulate the inflammatory response in normal human keratinocytes by: a) activating the peroxisome proliferator-activated receptor γ (PPARγ); b) inhibiting the trans-activation of nuclear factor-kB (NF-kB); c) inhibiting the production of pro-inflammatory cytokines and d) inhibiting the release of ROS from neutrophils, as well as direct scavenging effects on existing ROS.
In addition, azelaic acid has been shown to directly inhibit kallikrein-5 and cathelicidin expression in three models: in vitro (human keratinocytes), in murine skin and in the facial skin of patients with rosacea.
These anti-inflammatory properties of azelaic acid may play a role in the treatment of rosacea.
While the clinical significance of these findings regarding kallikrein-5 and cathelicidin and their impact on the pathophysiology of rosacea has not yet been fully demonstrated in a large clinical study, initial studies in human facial skin appear to confirm the in vitro and murine findings.
Pharmacokinetics: Azelaic acid penetrates into all layers of human skin after topical application of the gel. Penetration is faster into damaged skin than into intact skin. A total of 3.6 % of the dose applied is absorbed percutaneously after a single topical application of 1 g azelaic acid (5 g cream).
Clinical investigations in acne patients indicated similar absorption rates of azelaic acid from Azelaic acid (Skinoren) gel and cream.
A portion of the azelaic acid absorbed through the skin is excreted in unchanged form in the urine. The remaining portion is broken down by β-oxidation into dicarboxylic acids with shorter chain length (C₇, C₅) which have likewise been found in the urine.
Steady-state plasma levels of azelaic acid in rosacea patients after 8 weeks twice daily treatment with Azelaic acid (Skinoren) gel were within the range also observed in volunteers and acne patients on normal diets. This indicates that the extent of percutaneous absorption of azelaic acid following twice daily application of Azelaic acid (Skinoren) gel does not alter the systemic burden of azelaic acid derived from dietary and endogenous sources in a clinically meaningful way.