Michelle Garay

Anti-inflammatory and anti-itch activity of sertaconazole nitrate

Cutaneous fungal infections are frequently associated with an inflammatory component including irritated skin, itching and stinging/burning. Therapeutic anti-fungal agents that have anti-inflammatory activity have the potential to provide clinical benefit beyond fungus eradication. Recently, certain anti-fungal agents have been shown to have intrinsic anti-inflammatory activity, therefore we sought to determine the extent of the anti-inflammatory activity of these compounds. The anti-inflammatory activities of eight anti-fungal agents (butoconazole, ciclopirox olamine, fluconazole, miconazole nitrate, sertaconazole nitrate, terconazole, tioconazole and ketoconazole) were compared in a number of preclinical models of dermal inflammation and pruritus. While butoconazole, ciclopirox olamine, fluconazole, and miconazole nitrate were all found to have anti-inflammatory activity, only sertaconazole nitrate reduced the release of cytokines from activated lymphocytes and mitigated inflammation in animal models of irritant contact dermatitis and neurogenic inflammation. In addition, sertaconazole nitrate inhibited contact hypersensitivity and scratching responses in a murine model of pruritus. Furthermore, the in vitro and in vivo anti-inflammatory activity of sertaconazole nitrate was found to be greater than other topical anti-fungal agents examined. These studies demonstrate that topical administration of clinically relevant concentrations of sertaconazole nitrate resulted in an efficacious anti-inflammatory activity against a broad spectrum of dermal inflammation models and itch. The anti-inflammatory properties of sertaconazole may contribute to the efficacy of the drug in the treatment of cutaneous fungal conditions and provide greater anti-inflammatory activity compared with other anti-fungal agents.

The StrataTest® human skin model, a consistent in vitro alternative for toxicological testing

Three-dimensional in vitro skin models provide an alternative to animal testing for assessing tissue damage caused by chemical or physical agents and for the identification and characterization of agents formulated to mitigate this damage. The StrataTest® human skin model made with pathogen-free NIKS® keratinocyte progenitors is a fully-stratified tissue containing epidermal and dermal components that possesses barrier function as determined by measurements of electrical impedance. Independent batches of skin tissues responded consistently to known chemical irritants even after refrigerated storage for up to 7 days. Reactive oxygen species (ROS) were detected after exposure of skin tissues to ozone, cigarette smoke or ultraviolet (UV) irradiation. Pretreatment with the antioxidant parthenolide-depleted (PD)-Feverfew extract prevented cigarette smoke-induced or UV irradiation-mediated increases in ROS. Interleukin (IL)-1α and IL-1 receptor antagonist (IL-1RA) secretion increased in a dose dependent manner following UV irradiation but cytokine release was abrogated by pretreatment with a UVA/UVB sunscreen. Similarly, immunohistochemical detection showed increased thymidine dimer formation in UV-irradiated skin tissue that was prevented with sunscreen pretreatment. These results demonstrate that the StrataTest® human skin model is broadly applicable to a wide range of in vitro toxicological assays.

Galvanic zinc–copper microparticles produce electrical stimulation that reduces the inflammatory and immune responses in skin

The human body has its own innate electrical system that regulates the body’s functions via communications among organs through the well-known neural system. While the effect of low-level electrical stimulation on wound repair has been reported, few studies have examined the effect of electric potential on non-wounded, intact skin. A galvanic couple comprised of elemental zinc and copper was used to determine the effects of low-level electrical stimulation on intact skin physiology using a Dermacorder device. Zn–Cu induced the electrical potential recorded on intact skin, enhanced H2O2 production and activated p38 MAPK and Hsp27 in primary keratinocytes. Treatment with Zn–Cu was also found to reduce pro-inflammatory cytokines, such as IL-1α, IL-2, NO and TNF-α in multiple cell types after stimulation with PHA or Propionibacterium acnes bacteria. The Zn–Cu complex led to a dose-dependent inhibition of TNF-α-induced NF-κB levels in keratinocytes as measured by a dual-luciferase promoter assay, and prevented p65 translocation to the nucleus observed via immunofluorescence. Suppression of NF-κB activity via crosstalk with p38 MAPK might be one of the potential pathways by which Zn–Cu exerted its inflammatory effects. Topical application of Zn–Cu successfully mitigated TPA-induced dermatitis and oxazolone-induced hypersensitivity in mice models of ear edema. Anti-inflammatory activity induced by the Zn–Cu galvanic couple appears to be mediated, at least in part, by production of low level of hydrogen peroxide since this activity is reversed by the addition of Catalase enzyme. Collectively, these results show that a galvanic couple containing Zn–Cu strongly reduces the inflammatory and immune responses in intact skin, providing evidence for the role of electric stimulation in non-wounded skin.