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Philippe Daull, Samuel Guenin, Jean-Sebastien Garrigue; Mechanism of action of cationic emulsions in the management of ocular surface inflammation and wound healing. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5053.
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© ARVO (1962-2015); The Authors (2016-present)
Preservative-free cationic emulsions-based artificial tears (AT) or drug vehicles are innovative eye drop formulations with tear film stabilization and drug delivery properties, and interesting anti-inflammatory and wound healing properties. They recently reached the market as an AT for the management of dry eye disease (DED) symptoms (ie. Cationorm), or as drug vehicle for cyclosporine in Ikervis. The aim of the present study was to explore the mechanism of action underlying the intrinsic anti-inflammatory and wound healing efficacies harbored by the cationic emulsions of cetalkonium chloride (CE-CKC).
Anti-inflammatory efficacy of two CE-CKC (0.002% and 0.005% CKC) was evaluated by assessing the secretion of various biomarkers or the expression of inflammatory genes in the following cell lines stressed by different agents (in parentheses): CD4+ Tcells (anti-CD3/anti-CD28), CD14+ monocytes (LPS), PBMC (anti-CD3/anti-CD28 & LPS), NHEK (poly I:C), and HCE-2 (LPS). The cells were incubated 30 min with a 10% dilution of both CE-CKC, and cultured 24h in presence of the various challenging agents. The supernatant was collected and the secreted biomarkers quantitated with the appropriate ELISA tests. The cells were harvested and inflammatory genes expression measured by RT-PCR. In vitro PKC binding assay for IC50 determination was performed using standard procedures.
Both CE-CKC inhibited the secretion of IL17 (from CD4+ Tcells), TNFα, IFNg and IL2 (from PBMC), IL6 and IL8 (from HCE-2 and NHEK), and CE-CKC (0.005%) also inhibited TNFα (from CD14+ monocytes). The CE-CKC decreased inflammatory genes expression in PBMC (IFNg, IL17A, CXCL9, TNFα), and NHEK (ICAM1, IL8, IL1A, IL17C, TNFα, MMP9). The in vitro PKC binding assay revealed that CKC, the cationic agent used to bring the positive charge to the emulsions, is a specific PKCα inhibitor. In addition, tyloxapol, another excipient shows some anti-inflammatory activity on IL6 and IL8 in HCE-2 cells.
This study indicates that the CE-CKC are able to modulate the secretion and expression of pro-inflammatory cytokines and chemokines. It also suggests that CKC and tyloxapol are pharmacologically active excipients with potentially beneficial effects in vivo. These data shed new light on the observed efficacy on DED signs of these CE-CKC in clinical trials.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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