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Natasha Babar, Jessica R Cohen, Michael J Fernandez, Anna Takaoka, Xia Li, Mi Jung Kim, Kristin M Myers, Stephen L Trokel, David C Paik; Cosmetic preservatives as therapeutic corneoscleral tissue cross-linking (XL) agents. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4214.
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The growing clinical success of riboflavin photochemical corneal cross-linking (CXL) suggests that inducing mechanical tissue strength in vivo can be beneficial. Alternatively, tissue cross-linking (XL) can be induced by aliphatic β-nitroalcohols, which deliver formaldehyde via a base-catalyzed reverse Henry reaction. There are a number of related agents, known as “formaldehyde releasers” (FARs), that are in commercial use as preservatives in cosmetics and other personal care products. Thus, the present study was undertaken in order to screen such compounds for potential clinical utility.
A chemical registry was created from a literature review and included characteristics relevant to XL such as molecular weight, carcinogenicity/mutagenicity, toxicity, hydrophobicity, and commercial availability. From this registry, compounds were then selected for efficacy screening using an ex vivo rabbit corneal cross-linking simulation set up. XL solution was administered via a corneal reservoir for 30 min in 0.1M NaHCO3 at either pH 7.4 or 8.5. The epithelium was left intact and 0.5% proparacaine was applied prior to XL. The control contralateral eye was treated identically with vehicle. Effectiveness of XL was based on shifts in thermal denaturation temperature (Tm) as measured by differential scanning calorimetry (Perkin-Elmer DSC 6000). Favorable DSC results were validated using biomechanical inflation tests with digital image correlation (DIC) as previously described by Myers et al.
Sixty-four FARs (regularly found in cosmetics) were identified from the literature. Three compounds have been tested thus far [diazolidinyl urea (DAU), imidazolidinyl urea, and 5-Ethyl-3,7-dioxa-1-azabicyclo [3.3.0] octane]. Of the three, DAU has showed effective XL at pH 8.5. Compared to the controls, the Tm using DAU was shifted 1.92°C ± 0.14°C (n=2). Mechanical inflation testing confirmed increased tissue stiffness in pressure ranges mimicking physiological pressures (1.875-45mmHg). Tissue creep was also diminished under the current loading protocol (Fig. 1).
DAU is a potentially useful corneal XL agent as indicated by thermal denaturation and biomechanical inflation testing. Continued screening of compounds from the compiled chemical registry should lead to identification of additional potent agents.
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