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D. C. Paik, S. L. Trokel, Q. Wen, J. P. Dillon, S. Airiani, R. E. Braunstein; Short Chain Aliphatic β-nitro Alcohols for Corneal Cross-Linking: Thermal Shrinkage Temperature Effects. Invest. Ophthalmol. Vis. Sci. 2008;49(13):663.
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Corneal collagen cross-linking through riboflavin photolysis is gaining recognition as an effective treatment for keratoconus and related disorders. However, several benefits could be realized through use of a topical pharmacologic alternative. In recent studies, we have determined that short chain aliphatic β-nitro alcohols can cross-link collagenous tissues. Thus the present study was undertaken in order to evaluate these compounds for corneal cross-linking.
10 x 4mm corneal strips were taken from fresh adult pig eyes and incubated in various concentrations (1-100mM) of 2-nitroethanol (2ne), 2-nitro-1-propanol (2nprop), and 3-nitro-2-pentanol (3n2pent) at pH 7.4, 34oC. For experiments using 1mM, the solution was exchanged daily. Following a 4 day (for 10 and 100mM) and 7 day (for 1mM) incubation period, the samples were assayed for cross-linking effect using thermal shrinkage temperature (Ts) analysis. The Ts curves were fitted using a Boltzmann sigmoidal function (R2>.99) to determine initial shrinkage temperature (Ti) and the temperature of maximal rate of change (i.e. T50). T50 values were compared to controls using a non-paired Student’s t-test.
2ne was found to be the most potent cross-linker of the group, followed by 2nprop and 3n2pent. Exchanging the incubation fluid daily for 7 days at 1mM resulted in comparable shifts to those observed by reacting at 10mM for 4 days without fluid exchanges. This indicates that it may be possible to achieve cumulative effects through long term dosing in vivo. In addition, a comparison with reported values for corneal cross-linking with riboflavin photolysis indicates that these compounds are capable of inducing comparable levels of cross-linking (see table).
Short chain aliphatic β-nitro alcohols can induce corneal cross-linking in vitro at physiologic pH and temperature. These early results raise the possibility that such compounds could be used as pharmacologic topical stiffening agents for keratoconus and related disorders. Future studies will determine the in vivo efficacy and safety of this approach.
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