title: Aliphatic beta-nitro alcohols for non-enzymatic collagen cross-linking of scleral tissue.
abstract: The success of riboflavin photochemical cross-linking of the cornea in treating keratoconus and post-surgical keratectasia has prompted interest in cross-linking scleral tissue with a potential application to stabilize myopic progression. Applying an UVA light source to the sclera is difficult, particularly in the posterior region. An alternate pharmacologic approach to scleral cross-linking may be possible. The present study was undertaken in order to identify nitrite related compounds capable of inducing scleral tissue cross-linking and to gain information regarding the possible chemical mechanisms involved. 8x4 mm strips of porcine and human sclera were incubated in various concentrations of nitrite related agents (1-100mM) at 37 degrees C. pH 7.4 was used for all experiments except those involving NaNO(2). Following a 24-96 h incubation period, the samples were tested for cross-linking effects using thermal shrinkage temperature (T(s)) analysis. Several compounds were studied including NaNO(2), 2-nitroethanol, 2-nitro-1-propanol, 3-nitro-2-pentanol, 2-nitrophenol, 2-nitroethane, 2-aminoethanol, isopentyl nitrite, DPTA/NO, DETA/NO, and urea, a nitrous acid trap. The results indicate that short chain aliphatic beta-nitro alcohols (2-nitroethanol, 2-nitro-1-propanol, and 3-nitro-2-pentanol) are particularly effective cross-linking agents at pH 7.4, showing both time and concentration dependent effects. Furthermore, nitrosation does not appear to induce tissue cross-linking. In conclusion, aliphatic beta-nitro alcohols can cross-link scleral tissue at physiologic pH and temperature. Since beta-nitro alcohols are known to have reasonable toxicity profiles, these agents could find utility as pharmacologic cross-linking agents for scleral thinning disease.
authors.affiliation: Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. dcp14@columbia.edu
authors.forename: David C
authors.initials: DC
authors.lastname: Paik
authors.forename: Quan
authors.initials: Q
authors.lastname: Wen
authors.forename: Suzanna
authors.initials: S
authors.lastname: Airiani
authors.forename: Richard E
authors.initials: RE
authors.lastname: Braunstein
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Trokel
mesh_terms: D000818:Animals; D003094:Collagen / Q000187:drug effects* / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009574:Nitro Compounds / Q000494:pharmacology*; D015538:Nitrosation; D012590:Sclera / Q000187:drug effects* / Q000378:metabolism; D012977:Sodium Nitrite / Q000494:pharmacology; D034421:Sus scrofa; D013696:Temperature; D046509:Tissue Culture Techniques
chemical_list: D003432:Cross-Linking Reagents; D009574:Nitro Compounds; D000431:Ethanol; D003094:Collagen; D012977:Sodium Nitrite