title: Aliphatic β-nitroalcohols for therapeutic corneoscleral cross-linking: corneal permeability considerations.
abstract: OBJECTIVE
  Our recent tissue cross-linking studies have raised the possibility of using aliphatic β-nitroalcohols (BNAs) for pharmacologic, therapeutic corneal cross-linking. The present study was performed to determine the permeability of BNAs and to explore the use of permeability-enhancing agents.
  
  
  METHODS
  Ex vivo rabbit corneas were mounted in a typical Franz diffusion chamber. BNA permeability was determined by assaying the recipient chamber over time using a modification of the Griess nitrite colorimetric assay. The apparent permeability coefficient (Ptot) was determined for 2 mono-nitroalcohols [2-nitroethanol (2ne) and 2-nitro-1-propanol (2nprop)], a nitrodiol [2-methyl-2-nitro-1,3-propanediol (MNPD)], and a nitrotriol [2-hydroxymethyl-2-nitro-1,3-propanediol (HNPD)]. Permeability-enhancing effects using benzalkonium chloride (BAC) (0.01% and 0.02%), ethylenediaminetetraacetic acid (0.05%), and a combination of 0.01% BAC + 0.5% tetracaine were also studied.
  
  
  RESULTS
  The Ptot (±SE) values (in centimeters per second) were as follows: 4.33 × 10 (±9.82 × 10) for 2ne [molecular weight (MW) = 91 Da], 9.34 × 10 (±2.16 × 10) for 2nprop (MW = 105 Da), 4.37 × 10 (±1.86 × 10) for MNPD (MW = 135 Da), and 8.95 × 10 (±1.93 × 10) for HNPD (MW = 151 Da). Using the nitrodiol, permeability increased approximately 2-fold using 0.01% BAC, 5-fold using 0.02% BAC, and 5-fold using the combination of 0.01% BAC + 0.5% tetracaine. No effect was observed using 0.05% ethylenediaminetetraacetic acid.
  
  
  CONCLUSIONS
  The results indicate that the corneal epithelium is permeable to BNAs, with the apparent permeability corresponding to MW. The findings are consistent with previous literature indicating that the small size of these compounds (<10Å) favors their passage through the corneal epithelium via the paracellular route. This information will help to guide dosing regimens for in vivo topical cross-linking studies.
authors.affiliation: Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Wen
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Trokel
authors.forename: MiJung
authors.initials: M
authors.lastname: Kim
authors.forename: David C
authors.initials: DC
authors.lastname: Paik
mesh_terms: D000818:Animals; D001548:Benzalkonium Compounds / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism*; D003315:Cornea / Q000187:drug effects / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000378:metabolism* / Q000627:therapeutic use; D015194:Diffusion Chambers, Culture; D004338:Drug Combinations; D004492:Edetic Acid / Q000494:pharmacology*; D009574:Nitro Compounds; D010539:Permeability / Q000187:drug effects; D020005:Propanols / Q000378:metabolism* / Q000627:therapeutic use; D011817:Rabbits; D013748:Tetracaine / Q000494:pharmacology*
chemical_list: D001548:Benzalkonium Compounds; D003432:Cross-Linking Reagents; D004338:Drug Combinations; D009574:Nitro Compounds; D020005:Propanols; D013748:Tetracaine; D003094:Collagen; D004492:Edetic Acid