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Aliphatic β-Nitroalcohols for Therapeutic Corneoscleral Cross-Linking: Corneal Permeability Considerations

Wen, Quan MD; Trokel, Stephen L. MD; Kim, MiJung PhD; Paik, David C. MD

doi: 10.1097/ICO.0b013e31825646de
Basic Investigation

Purpose: 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 × 10−5 (±9.82 × 10−6) for 2ne [molecular weight (MW) = 91 Da], 9.34 × 10−6 (±2.16 × 10−7) for 2nprop (MW = 105 Da), 4.37 × 10−6 (±1.86 × 10−7) for MNPD (MW = 135 Da), and 8.95 × 10−7 (±1.93 × 10−8) 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.

Department of Ophthalmology, College of Physicians and Surgeons, Columbia University, New York, NY.

Reprints: David C. Paik, Laboratory for Tissue Cross-Linking, Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University, College of Physicians and Surgeons, 160 Fort Washington Avenue, Room 715, New York, NY 10032 (e-mail:

Supported in part by Research to Prevent Blindness and National Institutes of Health/National Eye Institute R21EY018937 (D.C.P.), R01EY020495 (D.C.P.), 5P30EY019007-02 (core grant), and Columbia University's CTSA grant No. UL1RR024156 from NCATS-NCRR/NIH.

The authors state that S.L.T. and D.C.P. have a patent pending related to nitroalcohol tissue cross-linking US patent 12/517,382.

Received January 19, 2012

Accepted March 18, 2012

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