Topography and Pachymetry Guided, Rapid Epi-on Corneal Cross-Linking for Keratoconus: 7-year Study Results.

PURPOSE: To evaluate custom fast cross-linking (cfCXL) treatment of keratoconus. METHODS: "Custom fast cross-linking" or "cfCXL" is a keratoconus treatment algorithm featuring no epithelial disruption, 15 minutes of corneal presoaking with a riboflavin-vitamin E TPGS solution, and a 370-nm ultraviolet A radiation beam centered on the most highly curved corneal region. Ultraviolet A radiation beam fluence, total energy, and exposure time are significantly less than those in the Dresden protocol. In this study, refraction, spectacle-corrected distance visual acuity, Kmax, and corneal hysteresis were monitored in 81 eyes of 81 patients for 7 years with 100% follow-up. Pretreatment Kmax and patient age averaged 53.01 ± 4.87 D and 25.9 ± 4.7 years, respectively. RESULTS: Average refractive cylinder magnitude was reduced by 26.1% at 1 month postoperatively and by 44.2% at 7 years postoperatively. Logarithm of the minimum angle of resolution average spectacle-corrected distance visual acuity (best spectacle-corrected distance visual acuity) improved from +0.26 ± 0.34 (20/36.4) to +0.15 ± 0.23 (20/28.25), +0.05 ± 0.20 (20/22.4), and +0.06 ± 0.20 (20/22.96) at 1 month, 1 year, and 7 years postoperatively, respectively. Best spectacle-corrected distance visual acuity improved in 54.3%, 74.1%, 84.0%, 87.7%, 84.0%, 84.0%, and 82.7% of patients at postoperative months 1, 3, 6, 12, 24, 48, and 84, respectively. Kmax did not increase in 96.3% of patients at 1 month, 97.5% at 1 year, and 98.8% at 7 years postoperatively, with average corneal apex flattening at 1 month and 7 years of -2.79 ± 1.70 D and -4.00 ± 2.40 D, respectively. CONCLUSIONS: Custom fast cross-linking, epi-on, rapid, narrowed beam apex-centered treatment of keratoconus with riboflavin-vitamin E TPGS produced a significant, rapid, and lasting cone progression stoppage, astigmatism reduction, and visual acuity improvement.

Customized Corneal Cross-Linking-A Mathematical Model.

PURPOSE: To improve the safety, reproducibility, and depth of effect of corneal cross-linking with the ultraviolet A (UV-A) exposure time and fluence customized according to the corneal thickness. METHODS: Twelve human corneas were used for the experimental protocol. They were soaked using a transepithelial (EPI-ON) technique using riboflavin with the permeation enhancer vitamin E-tocopheryl polyethylene glycol succinate. The corneas were then placed on microscope slides and irradiated at 3 mW/cm for 30 minutes. The UV-A output parameters were measured to build a new equation describing the time-dependent loss of endothelial protection induced by riboflavin during cross-linking, as well as a pachymetry-dependent and exposure time-dependent prescription for input UV-A fluence. The proposed equation was used to establish graphs prescribing the maximum UV-A fluence input versus exposure time that always maintains corneal endothelium exposure below toxicity limits. RESULTS: Analysis modifying the Lambert-Beer law for riboflavin oxidation leads to graphs of the maximum safe level of UV-A radiation fluence versus the time applied and thickness of the treated cornea. These graphs prescribe UV-A fluence levels below 1.8 mW/cm for corneas of thickness 540 µm down to 1.2 mW/cm for corneas of thickness 350 µm. Irradiation times are typically below 15 minutes. CONCLUSIONS: The experimental and mathematical analyses establish the basis for graphs that prescribe maximum safe fluence and UV-A exposure time for corneas of different thicknesses. Because this clinically tested protocol specifies a corneal surface clear of shielding riboflavin on the corneal surface during UV-A irradiation, it allows for shorter UV-A irradiation time and lower fluence than in the Dresden protocol.

Corneal Cross-Linking: Evaluating the Potential for a Lower Power, Shorter Duration Treatment.

PURPOSE: To determine the cross-linking effect of a riboflavin ultraviolet-A (UV-A) corneal cross-linking treatment that is both shorter and has lower energy than the Dresden protocol. METHODS: In a first experiment, 12 human corneas were presoaked with riboflavin and then irradiated with UV-A at 3 mW/cm after clearing the surface of riboflavin, with no added riboflavin during irradiation. Percent UV-A transmission through the corneas was measured at intervals up to 30 minutes. A second experiment involved 24 porcine corneas. Eight were de-epithelialized, presoaked in riboflavin for 30 minutes, and irradiated at 1.5 mW/cm for 10 minutes. An additional 8 were riboflavin treated and similarly irradiated, but with epithelium intact and a final 8 corneas were not treated. Young modulus was measured in all 24 corneas at the end of the experiment. RESULTS: The first experiment showed essentially complete riboflavin oxidation after only 10 minutes. Based on these results, a shortened UV-A exposure cross-linking experiment was designed using a reduced UV-A fluence of 1.5 mW/cm, an endothelial exposure within safety limits in humans. With this protocol Young modulus was the same in the irradiated porcine corneas but with epithelium intact as in the untreated corneas. In contrast, Young modulus increased by a factor of 1.99 in the UV-A cross-linked corneas at 1.5 mW/cm for 10 minutes with the epithelium removed. CONCLUSIONS: A shorter, lower energy protocol than the Dresden protocol seems to provide a significant increase in Young modulus, similar to published results with higher energy, longer exposure protocols.

Transepithelial Corneal Cross-Linking With Vitamin E-Enhanced Riboflavin Solution and Abbreviated, Low-Dose UV-A: 24-Month Clinical Outcomes.

PURPOSE: To report the clinical outcomes with 24-month follow-up of transepithelial cross-linking using a combination of a D-alpha-tocopheryl polyethylene-glycol 1000 succinate (vitamin E-TPGS)-enhanced riboflavin solution and abbreviated low fluence UV-A treatment. METHODS: In a nonrandomized clinical trial, 25 corneas of 19 patients with topographically proven, progressive, mild to moderate keratoconus over the previous 6 months were cross-linked, and all patients were examined at 1, 3, 6, 12, and 24 months. The treatments were performed using a patented solution of riboflavin and vitamin E-TPGS, topically applied for 15 minutes, followed by two 5-minute UV-A treatments with separate doses both at fluence below 3 mW/cm(2) that were based on preoperative central pachymetry. RESULTS: During the 6-month pretreatment observation, the average Kmax increased by +1.99 ± 0.29 D (diopter). Postoperatively, the average Kmax decreased, changing by -0.55 ± 0.94 D, by -0.88 ± 1.02 D and by -1.01 ± 1.22 D at 6, 12, and 24 months. Postoperatively, Kmax decreased in 19, 20, and 20 of the 25 eyes at 6 months, 12 months, and 24 months, respectively. Refractive cylinder was decreased by 3 months postoperatively and afterward, changing by -1.35 ± 0.69 D at 24 months. Best spectacle-corrected visual acuity (BSCVA) improved at 6, 12, and 24 months, including an improvement of -0.19 ± 0.13 logarithm of the minimum angle of resolution units at 24 months. There was no reduction in endothelial cell count. No corneal abrasions occurred, and no bandage contact lenses or prescription analgesics were used during postoperative recovery. CONCLUSIONS: Transepithelial cross-linking using the riboflavin-vitamin E solution and brief, low-dose, pachymetry-dependent UV-A treatment safely stopped keratoconus progression.

(3R)-Chiral Control of 3-Alkyl-3-hydroxy-beta-lactams via Addition Reaction of Imines to Enolates of 1,3-Dioxolan-4-ones.

A method is described for the chiral construction of (3R)-3-alkyl-3-hydroxy-beta-lactams in a versatile and predictable manner. This protocol follows Seebach's synthetic principle of self-regeneration of stereocenters and has been applied to addition reactions among a selected number of imines and (2S)-chiral enolates of 1,3-dioxolan-4-ones. These reagents are easily available from the acetalization of (S)-alpha-hydroxy acids (lactic, mandelic, isovaleric, malic) and pivalaldehyde or pinacolone. In several cases, the addition of the enolate to the imine, the cyclization, and the removal of the auxiliary center occur in a one-step sequence, affording the corresponding beta-lactams as (3R,4S)-Z and (3R,4R)-E diastereomeric mixtures with high enantiomeric excesses. Four N-unsubstituted (3R,4S)-3-hydroxy-3-methyl-beta-lactams bearing 2-furyl (4e), phenylethenyl (4h), methoxycarbonyl (4i), and 2-thienyl (4l) substituents at C4 were obtained as major diastereomers and were purified by crystallization. The simultaneous presence of these substituents at C3 and C4 make these beta-lactams useful intermediates for the synthesis of new taxoids with interesting structural modifications at the isoserine moiety.