Research Digest

Levofloxacin Safe Even at High Concentrations and Frequent Dosing, Study Shows

A recent study¹ shows that levofloxacin 1.5% (Iquix, Vistakon Pharmaceuticals) had no adverse effect on the corneal endothelium even after intensive dosing. The prospective, randomized, investigator-masked study evaluated endothelial cell density (ECD), morphology and central corneal thickness (CCT) in 48 healthy humans over a 3-week period. The dosing regimen used in the study was similar to that indicated for a corneal ulcer on the package insert: for each of the first 3 days, 1 drop was administered in the test eye every 30 minutes between 8 a.m. and 8 p.m., followed by 1 drop at 12 a.m. and another at 2 a.m.; for day 4 through day 14, 1 drop was administered in the test eye every hour while awake from 8 a.m. to 8 p.m.

Forty-eight eyes were treated, with a total of 224 drops administered to each eye over 14 days. Researchers at Ophthalmic Research Associates of Andover, Mass., performed specular microscopy and pachymetry at baseline and on day 21.

No significant changes were found in all endpoints at pre- and post-dose evaluations, researchers reported. Mean ECD was 2767±317 and 2786±295 cells/mm², respectively; mean cell size variability was 31.4±5.2 and 31.8±5.9, respectively.; mean percentage hexagonal cells was 59.8±10.8 and 61.9±11.3, respectively.; and mean CCT was 560±36 and 568±46μm at pre- and post-dose evaluations, respectively.

"Toxicity is an important consideration, particularly when the cornea is compromised" says lead investigator Mark B. Abelson, M.D., senior clinical scientist at Schepens Eye Research Institute, Harvard Medical School. "Due to the frequent dosing required in treating a corneal ulcer, absence of cytotoxicity with Iquix can help doctors maintain the integrity of the corneal epithelium by minimizing the eye's exposure to additional toxic agents." There are currently no plans for a follow-up study.

The findings further demonstrate that the high concentration of levofloxacin in Iquix is safe, the manufacturer points out. The study was supported by funding from Vistakon Pharmaceuticals.

Reference

1. Abelson M. Corneal Safety of 1.5% Levofloxacin Ophthalmic Solution (Iquix) in Humans. Poster presentation at ASCRS 2008, Chicago, April 4-9, 2008.

Resolvins Suppress Cytokine Release

An experimental study¹ presented at the 2008 Association for Research in Vision and Ophthalmology meeting shows that resolvin E1 (Resolvyx) is able to suppress a hypertonicity-induced release of proinflammatory mediators in human corneal epithelial cells.

Resolvins are lipo-oxygenase products of the omega-3 PUFA eicosapentaenoic acid. Investigators studied resolvin E1/RX-10001 (RvE1) and its analog RX-10008. Following starvation overnight, a human corneal epithelial cell line was exposed for 24 hours to a series of increasing osmotic conditions: 300mOsm (normal reference level), 375mOsm, 450mOsm and 500mOsm to represent the conditions of moderate to severe dry eye syndrome. Hypertonicity induced the release of interleukins (IL), specifically 6 and 8.

"What we have done is mimic that clinical situation [of dry eye syndrome]," says co-investigator Per Gjorstrup, Ph.D., chief medical officer at Resolvyx. "We've exposed these corneal cells to an artificial tear fluid, but now with an increased salt content, similar to what happens in the tear film of dry eye patients. When we do that, the chemical mediators that promote inflammation increase."

When the corneal cells were exposed to the fluid, they responded with increased production of proinflammatory mediators. But the investigators found that the both RX-10001 (RvE1) and RX-10008 caused a dose-dependent suppression of cytokine/chemokine release from these human corneal cells. Invest igators further found that resolvins may control both the primary epithelial immune response to stress and the following leukocyte influx.

Clinical studies are planned for the fall, Dr. Gjorstrup reports, and should include 150 to 200 patients.

The study was co-sponsored by a grant from the National Institutes of Health.

Reference

1. Pan Z, Gjorstrup P, Reinach P. Resolvins Inhibit Hypertonicity-induced Proinflammatory Cytokine Increases in Human Corneal Epithelial Cells. Poster presentation at ARVO 2008, Ft. Lauderdale, FL, April 27-May 1, 2008.

Optic Neuritis 15-Year Follow-up Data on Visual Outcomes and Multiple Sclerosis Risk

The landmark Optic Neuritis Treatment Trial, a multicenter effort to assess long-term visual outcomes in optic neuritis (ON), recently concluded with a final report on outcomes 15 years after the acute event.¹ The study assessed corticosteroid therapy in 454 patients with acute unilateral ON seen between 1988 and 1991. Pa tients were randomized into three groups: (1) intravenous followed by oral corticosteroids, (2) oral corticsteroid therapy and (3) placebo. Of the original study group, 294 patients were available for follow-up in 2006.

Visual acuity of 20/20 was seen in 72% of treated eyes, and bilateral visual acuity of 20/20 was reported in 66% of patients. Those with multiple sclerosis (MS) tended to have less favorable visual outcomes. Acuity remained stable for the majority of patients between the 10-year and 15-year follow-up exams. No significant differences were found between the three groups, prompting the authors to suggest that intravenous corticosteroid therapy following the acute episode may hasten visual recovery but does not affect long-term visual outcome.

As a result, the decision to use intravenous corticosteroids in a patient with optic neuritis and visual loss should be made on a case-by-case basis, according to Steven L. Galetta, M.D., director of neuro-ophthalmology services at the University of Pennsylvania, who adds that IV steroids may have a short-term effect in delaying MS onset in patients with ON and an abnormal baseline brain MRI. Most authorities recommend intravenous corticosteroids to such patients. "Oral prednisone has no benefit in delaying onset of MS and may be associated with an increased risk of developing recurrent optic neuritis," Dr. Galetta says. "Therefore, the use of oral corticosteroids at a standard dose of prednisone 60 mg a day is not recommended."

Another report from the group² found the probability of developing MS 15 years after the acute ON event was 50%. Risk correlated strongly with presence of brain lesions on non-contrast MRI: 72% of such patients developed MS; however, 25% of patients with no lesions at baseline did go on to develop MS. Patients with a very low risk of developing MS include those with a normal baseline MRI and any of the following: (1) NLP vision at onset,(2) disc hemorrhages, (3) macula exudates, (4) severe disc swelling, and (5) no pain at onset. The authors recommend with-holding treatment for MS after an initial event in patients with a normal baseline MRI, given the high percentage of patients who do not go on to develop MS.

References

1. Optic Neuritis Study Group. Visual Function 15 Years after Optic Neuritis: A Final Follow-up Report from the ONTT. Ophthal mology. 2008;115:1079-1082.

2. Optic Neuritis Study Group. Multiple Sclerosis Risk After Optic Neuritis: Final Optic Neuritis Treatment Trial Follow-up. Arch Neurol 2008;65(6):727-732

Canaloplasty Plus Phaco: 12-month Results

A study presented at the 2008 American Society of Cataract and Refractive Surgery meeting¹ showed promising 12-month interim clinical results for combined canaloplasty and clear corneal phacoemulsification cataract surgery for the surgical treatment of open-angle glaucoma.

Canaloplasty was performed on 57 eyes that had presented with visually significant cataract at 14 surgical centers. Preoperative study eyes presented with an average IOP of 24.1 mmHg (N=57,SD=6.1) with an average of 1.5 glaucoma medications. At 3 months, the average IOP was 14.2mmHg (N=43, SD=3.6) with 0.1 medications. At 6 months, the average IOP was 13.mmHg (N=45, SD=2.9) with 0.1 medications. At 12 months the average IOP was 14.0mmHg (N=29, SD=4.3) with 0.2 medications.

The investigators found that visual acuity improved by 0.2 LogMAR (~2 lines) on average, with no eye demonstrating a loss of visual acuity of 0.3 LogMAR (~3 lines) or greater. No sight-threatening complications were reported and the incidence of surgical complications was low.

"Canaloplasty has as one of its major advantages the surgical ability to improve IOP control without creation of a filtration bleb," says lead investigator Bradford J. Shingleton, M.D. "The fact that it can be easily coupled with phacoemulsification and provide significant reduction in IOP is another very important point and expands our surgical options for patients with coexisting cataract and glaucoma." OM

Reference

1. Shingleton BJ. Canaloplasty Combined with Phacoemulsification Cataract Surgery: Twelve-Month Interim Clinical Results. Poster presentation at ASCRS 2008, Chicago, April 4-9, 2008.