Agents address wound-healing cascade

March 15, 2011

Approaches to wound modulation after filtration surgery have not changed much over the past 20 years.

Focusing on intraoperative strategies, Dr. Kahook said that while current use of either mitomycin-C (MMC) or 5-fluorouracil is helpful for increasing surgical success rates, the benefit of these antimetabolites is accompanied by increased risks of short- and long-term complications. Combination therapy for modulating wound healing after filtration surgery has not received much attention in the past, but is of interest because of its potential to improve both efficacy and safety.

"Combination therapy using multiple agents simultaneously or sequentially could address different steps in the wound-healing cascade, including collagen synthesis, inflammation, fibroblast proliferation, and angiogenesis, and potentially offer synergistic therapeutic activity while allowing use of a lower dose of each agent, which could minimize side effects," said Dr. Kahook, associate professor of ophthalmology, University of Colorado School of Medicine, Denver.

Results of an animal study reported by Sherwood [Trans Am Ophthalmol Soc. 2006;104:478-492] provide evidence supporting the concept of using a sequential treatment regimen incorporating multiple novel agents targeting different mediators of wound healing. Also, a pilot clinical trial conducted by Dr. Kahook yielded encouraging results about a combination regimen consisting of the anti-vascular endothelial growth factor (VEGF) agent, ranibizumab (Lucentis, Genentech), and MMC [Am J Ophthalmol. 2010;150:399-403].

The latter study was an open-label, phase I/II safety trial enrolling 10 patients with primary open-angle glaucoma undergoing trabeculectomy. They were randomly assigned equally into two groups to receive topical MMC alone or combined with intravitreal ranibizumab. The primary endpoint was bleb morphology and vascularity scored using the Moorfields bleb grading system.

The two study groups were similar in their preoperative mean IOP and mean bleb scores on the first day after surgery. However, at the end of the 6-month postoperative follow-up, there were statistically significant differences favoring the combination group in three of the grading system categories: peripheral bleb area, peripheral bleb vascularity, and non-bleb-related peripheral conjunctiva vascularity. There were no cases of bleb leaks, all patients remained off medications, and vision remained stable.

"Ranibizumab also has an anti-inflammatory effect, and I was struck by the quiet nature of the eyes that had been treated with this anti-VEGF agent. Now, further studies are needed to validate these early findings and understand better the role of anti-VEGF treatment at the time of trabeculectomy," said Dr. Kahook, who added a follow-up trial is under way that includes a third arm in which patients receive only ranibizumab at the conclusion of surgery.