From bedside to bench

Key Points

Boston-Selective laser trabeculoplasty (SLT) is a very effective approach in lowering IOP in patients with glaucoma, but in combination with certain topical therapies, SLT can prove to be less effective in lowering IOP. This reduction in efficacy is likely due to sharing one mechanism of action in common between SLT and certain topical glaucoma therapies, according to the results of recent basic and pilot clinical studies.

A recent study showed that SLT and topical prostaglandin analogs (PGAs) both share one mechanism of action related to the regulation of the conductivity across Schlemm's canal endothelial cells (SCEs). This interaction might explain why when SLT and PGAs are used together as a combination therapy, the IOP-lowering effect detected after SLT may be less effective. According to Jorge A. Alvarado, MD, speaking at the World Glaucoma Congress, these revealing data can have far-reaching implications when choosing appropriate therapeutic strategies in the treatment of glaucoma.

Current treatments

In addition to reducing the number of needed pressure-lowering eye drops in some cases, SLT is associated with high efficacy (i.e., ~30% IOP-lowering effect in some reports), and perhaps the performance of repeated laser irradiation. These advantages of SLT may in turn have an impact on compliance and cost issues.

"Though SLT and topical glaucoma medications are individually effective in reducing IOP when used as monotherapy, possible competing interactions of both of these approaches when used in combination may result in less than optimal IOP-lowering effects and may be the reason why SLT therapy sometimes achieves only a modest reduction in IOP," said Dr. Alvarado, professor, Department of Ophthalmology, Beckman Vision Center, Vision Care and Research Unit, University of California San Francisco, San Francisco.

Common mechanism

Dr. Alvarado recently conducted a laboratory study in which he sought to determine whether SLT and certain glaucoma medications share a common mechanism of action. Subsequently, his team of clinical investigators assessed whether removing the competing PGAs while performing SLT was associated with a predictable and higher success rate compared with that formerly achieved in their clinic when SLT was performed in the presence of PGAs.

In the laboratory study, the effect of SLT on the barrier function of cultured human SCEs was assessed in perfusion experiments by measuring the conductivity (permeability) in treated and controlled preparations. The SCE barrier was visualized in the living state using transfection methods with a plasmid construct containing genes for the intercellular junction protein ZO-1 and a green fluorescent protein.

The SCEs were exposed to six topical glaucoma medications, including PGAs (latanoprost, bimatoprost, travoprost), selective alpha agonists (brimonidine), beta-blockers (timolol), and carbonic anhydrase inhibitors (dorzolamide), as well as media conditioned by SLT-treated trabecular meshwork endothelial cells (TMEs). The junctional assembly/disassembly of SCEs exposed to the six topical medications and the SLT-irradiated TMEs was documented using time-lapse confocal fluorescent microscopy and flow-meters to document the effect on the SCE conductivity by all the treatments tested, including SLT.

The results showed that latanoprost, bimatoprost, and travoprost all shared a common mechanism of action with SLT. Each of these PGAs and SLT induced widening of the paracellular fluid-flow pathway of SCEs, induction of intercellular junction disassembly, and decreased transendothelial fluid flow across SCEs. Results also showed that brimonidine, timolol, and dorzolamide, which are all used clinically for their ability to reducing the formation of aqueous, and thus the IOP, did not affect the SCE barrier function.

"We found that the SCE barrier plays an important role in controlling the outflow of aqueous from the eye, and both SLT and the PGAs work by increasing the permeability of the SCE barrier," Dr. Alvarado said. "Therefore, because SLT and PGAs compete for at least this one barrier mechanism, when used as a combination therapy, they may be less effective in reducing IOP."

Regulating permeability

In a previous experiment, Dr. Alvarado showed that the TMEs play a key role in regulating the permeability of the SCEs and therefore have an instrumental role in regulating the outflow of aqueous indirectly. This driving force behind the permeability control of the SCEs is key in better understanding not only the pathogenesis of glaucoma but treatments that can increase permeability of the SCEs, such as laser and topical drop therapies, resulting in IOP reduction.

Dr. Alvarado suggested that the IOP-lowering response of an individual to a PGA may be predictive of response to SLT and proposed that if competing medications were removed, SLT results could potentially be more successful. In a clinical study involving a small series of glaucoma patients, Dr. Alvarado removed the PGAs just prior to SLT therapy. The preliminary review of the clinical data suggests that SLT may in fact be more effective in lowering IOP when used as a monotherapy without the concomitant effects of the PGAs.

"Treating glaucoma patients with both SLT and PGAs at the same time may be at best minimally additive. Both of these approaches have one demonstrated major and common mechanism of action involving regulation of the barrier property of SCEs," Dr. Alvarado concluded. "Therefore, employing only one of these treatments is sufficient to a large extent. Moreover, SLT used alone without concomitant PGA therapy appears to be able to achieve a better IOP-lowering effect than when used together with PGAs."