Despite the introduction of innovative surgical procedures, medical therapy remains the backbone of glaucoma treatment for the majority of glaucoma patients. The Ocular Hypertension Treatment Study (OHTS) demonstrated the utility of medically treating high-risk glaucoma suspects.1 The Early Manifest Glaucoma Trial (EMGT), Collaborative Normal Tension Glaucoma Trial, and Collaborative Initial Glaucoma Treatment Study (CIGTS) showed that pharmacologic IOP lowering decreases the risk of glaucomatous progression in early glaucoma, normal-tension glaucoma, and primary open-angle glaucoma, respectively.2-4 Defined concepts prevail such as setting a target IOP, utilizing the minimal amount of therapy needed to achieve the target IOP, and educating patients about the longterm use of their medications. New treatments on the horizon are exploring novel mechanisms of action and seek to improve tolerability and patients' compliance.

SOMETHING OLD

Unoprostone isopropyl (Rescula; Novartis Ophthalmics, Inc.) is a novel prostone that the FDA approved in 2000 for the treatment of open-angle glaucoma and ocular hypertension. The drug has been off the market in the United States since 2005, but the commercialization rights were licensed in 2009 to Sucampo Pharmaceutials, Inc. Sucampo has submitted a supplemental New Drug Application to the FDA in anticipation of relaunching the product.

Clinical studies have demonstrated that, although not as potent a hypotensive agent as the prostaglandin analogues, unoprostone has similar IOP-lowering effects as timolol and is additive to timolol as well. The drug is prescribed twice daily and has few systemic side effects. Recent studies suggest a unique mechanism of action for unoprostone compared with the prostaglandin derivatives. Unlike prostaglandins, unoprostone demonstrates a poor affinity for the prostaglandin EP and FP receptors, and it has been shown to activate the BK potassium channels and the C1C chloride channels.5 Reports of increased facility of outflow with unoprostone suggest that it may improve conventional outflow through the trabecular meshwork. 6 Unoprostone has also been shown to block the vasoconstrictive effect of endothelin-1, thereby relaxing the cells of the trabecular meshwork and vascular smooth muscle. The subconjunctival injection of unoprostone prevented an endothelin-1–induced diminution in optic nerve blood flow, ganglion cell loss, and optic nerve rim loss in the rabbit.7 Studies are underway to further elucidate the therapeutic potential of this drug.

SOMETHING NEW

Currently under development, nitric oxide-donating prostaglandins aim to combine the complementary mechanisms of PGF2α and nitric oxide in the treatment of glaucoma. Latanoprost is well known as a potent IOPlowering medication that increases uveoscleral outflow by causing remodeling of the extracellular matrix of the ciliary body. Nitric oxide is a diffusible gas that potentiates cGMP production; nitric oxide synthetase is expressed in the trabecular meshwork, ciliary body, and Schlemm canal, suggesting a role for nitric oxide in the regulation of IOP. Preliminary animal studies of two nitric oxide-donating latanoprost analogues have shown superior IOP lowering compared with latanoprost.8

NicOx SA originally partnered with Pfizer Inc. to develop a nitric oxide latanoprost analogue for the treatment of glaucoma. In 2008, when midstage clinical trials did not meet the primary endpoint, Pfizer returned the rights to the drug to NicOx. In March 2010, Bausch + Lomb licensed the drug from NicOx for further development and is proceeding with clinical trials. A phase 2b trial is underway comparing the various concentrations of the nitric oxide-donating prostaglandin BOL-303259x with latanoprost.

SOMETHING BORROWED

Tafluprost, a prostaglandin analogue developed by Santen, Inc., has been available in Europe and Japan since 2008. Both preserved and preservative-free forms have been on the market internationally. In the United States, tafluprost is licensed to Merck & Co., Inc., which has a New Drug Application under review by the FDA for a preservative-free formulation.

Reports have demonstrated similar efficacy between tafluprost and latanoprost in eyes with elevated IOP and in those with normal tension.9,10 A recent phase 3 trial found comparable IOP reduction with once-daily preservativefree tafluprost compared to twice-daily preservative-free timolol.11 In vitro toxicology studies of preservative-free tafluprost found good tolerability without the corneal epithelial degeneration seen with prostaglandins preserved with benzalkonium chloride.12 Pending FDA approval, tafluprost will become the first preservative-free prostaglandin analogue.

Along the same lines, Catioprost (Nova21027) is a preservative- free formulation of latanoprost under development by Novagali Pharma. The company received FDA approval for its Investigational New Drug Application to conduct a phase 3 clinical trial in the United States. In addition to being free of benzalkonium chloride, Catioprost utilizes Novasorb, a patented cation emulsion used to treat dry eye. The approval of generic latanoprost in 2011 has greatly improved the affordability of prostaglandin analogues. Because a number of generic latanoprost preparations became available simultaneously, however, physicians must be cautious about possible variability in their tolerability and efficacy.

SOMETHING BLUE

Currently designated by a dark blue top, fixedcombination drops play an important role in glaucoma medical therapy. The OHTS demonstrated that, after 5 years, 40% of patients with elevated IOP required two or more medications to achieve a 20% decrease in IOP from baseline.1 Fixed-combination medications permit the convenient administration of two medications with equivalent efficacy to their concomitant administration. Combined products minimize the potential washout of sequentially administered drops and decrease patients' cumulative exposure to preservatives. The use of fixed-combination drops may help improve compliance by increasing convenience and decreasing the number of drops and bottles.

In the United States, a fixed combination of timolol and dorzolamide has been available as a brand-name product (Cosopt; Merck & Co., Inc.) since 1998 and as a generic preparation since 2008. A fixed combination of timolol and brimonidine has been available since 2007 as Combigan (Allergan, Inc.). A number of products combining a prostaglandin analogue with a ß-blocker are available worldwide, but none is FDA approved. Alcon Laboratories, Inc., is currently conducting a phase 3 clinical trial of a fixed combination of brinzolamide 1% and brimonidine 0.2%, which could expand the use of combined drops to patients who cannot take ß-blockers.

CONCLUSION

The CIGTS demonstrated that medications could achieve greater than a 35% reduction of IOP and provide comparable stabilization of glaucoma compared with trabeculectomy.4 Fixed-combination drops may increase patients' compliance with prescribed medical therapy, preservative-free formulations may increase drugs' tolerability, and generic formulations may increase the availability and affordability of glaucoma pharmacological therapies. New drops on the horizon hold the promise of greater efficacy in the treatment of glaucoma. The Low-Pressure Glaucoma Treatment Study (LoGTS), however, forces clinicians to focus on factors other than daytime IOP (see Food for Thought: the Low- Pressure Glaucoma Treatment Study). Although surgical innovations are challenging physicians' approach to the glaucoma patient, the pharmacological foundation of glaucoma treatment continues to expand.

Jody Piltz-Seymour, MD, is director of the Glaucoma Care Center, PC, in Philadelphia and an adjunct associate professor of ophthalmology for the University of Pennsylvania Health System. Dr. Piltz-Seymour is in private practice with Century Eye Care, LLC, in Bristol, Pennsylvania. She receives research support from Alcon Laboratories, Inc.; Allergan, Inc.; and Pfizer Inc. She serves as a consultant to Sucampo Pharmaceuticals, Inc. Dr. Piltz-Seymour may be reached at (215) 781-2020; jody.piltz@verizon.net.

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