In recent years, investigators and pharmaceutical companies have delivered new drugssuch as fourth-generation fluoroquinolones and prescription- strength dry eye therapythat have taken our treatment to another level. The coming years hold the promise of raising the standard even higher. Heres a look at some of the ophthalmic treatments expected to emerge on the stage.

GLAUCOMA
Combination Drugs
Many glaucoma medications currently going through FDA clinical trials are combinations of currently available medications. Individually, these drugs are nothing new, but combined, they may enhance patient convenience when more than one medication is required to reach the target intraocular pressure. The more alternatives available, the better the opportunity we have to control elevated intraocular pressure successfully.

Combination glaucoma medications include Cosopt (dorzolamide/ timolol, Merck), which is currently available, and the following drugs on the horizon:

Extravan (travoprost/timolol, Alcon). In a company-sponsored study, once-daily Extravan demonstrated comparable efficacy to concomitant therapy (i.e., timolol taken in the morning plus travoprost taken at night).¹ The concomitant therapy, however, showed significantly greater IOP reduction at two diurnal time points.

Xalcom (latanoprost/timolol, Pfizer). This combination was approved in Europe three years ago. A recent study in the United States found that Xalcom provided greater efficacy in lowering IOP when compared with latanoprost used in adjunctive therapy with either a carbonic anhydrase inhibitor, an alpha agonist or a beta-blocker.² Also, Xalcom was as effective as latanoprost used adjunctively with Cosopt. However, a previous study in Europe found that Xalcom showed less efficacy than concomitant use of latanoprost plus timolol.³

Combigan (brimonidine/timolol, Allergan). This drug was approved in Canada last year. A recent study showed that Combigan lowered IOP more effectively than either brimonidine or timolol used as monotherapy.⁴ Mean diurnal IOP was reduced to less than 18mm Hg in 40% of patients in the combination group, compared with 15% in the brimonidine group and 26% in the timolol group.

Calcium Channel Blockers
Vasospasm may contribute to ocular ischemia and subsequent visual loss in patients with normal-tension glaucoma. For these patients, calcium channel blockers could be a potential therapy.^5,6

Calcium channel blockers reduce vasospasm through the inhibition of calcium influx, which results in relaxation of vascular smooth muscle and a reduction in vascular tone. The calcium channel blockers have been found to increase blood flow and volume to the optic nerve and to increase trabecular meshwork outflow.^7,8

Some patients are currently being put on Calan (verapamil, Pfizer) or other oral calcium channel blockers. Topical verapamil is in development.

Neuroprotective Agents
The role of neuroprotection in glaucoma continues to intrigue researchers and clinicians. Numerous clinical studies are under way to find neuroprotective agents that might protect the optic nerve and retinal ganglion cells in glaucoma. Many of these agents are the result of work done on other central nervous system (CNS) diseases such as Parkinsons disease, multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrigs disease).

Namenda (memantine, Forest Pharmaceuticals). Namenda is in Phase III clinical trials for the treatment of glaucoma. It is an oral systemic medication currently available in the United States for the treatment of Parkinsons and other neurodegenerative diseases. Memantine seems to possess neuroprotective properties and helps prevent retinal ganglion cell loss in glaucoma patients.^9,10

Memantine appears to work by binding to the glutamate receptor molecules on the cell surface. This prevents the attachment of glutamate to the nerve cells. Without glutamate, calcium cannot enter the nerve cells, thus protecting the nerve cells from excess calcium and reducing cell toxicity. Memantine is likely to become the first medication available in the United States as a specific neuroprotective agent for the treatment of glaucoma.

Copaxone (glatiramer acetate, Teva Pharmaceuticals). Copaxone an injectable drug currently used to treat multiple sclerosisis also being investigated as a possible neuroprotective agent to protect the optic nerve from the effects of glutamate in people with glaucoma.¹¹ Glatiramer acetate is a synthetic copolymer that has antigenic specificity for the immune mechanism that acts as a neuroprotector of retinal ganglion cells. Copaxone seems to protect the optic nerve from the effects of toxic levels of glutamate, produced by the death of cells from increased IOP.

ANTIBIOTICS
Third- and fourth-generation fluoroquinolones have become the treatment of choice for many ocular infections. Currently, fluoroquinolones offer the broadest range of coverage for ocular pathogens.¹² Besides the two recently approved fourth-generation fluoroquinolones, the following investigational antibiotics may soon become available.

Trovan (trovafloxacin, Pfizer). The newest fluoroquinolone to be investigated for ophthalmic use is trovafloxacin. For intravitreal administration, it has been evaluated for the treatment of acute bacterial endophthalmitis. Topical trovafloxacin 0.5% has been evaluated for the treatment of bacterial keratitis.¹³

Zylet (tobramycin/loteprednol, Bausch & Lomb). A combination of the aminoglycoside antibiotic tobramycin with the corticosteroid loteprednol etabonate is being evaluated in FDA clinical trials. This combination medication is expected to be available within the year for the treatment of blepharitis, meibomianitis and inflammatory dry eye disease.

AzaSite (azithromycin, InSite Vision). Topical antibiotics azithromycin (AzaSite) and clarithromycin are being evaluated for the treatment of corneal infections. Of the two, azithromycin has better corneal penetration after topical application.¹⁴ Potential indications for topical azithromycin include the treatment of trachoma.¹⁵

AzaSite is in Phase III FDA clinical trials. Depending on the outcome of the clinical trials, FDA approval may occur in about two years.

RNA Drugs May Silence Viruses and Eye Disease

An exciting new avenue of drug research is the use of RNA interference (RNAi), small interfering RNA (siRNA) and micro RNA to control viral infections, among other conditions.22-24 This technology has opened the door to major new pharmaceutical development. RNAi is a type of gene regulation based on sequence-specific targeting and degradation of ribonucleic acid. By silencing particular genes with RNA interference, micro RNA can be used to seal off human cells from disease-causing viruses, or to disable viruses that gain entry into the cell. Small interfering RNA, the active fragment of RNA interference, has been shown to inhibit infection by HIV-1, polio and hepatitis C viruses in a sequence-specific manner, offering the potential to shut off viral infection in specific sites, such as the eye. RNAi has also shown promise in other areas of ophthalmic treatment. A recent study on subconjunctival injection of RNAi showed significant reduction in ocular inflammation, such as that following laser and glaucoma surgery, in a mouse model.25 Meanwhile, at least three pharmaceutical companiesAcuity Pharmaceuticals, Sirna Therapeutics and Alnylam Pharmaceuticalsare investigating RNA interference for wet age-related macular degeneration. In fact, Acuity has plans for a small investigational trialthe first ever RNA interference trial in humansfor using RNAi to shut down vascular endothelial growth factor (VEGF).26 But RNAi therapy is by no means perfected. The major hurdle is delivering the RNAi agent to its target site intact. Researchers are still trying to determine the most effective delivery method. H.B.

DRY EYE MEDICATION
New medications for ocular surface disease treatment are expanding our therapeutic management. For example, Evoxac (cevimeline hydrochloride, Daiichi Pharmaceutical) has been approved for the treatment of the symptoms of dry mouth for patients with Sjgrens syndrome and could also be considered for off-label treatment of severe dry eyes.¹⁶ The medication is available in capsule form.

Other promising medications for the treatment of dry eye include:

Secretagogues. These agents increase mucin production and, when applied to the cornea, cause the secretion of mucin from the epithelial layer.¹⁷

There are two secretagogues under investigation by major drug companies for dry eye treatment: diquafosol tetrasodium and hydroxyeicosatetraenoic acid.

The original purpose for diquafosol (INS365, Inspire/ Allergan), a purinoceptor P2Y2 agonist, was for the treatment of chronic bronchitis. In a recent study, patients on diquafosol had significantly less corneal staining than those on placebo (vehicle) and some reduction in symptoms such as foreign-body sensation.¹⁸

Another secretagogue, hydroxyeicosatetraenoic acid (15(S)-HETE, Alcon) is a fatty acid that occurs naturally within the body. The administration of this compound stimulates the production of mucin by ocular surface cells.¹⁹

Mucomimetics. Milcin (Vista Scientific) is being researched for use in the treatment of dry eye symptoms. It supplements the tear film by acting as a mucomimetic. More specifically, Milcin becomes incorporated into the mucin layer and mimics secreted mucin.

Androgens. Androgens seem to have a positive influence on the lacrimal gland. Topical beta-estradiol and topical testosterone eye drops are being investigated for the treatment of dry eye syndrome. The hormones seem to enhance lacrimal gland secretory function and have some positive effects for healing of the ocular surface.

Immunosuppressive agents. Prograf (tacrolimus, Fujisawa Healthcare) is an immunosuppressive agent being evaluated for the treatment of dry eye and seasonal allergic conjunctivitis.

Carbomer gels. These are also in FDA clinical trials for the treatment of keratoconjunctivitis sicca and have achieved some success in the improvement of dry eye symptoms.²⁰

NSAIDS
The NSAIDs are valuable for modulating the healing and reducing the pain of corneal abrasions and corneal erosions.

Topical non-steroidal anti-inflammatory solutions raise the sensory threshold of peripheral nerve endings so that the sensations of pain and itching are abated. Their use in conjunction with refractive procedures has helped reduce complications and helps reduce the mild to moderate pain associated with corneal procedures. Current NSAIDs are also approved for inflammation control following cataract surgery.

The newer NSAIDs are:
Acular LS (ketorolac tromethamine, Allergan). This is a 0.4% concen- tration rather than the 0.5% concentration of Acular. Acular LS also has a milder preservative and a different pH than Acular, resulting in less burning and stinging upon installation. Acular LS is approved by the FDA for use with refractive procedures.

Xibrom (bromfenac sodium, ISTA Pharmaceuticals). In two Phase III studies, Xibrom showed statistically significant reduction in ocular inflammation compared with placebo.²¹ The different thing about Xibrom is that it allows twice-daily dosing instead of the q.i.d. dosing of other NSAIDs.

In addition, other promising investigational drugssome with radically new mechanisms of actionare also on the horizon. Our first lines of therapy will continue to change for the better. 

Dr Bonner practices in Billings, Mont. He writes and lectures on new and emerging pharmaceuticals and ophthalmic technology.

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