AGS meeting highlights prostaglandins, genetics, prostamides, new technology

The American Glaucoma Society’s (AGS’s) annual meeting is one of the pre-eminent conferences dedicated exclusively to glaucoma. Some interesting research was reported at the most recent meeting.

Genetics

Genetics is an exciting and developing area as it relates to primary open-angle glaucoma. Genetic analysis offers the opportunity to detect individuals at risk for open-angle glaucoma at an early age — before damage or even IOP elevation has occurred. The testing can be offered to individuals at great risk, such as those with a significant family history. If individuals are found to be positive for the gene, the follow-up intervals may be sooner and more exhaustive.

Either a cheek swab or a blood test is used to collect material for lab analysis. In addition to diagnostic implications, genetic analysis may lead to therapies directed at specific abnormalities with the hope that these mechanisms may be modified to prevent the development of glaucoma.

The myocilin gene (GLC1A) has been described previously and is involved in approximately 3% to 4% of all forms of open-angle glaucoma. In the Feb. 8, 2002, issue of Science, Rezaie and colleagues described a new gene — OPTN — that appears to be responsible for 16.7% of open-angle glaucoma. This discovery was elucidated in detail at the meeting.

This gene lies on chromosome 10 and codes for a protein called optineurin (optic neuropathy-inducing protein). It is primarily involved in normal tension forms of glaucoma and is believed to have some neuroprotective effect. When defective, the development of glaucoma occurs in greater numbers. The OPTN gene, GLC1E, is expressed in the trabecular meshwork, retina and brain. InSite Vision has obtained rights to test for the OPTN gene, and it is expected to be included in the Ocugene test, which currently screens for variants to the TIGR/myocilin gene.

Bimatoprost

Kirk Maxey presented a paper titled “The hydrolysis of bimatoprost in corneal tissue generates a potent prostanoid FP receptor agonist,” which examined whether bimatoprost, the active ingredient in Allergan’s new glaucoma medication Lumigan, is a pro-drug, with its free acid present in the anterior chamber. Allergan has stated that bimatoprost is not a pro-drug or even a prostaglandin, but rather is in an entirely new class of drugs called prostamides. Prostamides are derived from a different pathway than the other prostaglandins.

The questions raised include whether bimatoprost is a prostaglandin, whether it acts at prostanoid receptors or whether it is in a different class of agents as compared with other prostaglandin analogs. Dr. Maxey is a chemist and owner of Cayman Chemical in Ann Arbor, Mich. This company sells raw ingredients to pharmaceutical manufacturers that are developed into prostaglandin agents. Dr. Maxey described his need to know whether bimatoprost was a pro-drug, because he must include this information in the product description for the raw compound 17-phenyl-18, 19, 20-trinor-prostaglandin F2-N-ethyl-amide.

Dr. Maxey provided convincing evidence that bimatoprost is hydrolyzed in human corneal tissue to its free acid and is a pro-drug. Allergan did not reveal the chemical structure of bimatoprost until the Food and Drug Administration approved the medication, so independent researchers could not evaluate the compound. Dr. Maxey’s findings are unusual and will be studied further.

Bimatoprost appears to be a pro-drug of a very potent and selective FP agonist (identical to the free acid of latanoprost with the exception of a double bond between C 13-14). When using the amide rather than isopropyl ester form, as in latanoprost, the potency is reduced, accounting for the higher concentration found in bimatoprost.

Focal arteriolar narrowing

A recently described sign of glaucomatous optic neuropathy is peripapillary focal arteriolar narrowing. In this situation, the arteriole constricts as the vessel approaches the optic disc. It is felt to be a secondary sign of glaucomatous optic nerve damage.

Andrew Lam presented a paper titled, “Visual field loss in glaucoma patients with asymmetric peripapillary focal arteriolar narrowing,” in which fundus photographs from 325 consecutive glaucoma patients were examined for evidence of focal arteriole narrowing and were compared with their visual fields.

Thirty-one patients (9.54%) were found to have focal arteriole narrowing. In this group, visual field loss was worse (mean deviation –8.77 dB vs. –4.52 dB). Clinically, it appears that focal arteriole narrowing is associated with greater visual field loss in glaucoma and does not indicate early glaucoma damage.

SITA standard, SITA fast

Swedish Interactive Threshold Algorithm (SITA) has been the preferred algorithm for the Humphrey Visual Field Analyzer (Zeiss Humphrey, Dublin, Calif.) for more than 6 years, and its benefits of reduced test time with comparable accuracy to the full-threshold (FT) form have been well documented.

Donald Budenz delivered a paper titled “Comparison of glaucomatous visual field defects using standard full threshold vs. Swedish Interactive Threshold Algorithms (SITA standard and SITA fast).” Seventy-seven glaucoma patients underwent FT, SITA standard (SS) and SITA fast (SF) 30-2 perimetry on two separate occasions in a 1-month period.

The severity of defects was compared among algorithms. The mean deviation for the FT algorithm was worse (–20.6 dB) when compared to SS (–9.6 dB) or SF (–9.1 dB). The size of the glaucomatous defects varied slightly and, most importantly with the FT algorithm, defects were deeper than with the other algorithms.

Based on this paper, it appears that when using SITA standard and fast, the defects will not be as deep. This is most significant as we change tests in following patients. When we switch to SITA perimetry from the older FT algorithms, the fields will often improve due to differences between tests and not to a clinical improvement. We need to establish a new baseline when we go to a new visual field test.

Pigmentary glaucoma

Douglas Johnson looked at the risk of developing pigmentary glaucoma (PG) from pigment dispersion syndrome (PDS). A retrospective, population-based study was performed on all newly diagnosed cases of PDS and PG from 1976 to 1999 in Olmsted County, Minn. The criteria for PDS were that two of three signs had to be present: iris transillumination defects, Krukenberg spindles or heavy trabecular meshwork pigmentation with gonioscopy. Criteria for PG were PDS and two or three findings: IOP higher than 21 mm Hg, disc damage or visual field loss.

The results showed that 119 newly diagnosed individuals had PDS during the 23-year period. Of these, 31 developed PG or PDS with elevated IOP requiring therapy. The probability of converting to PG was 13% at 5 years and 23% at 15 years. Also, 26 patients were diagnosed directly with PG without a previous diagnosis of PDS during the 23-year period. The mean age at diagnosis for PDS was 41 years, and the mean age at diagnosis of PG was 44 years. Fifty-seven percent of PDS patients were men, and 87% of PG patients were men.

Based on these study results, it appears that about one in four individuals with PDS will convert to PG. Unfortunately, we still do not know which of the PDS patients are at greatest risk with regard to clinical signs.

Home IOP monitoring

IOPs fluctuate in all individuals throughout the day, and the variability is often greater in individuals with glaucoma. A single IOP measurement has a limited usefulness in patients with glaucoma, and previous studies have shown that spikes in IOP often occur outside the office environment and may be an additional risk factor for glaucoma. Obtaining diurnal IOPs requires patients to spend time in the office, as an at-home IOP monitoring device was not available until recently. This past summer, Bausch & Lomb released the Proview Home Pressure Monitor, which allows patients to monitor their IOPs at home.

Jacob Wilensky presented a poster titled, “The role of diurnal IOP curves in the management of glaucoma patients.” Dr. Wilensky evaluated IOP measurements obtained from 35 patients who used the Proview Home Pressure Monitor and compared them to Goldmann applanation tonometry. Preliminary results indicated that a correlation between the two instruments exists, and that this instrument may be useful to follow select patients who may need home IOP monitoring.

Prostaglandins

Prostaglandins have become a very important medication in the realm of glaucoma therapy. There are now four medications in this class of drugs, and one question is whether a clinician can prescribe two different prostaglandins concurrently.

Sanjay Asrani and colleagues looked at this issue with the poster, “Paradoxical intraocular pressure elevation after combined therapy with latanoprost and bimatoprost.” Three case reports showed large IOP increases when Lumigan was added to Xalatan (latanoprost ophthalmic solution, Pharmacia) in individuals being treated for glaucoma. The IOP returned to baseline levels with discontinuation of Lumigan.

While the series is small, it is not recommended that a patient be placed on more than one prostaglandin agent at any one time. Reported side effects of prostaglandins include hyperemia, anterior uveitis, cystoid macular edema, reactivation of herpes simplex keratitis, iris color changes, skin darkening and an increase in eyelash length.

In a poster, Leon Herndon reported on increased eyelid pigmentation associated with the use of ocular hypotensive lipids. Four case reports were discussed in which increased eyelid pigmentation was noted 1 to 5 months after therapy was initiated with either latanoprost or bimatoprost in African Americans. What made the results unique is that the eyelid pigmentation reversed once therapy was discontinued. This is different than what is found with iris darkening, in that those changes tend to be irreversible.

Prostaglandin advantages

One advantage of prostaglandins is that they may be more forgiving with regard to IOP spikes if a dose is missed, as compared to other glaucoma medications. Harvey DuBiner and colleagues reported findings from their work, “A study of the IOP lowering efficacy of Travatan measured every 4 hours throughout a 36-hour period and up to 84 hours following discontinuation of dosing.” This study looked at the IOP reduction over time with travoprost.

Twenty-one open-angle glaucoma patients were enrolled. Following washout of their prior glaucoma medication(s), IOPs measurements were taken every 4 hours for a 24-hour period. Patients were then placed on Travatan (travoprost ophthalmic solution, Alcon) for 2 weeks. At the week 2 visit, IOP was measured just before Travatan was instilled (8 p.m.), and then it was measured every 4 hours for the next 36 hours. Additional IOP measurements were taken at 60 and 84 hours. IOP reduction was maintained at 36 hours, with significant IOP reduction present at 60 and 84 hours. It appears that while the medication is meant for once-per-day dosing, if a dose is inadvertently missed, the IOP will not spike upward dramatically.

Alfred Solish investigated whether either bimatoprost or travoprost may be effective in patients who did not respond to latanoprost. In this study, 193 patients with insufficient IOP control had their therapy replaced with either bimatoprost (116) or travoprost (77). In most cases, the prior agent was latanoprost. For bimatoprost, 57% achieved a significant reduction in IOP while 4% could not tolerate the drug. For travoprost, 45.5% achieved a significant IOP reduction. Based on these findings, it appears that if latanoprost is not effective, it is worth trying another of the prostaglandin agents rather than moving on to a different class of drugs.

Both the diagnosis and management of glaucoma is evolving, with newer medications and diagnostic agents available. The challenge for clinicians is to understand how each new development fits into their clinical patient management. Meetings such as the AGS provide information to allow scientific developments to be placed in a clinical context.

For Your Information:

• Murray Fingeret, OD, is chief of the optometry section at the Department of Veterans' Affairs Medical Center in Brooklyn and Saint Albans, N.Y., and a clinical associate professor at SUNY College of Optometry. He is also a member of the Primary Care Optometry News Editorial Board. He may be contacted at St. Albans VA Hospital, Linden Blvd., and 179th St., St. Albans, NY 11425; (718) 526-1000; fax: (516) 569-3566; e-mail: murray@liii.com. Dr. Fingeret has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.