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February 2006

 
News in Review
A Look at Today’s Ideas and Trends
By Linda Roach, Contributing Writer
Edited by Brian A. Francis, MD
 
 

• Eyedrops in Trials May Prevent Cataracts
• Low Rates of Cataract Sx in Nursing Home Patients
• New Scale Helps Predict AMD Progression
• Flavonoids Benefit Eyes, Too


Eyedrops in Trials May Prevent Cataracts

Population-based studies have laid out the risk factors that, usually at an advanced age, lead to cataract surgery. But what if someone in late middle age could avoid pseudophakia by shielding the crystalline lens from accumulating further oxidative damage?

That’s the possibility raised by a new phase 2 drug trial to determine whether cataracts after vitrectomy can be prevented—with an antioxidant eyedrop. By the end of March, Othera Pharmaceuticals Inc. expects to complete enrollment in a planned 12-month trial of its drug OT-551 in 126 patients after vitrectomy.

Additionally, because re-active oxygen species are thought to trigger age-related macular degeneration, a clinical trial of the eyedrops against the dry form of AMD will begin in mid-2006, said David S. Joseph, chairman and CEO of Othera, in Exton, Pa.

“To have the potential for a drug that is topically dosed and can treat more than one ocular indication could be very interesting and very exciting—time will tell,” said Mr. Joseph.

The active drug in OT-551 is Tempol-H (TP-H), which was identified, characterized and patented as an ocular antioxidant by the NEI.

J. Samuel Zigler Jr., PhD, chief of NEI’s lens and cataract biology section, said the effort began in the early 1990s at the behest of founding NEI director Carl Kupfer, MD. “He was very interested in cataract, and he really pushed us to try to come up with something that would be beneficial therapeutically,” said Dr. Zigler, whose name is one of five listed on the patent.

Dr. Zigler recalls a pains-taking process of adding antioxidants, one at a time, to cultures of crystalline animal lenses under oxidative stress. This was fruitless until they tried TP-H, the reduced, hydroxylamine form of the superoxide dismutase TEMPOL (4-hydroxy- 2,2,6,6-tetramethylpiperidine-l-oxyl).

They discovered that TP-H rapidly oxidized in the lenses to TEMPOL, which in turn reduced back to TP-H. This ability of the TP-H to cycle between its reduced and oxidized forms produced biochemical equilibrium, and blocked cataract formation without the toxicity that occurred when the oxidized form of Tempol was ad-ministered by itself, Dr. Zigler recalled.

However, although TP-H entered the lens easily in culture, in vivo it couldn’t pass through the cornea. “We tried to use it in some live animal studies, and we couldn’t de-tect anything inside the eye,” Dr. Zigler said.

Othera modified the molecule into OT-551, an eyedrop that penetrated into both lens and vitreous of study animals, Dr. Zigler said. The prodrug quickly is converted inside the eye into TP-H to begin the antioxidant activity, Mr. Joseph said.

Othera’s postvitrectomy cataract study will test OT-551’s effectiveness at blocking exposure of the lens to oxygen free radicals produced by the retina. Lens opacities in these cases usually occur within nine months of vitrectomy, and are nuclear cataracts—also the predominant type in age-related cataracts.

Although the company couldn’t make claims without further testing, success in the vitrectomy trial would offer hope that today’s 40- and 50-somethings who undergo vitrectomy might keep their vision clear with eyedrops instead of surgery.

Dr. Zigler said, “In the end, we should have a clear idea of whether this drug works or not in the human situation. It may not—but just finding out is worth a lot.”

Geriatric Care

Low Rates of Cataract Sx in Nursing Home Patients

Maryland researchers got a surprise in their study of the availability of cataract surgery for nursing home residents. It wasn’t a lack of support services that prevented the surgeries from occurring, they found, but instead it was the reluctance of patients, guardians and even consulting ophthalmologists to choose the surgery.¹

The Johns Hopkins University researchers noted that exams revealed 176 out of 633 patients with visual acuity less than 20/40 in their better-seeing eye. In 75 percent, acuity was lower than 20/60 in the better eye.

The study provided transportation to pre- and postoperative exams, and to the surgical facility, from homes where 77 of the patients lived. (Of these, three were too sick or died before surgery could be scheduled.) Another 99 patients in the study had only the normal support services available at the nursing home.

In facilities without this special transportation, only 2 of 99 patients underwent cataract surgery. Among the 74 who did have the extra transport, the number of surgeries rose to 24.

Despite that tenfold increase, in 48 out of the 74 patients in the intervention group surgery was not performed because patients or their guardians either refused to visit an ophthalmologist or declined the ophthalmologist’s recommendation for surgery. In two cases, it was the ophthalmologist who called off a scheduled surgery. 

Depression in the elderly might be partly to blame, the authors suggest. “The high rates of refusal (> 50 percent) to be evaluated by a second ophthalmologist for a relatively benign, sight-restoring intervention points to the resignation that many residents and guardians feel about their poor vision. Many stated that they were unwilling to undergo any procedure, even if it improved their quality of life,” the researchers write.

But attitudes among the surgeons might have had an impact also, they add. “Several physicians expressed concerns about the ability of residents to tolerate or benefit from surgery. . . . More than 20 percent of residents referred to ophthalmologists for surgery were told not to bother, even though they had vision-impairing cataracts,” the researchers write.

That reluctance might not be a bad thing, though, said an ophthalmologist who has been active in population-based studies of barriers to ophthalmic care, Rohit Varma, MD, MPH, assistant professor of ophthalmology and preventive medicine at the University of Southern California.

“There is an underlying assumption that all patients who have cataract and visual impairment would benefit. This may not be true,” Dr. Varma said.

“I think in order to be sure that guardian/caregiver/physician bias against surgery in these patients is a barrier to their improved quality of life, one needs to confirm that these patients have an improved quality of life after cataract surgery. We need to ask and seek from the patient, if possible, their needs and desires before intervening, since they are the ones who may or not benefit from surgery.”

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1 Friedman, D. S. et al. Arch Ophthalmol 2005;123:1581–1587.

Retina in Practice

New Scale Helps Predict AMD Progression

There’s something for both community and research ophthalmologists in the newly proposed scales for rating the severity and progression of age-related macular degeneration.

That’s because leaders of the long-running Age-Related Eye Disease Study (AREDS) put forth not only a finely detailed scale—essential to judging clinical trial results —but also a simplified version that physicians can remember and patients can understand.¹,²  

“The clinical people really like the simple scale because of its ease of use,” said Frederick Ferris III, MD, clinical director at the NEI and a lead investigator in AREDS. “And it’s helpful for patients to put their disease in some perspective, with regard to their risk of losing vision in the next five years.”

“Both scales have been validated against the risk of progression to advanced AMD in the AREDS natural history study,” write Paul Mitchell, MD, and Suriya Foran, MBBS, PhD, in an accompanying editorial.³ “In developing these severity scales, the AREDS Research Group has done an enormous service to practicing ophthalmologists and researchers alike. The reports have immense practical value, and the scales should be adopted.”

The AREDS Simplified Severity Scale estimates the five-year risk for progression to advanced AMD in at least one eye. Based on data from AREDS, the scale runs from 0 to 4, with one point added per eye if ophthalmoscopy or slit-lamp biomicroscopy reveals one or more large drusen (> 125 micrometers in size) or any pigmentary abnormality.

The scores for each eye are summed to yield the person’s overall risk score. (If there are no large drusen, presence of intermediate drusen in both eyes adds 1 risk point to the score.) The scale’s risk estimates are: 0 factors, 0.5 percent; 1 factor, 3 percent; 2 factors, 12 percent; 3 factors, 25 percent; and 4 factors, 50 percent.

“We were very lucky the way the numbers worked out. Fifty percent is an easy number to remember. And then you cut it in half,” Dr. Ferris said.

He added that clinicians still will need to use judgment to interpret the numbers for patients.

“If you’re a smoker and you’re obese and you have a strong family history, you’re probably at an even higher risk than someone else with the same number of risk points, but who doesn’t have your added risk factors,” he said. “Similarly, if you have a diet that’s rich in omega-3 fatty acids and lutein, maybe you’ll probably be at lower risk, even if you have large drusen.”

The other, more complicated AMD Severity Scale consists of a nine-point rating system for retinal photographs. It incorporates a six-step drusen area scale and a five-step pigmentary abnormality scale, and tops out at a 50 percent risk for a score of 9 on the scale. Like the ETDRS (Early Treatment Diabetic Retinopathy Study) retinopathy grading system, the scale is intended to standardize the signposts of AMD progression—an important step toward having surrogate markers that can be used to show whether proposed treatments work, Dr. Ferris said. If the FDA agreed, this would shorten the time an AMD trial takes to produce results.

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1 Davis, M. D. et al. Arch Ophthalmol 2005;123:1484–1498.
2 Ferris, F. R. Arch Ophthalmol 2005;123:1570–1574.
3 Arch Ophthalmol 2005;123:1598–1599.

Retina Update: Flavonoids Benefit Eyes, Too

Bad news for the chocolate lover. While it has been found that flavonoids can protect against retinal ganglion cell death, the bioflavonoids that do the most comprehensive job of shielding these cells from apoptosis due to oxidative stress don’t bear any relationship to a chocolate truffle.

Two scientists from the Salk Institute reported finding that only three of the 30 flavonoids they tested blocked more than a single pathway toward cell death.¹

Two of the best for preserving retinal ganglion cells, the flavonols fisetin and quercetin, reside in decidedly unchocolate foods—like yellow onions, kale, citrus fruits, apples, olives, broccoli and tea. The third, galangin, is in Chinese ginger.

Apple-ginger spice cake, anyone?
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1 Maher, P. and A. Hanneken. Invest Ophthalmol Vis Sci 2005;46:4796-4803.