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Better pressure lowering by latanoprost seen in eyes with iris pigment change
Anecdotal observations lead surgeons to investigate eyes that turn dark with the drug.
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LONDON - Eyes with irides that turn dark from latanoprost (Xalatan, Pharmacia) may show a better intraocular pressure (IOP)-lowering response than other eyes, according to Miguel A. Teus, MD, PhD, an associate professor of ophthalmology at the University of Alcala in Spain.
---Miguel A. Teus, MD, PhD
Pigment-related glaucomas and, to some extent, pseudoexfoliative glaucoma caused concern about the increasing iris pigment and the IOP control, Dr. Teus said.
"When latanoprost was first available for clinical use, one concern regarding the ability of the drug to darken the iris was whether the eyes showing an increase in iris pigmentation would have a worsening in their IOP control," he told Ocular Surgery News.
Clinicians routinely take photographs of the eyes under therapy with latanoprost to detect changes in iris color. Dr. Teus and colleagues saw that some eyes showing a marked increase in iris pigmentation also showed a nice IOP response to the drug. These anecdotal observations prompted them to study the relationship between iris color change and the IOP-lowering efficacy of latanoprost.
He presented results in a poster called "Ocular hypotensive effect of latanoprost in eyes that have a latanoprost-related increase in iris pigmentation: A pilot study" at the European Glaucoma Society (EGS) meeting.
"It is accepted that the bad pigment, as far as glaucoma is concerned, is the epithelial pigment layer, which is thought not to be affected by latanoprost," Dr. Teus said. "It has been shown that IOP control of pigmentary glaucomas is good with latanoprost."
Variable effects
Some investigators have noticed that the hypotensive effect of latanoprost seems to vary from patient to patient, as there are some patients in whom latanoprost is very effective, and others in whom it does not seem to work at all, Dr. Teus said.
Latanoprost is not the only antiglaucoma drug showing this pattern of "heterogeneous response" in the primary open-angle glaucoma (POAG) population, he added. Epinephrine also induces a quite "heterogeneous hypotensive response," in contrast with timolol, which seems to induce a rather homogeneous hypotensive response.
"It would be very interesting to know the eye conditions that may predispose to a good hypotensive response to latanoprost," Dr. Teus said. "This is why we studied the relationship between the ocular hypotensive response and the latanoprost-induced iris darkening."
Dr. Teus prospectively selected 75 POAG patients scheduled to receive latanoprost monotherapy. Enrolled were either newly diagnosed POAG patients in whom latanoprost was warranted or patients already receiving medical therapy and who needed to switch to latanoprost monotherapy because of poor IOP control.
No patients had a history of intraocular surgery or laser therapy. All patients had a normal anterior segment examination without iris atrophy, occludable angles or signs of ocular trauma. Base IOP was the untreated IOP in newly diagnosed patients or the IOP after a 3-week washout period in patients already receiving medical therapy.
Latanoprost was administered once daily, at night, and as monotherapy in all cases. A masked observer measured IOP using the same calibrated applanation tonometer at 1, 3 and 6 months after instituting latanoprost therapy. Researchers also took photographs of the anterior segment of both eyes of each patient.
When the IOP reduction from the base value was 10% or less, researchers defined the eye as a hyporesponder, and when the IOP reduction was 40% or more, they defined the eye as a hyperesponder.
When both eyes of a given patient fulfilled the inclusion criteria, one eye was randomly chosen to analyze.
At the end of the study, two independent, masked observers used a stereo viewer to simultaneously examine the base slide and the slide of the 6-month visit of each eye.
Examiners closed each of their eyes, so both slides of each patient could be easily compared through the stereo viewer. They classified the slides as showing no difference in iris color or as having a mild, moderate or severe increase in iris pigmentation.
Only eyes showing a moderate or severe change at the 6-month visit were considered to have an increase in iris pigmentation, Dr. Teus said. If a discrepancy was noted between the two examiners regarding the iris color classification of the eyes, the disputed slides were reviewed again by the same observers, who reached a consensus.
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Efficacy, pigmentation
Of the 75 eyes, researchers analyzed 35 as having a moderate or severe iris darkening (darkened group), and 40 eyes remained the same color or with only a mild change in iris pigmentation (control group). The distribution of base iris color was similar in both groups.
Base IOP was 24.8 ± 5 mm Hg in the darkened group, and 24.4 ± 4 mm Hg in the control group. The IOP was 16.6 ± 3 mm Hg, 15.8 ± 3 mm Hg and 16.03 ± 3 mm Hg in the darkened group at 1, 3 and 6 months of follow-up, respectively.
The IOP was 18.5 ± 3 mm Hg, 17.3 ± 3 mm Hg and 17.5 ± 3 mm Hg in the control group at 1, 3 and 6 months of follow-up, respectively. Values were significantly lower in the darkened group at 1 and 3 months (P=0.01 and P=0.04), and the difference was not statistically significant at 6 months (P=0.07), Dr. Teus said.
"The prevalence of hyperesponders to latanoprost was much higher in the darkened group than in the control group at every visit," he said. "On the other hand, the prevalence of hyporesponders to latanoprost was much lower in the darkened group than in the control group."
Researchers saw that the IOP was statistically different only at the 1- and 3-month visits. the IOP difference at the 6-month visit was borderline. In spite of this, the hyperesponder/hyporesponder ratio was highly statistically different at every visit.
This led researchers to conclude that the hypotensive efficacy of latanoprost was higher in the "darkened" group at every visit.
"Interestingly, the differences in IOP lowering were evident beginning with the first month, well before the increase in iris pigmentation develops," Dr. Teus said. "It seems that it is not the increase in the melanin content of the iris induced by latanoprost that makes the iris more prone to developing a good IOP response to latanoprost, but the susceptibility to develop a change in iris color."
Data show an increase in iris pigmentation after 6 months of therapy with latanoprost, and patients respond much better to this therapy than eyes that remain stable after 6 months of therapy, Dr. Teus said. The relationship of the iris color to the effect of ocular drugs is well known and seems to be related to drug binding and the later release of the drug by ocular melanin.
"Interestingly, although the change in iris color needs time to develop, the higher IOP decrease seen in the darkened group was noticeable beginning with the 1-month visit, when the color of the iris was still unchanged," he said.
"In addition, latanoprost is thought not to have a significant affinity for melanin binding in contrast with other ocular drugs," he added. "These facts suggest that the reason why the eyes in the darkened group show a higher response to latanoprost than the control eyes may be that the mechanisms of action of latanoprost for both the effect on IOP and the effect on iris pigmentation could be closely related, as the eyes seem to have a similar sensitivity for both effects."
Dr. Teus found one report in the literature that showed a relationship between the iris color and the hypotensive efficacy of latanoprost. Published reports showed that the IOP decrease induced by latanoprost was significantly higher in hazel-colored eyes than in blue/green/gray eyes. They found no difference in the IOP response between blue and brown eyes.
"Interestingly, hazel (yellow-brown) eyes seem to have a great tendency to develop a change in iris color after latanoprost therapy, while homogeneous blue or brown eyes have a much lower tendency to show an increase in iris pigmentation," Dr. Teus said. "In our study, however, we found no difference in the prevalence of the different eye colors between both study groups."
Predictions not possible
One of the warnings ophthalmologists give to candidates for latanoprost therapy is the possibility of developing a change in iris color, Dr. Teus said.
"The sensitivity to the hypotensive effect of latanoprost seems to be related to the sensitivity to develop an increase in iris pigmentation," he said. "This relationship does not seem to be caused by an increase in the drug-binding ability of the eye or by the amount of melanin present in the eye before the therapy is begun."
Instead, the increase in iris pigmentation seems to be related to the ocular hypotensive efficacy of latanoprost, Dr. Teus said. More studies are needed to show whether the differences in IOP lowering are long-lasting.
"We feel that, in terms of this side effect, the risk/benefit ratio of the therapy is much lower than we previously thought, just because if the eye is going to show an acquired darkening, it should also be expected to show a nice IOP response," Dr. Teus said.
Albert Alm, MD, discussed the poster presentation at the EGS meeting.
"Can we expect that a good responder to the drug is also more likely to develop side effects?" he asked. "From a pharmacological point of view, I'm not sure that I would have expected that. In fact, with the prostaglandins, I looked for a correlation between the hyperemia and the IOP to be able to predict whether they would be good responders or not, but there was no correlation."
Brown eyes studied
While studies of irides of different colors were conducted in Europe, studies in the consistently dark-brown irides of Japanese patients also added evidence to the debate over latanoprost's effects in hyperpigmented eyes.
Takeshi Hara, MD, of Omiya Red Cross Hospital, in Omiya, Japan, spoke about "increased iris pigmentation after use of latanoprost in Japanese brown eyes" at the EGS meeting.
Previous studies reported hazel eyes showed remarkable iris color changes, while homogeneously brown or blue-gray or green eyes were seldom affected, Dr. Hara told Ocular Surgery News.
He had participated in a study of timolol and latanoprost in 1995 and followed 16 patients for 3 years. In this study, after 2 years, iris color of the patients in the latanoprost group showed remarkable changes compared to the timolol groups.
"I was convinced of a high incidence of iris color changes in homogeneous brown eyes and undertook the study as soon as latanoprost was approved in Japan in May 1999," he said.
Dr. Hara enrolled 102 patients, all of whom had homogeneous brown irides. Patients' mean age was 63.8 ± 8.3 years. Patients were followed an average of 10.3 ± 1.4 months.
Observers photographed the iris before beginning latanoprost therapy. They administered slit lamp exams before use and at every month after starting latanoprost. When increase in iris color was suspected, it was judged by comparison with the photograph. Researchers used the Kaplan-Meier life table method to evaluate the incidence of the increased iris pigmentation.
Researchers calculated the incidence of the increased iris pigmentation as 11.6% at 3 months, 37.1% at 6 months, 51.6% at 9 months and 54.3% at 12 months after use.
Granule pigmentation progressed as a "concentric pattern" or a "sunrise pattern." Some pigmentation occurred at 1 month after use and progressed. No patients noted their own iris color change; it was usually discovered by relatives. Color changes of brown irides were considered less strong than in hazel (green or blue/gray eyes, or yellow combined with brown) eyes.
Increased iris pigmentation is due to increased synthesis of melanin in the melanocytes, Dr. Hara said. Careful observations were needed for other homogeneous color irides, such as blue or green or gray.
A new method is needed to assess iris color change by pattern or intensity, he said. "Assessment of iris color change is entrusted to the experience of each doctor," Dr. Hara said. "It is difficult to judge positive or not, strictly or objectively."
According to Dr. Alm, in Japanese brown eyes, a change in iris color was seen in 54% of patients within 12 months, "which is very, very close to what we've found in irises that were green mixed with brown." Other studies used European patients, who did not have many brown irises.
"The more brown you have, the larger the probability that there will be a change," Dr. Alm said. "A greenish color in the eyes means that they have a bit of melanin already." So it makes sense that the researchers found a higher degree of pigmentation than in other studies of blue-eyed patients, he said.
For Your Information:
- Miguel A. Teus, MD, PhD, is an associate professor of ophthalmology at the Hospital Universitario "Principe de Asturias", University of Alcala, Corazon de Maria, 47 1C Madrid, 28043, Spain; (34) 91-510-0614; fax:(34) 91-519-6004; e-mail: mteus@teleline.es. Dr. Teus has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
- Takeshi Hara, MD, practices at the Omiya Red Cross Hospital, 8-3-33 Kamiochiai, Yono-city, Saitama 338-0001; (48) 852-1111; fax: (48) 852-3120.
- Albert Alm, MD, can be reached at Uppsala University Hospital, Department of Ophthalmology, Uppsala S 75185, Sweden; (46) 18-611-5136; fax: (46) 18-504-857. Dr. Alm has no direct financial interest in the products mentioned in this article. He is a paid consultant for Pharmacia.