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Prostaglandins extremely effective at reducing IOP
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OMAHA, Neb. — Although the efficacy of prostaglandin analogs for the treatment of glaucoma has been well documented, there continue to be lingering concerns over potential adverse side effects. Several experts believe, however, that the incidence of these effects — some of which appear to be only cosmetic — should not be a deterrent to prescribing latanoprost (Xalatan, Pharmacia & Upjohn). Last June, the once daily eye drop became the first prostaglandin the Food and Drug Administration (FDA) approved for glaucoma therapy.
"There have never been any side effects that could be attributed to the drug, systemically speaking," said Carl B. Camras, MD, a professor and vice chairman of the department of ophthalmology at the University of Nebraska Medical Center here.
"Based on its pharmacokinetic properties and the very low doses that we use to lower pressure, latanoprost is not expected to cause systemic side effects," he said. Dr. Camras, along with his colleagues, organized a two-part, special interest group discussion on prostaglandin analogs for glaucoma therapy at the annual meeting of the Association for Research in Vision and Ophthalmology.
Isopropyl unoprostone
A second analog, isopropyl unoprostone (Rescula, Otsuka), is approved for commercial use in Japan and "recently was approved in some of the South American countries," Dr. Camras said.
However, the only comparative study of latanoprost and unoprostone has been in monkeys. "The investigators found that latanoprost is more effective at reducing intraocular pressure (IOP) in the glaucoma monkey model compared with unoprostone," said Dr. Camras, a pioneer in the use of prostaglandins specifically for IOP reduction.
One concern that has been expressed about both latanoprost and unoprostone over the years is an increase in iris pigmentation.
"The question is whether this is a potentially deleterious effect," Dr. Camras said. "We won’t know the final answer to that until the agents are used for many, many years. But thus far, neither has been shown to cause any deleterious effects in the eye. It seems to be a cosmetic change in the iris color produced by the drug, due to stimulation of melanin synthesis (melanogenesis) within iridial melanocytes."
Nonetheless, patients should be notified that a prostaglandin can cause a change in iris pigmentation. "It doesn’t seem to occur in uniformly blue eyes, and it’s very rare in uniformly brown eyes," he said. "It only seems to occur in a hazel-type of eye color."
Color change is generally not noticed by the patient or family members if both eyes are treated at the same time.
Other risks
A minor side effect associated with prostaglandins compared with timolol is an increase in the incidence of conjunctival hyperemia. "Latanoprost causes very slight hyperemia in approximately 10% more patients than timolol. No patients were dropped from the multicenter trials because of intolerable conjunctival hyperemia," he explained.
One potential risk that was raised at the meeting is the formation of cystoid macular edema. "There have been very few cases reported," Dr. Camras said. "The question is whether there is a causal relationship. Those cases that have been reported already have a high risk for developing cystoid macular edema. In fact, many of these patients had a history of cystoid macular edema, so these are complicated eyes to begin with."
The role of prostaglandins in inflammation has raised some questions about potential inflammatory reactions to prostaglandin derivatives.
"Prostaglandins in the past have been linked to intraocular inflammation. But there is little scientific basis for any inflammation produced by the drug," Dr. Camras said. "There have been some anecdotal reports that there is inflammation when the drug is started. Of the 800,000 patients who have been treated with latanoprost in the United States to date, the incidence of inflammation seems to be no higher than in the general population."
Circadian IOP reduction
The moderator of the special interest group was another pioneer and leader in research Laszlo Z. Bito, PhD, a professor of ocular physiology at Columbia University in New York. "The greatest myth that I would like to shatter eventually is that circadian IOP reduction does not have much to do with improving glaucoma," he said. "It is thought that many glaucoma agents, including timolol, do not have a beneficial effect during the night. But latanoprost has been shown to have the same IOP reduction during the night as in the day."
The mechanism of IOP reduction with latanoprost is also different from timolol. "It increases uveoscleral outflow. This uveoscleral outflow is independent of episcleral venous pressure," Dr. Bito said.
Systemic side effects are extremely rare because "we are putting only 3 micrograms of drug into the eye per day. In contrast, the body produces milligram amounts; 1,000 times more prostaglandin is produced in the body every day. Prostaglandin is excreted very effectively. The half-life is only about 17 minutes," he explained.
Eyelashes affected
SpeakerJeffrey M. Liebmann, MD, an associate clinical professor of ophthalmology at the New York Eye and Ear Infirmary, has been prescribing latanoprost for the past 5 years and was part of the phase 3 trials.
He noted that many of his patients experienced darkening and lengthening of eyelashes. "For some, this is a concern because they are receiving unilateral therapy," he said.
Like Dr. Bito, Dr. Liebmann is excited that latanoprost achieves IOP reduction by enhancing the uveoscleral outflow pathway. "There is no other drug that lowers pressure in this fashion. This is the first in its class," he said.
As for apprehension over iris pigmentation, "It’s a legitimate concern," Dr. Liebmann said. "But in a way, we’re trading potential ocular effects for systemic side effects. For example, beta-blockers have very few ocular side effects, but they have potentially lethal systemic side effects. Obviously, a local risk is better than a systemic one."
Dr. Camras is impressed by the drug’s efficacy. "Of the eye drops we currently have available to treat glaucoma, this seems to be the most effective drug in reducing pressure," he said.
Further, the once-a-day medication (usually at bedtime) may enhance patient compliance. "It is one of the few types of eye drops that can be applied once daily," said Dr. Camras, noting that some glaucoma agents must be administered four times a day.
"Latanoprost is more effective once every 24 hours than when given twice daily," Dr. Camras said.
Gene therapy?
Paul L. Kaufman, MD, a professor of ophthalmology and visual sciences at the University of Wisconsin Medical School in Madison, said there are lessons to be gleaned from prostaglandins as antiglaucoma drugs: enhancement of uveoscleral outflow is a potential way to treat glaucoma and anything that increases the expression of certain enzymes produced by the ciliary muscle is possible therapy. Enzymes could be manipulated by gene therapy in the future.
"Because prostaglandins are hormones, they are chemical signalers," Dr. Kaufman said. "What seems to be happening with latanoprost is that the connective tissue in the spaces between the ciliary muscle bundles are being remodeled in such a way that it’s easier for fluid to pass through. Therefore, you may be able to change the genetic program of the cells to express those enzymes in higher concentrations.
"If you could tell the tissue to make more of the enzyme by altering the genetic instruction, then you wouldn’t have to give the prostaglandin every day. You could change the gene one time — maybe for up to 30 years," he added.
For Your Information:
- Carl B. Camras, MD, can be contacted at 600 South 42nd St., Omaha, NE 68198-5540; (402) 559-4276; fax: (402) 559-5514. Dr. Camras has no direct financial interest in the products mentioned in this article. He is a paid consultant to Pharmacia & Upjohn.
- Laszlo Z. Bito, PhD, can be contacted at, 630 West 168th St., New York, NY 10033; (212) 305-5667; fax: (212) 568-3954. Dr. Bito has a direct financial interest in Pharmacia & Upjohn.
- Jeffrey M. Liebmann, MD, can be contacted at 310 East 14th St., New York, NY 10003; (212) 979-4491; fax: (212) 420-8743. Dr. Liebmann has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
- Paul L. Kaufman, MD, can be contacted at 600 Highland Ave., Madison, WI 53792-3220; (608) 263-6074; fax: (608) 263-1466. Dr. Kaufman has no direct financial interest in the products mentioned in this article. He is a paid consultant for Pharmacia & Upjohn and Ciba Vision.
- Xalatan is available from Pharmacia & Upjohn, (614) 764-8100; fax: (614) 764-3667.
- References: Nagasubramanian et al. Ophthalmology. 1993;100:1305.
- Alm et al. Br J Ophthalmol. 1995;79:12.