Cosopt alters retinal circulation, tests show

An array of imaging technologies are needed to clinically assess retinal blood flow.

LONDON — Cosopt (dorzolamide HCl, timolol maleate ophthalmic solution, Merck) significantly accelerates retinal circulation compared with timolol alone and lowers intraocular pressure (IOP) more than timolol, according to Alon Harris, PhD. Comprehensive analysis of circulation with several techniques consistently found acceleration of retinal circulation with Cosopt said Dr. Harris, here at the European Glaucoma Society meeting.

Improved retinal circulation is important because glaucoma patients may have vascular abnormalities that impair retinal circulation, Dr. Harris told Ocular Surgery News.

Retinal abnormalities can include vasospasm — the faulty autoregulation of the eye against drops in blood pressure. Also, as IOP rises, there is a decrease in circulation in the back of the eye and the posterior ciliary arteries.

“The concept deals with managing not only the pressure in glaucoma but also trying to correct for the abnormal circulation,” Dr. Harris said. “We’re trying to find ways to lower IOP, increase circulation and correct for the faulty autoregulation of vasospastic problems in these patients.”

While researchers have suspected the existence of circulatory factors in glaucoma, it has been difficult to measure them.

“Technology is really at the stage and point where if you work cautiously and use a comprehensive approach — that means you don’t use one single instrument — you can actually see a lot of things that relate to the faulty circulatory status of the eye,” Dr. Harris said. In fact, he concluded that the only accurate way to assess ocular blood flow at the moment is by combining five different technologies to perform a comprehensive vascular exam.

Blood flow technologies

Several instruments have contributed to the growing body of evidence that vasospasm is present in glaucoma.

Dr. Harris uses scanning laser ophthalmoscopy with the Rodenstock SLO with fluorescein to measure retinal circulation or with indocyanine green to measure choroidal blood flow.

He also uses color Doppler imaging to analyze the back of the eye and look at the retrobulbar vessels, and he uses the Heidelberg Retinal Flowmeter (Heidelberg Technologies; Carlsbad, Calif.) to examine capillary and tissue blood flow in various areas of the retina.

He then uses custom software to perform a pixel-by-pixel analysis of the image.

Put them together

“We put all of these technologies together, and then we assess the ocular circulation,” Dr. Harris said. “We don’t believe in using one single technique. Let’s say that you pick up a drug effect in the retina. Is that a true effect or is that resulting from a steal phenomenon in another area? To be able to conclude that there wasn’t a steal phenomenon, and because there was no technology that can assess all relevant vascular beds, we strongly support and believe in a comprehensive approach.”

He compares the results from these tests with normative databases compiled over the past decade. He has also worked with oxygen, a potent vasoconstrictor, and carbon dioxide, a potent vasodilator, to validate the various imaging technologies.

Phantom models provide data on stress testing, similar to tests done on cardiology equipment.

“With all the different techniques, I can look at the retina, I can look at the choroid, I can look at the retrobulbar vessels, carotid vessels and the optic nerve head and brain blood flow,” Dr. Harris said.

In vivo studies

Dr. Harris assessed the vasodilative effects of Cosopt with his comprehensive imaging methods. Cosopt combines a beta-blocker and a carbonic anhydrase inhibitor (CAI). Previously published papers show that topical CAIs such as dorzolamide (Trusopt, Merck) lower IOP but also enhance retinal circulation.

“We know there are some brain studies, for example, that show that CAIs dilate retinal brain and retinal circulation and that they have a similar effect on those vessels as CO₂,” Dr. Harris said. The suspected mechanism of action is a local reduction in pH, which is a known stimulant for dilating vessels and increasing circulation.

To confirm his theory, Dr. Harris enrolled 16 patients in a crossover study. Patients received either timolol or Cosopt for 4 weeks. Dr. Harris recorded results from tonometry, color Doppler imaging for retrobulbar artery velocities and scanning laser ophthalmoscopy angiography for arteriovenous passage time (AVPT).

He used a double blind crossover design with placebo. Patients acted as their own control to help prove accuracy and validity.

Cosopt reduced IOP more than timolol, and AVPT was significantly reduced from baseline by Cosopt (P=.0113). Cosopt did not significantly affect retrobulbar, choroidal or optic nerve head circulation.

Cosopt improved AVPT by 20% to 25%.

“In many of the glaucoma patients that we tested, there was a reduction of circulation of 20% to 25%. So we believe that increasing it might be beneficial to these patients,” Dr. Harris said.

The ultimate answer, he said, will come from long-term, multi-center studies he is currently conducting, combining blood flow studies with nerve fiber thickness, visual function and IOP in patients followed for 2 years.

For Your Information:

• Alon Harris, PhD, is director of the glaucoma research and diagnostic center and professor of ophthalmology and physiology at the Indiana University Department of Ophthalmology, 702 Rotary Circle, Indianapolis, IN 46202-5175; (317) 278-2566; fax: (317) 278-1007. Dr. Harris has no direct financial interest in any of the products mentioned in this article, nor is he a paid consultant for any company mentioned.