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and then study with either timolol or the combination of cupping, or evidence for disk hemorrhage resulted in
timolol and dorzolamide (Cosopt ; Merck, Inc, White- termination of participation for that subject.
house Station, New Jersey). All procedures were reviewed At each of the four study visits, subjects were tested for
and approved by an institutional review board at Indiana visual acuity (logarithm of minimal angle of resolution
University School of Medicine, and subjects signed in- [logMAR] chart), contrast sensitivity (CSV-1000 chart),
formed consent before entry into the study. All experimen- visual fields (Humphrey HFA-2), brachial artery pressure
tal procedures conformed to the tenets of the Declaration (sphygmomanometry), radial pulse, and intraocular pres-
of Helsinki. sure (Goldmann applanation tonometry). At each visit,
Patients with primary open-angle glaucoma referred or retinal arteriovenous transit time was determined using
recruited on approval from their ophthalmologist were scanning laser ophthalmoscopy and fluorescein angiogra-
included in the study. Patients exhibited characteristic phy, choroidal perfusion was measured using scanning laser
glaucomatous visual field loss and optic nerve head dam- ophthalmoscopy and indocyanine green angiography, and
age. Subjects had corrected visual acuity of 20/40 or better retrobulbar arterial flow velocities were measured using
and were older than 18 years. Patients with mean devia- color Doppler imaging. For each patient, visits were
tion greater than or equal to 20 dB of visual field, as scheduled and performed at the same time of day. These
measured by the Humphrey Visual Fields central 24-2, or blood flow techniques are described in greater detail below.
who had a cup to disk ratio of 0.9 or greater, were not Scanning laser angiography (Rodenstock scanning laser
included in the study. Female subjects who were pregnant, ophthalmoscope, SLO 101; Rodenstock GmbH, Ottobrun,
nursing, or planning on becoming pregnant within 1 Germany) was used to evaluate retinal arteriovenous
month of the study conclusion were excluded. Recruited passage time. Five milliliters of fluorescein sodium was
subjects had no current or history of ocular disease apart injected into a peripheral vein, and the angiogram was
from glaucoma, no history of orbital trauma, no history of videotaped. The video frames were analyzed using a digital
asthma or emphysema, and no history of allergy to sulfa image analysis system (HRX; Amtronics, Inc, New Or-
drugs, fluorescein, iodine, shellfish, or dyes. This last leans, Louisiana). The first step of analysis was the digiti-
zation of a series of frames from the videotape after
restriction was required because of our use of angiographic
techniques requiring the intravenous infusion of indocya- correction for eye movements. Two 3-pixel by 3-pixel
areas, one each on the superior temporal artery and vein,
nine green and fluorescein. All subjects were free from were selected for measurement of density variations in the
other medications with significant cardiovascular, renal, digitized images. Intensity curves (dye dilution curves)
respiratory, or hepatic side effects. were plotted, and the appearance of fluorescein dye was
Subjects were studied under two treatment conditions:
timolol 0.5%, one drop twice each day in each eye, and characterized by increasing intensity. Arteriovenous pas-
sage time was determined as the difference between ap-
timolol 0.5% plus dorzolamide 2% (Cosopt ), one drop pearance time in the artery and the corresponding vein.
twice each day in each eye. The two drug treatment For scanning laser ophthalmoscopy after indocyanine
regimens were administered in randomized, double-masked green injection, 12.5 mg indocyanine green dissolved in 1
fashion. Before entry into the study, patients ceased taking ml saline, was injected into a peripheral vein; the injection
other eye medications for a washout period that ranged was immediately followed by a 2-ml saline flush. Red-free
from 4 weeks (topical blockers) to 3 weeks (prostaglan- images were obtained with a 488-nm argon laser at 40
dins) to 2 weeks ( agonists and miotics) to 1 week (oral degrees to locate the macula relative to the optic disk. The
or topical carbonic anhydrase inhibitors). To decrease argon laser was shut down, and a 795-nm near infrared
complications of washout, and to provide baseline com- laser was used to perform the angiogram. Verbal commands
parison data, all patients were placed on timolol 0.5% (one were used to guide subject fixation so that the nasal edge of
drop in each eye twice each day). After completion of the the disk was at the edge of the video frame centered
washout period for medications other than timolol, pa- vertically, with the macula toward the center of the screen.
tients reported to the clinic for baseline (timolol only) The examination was videotaped and processed off-line.
measurements and were then assigned to one of the two The entire 40-degree indocyanine green angiogram was
treatment conditions for 1 month. After a second exami- divided into six 6-degree regions (two peripapillary regions
nation, subjects were placed again on timolol alone, and and four perimacular regions ), and dilution curves were
6
after 1 month were studied for a second baseline measure- created for each region. Simultaneous dilution curves
ment. They then were switched in double-masked fashion allowed comparison of relative indocyanine green concen-
to the other drug treatment (timolol or timolol plus trations between different locations. The average bright-
dorzolamide) and were then studied for a fourth time after ness of each area was computed for each frame of the
another month. At each visit, an adverse events check was angiogram. Three parameters were derived from graphical
performed and a pupil dilation with slit-lamp examination analysis of brightness changes with time: slope, 10% dye
of the fundus was carried out. Any clinically significant arrival time, and dye duration. Slope was analyzed as the
deterioration of visual acuity, optic disk pallor, increase in mean for each of the six areas, as the regional spread, and

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