Impotence Medications

Fourteen male AMD patients (13 Caucasians and 1 African-American) with a mean age of 75
7 years (
1SD) were included in this double-masked, randomized, placebocontrolled, crossover study. AMD features of enrolled patients were similar or worse than those present in eyes graded as AMD category 3 in the AREDS study. Only one eye of each patient was included in the study. Study eyes had clear ocular media, intraocular pressure (IOP) of 21 mm Hg or less, pupillary dilatation of 5 mm or more, steady fixation, no intraocular diseases other than AMD and no choroidal neovascularization (CNV). Right eyes were chosen in ten patients and left eyes in the other four. All study eyes had large drusen and eight eyes had retinal pigment epithelium hyperpigmentary changes. Five patients had small areas of extrafoveal geographic atrophy in the study eye or the fellow eye. Two patients had exudative AMD with a disciform scar present in the fellow eye. External and slit lamp examinations were normal except for the presence of mild lens nuclear sclerosis in nine study eyes and intraocular lens implants in three eyes.

A history of well-controlled systemic hypertension was reported in nine patients. All of them were taking antihypertensive medications. None of the 14 subjects enrolled in the study had a history of systemic hypotension or serious heart condition or was receiving nitrate therapy. All study subjects took the same medications throughout the length of the study, and none of the study participants was under fasting conditions.

The study was carried out after the approval from University of Pennsylvania Institutional Review Board. The tenets of Declaration ofHelsinkiwere followed.All subjects signed an appropriate IRBapproved consent formafter the detailed explanations of the study procedures. We have previously reported our findings on the effect of sildenafil citrate on the choroidal blood flow in this cohort of patients (Metelitsina et al., 2005).

The study design included two separate study visits, with all patients being randomized to receive a single oral dose of either 100 mg of sildenafil citrate (Viagra; Pfizer Inc, New York) or matching placebo on the first study visit. The alternative drug was tested on the second study visit. Placebo pills were identical to the sildenafil ones, but they did not contain the active component. The same protocol was performed on both study days, which were separated by a wash out period of three or more days. In order to prevent bias, both patients and investigators were masked to the treatment modalities.

After pupillary dilation was achieved with tropicamide 1% (Alcon, Fort Worth, TX) and phenylephrine hydrochloride 10% (Sanofi Winthrop, New York, NY), monochromatic fundus photographs (l ¼ 570 nm) were obtained with a Zeiss fundus camera (Oberkochen, Germany) on Kodak Plus-X pan film (Rochester, New York, USA). Photos of the study eye of each patient were obtained while the subjects were seated in the darkened room. Intraocular pressure (IOP), brachial artery systolic and diastolic blood pressure (BPs and BPd) and heart rate (HR) were obtained immediately after the photographs were taken. Tono-pen XL (Mentor Ophthalmics, Norwell, MA) and automated sphygmomanometer (Accutorr 1A, Datascope, Paramus, NJ) were used to measure IOP and BP respectively. The mean brachial artery pressure (BPm) was calculated according to the following formula:

BPm ¼ BPdþ1=3ðBPsBPdÞ

Perfusion pressure (PP) for the study eye was estimated according to the following formula:

PP ¼ 2=3BPmIOP

All tests mentioned above were performed prior to the administration of the drug, and then 30, 90, 180 and 300 min, thereafter. These times were chosen to coincide with the maximal serum concentration levels of sildenafil, which are reached in 30e60 min. Plasma half-life of sildenafil is about 4h(Marmor and Kessler, 1999).

Approximately ten fundus photographs were obtained at each time point for each patient. Photographic negatives were scanned and digitized, using a Nikon SF-2000 35 mm film scanner (Tokyo, Japan). Out of the ten digital images, five photographs with the sharpest focus were selected for further analysis in a masked fashion.

Retinal vein diameter was measured with ‘‘Vessel map’’ static vessel analysis program software (IMEDOS GmbH, Weimar, Germany). This program enables the determination of retinal vessel diameter from digitized photographs. The vessel diameter is determined segment by segment along the length of a blood vessel in a predefined measurement window The instrument creates an intensity or brightness profile perpendicular to the vessel. The width of the vessel is defined as the distance from wall to wall through the midpoint of the vessel.

Two reference points were identified on vessel bifurcation for each photograph (see Fig. 1). This allowed us to overlap all images of one subject assuring that all fundus details from one picture corresponded to the same fundus details in all images of the same patient. This preliminary step enabled multiple measurements of the same vessel simultaneously on multiple images.

A predefined measurement window of about 1/2 disk diameter ensured that the length of the vessel segment measured was the same for all images of the same subject (Fig. 1). The same segment of the vessel chosen for analysis (Fig. 1) was evaluated in all photos of the same patient. To make sure that the location of the measurement window was consistent on all images, a transparent plastic template with an outline of the disk and the major vessels was superimposed on all photographs before measurements.

Measurements were performed on straight segments of the vessels within 1.5 disk diameters from the edge of the optic nerve head. We avoided vascular bifurcations and arteriovenous crossings. Major veins were chosen for analysis. In ten patients, two major veins were measured. In four patients only one major vein was analyzed because a second vein in proper focus was not available in all photographs. Thus a total number of 24 veins were included in our analysis. All circulatory measurements are shown in arbitrary units (AU).

Statistical analysis of the data comparing the differences in retinal vessel diameters before and after administration of sildenafil and placebo was performed using analysis of variance (ANOVA) for repeated measures. To compare the differences between these two groups at each time point (baseline, 30, 90, 180 and 300 min), alpha level adjustments for multiple comparisons by means of Bonferroni approach were also carried out. Because we had five time points comparisons, we considered P ¼ 0.01 (0.05/5 ¼ 0.01) as statistically significant. Regression analyses between vein diameter changes from baseline and pressure changes (IOP, PP and BP) from baseline were also performed and a P value of 0.05 was considered to be statistically significant. Since the diameters from two veins were measured for most of the patients, the generalized estimating equations (GEE) were used to adjust the correlation from multiple veins from the same eye. SAS 9.1 software (Cary, North Carolina, USA) was used for the analysis of the data.