Evaluation of the acute effect of Sildenafil citrate on visual function in patients with earlystage agerelated macular degeneration
【摘要】 To assess the effect of a single dose of Sildenafil citrate on the visual function in men with earlystage agerelated macular degeneration(AMD).METHODS: Forty men (mean age 71, range from 5586 years)with earlystage AMD were prospectively randomized to receive either placebo or Sildenafil citrate (Viagra; Pfizer Inc, New York, NY) 100mg as a single oral dose. Subjects underwent visual acuity, Amsler grid and color discrimination in each eye before and at specific intervals within 9 hours after dosing.RESULTS: Compared with placebo, no pattern of errors were evident in any visual function test following Sildenafil administration. No statistically or clinically relevant changes from baseline were observed in visual acuity or color discrimination. No clinically relevant changes were observed in the Amsler grid. Sildenafil treatment was associated with transient mild or moderate headache and flushing. CONCLUSION: A single 100mg dose of Sildenafil was well tolerated and produced no significant acute visual effects in a sample of men with earlystage AMD.
【关键词】 Sildenafil citrate visual function age related macular degeneration
INTRODUCTION
Cyclic guanosine monophosphate (cGMP)DEpendent phosphodiesterase type 6 (PDE6) is present in high concentrations in cone and rod cells and plays a key role in retinal light signal photo transduction. Activated PDE6 hydrolyzes cGMP to effect a reduction in cGMP concentration in the outer segments of rods and cones. This reduction in cGMP triggers the sequential closure sodium channels resulting in hyperpolarization of the photoreceptors, release of neurotransmitter, and propagation of visual signals to post synaptic cells[1]. Sildenafil citrate (VIAGRA; Pfizer Inc, New York, New York) is effective in treating erectile dysfunction by selectively inhibiting cGMPdependent PDE5 in corpus cavernosum smooth muscle cells[2]. It also weakly inhibits PDE6, reflecting an affinity for PDE6 that is one tenth of its affinity for PDE5[3]. Therefore, the potential for Sildenafil to produce visual effects secondary to PDE6 inhibition was evaluated during its clinical development. As documented in doubleblind placebocontrolled phase II studies in healthy male volunteers and patients with erectile dysfunction, no clinically significant changes in visual acuity, intraocular pressure(IOP), contrast sensitivity, photostress test, or pupillometry measurements and minimal changes in electroretinograms (ERGs) were observed at Sildenafil doses ranging from 50200mg, compared with placebo[4,5]. Overall, abnormal vision, described as mild occurrences of a transient blue tinge to vision or as increased brightness of or sensitivity to lights, was reported by 3% of patients receiving 50mg doses and 11% of patients receiving 100mg doses of Sildenafil in phase II/III clinical trials[6]. Color vision testing using the FarnsworthMunsell 100hue (FM 100hue) test indicated that modest transient abnormalities in color vision, particularly in the bluegreen range, occur predominantly at the maximum recommended dose of Sildenafil (100mg) or at twice the highest recommended dose (200mg)[1,4,5] .
Patients with early stages of macular degeneration, defined as minimal visual impairment and large drusen in the macula, have partial impairment of visual function (including visual acuity, contrast sensitivity, and color vision)[7]. Thus, inhibition of PDE6 could theoretically exacerbate visual difficulties in subjects with macular degeneration. Additionally, since agerelated macular degeneration (AMD) becomes more frequent over the age of 60, many elderly patients receiving Sildenafil treatment for erectile dysfunction undoubtedly also have some degree of macular degeneration. Although visual function is partially compromised in this patient group, it is still measurable and sufficient enough to provide meaningful qualitative and quantitative information[8]. We therefore conducted this study to assess the effect of a single dose of Sildenafil citrate on the visual function in men with earlystage AMD.
MATERIALS AND METHODS
Forty male subjects aged 55 years or older with documented earlystage AMD characterized by coalescent soft drusen, who had corrected visual acuity of 20/40 or better in at least one eye were chosen from the out patient clinic of the Research Institute of Ophthalmology Giza, Egypt within the period between February 2006 and May 2008.
Subjects were excluded if they had taken nitrates during the previous 3 weeks or any other drugs known to affect visual function within 1 month before the start of the study. Subjects were also excluded if they had eye disorders other than macular degeneration, including diabetic retinopathy, retinal detachment, cataract or glaucoma requiring treatment, color blindness, or corrected visual acuity of 20/50 or worse.
Subjects were randomized to doubleblind treatment with a single dose of either placebo or Sildenafil 100mg. Study drug doses were taken between 8am10am, at least 1 hour after a light breakfast with 240mL of water. Subjects were not allowed to take any other drug known to affect visual or retinal function for the duration of the study.
The effects of Sildenafil on visual function were assessed using a battery of visual function tests performed in the following order visual acuity, Amsler grid test and color discrimination. Subjects completed all visual tests in each eye, starting with the eye with the better visual acuity (or the right eye if acuity was identical) 1 hour before dosing then 1, 5 and 7 hours postdose.
Bestcorrected visual acuity (BCVA) was assessed for each eye using Snellen chart at a distance of 6m. The smallest line on which the majority of letters could be read by each eye was recorded. A change from the predose (baseline) value was determined in each eye and classified as deterioration, improvement, or no change in visual acuity at each post dose assessment. Improvement or deterioration was defined as a change of at least two lines.
While viewing the Amsler grid, the subjects were asked to assess whether their vision was normal. If not, they were asked whether they noted a central or peripheral scotoma or distortion of vision (metamorphosia). A change from predose during the Amsler grid test for each eye was classified as worse, better, or the same at each postdose assessment.
The subjects were also asked for color discrimination by the PseudoIsochromatic Plates using Ishihara color blindness test to get an idea of subjects color efficiency or deficiency.
RESULTS
The median visual acuity scores following treatment with Sildenafil or placebo did not change significantly from predose scores and there was no clinically relevant difference between treatments. The median scores for the right eye were 6/9 before Sildenafil dosing and 6/9 and 6/6, respectively, at 5 and 7 hours after Sildenafil dosing. The median scores for the left eye were 6/9 before Sildenafil dosing and 6/9 and 6/9, respectively, at 5 and 7 hours after Sildenafil dosing. In comparison, the median scores for the right eye were 6/9 before placebo dosing and 6/6 and 6/6, respectively, at 5 and 7 hours after placebo dosing. For the left eye, the median scores were 6/18 before placebo dosing and 6/9 and 6/9, respectively, at 5 and 7 hours after placebo dosing.
All subjects showed no change in visual acuity following treatment with Sildenafil. Two subjects showed an improvement in visual acuity following placebo.
Pretreatment results for Amsler grid test in the right eye indicated normal vision in thirty six subjects and abnormal vision due to metamorphopsia in four subjects. The vision of all subjects that were normal remained normal following Sildenafil treatment. One subject with abnormal findings showed increased metamorphopsia at 1, 5, and 7 hours after Sildenafil dosing.
Pretreatment results of the Amsler grid test for left eye indicated thirty five subjects with normal vision and five with abnormal vision due to metamorphopsia. The vision of all that were normal remained normal following treatment with Sildenafil. The five with abnormal Amsler grid findings, one subject had better vision 5 hours after and one subject had worse vision 7 hours after receiving Sildenafil. There was no evidence that these changes were related to Sildenafil treatment. Following treatment with placebo, the Amsler grid findings of all subjects were the same as in the predose period for both right and left eyes.
No significant or clinically relevant differences between treatments were observed for color discrimination suggesting a lack of additional effect of Sildenafil on the subjects ability to distinguish colors.
Independent of the visual test measurements, there were no visual disturbances reported. So no visual disturbance questionnaires were completed. There were no laboratory test abnormalities related to study drug administration or clinically significant changes in blood pressure or pulse rate.
DISCUSSION
In addition to its inhibitory effect on PDE5, the target enzyme for therapeutic efficacy in patients with erectile dysfunction, Sildenafil exerts a minor inhibitory effect on PDE6. Because PDE6 plays an important role in retinal photo transduction, its partial inhibition may account for the infrequent occurrence of visual effects observed in flexible dose controlled clinical trials of Sildenafil in men with erectile dysfunction[8,9]. Some concerns have been expressed about the use of Sildenafil by individuals with preexisting retinal disorders and its possible effects on their visual function. In the present study, treatment with a single maximum recommended dose of Sildenafil (100mg) produced no acute visual effects compared with placebo in a group of forty men with earlystage AMD and some degree of reduced visual acuity.
No clinically relevant changes from baseline in visual function in either the right or left eye were observed, as assessed by a battery of visual function tests. Furthermore, there was no evidence of a discernible pattern of errors in any visual test as a function of time after dosing with Sildenafil nor a consistent pattern of errors within one subject. Bearing in mind the inherent limitations conferred by the small number of study patients, in clinical practice, the lowest effective dose of Sildenafil should be prescribed for patients with AMD.
The results of this study are consistent with the results of a retrospective analysis of data from a subgroup of 66 participants in phase II/III studies who had both erectile dysfunction and a history of eye disorders, including diabetic retinopathy, glaucoma, and macular degeneration[10]. That analysis showed little evidence of a trend toward an increase in visual adverse events AEs during treatment with fixed or flexible doses of Sildenafil ranging from 5mg to 200mg(n=39) or placebo (n=27) for 426 weeks. The incidence of visual AEs in the patients receiving Sildenafil was 6/39 (15%) and in patients receiving placebo was 2/27 (7%).
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