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G.L. Mayo, R.F. Melendez, N. Kumar, J.R. Graybill, R.D. Glickman; Voriconazole May Cause Visual Disurbances Via Retinal Phosphodiesterase Inhibition . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1525.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Pronounced but transitory visual disturbances, including photophobia, blurred vision, color vision changes, and difficulty in distinguishing blue and green colors have been reported by up to 30 % of patients taking systemic voriconazole (VCZ)(Vefend®), a second generation triazole antifungal agent with specificity for aspergillus, fusarium, and candida. Decreased A- and B- wave amplitudes have also been found in electroretinographic studies in people after VCZ treatment. Similar dose-related visual side effects have been noted in patients taking sildenafil (Viagra®), which have been attributed to inhibition of retinal phosphodiesterase (PDE). This commonality suggested that VCZ might have a similar mechanism of action. The purpose of this study was to assess the inhibitory activity of VCZ on retinal PDE. Methods: A crude preparation of photoreceptor PDE was extracted from bovine retinas. VCZ was obtained from Pfizer Central Research, Sandwich, UK. PDE activity was determined by measuring the decrease in pH caused by H+ released during hydrolysis of cyclic guanosine monophosphate (cGMP). The assay method previously described by Liebman & Evanczuk (Meth Enzymol 81:532, 1982) was modified by adding calcium chloride, guanosine triphosphate, calmodulin from bovine brain, and cGMP (all from Sigma) in Tris buffer at pH 7.5. Reactions were run at 30 oC in the presence or absence of VCZ (67 µg/ml), and pH was measured with a standard electrode. Results: In the absence of VCZ, the activity of PDE produced a decrease in the pH of the reaction mixture that sometimes exceeded 1.0 pH unit within the first five minutes. In the presence of 67 µg/ml), there was no pH change in four experiments, while in two other experiments there was a small initial decrease in pH (<0.7 pH units) that stabilized at 2 minutes. Conclusions: VCZ appears to inhibit PDE activity, based on the minimal pH change in this in vitro assay. If VCZ inhibits retinal PDE in vivo, this may be the mechanism underlying the visual disturbances experienced by patients receiving systemic VCZ. There is insufficient clinical data at present to indicate whether topical ophthalmic VCZ induces similar visual side effects. If present, a common inhibitory effect on retinal PDE may be responsible.
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