BACKGROUND: THE DEVELOPMENT OF VIAGRA

Early in preclinical development, it was found that sildenafil inhibits retinal PDE6 enzymes with an IC50 of 27-58 nM. Although this was substantially less than its effect on the intended target, PDE5 (IC50 3.9 nM), it led to the evaluation of safety of high doses of sildenafil on retinal histopathology in rats and dogs and on electroretinograms (ERGs) in the dog. To assess toxicologic effects, oral sildenafil (60 mg/kg, or approximately 50 times the maximum human recommended dose) was administered to rats daily for 6 months. No histopathologic evidence of toxicity was observed to the eye or visual pathways after long-term exposure to high doses of sildenafil. Likewise, when oral sildenafil was administered daily to dogs for 12 months (80 mg/kg, or approximately 65 times the maximum human recommended dose), there was no histopathological evidence of toxicity to visual pathways. Thus, in long-term testing in the rat and dog, there was no evidence of any toxicologic effect on the retina . In the dog, the concentrations required for a threshold ERG effect were equivalent to a 400 mg dose in man or four times the highest recommended therapeutic dose. Free plasma sildenafil levels of 51 to 540 ng/mL induced dose-related increases in the implicit time of the a- and b-wave and reduced the amplitude of the a-wave of ERGs (Fig 3).

Effects of intravenously administered sildenafil citrate on electroretinogram (ERG) evoked by a flash (50 |Xsec) of blue light on the dark-adapted anesthetized dog. Each curve represents average response to five consecutive light challenges.

All effects on ERGs were transient and reversible. They declined in a manner consistent with the plasma half-life of sildenafil.

Leave a Reply

Your email address will not be published. Required fields are marked *

CAPTCHA image
*