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Unfortunately, much less effort has gone into identification of activators of PDEs although much of the same technology could be applied. At the functional level the identification of new PDE enzymes has been greatly aided by developments in molecular biology. In particular the publication of the human and mouse genomes has led to the discovery of new PDE isoforms and the identification of variants of previously known ones. These advances have implicated the involvement of PDEs in many pathological conditions. Newer genetic techniques for probing PDE function such as RNA interference and tissue-specific conditional mouse gene disruptions and conditional RNA interference expression should allow for the validation of newly discovered enzymes as targets in specific diseases and forewarn of potential inhibitor side effects. Paul Shekelle, MD, PhD; and While pulling back may not be helpful, trying harder isn't the answer either. 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Among more than 4000 patients in clinical studies of tadalafil, the incidence of myocardial infarction in the treatment group was 0.39 per 100 patient-years, as compared with 1.1 per 100 patient-years in the placebo group.44 Advertising Disclaimer Sildenafil was recently studied in a large series of diabetic men with erectile dysfunction and was found to be well tolerated and effective.22 In this randomized, controlled trial, 74 of 131 patients taking sildenafil reported improved erections compared with only 13 of 127 patients taking a placebo. The incidence of mild adverse effects was higher in the group taking sildenafil, but the incidence of cardiovascular events was similar in both groups. CONCLUSIONS: Sildenafil, vardenafil, and tadalafil are safe and effective PDE5 inhibitors for the treatment of ED. 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