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By Peter A. McCullough, MD, MPHThe clinical indications of most drugs today arrive by serendipity. That is certainly the case for is the phosphodiesterase-5 (PDE5) inhibitors.Sildenafil(Viagra®, Revatio®)Tadalafil(Cialis®, Adcirca®), generic approved for daily use, 2.5, 5.0 mgVardenafil(Levitra®, Staxyn®)Avanafil(Stendra®) on demandIntroductionWhen sildenafil citrate was synthesized in a Pfizer laboratory in Sandwich, Kent in 1989, the researchers were chasing a hypertension drug. The erections were a side effect. What almost nobody anticipated — and what the pharmaceutical industry has shown remarkably little interest in exploring — is that this class of drugs, the phosphodiesterase-5 (PDE5) inhibitors, might represent one of the more promising repurposing opportunities in oncology.The PDE5 inhibitors — sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra) — work by blocking the enzyme that degrades cyclic guanosine monophosphate (cGMP). Elevated cGMP relaxes vascular smooth muscle, hence the vasodilation and the famous indication. But cGMP signaling also intersects with pathways that govern apoptosis, proliferation, immune surveillance, and drug resistance in malignant cells. These are not marginal effects. The preclinical evidence is substantial.Subscribe nowRead more