PDE5 inhibitors, erectile dysfunction and beyond : How, sometimes, indications are the consequences of marketing strategies and/or serendipity

Phosphodiesterase inhibitors (PDE5i) have an established role in the treatment of erectile dysfunction (ED) and pulmonary arterial hypertension (PAH) but, at the same time, they represent a paradigmatic example of a class of drugs, originally tested for a clinical indication, shifted to another one, for the unexpected emergence of strong evidences opening towards a new market, at that time still to be defined, but with an enormous potential. Sildenafil, the primer of PDE5i drugs patented in 1996, was designed and thought as anti-hypertensive/anginal, early relocated for ED and approved for this in 1998 despite emerging evidences of a further possible use, albeit numerically limited, in PAH. The apparent lack of interest in other fields of application continue at least until 2004 when, possibly, due to the upcoming of 2 new PDE5i on the market, the request for PAH, supported by a trial, was finally submitted and obtained by FDA in 2005. It is noteworthy that in medicine, when a relevant cellular mechanism is identified and targeted with a new drug, the results are not always predictable and/or are in agreement with the interests of the market but serendipity can help. Thus development/marketing of drugs is a multifactorial phenomenon that includes, also, potential/effectiveness of the molecules, beliefs/curiosity of the researchers, doctor/patient expectations, and, first of all, the economical interest related to their economic exploitation. In this review we wanted to explore the potentials, if any, of PDE5i beyond ED, by searching the literature for off-label applications.