Editorial [Hot Topic: Phosphodiesterase 5 Inhibitors: Pharmacology and Therapeutic Perspectives (Executive Editor: Giuseppe Barbaro)]

The most fascinating aspect in the process of drug development is the astonishing modification of perspective from which a newly discovered pharmaceutical agent can be viewed. Sometimes it may only be a matter of definition as to whether a pharmaceutical action is labeled as effect or side effect. Primary effects become side effects, and side effects may soon become the new focus of research. One of the most intriguing stories in this context has been told by phospodiesterase 5 (PDE 5)- inhibitors. PDE-5 is one of eleven members of the mammalian phosphodiesterase family that hydrolyzes cyclic guanosine monophosfate (cGMP) and cyclic adenosine monophosphate. PDE-5 degrades cGMP in smooth muscle cells, reducing the muscular tone. In addition, PDE-5 is involved in other physiological processes, such as neurogenesis and apoptosis. PDE-5 inhibitors were initially developed as new therapeutic principles for the treatment of cardiovascular disease. When sildenafil was investigated in clinical studies on coronary artery disease, it turned out to be of limited anti-anginal potential. However, a substantial number of volunteers, participating in the initial studies, reported a notable side effect: sildenafil appeared to enhance penile erections. Soon further research focused on this particular side effect, and erectile dysfunction (ED) became the first indication for which sildenafil was approved shortly thereafter in 1998. Sildenafil, vardenafil and tadalafil, are now approved for the treatment of ED. However, for their action on the cardiovascular system, new therapeutic applications have been proposed for PDE-5 inhibitors in the treatment of some specific cardiovascular disease, such as pulmonary arterial hypertension. This issue of Current Pharmaceutical Design focuses on the most recent knowledges regarding PDE-5 inhibitors, from molecular and biochemical aspects of PDE-5 to pharmacological properties and therapeutic applications of PDE-5 inhibitors. Lin et al. [1] carefully analyse the tissue expression, distribution and regulation of PDE-5. In their analysis the authors intend not only to inspire the development of the “next generation” PDE-5-specific inhibitors but also the design of drugs targeting other PDEs. Supuran et al. [2] describe PDE-5 inhibitors differentiation based on receptorial selectivity, chemical structure, pharmacokinetic and efficacy profile. Aversa et al. [3] report a systematic review on the use of PDE-5 inhibitors in ED, with a careful clinical differentiation among PDE-5 inhibitors according to the most recent and selected literature in the field. About 70% of ED population report the presence of one or more comorbidities (i.e., hypertension, diabetes, cardiovascular disease, dyslipidemia) which may impair endothelial function. The recent discovery that chronic not on-demand administration of PDE- 5 inhibitors may improve erectile and endothelial response in men previously unresponding to on-demand regimes, opens a new scenario in the treatment of men with ED and comorbidities. Reffelman and Kloner [4] discuss in their review about basic mechanisms, pharmacological and patho-physiological aspects of PDE-5 inhibitors, including theoretical concepts on adverse cardiovascular effects. Moreover, they analyse the effects of PDE-5 inhibitors in the cardiovascular system, as measured in various human and animal studies, with respect to both descriptive studies and statistical evaluations. They speculate also on novel therapeutic applications of these pharmaceutical agents in various cardiovascular diseases. In June 2005 sildenafil was approved in the United States for treatment of pulmonary arterial hypertension.Furthermore, recent basic science reports focus on potentially direct cardioprotective, preconditioning-like and anti-apoptotic effects, which might open another interesting field of research close to the initial roots in cardiovascular pathophysiology. It's my hope that the issue be helpful for the scientific and clinical community working in this area. I would like to thank all the authors for their important contributions. References [1] Lin CS, Lin G, Xin ZC, Lue TF. Expression, Distribution and Regulation of Phosphodiesterase 5. Curr Pharm Des 2006; 12(27): 3439-3457. [2] Supuran C, Mastrolorenzo A, Barbaro G, Scozzafava A. PDE5 Inhibitors - Drug design and differentiation based on selectivity, pharmacokinetic and efficacy profiles. Curr Pharm Des 2006; 12(27): 3459-3465. [3] Aversa A, Bruzziches R, Pili M, Spera G. Phosphodiesterase 5 inhibitors in the treatment of erectile dysfunction. Curr Pharm Des 2006; 12(27): 3467-3484. [4] Reffelmann T, Kloner RA. Cardiovascular effects of phosphodiesterase 5 inhibitors. Curr Pharm Des 2006; 12(27): 3485-3494.