Phosphodiesterase Type 5 Inhibitors: Unmet Needs

Abstract

Erectile dysfunction (ED) has been revolutionized during the last two decades, as several treatment options are available today. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil) are currently the first choice treatment option for ED by most physicians and patients due to their high efficacy rates and favourable safety profiles. Despite the fact that more than 50 million ED patients have been treated successfully worldwide with PDE5i several issues remain to be addressed. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5i. Inappropriate instructions, lack of follow-up and lack of patient-centered care models have been identified as main reasons for "nonresponse", leading to drop-out rates of even > 50%. Preservation of corporal smooth muscle with chronic administration of PDE5i has been reported and there is a substantial body of evidence for beneficial effects of these drugs on endothelium and cardiovascular function. Finally, improvement of lower urinary symptoms after PDE5i administration has been reported and a possible role on treatment of premature ejaculation has been proposed. Many new PDE5i are candidates to enter the market in the forthcoming years. However, pharmacokinetic differences should be obvious to consider a truly better option for patients. Patients must be aware of all treatment options since no ideal treatment exists and physicians must offer personalized medicine to their patients in the future. The development and adaptation of a patient-centered care model in sexual medicine will increase efficacy and safety of current and future treatments.

Intracavernous administration of bone marrow mononuclear cells: a new method of treating erectile dysfunction?

“…Major factors associated with this include atherosclerosis, nerve damage and smooth muscle atrophy [16]. Several approaches have demonstrated some promise in the improvement of responsiveness to PDE5 inhibitors including propionyl-L-carnitine [17,18], intracavernous PGE1 [19], and testosterone gel [20,21].…”

Ligand‐Promoted meta‐C−H Functionalization of Benzylamines

“…6 Thus, developing general and practical meta -C–H transformations of benzylamines will provide synthetic chemists a reliable method for rapid diversification of these important scaffolds. Unlike the well-developed ortho -C–H functionalizations of benzylamine substrates, 7 meta -C–H functionalizations of benylamines are currently plagued by inefficiencies in both substrate and coupling partner scope.…”

“…Importantly, the directing group can be easily removed following a modified known procedure 9 to afford the N -Boc benzylamine 7 in 91% yield, a key intermediate to access the RPR 128515 analogues. 6a …”

The role of intraurethral alprostadil as a first-choice erectile dysfunction treatment option in special populations: a proposed treatment algorithm

“…However, based on data reported in the MALES study, despite the advent of oral PDE5 inhibitors, only 58% of males with ED consult a physician about their problem, and only 16% of men with self-reported ED maintain their use of oral therapy [3]. It is estimated that the failure rate with PDE5 inhibitors is approximately 25% [102] and can reach levels as high as 60% in some cases (e.g., severe neurological damage, severe vascular disease, radical pelvic surgery and diabetes) [24][25][26], with the two most common reasons why patients fail to respond to PDE5 inhibitors being incorrect drug use or inefficacy of the drug [103]. Furthermore, males most likely to fail oral PDE5 inhibitors are those with severe ED [27] and peripheral nerve damage after radical prostatectomy or severe vascular disease and long-standing diabetes with subsequent myopathy, vasculopathy and neuropathy [24]; as discussed in greater detail later, as the underlying pathology is known in advance, intraurethral alprostadil represents the first-choice treatment option in these patients.…”