Current Pharmaceutical Design - Volume 15, Issue 30, 2009

The introduction of orally administered phosphodiesterase-5 inhibitors into clinical practice 10 years ago has been a revolution in the field of urology. The availability of a convenient to use, safe -despite initial concerns- and effective treatment for erectile dysfunction of varying severity and etiology, has radically changed the way that physicians, but most importantly patients, approach this condition. Most of the expectations raised have been fulfilled, and more than 10 years of experience and research with sildenafil, vardenafil and tadalafil has increased our understating of erectile dysfunction pathophysiology, its psychosocial correlates and factors associated with treatment success or failure. Despite this, efforts to satisfy unmet needs are ongoing: new PDE-5 inhibitors are being developed and novel formulations of existing ones, like once-a-day tadalafil, have already enter the pharmaceutical market. Now that treatment options are more than ever before patient preference and adherence issues have become important and the focus of significant amount of research. PDE-5 inhibitors have been successfully used not only for correcting erectile dysfunction but also to preserve erectile function in men treated with radical prostatectomy for prostate cancer. In this setting PDE-5 inhibitors have been shown to be a useful adjunct to improved surgical nerve-sparing techniques. Research is ongoing, aiming to establish the optimal treatment regimen for penile rehabilitation. Evidence is accumulating suggesting that PDE-5 inhibitors may be used in the future by urologists not only for ED treatment but management of BPH- related lower urinary tract symptoms, premature ejaculation, priapism and male infertility. PDE-5 inhibitors are mainly used in urology but the approval of sildenafil for the treatment of pulmonary hypertension a few years ago renewed interest in cardiovascular applications, the field where this drug class was originally studied. The role of PDE-5 inhibitors in the management of heart failure, hypertension, and ischemic heart disease is being actively investigated with promising results.

PDE5 inhibitors have been clearly established as first-line therapy for the treatment of erectile dysfunction (ED). Three PDE5 inhibitors - sildenafil (Viagra®), vardenafil (Levitra®) and tadalafil (Cialis®) - are currently approved by the FDA and the EMEA for use in ED, whereas sildenafil is also marketed under a different proprietary name (Revatio®) for the treatment of pulmonary arterial hypertension (PAH). A forth PDE5 inhibitor, udenafil (Zydena®), is currently marketed. In the present review the molecular basis and the mechanism of action of PDE5 inhibitors is discussed. In addition experimental and clinical data concerning their effects on different tissues, organs and systems is systematically reviewed and their possible beneficial action in numerous disorders is presented.

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.

Erectile dysfunction (ED) is a common medical condition that has a negative impact on men and their partners. The field has revolutionised over the last two decades and more treatment options are available now for the treatment of ED than ever before. Among available treatment options, the most commonly prescribed therapies are oral phosphodiesterase type 5 (PDE5) inhibitors. The first drug in this class, sildenafil citrate, generally provides patients and their partners with efficacious, safe, and discreet treatment that rapidly has become the first-line treatment option. Its successful introduction into clinical practice was soon followed by the launch of two other PDE5 inhibitors: tadalafil and vardenafil. The existence of these drugs has resulted in an increase in their marketing. However, the abundance of choices made the question “which PDE-5 inhibitor?” relevant for clinicians, patients and their partners. It is widely accepted that there are no significant differences in their safety and efficacy, a fact that has led to the initiation of studies aiming to evaluate them regarding patient preference. Nevertheless, the results are rather conflicting. Also a significant percentage of men initiating treatment switch between inhibitors or discontinue therapy. This article examines the peer-reviewed published data addressing patient’s preference and adherence to ED treatment with PDE5 inhibitors. It also examines strategies to improve compliance and satisfaction with treatment.

Erectile dysfunction (ED) is one of the most challenging complications associated with radical prostatectomy (RP) for clinically localized prostate cancer. Currently, a broad spectrum of therapeutic options are available to improve sexual health after surgical treatment. Several basic science reports highlighted a potential role for phosphodiesterase type 5 inhibitors in the prevention of endothelial damage related to ischemia reperfusion and/or denervation following surgery. Recent studies have shown that pharmacological prophylaxis soon after RP can significantly improve the rate at which erectile function is recovered after surgery. Use of on-demand treatments for ED in patients who have undergone RP has been shown to be highly effective. In this context, pharmacological prophylaxis potentially may have a significantly expanded role in future strategies aimed at preserving postoperative erectile function. We analyzed the factors affecting erectile function after RP and evaluated the evidence suggesting the role of pharmacological prophylaxis and treatment of ED after surgery.

Both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) have a negative impact on patients' quality of life. The co-prescription of two active agents for these conditions will improve each condition and the addition of one drug to the other may potentiate the primary response of the first treatment and thereby improve the QoL of patients. Several epidemiological studies have indicated that the association between LUTS and ED is more than a co-incidence of age, with a possible cause and effect relationship. LUTS is more common in men with ED and there is a strong relationship between the severity of LUTS and the degree of erectile difficulty. Four pathophysiologies have been suggested to explain the relationship between LUTS and ED. There is a complex interaction between these mechanisms and there may be additional processes involved. These are: (1) alteration in nitric oxide levels; (2) autonomic hyperactivity; (3) changes in the Rho-kinase/endothelin pathway; and (4) pelvic vasculature atherosclerosis. Studies of all three easily available PDE-5 inhibitors have shown improvements in both LUTS and ED in men with significant problems in both areas without any substantial increase in side effect profile. Studies have also shown that the greatest improvements occurred with the combination of an alpha blocker and PDE-5 inhibitor when compared with either drug alone. Whilst significant improvements were seen in LUTS symptom scores, there was no significant improvement in flow rates with PDE-5 inhibitors when compared with placebo. High quality basic science studies of PDE-5 inhibitors on bladder muscle and alpha blocker agents on penile cavernosal tissue have provided several explanations for their modes of action. Even so, the mechanism of action of PDE-5 inhibitors in LUTS remains far from certain. More well-designed, placebo-controlled studies are needed to confirm the impact of these drugs, alone or in combination, on both ED and LUTS. However combination therapy appears appropriate for patients with both LUTS and ED. At present though, we should not routinely offer a combination of PDE-5 inhibitors and alpha blocker for the treatment of LUTS alone.

This review study refers to the possibility to employ PDE5 inhibitors as an adjunct tool for the therapeutic management of male infertility. The literature tends to suggest that PDE5 inhibitors enhance the Leydig cell secretory function and play a role in the regulation of the contractility of the tunica albuginea and the epididymis. In addition, the literature suggests that PDE5 inhibitors increase the prostatic secretory function that results in an improvement in sperm motility in several cases. Some studies additionally demonstrate a role of PDE5 inhibitors in the regulation of sperm capacitation process. Additional placebo-controlled, randomized, blind studies are necessary to unequivocally suggest a therapeutic role of PDE5 inhibitors in the alleviation of semen disorders and male infertility.

Phosphodiesterase type-5 (PDE5) inhibitors are widely used as first-line therapy for erectile dysfunction (ED). Their efficacy and safety combined with an increasing understanding of cyclic guanosine monophosphate (cGMP)- regulated mechanisms, have triggered a number of attempts to determine their effects and potential benefits in nonurological conditions. In recent years, extensive and diverse preclinical and clinical evidence has been made available. PDE5 inhibition has shown collateral benefits for a multitude of risk factors or diseases associated with, or accompanying ED. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary arterial hypertension and both sildenafil and tadalafil are approved for this indication. However, PDE5 inhibitors appear to have the potential of further expanding their indications. Importantly, accumulating data show that the therapeutic potential extends to the cardiovascular, gastrointestinal, cutaneous and nervous system and that these agents may be beneficial in a multitude of conditions such as Raynaud's phenomenon, heart failure, essential hypertension and stroke. PDE5 inhibitors are a conceptually attractive therapeutic class of agents with pleiotropic effects. The present review discusses recent findings regarding the effects of PDE5 inhibitors on non-urological conditions and highlights current and future clinical applications beyond ED.

PDE-5 inhibitors were originally studied in cardiovascular indications but were later developed and approved for on-demand treatment of erectile dysfunction (ED). A few years ago sildenafil was approved for the treatment of pulmonary hypertension, thus renewing interest in cardiovascular applications, and tadalafil became available in oncedaily formulations for erectile dysfunction management. Given the wide distribution of phosphodiesterase-5 throughout the body and its involvement in multiple functions, what can one expect in the future? To answer this we reviewed studies involving PDE-5 inhibitors that were published within the past three years and searched the US National Institutes of Health clinical trial registry for ongoing ones. PDE-5 inhibitors are being actively investigated in many disease states, with interest focusing mainly on urology and cardiovascular medicine. In urology erectile dysfunction is the primary target, followed by BPH-related lower urinary tract symptoms. As far as cardiovascular medicine is concerned, treatment of heart failure is the indication where PDE-5 inhibitors seem to be closer to clinical application but preclinical data also support a role in cardiac preconditioning.

Recent progresses in the development of fluorescent technologies become a reliable device for drug discovery research. The fluorescence tools offer attractive options for an opportunity to visualize the effects of drug candidates in the cells. The fluorescent tools, such as fluorescent protein, are regularly used in a range of drug discovery processes. A better understanding and use of fluorescent technologies facilitate drug discovery research faster and can open up new applications. Therefore, we have provided information about some new generation fluorescent reagents (GFP and fluorophores). This review illustrates how fluorescent technologies and fluorescent tools are contributing to the drug discovery process mainly high-throughput screening (HTS), disease mechanism based target discovery, disease-genes-based target discovery, ‘target classes’ based target candidate discovery, physiology-based drug discovery, genomics-based drug discovery, target validation and their future perspectives.

Calcitonin gene-related peptide (CGRP) is a polypeptide produced by alternative processing of calcitonin gene transcripts and is endowed with important systemic physiological effects. The recent characterization of its receptor and the discovery of stable antagonists has addressed them in the indication migraine. Beside this, several studies have been focused on role of CGRP at gastric level. CGRP is considered a marker of afferent fibers in the upper gastrointestinal tract being almost completely depleted following treatment with the selective neurotoxin capsaicin that targets these fibers via transient receptor potential vanilloid of type-1. The exogenous administration of the peptide was able to afford protection against experimental ulcers induced by an increase in gastric secretion. The use of CGRP knockout mice has let to characterize the endogenous role of CGRP showing that the local release of this neuropeptide protects from ethanol injury and favours ulcer healing. Decreased levels of gastric CGRP-like immunoreactivity (li) were observed during acetic acid-, cysteamine-, concentrated ethanol- or water immersion stress-ulcers. Restoration of CGRP-li was found in animals bearing ulcers in healing status and delayed healing in mice knockout to CGRP. CGRP was able to release somatostatin from gastric D cells but its main effects on the stomach homeostasis rely on local vasodilator action during increased acidback diffusion.

Angiogenesis and inflammation are closely integrated processes. Fibroblast growth factor-2 (FGF2) is a prototypic angiogenesis inducer belonging to the family of the heparin-binding FGF growth factors. FGF2 exerts its proangiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. A tight cross-talk exists between FGF2 and the inflammatory response in the modulation of blood vessel growth. Pentraxins act as soluble pattern recognition receptors with a wide range of functions in various pathophysiological conditions. The long-pentraxin PTX3 shares the C-terminal pentraxin-domain with shortpentraxins and possesses a unique N-terminal domain. These structural features indicate that PTX3 may have distinct biological/ligand recognition properties when compared to short-pentraxins. Co-expression of PTX3 and FGF2 has been observed in different inflammation/angiogenesis-dependent diseases. PTX3 binds FGF2 with high affinity and specificity. The interaction prevents the binding of FGF2 to its cognate tyrosine kinase receptors, leading to inhibition of the angiogenic activity of the growth factor. This suggests that PTX3 may exert a modulatory function by limiting the angiogenic activity of FGF2. An integrated approach that utilized PTX3 fragments, monoclonal antibodies, and surface plasmon resonance analysis has identified the FGF2-binding domain in the unique N-terminal extension of PTX3. On this basis, PTX3-derived synthetic peptides have been designed endowed with a significant antiangiogenic activity in vitro and in vivo. They may provide the basis for the development of novel antiangiogenic FGF2 antagonists.