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The coexistence of cardiovascular disease and erectile dysfunction is widespread, possibly owing to underlying endothelial dysfunction in both diseases. Millions of patients with cardiovascular disease are prescribed phosphodiesterase-5 (PDE5) inhibitors for the management of erectile dysfunction. Although the role of PDE5 inhibitors in erectile dysfunction therapy is well established, their effects on the cardiovascular system are unclear. Preclinical studies investigating the effect of PDE5 inhibitors on ischemia–reperfusion injury, pressure overload-induced hypertrophy, and chemotoxicity suggested a possible clinical role for each of these medications; however, attempts to translate these findings to the bedside have resulted in mixed outcomes. In this review, we explore the biologic preclinical effects of PDE5 inhibitors in mediating cardioprotection. We then examine clinical trials investigating PDE5 inhibition in patients with heart failure, coronary artery disease, and ventricular arrhythmias and discuss why the studies likely have yet to show positive results and efficacy with PDE5 inhibition despite no safety concerns. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to investigate the real benefit and safety of phosphodiesterase 5 inhibitor (PDE 5I) for benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) by determining the affecting factors and to overcome the previous meta-analysis studies. Methods: We conducted a systematic review of improvements in LUTS using International Prostate Symptom Score (IPSS), voiding subscore of IPSS (voiding IPSS), storage subscore of IPSS (storage IPSS), quality of life (QoL), maximal urinary flow rate (Qmax), and post-voided residual volume (PVR), and also investigated adverse events and relevant withdrawal rate. Results: Final included studies were 28 studies with 19,820 subjects (9800 treatment group and 10,020 control group). The overall weighted mean differences of total IPSS, voiding IPSS, storage IPSS, and QoL showed significant improvement. Single placebo group showed significant improvement in all outcomes except PVR. The weighted prevalence of overall withdrawal rate and adverse event-specific withdrawal rate was 10 and 3%, respectively. Meta-regression showed that baseline IPSS, dosage of PDE 5I, and country affect clinical improvement compared with placebo. Conclusions: This study clarifies the efficacy of PDE 5I on treatment of BPH/LUTS as an initial treatment strategy. However, baseline IPSS, dosage of PDE 5I and country affected the clinical improvement. Moreover, adverse event-specific withdrawal rate was not as high as suspected based on the overall withdrawal rate. [ABSTRACT FROM AUTHOR]

Renal fibrosis is an important factor for end-stage renal failure. However, only few therapeutic options for its treatment are established. Zaprinast, a phosphodiesterase 5 inhibitor, and serelaxin, the recombinant form of the naturally occurring hormone relaxin, are differently acting modulators of cyclic guanosine monophosphate (cGMP) signaling. Both agents enhance cGMP availability in kidney tissue. These substances alone or in combination might interfere with the development of kidney fibrosis. Therefore, we compared the effects of combination therapy with the effects of monotherapy on renal fibrosis. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) for 7 days in wild-type (WT) and cGKI knockout (KO) mice. Renal antifibrotic effects were assessed after 7 days. In WT, zaprinast and the combination of zaprinast and serelaxin significantly reduced renal interstitial fibrosis assessed by α-SMA, fibronectin, collagen1A1, and gelatinases (MMP2 and MMP9). Intriguingly in cGKI-KO, mRNA and protein expression of fibronectin and collagen1A1 were reduced by zaprinast, in contrast to serelaxin. Gelatinases are not regulated by zaprinast. Although both substances showed similar antifibrotic properties in WT, they distinguished in their effect mechanisms. In contrast to serelaxin which acts both on Smad2 and Erk1, zaprinast did not significantly diminish Erk1/2 phosphorylation. Interestingly, the combination of serelaxin/zaprinast achieved no additive antifibrotic effects compared to the monotherapy. Due to antifibrotic effects of zaprinast in cGKI-KO, we hypothesize that additional cGKI-independent mechanisms are supposed for antifibrotic signaling of zaprinast. [ABSTRACT FROM AUTHOR]

We would like to congratulate the authors for performing such an extensive network meta-analysis for safety and efficacy of phosphodiesterase 5 inhibitors for erectile dysfunction. Keywords: Phosphodiesterase 5 inhibitor; Erectile dysfunction; Network meta-analysis EN Phosphodiesterase 5 inhibitor Erectile dysfunction Network meta-analysis 2815 2816 2 08/05/21 20210701 NES 210701 This comment refers to the article available online at https://doi.org/10.1007/s00345-020-03233-9. Phosphodiesterase 5 inhibitor, Erectile dysfunction, Network meta-analysis. [Extracted from the article]

Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach when starting new drug discovery projects. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compounds' databases. This in silico approach can be combined with physico-chemical parameter filtering based on the property space of the active compounds and 3D virtual screening if the structure of the target protein is available. A multi-step virtual screening procedure was developed and applied to select potential phosphodiesterase 5 (PDE5) inhibitors in real time. The combined 2D/3D in silico method resulted in the identification of 14 novel PDE5 inhibitors with <1 μMIC values and the hit rate in the second in silico selection and in vitro screening round exceeded the 20%. [ABSTRACT FROM AUTHOR]

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Premature ejaculation is the most common male sexual dysfunction. The International Society of Sexual Medicine recently defined premature ejaculation as ejaculation less than about 1 min after penetration, inability to control ejaculation, and resulting negative personal consequences. Evolving treatments target the modulation of the neurobiological causes of the disorder. Current pharmaceuticals focus on aerosolized topical agents, selective serotonin reuptake inhibitors, 5-hydroxytryptamine receptor modulators, and opioid agonists. These emerging medications and the ability to tailor treatments based on genetic information likely will change the paradigm of this disorder and how it will be treated by clinicians. [ABSTRACT FROM AUTHOR]

An efficacy study of tadalafil (5 mg once daily) for treating erectile dysfunction included sexual satisfaction and psychosocial outcome measures such as Treatment satisfaction (THX) domain of Sexual Life Quality Questionnaire, Self-Esteem And Relationship (SEAR) questionnaire, Sexual Encounter Profile questions 4 (SEP4; hardness satisfaction) and 5 (SEP5; overall satisfaction), intercourse satisfaction (IS) and overall satisfaction (OS) domains of International Index of Erectile Function (IIEF), and partner SEP question 3 (pSEP3). After a 4-week run-in phase, participants were randomized to receive either tadalafil (N=264) or placebo (N=78) for 12 weeks. Participants and partners were more satisfied (THX) with tadalafil (75 and 73, respectively) than with placebo (51 and 55, respectively, P<0.001). Statistically significant improvements in sexual relationship, confidence, self-esteem and overall relationship (SEAR), in addition to IS, OS, SEP5 and pSEP3 for tadalafil compared with placebo (P<0.001) correlated with erectile function (EF) improvement (assessed by change from baseline in IIEF-EF score). Tadalafil significantly improved treatment and sexual satisfaction, while improving multiple outcomes measured by SEAR.International Journal of Impotence Research (2009) 21, 240–248; doi:10.1038/ijir.2009.22; published online 18 June 2009 [ABSTRACT FROM AUTHOR]

The phosphodiesterase type 5 (PDE-5) inhibitors are effective in treating erectile dysfunction (ED). ED and heart failure (HF) share similar risk factors, and commonly present together. This association has led to questions ranging from the safety and efficacy of PDE-5 inhibitors in HF patients to a possible role for this class of medication to treat HF patients with or without ED. In addition to endothelial dysfunction, there are causes of ED specific to patients with HF including low exercise tolerance, depression and HF medications. Before treating HF patients with PDE-5 inhibitors, patients should be assessed for their risk of a cardiac event during sexual activity. PDE-5 inhibitors are safe and effective in treating ED in HF patients. An improvement in erectile function by PDE-5 inhibitors was associated with an improvement in quality of life and reduction in depression. Several studies demonstrated the effect of PDE-5 inhibitors on HF per se. PDE-5 inhibitors improved endothelial dysfunction, increased exercise tolerance, decreased pulmonary vascular resistance and pulmonary artery pressure, and increased cardiac index. Several mechanisms whereby PDE-5 inhibitors improve HF have been proposed. PDE-5 inhibitors already have a role in treating primary pulmonary hypertension; however additional studies are needed to determine if they will become a standard therapy for HF patients.International Journal of Impotence Research (2009) 21, 149–157; doi:10.1038/ijir.2009.11; published online 23 April 2009 [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the effect of phosphodiesterase 5 inhibitor, DA-8159, on erectile function throughout the quantitative analysis of vascular endothelial cell, smooth muscle (SM), TGF-ß1 expression in rat corpus cavernosum and measurement of intracavernous pressure (ICP) in diabetic rats. DA-8159 (0, 5, 10, 20?mg/kg) was administered orally once a day to diabetic rats. After 8 weeks, immunohistochemistry and computerized image analysis were performed to quantify the percent area within the Corpora Cavernosa occupied by the endothelial cells, SM cells and fibrotic tissues. ICP/mean arterial pressure (MAP) was also measured by electrostimulation of the cavernous nerve. Diabetic rats showed a significant decrease in the SM and endothelial cell content, and an increase in the TGF-ß1 expression level within the cavernosa areas compared to the normal rats. The mean cavernous SM, endothelial cell content and TGF-ß1 expression level were 9.7±0.7, 4.5±0.7 and 17.9±2.1%, respectively. DA-8159 prevented reduction of SM (12.3±0.4%(5?mg/kg), 13.8±0.4%(20?mg/kg)) and endothelial cell content (5.6±0.5%(5?mg/kg), 6.3±0.6%(20?mg/kg)). Immunoreactivity of TGF-ß1 and intracorporal fibrosis were also significantly lower in DA-8159-treated groups (11.8±1.2%(5?mg/kg), 9.5±1.1%(20?mg/kg)). Electrostimulation of the cavernous nerve induced significant increase in maximum ICP (62.2±13.6?mmHg in 10?mg/kg vs 37.5±17.5?mmHg in diabetic group) and area under the curve of the ratio of ICP/MAP (8891.09±1957 in 10?mg/kg vs 6315.87±2272 in diabetic group). These results suggest that subchronic treatment of DA-8159 can prevent the development of erectile dysfunction (ED), and provides a rationale for the use of DA-8159 as treatment of diabetic ED.International Journal of Impotence Research (2005) 17, 134-141. doi:10.1038/sj.ijir.3901295 Published online 2 December 2004 [ABSTRACT FROM AUTHOR]

DA-8159, a new Phosphodiesterase (PDE) 5 inhibitor, has exhibited potent erectogenic potential in a penile erection test in rats and anesthetized dogs. In this study, we investigated the mechanism of its erectogenic activity by measuring the activity of DA-8159 against a various PDE isozymes and assessing cGMP and cAMP formation in a rabbit corpus cavernosum in vitro. DA-8159 inhibited the PDE 5 activity in rabbit and human platelets, which the IC50 was 5.84± 1.70 nM and 8.25± 2.90 nM, respectively. The IC50 of DA-8159 on PDE 1, PDE2, PDE 3 and PDE 6 were 870±57.4 nM, 101 ± 15 μM, 52.0±3.53 μM and 53.3±2.47 nM, respectively. This suggests that DA-8159 is a potent, highly selective, competitive inhibitor of PDE 5-catalyzed cGMP hydrolysis. The rates of cGMP hydrolysis catalyzed by human platelets-derived PDE 5 as a function of the cGMP concentration (5~100 nM) and two-fixed DA-8159 concentration (11.3 and 18.8 nM) were investigated in order to characterize the mode of PDE 5 inhibition by DA-8159. DA-8159 increased the apparent Km value for cGMP hydrolysis but had no effect on the apparent Vmax, indicating a competitive mode of inhibition. DA-8159 increased the cGMP concentrations in the rabbit corpus cavernosum dose dependently. In the presence of sodium nitroprusside (SNP), DA-8159 significantly stimulated the accumulation of cGMP when compared to the control level. This indicated that the enhancement of a penile erection by DA-8159 involved the relaxation of the cavernosal smooth muscle by NO-stimu-lated cGMP accumulation. In conclusion, DA-8159 is a selective inhibitor of PDE 5-catalyzed cGMP hydrolysis and the enhancement of a penile erection by DA-8159 is mediated by the relaxation of the cavernosal smooth muscle by the NO-stimulated cGMP accumulation. [ABSTRACT FROM AUTHOR]

DA-8159, a new phosphodiesterase 5 inhibitor, was assessed for its erectogenic potential by a penile erection test in rats, the relaxation of isolated rabbit corpus cavernosum (CC), and estimation of the intracavernous pressure (ICP) in the anesthetized dog. Oral administration of DA-8159 (0.3 to 1 mg/kg) increased the number of erections in rats with increasing dosage, with the highest penile erection index at 10 mg/kg. DA-8159 induced the relaxation of phenylephrine (PHE)-induced contractions in the rabbit CC and decreased the IC50 of the nitric oxide donor sodium nitroprusside (SNP) in a dose-dependent fashion. In pentobarbital-anesthetized dogs, the intravenous administration of DA-8159 (1≈300 μg/kg) potentiated the increase in ICP induced by the intracavernosal SNP in a dose-related manner. These findings suggest that DA-8159 has significant therapeutic potential in the treatment of erectile dysfunction. [ABSTRACT FROM AUTHOR]