Proceedings of PRINCETON IV: PDE5 inhibitors and cardiac health symposium.

INTRODUCTION: Prior consensus meetings have addressed the relationship between phosphodiesterase type 5 (PDE5) inhibition and cardiac health. Given significant accumulation of new data in the past decade, a fourth consensus conference on this topic was convened in Pasadena, California, on March 10 and 11, 2023. OBJECTIVES: Our meeting aimed to update existing knowledge, assess current guidelines, and make recommendations for future research and practice in this area. METHODS: An expert panel reviewed existing research and clinical practice guidelines. RESULTS: Key findings and clinical recommendations are the following: First, erectile dysfunction (ED) is a risk marker and enhancer for cardiovascular (CV) disease. For men with ED and intermediate levels of CV risk, coronary artery calcium (CAC) computed tomography should be considered in addition to previous management algorithms. Second, sexual activity is generally safe for men with ED, although stress testing should still be considered for men with reduced exercise tolerance or ischemia. Third, the safety of PDE5 inhibitor use with concomitant medications was reviewed in depth, particularly concomitant use with nitrates or alpha-blockers. With rare exceptions, PDE5 inhibitors can be safely used in men being treated for hypertension, lower urinary tract symptoms and other common male disorders. Fourth, for men unresponsive to oral therapy or with absolute contraindications for PDE5 inhibitor administration, multiple treatment options can be selected. These were reviewed in depth with clinical recommendations. Fifth, evidence from retrospective studies points strongly toward cardioprotective effects of chronic PDE5-inhibitor use in men. Decreased rates of adverse cardiac outcomes in men taking PDE-5 inhibitors has been consistently reported from multiple studies. Sixth, recommendations were made regarding over-the-counter access and potential risks of dietary supplement adulteration. Seventh, although limited data exist in women, PDE5 inhibitors are generally safe and are being tested for use in multiple new indications. CONCLUSION: Studies support the overall cardiovascular safety of the PDE5 inhibitors. New indications and applications were reviewed in depth.

PDE5 inhibition mitigates heart failure in hyperlipidemia.

PDE5 inhibitors was reported to play a protective role in both regulating lipid metabolism and reducing heart failure (HF). This study aimed to clarify the effectiveness of PDE5 inhibitors against hyperlipidemia-related HF by combining evidence from population-based study and animal models. The nationwide cohort study found that post-diagnostic use of PDE5 inhibitors was associated with a significantly lower risk of HF compared with patients who used alprostadil, especially among individuals with hyperlipidemia (adjusted HR = 0.56, 95% CI = 0.40-0.78). In animal models, sildenafil significantly recovered the cardiac structure and function induced by AAB surgery, as well as reversed liver dysfunction and ameliorated hyperlipidemia induced by HFD via reducing the level of ALT, AST and serum lipids. Lipidomic analysis identified four lipid metabolites involved in sildenafil administration, including FA 16:3, LPC O-18:1, DG24:0_18:0 and SE28:1/20:4. This study revealed the protective effect of PDE5 inhibitors against HF in hyperlipidemia, indicating the potential of being repurposed as an adjuvant for HF prevention in patients with hyperlipidemia if these findings can be further confirmed in clinical trials.

The Association between PDE5 Inhibitors and Aneurysm/Arterial Dissection:A Pharmacovigilance Study Using WHO Safety Database.

Aneurysm and arterial dissection have been reported as adverse drug events, associated with angiogenesis inhibitors and fluoroquinolones. Specifically, several cases of severe arterial disease following cGMP-specific phosphodiesterase type 5 (PDE5) inhibitors usage have recently been reported. It is necessary to ascertain the risks of serious adverse events caused by PDE5 inhibitors. We aimed to evaluate the association of aneurysm and artery dissection with PDE5 inhibitors using VigiBase, which is a World Health Organization database of spontaneously reported adverse events, for explorative hypothesis-generating analysis. We performed disproportionality analysis using a dataset from inception in 1967 to December 2022 and calculated reporting odds ratios (ROR) between PDE5 inhibitors and arterial diseases. We extracted 195,839 reports on PDE5 inhibitors with 254 reports of arterial disease as adverse events from VigiBase. Disproportionality analysis showed disproportional signals for PDE5 inhibitors (ROR, 2.30;95% confidence intervals, 2.04-2.61);disproportional signals were detected in analyses restricting the lesion site to the aorta or cerebral arteries. From stratified analysis, disproportional signals were noted in females, as well as males, generally recognized as a risk factor for artery diseases. This real-world data analysis suggests that PDE5 inhibitors may play a role in the development of lethal arterial disease. J. Med. Invest. 71 : 134-140, February, 2024.

Role of Nutraceuticals in Treating Erectile Dysfunction via Inhibition of Phosphodiesterase-5 Enzyme: A Mini Review.

Drug repurposing is an ongoing and clever strategy that is being developed to eradicate tuberculosis amid challenges, of which one of the major challenges is the resistance developed towards antibiotics used in standard directly observed treatment, short-course regimen. Surpassing the challenges in developing anti-tuberculous drugs, some novel host-directed therapies, repurposed drugs, and drugs with novel targets are being studied, and few are being approved too. After almost 4 decades since the approval of rifampicin as a potent drug for drugsusceptible tuberculosis, the first drug to be approved for drug-resistant tuberculosis is bedaquiline. Ever since the urge to drug discovery has been at a brisk as this milestone in tuberculosis treatment has provoked the hunt for novel targets in tuberculosis. Host-directed therapy and repurposed drugs are in trend as their pharmacological and toxicological properties have already been researched for some other diseases making the trial facile. This review discusses the remonstrance faced by researchers in developing a drug candidate with a novel target, the furtherance in tuberculosis research, novel anti-tuberculosis agents approved so far, and candidates on trial including the host-directed therapy, repurposed drug and drug combinations that may prove to be potential in treating tuberculosis soon, aiming to augment the awareness in this context to the imminent researchers.

Application of terahertz Time-Domain spectroscopy and chemometrics-based whale optimization algorithm in PDE5 inhibitor detection.

Combating the illicit use of PDE5 inhibitor drugs is a focal point in forensic science research. In order to achieve rapid identification of such drugs, this study applies terahertz time-domain spectroscopy combined with chemometrics to establish a fast and accurate detection method for PDE5 inhibitors. The optimal detection method is determined by comparing the spectral performance of three optical parameters, namely absorption coefficient, refractive index, and dielectric constant. Linear discriminant models based on different spectral parameters, whale optimization algorithm optimized extreme learning machine models, and whale optimization algorithm optimized random forest models are established. The effectiveness and performance of principal component analysis and competitive adaptive reweighted sampling algorithm for spectral feature data selection are also investigated. The PDE5 inhibitor identification model based on the competitive adaptive reweighted sampling - whale optimization algorithm - random forest (CARS-WOA-RF) model achieves an accuracy of 98.61%, and the identification model for two concentrations of Sildenafil achieves 100% accuracy. The results demonstrate that terahertz time-domain spectroscopy combined with chemometrics can effectively detect various common types of PDE5 inhibitor drugs and different concentrations.

A Review of Combined Phosphodiesterase-5-Inhibitors and α-Blockers versus Phosphodiesterase-5-Inhibitors Alone for Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia.

Guidelines from the American Urological Association (AUA) and the European Association of Urology (EAU) present conflicting recommendations regarding combination therapy of phosphodiesterase 5 inhibitors (PDE5is) with α-blockers to treat benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS). Use of PDE5is is widespread in the population of patients with LUTS/BPH. In this scoping review, we examine the evidence regarding the safety and efficacy of combined PDE5is and α-blockers compared to PDE5i medications alone. A search was conducted using PubMed, Cochrane, and Web of Science to identify manuscripts discussing the safety of PDE5i and α-blockers in combination or comparing this combination to PDE5is alone in the treatment of LUTS/BPH. Study designs, data, and conclusions were qualitatively analyzed. Combination therapy was found to be safe across all studies; importantly, no evidence documents increased risk of hypotension. Most studies reported added improvement in symptom and quality of life scores compared to PDE5i alone, with additional International Prostate Symptom Score (IPSS) change ranging from -1.30 to -8.50 and IPSS quality of life score change ranging from -0.15 to -1.50. Objective metrics such as postvoid residual volumes and maximum flow rate were inconsistently reported. Taken together, the current body of data suggests that combining PDE5i α-blocker therapy is safe and that there are opportunities for additional symptomatic improvement, though it should be utilized for select patients. Situations with particular utility could include patients with comorbid erectile dysfunction or without sufficient improvement on monotherapy.

KEY POINTS combination therapy with PDE5i and α-blockers is more effective than PDE5i medications alone for lowering IPSScombination therapy with PDE5i and α-blockers is not associated with a significantly greater number of adverse events than PDE5i medications alonethe improvements seen in IPSS with combination therapy compared to PDE5i alone may or may not reach the threshold of clinical significancePDE5i and α-blocker combination therapy should be considered a safe regimen that can be used in appropriate clinical situations, like for patients with comorbid ED and those who do not achieve sufficient control of symptoms with a daily PDE5i alone.

Pulmonary hypertension secondary to valvular heart disease: a state-of-the-art review.

Pulmonary hypertension (PH) is a common disease affecting up to 1% of the population and at least 50% of patients diagnosed with heart failure (HF) (Hoeper et al. in Lancet Respir Med 4(4):306-322, 2016). It is estimated that PH is present in 15% to 60% of patients with valvular heart disease (VHD) which can result from an increase in pulmonary blood flow and subsequently in pulmonary venous congestion and pulmonary vascular resistance (PVR). It is important to identify the severity of PH in patients with VHD to appropriately risk stratify and manage these patients (Magne et al. in JACC Cardiovasc Imaging 8(1):83-99, 2015). In this review, we examine the diagnostic criteria for PH and its pathophysiology. We also focus on the growing evidence supporting the presence of PH secondary to VHD and describe the contemporary surgical and medical therapeutic interventions in this patient population (Fig. 1).

Efficacy and safety of PDE5 inhibitors in middle-aged and old patients with and without hypogonadism.

PURPOSE: Although several reviews have evaluated the use of PDE5 inhibitors (PDE5i) for treating erectile dysfunction (ED), their specific use in middle-aged and old patients has not been fully evaluated. Given that elderly patients with ED often have a complex combination of systemic and sexual health risk factors, the safety and efficacy of PDE5i in such a context are hereby reviewed. MATERIALS AND METHODS: A thorough examination of existing literature has been conducted on PubMed. RESULTS: PDE5i has good safety and efficacy, but the situation is more complex for patients with hypogonadism than those with normal testosterone levels, with reduced responsiveness to PDE5i. In this case, combination therapy with testosterone is recommended, safe and effective. CONCLUSIONS: Eliminating or reducing reversible risk factors and controlling or slowing the development of irreversible factors is an important foundation for using PDE5i to treat ED in all patients, especially middle-aged and elderly ones.

Erectile response profiles of men using PDE5 inhibitors combined with intracavernosal injections as part of a penile rehabilitation program after radical prostatectomy.

BACKGROUND: Phosphodiesterase type 5 (PDE5) inhibitor labeling states that these agents should not be used in conjunction with other erectogenic medications for fear of priapism occurring. AIM: We explored the risk of priapism and prolonged erections in men in our post-radical prostatectomy (RP) penile injection program who were using regular PDE5 inhibitor and intracavernosal injections (ICIs) as part of their rehabilitation program. METHODS: The study cohort included men on penile injection therapy who (1) were taking tadalafil 5 mg daily or taking sildenafil 25 mg on noninjection days, (2) had an RP, (3) were using their respective PDE5 inhibitor regularly at the time of penile injection training, and (4) complied with the program instructions regarding penile injection use. Demographics, comorbidity details, PDE5 inhibitor dose and utilization, and injection dose and utilization data were collected. All patients underwent in-office injection training and used trimix (papaverine/phentolamine/prostaglandin E1) as the intracavernosal medication. OUTCOMES: Priapism was defined as a patient self-reported penetration hardness erection ≥4 hours in duration, while prolonged erection was defined as a penetration hardness erection lasting ≥2 hours. RESULTS: A total of 112 tadalafil users and 364 sildenafil users were compared. Mean age and duration post-RP were 62 ± 14 years and 5.2 ± 12 months, respectively, and there was no difference between tadalafil and sildenafil groups. The mean trimix dose was tadalafil 24 ± 24 units and sildenafil 31 ± 37 units (P < .05). Priapism occurred in 2 (1.7%) of 112 tadalafil users and 5 (1.4%) of 364 sildenafil users (P = .47). Excluding those men experiencing priapism on any occasion, those with any reported penetration hardness erection lasting ≥2 hours were 7 (6.3%) of 112 tadalafil users and 12 (3.3%) of 364 sildenafil users (P < .01). A total of 53% of these prolonged erections occurred within the first 6 injections at home (no difference between tadalafil and sildenafil groups). CLINICAL IMPLICATIONS: We emphasize the need for continued monitoring and education on proper injection techniques to minimize the risk of adverse events in ICI and PDE5 inhibitor combination therapy. STRENGTHS & LIMITATIONS: This study has a relatively large patient population with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions for priapism and prolonged erections, enhances the accuracy and reliability of the results. However, there are some limitations, such as social desirability, confounding factors, and recall bias. CONCLUSION: There is no significant difference in the incidence of priapism in an ICI program in which men combine ICI with tadalafil or sildenafil. However, tadalafil patients had a higher rate of prolonged erections, which was found to occur mostly early during the titration phase.

Safety profile and signal detection of phosphodiesterase type 5 inhibitors for erectile dysfunction: a Food and Drug Administration Adverse Event Reporting System analysis.

Background: Phosphodiesterase type 5 inhibitors (PDE5Is) are generally well tolerated but have been associated with uncommon and significant adverse events (AEs). Aim: This study aims to investigate and compare the characteristics of AEs associated with PDE5Is used for erectile dysfunction and identify any safety signals in a postmarketing surveillance database between 2010 and 2021. Methods: A descriptive analysis was conducted for all AEs reported to the Food and Drug Administration Adverse Event Reporting System for 4 PDE5Is-avanafil, sildenafil, tadalafil, and vardenafil-indicated for erectile dysfunction between January 2010 and December 2021. The frequency of the most reported AEs and outcomes were identified. A disproportionality analysis based on proportional reporting ratio (PRR) and reporting odds ratio (ROR) was conducted for the most common and clinically important AEs to identify signals to gain insights into potential differences in safety profiles. Outcomes: The outcome measures of the study are frequency of reported AEs and outcomes following AE. Results: A total of 29 236 AEs were reported for PDE5Is during the study period. The most reported AE was "drug ineffective" with 7115 reports (24.3%). Eight safety signals were detected across the 4 drugs. Key signals were sexual disorders (PRR, 3.13 [95% CI, 2.69-3.65]; ROR, 3.24 [95% CI, 2.77-3.79]) and death (PRR, 3.17 [2.5-4.01]; ROR, 3.211 [2.52-4.06]) for sildenafil, priapism (PRR, 3.63 [2.11-6.24]; ROR, 3.64 [2.12-6.26]) for tadalafil, and drug administration error (PRR, 2.54 [1.84-3.52]; ROR, 2.6 [1.86-3.63]) for vardenafil. The most reported outcomes were other serious events with 6685 events (67.2%) and hospitalization with 1939 events (19.5%). Clinical Implications: The commonly reported AEs and detected signals may guide clinicians in treatment decision making for men with erectile dysfunction. Strengths and Limitations: This is the first comprehensive report and disproportionality analysis on all types of AEs associated with PDE5Is used for erectile dysfunction in the United States. The findings should be interpreted cautiously due to limitations in the Adverse Event Reporting System, which includes self-reports, duplicate and incomplete reports, and biases in reporting and selection. Therefore, establishing a causal relationship between the reported AEs and the use of PDE5Is is uncertain, and the data may be confounded by other medications and indications. Conclusion: PDE5Is demonstrate significantly increased risks of reporting certain clinically important AEs. While these events are not common, it is imperative to continually monitor PDE5I use at the levels of primary care to national surveillance to ensure safe utilization.

Fluorescence "turn-on" sensing for five PDE5 inhibitors in functional food based on bimetallic nanoclusters.

Some phosphodiesterase type-5 (PDE5) inhibitors are active ingredients of prescription drugs that are widely used in the treatment of erectile dysfunction (ED). Recently, a large number of substances with this activity have been developed. Illegal addition of PDE5 inhibitors to foods could lead to cardiovascular diseases and even death, which poses a serious threat to food safety, therefore an on-site rapid screening method is urgently needed. Herein, a host functionalized bimetallic nanoclusters, CD/Au Ag NCs, were synthesized through self-assembly of 6-Aza-2-thiothymine gold nanoclusters (ATT-Au NCs), Arginine silver nanoclusters (Arg-Ag NCs) and carboxymethyl ß-cyclodextrin (ß-CMCD). The introduction of Rhodamine 6G (R6G) could quench the fluorescence of CD/Au Ag NCs based on the inner filter effect (IFE) and fluorescence resonance energy transfer effect (FRET). Importantly, it was discovered that several PDE5 inhibitors exhibited a higher binding affinity to ß-CMCD and could displace R6G binding with CD cavity, which disrupted the fluorescence quenching effects and resulted in the fluorescence recovery of CD/Au Ag NCs. This fluorescence turn-on signal could be utilized for the detection of PDE5 inhibitors. At present, emerging PDE5 inhibitor analogues pose a great challenge to food safety due to their unknown efficacy and safety. The proposed method holds the advantages of high sensitivity, simple probe synthesis, easy operation, and simultaneous detection of multiple PDE5 inhibitors. Meanwhile, the successful application in functional food sample demonstrated its high application potential in multiple PDE5 inhibitors screening.

PDE5 inhibitor drugs for use in dementia.

Alzheimer's disease and related dementias (ADRD) remain a major health-care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase-5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration-approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real-world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half-life, and off-target effects. HIGHLIGHTS: Potent phosphodiesterase-5 (PDE5) inhibitors are in clinical use as vasodilators.In animals PDE5 inhibitors enhance synaptic function and cognitive ability.In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease.Licensed PDE5 inhibitors have potential for repurposing in dementia.Prospective clinical trials of PDE5 inhibitors are warranted.

Exploring the application of sildenafil for high-fat diet-induced erectile dysfunction based on interleukin-18-mediated NLRP3/Caspase-1 signaling pathway.

Background: Inflammation is a key risk factor for heart disease and has also been linked to erectile dysfunction (ED). Sildenafil is a phosphodiesterase type 5 inhibitor with a strong antioxidant effect. Interleukin (IL)-18 is a proinflammatory factor. Excessive production and release of IL-18 disrupt the balance between IL-18 and IL-18 binding proteins in certain inflammatory diseases, leading to the occurrence of pathological inflammation. Aim: We evaluated the effects of sildenafil on erectile function in a rat model of high-fat diet-induced ED. Methods: Male Sprague Dawley rats (6 weeks old) were divided into 5 groups: control, ED, sildenafil, IL-18, and IL-18 + sildenafil. Subsequently, intracavernous pressure and mean arterial pressure were used to assess the erectile function of these rats. The expression of endothelial nitric oxide synthase, pyroptosis factors, and the ratio of smooth muscle cells and collagen fibers were evaluated in the serum and corpora tissue. Outcomes: Exploring the role and mechanism of sildenafil in ED through NLRP3-mediated pyroptosis pathway. Results: In comparison to the ED and IL-18 groups, there were statistically significant increases in the ratio of intracavernous pressure to mean arterial pressure, endothelial nitric oxide synthase expression, and the ratio of smooth muscle cells to collagen fibers following sildenafil intervention (P < .05). The sildenafil group and IL-18 + sildenafil group also showed statistically significant decreases the expression of NLRP3, caspase-1, and gasdermin D (P < .05). Clinical Implications: Sildenafil can improve erectile dysfunction by inhibiting inflammation. Strengths and Limitations: Strengths are that the relationship between pyroptosis and ED has been verified through in vitro and in vivo experiments. The limitation is that the conclusions drawn from animal and cells experiments need to be confirmed in clinical research. Conclusion: Sildenafil may reduce the effect of IL-18-induced inflammation in high-fat diet-induced ED rats through NLRP3/caspase-1 pyroptosis pathway.

The potential therapeutic effect of phosphodiesterase 5 inhibitors in the acute ischemic stroke (AIS).

Acute ischemic stroke (AIS) is a focal neurological disorder that accounts for 85% of all stroke types, due to occlusion of cerebral arteries by thrombosis and emboli. AIS is also developed due to cerebral hemodynamic abnormality. AIS is associated with the development of neuroinflammation which increases the severity of AIS. Phosphodiesterase enzyme (PDEs) inhibitors have neuro-restorative and neuroprotective effects against the development of AIS through modulation of the cerebral cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP)/nitric oxide (NO) pathway. PDE5 inhibitors through mitigation of neuroinflammation may decrease the risk of long-term AIS-induced complications. PDE5 inhibitors may affect the hemodynamic properties and coagulation pathway which are associated with thrombotic complications in AIS. PDE5 inhibitors reduce activation of the pro-coagulant pathway and improve the microcirculatory level in patients with hemodynamic disturbances in AIS. PDE5 inhibitors mainly tadalafil and sildenafil improve clinical outcomes in AIS patients through the regulation of cerebral perfusion and cerebral blood flow (CBF). PDE5 inhibitors reduced thrombomodulin, P-selectin, and tissue plasminogen activator. Herein, PDE5 inhibitors may reduce activation of the pro-coagulant pathway and improve the microcirculatory level in patients with hemodynamic disturbances in AIS. In conclusion, PDE5 inhibitors may have potential roles in the management of AIS through modulation of CBF, cAMP/cGMP/NO pathway, neuroinflammation, and inflammatory signaling pathways. Preclinical and clinical studies are recommended in this regard.

Optimizing metabolic stability of phosphodiesterase 5 inhibitors: Discovery of a potent N-(pyridin-3-ylmethyl)quinoline derivative targeting synaptic plasticity.

Phosphodiesterase 5 (PDE5) is a cyclic guanosine monophosphate-degrading enzyme involved in numerous biological pathways. Inhibitors of PDE5 are important therapeutics for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). We previously reported the first generation of quinoline-based PDE5 inhibitors for the treatment of AD. However, the short in vitro microsomal stability rendered them unsuitable drug candidates. Here we report a series of new quinoline-based PDE5 inhibitors. Among them, compound 4b, 8-cyclopropyl-3-(hydroxymethyl)-4-(((6-methoxypyridin-3-yl)methyl)amino)quinoline-6-carbonitrile, shows a PDE5 IC50 of 20 nM and improved in vitro microsomal stability (t1/2 = 44.6 min) as well as excellent efficacy in restoring long-term potentiation, a type of synaptic plasticity to underlie memory formation, in electrophysiology experiments with a mouse model of AD. These results provide an insight into the development of a new class of PDE5 inhibitors for the treatment of AD.

A review on pharmacological options for the treatment of erectile dysfunction: state of the art and new strategies.

INTRODUCTION: Erectile dysfunction (ED) affects between 12.9% and 28.1% of men worldwide, presenting a strong aged-correlated prevalence. Several pharmacological treatments are currently available for ED, which can be classified into oral, injection, and topical/intraurethral therapies. AREAS COVERED: Extensive research on PubMed/MEDLINE until February 2023 was performed. For each of the aforementioned drug classes, available molecules, and formulations, their efficacy and most common adverse events as well as general guidelines on prescription were investigated and extensively described. A glimpse into future directions regarding ED pharmacotherapy is also present. EXPERT OPINION: In recent years, there have been significant developments in pharmacological treatments for ED. It is essential for physicians to identify the best treatment option for patients based on their preferences and sexual habits. The treatment approach for ED has shifted from a sequential to a parallel paradigm, where all treatment options are available as first-line therapies. While there are promising regenerative therapies for ED, such as shockwaves and platelet-rich plasma injections, pharmacological treatment is still the most effective option for most patients.

Long-Term Outcomes of Drug-Eluting Stent Implantation for Patients With Atherosclerotic Erectile Dysfunction not Responding to PDE-5-Inhibitors.

PURPOSE: Endovascular therapy of erection-related arteries was shown to be a promising treatment option for patients with severe erectile dysfunction. Purpose of this study was to assess the longer-term safety and clinical success rate of endovascular revascularization of erection-related arteries with the Angiolite BTK stent in patients with arteriogenic erectile dysfunction. MATERIALS AND METHODS: A total of 147 consecutive men (63.5±9.3 years) with erectile dysfunction due to 345 atherosclerotic lesions underwent endovascular revascularization. Patients received an International Index of Erectile Function (IIEF)-15 questionnaire at 30.3±7.2 months (follow-up [FU] period no less than 18 months) after stenting. An improvement by 4 points in the erectile function domain consisting of 6 questions (IIEF-6) was defined as minimal clinically important difference (MCID). RESULTS: Technical success was achieved in 99% of lesions. One major adverse event occurred after endovascular revascularization. Sixty-eight (46%) patients completed their latest FU at least 18 months following the last intervention. Minimal clinically important difference was achieved in 54% (37/68) of patients. CONCLUSIONS: In patients with arteriogenic erectile dysfunction not responding to phosphodiesterase-5-inhibitors (PDE-5-Is), endovascular therapy with a novel thin-strut sirolimus-eluting stent is a safe and effective treatment option during short- and longer-term FU. CLINICAL IMPACT: Patients with severe erectile dysfunction profit greatly from endovascular therapy of erection-related arteries. Stable clinical outcomes are seen beyond a 1-year timeframe. It is proven that, the drug-eluting stent therapy for atherosclerotic ED in patients who have not responded to PDE-5-I therapy is safe and effective during longer-term follow-up.

PDE5 inhibitors and gastric mucosa: implications for the management of peptic ulcer disease.

Peptic ulcer disease (PUD) continues to be a cause of significant morbidity and mortality worldwide. Almost two-thirds of PUD cases are asymptomatic. In symptomatic patients, epigastric pain is the most common presenting symptom of PUD, which is manifested by nausea, abdominal fullness, bloating, and dyspepsia. Most PUD cases are associated with the use of COX inhibitors or Helicobacter pylori infection, or both. The traditional management of PUD includes the use of proton pump inhibitors to reduce the gastric acid secretion and antibacterial drugs to combat H. pylori. Timely diagnosis and treatment of PUD are vital to reduce the risk of associated morbidity and mortality, as is prevention of PUD among patients at high risk, including COX inhibitors users and those infected with H. pylori. PDE5 inhibitors have been used for the management of erectile dysfunction and pulmonary hypertension for decades. In recent years, studies have mentioned tremendous pleiotropic effects of PDE5 inhibitors on gastrointestinal, urogenital, musculoskeletal, reproductive, cutaneous, and neurologic disorders. Recent data shows that PDE5 inhibition augments gastric mucosa protection, and here, we review the most recent findings regarding the use of PDE5 inhibitors for the prevention and management of PUD.

Pyrazolopyrimidinone Based Selective Inhibitors of PDE5 for the Treatment of Erectile Dysfunction.

Continuing research with our earlier finding of sildenafil based analogs in the search of new inhibitors of PDE5 for erectile dysfunction suggested that there is a scope of modifications at N-methylpiperazine ring with hydrophobic region followed by hydrogen bond donor or acceptor region. However, the leads identified earlier had some limitations like poor pharmacokinetic (PK) profile, low aqueous solubility and poor bioavailability. In this direction, a new series of sildenafil based analogs were designed, synthesized and screened for their PDE5 inhibitory activity. In this series compound 18 was found to have excellent in vitro activity with selectivity towards PDE5 isozyme, also the in vivo activity and pharmacokinetic profile was excellent. The cyp inhibition and CaCO2 permeability was also excellent for compound 18.

The POWER saga from 2007 to 2022: An example of a sexual enhancement dietary supplement tainted by different adulterants and still on the market.

Ten POWER dietary supplements, chronologically called tabs, pills then caps, and advertised as 100% natural aphrodisiacs, were analyzed by 1H NMR from 2007 to 2022. They were all tainted by PDE-5 inhibitors. Eight different adulterants were identified (sildenafil (1), sildenafil analogues (6), and vardenafil analogue (1)). Their amounts ranged from 15 to 145 mg/capsule. Four supplements contained at least 100 mg/capsule of PDE-5 inhibitor or analogue, the maximal recommended dose of sildenafil. The nature of the adulterant has changed over time, probably to evade its detection by regulatory agencies routine screening tests. Despite several warnings and/or seizures from several European food and/or health authorities, the dietary supplement POWER is still on sale on the Internet, thus demonstrating the impossibility of controlling this market. Faced with this situation, the consumer should be better informed by establishing at the European level a public database of tainted dietary supplements on the model of that of the US Food and Drug Administration. It should indicate the product name, its photo, the adulterant name, and be easily accessible to everyone.