Off-target effect of high-dose sildenafil on adenosine 5'- diphosphate and collagen-induced platelet activation through mitogen-activated protein kinase pathway in treated BALB/C mice and in vitro experiments: A preliminary study.

ABSTRACT: Sildenafil, a common over-the-counter pill often self-administered at high doses for erectile dysfunction, has been reported to rarely cause prothrombotic events and sudden cardiac death in a few case reports. Therefore, we investigated the in vitro and in vivo effect of sildenafil treatment and dosage on platelet activation and mitogen-activated protein kinase (MAPK) phosphorylation. BALB/C mice were segregated into four groups, each having four mice each (control, low [3.25 mg/kg], medium [6.5 mg/kg], and high [13 mg/kg] sildenafil), and after the treatment, blood was drawn from each mouse and washed platelets prepared. Washed platelets were incubated with CD41 PE-Cy7 and Phospho-p38 MAPK PE antibodies and analyzed using a flow cytometer for platelet activation and adenosine 5'- diphosphate (ADP)/collagen-induced MAPK phosphorylation. Washed platelets obtained from the venous blood of 18 human volunteers, were incubated with PAC-1 FITC and Phospho-p38 MAPK PE antibodies, and platelet activation (ADP and collagen), followed by flow cytometry analysis. There was a significant increase in both platelet activation as well as MAPK phosphorylation in the presence of collagen in the high-dose (13 mg/kg) sildenafil group (P = 0.000774). Further, increased platelet activation was observed in samples that were treated with high-dose sildenafil as compared to the untreated samples (P < 0.00001). These studies show the risk of prothrombotic episodes in patients on high-dose sildenafil (100 mg), in those with even mild endothelial dysfunction due to ADP, and collagen-induced platelet activation through MAPK phosphorylation, which was not seen in the low-and intermediate-dose cohorts.

Conservative treatment of Peyronie's disease: a guide.

PURPOSE: To review the literature on the topic, to suggest a common line of treatment applicable across a wide community of specialists, and to contribute in maintaining the high level of interest in this disease. METHODS: A comprehensive and exhaustive review of the literature was performed, identifying hundreds of articles on the topic. RESULTS: Peyronie's disease is a condition that has been recognized, studied, and treated for centuries; despite this, if one excludes surgery in cases in which the deformity is stable, no clear treatment (or line of treatment) is available for complete relief of signs and symptoms. Treatment options were divided into local, oral, and injection therapy, and a wide variety of drugs, remedies, and options were identified. CONCLUSIONS: Low-intensity extracorporeal shock wave therapy, vacuum therapy, penile traction therapy, phosphodiesterase type 5 inhibitors, hyaluronic acid, and collagenase of Clostridium histolyticum may be recommended only in specific contexts. Further studies on individual options or potential combinations are required.

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.

Prognostic Value and Determinants of High-Sensitivity Cardiac Troponin T in Patients With a Systemic Right Ventricle: Insights From the SERVE Trial.

BACKGROUND: The determinants and prognostic value of high-sensitivity cardiac troponin T (hs-cTnT) among patients with a systemic right ventricle are largely unknown. METHODS AND RESULTS: Ninety-eight patients from the randomized controlled SERVE (Effect of Phosphodiesterase-5 Inhibition With Tadalafil on Systemic Right Ventricular Size and Function) trial were included. The correlation between baseline hs-cTnT concentrations and biventricular volumes and function quantified by cardiac magnetic resonance or cardiac multirow detector computed tomography was assessed by adjusted linear regression models. The prognostic value of hs-cTnT was assessed by adjusted Cox proportional hazards models, survival analysis, and concordance statistics. The primary outcome was time to the composite of clinically relevant arrhythmia, hospitalization for heart failure, or all-cause death. Median age was 39 (interquartile range, 32-48) years, and 32% were women. Median hs-cTnT concentration was 7 (interquartile range, 4-11) ng/L. Coefficients of determination for the relationship between hs-cTnT concentrations and right ventricular end-systolic volume index and right ventricular ejection fraction (RVEF) were +0.368 (P=0.046) and -0.381 (P=0.018), respectively. The sex- and age-adjusted hazard ratio for the primary outcome of hs-cTnT at 2 and 4 times the reference level (5 ng/L) were 2.89 (95% CI, 1.14-7.29) and 4.42 (95% CI, 1.21-16.15), respectively. The prognostic performance quantified by the concordance statistics for age- and sex-adjusted models based on hs-cTnT, right ventricular ejection fraction, and peak oxygen uptake predicted were comparable: 0.71% (95% CI, 0.61-0.82), 0.72% (95% CI, 0.59-0.84), and 0.71% (95% CI, 0.59-0.83), respectively. CONCLUSIONS: Hs-cTnT concentration was significantly correlated with right ventricular ejection fraction and right ventricular end-systolic volume index in patients with a systemic right ventricle. The prognostic accuracy of hs-cTnT was comparable to that of right ventricular ejection fraction and peak oxygen uptake predicted. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03049540.

Phosphodiesterase 5A regulates the vomeronasal pump in mice.

The vomeronasal organ (VNO) is a specialized chemoreceptive structure in many vertebrates that detects chemical stimuli, mostly pheromones, which often elicit innate behaviors such as mating and aggression. Previous studies in rodents have demonstrated that chemical stimuli are actively transported to the VNO via a blood vessel-based pumping mechanism, and this pumping mechanism is necessary for vomeronasal stimulation in behaving animals. However, the molecular mechanisms that regulate the vomeronasal pump remain mostly unknown. In this study, we observed a high level of expression of phosphodiesterase 5A (PDE5A) in the vomeronasal blood vessel of mice. We provided evidence to support the potential role of PDE5A in vomeronasal pump regulation. Local application of PDE5A inhibitors-sildenafil or tadalafil-to the vomeronasal organ (VNO) reduced stimulus delivery into the VNO, decreased the pheromone-induced activity of vomeronasal sensory neurons, and attenuated male-male aggressive behaviors. PDE5A is well known to play a role in regulating blood vessel tone in several organs. Our study advances our understanding of the molecular regulation of the vomeronasal pump.

Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients. METHODS: Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation. RESULTS: Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway. CONCLUSION: Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.

Phosphodiesterase type 5 inhibitors related hearing impairment: a real world study based on the FDA adverse event reporting system.

Recent studies focused on exploring phosphodiesterase type 5 inhibitors (PDE5Is)-related hearing impairment. This study aimed to comprehensively explore real-world hearing impairment associated with PDE5Is based on the US Food and Drug Administration Adverse Event Reporting System (FAERS). The characteristics and correlation of PDE5Is-related hearing impairment reported in the FAERS database from the fourth quarter of 2003 to the second quarter of 2023 were analyzed using disproportionality analysis. The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) were used to analyze the adverse events (AEs) of hearing impairment. A total of 1,438 reported cases of hearing impairment were associated with four PDE5Is, revealing statistically significant reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) with the SMQ. The average age of all patients was more than 55 years, over 70% of AEs were reported in men. Most of the reported cases were from the United States. Reports for all the drugs indicated an increase since 2008, except for avanafil. This study showed that the disability rates of PDE5Is were 8.14-40%, the rates of initial or prolonged hospitalization were 6.21-10.24%, and the rates of required intervention were 3.31-9.45%. The pharmacovigilance study identified a potential risk of hearing impairment associated with PDE5Is, indicating the need for continuous monitoring and appropriate management.

Possible retinotoxicity of long-term vardenafil treatment.

Phosphodiesterase (PDE) inhibitors - such as vardenafil - are used primarily for treating erectile dysfunction via increasing cyclic guanosine monophosphate (cGMP) levels. Recent studies have also demonstrated their significant cardioprotective effects in several diseases, including diabetes, upon long-term, continuous application. However, PDE inhibitors are not specific for PDE5 and also inhibit the retinal isoform. A sustained rise in cGMP in photoreceptors is known to be toxic; therefore, we hypothesized that long-term vardenafil treatment might result in retinotoxicity. The hypothesis was tested in a clinically relevant animal model of type 2 diabetes mellitus. Histological experiments were performed on lean and diabetic Zucker Diabetic Fatty rats. Half of the animals were treated with vardenafil for six months, and the retinal effects were evaluated. Vardenafil treatment alleviated rod outer segment degeneration but decreased rod numbers in some positions and induced changes in the interphotoreceptor matrix, even in control animals. Vardenafil treatment decreased total retinal thickness in the control and diabetic groups and reduced the number of nuclei in the outer nuclear layer. Müller cell activation was detectable even in the vardenafil-treated control animals, and vardenafil did not improve gliosis in the diabetic group. Vardenafil-treated animals showed complex retinal alterations with improvements in some parameters while deterioration in others. Our results point towards the retinotoxicity of vardenafil, even without diabetes, which raises doubts about the retinal safety of long-term continuous vardenafil administration. This effect needs to be considered when approving PDE inhibitors for alternative indications.

Fixed-dose combination therapy in pulmonary arterial hypertension: Pros & cons.

Quality of life of patients suffering from chronic diseases is inevitably conditioned by the number of pills taken during the day. To improve patients' tolerability, compliance and quality of life and reduce healthcare costs, pharmaceutical companies are focusing on the commercialization of fixed-dose combination (FDC) therapies. The last ESC/ERS guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend initial dual combination therapy for newly diagnosed patients at low or intermediate mortality risk. In this regard, polypills including an endothelin receptor antagonist (ERA) and a phosphodiesterase 5 inhibitor (PDE5-i) could represent an useful therapeutic strategy, although with some limitations. To date, evidence about the use of FDCs in PAH is limited but future studies evaluating their safety and efficacy are welcome.

Role of Aortic Stiffness in Predicting Response to Phosphodiesterase-5 Inhibitors in the Treatment of Erectile Dysfunction. / Papel da Rigidez Aórtica na Previsão da Resposta aos Inibidores da Fosfodiesterase-5 no Tratamento da Disfunção Erétil.

BACKGROUND: It is known that aortic stiffness (AS) increases in patients with erectile dysfunction (ED). Phosphodiesterase type-5 (PDE-5) enzyme inhibitors are used in the treatment of ED, and patients' responses to this treatment may vary. OBJECTIVES: We aimed to investigate the role of AS in predicting the response of patients planned to take PDE-5 enzyme inhibitors due to ED. METHODS: A total of 96 male patients with ED were included in the study. The International Index of Erectile Function (IIEF) questionnaire was used to evaluate the presence and severity of ED and the response to treatment. Transthoracic echocardiography was used to evaluate AS. RESULTS: There was a statistically significant difference between the aortic strain and aortic distensibility values of the study groups (p<0.001). The delta IIEF score had a high level of positive correlation with aortic strain (p<0.01, r=0.758) and a moderate level of positive correlation with aortic distensibility (p<0.01, r=0.574). CONCLUSION: We determined that in patients with ED, aortic strain and aortic distensibility measured non-invasively using transthoracic echocardiography are important parameters in predicting patients' response to PDE-5 inhibitor therapy.

FUNDAMENTO: Sabe-se que a rigidez aórtica (RA) aumenta em pacientes com disfunção erétil (DE). Os inibidores da enzima fosfodiesterase tipo 5 (PDE-5) são usados no tratamento da DE, e as respostas dos pacientes a esse tratamento podem variar. OBJETIVOS: Nosso objetivo foi investigar o papel da RA na previsão da resposta de pacientes planejados para tomar inibidores da enzima PDE-5 devido à DE. MÉTODOS: Um total de 96 pacientes do sexo masculino com DE foram incluídos no estudo. O questionário do Índice Internacional de Função Erétil (IIEF) foi utilizado para avaliar a presença e gravidade da DE e a resposta ao tratamento. A ecocardiografia transtorácica foi utilizada para avaliar RA. RESULTADOS: Houve diferença estatisticamente significativa entre os valores de deformação aórtica e distensibilidade aórtica dos grupos de estudo (p<0,001). O escore delta IIEF apresentou alto nível de correlação positiva com a deformação aórtica (p<0,01, r=0,758) e um nível moderado de correlação positiva com a distensibilidade aórtica (p<0,01, r=0,574). CONCLUSÃO: Determinamos que em pacientes com DE, a deformação aórtica e a distensibilidade aórtica medidas de forma não invasiva por meio de ecocardiografia transtorácica são parâmetros importantes na previsão da resposta dos pacientes à terapia com inibidores da PDE-5.

PKC Inhibition Improves Human Penile Vascular Function and the NO/cGMP Pathway in Diabetic Erectile Dysfunction: The Role of NADPH Oxidase.

Erectile dysfunction (ED) is a frequent and difficult-to-treat condition in diabetic men. Protein kinase C (PKC) is involved in diabetes-related vascular and cavernosal alterations. We aimed to evaluate the role of PKC in endothelial dysfunction and NO/cGMP impairment associated with diabetic ED in the human corpus cavernosum (CC) and penile resistance arteries (PRAs) and the potential mechanisms involved. Functional responses were determined in the CC and PRAs in patients with non-diabetic ED and diabetic ED undergoing penile prosthesis insertion. PKC activator 12,13-phorbol-dibutyrate (PDBu) impaired endothelial relaxations and cGMP generation in response to acetylcholine in the CC from non-diabetic ED. PDBu also impaired responses to a PDE5 inhibitor, sildenafil, in non-diabetic ED patients. Conversely, a PKC inhibitor, GF109203X, improved endothelial, neurogenic, and PDE5-inhibitor-induced relaxations and cGMP generation only in the CC in diabetic ED patients. Endothelial and PDE5-inhibitor-induced vasodilations of PRAs were potentiated only in diabetes. Improvements in endothelial function in diabetes were also achieved with a specific inhibitor of the PKCß2 isoform or an NADPH-oxidase inhibitor, apocynin, which prevented PDBu-induced impairment in non-diabetic patients. PKC inhibition counteracted NO/cGMP impairment and endothelial dysfunction in diabetes-related ED, potentially improving response to PDE5 inhibition.

Major adverse cardiovascular events related to phosphodiesterase 5 inhibitors: analysis of real-life data from Eudra-Vigilance database.

BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5i) are the standard medical treatment for erectile dysfunction. Aim of our study was to evaluate the rate of major adverse cardiovascular events (MACE) reported during PDE5i treatment based on Eudra-Vigilance (EV) reports. METHODS: EV database is the system for managing and analyzing data on suspected adverse reactions to medicines which have been authorized or being studied in clinical trials in the European Economic Area. MACE are defined as non-fatal stroke, non-fatal myocardial infarction, non-fatal congestive heart failure, revascularization after aorto-coronary graft bypass and cardiovascular death. We recorded the number of MACE for sildenafil, tadalafil, vardenafil, avanafil per category and severity until 1st July 2023. Pooled Relative Risk (PRR) was used to compare data between drugs. RESULTS: Overall, 951 MACE events were reported. Most of them were observed in younger patients <65 years old (452/951 events, 48%). Overall, 377/8939 (4%) MACE events were observed for sildenafil, 221/5213 (4%) for tadalafil, 50/1029 (4%) for vardenafil and no events for avanafil. No significative differences were reported comparing sildenafil and tadalafil (PRR 0.71-0.99, IQR 0.61-1.35, P>0.05), neither sildenafil vs. vardenafil (PRR 0.68-0.79, IQR 0.43-1.55, P>0.05), neither tadalafil vs. vardenafil (PRR 0.77-0.95, IQR 0.64-1.30. P>0.05) even when compared for age. Comparison between different classes of age showed MACE were more frequent in patients younger than 65 years old taking sildenafil and tadalafil when compared to patients older than 85 years old (PRR 0.02-0.11. IQR 0.01-0.40. P<0.01) and when compared to patients in 65-85 class of age (PRR 0.02-0.12, IQR 0.01-0.95, P<0.01). CONCLUSIONS: Real life data is consistent with MACE related to PDE5i. PDE5is are infrequently (<5%) associated with MACE. However, risk seems higher in younger patients, particularly for sildenafil (452/951 events, 48%). Clinicians should consider these data when prescribing PDE5i especially in young patients.

Bifunctional Sildenafil Diazeniumdiolates Acting as Phosphodiesterase 5 Inhibitors and Nitric Oxide Donors- Towards Wound Healing.

Inefficient wound healing poses a global health challenge with a lack of efficient treatments. Wound healing issues often correlate with low endogenous nitric oxide (NO) levels. While exogenous delivery with NO-releasing compounds represents a promising therapeutic strategy, controlling the release of the highly reactive NO remains challenging. Phosphodiesterase 5 (PDE5) inhibitors, like sildenafil, have also been shown to promote wound healing. This study explores hybrid compounds, combining NO-releasing diazeniumdiolates with a sildenafil-derived PDE5 inhibitor. One compound demonstrated a favorable NO-release profile, triggered by an esterase (prodrug), and displayed in vitro nanomolar inhibition potency against PDE5 and thrombin-induced platelet aggregation. Both factors are known to promote blood flow and oxygenation. Thus, our findings unveil promising prospects for effective wound healing treatments.

Association of sildenafil use with age-related macular degeneration: a retrospective cohort study.

OBJECTIVE: Despite significant advances in clinical care and understanding of the underlying pathophysiology, age-related macular degeneration (AMD)-a major cause of global blindness-lacks effective treatment to prevent the irreversible degeneration of photoreceptors leading to central vision loss. Limited studies suggest phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may prevent AMD by increasing retinal blood flow. This study explores the potential association between sildenafil use and AMD risk in men with erectile dysfunction using UK data. METHODS AND ANALYSIS: Using the UK's IQVIA Medical Research Data, the study analysed 31 575 men prescribed sildenafil for erectile dysfunction and no AMD history from 2007 to 2015, matched with a comparator group of 62 155 non-sildenafil users in a 1:2 ratio, over a median follow-up of approximately three years. RESULTS: The primary outcome was the incidence of AMD in the two groups. The study found no significant difference in AMD incidence between the sildenafil users and the non-users, with an adjusted hazard ratio (HR) of 0.99 (95% CI 0.84 to 1.16), after accounting for confounders such as age, ethnicity, Townsend deprivation quintile, body mass index category, and diagnosis of hypertension and type 2 diabetes. CONCLUSION: The study results indicated no significant association between sildenafil use and AMD prevention in UK men with erectile dysfunction, suggesting sildenafil's protective effect on AMD is likely insignificant.

Medical Advancements in Benign Prostatic Hyperplasia Treatments.

PURPOSE OF REVIEW: This review aims to identify and summarize the current literature on the most recent therapeutic agents and combination strategies for the medical management of lower urinary tract symptoms resulting from benign prostatic hyperplasia. RECENT FINDINGS: The latest advancements in BPH therapy have been in combination strategies. Alpha blockers continue to be the mainstay of treatment, but research is exploring the synergistic benefits of combining them with 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase-5 (PDE5) inhibitors, and beta-3 agonists. The alpha-blocker + 5-ARI combination remains ideal for enlarged, significantly reducing clinical progression risk compared to monotherapy. Alpha-blocker + PDE5 inhibitor combinations appear safe and potentially beneficial for men with concomitant erectile dysfunction; sildenafil might hold an edge over tadalafil based on limited data. Beta-3 agonists show synergistic effects with alpha blockers for residual storage symptoms, offering similar efficacy to anticholinergics but with a better side effect profile.

Rapid screening and identification of targeted and non-targeted illegal added drugs in functional foods by MRSIT-HRMS based on NIST screening database.

The last few decades have witnessed the increasing consumption of functional foods, leading to the expansion of the worldwide market. However, the illegal addition drugs in functional foods remains incessant despite repeated prohibition, making it a key focus of strict crackdowns by regulatory authorities. Effective analytical tools and procedures are desperately needed to rapidly screen and identify illegally added drugs in a large number of samples, given the growing amount and diversity of these substances in functional foods. The MRSIT-HRMS (Multiple Sample Rapid Introduction combined with High Resolution Mass Spectrometry) without chromatographic separation, after direct sampling, utilizes NIST software (National Institute of Standards and Technology) matching with a home-built library to target identification and non-targeted screen of illegal additives. When applied to 50 batches of suspicious samples, the targeted method detected illegal added drugs in 41 batches of samples, while the non-targeted method screened a new phosphodiesterase-5 (PDE-5) inhibitor type structural derivative. The positive results obtained by the targeted method were consistent with LC-MS/MS (QQQ). The novel MRSIT-HRMS with a limit of quantification (LOD) of 1 µg/mL achieved 100 % correct identification for all 50 batches of actual samples, demonstrating its potential as a highly promising and powerful tool for fast screening of illegally added drugs in functional food, especially when compared to traditional LC-MS/MS methods. This is essential for ensuring drug safety and public health.

Sildenafil delays bone remodeling of fractured femora in aged mice by reducing the number and activity of osteoclasts within the callus tissue.

The elderly exhibit a reduced healing capacity after fracture, which is often associated with delayed or failed bone healing. This is due to a plethora of factors, such as an impaired bone vascular system and delayed angiogenesis. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil exerts pro-angiogenic and pro-osteogenic effects. Hence, we herein investigated in aged mice whether sildenafil can improve fracture healing. For this purpose, 40 aged CD-1 mice (16-18 months) were daily treated with 5 mg/kg body weight sildenafil (n = 20) or vehicle (control, n = 20) by oral gavage. The callus tissue of their femora was analyzed at 2 and 5 weeks after fracture by X-ray, biomechanics, micro-computed tomography (µCT), histology, immunohistochemistry as well as Western blotting. These analyses revealed a significantly increased bone volume and higher ratio of callus to femoral bone diameter in sildenafil-treated mice at 5 weeks after fracture when compared to controls. This was associated with a reduced number and activity of osteoclasts at 2 weeks after fracture, most likely caused by an increased expression of osteoprotegerin (OPG). Taken together, these findings indicate that sildenafil does not improve fracture healing in the elderly but delays the process of bone remodeling most likely by reducing the number and activity of osteoclasts within the callus tissue.

The association of tadalafil exposure with lower rates of major adverse cardiovascular events and mortality in a general population of men with erectile dysfunction.

BACKGROUND: Tadalafil is a long-acting phosphodiesterase-5 inhibitor (PDE-5i) indicated for erectile dysfunction (ED). HYPOTHESIS: Our hypothesis was that tadalafil will reduce the risk of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction, coronary revascularization, unstable angina, heart failure, stroke) and all-cause death in men with ED. METHODS: A retrospective observational cohort study was conducted in a large US commercial insurance claims database in men with a diagnosis of ED without prior MACE within 1 year. The exposed group (n = 8156) had ≥1 claim for tadalafil; the unexposed group (n = 21 012) had no claims for any PDE-5i. RESULTS: Primary outcome was MACE; secondary outcome was all-cause death. Groups were matched for cardiovascular risk factors, including preventive therapy. Over a mean follow-up of 37 months for the exposed group and 29 months for the unexposed group, adjusted rates of MACE were 19% lower in men exposed to tadalafil versus those unexposed to any PDE-5i (hazard ratio [HR] = 0.81; 95% confidence intervals [CI] = 0.70-0.94; p = .007). Tadalafil exposure was associated with lower adjusted rates of coronary revascularization (HR = 0.69; 95% CI = 0.52-0.90; p = .006); unstable angina (HR = 0.55; 95% CI = 0.37-0.81; p = .003); and cardiovascular-related mortality (HR = 0.45; CI = 0.22-0.93; p = .032). Overall mortality rate was 44% lower in men exposed to tadalafil (HR = 0.56; CI = 0.43-0.74; p < .001). Men in the highest quartile of tadalafil exposure had the lowest rates of MACE (HR: 0.40; 95% CI: 0.28-0.58; p < .001) compared to lowest exposure quartile. CONCLUSION: In men with ED, exposure to tadalafil was associated with significant and clinically meaningful lower rates of MACE and overall mortality.