Phosphodiesterase-5 Inhibitors Research Articles

The effect of Sildenafil, a phosphodiesterase-5 inhibitor, on tendon healing: an experimental study in rat model of achilles tendon injury.

Sildenafil Citrate has various effects on the body, including widening blood vessels, inhibiting platelet aggregation, promoting the growth of blood vessels, stimulating apoptosis and adhesion of fibroblasts, and reducing inflammation. This research aims to explore how Sildenafil Citrate affects surgically treated Achilles tendons, both in terms of tissue structure and mechanical properties. Forty-eight Wistar-albino rats weighing 350-400g were randomly divided into groups, 6 in each group, as the study group was given Sildenafil Citrate and the control group given saline, respectively. The Achilles tendon rupture model was created under ketamine and xylazine anesthesia. During the entire experiment, rats were housed in eight separate cages, six of them each. The study group and control group of the first group were sacrificed at the end of 1week, and Achilles tendon samples were taken. After that, Achilles tendon samples were taken after sacrificing the second group at 14days, the third group at 21days, and the fourth group at 28days, respectively. Neovascularization, inflammation, fibrosis and fibroblastic activities of the harvested Achilles tendons were evaluated histopathologically. Biomechanically, stretching was applied to the Achilles tendons and continued until the tendon ruptured. the maximum force values at the moment of rupture were calculated. The mean maximum strength value of group T21, which was given sildenafil citrate for 21days, was 31.1 ± 4.36 N, and the mean maximum strength value of group C21, which was the control group, was 20.56 ± 6.92 N. A significant difference was observed between the groups (p: 0.008). Group T28 (45.17 ± 5.54 N) also demonstrated greater strength than group C28 (34.62 ± 3.21 N) in the comparison (p: 0.004). The study also noted significant differences between the groups in neovascularization, in the first week, 1 mild, 3 moderate and 2 prominent neovascularization was observed in group T7, in group T28, moderate neovascularization was observed in 4 specimens and prominent neovascularization was observed in 2 specimens (p: 0.001). Furthermore, the groups showed significant differences in their levels of fibrosis, inflammation and fibroblastic proliferation (p: 0.017, p: 0.036, (p: 0.035) respectively). Study has demonstrated that sildenafil citrate can enhance the biomechanical and histopathological aspects of tendon healing, resulting in a stronger tendon.

Histopathology and electron microscopy evaluation of the sildenafil effect on diabetic rats' retinae.

Although there is increasing evidence that phosphodiesterase-5 (PDE-5) inhibitors modify the effect of diabetes on different tissues, its effect on diabetic retinopathy is not well studied. Forty male Sprague-Dawley (SD) rats were divided into four groups: group I = control group that received no treatment; group II (diabetic group), in which diabetes was induced by a single streptozotocin injection; group III (sildenafil small dose, SSD), in which diabetes was similarly introduced (however, rats received daily oral 1 mg/kg sildenafil citrate (SC) for 3 months); and group IV (sildenafil large dose, SLD), which was as in group 3, but SC was 2.5 mg/kg. After 3 months, globes were removed and retinae were dissected; one globe from each rat was examined by light microscopy (LM), and the other by electron microscopy (EM). In contrast to the control group, diabetic rats in group II demonstrated well-established diabetic changes in the form of capillary congestion, decreased cell population, hyaline changes of capillary walls, and degenerated nerve fiber layer by LM. Similarly, EM demonstrated photoreceptor degeneration, mitochondrial cristolysis, and vacuolated depleted cells among other features in group II. These diabetic features were less prominent in group III and nearly absent in group IV. SC use in the early stages of DR may prevent/delay diabetic retinopathy development or progression in diabetic rat models, an effect that seems to be dose-related.

Modulating NO-GC Pathway in Pulmonary Arterial Hypertension.

The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.

The Complexity of Bariatric Patient's Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass.

Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1-5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery.

A drug target for erectile dysfunction to help improve fertility, sexual activity, and wellbeing: mendelian randomisation study

ObjectiveTo investigate the association of genetically proxied (using a surrogate biomarker) inhibition of phosphodiesterase 5 (PDE5), an established drug target for erectile dysfunction, with fertility, sexual behaviour, and subjective wellbeing.DesignTwo...

Identifying Phosphodiesterase-5 Inhibitors with Drug Repurposing Approach: Implications in Vasodysfunctional Disorders.

Phosphodiesterase type 5 (PDE5) is a multidomain protein that plays a crucial role in regulating cellular cyclic guanosine monophosphate (cGMP), a key signaling molecule involved in various physiological processes. Dysregulation of PDE5 and cGMP signaling is associated with a range of vasodysfunctional disorders, necessitating the development of effective therapeutic interventions. This study adopts comprehensive approach, combining virtual screening and molecular dynamics (MD) simulations, to repurpose FDA-approved drugs as potential PDE5 inhibitors. The initial focus involves selecting compounds based on their binding affinity. Shortlisted compounds undergo a meticulous analysis for their drug profiling and biological significance, followed by the activity evaluation and interaction analysis. Notably, based on binding potential and drug profiling, two molecules, Dutasteride and Spironolactone, demonstrate strong potential as PDE5 inhibitors. Furthermore, all atom MD simulations were employed (500 ns) to explore dynamic behavior of Dutasteride and Spironolactone in complexes with PDE5. Principal components analysis (PCA) and free energy landscape (FEL) analyses are further leveraged to decipher that the binding of Dutasteride and Spironolactone stabilizes the structure of PDE5 with minimal conformational changes. In summary, Dutasteride and Spironolactone exhibit remarkable affinity for PDE5 and possess characteristics that suggest their potential as therapeutic agents for conditions associated with PDE5 dysfunction.

Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility.

Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants. The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001. After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs. PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.

The effectiveness of medical penile rehabilitation after radical prostatectomy

Background. Among the drug methods of penile rehabilitation in patients after nerve-sparing prostatectomy, the use of phosphodiesterase-5 (PDE-5) inhibitors is proposed as the first line of therapy, which have shown high efficiency, ease of use, good tolerability and safety, improving the quality of life of patients.Aim. To evaluate the effectiveness of drug-induced penile rehabilitation after nerve-sparing prostatectomy in the restoration of erectile function (EF) with an analysis of the factors influencing it.Materials and methods. The study included 108 patients with localized prostate cancer who underwent nerve-sparing prostatectomy. All patients were randomized into two groups. In Group 1 patients did not receive drug therapy for the prevention and treatment of erectile dysfunction. In Group 2 patients in the postoperative period received daily PDE-5 inhibitors (tadalafil) at a minimum dosage of 5 mg for 12 months as a drug therapy. Initially and at the annual stage of the study, the state of EF, erectile rigidity, night penile test, and quality of life were assessed. An analysis was also made of the factors affecting the preservation of EF one year after nerve-sparing radical prostatectomy.Results. The best reliable results in terms of maintaining EF at the annual stage of the study were obtained in the group whose patients received postoperative drug therapy with PDE-5 inhibitors. It was possible to identify the most significant factors influencing the state of EF in the postoperative period after radical prostatectomy: the type of operation – bilateral nerve sparing, taking PDE-5 inhibitors, the patient’s age, the presence/absence of diabetes mellitus, the state of EF (International Index of Erectile Function-5 value) before the operation.Conclusion. Daily intake of PDE-5 inhibitors at a low dose of 5 mg is indicated for patients after nerve-sparing prostatectomy as an effective means of penile rehabilitation in order to preserve EF, as it provides better results compared to no drug therapy. Patients who meet criteria such as young age, no diabetes, high preoperative International Index of Erectile Function-5 levels may benefit most from nerve-sparing surgical techniques and early postoperative participation in a penile rehabilitation program for erectile dysfunction.

Randomized Controlled Double Blind Feasibility Trial of Tadalafil with Hydroxyurea Versus Hydroxyurea with Placebo for Secondary Prevention of Recurrent Priapism in Men with Sickle Cell Anemia: Pin Trial Final Results

Background: Recurrent ischemic priapism is a common complication of sickle cell anemia (SCA) with devastating sequelae of sexual dysfunction, reported at least once in 33% of men, with no evidence-based preventive treatment. Pre-clinical and observational studies with inadequate power have shown the potential benefits of phosphodiesterase-5 (PDE-5) inhibitors in preventing future priapism in transgenic mouse models and humans. Therefore, we hypothesized that a trial of PDE-5 inhibitor (tadalafil) for the prevention of priapism in men with SCA would be feasible, with an acceptable safety profile. Methods: We conducted a randomized, controlled, double-blind phase 2 feasibility trial to assess the composite primary outcome of recruitment, retention, and adherence rates of at least 75%. With a sample size of ³30 and an observed compliance rate of 83% and higher, we would obtain a lower bound of 75.6% or greater (above our lowest acceptable rate of 75% recruitment, retention, and adherence) using the Clopper-Pearson formula. The clinical outcomes were priapism rate (person-month), priapism pain intensity (1-5 Likert scale), priapism duration (minutes), and hospitalization for pain. The trial included men with SCA aged 18 to 40 years who had experienced a minimum of three priapism episodes, each lasting at least an hour, in the past 12 months, Figure 1. After satisfying the eligibility criteria and signing informed consent, the participants passed through a screening phase (2-4 weeks) and were subsequently randomized 1:1 into a treatment arm (tadalafil 5mg/day and hydroxyurea 20mg/kg/day) and standard care/placebo arm (hydroxyurea 20mg/kg/day and placebo). The treatment phase lasted 4 to 12 months, with priapism episodes tracked by: 1) daily text messages to each participant and 2) a paper diary to complement the daily text messages. The data was analyzed based on the intention to treat using negative binomial regression. The trial was approved by the IRB of Vanderbilt University Medical Center and Aminu Kano Teaching Hospital. The protocol was registered with Clinicaltrials.gov (NCT05142254) and PACTR (PACTR202105561969346). Results: The trial opened on 13th April 2022 and was stopped by the Data Safety and Monitoring Board on 12th June 2023 due to futility, based on the data as of 27 th February 2023. All 84 men approached for the trial consented to screening (100% recruitment rate), but only 64 (76.2%) met the eligibility criteria and were randomized, Figure 1. Thirty-two participants received the treatment in each arm. One participant was dropped by the investigator for non-compliance. Two participants (one in each arm) died before the trial completion (but none of the deaths was related to the investigational drugs), and 61 completed the trial (30 in the tadalafil arm and 31 in the placebo arm) The median age was 27.2 years and 23.3 years in the tadalafil and placebo arm, respectively, Table 1. The trial's retention rate and compliance rate to monthly visits were 98.6% and 97.4%, respectively. Based on pill count, the adherence rates to taladafil and hydroxyurea were 93% and 94%, respectively. The rates of priapism during the trial treatment period per month were 3.1 and 2.7 in the tadalafil and placebo arms, respectively; the incidence rate ratio (IRR) was 1.21 (95% CI: 0.52-2.80; p= 0.654). Serious adverse events, acute pain rate, hospitalizations, and emergency visits were not significantly different between the two arms. Conclusions: Our phase 2 trial's primary outcome results (recruitment, retention, and adherence rates) strongly support the feasibility of conducting a definitive phase RCT phase 3 trial for secondary priapism prevention in a low-resource setting where 50% of the global SCA births are located. Although not the primary intent of the phase 2 trial, we did not provide evidence that tadalafil with hydroxyurea was superior to hydroxyurea alone for secondary priapism prevention. We will continue to recommend a fixed dose of 20 mg/kg/day hydroxyurea therapy for secondary priapism prevention.

Breast Cancer Resistance Protein Limits Fetal Transfer of Tadalafil in Mice

Tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, is a candidate therapeutic agent for fetal growth restriction and hypertensive disorders of pregnancy. In this study, we elucidated the fetal transfer of tadalafil in comparison with that of sildenafil, the first PDE5 inhibitor to be approved. We also examined the contributions of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) to fetal transfer. Tadalafil or sildenafil was administered to wild-type, Mdr1a/b-double-knockout or Bcrp-knockout pregnant mice by continuous infusion from gestational day (GD) 14.5 to 17.5, and the fetal-to-maternal plasma concentration ratio of unbound drug (unbound F/M ratio) was evaluated at GD 17.5. The values of unbound F/M ratio of tadalafil and sildenafil in wild-type mice were 0.80 and 1.6, respectively. The unbound F/M ratio of tadalafil was increased to 1.1 and 1.7 in Mdr1a/b-knockout and Bcrp-knockout mice, respectively, while the corresponding values for sildenafil were equal to or less than that in wild-type mice, respectively. A transcellular transport study revealed that basal-to-apical transport of both tadalafil and sildenafil was significantly higher than transport in the opposite direction in MDCKII-BCRP cells. Our research reveals that tadalafil is a newly identified substrate of human and mouse BCRP, and it appears that the fetal transfer of tadalafil is, at least in part, attributed to the involvement of BCRP within the placental processes in mice. The transfer of sildenafil to the fetus was not significantly constrained by BCRP, even though sildenafil was indeed a substantial substrate for BCRP.

Post-infection erectile dysfunction risk - comparing COVID-19 with other common acute viral infections: a large national claims database analysis.

It is unknown if the risk of erectile dysfunction (ED) following Coronavirus-19 (COVID-19) infection is virus-specific. Our study assessed the risk of ED in COVID-19 patients as compared to patients with other common viral infections. The TriNetX COVID-19 Research Network was queried. We examined cohorts of men aged ≥18 years infected with: COVID-19, influenza, respiratory syncytial virus, enterovirus, acute viral hepatitis, mononucleosis, and herpes zoster. Men were included if they had at least one outpatient follow-up visit within 18 months and excluded if they had one of the other viruses of interest or a prior ED diagnosis or treatment, prostatectomy, pelvis radiation, or chronic hepatitis infection. Cohorts were propensity score matched and compared for differences in new ED diagnosis and/or prescription of phosphodiesterase-5 inhibitors (PDE5i). COVID-19 positive men were less likely to develop ED or have a PDE5i prescription than men with infected with herpes zoster [Relative Risk(RR): 0.37, 95% Confidence Interval (CI) 0.27-0.49] and more likely to develop ED or have a PDE5i prescription than men with no acute viral illness (RR: 1.33, 95% CI 1.25-1.42). In this national propensity-matched cohort study comparing post-infection ED risk and PDE5i prescriptions, we found that COVID-19 was no more likely to result in a diagnosis of ED or prescription of PDE5i when compared to all acute viral illnesses except herpes zoster, which was more likely to result in a diagnosis of ED or prescription of PDE5i when compared to COVID-19. These findings suggest an inflammatory etiology (perhaps due to cytokine release, endothelial dysfunction, or blunted hormone signaling) behind any acute infection can result in a heightened ED risk; however, further studies are required to investigate the connection between other viral infections and ED.

Patient and Therapeutic Profiles of Pulmonary Hypertension in Chronic Lung Diseases in Japan: A Cohort Study Using a Claims Database.

Pulmonary hypertension (PH) is often complicated by chronic lung diseases (CLDs) such as chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Differentiating between PH associated with CLD (group3 PH) and pulmonary arterial hypertension (PAH) in CLD is often difficult and reporting on the efficacy of PAH-specific therapies is inconsistent as a result of the lack of understanding of the heterogeneity of patients with PH. A retrospective observational cohort study was conducted to understand the baseline characteristics, comorbidities, and treatment profiles of patients with PH in CLD in a real-world setting using a large-scale claims database (Medical Data Vision). Administrative and clinical data for patients admitted to acute-care hospitals in Japan between April 2008 and January 2021 were analyzed. A total of 115,921 patients with CLD (109,578 with COPD and 6343 with ILD, of whom 569 and 176 had PH, respectively) were analyzed. This study found lower PH diagnosis rates among patients with COPD and patients with ILD than in previous studies. The majority of PH with CLDpatients were elderly (mean age 75.7years) and male (80.81%). Among patients with CLD prescribed PAH-specific therapies (105 patients with COPD; 64 patients with ILD), most received these as monotherapy (COPD, 84.76%; ILD, 75.56%); the most common were phosphodiesterase5 inhibitors (COPD, 42.70%; ILD, 18.37%), prostacyclins (oral; COPD, 48.31%; ILD, 24.49%), and endothelin receptor antagonists (ERA) (COPD, 8.99%; ILD, 18.37%). Comorbidities (e.g., pulmonary, cardiac, kidney), home oxygen therapy (HOT), and echocardiography (ECHO) were factors associated with the diagnosis of PH. This is the first study using an administrative database that provides real-world data on patients with PH in CLD in Japan. Our results indicate that PH may be misdiagnosed or underdiagnosed in Japan which may lead to suboptimal treatment for patients, and supports the need for further evidence to guide appropriate treatment.

Adults with congenital heart disease and pulmonary arterial hypertension: Quantitative assessment of haemodynamic parameters under disease targeting therapy - A retrospective multicentre analysis

Abstract Background Pulmonary arterial hypertension (PAH) occurs in approximately 10% of adults with congenital heart disease (ACHD), usually develops secondary to intra- or extra-cardiac shunts resulting in pressure and/or volume overload in the pulmonary circulation, and is associated with increased morbidity and mortality. Treatment strategies for PAH-ACHD include disease targeting therapies (DTT), such as phosphodiesterase-5 inhibitors (PDE5i) and endothelin receptor antagonists (ERA). Data regarding the impact of DTT on cardiopulmonary haemodynamics in PAH-ACHD are scarce. Purpose Aim of this study was to quantify effects of DTT on cardiopulmonary haemodynamics (assessed by right heart catheterisation [RHC]) and on key non-invasive functional parameters contributing to ESC/ERS risk status in PAH-ACHD patients, as applied in real-world clinical practice. Methods We retrospectively analysed the effect of DTT in PAH-ACHD patients who had undergone RHC in adulthood at baseline (treatment-naïve) between 2000 and 2022, with at least one follow-up RHC during DTT, in six expert centres in Europe. Clinical characteristics (WHO functional class [WHO-FC], 6-minute walking distance [6MWD], N-terminal pro-brain natriuretic peptide [NTproBNP] and measures of RHC (systemic/ pulmonary cardiac output, systolic/diastolic/mean pulmonary arterial pressure [sPAP, dPAP, mPAP], and pulmonary arterial wedge pressure [PAWP]) were collected. Pulmonary vascular resistance/arterial compliance (PVR+PAC) and stroke volume index (SVI) were calculated. Results 44 patients (70% female, mean age 45±15 years) were included. Underlying CHD was a pre- or post-tricuspid shunt in 35% and 63%, respectively. 14% had complex CHD, 7% had innate left heart disease, and 21% presented with Eisenmenger´s syndrome. At baseline 71% were in WHO-FC III/IV, 6MWD was 371±105 m, and NTproBNP was 673 [446–1021] ng/l. On RHC, mPAP was 58±15 mmHg, PVR 11 [7–17] wood units (WU), SVI 32 [27–44] ml/min/m2, CI 2.7±1.0 l/min/m2, and PAC 1.0 [0.7–1.4] ml/mmHg. DTT was started in all patients after baseline RHC. 81% received monotherapy (34% PDE5i, 66% ERA) and 19% received upfront combination therapy (PDE5i+ERA). Follow-up RHC was performed 15 [5–33] months after baseline RHC. At follow-up, WHO-FC and NTproBNP (562 [428-762] ng/l) significantly improved (p&amp;lt;0.001 and p=0.021, respectively), as did hemodynamic measures: mPAP (53±15 mmHg, p&amp;lt;0.001), PVR (9 [5–10] WU, p&amp;lt;0.001), SVI (37 [30–49] ml/min/m2, p=0.010), PAC (1.3 [1.0–1.7] ml/mmHg, p&amp;lt;0.001), and CI (3.1±1.1 l/min/m2, p=0.001). In contrast, 6MWD showed subtle change (379±111 m, p=0.164). After follow-up RHC, DTT was escalated in 78% of patients. Conclusions In PAH-ACHD patients, DTT was associated with a moderate but sustained haemodynamic and functional improvement after 15 months. Repeat RHC triggered treatment escalation in most patients. Therefore, ongoing vigilance for PAH-ACHD patients and subsequent treatment optimisation is warranted.

Abstract 13680: Assessing the Role of Phosphodiesterase-5 Inhibitors in the Management of Left Ventricular Assist Device Patients: A Systematic Review and Meta-Analysis

Introduction: The advent of left ventricular assist device (LVAD) therapy revolutionized the management of severe heart failure. Right ventricular failure (RVF) remains a principal cause of mortality among these patients. Previous reports suggest phosphodiesterase-5 inhibitors (PDE-5is) can decrease pulmonary pressure, enhance ventricular function, and lower the risk of thrombosis and stroke. Nonetheless, certain studies present conflicting data, indicating potential increases in bleeding and mortality among patients using PDE-5is. Hypothesis: This study aimed to assess the outcomes of LVAD patients who were administered PDE-5is. Methods: A comprehensive search of PubMed/Medline, EMBASE, Cochrane, Web of Science, Scopus, and grey literature was conducted until January 2022. We included studies that directly compared outcomes of LVAD patients who used PDE-5is versus those who did not. Primary outcomes focused on postoperative RVF and all-cause mortality, while secondary outcomes included stroke, gastrointestinal bleeding, and pump thrombosis. The statistical analysis was performed using "R" statistical computing software (version 4), utilizing the metafor and meta packages. Results: Eight studies encompassing 3035 PDE-5i users and 3023 non-users were included in our analysis. PDE-5i use was not significantly associated with postoperative RVF (RR: 0.84; 95% CI 0.58-1.21, P=0.35; I2 = 83.2%). Similarly, there was no significant correlation between PDE-5i use and all-cause mortality (RR: 0.99; 95% CI 0.96-1.02, P=0.75; I2 = 0%), pump thrombosis (RR: 0.66; 95% CI 0.61-0.72, P=0.45; I2 = 0%), stroke (RR: 0.96; 95% CI 0.84-1.08, P=0.58; I2 = 0%), or gastrointestinal bleeding (RR: 1.13; 95% CI 0.77-1.67, P=0.65; I2 = 0%). Conclusions: Our analysis suggests that PDE-5i use is not associated with increased adverse outcomes such as bleeding, stroke, thrombosis, or all-cause mortality in LVAD patients. However, given the heterogeneity of the included studies and a lack of robust evidence supporting PDE-5i use, high-quality randomized controlled trials are needed to assess the potential benefits, efficacy, and safety of PDE-5is in reducing RVF, thrombosis, and all-cause mortality in LVAD patients.

Abstract 18596: Sildenafil Modulates Metabolic Remodeling by Increasing Fatty Acid β-Oxidation in Single Ventricle Congenital Heart Disease

Introduction: Sildenafil, a phosphodiesterase-5 inhibitor (PDE5i), is used to treat heart and circulatory failure (HF) in single ventricle congenital heart disease (SV). We previously demonstrated that human SVHF myocardium is characterized by increased PDE5 activity and impaired mitochondrial energetics, which are improved with PDE5i. Using an in vitro model in combination with SV myocardial tissue, we test the hypothesis that mitochondrial fatty acid β-oxidation (FAO) is improved with PDE5i therapy via activation of sirtuin-3 (Sirt3) and resulting protein deacetylation. Methods: Primary cardiomyocytes (neonatal rat ventricular myocytes, NRVMs) were treated with 2% serum from SVHF patients or non-failing (NF) controls +/-PDE5i (72 hours). To mechanistically interrogate whether PDE5i acts via Sirt3, we utilized siRNAs against Sirt3 +/-PDE5i. FAO was directly assessed via the Seahorse Bioanalyzer (Agilent). Mitochondrial protein levels and acetylation profiles were quantified via Western blot. Sirt3 activity was measured in isolated mitochondria from SVHF myocardium using a fluorescent-based enzymatic assay. Statistical analysis was performed using a Welch ANOVA with post-hoc Dunnett’s multiple comparisons test (FAO) or a paired T test (Sirt3 activity). Results: NRVMs treated with SVHF serum have impaired mitochondrial FAO and while PDE5i therapy results in improved FAO, siRNA knockdown of Sirt3 abolishes the PDE5i protective effect (A). Mitochondria isolated from SVHF myocardium are hyperacetylated, and ex vivo PDE5i treatment enhances Sirt3 deacetylase activity (B-C), and deacetylates mitochondrial proteins. Conclusions: SVHF serum treatment of cardiomyocytes is a novel in vitro platform for mechanistic investigations of SV-related pathophysiology. These data suggest PDE5i directly augments mitochondrial FAO via Sirt3-mediated protein deacetylation and provides important insight into the myocardial specific mechanisms of PDE5i.

Phosphodiesterase 5 inhibitors (PDE5i) for the treatment of Raynaud's phenomenon.

Raynaud's phenomenon is a vasodilatory phenomenon characterised by digital pallor, cyanosis, and pain of the extremities. Primary Raynaud's phenomenon has no underlying disease associated with it, while secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis. Systemic sclerosis causes fibrosis and commonly affects the skin and internal organs such as the gastrointestinal tract, lungs, kidney, and heart. Phosphodiesterase 5 inhibitors (PDE5i) are a class of drugs that increases blood flow to the extremities and may be beneficial in the treatment of Raynaud's phenomenon. To assess the benefits and harms of PDE5i compared to placebo for the treatment of Raynaud's phenomenon. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial registries up to June 2022. We did not apply any language restrictions. We searched the bibliographies of retrieved articles and contacted key experts in the field for additional and unpublished data. Randomised controlled trials (RCTs) comparing PDE5i to placebo in people with primary and secondary Raynaud's phenomenon. We used standard methodological procedures expected by Cochrane. This review included nine RCTs which ranged in duration from four to eight weeks and included a total of 411 participants. The majority had Raynaud's phenomenon secondary to systemic sclerosis. Tadalafil was assessed in four studies, sildenafil in three studies, vardenafil in one study, and a new PDE5 inhibitor known as "PF-00489791" in one study. Three studies were parallel design and six studies were cross-over. The frequency of attacks per week was 24 with placebo and PDE5i reduced the frequency of attacks by an average of three attacks per week (mean difference (MD) -3.07, 95% confidence interval (CI) -5.15 to -1.00; 8 studies; low-certainty evidence). The duration of attacks per day was 55 minutes with placebo and PDE5i reduced the duration of attacks by an average of five minutes (MD -5.31, 95% CI -8.90 to -1.71; 8 studies; low-certainty evidence). Very low-certainty evidence from one study with eight participants showed severity of Raynaud's attacks (assessed on a 10 cm visual analogue scale with lower scores indicating less severity) was 20% lower with a PDE5i (3.7 with placebo compared to 1.6 with treatment; MD -2.1, 95% CI -2.7 to 1.4; very low-certainty evidence). Pain and patient global assessment were assessed on a 10 cm visual analogue scale with lower scores indicating improvement. Low-certainty evidence showed that the use of PDE5i may result in little to no difference compared to placebo in reducing the average pain of Raynaud's attacks (3 to 2.9; MD -0.10, 95% CI -0.78 to 0.57; 4 studies). Global scores were 36% lower with the use of a PDE5i compared to placebo (9.2 to 5.6; MD -3.59, 95% CI -4.45 to -2.73; 1 study, 24 participants; low-certainty evidence). The rate of withdrawals during treatment with PDE5i ranged from 4% to 20% compared with 2% in the placebo group in five studies. Four studies reported no withdrawals due to adverse events. Seven studies reported no serious adverse events. The rate of serious adverse events reported in two studies ranged from 2% during treatment to 4% with placebo. The majority of the studies were judged as low or unclear risk of bias for selection, performance, and detection bias. Almost half were judged at high risk of attrition bias and unclear risk for selective reporting bias. We downgraded frequency of attacks, duration of attacks, pain intensity, and patient global assessment for small sample sizes and concerns about inconsistency and graded each as low certainty of evidence. We downgraded severity of attacks to very low certainty due to serious concerns about imprecision and publication bias. We downgraded withdrawals due to adverse events and serious adverse events to moderate certainty of evidence due to a low number of reported events. Based on low-certainty evidence, PDE5i may reduce the frequency of attacks of Raynaud's phenomenon by a small amount per week, result in a small reduction in the duration of attack, improve patients' global assessment of their disease, and result in little to no difference in pain. PDE5i probably result in little or no difference in serious adverse events but slightly increase the likelihood of withdrawing from treatment due to an adverse event.

Phosphodiesterase-5 inhibitors tadalafil and sildenafil potentiate nitrergic-nerve mediated relaxations in the bladder vasculature

Recent studies suggest that lower urinary tract dysfunction may arise due to changes in local perfusion. Phosphodiesterase-5 inhibitors can improve urinary bladder blood flow, although the local mechanisms have not been fully elucidated. The aim was to pharmacologically characterise the vascular supply to the bladder and determine the mechanisms underlying the effects of the phosphodiesterase-5 inhibitors tadalafil and sildenafil. Responses of isolated rings of porcine superior vesical arteries to electrical field stimulation (EFS) were measured in the absence and presence of inhibitors of key neurotransmitter systems. Vasodilation responses to nitric oxide (NO) donors were also recorded, and the effects of phosphodiesterase-5 inhibitors on all responses determined. EFS caused biphasic responses with an initial vasoconstriction and a slower developing vasodilation. Vasoconstriction was mediated by ATP (55%) and noradrenaline (45%) release, whilst vasodilation was reduced by L-NNA (100 μM) (80%) and propranolol (1 μM) (20%). The nitrergic component was inhibited (81%) by L-NPA, a selective inhibitor of neuronal nitric oxide synthase (nNOS). Endothelial removal did not affect vasodilation. Tadalafil and sildenafil depressed noradrenaline-evoked vasoconstriction (by 26.8% and 35.5% respectively, P < 0.01), enhanced vasodilation to EFS (by 27.8% and 51.8% respectively, p < 0.01) and enhanced responses to NO donors nitroprusside, SIN-1, and SNAP, increasing pIC50 values (P < 0.01), without affecting maximal responses. In conclusion, neuronal NOS has a predominant role in regulating vascular tone of the porcine superior vesical artery and potentiation of nNO-mediated vasodilation is the primary mechanism underlying effects of phosphodiesterase-5 inhibitors in the bladder vasculature.

Current and future strategies for targeting the endothelin pathway in cardiovascular disease.

The first endothelin (ET)-1 receptor antagonist was approved for clinical use over 20 years ago, but to date this class of compounds has been limited to treating pulmonary arterial hypertension, a rare disease. Translational research over the last 5 years has reignited interest in the ET system as a therapeutic target across the spectrum of cardiovascular diseases including resistant hypertension, microvascular angina and post-coronavirus disease 2019 conditions. Notable developments include approval of a new ETA receptor antagonist and, intriguingly, combining the actions of ETA and an angiotensin II type 1 receptor antagonist within the same novel small molecule. Combinations of ET receptor blockers with other drugs, including phosphodiesterase-5 inhibitors and sodium-glucose co-transporter-2 antagonists, may drive synergistic benefits with the prospect of alleviating side effects. These new therapeutic strategies have the potential to dramatically widen the scope of indications targeting the ET-1 pathway.

Improving Erectile Dysfunction Management Among Asian Men With Diabetes Using the Knowledge Translation Intervention.

Erectile dysfunction (ED) is frequently undermanaged due to communication barriers, particularly among Asian men. We looked at how ED discussion and treatment were affected by the patient's prompt sheet and the Knowledge Translation Tools in the Management of Erectile Dysfunction (LASTED). We conducted a quasi-experimental study in a primary care clinic in Kedah, Malaysia involving 120 Asian men with diabetes. In the intervention group, patients were given a prompt sheet to indicate their intention to discuss or receive ED treatment, and physicians were provided with LASTED to assist with ED consultation. The control group patients received standard care from their physicians. The intervention increased the initiation of ED discussion up to 66.7% compared with 8.3% in the control group. In the intervention group, 57.5% of patients were prescribed phosphodiesterase-5 inhibitors and men with ED of moderate severity were more likely to be prescribed oral ED medication. Use of the LASTED flipchart was associated with prescription of phosphodiesterase-5 inhibitors (P = .011) and patient satisfaction with ED consultation (P <.001). Our study suggests that using the LASTED flipchart and patient's prompt sheet together may encourage ED conversation and medication prescription particularly when working with Asian men who frequently view ED as a taboo subject.

Combined Inhibition of Phosphodiesterase-5 and -9 in Experimental Heart Failure

BackgroundIntracellular second messenger cyclic guanosine monophosphate (cGMP) mediates bioactivity of the natriuretic peptides and nitric oxide, and is key to circulatory homeostasis and protection against cardiovascular disease. Inhibition of cGMP-degrading phosphodiesterases (PDEs) PDE5 and PDE9 are emerging as pharmacological targets in heart failure (HF). ObjectivesThe present study investigated dual enhancement of cGMP in experimental HF by combining inhibition of PDE-5 (P5-I) and PDE-9 (P9-I). MethodsEight sheep with pacing-induced HF received on separate days intravenous P5-I (sildenafil), P9-I (PF-04749982), P5-I+P9-I, and vehicle control, in counterbalanced order. ResultsCompared with control, separate P5-I and P9-I significantly increased circulating cGMP concentrations in association with reductions in mean arterial pressure (MAP), left atrial pressure (LAP), and pulmonary arterial pressure (PAP), with effects of P5-I on cGMP, MAP, and PAP greater than those of P9-I. Only P5-I decreased pulmonary vascular resistance. Combination P5-I+P9-I further reduced MAP, LAP, and PAP relative to inhibition of either phosphodiesterase alone. P9-I and, especially, P5-I elevated urinary cGMP levels relative to control. However, whereas inhibition of either enzyme increased urine creatinine excretion and clearance, only P9-I induced a significant diuresis and natriuresis. Combined P5-I+P9-I further elevated urine cGMP with concomitant increases in urine volume, sodium and creatinine excretion, and clearance similar to P9-I alone, despite the greater MAP reductions induced by combination treatment. ConclusionsCombined P5-I+P9-I amalgamated the superior renal effects of P9-I and pulmonary effects of P5-1, while concurrently further reducing cardiac preload and afterload. These findings support combination P5-I+P9-I as a therapeutic strategy in HF.