Search

Background: Chronic obstructive pulmonary disease (COPD) is a complex progressive disease. Some vasodilators have been reported with therapeutic potential to protect vascular function therefore may delay the progression of COPD., Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, OVID and Clinicaltrials.gov database for eligible randomized controlled trials (RCTs) published before January 1, 2024. RCTs which treatment with vasodilators to COPD patients were included. Gas-blood exchange indicators were the primary outcomes, and ventilation function and quality of life indicators were the secondary outcomes. Mean differences with 95% confidence intervals were extracted. Subgroup analysis of vasodilator category and COPD complicated with or without pulmonary hypertension (PH) were performed. The risk of bias was assessed using Cochrane risk of bias tool, and the meta-analysis was conducted., Results: Twenty studies with a total sample size of 986 were included. The results showed that the 2 types of drugs in vasodilators included PDE-5 inhibitors could improve DLCO (MD = 6.56 [95% CI (1.74, 11.39)], P = .008) and iNO could reduce PaCO2 (MD = -0.10 [95% CI (-0.17, -0.03)], P = .006). Vasodilators could reduce PaCO2 in COPD complicated with PH (COPD-PH) (MD = -0.10 [95% CI (-0.17, -0.03)], P = .006). There were no statistically significant differences in FEV1 (MD = 0.02 [95% CI (-0.11, 0.16)], P = .74), FEV1% predicted (MD = 0.07 [95% CI (-1.90, 2.05)], P = .94), FEV1/FVC (MD = 0.70 [95% CI (-4.02, 5.42)], P = .77) and VE/VCO2 (MD = -0.17 [95% CI (-2.39, 2.05)], P = .88) levels. The total SGRQ score was significantly lower in vasodilator groups (MD = -5.53 [95% CI (-9.81, -1.24)], P = .01)., Conclusions: The therapeutic effects of vasodilators for COPD are controversial. In this meta-analysis, vasodilators have benefits in improving gas-blood exchange function and quality of life in COPD patients. However, vasodilators may have a limited capacity to improve pulmonary function., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation., Methods: The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg via dry powder inhalation for 12 weeks., Objectives: The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH., Results: 168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences versus placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg)., Conclusions: In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect., Competing Interests: Conflict of interest: M. Humbert reports grants/contracts from Gossamer Bio and Merck & Co., Inc., Rahway, NJ, USA, consultancy for 35 Pharma, Aerovate Therapeutics, Inc., AOP Orphan Pharmaceuticals, Bayer, Chiesi Farmaceutici SpA, Ferrer Internacional SA, Gossamer Bio, Janssen Pharmaceuticals, Keros Therapeutics, Liquidia Corp., Merck & Co., Inc., Rahway, NJ, USA, Novartis, Respira Therapeutics, Roivant Sciences Ltd and United Therapeutics Corp., honoraria from Janssen Pharmaceuticals and Merck & Co., Inc., Rahway, NJ, USA, and participation on a data safety monitoring or advisory board for 35 Pharma, Aerovate Therapeutics, Inc., Janssen Pharmaceuticals, Keros Therapeutics, Merck & Co., Inc., Rahway, NJ, USA, Novartis and United Therapeutics Corp. P.M. Hassoun reports participation on a scientific steering committee for MSD and participation on a scientific advisory board for ARIA-CV. K.M. Chin reports fees for work on steering, advisory or adjudication committees from Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics, and research support to institution for clinical studies overseen by her from Altavant, Gossamer Bio, Janssen, Merck & Co., Inc., Rahway, NJ, USA, and United Therapeutics. G. Bortman reports consultancy for Biosidus Argentina, Tuteur SA, Aerovate Therapeutics Inc., Baliarda Argentina, Merck & Co, Inc., Glaxo Inc. and Tecnopharma/Raffo, Inc. M.J. Patel, C. La Rosa, W. Fu and M.J. Loureiro are current employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may hold stock and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. M.M. Hoeper reports consultancy for Acceleron Pharma, Inc., Actelion Pharmaceuticals, Aerovate, AOP Orphan Pharmaceuticals, Bayer HealthCare, Ferrer Internacional SA, Gossamer Bio, Janssen Global Services, LLC, Keros, Merck & Co., Inc., Rahway, NJ, USA, and Novartis., (Copyright ©The authors 2024.)

Target identification plays a critical role in preclinical drug development. The in silico approach has been developed and widely applied to assist medicinal chemists and pharmacologists in drug target identification. There are many target prediction web servers available today that have revealed both advantages and shortcomings in practical applications. Here, we present 3DSTarPred, a web server for three-dimensional (3D) shape similarity-based target prediction of small molecules. A benchmark study showed that 3DSTarPred achieved a target prediction success rate of 76.27%, which was higher than that of existing target prediction web servers. In addition, the performance of 3DSTarPred in the target prediction of diverse substructures/superstructures was also better than that of the existing target prediction web servers. In case studies, 3DSTarPred was used to identify the potential targets of two small molecules, one being kaempferol, a natural lead compound for the treatment of Alzheimer's disease (AD), and the other being sildenafil, a candidate for drug repurposing in AD. The case studies further demonstrated the reliability and success of 3DSTarPred in practice. The 3DSTarPred server is freely available at http://3dstarpred.pumc.wecomput.com.

Introduction: Erectile dysfunction (ED) is a neglected complication in patients with pre-diabetes or diabetes mellitus (DM)., Areas Covered: A summary and review of the role of standard ED treatment and the contribution of lifestyle modification and hypoglycemic drugs., Expert Opinion: Oral phosphodiesterase type 5 inhibitors (PDE5i) represent the first-line therapy even in patients with DM. Testosterone replacement therapy (TRT) is mandatory in all hypogonadal (total testosterone < 12 nmol/l) subjects. Alprostadil and/or combined approaches can be considered when PED5i with or without TRT fail. The glycometabolic optimization through lifestyle modification and the use of hypoglycemic drugs represents a crucial step, even for ED treatment. Considering the strong association between ED and forthcoming cardiovascular diseases, the selection of glucagon-like peptide type 1 analogues or sodium glucose cotransporter-2 inhibitors seems to represent the best option due to their long-term effect on chronic complication prevention. Metformin can be considered a possible alternative in less complicated subjects. Penile prostheses (PP) can be offered when all other options are not effective, but the patients should be informed that poor glycometabolic control can increase the risk of PP infection.

Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5'-GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti-inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3',5'-cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease-modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field., (© 2024 Wiley Periodicals LLC.)

Introduction: Historically, patients recently (≤ 6 months) diagnosed with pulmonary arterial hypertension (PAH; incident) have had poorer survival than those with a longer (> 6 months) time from PAH diagnosis (prevalent). Despite guideline recommendations for initial combination therapy for most patients with PAH, many are initiated and maintained on monotherapy. Real-world evidence to evaluate the benefit of early combination treatment in newly-diagnosed patients is lacking., Methods: Patients with PAH initiating combination therapy with the endothelin receptor antagonist macitentan and the phosphodiesterase-5 inhibitor tadalafil (M+T) were identified from the combined dataset of the US, multicenter OPUS (prospective, observational drug registry; NCT02126943) and OrPHeUS (retrospective, medical chart review; NCT03197688) studies (2013-2020). Descriptive analyses were performed for the incident and prevalent cohorts, as well as the subcohort of incident patients who received M+T as first-line combination therapy (incident initial combination)., Results: In OPUS/OrPHeUS, 1336 patients with PAH received M+T during the observation period. For the incident [n = 453 (33.9%)], incident initial combination [n = 272 (20.4%)], and prevalent [n = 837 (62.6%)] cohorts: median (Q1, Q3) M+T exposure was 14.2 (4.2, 27.5), 12.2 (3.2, 25.5), and 14.7 (4.5, 28.0) months. 12-month Kaplan-Meier estimates (95% confidence limits) for survival were 91.2% (87.7, 93.7), 88.5% (83.2, 92.2), and 92.9% (90.6, 94.6), for patients free from hospitalization were 59.4% (54.1, 64.4), 56.3% (49.1, 62.9), and 62.3% (58.5, 65.9), and for patients persisting on combination therapy were 68.6% (63.9, 72.8), 65.0% (58.8, 70.6) and 66.9% (63.5, 70.0). Adverse events (OPUS only) were reported in 77.8%, 80.2%, and 80.3% of patients, respectively, with no unexpected adverse events observed., Conclusions: Despite a historically worse prognosis, incident patients receiving M+T, including as initial combination therapy, had similar survival and hospitalization as prevalent patients. Safety profiles were similar across cohorts. Together, these data support the use of early combination therapy with macitentan and tadalafil., (© 2024. The Author(s).)

Background: Tadalafil, commonly prescribed for benign prostatic hyperplasia (BPH), may benefit patients with Type 2 diabetes mellitus (T2DM) for glycemic markers and complications. However, the association between the long-term use of tadalafil and the incidence of T2DM has not been investigated., Methods: We emulated a target trial of tadalafil use (5 mg/day) and the risk of T2DM using a population-based claims database in Japan. Patients who initiated tadalafil or alpha-blockers for BPH and had no history of diabetes diagnosis, no dispensing of glucose-lowering drugs, and no history of hemoglobin A1c levels of ≥6.5% (47-48 mmol/mol) were included. The primary outcome was the incidence of T2DM. Pooled logistic regression was used to estimate adjusted risk ratios (RRs) and 5-year cumulative incidence differences (CIDs)., Results: A total of 5180 participants initiated tadalafil treatment and were compared with 20,049 patients who initiated alpha-blockers. The median follow-up time for each arm was 27.2 months (interquartile range [IQR], 12.0-47.9) in tadalafil users and 31.3 months (IQR, 13.7-57.2) in alpha-blocker users. The incidence rates of T2DM in tadalafil and alpha-blocker users were 5.4 (95% confidence interval [CI], 4.0-7.2) and 8.8 (95% CI, 7.8-9.8) per 1000-person years, respectively. Initiation of tadalafil was associated with a reduced risk of T2DM (RR, 0.47; 95% CI, 0.39-0.62; 5-year CID, -0.031; 95% CI, -0.040 to -0.019)., Conclusion: The incidence of T2DM was lower in men with BPH treated with tadalafil than in those treated with alpha-blockers. Thus, tadalafil may be more beneficial than alpha-blockers in preventing T2DM., (© 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Background: Erectile dysfunction (ED) is prevalent not only among older males but also in younger. The physical activity has been considered a potential protective factor against ED. However, there is a lack of comprehensive research on the impact of exercise interventions specifically on ED patients., Objectives: This study aimed to assess the effectiveness of the physical activity in addressing ED symptoms among adult males, without the use of the phosphodiesterase-5 inhibitors (PDE5i) therapy. Additionally, subgroup analysis was performed to evaluate the effects of different exercise modes., Methods: Employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic literature search. A registered protocol is available at PROSPERO (CRD42023441717). Our search spanned PubMed, Web of Science, Embase, and Cochrane Library, with data collection ending on 11 April 2024. The Cochrane Risk of Bias tool was applied by two independent authors to assess randomized controlled trial (RCT) quality. The primary endpoint was determined as the International Index of Erectile Function (IIEF) scores., Results: A total of seven RCTs were included. Utilizing a random-effects model, the estimated standardized mean difference (SMD) was 0.69 (95% confidence interval [CI] 0.37 to 1.02, p < 0.0001) for the overall impact of the physical activity. Subgroup analysis revealed SMDs of 0.81 (95% CI 0.56 to 1.06; p < 0.00001) for aerobic training alone. However, no significant improvement was observed with pelvic floor muscle training (PFMT) (SMD 0.03; 95% CI -0.68 to 0.75; p = 0.93) and a combination of aerobic and resistance training (SMD 0.84; 95% CI -0.41 to 2.09; p = 0.19) CONCLUSION: The findings of this study highlight a significant improvement in the erectile function following exercise interventions for adult men with ED, who are not receiving the PDE5i therapy, especially in conducting aerobic training alone. However, PFMT and a combination of aerobic and resistance training did not show significant improvements in erectile function from this study., (© 2024 American Society of Andrology and European Academy of Andrology.)

Objective: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes., Design: Superiority, double-blind randomised controlled trial., Setting: A total of 20 UK fetal medicine units., Population: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22 +0 and 29 +6  weeks of gestation., Methods: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation., Main Outcome Measures: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85., Results: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm)., Conclusions: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Several previous studies on YouTube TM information on medical topics have already been published. The current study aimed to evaluate the quality information of YouTube TM videos on Phosphodiesterase 5 inhibitors (PDE5-is). A systematic search on YouTube™ was conducted using 30 keyword combinations. For each keyword's combination, the first 50 videos were recorded. The quality of videos on YouTube™ was assessed with Patient Education Materials Assessment Tool for audio-visual content (PEMAT A/V), DISCERN score and a specified created Misinformation tool. According to the selection criteria, 229 YouTube™ videos were suitable for the analyses. Videos were stratified according to the five main identified topics: sildenafil [n = 98; 42.79%] vs tadalafil [n = 50; 21.83%] vs vardenafil [n = 44;19.21%] vs avanafil [n = 17; 7.42%] vs PDE5-is in general [n = 20; 8.73%]. The median overall PEMAT A/V Understandability score and Actionability score were 55% (interquartile range [IQR]: 42-75) and 0% (IQR = 0-67), respectively. Specifically, according to our stratification, YouTube Videos on avanafil reached higher values of both Understandability and Actionability (72.7% and 66.7, respectively) in contrast to other categories. According to DISCERN tool, the total overall median score was 29.5 (IQR = 18-41). According to Misinformation scale, the item 1 ('sexual stimulation') harboured an overall median score of 2 (IQR = 1-2); the item 2 ('side effects') an overall median score of 2 (IQR = 1-3); the item 3 ('treatment choices') an overall median score of 1 (IQR = 1-2); the item 4 ('contraindications') an overall median score of 2 (IQR = 1-2). YouTube™ is a fast and open-access source for mass information. The overall quality of the PDE5-is contents provided is sadly unsatisfactory. Nowadays, YouTube™ cannot be recommended as a reliable source of information on PDE5-is., Competing Interests: Competing interests The authors declare no competing interests., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The management of Alzheimer's disease (AD) poses considerable challenges, necessitating the pursuit of innovative therapeutic approaches. Recent research has spotlighted the promising role of phosphodiesterase type 5 inhibitors (PDE5Is) in reducing the prevalence of AD, utilizing their vasodilatory properties to suggest a potential neuroprotective effect. This meta-analysis and systematic review aims to assess the relationship between the use of PDE5Is and the risk of AD., Methods: A detailed examination was carried out across several electronic databases till March 2024, including PubMed, Web of Science, Scopus, CENTRAL, and Embase. The focus was on identifying studies that compare the occurrence of AD among PDE5I users vs non-users. Through a random-effects model, pooled hazard ratios (HRs) were calculated, in alignment with guidelines from the Cochrane Handbook for Systematic Reviews and Meta-Analysis and the PRISMA standards., Results: This analysis included six studies, cumulating a participant count of 8,337,313, involving individuals treated with sildenafil, tadalafil, and vardenafil, against a control group undergoing other or no treatments. The cumulative HR for AD risk among PDE5I users versus the control group was 0.53 (95% CI: 0.32-0.86, p = 0.008), signaling a markedly reduced likelihood of AD development in the PDE5I group. Particularly, sildenafil usage showed a significant risk reduction (HR: 0.46, 95% CI: 0.31-0.70, p < 0.001), while findings for tadalafil and vardenafil were not significant. Test of subgroup differences found no difference between male and female participants in the risk of AD., Conclusions: Our findings suggest that the use of PDE5Is is associated with a reduced risk of AD, highlighting its potential as a protective agent against neurodegenerative diseases. Given the very low quality of evidence and the heterogeneity among the included studies, further high-quality research is warranted to confirm these findings and elucidate the underlying mechanisms. Register number PROSPERO 2024: CRD42024522197., (© 2024. The Author(s).)

Purpose: To examine posterior ocular structures with optical coherence tomography (OCT) in individuals using a phosphodiesterase 5 inhibitor (PDI, tadalafil)., Method: This prospective study included 26 eyes of 26 patients who used 1 tablet of 5-mg tadalafil regularly every day for 1 month due to erectile dysfunction. The routine ophthalmological examinations of the participants were performed at the pre-tadalafil and post-tadalafil first-month visits. At both visits, OCT was used to measure the central retinal thickness (CRT), ganglion cell layer + inner plexiform layer (GCL + IPL) thicknesses, and peripapillary retinal nerve fiber layer (pRNFL; average and superior, temporal, inferior, and nasal quadrants) thicknesses. The disc area, rim area, average and vertical cup/disc ratio, and cup volume of the optic disc head were evaluated. Choroidal thickness was measured from five points: the subfoveal area and the nasal and temporal areas 500 and 1500 microns from the fovea. Choroidal vascular area values and choroidal vascular index (CVI) were calculated using a special binarization technique., Results: The mean age of the patients was 56 ± 8(range 34-72) years. No significant difference was detected in the CRT,GCL + IPL thicknesses,or pRNFL thicknesses in any of the quadrants before and after tadalafil use. The optic disc head measurements and choroidal thickness values measured from five points were similar between the two visits. The luminal choroidal area was 0.15 ± 0.04 mm 2 before tadalafil use and 0.17 ± 0.05 mm 2 after 1-month tadalafil use, with no statistically significant difference. The remaining choroidal vascular parameters, namely the stromal and total choroidal area and CVI values, were similar between the two visits., Conclusion: This study showed no significant change in the posterior ocular structures in individuals using tadalafil regular daily use for 1 month due to erectile dysfunction.

Background: Although nutraceutical-based treatments are often offered for erectile dysfunction (ED), their efficacy remains doubtful, and the choice of one substance over the other is challenged by the dearth of head-to-head comparative studies., Aim: We aimed to compare the efficacy of available nutraceutical interventions, alone or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in improving erectile function in men with ED through a network meta-analysis (NMA), which incorporates direct and indirect evidence into one model thus generating a hierarchy of effectiveness., Methods: PubMed, Scopus, Web of Sciences, and Cochrane Library databases were searched for randomized placebo-controlled trials (RCTs) assessing the effect of any nutraceutical regimen in improving erectile function when compared to each other, placebo, and/or PDE5i in men with ED. Data were included in a random-effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). Two NMAs were also conducted separately for organic and non-organic ED. Reciprocal comparisons between all treatments were analyzed by league tables., Outcomes: The main outcome was the standardized mean difference in the score of the International Index of Erectile Function (IIEF)-5 or IIEF-6., Results: Fifteen RCTs provided information on 1000 men with ED. In the overall NMA, compared to placebo, the combination propionyl L-carnitine (PLC) + acetyl L-carnitine (ALC) + Sildenafil was associated with the highest SUCRA (97%) in improving erectile function score, followed by L-Arginine + Tadalafil (84%), Sildenafil (79%), Tadalafil (72%), and L-Arginine (52%). No other treatment regimen showed efficacy with statistical significance. In patients with organic ED, the efficacy of Sildenafil and Tadalafil was significantly improved by PLC + ALC and L-Arginine, respectively. On the contrary, in non-organic ED, nutraceuticals did not improve the therapeutic performance of daily Tadalafil., Clinical Implications: This NMA contributes valuable insights into the potential of nutraceutical interventions for ED., Strengths and Limitations: We employed strict inclusion criteria related to study design and diagnostic tool, ensuring the assumption of transitivity and the consistency of the analysis., Conclusion: Against a background of general ineffectiveness of most nutraceutical interventions, L-Arginine and the mix PLC + ALC appeared to be of some usefulness in improving erectile function, especially in combination with PDE5i in organic ED., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Growing evidence suggests that neuroinflammation is not just a consequence of neurodegeneration in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic lateral sclerosis, but it is rather a determinant factor, which plays a pivotal role in the onset and progression of these disorders. Neuroinflammation can affect cells and processes in the central nervous system (CNS) as well as immune cells, and might precede protein aggregation, which is a hallmark of the neurodegenerative process. Standard treatment methods are far from being able to counteract inflammation and delay neurodegeneration. Remarkably, phosphodiesterase 5 inhibitors (PDE5is), which represent potent vasoactive drugs used as a first-line treatment for erectile dysfunction (ED), display important anti-inflammatory effects through cyclic guanosine monophosphate (cGMP) level stabilization. Since PDE5 hydrolyzes cGMP, several studies positioned PDE5 as a therapeutic target, and more specifically, PDE5is as potential alternative strategies for the treatment of a variety of neurological disorders. Indeed, PDE5is can limit neuroinflammation and enhance synaptic plasticity, with beneficial effects on cognitive function and memory. The aim of this review is to provide an overview of some of the main processes underlying neuroinflammation and neurodegeneration which may be potential targets for PDE5is, focusing on sildenafil, the most extensively studied. Current strategies using PDEis for the treatment of neurodegenerative diseases will be summarized.

Diabetic bladder dysfunction (DBD) comprises a wide spectrum of lower urinary tract symptoms that impact diabetic patients' lives, including urinary frequency, urgency, incontinence, and incomplete bladder emptying. To relieve symptoms, anticholinergics have been widely prescribed and are considered an effective treatment. There is increasing evidence that diabetic patients may benefit from the use of phosphodiesterase 5 (PDE5) inhibitors. This narrative review aims to provide a brief overview of the pathophysiology of DBD along with a focus on cholinergic and phosphodiesterase inhibitors as therapies that benefit DBD. An examination of the literature suggests compelling avenues of research and underscores critical gaps in understanding the mechanisms underlying DBD. New tools and models, especially rodent models, are required to further elucidate the mechanisms of action of current therapies in the treatment of DBS.

Objective: Molecular docking studies were conducted to assess the binding affinities of five potential inhibitor candidates [PDB (Protein Data Bank) ID: 6L6E] against Phosphodiesterase 5 (PDE5), with Sildenafil used as the reference compound. The aim of this study is to reveal the potential inhibitory role of plant-derived compounds compared to Sildenafil, a PDE5 inhibitor., Materials and Methods: Autodock Vina v. 1.2.5 software was used to dock the protein and each ligand individually. Molecular dynamics simulations assessed the binding affinity of two compounds to the Phosphodiesterase 5A1 (PDE5 A1) enzyme and were carried out using GROMACS 2022.2 RESULTS: Boesenbergin A exhibited the highest affinity at -8.8 kcal/mol, followed by Ginkolide B at -8.5 kcal/mol, Sildenafil at -8.1 kcal/mol, Montanol at -7.8 kcal/mol, Beta-sitosterol at -7.1 kcal/mol, and Eugenol acetate at -6.9 kcal/mol, ranked in descending order. As a result of molecular docking studies, molecular dynamic simulations were performed for Boesenbergin A, which has the highest affinity, and Sildenafil, which is the standard molecule., Conclusions: Among the two ligands tested, Boesenbergin A exhibited superior binding affinity, surpassing even the standard molecule, Sildenafil. This suggests their potential for modulating enzyme activity and potential relevance in erectile dysfunction treatment.

Aim: The purpose of this study is to identify the clinical outcomes of patients during acute phase of Peyronie's disease (PD) treated with daily Tadalafil 5 mg associated with non-surgical treatments such as intra-plaque verapamil injections (IVI), vacuum erection devices (VED) or extra corporeal shockwave therapy (ESWT)., Methods: 445 patients with PD in acute stage were treated as it follows: Group 1(G1) 117 men with only Tadalafil 5 mg once a day for 3 months; Group 2(G2) 106 men with IVI plus Tadalafil 5 mg for a period of 12 weeks; Group 3(G3) 124 men that received ESWT for 6 weeks plus Tadalafil with the same protocol of G1; Group 4(G4) 98 men with VED plus Tadalafil 5 mg for 3 months. There were assessed at baseline and follow-up: Erectile dysfunction (ED), presence and severity of painful erections, penile plaque size and penile curvature degree. The results were evaluated at baseline and 3,6,12 months., Results: Not statistically significant differences emerged between the two groups at baseline, except for higher presence of patients with ED in in G3(7.4%) vs other groups(p < 0.001). Three months after the treatment in G3 men had a significant reduction of penile curvature degrees after 1 year by treatments, whereas pain in an erection or during intercourse was resolved completely in 75% of the patients., Conclusions: Our study highlights that multimodal therapy has beneficial long-term effects not only in the decrease of ED symptoms, but also in the relief of the penile curvature and the quality of life., (© 2024. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

The prevalence of neurocognitive disorders (NCD) increases every year as the population continues to age, leading to significant global health concerns. Overcoming this challenge requires identifying biomarkers, risk factors, and effective therapeutic interventions that might provide meaningful clinical benefits. For Alzheimer's disease (AD), one of the most studied NCD, approved drugs include acetylcholinesterase inhibitors (rivastigmine, donepezil, and galantamine), an NMDA receptor antagonist (memantine), and anti-amyloid monoclonal antibodies (aducanumab and lecanemab). These drugs offer limited relief, targeting singular pathological processes of the AD. Given the multifactorial nature of the NCDs, a poly-pharmacological strategy may lead to improved outcomes compared to the current standard of care. In this regard, phosphodiesterase 5 (PDE5) inhibitors emerged as promising drug candidates for the treatment of neurocognitive disorders. These inhibitors increase cGMP levels and CREB signaling, thus enhancing learning, memory and neuroprotection, while reducing Aβ deposition, tau phosphorylation, oxidative stress, and neuroinflammation. In the present article, we evaluate the therapeutic potential of different PDE5 inhibitors to outline their multifaceted impact in the NCDs.

In Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) (NCT02891850), improvements in risk status were observed in patients with pulmonary arterial hypertension (PAH) at intermediate risk switching to riociguat versus continuing phosphodiesterase-5 inhibitors (PDE5i). This post hoc study applied the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 and Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary (COMPERA) 2.0 risk-assessment tools to REPLACE to investigate the impact of baseline risk status on clinical improvement. The proportions of riociguat- and PDE5i-treated patients achieving the primary end-point at REVEAL Lite 2 low, intermediate, and high baseline risk reflected the overall population. Proportions of riociguat-treated patients achieving the primary end-point were comparable between the COMPERA 2.0 intermediate-low risk (39%) and intermediate-high risk (43%) groups. Our findings show that patients in REPLACE achieved clinical improvement by switching from PDE5i to riociguat across all COMPERA 2.0 and most REVEAL Lite 2 baseline risk strata., (Copyright © 2024. Published by Elsevier Inc.)

Erectile dysfunction (ED) is prevalent among males experiencing fertility challenges, yet attitudes towards actively treating ED in this group are under-researched. From a cohort of 1256 men with reproductive needs, 303 were identified with ED. The survey encompassed 296 respondents who correctly completed the second questionnaire, revealing that 50.3% sought ED treatment, with higher ED severity increasing the likelihood of seeking treatment. Infertile men were more likely to seek treatment than those with pregnancy loss (OR 3.18, 95% CI 1.74-5.83). Men with normal semen parameters were more open to ED therapy (OR 3.02, 95% CI 1.69-5.36), whereas those undergoing Assisted Reproduction Treatment were less inclined (OR 0.32, 95% CI 0.18-0.58). PDE-5 inhibitors (PDE-5Is) were preferred by 51.0% of those seeking treatment, with 29.7% of men with pregnancy loss and 60.1% of infertile men choosing PDE-5Is as their first option. Concerns included potential adverse effects of PDE-5Is on fetal health (78.7% of men with pregnancy loss) and on sperm quality (44.2% of infertile men). In conclusion, the different fertility requirements, semen parameters, and whether received ART are significant factors influencing the acceptance of treatment, PDE-5Is utilization among individuals in men with couple pregnancy loss is notably limited., (© 2024. The Author(s).)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The phosphodiesterases type 5 (PDE5) are catalytic enzymes converting the second messenger cyclic guanosine monophosphate (cGMP) to 5' GMP. While intracellular cGMP reduction is associated with several detrimental effects, cGMP stabilization associates with numerous benefits. The PDE5 specific inhibitors, PDE5i, found their explosive fortune as first-line treatment for erectile dysfunction (ED), due to their powerful vasoactive properties. The favorable effect for ED emerged as side-effect when PDE5i were originally proposed for coronary artery disease (CAD). From that point on, the use of PDE5i captured the attention of researchers, clinicians, and companies. Indeed, PDE5-induced intracellular cGMP stabilization offers a range of therapeutic opportunities associated not only with vasoactive effects, but also with immune regulatory/anti-inflammatory actions. Chronic inflammation is acknowledged as the common link underlying most non-communicable diseases, including metabolic and cardiac diseases, autoimmune and neurodegenerative disorders, cancer. In this scenario, the clinical exploitation of PDE5i is undeniably beyond ED, representing a potential therapeutic tool in several human diseases. This review aims to overview the biological actions exerted by PDE5i, focusing on their ability as modulators of inflammation-related human diseases, with particular attention to inflammatory-related disorders, like cardiac diseases and cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paronetto and Crescioli.)

Importance: A subgroup analysis of a randomized clinical trial established the efficacy of selexipag plus background therapy (monotherapy or double oral therapy [DOT]) vs placebo plus background therapy and found that the addition of selexipag within 6 months had an added benefit. However, the timing of selexipag addition to DOT and the incremental benefit in clinical practice is not well studied., Objective: To compare triple oral therapy (TOT) consisting of selexipag, endothelin receptor antagonist (ERA), and phosphodiesterase type 5 inhibitor (PDE5i) vs DOT consisting of ERA and PDE5i., Design, Setting, and Participants: This comparative effectiveness study was conducted using data from the US Komodo claims database to emulate a randomized trial. Patients aged 18 years or older with pulmonary arterial hypertension (PAH) treated with ERA plus PDE5i with records from July 2015 through June 2022 were duplicated to TOT and DOT and artificially censored when observed treatment deviated from assigned treatment. Hypothetical randomization was emulated using inverse probability of treatment weighting, and the study accounted for censoring-induced selection bias using inverse probability of censoring weighting. A pooled logistic model estimated the per-protocol difference between treatment groups. Data were analyzed from November 2022 through July 2023., Interventions: TOT (addition of selexipag within 3, 6, and 12 months of initiating DOT) vs DOT., Main Outcomes and Measures: Adjusted risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression over a 2-year follow-up., Results: A total of 2966 patients with PAH (mean [SD] age, 54.3 [14.0] years; 2125 female [71.6%]) met eligibility criteria. Adding selexipag within 6 months of ongoing DOT was associated with a reduction in risk for all-cause hospitalization (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94), PAH-related hospitalization (aHR, 0.81; 95% CI, 0.70-0.95), and PAH-related progression (aHR, 0.82; 95% CI, 0.70-0.95) vs DOT alone. There were no associations if selexipag was initiated within 12 months for all-cause hospitalization, PAH-related hospitalization, or PAH-related disease progression. The association remained with a greater decrease in risk for disease progression vs DOT for selexipag initiation within 3 months (aHR, 0.74; 95% CI, 0.61-0.90)., Conclusions and Relevance: This study found that early selexipag addition to ERA plus PDE5i was associated with a reduction in risk of hospitalization and disease progression. These findings suggest that delays in selexipag initiation likely contribute to suboptimal patient and health system outcomes.

Benign prostatic hyperplasia, a prevalent condition in aging men, is characterized by the proliferation of prostatic epithelial and stromal cells, which leads to bladder outlet obstruction and the exacerbation of lower urinary tract symptoms. There is increasing evidence that chronic prostatic inflammation contributes to the pathogenesis and progression of benign prostatic hyperplasia. This review explores the complex relationship between chronic inflammation and benign prostatic hyperplasia, focusing on the underlying mechanisms, clinical implications, and current therapeutic approaches. The pathophysiology of benign prostatic hyperplasia is multifaceted, involving factors such as hormonal changes, hypoxia, urine reflux into prostatic ducts and stroma, autoimmune responses, and infection-induced inflammation. Inflammatory cytokines, particularly interleukin-17 and interleukin-8, may play key roles in tissue remodeling and smooth muscle contraction within the prostate, thereby influencing benign prostatic hyperplasia progression. Current therapies for benign prostatic hyperplasia include α1-blockers, phosphodiesterase 5 inhibitors, 5α-reductase inhibitors, and plant-based treatments (e.g., pollen extract). These therapies aim to alleviate symptoms by reducing prostatic inflammation, improving blood flow, and inhibiting hormonal pathways involved in prostatic enlargement. However, patients with chronic prostatic inflammation often experience more severe lower urinary tract symptoms and may be resistant to conventional treatments. This resistance has prompted the exploration of alternative therapies targeting inflammation. Chronic prostatic inflammation plays a central role in the pathogenesis and severity of benign prostatic hyperplasia. An understanding of its mechanisms will enable the development of more effective treatments to improve the quality of life among patients with benign prostatic hyperplasia., (© 2024 The Author(s). International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Introduction: Benign prostatic hyperplasia (BPH) is a condition that affects over 50% of men as they enter their fifth decade of life, often leading to lower urinary tract symptoms (LUTS). Primary treatment options include alpha blockers, 5-alpha reductase inhibitors, and phosphodiesterase-5 inhibitors. However, these medications can have some side effects, and there is a noticeable dearth of information addressing the long-term use of these medications. Thus, the exploration of all treatment modalities helps ensure patients receive personalized and effective care. Consequently, the primary objective of this review is to identify potential emerging medications for the treatment of BPH., Areas Covered: We conducted an extensive review of articles discussing pharmacotherapy for BPH spanning the last 15 years. Our information gathering process involved Scopus, PubMed-MEDLINE, Cochrane, Wiley Online Library Google Scholar, ClinicalTrials.gov, and the PharmaProjects database. This approach ensures that readers gain an in-depth knowledge of the existing therapeutic agents as well as promising avenues for managing BPH., Expert Opinion: BPH treatment targets a patient's specific constellation of symptoms. Therefore, a broad knowledge base encompassing various treatment options is paramount in ensuring optimal treatment. Looking forward, the emphasis on personalization promises to reshape the landscape of BPH treatment and improve patient outcomes.

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative symposium dedicated to optimizing sexual function and preserving cardiovascular health. The Fourth Princeton Consensus Conference was convened on March 10-11, 2023, at the Huntington Medical Research Institutes in Pasadena, California. Princeton panels I to III addressed the clinical management of men with erectile dysfunction (ED) who also had cardiovascular disease. Thirteen years since Princeton III, Princeton IV builds on previous foundations in several key areas. Mounting evidence supports the need for providers to treat men with ED as being at risk for cardiac events until proven otherwise. Algorithms for the diagnosis and treatment of ED are updated with new recommendations for coronary artery calcium scoring for advanced cardiovascular risk stratification. Optimization of oral phosphodiesterase type 5 inhibitors in the treatment of men with ED and cardiovascular disease is thoroughly explored, including recent evidence of potential cardioprotective effects of these drugs., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

This study retrospectively examined the effects of low-intensity extracorporeal shockwave therapy and tadalafil on erectile dysfunction patients. 116 patients got low-intensity extracorporeal shockwave therapy twice weekly for 3 weeks, 5 mg of tadalafil daily for 3 weeks, and adjuvant therapy for 6 months. Group A (1 year), Group B (2 years), Group C (3 years), and Group D (4+ years) were treated patients' follow-up groups. The patients' International Index of Erectile Function-5 (IIEF-5) scores were gathered at the start of treatment via face-to-face interviews and at the end of follow-ups by telephone conversations. IIEF-5 scores and the minimal clinically significant differences were the main outcomes. Mean follow-up length, age, and IIEF-5 scores of the patients were 2 ± 1.16 years, 47.34 ± 12.65 years, and 12.09 ± 3.66 points, respectively. Compared to baseline, treatment increased the median IIEF-5 scores of patients in groups A, B, C, and D by 7 [3-12], 6 [0-8], 7 [1-9], and 6.5 [2.5-10] points, respectively (p = 0.001). 71%, 63%, 65.8%, and 65% of treated patients in groups A, B, C, and D met the minimal clinically significant differences criteria (n = 77). Mild disease patients were 9.14 times more likely to respond to treatment than severe illness patients (OR, 9.14; 95% CI, 1.28-65.46; P = 0.02). Low-intensity extracorporeal shockwave therapy and 5 mg of tadalafil can treat erectile dysfunction for up to 4 years with sustained outcomes. This treatment is optimal for mild illnesses., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Competing Interests: The authors declare that they have no conflict of interest

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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: There is a rising concern about developing innovative, efficacious PDE5I molecules that provide better safety, efficacy, and tolerability with less adverse effects. Innovative PDE5I with dual targets have also been defined in the literature. Additionally, some of PDE5I are able to selectively inhibit other enzymes such as histone deacetylase, acetylcholine esterase, and cyclooxygenase or act as nitric oxide donors. This review presents knowledge concerning the advanced trends and perspectives in using PDE5I in treatment of ED and other conditions., Areas Covered: Pre-clinical and early clinical trials that investigated the safety, efficacy, and tolerability of novel PDE5I such as Udenafil, Mirodenafil, Lodenafil, Youkenafil, Celecoxib, and TPN729 in treatment of ED and other conditions., Expert Opinion: Preclinical and limited early clinical studies of the new molecules of PDE5I have demonstrated encouraging results; however, safety, efficacy, and tolerability are still issues that necessitate further long-term multicenter clinical studies to ensure justification of their uses in treatment of ED and other conditions. Progress in molecular delivery techniques and tailored patient-specific management and additional therapeutic technology will dramatically improve care for ED and other conditions. The dream of ED and many other conditions becoming more effectively managed may be feasible in the near future.

Introduction: Postmicturition dribble (PMD) is common in males. Little is known about PMD etiology, but it is either secondary to urethral/prostatic surgery or primary (no previous surgery). Despite PMD's high prevalence, the effectiveness of its treatment modalities remains lacking., Objective: To undertake a systematic review of the available treatments for primary PMD in adult males and meta-analysis of their effectiveness., Materials and Methods: We searched four electronic databases from inception to 2023 for original articles that evaluated PMD treatments in male adults without previous urethral/prostatic surgery (PROSPERO protocol CRD42023444591). Study quality and risk of bias were evaluated using established tools. We extracted a range of variables including treatment modality used and its effectiveness on PMD volume and patient complaint. Meta-analysis was undertaken where feasible, and where this was not feasible, narrative synthesis was conducted., Results: Out of 335 studies, four were included (four clinical trials, n = 344 patients). Two trials used physical/behavioral therapy (pelvic floor muscle exercises [PFMEs], urethral milking); the other two employed phosphodiesterase (PDE5) inhibitors (tadalafil, Udenafil). All studies were of good quality, but physical/behavioral therapy studies had some risk of bias. As the two physical/behavioral therapy studies used heterogenous outcome measures, narrative synthesis showed PMD volume improvement with PFMEs more than with urethral milking, both modalities were more effective than counseling, and in one study, PFMEs were effective in reducing PMD self-reported complaint than counseling. Meta-analyses of the two PDE5 inhibitors studies showed a large effect size with high heterogeneity for decreased PMD volume favoring PDE5 inhibitors over placebo (g = -0.86, 95% confidence interval [CI] -1.75; 0.02, p = 0.05; I 2  = 88%); and a significant improvement equivalent to -1.06 points on the Hallym PMD Questionnaire score with no discernable heterogeneity (95% CI -1.65; -0.47, p = 0.0004; I 2  = 0%), favoring PDE5 inhibitors compared to controls., Conclusions: Physical/behavioral therapy and PDE5 inhibitors are effective primary PMD treatments. PMD management studies in males with no previous urethral/prostatic surgery are very scarce and lack the use of consistent/comparable outcome measures. Further studies addressing these deficiencies would benefit this very thin evidence base., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Background: Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain., Methods: The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with the feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than 6 months before administration of study medication. Patients are treated for 3 months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper-pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests in a cognitive sub-study., Discussion: The ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in the year 2024., Trial Registration: Clinicaltrials.gov, NCT05173896. Registered on 30 December 2021., (© 2024. The Author(s).)

Background: On the one hand, the primary coronary slow flow phenomenon (CSFP) can cause recurrence of chest pain, prompting medical examinations and further healthcare costs, while on the other hand, it can lead to myocardial infarction, ventricular arrhythmia and sudden cardiac death. Nevertheless, there is not any agreement on the optimal treatment for primary CSFP, so we decided to examine the effectiveness of sildenafil in this context., Methods: This pilot study is a 12-week, triple-blind, randomised, placebo-controlled trial for receiving either 50 mg daily oral sildenafil or placebo. Twenty eligible patients aged 30-70 years from a tertiary hospital in Yazd were randomly allocated in a 1:1 ratio to two groups. The primary outcomes were the alterations in functional capacity (metabolic equivalents, METs), Duke treadmill score (DTS) and angina severity (Canadian Cardiovascular Society (CCS) class). The study protocol registration code is IRCT20220223054103N1., Results: The angina severity in the Sildenafil group improved, with all receivers achieving a state of being asymptomatic during regular physical activity (CCS I). Whereas just 40% of the recipients in the placebo group achieved the same level of improvement (p=0.011). Mean METs at baseline were 9.9 (SD: 3.1) and at week 12 were 13.1 (SD: 3.3) for sildenafil and 9.56 (SD: 2.1) and 9.63 (SD: 2.4) for placebo (difference favouring sildenafil with a median increase of 3.1 (IQR: 1.1 to 4.1, p=0.008)). Median DTS scores at baseline were 3 (IQR: 0 to 9) and at week 12 were 9.5 (IQR: 7.75 to 15) for sildenafil and 7 (IQR: -1.5 to 9.25) and 8 (IQR: 1.5 to 11.25) for placebo (difference favouring sildenafil with a median increase of 5.5 (IQR: 1 to 9.2, p=0.01))., Conclusions: We suggest that a daily low dose of sildenafil could be a valuable therapeutic option for primary CSFP., Trial Registration Number: IRCT20220223054103N1., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To study the effects of benign prostatic hyperplasia treatments, namely: alpha-adrenergic receptor blockers, 5-alpha-reductase inhibitors and phosphodiesterase-5 inhibitors on the risk of Parkinson's disease, Alzheimer's disease and mortality., Materials and Methods: All male Medicare enrollees aged 65 or above who were diagnosed with benign prostatic hyperplasia and received one of the study drugs between 2007-2020 were followed-up for the three outcomes. We used Cox regression analysis to assess the relative risk of each of the outcomes for each study drug compared to the most prescribed drug, tamsulosin, while controlling for demographic, socioeconomic and comorbidity factors., Results and Conclusions: The study analyzed 1.1 million patients for a mean follow-up period of 3.1 years from being prescribed one of the study drugs. For all outcomes, patients on tamsulosin were used as the reference for comparison. For mortality, alfuzosin was associated with 27% risk reduction (HR 0.73, 95%CI 0.68-0.78), and doxazosin with 6% risk reduction (HR 0.94, 95%CI 0.91-0.97). For Parkinson's disease, terazosin was associated with 26% risk reduction (HR 0.74, 95%CI 0.66-0.83), and doxazosin with 21% risk reduction (HR 0.79, 95%CI 0.72-0.88). For Alzheimer's disease, terazosin was associated with 27% risk reduction (HR 0.73, 95%CI 0.65-0.82), and doxazosin with 16% risk reduction (HR 0.84, 95%CI 0.76-0.92). Tadalafil was associated with risk reduction (27-40%) in all 3 outcomes. More research is needed to elucidate the underlying mechanisms of these observations. Given the availability of safer alternatives for treating benign prostatic hyperplasia, caution should be exercised when using tamsulosin in elderly patients, especially those with an increased risk of developing neurodegenerative diseases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension., Methods: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline., Results: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P =0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P =0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group., Conclusions: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points., Registration: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595., Competing Interests: Dr Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, AOP Health, Bayer, Ferrer, GossamerBio, Janssen, Keros, and MSD. Max Wissmüller has received lecture fees from Janssen. Hanno Leuchte has received fees for consultations and/or lectures from Acceleron, Jansse-Cilag, Bayer, Boehringer-Ingelheim, Ferrer, MSD, and Pfizer. Michael Halank has received fees for lectures and/or consultations from AstraZeneca, Janssen-Cilag, and MSD. In addition, he has received support for attending meetings and/or travel from AOP Health and Janssen-Cilag. Hans-Jürgen Seyfarth has received fees for lectures and/or consultations from Janssen-Cilag and MSD. Stephan Baldus has received fees for lectures and/or consultations from Abbott, Edwards, Jenavalve, AstraZeneca, Bayer, Daiicho Sankyo, and Amgen, as well as research grants from Abbott, AstraZeneca, and Daiichi Sankyo. Johann Bauersachs has received fees for lectures and/or consultations from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cardior, Corvia, CVRx, Edwards, Norgine, Novartis, Pfizer, Roche and Vifor. In addition, institutional grants have been provided by Abiomed, CVRx, Norgine, Roche, and Zoll. He holds patents for microRNA and downstream targets for diagnostics and therapeutic purposes (PCT/EP2007/008772 and PCT/EP2009/051986). Michael Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project No. 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor, Servier and Vifor. Hossein-Ardeschir Ghofrani has received honoraria for consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly, and Novartis. He is member of the Advisory Board for Acceleron, Bayer HealthCare AG, Pfizer, GSK, Actelion, Lilly, Merck, Encysive, and Ergonex. He has also received governmental grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Research, State Government of Hessen, and the German Ministry for Education and Research. Stavros Konstantinides reports personal lecture/advisory fees and research grants to his institution from Bayer AG, Boston Scientific, Daiichi-Sankyo, LumiraDx, and Penumbra, as well as personal lecture/advisory fees from MSD and Pfizer–Bristol-Myers Squibb. Karen M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, Ferrer, GSK, Janssen, MSD, Pfizer, and United Therapeutics. Rolf Wachter has received fees for lectures and/or consultation from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Medtronic, Novartis, Pfizer, Pharmacosmo, Sciarc, Servier, and Vifor. His institution has received research grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Union, and Medtronic. Carolyn S.P. Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corp, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and non–executive director of Us2.ai. Stephan Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Aerovate, AOP, AstraZeneca, Bayer, Boehringer-Ingelheim, Edwards, Ferrer, Gossamer, Janssen, MSD, and United Therapeutics. His institution has received research grants from Actelion, AstraZeneca, Bayer, Janssen, and Lempo. The other authors report no conflicts.

Introduction: Fetal growth restriction (FGR) is associated with a higher risk of perinatal morbidity and mortality, as well as long-term health issues in newborns. Currently, there is no effective medicine for FGR. Phosphodiesterase-5 (PDE-5) inhibitors have been shown in pre-clinical studies to improve FGR. This study aimed to evaluate the latest evidence about the clinical outcomes and safety of PDE-5 inhibitors for the management of FGR. Methods: Eight databases (PubMed, Embase, Medline, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Database and WangFang Database) were searched for English and Chinese articles published from the database inception to December 2023. Randomized controlled trials (RCTs) reporting the use of PDE-5 inhibitors in FGR were included. The quality of the RCTs was assessed using the Cochrane Risk of Bias Tool. Odds ratio and mean difference (MD) (95% confidence intervals) were pooled for meta-analysis. Results: From 253 retrieved publications, 16 studies involving 1,492 pregnant women met the inclusion criteria. Only sildenafil (15 RCTs) and tadalafil (1 RCT) were studied for FGR. Compared with the control group (placebo, no treatment, or other medication therapies), sildenafil increased birth weight, pregnancy prolongation and umbilical artery pulsatility indices. However, it also increased the risk of pulmonary hypertension in newborns, as well as headache and flushing/rash in mothers. There were no significant differences in gestation age, perinatal mortality or major neonatal morbidity, stillbirth, neonate death, infants admitted to neonatal intensive care unit, intraventricular hemorrhage and necrotizing enterocolitis in infants, as well as pregnancy hypertension and gastrointestinal side effects in mothers between the treatment and the control groups. Discussion: Sildenafil was the most investigated PDE-5 inhibitors for FGR. Current evidence suggests that sildenafil can improve birth weight and duration of pregnancy but at the same time increase the risk of neonatal pulmonary hypertension. It remains uncertain whether the benefits of sildenafil in FGR outweigh the risks and further high-quality RCTs are warranted. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=325909., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Un, Bai, Chan, Zeng, Lei, Li and Ung.)

Aims: Phosphodiesterase 5 inhibitors (PDE5i), which are widely used for the treatment of erectile dysfunction (ED), have been found to exhibit systemic vascular benefits by improving endothelial function. In this context, we sought to evaluate the effects of PDE5i on long-term cardiovascular outcomes and mortality., Methods and Results: A comprehensive search of electronic databases was conducted up to 30 May 2023. Cohort studies comparing PDE5i treatment at any dose with other ED treatment, placebo or no treatment and minimum follow-up duration of 6 months were considered eligible. The primary endpoints were: (1) major adverse cardiovascular events (MACE) and (2) all-cause mortality. Pooled risk ratios (RR) with 95% confidence intervals (CI) were calculated. Sixteen studies were included (1 257 759 subjects-10.5% treated with PDE5i). The majority of patients (99.4%) were men [median age 61.5 years (range 30-72.8)]. The median follow-up duration was 4.3 years (range 6 months-7.5 years). PDE5i use was associated with a significant reduction in the composite of MACE (RR 0.78, 95% CI 0.69-0.89). Moreover, the analysis of pooled data from 13 studies, demonstrated that the use of PDE5i was associated with a significantly lower risk of all-cause mortality (RR 0.70, 95% CI 0.56-0.87)., Conclusion: The use of PDE5i primarily in men with or without known coronary artery disease was associated with a lower risk for cardiovascular events and overall mortality. This information underlines that PDE5i could provide clinical benefit beyond ED treatment and could instigate the conduction of further, large-scale randomized clinical trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and resistant to immunotherapy. Although immune recognition can be enhanced with immunomodulatory agents including checkpoint inhibitors and vaccines, few patients experience clinical efficacy because the tumor immune microenvironment (TiME) is dominated by immunosuppressive myeloid cells that impose T cell inhibition. Inhibition of phosphodiesterase-5 (PDE5) was reported to downregulate metabolic regulators arginase and inducible NOS in immunosuppressive myeloid cells and enhance immunity against immune-sensitive tumors, including head and neck cancers. We show for the first time to our knowledge that combining a PDE5 inhibitor, tadalafil, with a mesothelin-specific vaccine, anti-programmed cell death protein 1, and anti-cytotoxic T lymphocyte-associated protein 4 yields antitumor efficacy even against immune-resistant PDAC. To determine immunologic advantages conferred by tadalafil, we profiled the TiME using mass cytometry and single-cell RNA-sequencing analysis with Domino to infer intercellular signaling. Our analyses demonstrated that tadalafil reprograms myeloid cells to be less immunosuppressive. Moreover, tadalafil synergized with the vaccine, enhancing T cell activation including mesothelin-specific T cells. Tadalafil treatment was also associated with myeloid/T cell signaling axes important for antitumor responses (e.g., Cxcr3, Il12). Our study shows that PDE5 inhibition combined with vaccine-based immunotherapy promotes pro-inflammatory states of myeloid cells, activation of T cells, and enhanced myeloid/T cell crosstalk to yield antitumor efficacy against immune-resistant PDAC.

Background: Pulmonary hypertension remains difficult to manage in congenital diaphragmatic hernia (CDH). Prenatal therapy may ameliorate postnatal pulmonary hypertension. We hypothesized that intra-amniotic (IA) injection of either sildenafil, a phosphodiesterase 5 inhibitor, or rosiglitazone, a PPAR-γ agonist, or both late in gestation would decrease the detrimental pulmonary vascular remodeling seen in CDH and improve peripheral pulmonary blood flow., Methods: Pregnant rats were gavaged with nitrogen on embryonic day (E) 9.5 to induce fetal CDH. Sildenafil and/or rosiglitazone were administered to each fetus via an intra-amniotic injection after laparotomy on the pregnant dam at E19.5, and fetuses delivered at E21.5. Efficacy measures were gross necropsy, histology, peripheral blood flow assessment using intra-cardiac injection of a vascular tracer after delivery, and protein expression analysis., Results: Intra-amniotic injections did not affect fetal survival, the incidence of CDH, or lung weight-to-body weight ratio in CDH fetuses. IA sildenafil injection decreased pulmonary vascular muscularization, and rosiglitazone produced an increase in peripheral pulmonary blood flow distribution. The combination of sildenafil and rosiglitazone decreased pulmonary artery smooth muscle cell proliferation. These intra-amniotic treatments did not show any negative effects in either CDH fetuses or control fetuses., Conclusion: IA injection of sildenafil and rosiglitazone late in gestation ameliorates the pulmonary hypertensive phenotype of CDH and may have utility in clinical translation., Level of Evidence: Not applicable., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: The study examined the impact of long term COVID-19 infection on the patients' erectile function and anxiety and depression in the same patients as well as the impact of daily tadalafil 5 mg supplementation on their erectile function., Methods: Recovered 114 men were evaluated by the validated Arabic version of the international index of erectile function (ArIIEF-5) and the Arabic versions of the patient health questionnaire-9 (PHQ-9) and the generalized anxiety disorder-7 (GAD-7) at time of presentation, at 3 months and at 6 months, respectively. Forty recovered patients who still complained of ED received tadalafil 5 mg daily for 2 months then were evaluated again at 3 and 6 months by penile duplex, the Arabic versions of the patient health questionnaire-9 (PHQ-9) and the generalized anxiety disorder-7 (GAD-7) at the same periods, respectively., Results: At the time of presentation, there was a positive correlation between the severity of COVID-19 infection, ArIIEF-5 and PHQ-9 ( r  = 0.249, p  = 0.008; r  = 0.241, p  = 0.010, respectively). Most of the patients showed normal penile duplex parameters. There were 40 ED patients at presentation, 5 ED patients at 3 months and 3 ED patients at 6 months, respectively., Conclusions: ED in COVID-19 patients who were not suffering from chronic illnesses before the affection, is primarily psychological and completely responsive to tadalafil., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Daily (once a day [OaD]) tadalafil intake is a valuable option for men favoring spontaneous over scheduled sexual intercourse., Aim: The study sought to assess the rate of and the clinical factors associated with spontaneous, medication-free erectile function (EF) recovery after discontinuation of tadalafil 5 mg OaD in a cohort of young men seeking first medical help for psychogenic erectile dysfunction (ED) as their primary complaint., Methods: Data from 96 consecutive patients <50 years of age seeking first medical help for ED and prescribed tadalafil 5 mg OaD were analyzed. Patients completed the International Index of Erectile Function (IIEF) and underwent baseline penile color Doppler ultrasound. Follow-up involved clinical assessments or phone interviews. Spontaneous medication-free EF recovery was defined as IIEF EF domain score >22 after tadalafil discontinuation, prompting cessation of follow-up. Descriptive statistics compared tadalafil OaD responders and nonresponders. Cox regression hazard models explored the association between baseline characteristics and EF recovery risk post-drug discontinuation. Kaplan-Meier analyses estimated EF recovery probability over time., Outcomes: The primary outcome was EF recovery after discontinuation of tadalafil 5 mg OaD., Results: Overall, median age was 39 (interquartile range [IQR], 32-45) years. Of all, 82 (85.4%) patients achieved EF recovery after tadalafil OaD discontinuation, while 14 (14.6%) patients were identified as nonresponders. Median tadalafil usage time (from beginning to discontinuation) was 3 (IQR, 2-11) months. The most common treatment-emergent adverse event was headache in 9 (9.4%) patients. Nonresponders were older (43 [IQR, 42-45] years vs 38 [IQR, 31-44] years; P = .03), had higher body mass index (25.5 [IQR, 23.4-29.9] kg/m2 vs 23.6 [IQR, 21.8-25.9] kg/m2; P = .04), and reported lower baseline IIEF EF domain scores (12 [IQR, 7-15] vs 15 [IQR, 10-22]; P = .02) than responders. Nonresponders and responders did not differ in terms of baseline ED severity, Charlson comorbidity index, smoking, alcohol consumption, regular physical exercise, and color Doppler ultrasound parameters. Upon Cox regression analysis, younger age (hazard ratio, 0.95; 95% confidence interval, 0.92-0.99; P = .01) was associated to EF recovery, after adjusting for baseline ED severity, body mass index, smoking, and Charlson comorbidity index ≥1. The Kaplan-Meier analysis displays the probability of EF recovery over time, indicating rates of 43%, 60%, and 72% at 3-, 6-, and 12-month follow-up intervals, respectively., Clinical Implications: Tadalafil 5 mg OaD is an effective short-term treatment for psychogenic ED, allowing its discontinuation after achieving a normal medication-free EF., Strengths and Limitations: The main limitations are the limited number of participants and the potential neglect of confounding factors., Conclusion: Almost 1 out of 2 young men with primary psychogenic ED who were prescribed with tadalafil 5 mg OaD recovered spontaneous medication-free EF after 3 months of treatment. Overall, the younger the patient was, the higher the chance there was of spontaneous EF recovery after drug discontinuation., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Objectives: We aimed to evaluate the effect of daily 5 mg tadalafil on the neutrophil/lymphocyte ratio (NLR) and the platelet/lymphocyte ratio (PLR) in patients with erectile dysfunction (ED)., Patients and Methods: 30 subjects with ED were given tadalafil as well as 30 subjects with ED who were not receiving tadalafil were recruited. 30 healthy individuals served as controls., Results: Receiver operating characteristic curve (ROC) showed that the best cut off point of pre-treatment and post treatment NLR in the ED treatment group was found <1.51, <1.51, sensitivity of 68.3%, 58.3%, specificity of 53.3%, 53.3%, lower bound of 0.558, 0.517, upper bound of 0.789, 0.757, total accuracy of 67.4%, 63.7% and p 0.003, 0.0025, respectively. Additionally, the best cut off point of pre-treatment and post treatment PLR in the ED treatment group was found <5.89, <5.99, sensitivity of 65%, 63.3%, specificity of 63.3%, 53.3%, lower bound of 0.515, 0.435, upper bound of 0.755, 0.687, total accuracy of 63.5%, 56.1% and p 0.027, 0.341, respectively., Conclusion: Daily 5 mg Tadalafil supplementation significantly improves erectile function through decreasing these markers as well as depression and anxiety., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: The aim of study was to investigate the effect of avanafil, a second-generation phosphodiesterase-5 (PDE5) inhibitor, on cerebral ischemia reperfusion (CI/R) model., Methods: 32 male albino Wistar rats were used. Four groups were constituted, as I: the healthy (sham), II: the CI/R group, III: the CI/R +I 10 mg/kg avanafil group, and IV: the CI/R + 20 mg/kg avanafil group. Avanafil was administered twice via oral gavage, first shortly after ischemia reperfusion and once more after 12 h. The rats were euthanized after 24 h. Histopathological and Real Time PCR analyzes were performed on cerebral tissues., Results: IL-1β, NLRP3 and TNF-α mRNA expressions were statistically higher in the CI/R group when compared to healthy (sham) group. Conversely, the IL-1β, NLRP3, and TNF-α mRNA expressions were significantly decreased in both of the avanafil-treated groups when compared to CI/R group. Histopathological results showed that both doses of avanafil also decreased cellular damage in cerebral tissue that occurred after CI/R., Conclusion: Avanafil, was found to have ameliorated inflammatory response and cellular injury caused by CI/R. The mRNA expression of IL-1β, NLRP3, and TNF-α decreased in the I/R groups and approached the control group levels with a high dose of avanafil.

Objective: The purpose of this study was to analyze the available evidence regarding the efficacy of iPDE5 in the treatment of female sexual dysfunction (FSD)., Methods: A comprehensive literature search was conducted in March 2023 through the main scientific databases., Results: A total of 53 articles were identified, out of which, 6 met the predefined inclusion criteria. All of these were randomized controlled trials. Among the included studies, 4 demonstrated the effectiveness of sildenafil in improving sexual response and addressing FSD, while 2 studies failed to establish its efficacy in this context., Conclusion: Overall, the efficacy of sildenafil in the treatment of FSD remains controversial and inconclusive based on the available evidence. Further research is necessary to clarify the therapeutic potential of iPDE5 in addressing FSD and to better understand the factors that influence treatment outcomes., Competing Interests: Conflicts to interest: none to declare.

Patients with sickle cell disease (SCD) display priapism, a prolonged penile erection in the absence of sexual arousal. The current pharmacological treatments for SCD-associated priapism are limited and focused on acute interventions rather than prevention. Thus, there is an urgent need for new drug targets and preventive pharmacological therapies for this condition. This review focuses on the molecular mechanisms linked to the dysfunction of the NO-cyclic guanosine monophosphate (cGMP)-phosphodiesterase type 5 (PDE5) pathway implicated in SCD-associated priapism. In murine models of SCD, reduced nitric oxide (NO)-cGMP bioavailability in the corpus cavernosum is associated with elevated plasma hemoglobin levels, increased reactive oxygen species levels that inactive NO, and testosterone deficiency that leads to endothelial nitric oxide synthase downregulation. We discuss the consequences of the reduced cGMP-dependent PDE5 activity in response to these molecular changes, highlighting it as the primary pathophysiological mechanism leading to excessive corpus cavernosum relaxation, culminating in priapism. We also further discuss the impact of intravascular hemolysis on therapeutic approaches, present current pharmacological strategies targeting the NO-cGMP-PDE5 pathway in the penis, and identify potential pharmacological targets for future priapism therapies. In men with SCD and priapism, PDE5 inhibitor therapy and testosterone replacement have shown promising results. Recent preclinical research reported the beneficial effect of treatment with haptoglobin and NO donors. SIGNIFICANCE STATEMENT: This review discusses the molecular changes that reduce NO-cGMP bioavailability in the penis in SCD and highlights pharmacological targets and therapeutic strategies for the treatment of priapism, including PDE5 inhibitors, hormonal modulators, NO donors, hydroxyurea, soluble guanylate cyclase stimulators, haptoglobin, hemopexin, and antioxidants., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown., Methods: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO 2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q., Results: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P =0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P =0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P <0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P =0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P =0.007), CVR-WMH (0.07, 0-0.14; P =0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P =0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P =0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P =0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P =4.9×10 -8 ; cilostazol-placebo, 0.06, 0.03-0.09; P =5.1×10 -5 ). Both drugs increased headaches ( P =1.1×10 -4 ), while cilostazol increased moderate-severe diarrhea ( P =0.013)., Conclusions: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease., Registration: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332., Competing Interests: A.J.S. Webb has received related funding from the Wellcome Trust, Alzheimer Society and British Heart Foundation and has received consulting fees from Woolsey Pharmaceuticals. J. Dawson is on advisory boards and has received speakers fees from AstraZeneca and Medtronic. D.J. Werring reports grant funding from the Stroke Association and British Heart Foundation; speaking honoraria from Bayer; speaking and chairing honoraria from Alexion and NovoNordisk; and consultancy fees from Alnylam, Bayer and NovoNordisk. The other authors report no conflicts.

Objective: The objective is to evaluate the efficacy of coadministration of garlic (as a hydrogen sulfide [H2S] donor) and tadalafil for patients with ED using a placebo-controlled, prospective, randomized, two-arm pilot study in patients responding poorly to tadalafil alone., Materials and Methods: The patients with complaints of ED (with normal penile Doppler) who failed to maintain sustained improvement in erectile function with tadalafil were recruited after excluding those with comorbidities. The study sample was randomized into two groups. Group A received garlic 5 g twice a day orally and Group B received a placebo twice daily orally for 4 weeks. Both groups continued tadalafil 5 mg in the night for 4 weeks. Their erectile function was assessed at the beginning and at the end of 4 weeks using the International Index of Erectile Function (IIEF-EF), erectile function domain and compared. A value of P ≤ 0.05 was considered statistically significant., Results: Nineteen patients in Group A (mean age 37.5 ± 10.6 years) and 16 patients in Group B (mean age 39.6 ± 9.6 years) participated in the pilot study conducted from May 2022 to August 2022. The participants treated with garlic (as an H2S donor) as a coadministrant had statistically significant improvement in IIEF-EF score (P ≤ 0.0001) at the end of 4 weeks compared to placebo., Conclusions: Garlic (as an H2S donor) as adjunctive therapy was beneficial in our study participants responding poorly to tadalafil alone., (Copyright © 2024 Copyright: © 2024 Indian Journal of Pharmacology.)

Objective: To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients., Methods: A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools., Results: Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk., Conclusion: The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.