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ObjectiveTo perform a cost analysis of generic and brand-name Phosphodiesterase Type 5 (PDE5) inhibitors at different dosages and pharmacies across the US.MethodsUsing an all-payer retail pharmacy-claims database, we analyzed prescription drug data for three generic and six brand-name oral PDE5 inhibitors at different dosages across US chain and independent pharmacies in 2019.ResultsWe obtained cash price data from 60,186 pharmacies (35,976 chain and 24,210 independent). The nationwide mean cash price per unit (PPU) ranged from $8.6 ± 5.2 (sildenafil 20 mg at chain pharmacies) to $107.1 ± 71 (Adcirca 20 mg at independent pharmacies) equal to 1145.3% difference. Chain pharmacies provided significantly lower average prices for one brand-name and six generic PDE5 inhibitors. Tadalafil PPU was cheaper at higher quantities, however, PPU increased with quantity prescribed for sildenafil. Looking at the top 10 metropolitan statistical areas, the highest PPUs were observed for tadalafil (Cialis) 10 mg and sildenafil (Viagra) 50 mg in Atlanta ($67.4 ± 8.7) and Los Angeles ($50.3 ± 24.0), while New York ($9.7 ± 2.6) and Miami ($27.9 ± 16.4) had the lowest PPUs for tadalafil (Cialis) 5 mg and sildenafil (Viagra) 100 mg, respectively.ConclusionA substantial variability in PDE5 inhibitor cash prices exists across manufacturer, dosage, quantity, pharmacy type, and location. In addition, the pricing does not necessarily correlate with the regional socioeconomic factors. This highlights the importance of provider awareness and patient counseling on drug price including potentially assisting patients in identifying opportunities for cost savings.

PurposeTo explore the differences of priapism events among a diverse cohort taking erectogenic medicines (i.e., phosphodiesterase type 5 inhibitors [PDE5i] and intracavernousal drugs).MethodsWe queried the World Health Organization global database of individual case safety reports (VigiBase) for records of the adverse drug reactions (ADR) with sildenafil, tadalafil, avanafil, vardenafil, papaverine, and alprostadil. Disproportionality analyses (case/non-case approach) were performed to assess the reporting odds ratio (ROR) of priapism reporting in PDE5i consumers compared to intracavernousal drug recipients.ResultsFrom a total of 133 819 ADR events for erectogenic medications, 632 were priapism (PDE5is: n = 550, 0.41%; intracavernousal drugs: n = 82, 9.92%). Priapism disproportionality signals from intracavernousal drugs were 25 times stronger than PDE5is (ROR = 34.7; confidence interval [CI] 95%: 27.12-43.94 vs. ROR = 1.38; 95% CI: 1.24-1.54). For all PDE5i agents, the 12-17 years age group had the highest ROR (9.49, 95% CI: 3.76-19.93) followed by 2-11 years (4.31, 95% CI: 1.57-9.4). Disproportionality signals for consumers under 18 for both all PDE5is as a whole (ROR = 4.57, 95% CI: 2.48-7.73) and sildenafil (ROR = 4.89, 95% CI: 2.51-8.62) were stronger than individuals 18 or older (ROR = 1.06, 95% CI: 0.93-1.21 and ROR = 1.08, 95% CI: 0.91-1.26, respectively).ConclusionsPDE5i use shows disproportionate priapism signals which are higher in young patients.

In pulmonary hypertension (PH) associated with chronic lung disease (CLD), identifying patients who would benefit from pulmonary vasodilators is a significant clinical challenge because the presence of PH is associated with poorer survival. This study evaluated the severity of pulmonary circulation impairment in patients with CLD‐PH using pulmonary perfusion single‐photon emission computed tomography/computed tomography (SPECT/CT). This single‐center, observational study enrolled patients with CLD‐PH who had a mean pulmonary arterial pressure (PAP) ≥ 25 mmHg, as confirmed by right heart catheterization. The primary outcome was to measure the percentage of pulmonary perfusion defect (%PPD), calculated by dividing the perfusion defect volume from perfusion SPECT images by the lung volume from CT scan images. The secondary outcome was to assess the correlation between %PPD and baseline characteristics. The median %PPD was 52.4% (interquartile range, 42.5%–72.3%) in 22 patients. In multivariate linear regression analysis, both forced vital capacity (β = 0.58, p = 0.008) and mean PAP (β = 0.68, p = 0.001) were significantly correlated with %PPD. In conclusion, significant correlation between mean PAP and %PPD in patients with CLD‐PH was observed. This noninvasive assessment of %PPD may be useful for evaluating the severity of pulmonary circulation impairment in CLD‐PH. [ABSTRACT FROM AUTHOR]

Objective: Liver is one of the most affected tissues after abdominopelvic surgery. Many substances were employed to prevent liver damage during surgery. In this study, we aimed to investigate effects of tadalafil, phosphodiesterase-5 (PDE-5) inhibitor, on the liver after intraperitoneal abrasion. Materials and Methods: Thirty rats were induced ileal and cecal abrasion model. Subsequently, group 1: received saline (control), group 2: tadalafil 1 mg/kg, group 3: tadalafil 10 mg/kg, group 4: tadalafil 1 mg/kg for 7 days, group 5: tadalafil 10 mg/kg for 7 days. After treatments, serum tumor necrosis factor-α (TNF-α), interleukin- 6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) and platelet-derived growth factor (PDGF) were analyzed by ELISA. Liver tissue samples were analyzed for tissue total oxidant/antioxidant status (TOS, TAS), thiol, TTL (total thiol level), NTL (native thiol level) using colorimetric appropriate methods. Results: We found that serum ICAM-1 in group 5 was higher than other groups, ICAM-1 in group 4 was higher than group 2 (g1 vs. g5 p<0.001, g2 vs. g4 p=0.016, g2 vs. g5 p<0.001, g3 vs. g5 p=0.004, g4 vs. g5 p=0.03). PDGF was higher in group 5 than group 1 (p=0.025). Tissue TTL and NTL were higher in group 5 than in group 1 (p=0.035, p=0.002). TOS was higher in group 5 than groups 1 and 4 (p=0.028, p=0.028). TAS was higher in group 5 than group 3 (p=0.018). Conclusion: High-dose and long-term administration of tadalafil increased oxidative and inflammatory responses in liver tissue. [ABSTRACT FROM AUTHOR]

After a focused telehealth visit, patients can now access phosphodiesterase-5 inhibitor (PDE5 inhibitor) prescriptions through online direct-to-consumer (DTC) healthcare companies. This study seeks to quantify the cost of DTC PDE5 inhibitor treatment compared to a traditional physician visit and local pharmacy prescription. Two DTC companies, two compounding pharmacies with national reach, three online Canadian pharmacies, and sixteen American pharmacy chains were queried for prices of 90-day regimens of common PDE5 inhibitors. Prices for chains were determined using their publicly available price on GoodRx® with coupon. Cost of physician visit was determined using 2020 Center for Medicare and Medicaid Services reimbursement for a level 3 new patient visit. For sildenafil 20 mg, a physician visit and local prescription cost a low of $125.45 compared to $144.35 for compounding, $169.34 for Canadian, and $195.00 for DTC. For sildenafil 100 mg, a physician visit and local prescription cost a low of $137.16 compared to $289.35 for compounding, $200.36 for Canadian, and $900.00 for DTC. For tadalafil 5 mg, a physician visit and local prescription cost a low of $125.80 compared to $169.35 for compounding, $195.34 for Canadian, and $720.00 for DTC. For tadalafil 20 mg, a physician visit and local prescription cost a low of $161.00 compared to $289.35 for compounding, $229.00 for Canadian, and $2880.00 for DTC. Thus, local pharmacies, in conjunction with online coupons, consistently provide a markedly less-expensive option for fulfillment of PDE5 inhibitor prescriptions than online DTC services.

Abstract In pulmonary hypertension (PH) associated with chronic lung disease (CLD), identifying patients who would benefit from pulmonary vasodilators is a significant clinical challenge because the presence of PH is associated with poorer survival. This study evaluated the severity of pulmonary circulation impairment in patients with CLD‐PH using pulmonary perfusion single‐photon emission computed tomography/computed tomography (SPECT/CT). This single‐center, observational study enrolled patients with CLD‐PH who had a mean pulmonary arterial pressure (PAP) ≥ 25 mmHg, as confirmed by right heart catheterization. The primary outcome was to measure the percentage of pulmonary perfusion defect (%PPD), calculated by dividing the perfusion defect volume from perfusion SPECT images by the lung volume from CT scan images. The secondary outcome was to assess the correlation between %PPD and baseline characteristics. The median %PPD was 52.4% (interquartile range, 42.5%–72.3%) in 22 patients. In multivariate linear regression analysis, both forced vital capacity (β = 0.58, p = 0.008) and mean PAP (β = 0.68, p = 0.001) were significantly correlated with %PPD. In conclusion, significant correlation between mean PAP and %PPD in patients with CLD‐PH was observed. This noninvasive assessment of %PPD may be useful for evaluating the severity of pulmonary circulation impairment in CLD‐PH.

In this study, a designed hapten possessing the classic structure of PDE-5 inhibitors was synthesized. A monoclonal antibody (mAb) with broad recognition for six PDE-5 inhibitors was further produced. For the determination of lodenafil, methisosildenafil, mirodenafil, udenafil and tadalafil, the limit of detection (LOD) and IC50 ranged from 1.01 to 26.91 ng mL-1 and 12.75 to 278 ng mL-1, respectively. Thereafter, a quantum dot bead-based lateral flow immunoassay (QB-LFIA) was developed, which improved the LOD and IC50 to 0.32-6.52 ng mL-1 and 7.45-133.8 ng mL-1, respectively. Method validation was conducted using honey and capsule samples spiked with PDE-5 inhibitors, and the recoveries of the intra- and inter-assays ranged from 81.01% to 108.16%, with coefficients of variation below 12.71%. In addition, the validity and the consistency have been confirmed with a comparison between QB-LFIA and HPLC-MS/MS (R2 = 0.9957). Furthermore, the developed QB-LFIA was employed for the inspection of real products, and several samples were found to be adulterated with lodenafil and methisosildenafil.

ObjectiveExamine prospective relationships between erectile dysfunction (ED) drugs EDand CD4 and CD8 T-cells, and immune markers among men who have sex with men (MSM).MethodsData from Multicenter AIDS Cohort Study, an observational prospective cohort study, with semi-annual follow-ups conducted in four U.S. centers from 1998 onwards was used. Marginal structural models using g-computation was fitted to estimate the mean differences for the effects of self-reported ED drug use on CD4 and CD8 T-cell outcomes and immune biomarkers.ResultsTotal of 1,391 men with HIV (MWH) and 307 men without HIV (MWOH) was included. Baseline mean CD4 cell count among MWH and MWOH was 499.9 cells/μL and 966.7 cells/μL, respectively. At baseline, 41.8% of MWH were virally suppressed. ED drug users reported a mean of 44.4 months of exposure to ED drugs. ED drug use was associated with increased CD4 cell outcomes among MWH but not MWOH. Mean differences in CD4 cell counts after 1 year of ED drug use was 57.6 cells/μL and increased to 117.7 after 10 years among MWH. CD8 counts were higher in ED drug users among MWH over 10 years than non-users; no consistent differences were found among MWOH. ED drug use appeared to reduce immune marker levels, such as IL-6 and increase markers, such as IL-10. We observed similar effects of ED drug use on biomarker levels among MWOH.ConclusionLong-term use of ED drugs do not adversely affect immune function among MWH or MWOH. Future studies on the relationships between different types of ED drugs and effects on T-cell subtypes are warranted.

Purpose: We investigated whether the use of a phosphodiesterase-5 inhibitor (PDE5i) after robot assited radical prostatectomy has a survival benefit over non-use patients because there are controversial results on the association between PDE5i use and survival outcomes for prostate cancer patients in literature. Materials and Methods: We designed a retrospective, matched, large-sample cohort study of 5,545 patients who underwent robot assisted radical prostatectomy (RARP) during 2013–2021 in a single institute. The exclusion criteria was patients who were aged >70 years at surgery, American Society of Anesthesiologists (ASA) physical status classification grade 4 or 5, history of other malignancies, patients who started PDE5i 6 months after survery and patients with follow up period less than 24 months after surgery. Among the 1,843 included patients, 1,298 were PDE5i users, and 545 were PDE5i non-users. We performed propensity score matching (PSM) of PDE5i users (n=529) with non-users (n=529) by adjusting for the variables of age, Gleason grade group, pathological T stage, preoperative ASA physical status grade, and International Index of Erectile Function score. Results: There were no significant difference in patient characteristics according to PSM. Kaplan–Meier curve revealed the difference of overall survival for PDE5i users and non-users (clustered log-rank test p

We investigated the longitudinal relationship between erectile dysfunction (ED) drug use with behavioral factors, including substance use and sexual activities in men who have sex with men from the Multicenter AIDS Cohort Study during 1998-2016 (n = 1636). We used a bivariate random-intercept model to evaluate ED drug use along with other behavioral factors to assess relationships between the two outcomes over time on a population level and also at the individual level. Average ED drug use among men who have sex with men (MSM) with HIV was positively correlated with average use of marijuana (r = .19), poppers (r = .27), and stimulants (r = .25). In this group, testosterone use (r = .32), multiple partners (r = .41), insertive anal intercourse with condom (r = .40), and insertive anal intercourse without condom (r = .43) all showed moderate correlations over time with average ED use (p

Purpose: In this study, we aimed to evaluate the clinical utility of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and monocyte/high-density lipoprotein cholesterol ratio (MHR) in predicting response to a phosphodiesterase type 5 inhibitor (PDE5i) when used as the first-line medical treatment of erectile dysfunction (ED). Materials and Methods: This study prospectively included 185 patients who were diagnosed with ED and started PDE5i treatment. After PDE5i treatment, 107 (57.8%) patients with an International Index of Erectile Function-5 (IIEF-5) score below 22 were assigned to Group 1, and 78 (42.2%) patients with an IIEF-5 score of 22 or above were assigned to Group 2. The outcome measures of the study were demographic characteristics and inflammation markers between the groups. Results: The mean IIEF-5 change after PDE5i treatment was 6.1±4.2 points in Group 1 and 11.5±3.2 points in Group 2 (p=0.001). The mean age was 54.6±9.2 years in Group 1 and 47.8±10.3 years in Group 2 (p

Purpose: To evaluate the efficacy and safety of udenafil 75 mg once daily in patients with erectile dysfunction following bilateral nerve-sparing robot-assisted laparoscopic radical prostatectomy (BNS-RALP). Materials and Methods: A multi-center, prospective, randomized, controlled, double-blind study was conducted. Among patients with localized prostate cancer with international index of erectile function-erectile function domain (IIEF-EF) score of 18 or higher before BNS-RALP, those who developed postoperative erectile dysfunction (IIEF-EF score 14 or less at 4 weeks after BNS-RALP) were enrolled. Enrolled patients were randomly assigned to the udenafil 75 mg daily group or the placebo group in a 2:1 ratio. Each subject was followed up at 8 weeks (V2), 20 weeks (V3), and 32 weeks (V4) to evaluate the efficacy and safety of udenafil. Results: In all, 101 patients were screened, of whom 99 were enrolled. Of the 99 patients, 67 were assigned to the experimental group and 32 to the control group. Ten (14.93%) patients in the experimental group and 10 (31.25%) in the control group dropped out of the study. After 32 weeks of treatment, IIEF-EF score of 22 or higher was seen in 36.51% (23/63) of patients in the experimental group and 13.04% (3/23) patients in the control group (p=0.021). The proportion of patients with IIEF-EF improvement of 25% or more compared to the baseline was 82.54% (52/63) in the experimental group and 62.96% (17/27) in the control group (p=0.058). Conclusions: Udenafil 75 mg once daily after BNS-RALP improved the erectile function without any severe adverse effects.

Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy in treating male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), a plethora of studies have unveiled their significance in the treatment of a myriad of other diseases, including cognitive functions, heart failure, multiple drug resistance in cancer therapy, immune diseases, systemic sclerosis and others. This comprehensive review aims to provide an updated assessment of the crucial role played by PDE5 inhibitors (PDE5-Is) as disease-modifying agents taking their limiting side effects into consideration. From a medicinal chemistry and drug discovery perspective, the published PDE5-Is over the last 10 years and their binding characteristics are systemically discussed, and advancement in properties is exposed. A persistent challenge encountered with these agents lies in their limited isozyme selectivity; considering this obstacle, this review also highlights the breakthrough development of the recently reported PDE5 allosteric inhibitors, which exhibit an unparalleled level of selectivity that was rarely achievable by competitive inhibitors. The implications and potential impact of these novel allosteric inhibitors are meticulously explored. Additionally, the concept of multi-targeted ligands is critically evaluated in relation to PDE5-Is by inspecting the broader spectrum of their molecular interactions and effects. The objective of this review is to provide insight into the design of potent, selective PDE5-Is and an overview of their biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects and emerging uses, thus guiding upcoming endeavors in both academia and industry within this domain. [ABSTRACT FROM AUTHOR]

Purpose Although pathogenic mechanisms of moyamoya disease (MMD) remain unknown, recent studies suggest that it is a caveolae disease. This study evaluated the effect of udenafil, a phosphodiesterase-5 inhibitor, on angiogenesis in in vitro and in vivo MMD models. Methods Angiogenesis and vessel maturation were assessed in in vitro models, caveolin- 1 (Cav-1) knockdown human umbilical vessel endothelial cells (HUVECs) and coronary artery smooth muscle cells (CASMCs), and in in vivo model of bilateral internal carotid artery occlusion (bICAo). Udenafil was administered (1,3,10, and 30 μM) in cell culture conditions, and functional studies (migration and tube formation assay) were performed and vessel maturation factors and cyclic guanosine monophosphate (cGMP) accumulation were measured. Results Udenafil (3 and 10 mg/kg) was orally administered once daily for 4 weeks in bICAo rat model, and histological analysis for angiogenesis and vessel maturation was performed. Udenafil increased vessel formation in both Cav-1 knockdown HUVEC and bICAo models without increased migration/proliferation of HUVECs and CASMCs. Udenafil increased CD31+ vessel density and NG2/Col4+ mural cell density in bICAo models. Cav-1 knockdown inhibited accumulation of cGMP, and udenafil treatment restored cGMP levels in Cav-1 knockdown HUVEC models. Vessel maturation factors (angiopoietin- 1 and platelet-derived growth factor receptor-β) and angiogenic factors (endothelial nitric oxide synthase) were increased after treatment with udenafil in vitro. Conclusion Our results indicate that udenafil reversed cellular levels of cGMP related to Cav-1 deficiency and induced angiogenesis and vessel maturation. Further studies are warranted to confirm the therapeutic effects of this strategy in MMD.

Lymphatic malformations (LMs) are rare congenital anomalies. LMs are often refractory to standard treatments, including surgical resection, debulking, and sclerotherapy. Use of sildenafil, a phosphodiesterase-5 inhibitor, for treatment of pediatric LMs has been reported with demonstrated benefit to some patients. This case series reports treatment of three patients (aged 14-37 years) suffering from complicated or refractory LMs with a low-dose oral phosphodiesterase-5 inhibitor, resulting in significant clinical improvement.

Purpose: To compare the efficacy and adverse events of sildenafil monotherapy for benign prostatic hyperplasia (BPH) with its FDA-approved counterpart, tadalafil. Materials and Methods: In this single-arm self-controlled clinical trial, 33 patients were enrolled. All patients underwent a 6-week treatment with sildenafil, followed by a 4-week washout period and finally a 6-week treatment with tadalafil. Patients were examined on each appointment and post-void residual (PVR) urine, International Prostate Symptom Score (IPSS) and Quality of life index (IPSS-QoL index) were recorded subsequently. Efficacy of each drug regimen was then evaluated by comparing these outcome parameters. Results: Both sildenafil and tadalafil were shown to improve PVR (both p < .001), IPSS (both p < .001) and IP- SS-QoL index (both p < .001) significantly. Sildenafil was more effective than tadalafil in reducing PVR (mean difference (95%CI) = 9.91% (4.11, 15.72), p < .001) and ameliorating IPSS-QoL index (mean difference (95%CI) = 19.3% (4.47, 34.41), p = .027). Moreover, although not significant, sildenafil reduced IPSS more than tadalafil (mean difference (95%CI) = 3.33% (-0.22, 6.87), p = .065). Concurrent erectile dysfunction did not affect respon- siveness to therapy with either sildenafil or tadalafil but age was inversely related to post-treatment IPSS in both sildenafil (B = 0.21 (0.04, 0.37), p = .015) and tadalafil (B = 0.14 (0.02, 0.26), p = .021) regimens with a more prominent role in responsiveness to sildenafil (β = 0.31) compared to tadalafil (β = 0.19). Conclusion: Considering the significantly better improvement of PVR and IPSS-Qol index with sildenafil, this drug can be nominated as a suitable alternative for tadalafil as a BPH treatment, especially in younger patients who don’t have any contraindications. [ABSTRACT FROM AUTHOR]

Purpose: In this study, we aimed to evaluate the clinical utility of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and monocyte/high-density lipoprotein cholesterol ratio (MHR) in predicting response to a phosphodiesterase type 5 inhibitor (PDE5i) when used as the first-line medical treatment of erectile dysfunction (ED). Materials and Methods: This study prospectively included 185 patients who were diagnosed with ED and started PDE5i treatment. After PDE5i treatment, 107 (57.8%) patients with an International Index of Erectile Function-5 (IIEF-5) score below 22 were assigned to Group 1, and 78 (42.2%) patients with an IIEF-5 score of 22 or above were assigned to Group 2. The outcome measures of the study were demographic characteristics and inflammation markers between the groups. Results: The mean IIEF-5 change after PDE5i treatment was 6.1±4.2 points in Group 1 and 11.5±3.2 points in Group 2 (p=0.001). The mean age was 54.6±9.2 years in Group 1 and 47.8±10.3 years in Group 2 (p<0.001), and the mean fasting blood glucose values of Groups 1 and 2 were 131.1±62.4 and 111.8±47.7 mg/dL, respectively (p=0.023). The LMR and MHR values were 2.39±0.23 and 13.8±7, respectively, for Group 1, and 2.03±0.22 and 17±6.6, respectively, for Group 2 (p=0.044 and p=0.002, respectively). On multivariable analysis, younger age and increased MHR were independent predictors of benefit from PDE5i treatment. Conclusions: This study showed that only MHR as an inflammatory biomarker was an independent predictor for response to PDE5i in the treatment of ED. Also, several factors were predictive of treatment failure. [ABSTRACT FROM AUTHOR]

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Abstract Background and objective Epimedii has long been used as a traditional medicine in Asia for the treatment of various common diseases, including Alzheimer's disease, cancer, erectile dysfunction, and stroke. Studies have reported the ameliorative effects of Icariside II (ICS II), a major metabolite of Epimedii, on acute ischemic stroke (AIS) in animal models. Based on network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we conducted a systematic review to evaluate the effects and neuroprotective mechanisms of ICS II on AIS. Methods First, we have searched 6 databases using studies with ICS II treatment on AIS animal models to explore the efficacy of ICS II on AIS in preclinical studies. The literature retrieval time ended on March 8, 2022 (Systematic Review Registration ID: CRD42022306291). There were no restrictions on the language of the search strategy. Systematic review follows the Patient, Intervention, Comparison and Outcome (PICO) methodology and framework. SYCLE's RoB tool was used to evaluate the the risk of bias. In network pharmacology, AIS-related genes were identified and the target-pathway network was constructed. Then, these targets were used in the enrichments of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO). Molecular docking and MD simulation were finally employed between ICS II and the potential target genes. Results Twelve publications were included describing outcomes of 1993 animals. The literature details, animal strains, induction models, doses administered, duration of administration, and outcome measures were extracted from the 12 included studies. ICS II has a good protective effect against AIS. Most of the studies in this systematic review had the appropriate methodological quality, but some did not clearly state the controlling for bias of potential study. Network pharmacology identified 246 targets with SRC, CTNNB1, HSP90AA1, MAPK1, and RELA as the core target proteins. Besides, 215 potential pathways of ICS II were identified, such as PI3K-Akt, MAPK, and cGMP-PKG signaling pathway. GO enrichment analysis showed that ICS II was significantly enriched in subsequent regulation such as MAPK cascade. Molecular docking and MD simulations showed that ICS II can closely bind with important targets. Conclusions ICS II is a promising drug in the treatment of AIS. However, this systematic review reveals key knowledge gaps (i.e., the protective role of ICS II in women) that ICS II must address before it can be used for the treatment of human AIS. Our study shows that ICS II plays a protective role in AIS through multi-target and multi-pathway characteristics, providing ideas for the development of drugs for the treatment of AIS.

Background: Chronic obstructive pulmonary disease-associated pulmonary hypertension (PH-COPD) results in a significant impact on symptoms, quality of life, and survival. There is scant and conflicting evidence about the use of pulmonary hypertension (PH) specific therapy in patients with PH-COPD. Study Design and Methods: PubMed, OVID, CINAHL, Cochrane, Embase, and Web of Science were searched using various MESH terms to identify randomized controlled trials (RCTs) or observational studies investigating PH-specific therapies in patients with severe PH-COPD, defined by mean pulmonary artery pressure (mPAP) of more than 35 mm Hg or pulmonary vascular resistance (PVR) of more than 5 woods units on right heart catheterization. The primary outcome was a change in mPAP and PVR. Secondary outcomes were changes in six-minute walk distance (6MWD), changes in the brain-natriuretic peptide (BNP), New York Heart Association (NYHA) functional class, oxygenation, and survival. Results: Thirteen studies satisfied the inclusion criteria, including a total of 328 patients with severe PH-COPD. Out of these, 308 patients received some type of specific therapy for PH. There was a significant reduction in mPAP (mean difference (MD) −3.68, 95% CI [−2.03, −5.32], p < 0.0001) and PVR (MD −1.40 Wood units, 95% CI [−1.97, −0.82], p < 0.00001). There was a significant increase in the cardiac index as well (MD 0.26 L/min/m2, 95% CI [0.14, 0.39], p < 0.0001). There were fewer patients who had NYHA class III/lV symptoms, with an odds ratio of 0.55 (95% CI [0.30, 1.01], p = 0.05). There was no significant difference in the 6MWD (12.62 m, 95% CI [−8.55, 33.79], p = 0.24), PaO2 (MD −2.20 mm Hg, 95% CI [−4.62, 0.22], p = 0.08), or BNP or NT-proBNP therapy (MD −0.15, 95% CI [−0.46, 0.17], p = 0.36). Conclusion: The use of PH-specific therapies in severe PH-COPD resulted in a significant reduction in mPAP and PVR and increased CI, with fewer patients remaining in NYHA functional class III/IV. However, no significant difference in the 6MWD, biomarkers of right ventricular dysfunction, or oxygenation was identified, demonstrating a lack of hypoxemia worsening with treatment. Further studies are needed to investigate the use of PH medications in patients with severe PH-COPD.

Background In murine heart failure models and in humans with diabetic-related heart hypertrophy, inhibition of phosphodiesterase 5 (PDE5) by sildenafil improves cardiac outcomes. However, the mechanism by which sildenafil improves cardiac function is unclear. We have observed a relationship between PDE5 and β2 adrenergic receptor (β2AR), which is characterized here as a novel mechanistic axis by which sildenafil improves symptoms of diabetic cardiomyopathy. Methods and Results Wild-type and β2AR knockout mice fed a high fat diet (HFD) were treated with sildenafil, and echocardiogram analysis was performed. Cardiomyocytes were isolated for excitation-contraction (E-C) coupling, fluorescence resonant energy transfer, and proximity ligation assays; while heart tissues were implemented for biochemical and histological analyses. PDE5 selectively associates with β2AR, but not β1 adrenergic receptor, and inhibition of PDE5 with sildenafil restores the impaired response to adrenergic stimulation in HFD mice and isolated ventriculomyocytes. Sildenafil enhances β adrenergic receptor (βAR)-stimulated cGMP and cAMP signals in HFD myocytes. Consequently, inhibition of PDE5 leads to protein kinase G-, and to a lesser extent, calcium/calmodulin-dependent kinase II-dependent improvements in adrenergically stimulated E-C coupling. Deletion of β2AR abolishes sildenafil's effect. Although the PDE5-β2AR association is not altered in HFD, phosphodiesterase 3 displays an increased association with the β2AR-PDE5 complex in HFD myocytes. Conclusions This study elucidates mechanisms by which the β2AR-PDE5 axis can be targeted for treating diabetic cardiomyopathy. Inhibition of PDE5 enhances β2AR stimulation of cGMP and cAMP signals, as well as protein kinase G-dependent E-C coupling in HFD myocytes.

Background and aimNitric oxide (NO) is the intracellular chemical responsible for initiating a penile erection. Despite conflicting clinical data, it continues to be publicized and promoted that orally administered l-arginine, the putative substrate for NO, enhances the erectile response presumably by stimulating NO production by the corporal tissues resulting in an increase in cGMP production. To shed light on this issue, an in vitro study was conducted to explore the effect of direct exogenous administration of l-arginine as well as its precursor and metabolite, l-citrulline, on the NO-cGMP pathway within the cavernosal smooth muscle (CSM) cell.Materials and methodsCSM cells obtained from 8 to 10 week old Sprague-Dawley rats were grown in Dulbecco media with 20% fetal calf serum and then incubated with or without l-arginine (L-ARG) or l-citrulline (L-CIT) in a time course and dose-response manner. Sildenafil (0.4 mM), IBMX (1 mM), l-NAME (3 μM), ODQ (5 μM) and Deta Nonoate (10 μM) were used as either inhibitors or stimulators of the NO-cGMP pathway. mRNA and protein were extracted and used for the determination of the phosphodiesterase 5 (PDE5). PDE5 activity was determined by luminometry. cGMP content was determined by ELISA. Nitrite formation, an indicator of NO production, was measured in the cell culture media by a colorimetric assay. The cationic (CAT-1) and neutral (SNAT-1) amino acid transporters for L-ARG and L-CIT, respectively, were determined by Western blot.ResultsWhen compared to untreated CSM cells, incubation with 0.25-4.0 mM of L-ARG or 0.3-4.8 mM of L-CIT anywhere between 3 and 24 h did not result in any additional nitrite or cGMP production. The addition of l-NAME, IBMX or ODQ to these L-ARG and L-CIT treated cells did not alter these results. L-CIT but not L-ARG increased PDE5 mRNA and protein content as well as the activity of the PDE5 enzyme. Both CAT-1 and SNAT-1 were expressed in the CSM cells.ConclusionsThis in vitro study demonstrates that exogenous administration of L-ARG or L-CIT failed to stimulate production of either NO or cGMP by the corporal CSM cells. A re-evaluation of the presumptive role of the exogenous administration of L-ARG in improving the synthesis of NO at least at the level of the CSM cells appears warranted.

Age-related macular degeneration (AMD) - the leading cause of vision loss in the elderly - share many risks factors as atherosclerosis, which exhibits loss of vascular compliance resulting from aging and oxidative stress. Here, we attempt to explore choroidal and retinal vascular compliance in patients with AMD by evaluating dynamic vascular changes using live ocular imaging following treatment with oral sildenafil citrate, a phosphodiesterase type 5 (PDE5) inhibitor and potent vasodilator. Enhanced-depth imaging optical coherence tomography (EDI-OCT) and OCT angiography (OCT-A) were performed on 46 eyes of 23 subjects, including 15 patients with non-exudative AMD in one eye and exudative AMD in the fellow eye, and 8 age-matched control subjects. Choroidal thickness, choroidal vascularity, and retinal vessel density were measured across the central macula at 1 and 3 hours after a 100 mg oral dose of sildenafil citrate. Baseline choroidal thickness was 172.1 ± 60.0 μm in non-exudative AMD eyes, 196.4 ± 89.8 μm in exudative AMD eyes, and 207.4 ± 77.7 μm in control eyes, with no difference between the 3 groups (P = 0.116). After sildenafil, choroidal thickness increased by 6.0% to 9.0% at 1 and 3 hours in all groups (P = 0.001-0.014). Eyes from older subjects were associated with choroidal thinning at baseline (P = 0.005) and showed less choroidal expansion at 1 hour and 3 hours after sildenafil (P = 0.001) regardless of AMD status (P = 0.666). The choroidal thickening appeared to be primarily attributed to expansion of the stroma rather than luminal component. Retinal vascular density remained unchanged after sildenafil in all 3 groups (P = 0.281-0.587). Together, our studies suggest that vascular response of the choroid to sildenafil decreases with age, but is not affected by the presence of non-exudative or exudative AMD, providing insight into changes in vessel compliance in aging and AMD.

PurposeTo examine the association between phosphodiesterase type 5 (PDE5) inhibitor use and melanoma by 1) conducting a systematic review of observational studies; and 2) determining if low PDE5A gene expression in human melanoma correlated with decreased overall survival.Materials and methodsA systematic search of observational studies examining the association between PDE5 inhibitor use and melanoma was performed through ClinicalTrials.gov, the Cochrane Library, EMBASE, PubMed, and Web of Science databases, and seven eligible studies were identified. PDE5A gene expression was analyzed with RNA sequencing data from 471 human melanoma samples obtained from The Cancer Genome Atlas.ResultsFour studies reported a positive association between PDE5 inhibitor use and melanoma, and three studies found no correlation. RNA sequencing data analysis revealed that under-expression of the PDE5A gene did not impact clinical outcomes in melanoma.ConclusionsThere is currently no evidence to suggest that PDE5 inhibition in patients causes increased risk for melanoma. The few observational studies that demonstrated a positive association between PDE5 inhibitor use and melanoma often failed to account for major confounders. Nonetheless, the substantial evidence implicating PDE5 inhibition in the cyclic guanosine monophosphate (cGMP)-mediated melanoma pathway warrants further investigation in the clinical setting.

Purpose: To investigate the efficacy, safety, and tolerability of oro-dispersible film (ODF) formulation of mirodenafil 50 mg and 100 mg for the treatment of patients with erectile dysfunction (ED) in Korea. Materials and Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 129 subjects was performed. Subjects were randomized to either placebo or mirodenafil ODF 50 mg or 100 mg to be taken in an “on demand” manner for 8 weeks. The primary efficacy variable was the International Index of Erectile Dysfunction (IIEF)-5 questionnaire. The secondary efficacy variables comprised Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3), the Global Assessment Question (GAQ), and the Life Satisfaction Checklist (LSC). Results: IIEF-5 was significantly increased in all groups after treatment. However, compared to the placebo group, only the mirodenafil ODF 100 mg group showed a significant difference. SEP2 and SEP3 were increased in both mirodenafil groups; however, the increase was not statistically significant for SEP2. In terms of GAQ and LSC, the mirodenafil ODF groups showed significant increases compared with the baseline. Most treatment-associated adverse events were mild and resolved spontaneously. Conclusions: Mirodenafil ODF is an effective and well-tolerated agent for the treatment of patients with ED in Korea.

Phosphodiesterase 5 (PDE5) inhibitors presented themselves as important players in the nitric oxide/cGMP pathway, thus exerting a profound impact on various physiological and pathological processes. Beyond their well-known efficacy in treating male erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), a plethora of studies have unveiled their significance in the treatment of a myriad of other diseases, including cognitive functions, heart failure, multiple drug resistance in cancer therapy, immune diseases, systemic sclerosis and others. This comprehensive review aims to provide an updated assessment of the crucial role played by PDE5 inhibitors (PDE5-Is) as disease-modifying agents taking their limiting side effects into consideration. From a medicinal chemistry and drug discovery perspective, the published PDE5-Is over the last 10 years and their binding characteristics are systemically discussed, and advancement in properties is exposed. A persistent challenge encountered with these agents lies in their limited isozyme selectivity; considering this obstacle, this review also highlights the breakthrough development of the recently reported PDE5 allosteric inhibitors, which exhibit an unparalleled level of selectivity that was rarely achievable by competitive inhibitors. The implications and potential impact of these novel allosteric inhibitors are meticulously explored. Additionally, the concept of multi-targeted ligands is critically evaluated in relation to PDE5-Is by inspecting the broader spectrum of their molecular interactions and effects. The objective of this review is to provide insight into the design of potent, selective PDE5-Is and an overview of their biological function, limitations, challenges, therapeutic potentials, undergoing clinical trials, future prospects and emerging uses, thus guiding upcoming endeavors in both academia and industry within this domain.

This study aimed to determine the influence of cyclic guanosine 35-monophosphate (cGMP) and cGMP-dependent kinase (PKG) during in vitro maturation (IVM) on lipolysis-related parameters in bovine cumulus-oocyte complexes (COCs), and on embryo development and cryosurvival. COCs were matured with cGMP/PKG modulators and assessed for metaphase II rates (MII), cGMP levels, lipid content in oocytes (OO), transcript abundance for genes involved in lipolysis (ATGL) and lipid droplets (PLIN2) in cumulus cells (CC) and OO, and presence of phosphorylated (active) hormone sensitive lipase (HSLser563) in OO. Embryo development, lipid contents and survival to vitrification were also assessed. Phosphodiesterase 5 inhibition (PDE5; cGMP-hydrolyzing enzyme) with 10-5M sildenafil (SDF) during 24 h IVM increased cGMP in COCs (56.9 vs 9.5 fMol/COC in untreated controls, p

BackgroundIschemia, in the absence of obstructive coronary artery disease, is prevalent in women, and associated with increased risk for major cardiovascular events. Coronary microvascular dysfunction is prevalent in these patients, and associated with impaired diastolic function. Despite our general understanding, however, optimal treatment of this cohort remains elusive.MethodsTo address this knowledge gap, we performed an open-label treatment trial to assess whether phosphodiesterase type 5 inhibition improves coronary microvascular perfusion and diastolic function in women with signs and symptoms of ischemia but no evidence of obstructive coronary artery disease. Left ventricular morphology and function, along with myocardial perfusion reserve index, were assessed by contrast-enhanced cardiac magnetic resonance imaging.ResultsA total of five women enrolled of which four completed the trial, while one was withdrawn by the investigators after developing dyspnea 1 week after treatment. Her symptoms resolved after cessation of the study medication. In contrast to our hypothesis, phosphodiesterase type 5 inhibition reduced the rate of circumferential strain in diastole in all four women who completed the trial (that is, diastolic dysfunction). This impairment could not be explained by changes in heart rate, contractility, blood pressure, or preload, and was not associated with a change in myocardial perfusion reserve index. Frequency of angina also tended to increase with treatment, with the greatest increase occurring in the patient with the greatest impairment in diastolic strain.ConclusionsTaken together, these data question the efficacy of phosphodiesterase type 5 inhibition to treat women with ischemic heart disease, and highlight the need for further investigation.

Background and objective: Epimedii has long been used as a traditional medicine in Asia for the treatment of various common diseases, including Alzheimer's disease, cancer, erectile dysfunction, and stroke. Studies have reported the ameliorative effects of Icariside II (ICS II), a major metabolite of Epimedii, on acute ischemic stroke (AIS) in animal models. Based on network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we conducted a systematic review to evaluate the effects and neuroprotective mechanisms of ICS II on AIS. Methods: First, we have searched 6 databases using studies with ICS II treatment on AIS animal models to explore the efficacy of ICS II on AIS in preclinical studies. The literature retrieval time ended on March 8, 2022 (Systematic Review Registration ID: CRD42022306291). There were no restrictions on the language of the search strategy. Systematic review follows the Patient, Intervention, Comparison and Outcome (PICO) methodology and framework. SYCLE's RoB tool was used to evaluate the the risk of bias. In network pharmacology, AIS-related genes were identified and the target-pathway network was constructed. Then, these targets were used in the enrichments of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO). Molecular docking and MD simulation were finally employed between ICS II and the potential target genes. Results: Twelve publications were included describing outcomes of 1993 animals. The literature details, animal strains, induction models, doses administered, duration of administration, and outcome measures were extracted from the 12 included studies. ICS II has a good protective effect against AIS. Most of the studies in this systematic review had the appropriate methodological quality, but some did not clearly state the controlling for bias of potential study. Network pharmacology identified 246 targets with SRC, CTNNB1, HSP90AA1, MAPK1, and RELA as the core target proteins. Besides, 215 potential pathways of ICS II were identified, such as PI3K-Akt, MAPK, and cGMP-PKG signaling pathway. GO enrichment analysis showed that ICS II was significantly enriched in subsequent regulation such as MAPK cascade. Molecular docking and MD simulations showed that ICS II can closely bind with important targets. Conclusions: ICS II is a promising drug in the treatment of AIS. However, this systematic review reveals key knowledge gaps (i.e., the protective role of ICS II in women) that ICS II must address before it can be used for the treatment of human AIS. Our study shows that ICS II plays a protective role in AIS through multi-target and multi-pathway characteristics, providing ideas for the development of drugs for the treatment of AIS. [ABSTRACT FROM AUTHOR]

Objective : Patients with mild ischemic stroke experience various sequela and residual symptoms, such as anxious behavior and deficits in movement. Few approaches have been proved to be effective and safe therapeutic approaches for patients with mild ischemic stroke by acute stroke. Sildenafil (SIL), a phosphodiesterase-5 inhibitor (PDE5i), is a known remedy for neurodegenerative disorders and vascular dementia through its angiogenesis and neurogenesis effects. In this study, we investigated the efficacy of PDE5i in the emotional and behavioral abnormalities in rats with mild ischemic stroke. Methods : We divided the rats into four groups as follows (n=20, respectively) : group 1, naïve; group 2, middle cerebral artery occlusion (MCAo30); group 3, MCAo30+SIL-pre; and group 4, MCAo30+SIL-post. In the case of drug administration groups, single dose of PDE5i (sildenafil citrate, 20 mg/kg) was given at 30-minute before and after reperfusion of MCAo in rats. After surgery, we investigated and confirmed the therapeutic effect of sildenafil on histology, immunofluorescence, behavioral assays and neural oscillations. Results : Sildenafil alleviated a neuronal loss and reduced the infarction volume. And results of behavior task and immunofluorescence shown possibility that anti-inflammation process and improve motor deficits sildenafil treatment after mild ischemic stroke. Furthermore, sildenafil treatment attenuated the alteration of theta-frequency rhythm in the CA1 region of the hippocampus, a known neural oscillatory marker for anxiety disorder in rodents, induced by mild ischemic stroke. Conclusion : PDE5i as effective therapeutic agents for anxiety and movement disorders and provide robust preclinical evidence to support the development and use of PDE5i for the treatment of mild ischemic stroke residual disorders. [ABSTRACT FROM AUTHOR]

Purpose: Male infertility is a worldwide problem with limitations in the treatment. Phosphodiesterase-5 inhibitors (PDE5is) is the first choice for the treatment of erectile dysfunction, more and more studies show that it has a certain effect on male infertility in recent years. But there was currently no high quality of systematic review to evaluate the effects of PDE5is on semen quality. Materials and Methods: We retrieved the electronic databases of MEDLINE, PubMed, Web of Science, EMBASE, etc. Related randomized controlled trials (RCTs) were collected and selected up to May 20, 2020. We have searched literature with terms “male infertility”, “phosphodiesterase-5 inhibitors”, “PDE5i”, “Tadalafil”, “Sildenafil”, “Vardenafil”, “Udenafil”, “Avanafil”, “semen”, and “sperm”. Mean value and its standard deviation were used to perform quantitative analysis. All statistical analyses were conducted by RevMan 5.3 and Stata software. Results: There were a total of 1,121 participants in the nine included studies. There was a statistically significant improvement treated with PDE5is compared with sham therapy, which including sperm concentration (mean difference [MD]=1.96, 95% confidence interval [CI]=1.70–2.21, p

Background Pharmacologic treatment for pulmonary arterial hypertension (PAH) improves exercise capacity, functional class, and hemodynamic indexes. However, monthly prescription costs often exceed $4000. We examined associations between (1) medication copayment and (2) annual household income with adherence to pulmonary vasodilator therapy among individuals with PAH. Methods and Results We used administrative claims data from an insured population in the United States to identify individuals diagnosed with PAH between 2015 and 2020. All individuals had ≥1 medication claim for endothelin receptor antagonists, phosphodiesterase type‐5 inhibitors, prostanoids or prostacyclin receptor agonists, or the soluble guanylate cyclase stimulator riociguat. We defined copayments as low, medium, or high, as determined by their distributions for each medication class. Annual household income was categorized as

The proliferation of adulterated health foods and beverages in the market demands a comprehensive analytical strategy to identify the adulterants, particularly those of isomeric phosphodiesterase 5 (PDE5) inhibitors. An instant coffee premix (ICP) purchased from an online retailer was flagged for suspected adulteration through PDE5 inhibition assay. The ICP was then analysed using suspected-target and non-targeted screenings of a liquid chromatography-quadrupole time-of-flight mass spectrometry. Based on these findings, a PDE5 inhibitor initially assigned as compound X was isolated from the ICP by employing a liquid chromatography-diode array detection before its structural elucidation with liquid chromatography-ultraviolet (LC-UV) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy. The suspected-target screening matched the protonated molecule ([M + H]+) precursor ion of compound X at m/z 499.2310 with two suspected analytes that are structural isomers of one another. The fragmentation patterns of compound X were comparable to those analogues in the dithiocarbodenafil group through the non-targeted screening. These findings, complemented by the LC-UV and NMR spectroscopy data, together with the chromatographic separation of related structural isomers, conclude the identity of compound X. To our best knowledge, this is the first study to report the presence of 3,5-dimethylpiperazinyl-dithiodesmethylcarbodenafil in an ICP sample. The herbal-based male sexual performance products' lucrative market has instigated their rampant adulteration, particularly with PDE5 inhibitors. The adulterated products may also contain analogues of the approved PDE5 inhibitors, which usually passed into the market undetected as they are not included in the routine targeted screening procedure. The present study detected, isolated, and identified an isomeric sildenafil analogue from an instant coffee premix sample using rapid qualitative assay and comprehensive analytical analysis. This paper highlighted the applicability of the established strategies for routine casework, particularly in a forensic drug testing laboratory. [ABSTRACT FROM AUTHOR]

Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease. Preclinical and experimental studies show that PDE5 inhibitors (PDE5is) exert protective effects in DN improving perivascular inflammation. Using a mouse model of diabetic kidney injury we investigated the protective proprieties of PDE5is on renal hemodynamics and the molecular mechanisms involved. PDE5i treatment prevented the development of DN-related hypertension (P

BackgroundAlthough pulmonary arterial hypertension (PAH) is a fatal disease, specific drugs have been used to treat PAH. These drugs predominantly target these three pathobiological pathways: Endothelin receptor antagonist (ERA), nitric oxide (NO), and prostanoids pathways. In this review, we aimed to analyze the efficacy and safety of oral targeted treatments for PAH.MethodsThe national library of medicine (MEDLINE), excerpta medica database (EMBASE), and Cochrane Central Register of Controlled Trials databases were searched. Randomized controlled trials that compared the oral targeted drugs with placebos were selected. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) for variables with dichotomous outcomes, and standardized mean differences with continuous outcomes variables. Additionally, the mean of the differences for the 6-min walk distance (6MWD) was analyzed.ResultsIn total, 23 studies involving 7,121 patients were included in this study. These studies show that orally PAH-specific drugs could decrease the risk of clinical worsening events, with an OR of 0.55 (p < 0.001). Furthermore, these drugs could improve exercise capacity, showing a 21.74-m increase in 6MWD (95% CI: 17.53–25.95 m) and cause a greater amelioration of functional class (OR = 0.60, 95% CI: 0.47–0.76). Additionally, subgroup analysis indicated that compared with placebo, ERAs, and drugs in the NO pathway were most effective and safe, which are associated with an improvement in exercise capacity, 6MWD, and worsening events-free survival rate.ConclusionNitric oxide exhibited the most prominent clinical effect on exercise tolerance. However, in the subgroup analysis, oral targeted drugs of different pathways show applicability to different populations, which highlights the need for precise treatment in the clinical setting.Systematic Review Registration[https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=297946], identifier [CRD 42022297946].

The potential renoprotective effects of vardenafil (VAR) have been evaluated in a very limited number of studies using acute kidney injury animal models other than contrast-induced nephropathy (CIN) with promising results, while avanafil (AVA) has not been evaluated in this respect before. The purpose of this study was to evaluate for the first time the potential renoprotective effect of VAR and AVA in a rat model of CIN. Twenty-five male Wistar rats were equally assigned into five groups: control, CIN, CIN+N-acetyl cysteine (NAC) (100 mg/kg/day) as a positive control, CIN+VAR (10 mg/kg/day) and CIN+AVA (50 mg/kg/day). CIN was induced by dehydration, inhibition of prostaglandin and nitric oxide synthesis as well as exposure to the contrast medium (CM). Serum Cr (sCr) levels were measured at 24 and 48 h after CIN induction. At 48 h of CM exposure, animals were sacrificed. Matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, kidney injury molecule 1 (KIM-1) and cystatin-C (Cys-C) were measured on renal tissue. Histopathological findings were evaluated on kidney tissue. All treatment groups had close to normal kidney appearance. sCr levels subsided in all treatment groups compared to CIN group at 48 h following CIN induction. A significant decline in the levels of MMP-2, MMP-9, KIM-1 and Cys-C compared to CIN group was observed. These results provide emerging evidence that VAR and AVA may have the potential to prevent CIN. [ABSTRACT FROM AUTHOR]

The proliferation of adulterated health foods and beverages in the market demands a comprehensive analytical strategy to identify the adulterants, particularly those of isomeric phosphodiesterase 5 (PDE5) inhibitors. An instant coffee premix (ICP) purchased from an online retailer was flagged for suspected adulteration through PDE5 inhibition assay. The ICP was then analysed using suspected-target and non-targeted screenings of a liquid chromatography-quadrupole time-of-flight mass spectrometry. Based on these findings, a PDE5 inhibitor initially assigned as compound X was isolated from the ICP by employing a liquid chromatography-diode array detection before its structural elucidation with liquid chromatography-ultraviolet (LC-UV) spectroscopy and nuclear magnetic resonance (NMR) spectroscopy. The suspected-target screening matched the protonated molecule ([M + H]+) precursor ion of compound X at m/z 499.2310 with two suspected analytes that are structural isomers of one another. The fragmentation patterns of compound X were comparable to those analogues in the dithiocarbodenafil group through the non-targeted screening. These findings, complemented by the LC-UV and NMR spectroscopy data, together with the chromatographic separation of related structural isomers, conclude the identity of compound X. To our best knowledge, this is the first study to report the presence of 3,5-dimethylpiperazinyl-dithiodesmethylcarbodenafil in an ICP sample. Key points The herbal-based male sexual performance products’ lucrative market has instigated their rampant adulteration, particularly with PDE5 inhibitors. The adulterated products may also contain analogues of the approved PDE5 inhibitors, which usually passed into the market undetected as they are not included in the routine targeted screening procedure. The present study detected, isolated, and identified an isomeric sildenafil analogue from an instant coffee premix sample using rapid qualitative assay and comprehensive analytical analysis. This paper highlighted the applicability of the established strategies for routine casework, particularly in a forensic drug testing laboratory.

Introduction: The effect of erectile dysfunction (ED) on sexual planning behaviors and outcomes in men taking phosphodiesterase type 5 inhibitors (PDE5Is) is not well studied. Aims: To assess sexual habits, behaviors, and treatment-related outcomes of PDE5I-treated men with ED. Methods: This cross-sectional observational study recruited men aged 30 to 70 years with mild-to-severe ED from 8 diverse countries (the United States, the United Kingdom, Italy, Russia, Turkey, Israel, China, and Japan) to complete an approximately 15-minute survey. Differences were evaluated using bivariate analyses, and data were summarized using descriptive statistics. Main Outcome Measures: Self-reported data were collected for demographics, health characteristics, treatment, sexual habits, ED severity, ED-specific quality of life, and treatment satisfaction. Results: The survey was completed by 1,575 men. Mean frequency of sexual intercourse was 5.7 times/month. Overall, 87.1% of men always, often, or sometimes planned for sexual activity. Of those planning in advance, 32.8% and 40.6% agreed or strongly agreed that they plan for specific days of the week and times of day, respectively. Sexual planning habits were similar for patients taking short-acting vs long-acting PDE5Is. The most commonly cited reasons for planning sexual activity were needing time to take medication (48.4%), needing to make sure medication has taken effect (43.4%), convenient time for sexual activity (34.9%), and needing the partner’s agreement (33.4%). Mean Self-Esteem and Relationship Questionnaire total score was 56.4. Conclusions: The differences in ED burden and sexual planning behavior observed across countries were not influenced by the type of PDE5I being taken, suggesting that cultural differences are an important factor when considering types of ED treatment. These findings provide a better understanding of burden, sexual habits, planning behaviors, quality of life, and treatment-related outcomes among PDE5I-treated men with ED in 8 Western and non-Western countries and may aid healthcare providers in selecting optimal treatments.Goldstein I, Giraldi A, Maculaitis MC, Real-World Assessment of the Impact of Erectile Dysfunction on Sexual Planning Behavior and Health- and Treatment-Related Outcomes Among Men in 8 Countries. J Sex Med 2020;8:338–349.

Purpose: To validate a novel arteriogenic erectile dysfunction (ED) model with atherosclerosis (AS) based on molecular and histologic evidence induced by chronic pelvic ischemia (CPI) and determine effect of phosphodiesterase-5 inhibitor treatment. Materials and Methods: Twenty 16-week-old male Sprague–Dawley rats were divided into three experimental groups (Group I, untreated sham-operated rats with regular diet; Group II, CPI with cholesterol diet; Group III, CPI model with cholesterol diet and mirodenafil). Erectile function was accessed using maximum intracavernous pressure (ICP) and ICP/mean arterial pressure (MAP). Molecular changes were examined by western blot analysis using hypoxia inducible factor 1-alpha (HIF-1α), endothelial nitric oxide synthase (eNOS), and transforming growth factor beta-1 (TGF-β1) antibodies. Collagen change was evaluated by Masson’s trichrome staining. Results: In vivo measurements of ICP and ICP/MAP in Group II were significantly lower than those in Group I (p

Objective To analyze role of phosphodiesterase 5 (PDE5) inhibitors on urodynamic parameters in patients with suprasacral spinal cord injury. Materials and Methods This was a prospective observational hospital-based study conducted on a cohort of patients, aged between 18 and 65 years with suprasacral spinal cord injury, who were registered in Department of Neurosurgery/Urology. Cutoff period since injury was 2 years. After taking consent, baseline urodynamic study was performed, which was repeated 2 hours after taking single oral dose of 20 mg tadalafil. Urodynamic parameters such as maximum detrusor filling/voiding pressures, maximum bladder capacity, and bladder compliance before and after taking drug were compared for final results and conclusion. Results Following administration of 20 mg of tadalafil, maximum bladder capacity in mL showed statistically significant improvement from 268.39 ± 130.0 to 298.55 ± 112.0.(p < 0.05). Bladder compliance improved from 18.68 ± 6.4 to 20.25 ± 7.5 mL/cm H2O (p > 0.05). Maximum detrusor filling pressure improved from 36.03 ± 20.54 to 32.90 ± 16.47 cm H2O (p > 0.05). Maximum detrusor voiding pressure improved from 64.65 ± 33.19 to 58.13 ± 20.7 cm H2O (0 > 0.05). In patients with injury above D6 spinal cord level, statistically significant improvement was seen in maximum bladder capacity and bladder compliance after 2 hours of single oral dose of tadalafil (p < 0.05). Conclusion Our study suggests a positive role of PDE inhibitors in improving urodynamic parameters in patients with suprasacral spinal cord injury with improvement in parameters such as bladder capacity, detrusor pressures, and bladder compliance. Because this is a small study group, more studies such as this are required to reach to final conclusion.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological changes, including the accumulation of β -amyloid plaques. Phosphodiesterase 5 inhibitors (PDE5I), -the active ingredient in Viagra, exert their effects by inhibiting Phosphodiesterase 5-mediated hydrolysis of cyclic guanosine monophosphate (cGMP). Sildenafil, which is a PDE5I acts mainly on smooth muscles cells, but it also impacts upon brain tissue where it helps in the modulation of neuronal function. The aim of this abstract is to consolidate findings from studies which highlight the relationship between PDE5I and Alzheimer's disease and to point out possible benefits. Material and methods: A systematic search of PubMed database with MESH terms: "Phosphodiesterase 5 inhibitors" and "Alzheimer's disease" for open access research articles was conducted. Articles from the years 2009-2024 were included. Results: The levels of PDE5 in patients with AD weresignificantly increased, whilst the inhibition of PDE5 caused raise in cGMP and resulting in impairment of cognitive function in AD mice. Tadalafil, another PDE5I, improved spatial memory by reducing Tau protein expression in an AD mouse model. Sildenafil taken orally raised cerebral oxygen metabolism and cerebral blood flow in Alzheimer patients, indicating PDE5I as a treatment for AD linked vascular dysfunction. A systematic review analysed studies where β-amyloid levels were assessed in AD rodents in the hippocampus. With one exception (a study using only female rodents), PDE5I was effective in lowering β -amyloid levels and furthermore it blocked cognitive decline in every study. A large cohort study analysed data from over 260,000 men demonstratedthat PDE5I in men with erectile dysfunction was linked with a lower risk of AD. The prescription frequency was indirectly proportional to the risk of AD. A computational analysis over six years from 2021 also revealed that sildenafil users had a 69% lower risk of developing AD indicating potential protective properties. Conclusions: Although the biological interactions between Alzheimer's and Sildenafil are not fully understood, a promising number of studies support the hypothesis that PDE5I can actually decrease the risk and/or slow down the development of AD. To increase the applicability in general, studies are needed which include both sexes because in most studies, only male populations were investigated. The findings suggest that there are potential implications for creating new drugs aimed at treating the underlying causes of AD and addressing cognitive decline. [ABSTRACT FROM AUTHOR]

Objectives: To highlight the efficacy of various psychological interventions (PI) when used in combination with, or in place of, phosphodiesterase-5 inhibitors (PDE-5i), as compared to the traditional treatment of men with erectile dysfunction (ED) with PDE-5i alone. Methods: A comprehensive literature review for the years 2005–2020 via MEDLINE and PubMed. We included randomised controlled trials that compared the use of either PDE-5i alone, PI alone or a combination of PDE-5i and PI in the treatment of psychogenic ED. All studies included were performed in adults aged 19–55 years and were written in English. Results: A total of 13 articles, with an overall sample of 597 men, were included in this systematic review. The results show that the combination of PI and PDE-5i was more effective than either PI or PDE-5i alone, on erectile function and long-term sexual satisfaction in men with psychogenic ED. Combined interventions were found to be significantly superior to medical treatment in seven studies and to PI alone in one study. In comparing PI to PDE-5i, two studies found PI to be significantly superior to PDE-5i use. In three other studies, PI was found significantly superior to no treatment at all, although some participants in the control group had taken PDE-5i. Conclusions: The combination of PDE-5i with PI shows real promise for the treatment of psychogenic ED. However, no conclusions could be made about what PI is more promising than the other and larger studies are needed to confirm these initial findings. Abbreviations: CBT: cognitive behavioural therapy; CBST: cognitive behavioural sex therapy; COVID-19: coronavirus disease 2019; ED: erectile dysfunction; EDITS: Erectile Dysfunction Inventory of Treatment Satisfaction; GPT, group psychotherapy: IIEF(-EF) (-OS) (-SD): International Index of Erectile Function (erectile functioning) (overall sexual satisfaction) (level of sexual desire); ITP: integrative treatment protocol; MHI: Mental Health Inventory; PDE-5i: phosphodiesterase-5 inhibitors; PI, psychological interventions; QoL: quality of life; RCT: randomised controlled trial; SHIM: Sexual Health Inventory for Men [ABSTRACT FROM AUTHOR]