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Abstract: Evodiamine (EVO) is a natural quinolone alkaloid firstly isolated from the fruit of Evodia rutaecarpa, which is one of the most frequently used traditional Chinese herb for treating a variety of ailments, including headaches, abdominal pain, vomiting, diarrhea, amenorrhea difficult menstruation, postpartum hemorrhage, and other diseases. Latest pharmacological studies showed that EVO possesses a broad spectrum of pharmacological activities through different mechanisms. However, its moderate activities and poor physicochemical properties have hampered its clinical application. In this regard, the modification of EVO aiming at seeking derivatives with more potency and better physicochemical properties has been extensively emerging. These derivatives exhibit diverse biological activities, including antitumor, anti-Alzheimer's disease, anti-pulmonary hypertension, anti-fungi, and thermogenic activities via a variety of mechanisms. Moreover, they are described to act as single, dual, or multiple inhibitors or agonists of many proteins, such as topoisomerase I, topoisomerase II, tubulin, histone deacetylase, sirtuins, butyrylcholinesterase, phosphodiesterase 5, and transient receptor potential vanilloid 1. However, hitherto, there is no comprehensive review to systematically summarize the derivatives of EVO. Considering this perspective, this paper aims to provide a comprehensive description of them by focusing on their diverse biological activities. For each biological activity, the mechanisms and the main structureactivity relationships (SARs) will be presented in cases where adequate information is available. Finally, future directions of this class of compounds will be discussed. This review will be helpful in understanding and encouraging further exploration of EVO.

Platelets are the "guardians" of the blood circulatory system. At sites of vessel injury, they ensure hemostasis and promote immunity and vessel repair. However, their uncontrolled activation is one of the main drivers of thrombosis. To keep circulating platelets in a quiescent state, the endothelium releases platelet antagonists including nitric oxide (NO) that acts by stimulating the intracellular receptor guanylyl cyclase (GC). The latter produces the second messenger cyclic guanosine-3',5'-monophosphate (cGMP) that inhibits platelet activation by stimulating protein kinase G, which phosphorylates hundreds of intracellular targets. Intracellular cGMP pools are tightly regulated by a fine balance between GC and phosphodiesterases (PDEs) that are responsible for the hydrolysis of cyclic nucleotides. Phosphodiesterase type 5 (PDE5) is a cGMP-specific PDE, broadly expressed in most tissues in humans and rodents. In clinical practice, PDE5 inhibitors (PDE5i) are used as first-line therapy for erectile dysfunction, pulmonary artery hypertension, and lower urinary tract symptoms. However, several studies have shown that PDE5i may ameliorate the outcome of various other conditions, like heart failure and stroke. Interestingly, NO donors and cGMP analogs increase the capacity of anti-platelet drugs targeting the purinergic receptor type Y, subtype 12 (P2Y12) receptor to block platelet aggregation, and preclinical studies have shown that PDE5i inhibits platelet functions. This review summarizes the molecular mechanisms underlying the effect of PDE5i on platelet activation and aggregation focusing on the therapeutic potential of PDE5i in platelet disorders, and the outcomes of a combined therapy with PDE5i and NO donors to inhibit platelet activation.

BackgroundPhosphodiesterase-5 inhibitors (PDE5-Is), used in the management of erectile dysfunction (ED), have potential cardioprotective benefits. The impact of PDE5-Is on reducing adverse cardiovascular outcomes in patients with diabetes mellitus (DM) and ED is uncertain. Using a systematic review and meta-analysis of observational cohort studies and randomised controlled trials (RCTs), we evaluated if (i) the association of PDE5-Is in people with ED and DM and their risk of cardiovascular disease (CVD) and mortality and (ii) ED confers an excess risk of CVD and mortality in patients with DM compared with no DM.MethodsStudies were identified from MEDLINE, Embase, the Cochrane Library, Web of Science citation search and search of bibliographies to April 2022. Study-specific risk ratios (RRs) with 95% confidence intervals (CIs) were pooled.ResultsEighteen unique studies reported on the cardiovascular impact of ED in patients with and without DM. In the general population, the RRs (95% CIs) of ED for composite CVD/MACE, all-cause mortality, CHD and stroke were 1.43 (1.31–1.55), 1.47 (1.31–1.65), 1.59 (1.39–1.82), and 1.34 (1.15–1.56), respectively. The respective estimates were 1.68 (1.15–2.45), 1.40 (0.90–2.18), 1.41 (1.24–1.61) and 1.32 (1.09–1.60) in the diabetes population. Interaction analyses suggested similar risk in both populations. Six studies reported the cardiovascular effects of PDE5-Is in people with ED and DM. Limited RCT data showed no significant differences in the risk of major adverse cardiac event (MACE), coronary heart disease (CHD) and all-cause mortality comparing PDE5-I use with non-use: RRs (95% CIs) of 3.47 (0.17–69.19), 1.31 (0.10–16.54) and 0.35 (0.12–1.05), respectively.ConclusionsED confers no excess risk of CVD and mortality in patients with DM compared with no DM. Limited and inadequately powered data shows no significant differences in the risk of adverse cardiovascular outcomes comparing use of PDE5-Is with non-use in patients with ED and DM.

Developing an easily-prepared, sensitive, and accurate point-of-need immunochromatographic assay (ICA) is significant in food safety screening, clinical diagnosis, and environmental monitoring. However, the current single-modal ICAs are limited in certain instinct drawbacks that restrict analytical performances. Herein, we introduce an ultrasensitive dual-modal colorimetric/reversed ratiometric fluorescence ICA based on facilely prepared immunoprobes with a high loading capacity of red quantum dots and AuNPs. By smartly integrating these red-colored/fluorescent signal probes with an immobilized green quantum dot antigen on the test lines, discrete "turn-on"visual inspection and reversed ratiometric quantification via a portable smartphone-based analyzer were accomplished. As an application, this method was employed to detect 11 phosphodiesterase-5 inhibitors in health foods with ultralow detection limits (0.0028-0.045 ng/mL), high repeatability (coefficient of variations of 0.3-1.91%), and reasonable accuracy (recoveries of 86.6-107%). The proposed method was further validated by the authorized liquid chromatography with tandem mass spectrometry method in actual sample detection. This new assay format can be extended to ultrasensitive flexible detection of other food contaminants, environmental pollutants, or tumor biomarkers within minutes, and it just requires simply prepared signal reporters, easy-to-operate procedures, and a low-cost miniaturized analyzer.

Due to the prevalence of erectile dysfunction and impotence among men in recent years, several pharmacotherapies have been considered for such problems. Systemic drug therapies in the treatment of erectile dysfunction have significant issues, including drug interactions and contraindications in a wide range of diseases, which makes researchers seek to design drugs and dosage forms with fewer side effects, interactions, and contraindications with maintained efficacy.5-Phosphodiesterase inhibitors (5-PDEIs or PDE5Is), previously used systemically to treat erectile malfunction, are now appropriate candidates for topical application with considerable potency and fewer complications.We sought to investigate the recent findings on the current subject in order to provide a comprehensive overview of the issue using an extensive literature search to pinpoint the latest scientific reports on this subject.In the present review, the function of 5-Phosphodiesterase inhibitors as topical formulations was evaluated with details including formulation type, adsorption, and comparative efficacy in all recent studies as an acceptable alternative therapy to systemic drugs.Due to the fact that the influential factors in erectile dysfunction interact with many diseases and delinquent treatments, the use of topical therapeutic agents can be promising in mild to moderate cases. The utilization of 5-PDEIs through novel topical and transdermal drug delivery techniques plays a vital role in improving this effectiveness. Hamzehnejadi M, Tavakoli MR, Abiri A, et al. A Review on Phosphodiesterase-5 Inhibitors as a Topical Therapy for Erectile Dysfunction. Sex Med Rev 2022;10:369-384.

Objectives To evaluate the effect of phosphodiesterase-5 (PDE-5) inhibitors on uteroplacental and fetal cerebral perfusion in pregnancies complicated with fetal growth restriction (FGR). Material and methods Relevant databases were searched from inception up to June 2021. The random-effects model was used to pool the weighted mean differences (WMDs) and the corresponding 95% confidence intervals (CIs). The primary outcomes were the effect of PDE-5 inhibitors on uterine (UtA-PI), umbilical (UA-PI) and middle cerebral artery (MCA-PI) pulsatility indices. Subgroup analyses were also performed based on the type of PDE-5 inhibitor medication, the dosage of medication, duration of treatment, sample size and onset of FGR. Results Seven clinical trials were eligible, 6 trials using sildenafil, and one using tadalafil. The random-effects models indicated PDE-5 inhibitors significantly decrease UtA-PI (WMD= -0.28, 95% CI= -0.46,-0.11) and UA-PI (WMD= -0.07, 95% CI= -0.13, -.01); however it failed to show a significant effect on MCA-PI (WMD= 0.24, 95% CI=-0.63, 1.11). Subgroup analyses showed similar significant effects of sildenafil on UtA-PI and UA-PI; however, no significant effect was observed after treatment with tadalafil. Conclusion PDE-5 inhibitors administration, especially sildenafil, may improve uteroplacental, but not fetal cerebral blood perfusion in pregnancies complicated by FGR.

Made available in DSpace on 2022-04-29T08:33:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-10-30 Acute kidney injury pathogenesis in envenoming by snakes is multifactorial and involves immunologic reactions, hemodynamic disturbances, and direct nephrotoxicity. Sildenafil (SFC), a phosphodiesterase 5 inhibitor, has been reported to protect against pathological kidney changes. Objective: This study aimed to investigate the protective effect of sildenafil against Bothrops alternatus snake venom (BaV)-induced nephrotoxicity. Methods: Kidneys from Wistar rats (n = 6, weighing 260–300 g) were isolated and divided into four groups: (1) perfused with a modified Krebs-Henseleit solution (MKHS) containing 6 g% of bovine serum albumin; (2) administered 3 μg/mL SFC; (3) perfused with 3 μg/mL BaV; and (4) administered SFC + BaV, both at 3 μg/mL. Subsequently, the perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), and percentage of electrolyte tubular sodium and chloride transport (%TNa+, %TCl−, respectively) were evaluated. The cyclic guanosine monophosphate (cGMP) levels were analyzed in the perfusate, and the kidneys were removed to perform oxidative stress and histopathological analyses. Results: All renal parameters evaluated were reduced with BaV. In the SFC + BaV group, SFC restored PP to normal values and promoted a significant increase in %TNa+ and %TCl−. cGMP levels were increased in the SFC + BaV group. The oxidative stress biomarkers, malondialdehyde (MDA) and glutathione (GSH), were reduced by BaV. In the SFC + BaV group, a decrease in MDA without an increase in GSH was observed. These findings were confirmed by histological analysis, which showed improvement mainly in tubulis. Conclusion: Our data suggest the involvement of phosphodiesterase-5 and cGMP in BaV-induced nephrotoxicity since its effects were attenuated by the administration of SFC. Department of Physiology and Pharmacology School of Medicine Federal University of Ceara, Coronel Nunes de Melo St., 1127 Drug Research and Development Center (NPDM) Federal University of Ceara, Coronel Nunes de Melo St., 1000 Department of Dental Clinic School of Pharmacy Dentistry and Nursing Federal University of Ceara, Monsenhor Furtado St. Center for the Study of Venoms and Venomous Animals Fazenda Experimental Lageado São Paulo State University, José Barbosa de Barros St. 1780 Center for the Study of Venoms and Venomous Animals Fazenda Experimental Lageado São Paulo State University, José Barbosa de Barros St. 1780

Background Pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD). While clinical guidelines recommend specific drug therapies for pulmonary arterial hypertension (PAH), these drug therapies are not recommended for PH due to lung disease. Methods This was a retrospective cohort study using the Optum® Clinformatics® Data Mart from January 2009–September 2019. An algorithm was designed to identify adults with ≥ 2 ICD-9-CM or ICD-10-CM diagnosis codes for PH and with ≥ 2 diagnosis codes for COPD. Sensitivity analyses were conducted among subgroups of patients with evidence of a right heart catheterization (RHC) or pulmonary function test (PFT). Patient characteristics, medications used, and durations of use of PAH and COPD medications were analyzed. Results A total of 25,975 patients met the study inclusion criteria. Their mean age was 73.5 (SD 10.0) years and 63.8% were female. Medications targeting PAH were prescribed to 643 (2.5%) patients, most frequently a phosphodiesterase-5 inhibitor (2.1%) or an endothelin receptor antagonist (0.75%). Medications for COPD were prescribed to 17,765 (68.4%) patients, most frequently an inhaled corticosteroid (57.4%) or short-acting beta agonist (50.4%). The median durations of use ranged from 4.9 to 12.8 months for PAH medications, and from 0.4 to 5.9 months for COPD medications. Of the subgroup of patients with RHC (N = 2325), 257 (11.1%) were prescribed a PAH medication and 1670 (71.8%) used a COPD medication. Of the subgroup with a PFT (N = 2995), 58 (1.9%) were prescribed a PAH medication and 2100 (70.1%) a COPD medication. Conclusions Patients with PH associated with COPD were identified in a US administrative claims database. Very few of these patients received any of the medications recommended for PAH, and only about two thirds received medications for COPD.

Aims: Therapy with phosphodiesterase-5 inhibitors (PDE5Is) after left ventricular assist device (LVAD) implantation has been associated with lower mortality and device thrombosis but increased risk for post-operative and gastrointestinal bleeding. We aimed to evaluate the impact of long-term PDE5Is on the overall bleeding risk after LVAD implantation. Methods and results: We retrospectively included patients who received a continuous-flow LVAD at our site and were prescribed with long-term oral PDE5Is after discharge from the index hospitalization. The primary endpoint was the occurrence of bleeding at 12 month follow-up. Secondary endpoints were all-cause death and the combination of bleeding and all-cause death. Our analysis included 109 patients of whom 75 (69%) received long-term PDE5Is. Mean age was 56 years, and 85% were male. At 12 months, 19 (17%) patients experienced at least one bleeding event. Patients on PDE5Is had higher bleeding rates (23% vs. 6%, P = 0.03) and more bleeding events per patient-year (0.32 vs. 0.06, P = 0.03) compared with patients not on PDE5Is. While overall bleeding incidence was excessively higher in the PDE5I group, there were no significant differences in the incidence of major bleeding (19% vs. 6%, P = 0.08) and gastrointestinal bleeding (11% vs. 3%, P = 0.18). Kaplan–Meier analysis revealed higher cumulative incidence of bleeding for the PDE5I group (log rank = 0.04) with no difference on all-cause death (log rank = 0.67) and the combination of bleeding and all-cause death (log rank = 0.13). Hospitalizations for bleeding and their duration were numerically higher in the PDE5I group (0.28 vs. 0.03, P = 0.07 and 2.4 vs. 0.2, P = 0.07, respectively). Conclusions: Phosphodiesterase-5 inhibitor treatment after LVAD implantation is associated with increased bleeding risk after LVAD implantation. The safety of long-term PDE5Is in LVAD patients remains unclear and needs to be further clarified in prospective studies with randomized study design. OA Förderung 2021

Supplemental Digital Content is available in the text., Rationale: PDE5 (phosphodiesterase 5) inhibition reduces the occurrence of ventricular arrhythmias following myocardial ischemia. However, the mechanisms of the antiarrhythmic effects of PDE5 inhibition are unknown. Diastolic calcium (Ca2+) waves lead to arrhythmias by inducing delayed afterdepolarizations (DADs). Ca2+ waves are initiated when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold level and the SR releases Ca2+ spontaneously and generates a depolarizing inward sodium-calcium exchange current. Objective: To determine the effects of PDE5 inhibition on the propensity for ventricular arrhythmias in a proarrhythmic large animal model and establish the role of alterations of intracellular Ca2+ cycling/SR Ca2+ content. Methods and Results: Arrhythmia burden, monophasic action potentials, and beat-to-beat variability of repolarization were measured in a sheep model using the IKr inhibitor dofetilide to induce QT prolongation and arrhythmia. Ca2+ transients, Ca2+ waves, and SR Ca2+ content were measured in isolated ventricular myocytes. PDE5 inhibition was achieved using acute application of sildenafil, and PKG (protein kinase G) was inhibited with KT5823. PDE5 inhibition reduced beat-to-beat variability of repolarization and suppressed afterdepolarizations, premature ventricular complexes, and torsade de pointes in vivo. In single cells, dofetilide-induced delayed afterdepolarizations and triggered action potentials were suppressed by PDE5 inhibition. PDE5 inhibition decreased Ca2+ wave frequency in all cells and abolished waves in 12 of 22 cells. A decrease in SR Ca2+ uptake, increased trans-sarcolemmal Ca2+ efflux, and reduced trans-sarcolemmal Ca2+ influx led to a reduction of SR Ca2+ content and Ca2+ wave abolition. These effects were dependent on PKG activation. Conclusions: PDE5 inhibition acutely suppresses triggered ventricular arrhythmias in vivo, and cellular data suggests this occurs via suppression of cellular Ca2+ waves. These novel antiarrhythmic properties of PDE5 inhibition are mediated by a reduction of SR Ca2+ content and are PKG dependent.

OBJECTIVES: To synthesize existing evidence on the effects of multimodal prehabilitation interventions in men affected by prostate cancer on physical, clinical, and patient-reported outcome measures. DATA SOURCES: A systematic review was conducted according to the PRISMA 2020 Statement Guidelines. Electronic databases (ie, Medline, Embase, CINAHL and Cochrane CENTRAL, and clinicaltrials.gov) were searched using key search terms. Articles were assessed according to prespecified eligibility criteria. Data extraction and quality appraisal was conducted. The findings were integrated in a narrative synthesis. CONCLUSION: Of the 5863 publications screened, 118 articles were assessed in full text and 17 studies met the prescreening eligibility criteria. There were a range of study designs that included randomized controlled clinical trials (n = 11), quasi experimental (n = 4), cohort (n = 1), and case series (n = 1), covering a total of 1739 participants. The prehabilitation interventions included physical activity, peer support, pelvic floor muscle training, diet, nurse-led prehabilitation, psychological, and prehabilitation administration of phosphodiesterase-5 inhibitors. IMPLICATIONS FOR NURSING PRACTICE: Significant heterogeneity existed in the prehabilitation intervention programs for men affected by prostate cancer in terms of the composition, duration, method of administration, and the outcomes measured to quantify their impact. This systematic review has identified that multimodal prehabilitation interventions are an emerging area for practice and research among men affected by prostate cancer. Importantly, there has been a lack of focus on the inclusion of partners as critical companions during this distressing phase of the cancer care continuum. For the moment, all members of the multidisciplinary team caring for people affected by prostate cancer are encouraged to use the findings in this review to inform holistic models of care.

Background/aim Phosphodiesterase 5 (PDE5) holds clinical relevance in several pathological states, including lung, breast, and prostate cancer. In this study, we examined PDE5 expression in oral squamous cell carcinoma (OSCC)-derived cell lines and tissues, and the anti-tumour effect of PDE5 inhibitor, sildenafil citrate (SC). Materials and methods Cell proliferation, cell invasion, and gap closure assays were performed in six OSCC-derived cell lines upon treatment with varying concentrations of SC. PDE5 expression was determined in primary OSCC tissues by western blotting and immunohistochemistry. Results Elevated PDE5 expression was observed in all cell lines. A concentration-dependent decrease in cell viability, invasion rate, and migration was observed after SC treatment. A significant correlation (p=0.05) was observed between elevated PDE5 expression and lymphatic infiltration in OSCC tissues. Conclusion PDE5 plays an important role in carcinogenesis of OSCC, and the specific inhibition of PDE5 may be an effective chemotherapeutic strategy.

This study determined the configuration of the isomers of tadalafil, nortadalafil, and homotadalafil in dietary supplements. The products purchased over the Internet studied included a honey product and a tablet, which contained tadalafil, and a candy, which contained nortadalafil and homotadalafil. Each of the pharmaceutical ingredients isolated from the products was measured with circular dichroism (CD).As a result, the CD spectrum of each isolated pharmaceutical ingredient was found to align with the standard CD spectrum of the 6R,12aR isomer, confirmed that each isolated tadalafil or tadalafil analogue included in a 6R,12aR isomer. According to a report, among the stereoisomers of tadalafil, the 6R,12aR isomers have the most potent inhibitory activities of phosphodiesterase-type-5. From the report, the potential strength of the inhibitory activity of the 6R,12aR isomers of nortadalafil and homotadalafil was suggested. Therefore, it seemed that the 6R,12aR isomer often used in the product.

INTRODUCTION Pulmonary arterial hypertension (PAH) is associated with high medical and pharmaceutical costs. Phosphodiesterase type 5 (PDE5) inhibitors have been found to be beneficial but costly. They are not subsidised in Singapore except via the Medication Assistance Fund (MAF) Plus scheme. In this study, we described the help-seeking behaviour of patients and funding strategies for Singaporean patients on PDE5 inhibitors in our registry. METHODS We consecutively recruited all patients with PAH who presented to our pulmonary hypertension specialty centre between 1 January 2003 and 29 December 2016. Singaporean patients on PDE5 inhibitors were included. Data recorded and analysed for this study included baseline demographics, whether the patients received MAF Plus funding, percentage of funding, and any additional source of subsidies. RESULTS 114 (77.0%) of 148 patients in the registry were Singapore citizens on PDE5 inhibitors. 75 (65.8%) of these 114 patients had been seen by a medical social worker, of whom 16 were on MAF Plus funding. 14 of the remaining 59 patients were subsidised by MediFund, whereas the remainder were self-paying. 30 (26.3%) patients in total were on some form of subsidy, and 28 (24.6%) patients were on combination therapy. Of this group, nine were receiving MAF Plus subsidies. CONCLUSION Fewer than expected patients were found to be receiving drug subsidies for PAH. This was partly due to insufficient referrals and lack of requests for financial assistance. Patients on combination therapy had greater financial challenges. This study should spur us on to study funding gaps further and address them.

Background Phosphodiesterase-5 inhibitors (PDE5i) have been used to treat pulmonary hypertension and right ventricular failure in patients with left ventricular assist devices (LVAD). The effects of PDE5i on post-LVAD outcomes including hemocompatibility-related adverse events are not well-established. This systematic review and meta-analysis aims to evaluate the effects of PDE5i on post-LVAD outcomes. Methods and Results A comprehensive literature search was conducted using Pubmed and Embase databases from inception through November 25, 2020, to compare post-LVAD outcomes in patients with or without PDE5i use. Pooled odds ratio (OR) with 95% confidence intervals (CI) and I2 statistic were calculated. Thirteen observational studies were included in this analysis. The use of PDE5i was not significantly associated with lower postoperative right ventricular failure (OR 0.38, 95% CI 0.02–5.96, P = .41). There was no significant association between PDE5i and gastrointestinal bleeding (OR 1.23, 95% CI 0.76–1.98, P = .2), overall stroke (OR 0.60, 95% CI 0.21–1.68, P = .17), ischemic stroke (OR 0.61, 95% CI 0.09–4.07, P = .38), or pump thrombosis (OR 0.71, 95% CI 0.14–3.54, P = .46). Conclusions Our meta-analysis showed no significant association between PDE5i and post-LVAD right ventricular failure. Despite the antiplatelet effects of PDE5i, there was no significant association between PDE5i and gastrointestinal bleeding, overall stroke, ischemic stroke, or pump thrombosis. Randomized controlled studies are warranted to evaluate the net benefits or harms of PDE5i in the LVAD population.

Eurycoma longifolia (EL) and Eurycoma harmandiana (EH) are natural medicinal plants belonging to the Simaroubaceae family, and are well-known for their ability to enhance male sexual performance. The present study investigated the phosphodiesterase-5 (PDE-5) inhibitory activity of intact roots of EL and EH. Additionally, canthin-6-one alkaloids, β-carboline alkaloids, and quassinoids were also screened for PDE-5 inhibitory activity. We developed in vitro root and callus cultures of EL and EH to determine their PDE-5 inhibitory activity. Our results indicated that canthin-6-one alkaloids, which include canthin-6-one-9-O-β-D-glucopyranoside, 9-methoxycanthin-6-one, canthin-6-one, and 9-hydroxycanthin-6-one, exhibited PDE-5 enzymatic inhibitory activity, with IC

Cyclic GMP–phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c < 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (−3.40°, −5.96; −0.84, P = 0.011) and fiber shortening (−1.19%, −2.24; −0.14, P = 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14 ++ CD16 − monocytes reduced, and Tie2 + monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.

This study focused on the effect of unripe (UPP) and ripe (RPP) plantain peels' extracts (200 and 400 mg/kg) on sexual behavior, hormonal profiles [testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH)], and enzymes [acetylcholinesterase (AChE), phosphodiesterase-5' (PDE-5), arginase, angiotensin-I converting enzyme (ACE), ecto-5'neucleotidase, and adenosine deaminase (ADA)] in paroxetine (PAR)-induced penile dysfunction rats. From the result, arginase, PDE-5', ACE, ecto-5'-nucleotidase ADA, and AChE activities, sexual activities, hormonal profile, and NO level were reduced, while thiobarbituric acid reactive species (TBARS) level increased (p .05) relative to normal control rats. However, treatment with UPP and URP reduced the activities of these enzymes, decreased TBARS levels, and increased hormones, and penile NO levels in PAR-induced rats. Thus, the use of UPP and RPP could be channeled towards the improvement of sexual performance in erectile dysfunction (ED) disorder. PRACTICAL APPLICATIONS: Plantain fruits are a tropical staple food crop commonly consumed at various stages of ripeness and cooking methods. However, its peels are regarded as a waste product with reported cases of environmental menace. Interestingly, plantain peel is being used as a major raw material for industrial applications in the agro-based industries and in folklore for the treatment of many human ailments due to its rich phytochemicals such as polyphenols, carotenoids, alkaloids, etc., which have been reported. A prelude study has also indicated its usefulness in ED management, but further pharmacological investigations are needed to proffer information on its effect in ED management and its anti-androgenic activity in male Wistar rats. The information from this study could be of pharmaceutical importance in designing natural remedies capable of improving penile rigidity, hormone profiles, and alteration of enzymes linked with ED.

Introduction Female sexual dysfunction (SD) is an under-recognized and undertreated problem in patients with systemic autoimmune rheumatic disorders (SARDs). Objectives To summarize and evaluate the existing treatment modalities for SD in females with SARDs. Methods A systematic review was conducted following the PRISMA guidelines. Electronic databases were searched up to April 2022 for studies that assessed the use of pharmacological and non-pharmacological treatment modalities for the management of SD in females with SARDs. Randomized and observational studies were included. (PROSPERO: CRD42022296381). Results Seven studies with 426 females with SD were included. Seven different treatment modalities belonging to 5 different classes (androgen therapy, phosphodiesterase-5 inhibitors, exercise, education and local creams) were evaluated in patients with systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis. The majority of the studies were of low methodological quality. Standardized patient education and 8-week aerobic walking programs were successful in improving female SD. Local creams improved dyspareunia in females with systemic sclerosis. Testosterone did not significantly improve SD in patients with systemic lupus erythematosus. Accordingly, tadalafil did not result in a significant improvement of SD in females with systemic sclerosis, based on the Female Sexual Function Index. Conclusion There is a lack of sufficient evidence to recommend a certain management strategy for SD in females with SARDs. Nonpharmacological therapy and lubricant creams may be beneficial in females with SARDs. No benefit was demonstrated after androgen therapy or tadalafil. Still, no definite conclusions can be drawn due to the important limitations of the available literature. Overall, our results may be considered preliminary and further research in the field is mandatory.

Plants and their derived molecules have been traditionally used to manage numerous pathological complications, including male erectile dysfunction (ED).

Modern lifestyle has led to an increase in the incidence of obesity as a public health concern; however, current anti-obesity medications often show limited efficacy with severe side effects. Therapeutic drugs that are selectively delivered to adipose tissue and accelerate energy consumption are promising strategies to overcome the limitations of existing anti-obesity treatment approaches. Herein, a drug delivery platform based on a macrophage cell membrane (Ma)-camouflaged recombinant high-density lipoprotein (rHDL) that was further decorated with a P3 peptide was fabricated to realize targeted drug delivery to adipose tissue. By co-delivering rosiglitazone (Rosi), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, and sildenafil (Sild), a phosphodiesterase type 5 (PDE5) inhibitor, a synergistic therapeutic outcome was achieved in the regulation of diet-induced obesity in a mice model. Body weight reduction and the metabolic status of obese mice were significantly improved after 28 days of treatment. More importantly, a sustainable self-reinforcement effect in multidose therapy was found after using this delivery system. The continuous treatment increased prohibitin (PHB) expression and capillary density in adipose tissue, which in turn improved the accumulation of the drugs in subsequent administration. Taken together, this constructed drug delivery system showed high effectiveness with good safety by combining two anti-obesity therapeutic agents, which exhibits promising research potential for adipose-targeted delivery. STATEMENT OF SIGNIFICANCE: Therapeutic strategies that directly target adipose tissue to increase energy consumption and regulate metabolism are promising but challenging. Herein, an adipose tissue-targeted delivery system was developed using a reconstituted high-density lipoprotein (rHDL) coated by a P3 peptide-decorated macrophage membrane. For the first time, we combined rosiglitazone (Rosi) and sildenafil (Sild) in the system and achieved synergy of adipose browning and angiogenesis for anti-obesity treatment. The therapy induced prohibitin expression and angiogenesis, which improved drug accumulation in adipose tissue in subsequent administrations. This resulted in a sustainable self-reinforcement effect with improved capacity for diet-induced obesity regulation. This study highlights the combination of adipose browning and angiogenesis in anti-obesity treatment and provides an innovative concept of enhancing adipose-targeted delivery.

Erectile dysfunction (ED), defined as the inability to develop or maintain an erection firm enough for satisfactory sexual intercourse, is a common urologic condition that increases in prevalence with age but can affect men of any age. As the discovery of the role of the nitric oxide pathway in inducing and maintaining erections, there have been numerous pharmacologic advancements for the treatment of ED. Here, we will review the mainstays of the pharmacologic treatment of ED: OTC/herbal supplements, phosphodiesterase type V inhibitors (PDE5I), intraurethral suppositories (MUSE), and intracorporal injections (ICI).

The nitric oxide (NO)-guanylate cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal function. Phosphodiesterase-5 inhibitors (PDE-5i) inhibit cGMP degradation, whereas both soluble guanylate cyclase (sGC) stimulators and sGC activators directly increase sGC. PDE-5i (e.g. sildenafil, tadalafil) and sGC stimulators (e.g. riociguat, vericiguat) have been extensively used in pulmonary artery hypertension (PAH) and heart failure (HF). PDE-5i have also been used in end-stage HF before and after left ventricular (LV) assist device (LVAD) implantation. Augmentation of NO-GC-cGMP signalling with PDE-5i causes selective pulmonary vasodilation, which is highly effective in PAH but may have controversial, potentially adverse effects in HF, including pre-LVAD implant due to device unmasking of PDE-5i-induced RV dysfunction. In contrast, retrospective analyses have demonstrated that PDE-5i have beneficial effects when initiated post LVAD implant due to the improved haemodynamics of the supported LV and the pleiotropic actions of these compounds. sGC stimulators, in turn, are effective both in PAH and in HF due to their balanced pulmonary and systemic vasodilation, and as such they are preferable to PDE-5i if the use of a pulmonary vasodilator is needed in HF patients, including those listed for LVAD implantation. Regarding the effectiveness of PDE-5i and sGC stimulators when initiated post LVAD implant, these two groups of compounds should be tested in a randomized control trial.

Despite the antidepressant potency of paroxetine, its side effect of erectile dysfunction is burdensome. Grapefruit peels (GFPs) are underutilized cultivar wastes with wide range of therapeutic potentials which have been attributed to their antioxidant behavior and phenolic contents' abilities to effectively inhibit enzymatic activities and manage endothelial dysfunction in cardiovascular disorders. This study aims to investigate the erectogenic potentials of GFP extract in a rat model of paroxetine-induced ED. Experimental rats were sectioned into five groups: [1: control; 2: paroxetine (10 mg/kg); 3: paroxetine + sildenafil (5 mg/kg); 4: paroxetine + GFP (50 mg/kg); 5: paroxetine + GFP (100 mg/kg)] and treated for 28 days. Sexual behavior of rats was assessed and effect of GFP on ecto-5' nucleotidases, phosphodiesterase-5, and adenosine deaminase (ADA) activities was determined in rats' penile tissues. The levels of malondialdehyde, nitric oxide (NO) as well as superoxide dismutase (SOD) and catalase activities were also determined. HPLC-DAD analysis showed the presence of naringin, rutin, caffeic acid, quercitrin, quercetin, and kaempferol glycoside. Oral administration of paroxetine reduced erectile response as revealed by their low intromission and mounting numbers as well as high intromission and mounting latencies. Paroxetine caused a significant elevation of ADA and phosphodiesterase-5 activities and malondialdehyde levels with drastic reduction in levels of NO, SOD, and catalase activities in rats' penile tissues. However, GFP extract reversed PDE-5, ADA, and antioxidant activities to normal levels, raised the concentration of NO. These results suggest the erectogenic effects and protective potentials of GFP extract against paroxetine-induced erectile dysfunction. PRACTICAL APPLICATION: Grapefruit peels are an environmental menace in many countries and this study showed that the peels can be used in the prevention / management of erectile dysfunction. The therapeutic potentials of the peels are due to the presence of bioactive compounds such as flavonoids and phenolic acids. Therefore, exploring the erectogenic potentials of the peels will translate to conversion of the wastes to therapeutic products.

Background: Elevated right ventricular afterload following continuous-flow left ventricular assist device (CF-LVAD) may contribute to late right heart failure (LRHF). PDE5i (phosphodiesterase-5 inhibitors) are used to treat pulmonary hypertension and right heart dysfunction after CF-LVAD, but their impact on outcomes is uncertain. Methods: We queried Interagency Registry for Mechanically Assisted Circulatory Support from 2012 to 2017 for adults receiving a primary CF-LVAD and surviving ≥30 days from index discharge. Patients receiving early PDE5i (ePDE5i) at 1 month were propensity-matched 1:1 with controls. The primary outcome was the cumulative incidence of LRHF, defined using prevailing Interagency Registry for Mechanically Assisted Circulatory Support criteria; secondary outcomes included all-cause mortality and major bleeding. Results: Among 9627 CF-LVAD recipients analyzed, 2463 (25.6%) received ePDE5i and 1600 were propensity-matched 1:1 with controls. Before implant, ePDE5i patients had more severe RV dysfunction (13.1% versus 9.6%) and higher pulmonary vascular resistance (2.8±2.7 versus 2.2±2.4 WU), both P P =0.07); mortality 38.6% versus 35.8% (hazard ratio, 0.99 [95% CI, 0.86–1.15]; P =0.93); major bleeding 51.2% versus 46.0% (hazard ratio, 1.12 [95% CI, 0.99–1.27]; P =0.06). Conclusions: Compared with propensity-matched controls, adult CF-LVAD patients receiving ePDE5i had similar rates of LRHF, mortality, and major bleeding. While intrinsic patient risk factors likely account for more adverse outcomes with ePDE5i in the unmatched cohort, there is no obvious benefit of ePDE5i in the LVAD population.

OBJECTIVE: To investigate the impact of penile rehabilitation on the recovery of erectile function after robot-assisted radical prostatectomy. METHODS: Patients who underwent robot-assisted radical prostatectomy in our department from 2010 to 2019 were included. For penile rehabilitation, a phosphodiesterase-5 inhibitor (tadalafil 20 mg) was administered twice a week for 1-6 months postoperatively. The International Index of Erectile Function questionnaire (question 1 and erectile function domain) and the Expanded Prostate Cancer Index Composite questionnaire (sexual function) were used. RESULTS: After propensity score matching, there were 79 patients in the penile rehabilitation group and 79 patients in the non-penile rehabilitation group. There was no significant difference in baseline characteristics between the two groups. Significantly higher scores were seen in the penile rehabilitation group compared with the non-penile rehabilitation group at postoperative 3, 6 and 9 months in the International Index of Erectile Function questionnaire-question 1, at 3, 6, 9 and 12 months in erectile function domain, and at 3, 6, 12 and 24 months in Expanded Prostate Cancer Index Composite questionnaire sexual function (P

Cardiac rupture is a fatal complication of acute myocardial infarction (MI), associated with increased inflammation and damaged extracellular matrix. C57BL/6 J wild type (WT) and Pde5a knockout (Pde5a−/−) mice were selected to establish MI model. The rupture rate of Pde5a−/− mice was significantly reduced (P

Vascular aging leads to structural and functional changes. Iliac arteries (IA) provide blood flow to lower urinary tract and pelvic ischemia has been reported as an important factor for bladder remodeling and overactivity. Dysfunction of the nitric oxide (NO)-cyclic guanosine monophosphate pathway (cGMP) is one factor involved in the development of lower urinary tract (LUT) disorders. Therefore, we hypothesized that ageing-associated LUT disorders is a consequence of lower cGMP productions due to an oxidation of soluble guanylate cylase (sGC) that results in local ischemia. In the present study IA from middle-aged and young rats were isolated and the levels of NO, reactive oxygen species (ROS), the gene expression of the enzymes involved in the NO-pathway and concentration-response curves to the soluble guanylate (sGC) stimulator (BAY 41-2272), sGC activator (BAY 58-2667), tadalafil, acetylcholine (ACh) and sodium nitroprusside (SNP) were determined. In IA from middle-aged rats the gene expression for endothelial nitric oxide synthase and the ROS were lower and higher, respectively than the young group. The relaxations induced by ACh and SNP were significantly lower in IA from middle-aged rats. In IA from middle-aged rats the mRNA expression of PDE5 was 55% higher, accompanied by lower relaxation induced by tadalafil. On the other hand, the gene expression for sGCα1 were similar in IA from both groups. Both BAY 41-2272 and BAY 58-2667 produced concentration-dependent relaxations in IA from both groups, however, the latter was 9-times more potent than BAY 41-2272 and produced similar relaxations in IA in both middle-aged and young groups. Yet, the sGC oxidant, ODQ increased the relaxation and the cGMP levels induced by BAY 58-2667. On the other hand, in tissues stimulated with SNP, tadalafil and BAY-2272, the intracellular levels of cGMP were lower in IA from middle-aged than young rats. In conclusion, our results clearly showed that the relaxations induced by the endothelium-dependent and -independent agents, by the PDE5 inhibitor and by sGC stimulator were impaired in IA from aged rats, while that induced by sGC activator was preserved. It suggests that sGC activator may be advantageous in treating ischemia-related functional changes in the lower urinary tract organs in situations where the NO levels are reduced.

Hypoxic coronary vasospasm may lead to myocardial ischaemia and cardiac dysfunction. Inosine 3′,5′‐cyclic monophosphate (cIMP) is a putative second messenger to mediate this pathological process. Nevertheless, it remains unclear as to whether levels of cIMP can be regulated in living tissue such as coronary artery and if so, what is the consequence of this regulation on hypoxia‐induced vasoconstriction. In the present study, we found that cIMP was a key determinant of hypoxia‐induced constriction but not that of the subsequent relaxation response in porcine coronary arteries. Subsequently, coronary arteries were treated with various phosphodiesterase (PDE) inhibitors to identify PDE types that are capable of regulating cIMP levels. We found that inhibition of PDE1 and PDE5 substantially elevated cIMP content in endothelium‐denuded coronary artery supplemented with exogenous purified cIMP. However, cGMP levels were far lower than their levels in intact coronary arteries and lower than cIMP levels measured in endothelium‐denuded coronary arteries supplemented with exogenous cIMP. The increased cIMP levels induced by PDE1 or PDE5 inhibition further led to augmented hypoxic constriction without apparently affecting the relaxation response. In intact coronary artery, PDE1 or PDE5 inhibition up‐regulated cIMP levels under hypoxic condition. Concomitantly, cGMP level increased to a comparable level. Nevertheless, the hypoxia‐mediated constriction was enhanced in this situation that was largely compromised by an even stronger inhibition of PDEs. Taken together, these data suggest that cIMP levels in coronary arteries are regulated by PDE1 and PDE5, whose inhibition at a certain level leads to increased cIMP content and enhanced hypoxic constriction.

Molecular recognition binding sites that specifically identify a target molecule are essential for life science research, clinical diagnoses, and therapeutic development. Corona phase molecular recognition is a technique introduced to generate synthetic recognition at the surface of a nanoparticle corona, but it remains an important question whether such entities can achieve the specificity of natural enzymes and receptors. In this work, we generate and screen a library of 24 amphiphilic polymers, preselected for molecular recognition and based on functional monomers including methacrylic acid, acrylic acid, and styrene, iterating upon a poly(methacrylic acid-co-styrene) motif. When complexed to a single-walled carbon nanotube, some of the resulting corona phases demonstrate binding specificity remarkably similar to that of phosphodiesterase type 5 (PDE5), an enzyme that catalyzes the hydrolysis of secondary messenger. The corona phase binds selectively to a PDE5 inhibitor, Vardenafil, as well as its molecular variant, but not to other potential off-target inhibitors. Our work herein examines the specificity and sensitivity of polymer "mutations" to the corona phase, as well as direct competitions with the native binding PDE5. Using structure perturbation, corona surface characterization, and molecular dynamics simulations, we show that the molecular recognition is associated with the unique three-dimensional configuration of the corona phase formed at the nanotube surface. This work conclusively shows that corona phase molecular recognition can mimic key aspects of biological recognition sites and drug targets, opening up possibilities for pharmaceutical and biological applications.

The surge in the consumption of food products containing herbal aphrodisiacs has driven their widespread adulteration. A rapid screening strategy is, therefore, warranted to curb this problem. This study established an enzyme inhibition assay to screen phosphodiesterase 5 (PDE5) inhibitors as adulterants in selected food products. Fluorescein-labelled cyclic-3',5'-guanosine monophosphate was utilised as substrates for the PDE5A1 enzyme, aided by the presence of nanoparticle phosphate-binding beads on their fluorescence polarisation. The sample preparation was optimised to improve the enzyme inhibition efficiency and applied to calculate the threshold values of six blank food matrices. The assay was validated using sildenafil, producing an IC50 of 4.2 nM. The applicability of the assay procedure was demonstrated by screening 55 distinct food samples. The results were subsequently verified using confirmatory liquid chromatography-high-resolution mass spectrometry (LC-HRMS) analysis. Altogether, 49 samples inhibited the PDE5 enzyme above the threshold values (75.7%-105.5%) and were registered as potentially adulterated samples. The remaining six samples were marked as nonadulterated with percentage inhibition below the threshold values (-3.3%-18.2%). The LC-HRMS analysis agreed with the assay results for all food products except for the instant coffee premix (ICP) samples. False-positive results were obtained for the ICP samples at 32% (8/25), due to possible PDE5 inhibition by caffeine. Contrarily, all other food samples were found to produce 0% (0/30) false-positive or false-negative results. The broad-based assay, established via a simple mix-incubate-read format, exhibited promising potential for high-throughput screening of PDE5 inhibitors in various food products, except those with naturally occurring phosphodiesterase inhibitors such as caffeine.

Our study aims to explore changes in bladder contractility and the phosphodiesterase type 5 (PDE5) signalling pathway in response to partial bladder outlet obstruction (PBOO). A surgically induced male rat PBOO model and human obstructed bladder tissues were used. Histological changes were examined by H&E and Masson's trichrome staining. Bladder strip contractility was measured via organ bath. The expressions of nitric oxide synthase (NOS) isoforms, PDE5, muscarinic cholinergic receptor (CHRM) isoforms and PDE4 isoforms in bladder were detected by RT‐PCR and Western blotting. The immunolocalization of the PDE5 protein and its functional activity were also determined. PBOO bladder tissue exhibited significant SM hypertrophy and elevated responsiveness to KCl depolarization and the muscarinic receptor agonist carbachol. NOS isoforms, PDE5, CHRM2, CHRM3 and PDE4A were up‐regulated in obstructed bladder tissue, whereas no change in PDE4B and PDE4D isoform expression was observed. With regard to PDE5, it was expressed in the SM bundles of bladder. Interestingly, obstructed bladder exhibited less relaxation responsiveness to sodium nitroprusside (SNP), but an exaggerated PDE5 inhibition effect. The up‐regulation of PDE5 could contribute to the lack of effect on Qmax for benign prostatic hyperplasia/lower urinary tract symptom (BPH/LUTS) patients treated with PDE5 inhibitors. Moreover, PDE5 (with presence of NO) and PDE4 may serve as new therapeutic targets for bladder diseases such as BPH‐induced LUTS and overactive bladder (OAB).

Cardiovascular diseases are the number one death worldwide. Nitric oxide (NO)—NO-sensitive (soluble) guanylyl cyclase (sGC)—cyclic guanosine monophosphate (cGMP) pathway regulates diverse set of important physiological functions, including maintenance of cardiovascular homeostasis. Resting and activated sGC enzyme converts guanosine triphosphate to an important second messenger cGMP. In addition to traditional NO generators, a number of sGC activators and stimulators are currently in clinical trials aiming to support or increase sGC activity in various pathological conditions. cGMP-specific phosphodiesterases (PDEs), which degrade cGMP to guanosine monophosphate, play key role in controlling the cGMP level and the strength or length of the cGMP-dependent cellular signaling. Thus, PDE inhibitors also have clear clinical applications. Here, we introduce a homogeneous quenching resonance energy transfer (QRET) for cGMP to monitor both sGC and PDE activities using high throughput screening adoptable method. We demonstrate that using cGMP-specific antibody, sGC or PDE activity and the effect of small molecules modulating their function can be studied with sub-picomole cGMP sensitivity. The results further indicate that the method is suitable for monitoring enzyme reactions also in complex biological cellular homogenates and mixture.