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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.

Phosphodiesterase 5 inhibition (PDE5i) activates cGMP-dependent protein kinase (PKG) and ameliorates heart failure; however, its impact on cardiac mitochondrial regulation has not been fully determined. Here, we investigated the role of the mitochondrial regulator peroxisome proliferator-activated receptor γ co-activator-1α (PGC1α) in the PDE5i-conferred cardioprotection, utilizing PGC1α null mice. In PGC1α(+/+) hearts exposed to 7 weeks of pressure overload by transverse aortic constriction, chronic treatment with the PDE5 inhibitor sildenafil improved cardiac function and remodeling, with improved mitochondrial respiration and upregulation of PGC1α mRNA in the myocardium. By contrast, PDE5i-elicited benefits were abrogated in PGC1α(−/−) hearts. In cultured cardiomyocytes, PKG overexpression induced PGC1α, while inhibition of the transcription factor CREB abrogated the PGC1α induction. Together, these results suggest that the PKG–PGC1α axis plays a pivotal role in the therapeutic efficacy of PDE5i in heart failure.

Phosphodiesterase 5 (PDE5) falls under a broad category of metallohydrolase enzymes responsible for the catalysis of the phosphodiesterase bond, and thus it can terminate the action of cyclic guanosine monophosphate (cGMP). Overexpression of this enzyme leads to development of a number of pathological conditions. Thus, targeting the enzyme to develop inhibitors could be useful for the treatment of erectile dysfunction as well as pulmonary hypertension. In the current study, several molecular modelling techniques were utilized including Bayesian classification, single tree and forest tree recursive partitioning, and genetic function approximation to identify crucial structural fingerprints important for optimization of tri-substituted pyrazoline derivatives as PDE5 inhibitors. Later, various machine learning models were also developed that could be utilized to predict and screen PDE5 inhibitors in the future.

Erectile dysfunction (ED) is one of the most common conditions affecting the sexual lives of middleaged and older men. The pathophysiology of penile erection is rather complex and concerns many specialists, such as andrologists, urologists, endocrinologists, and cardiologists. Recently, there has been a significant increase in our understanding of ED, detailed up to the gene and molecular level. Therefore, treatments for this disease are also more advanced and comprise numerous novel medications and therapies such as oral medications with phosphodiesterase type 5 inhibitor and modern penile prosthesis implantation. However, these therapeutic approaches have an impact in relieving the symptoms of ED and have not thoroughly resolved their reasons. Regenerative therapeutics including intracavernosal injection with platelet-rich plasma and stem cell therapy have gained considerable attention because of their ability to generate new penile tissue as well as reverse ED. The use of these novel ED treatments is emerging due to their safety and long-term efficacy based on substantial preclinical evidence. However, only a few clinical trials have been conducted and demonstrate promising outcomes. This article will briefly review the scientific evidence on these regenerative therapeutics for ED.

INTRODUCTION The cause of erectile dysfunction (ED) in diabetic patients is complex and involves both neurogenic and vasculogenic components and is often hard to treat. AIM To study the effect of low-intensity extracorporeal shock wave therapy (Li-ESWT) therapy on a subgroup of diabetic patients with ED who are responders (PDE5I-R) and non-responders (PDE5I-NR) to phosphodiesterase 5 inhibitors (PDE5I). METHODS Analysis of pooled data from 5 double-blind, sham-controlled trials was performed. In this sub-analysis, of 350 patients in the PDE5I-R group and with vasculogenic ED, we found 61 patients with diabetes mellitus who underwent LI-ESWT. Another 48 patients (of 53) belonged to the PDE5I-NR group. Baseline efficacy was evaluated with the International Index of Erectile Function-Erectile Function domain questionnaire (IIEF-EF) for the PDE5I-R and with Erection Hardness Score, IIEF-EF, and flow-mediated dilation technique for the PDE5I-NR. MAIN OUTCOME MEASURES Change in the IIEF-EF score after treatment of diabetes-induced ED with Li-ESWT in the PDE5i-R group vs the PDE5i-NR group. RESULTS LI-ESWT therapy was found to be effective in both subgroups of diabetic patients. Minimally clinical important difference in IIEF-EF score was achieved in 50%, 79.5%, 77.3%, and 65.9% of the subjects in the active group in after the sixth shockwave (SW) treatment evaluation (just before initiating the seventh SW session) and at 1 month, 6 months, and 12 months after the last SW treatment, respectively. The difference among the groups was significant (P < .05) after the sixth treatment and in all the follow-up periods. In the PDE5I-NR group, 55% of the active group were converted to PDE5I-5-R after LI-ESWT. The difference between the active and sham groups was statistically significant in all the tested measures (P < .001). CONCLUSION LI-ESWT is safe and effective for the treatment of ED in PDE5I-R and PDE5I-NR groups. Spivak L, Shultz T, Appel B, et al. Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction in Diabetic Patients. Sex Med Rev 2021;9:619-627.

PURPOSE: The urinary bladder generates phasic contractions via action potentials generated in pre- and then postganglionic neurons. Whilst the frequency-dependence of postganglionic neurons to generate contractions has been quantified, the dynamic range of preganglionic neurons is less clear and if intramural ganglia exert frequency-dependent modulation of transmission between pre- and postganglionic neurons. The phosphodiesterase type 5 inhibitor sildenafil reduces neurotransmitter release from postganglionic fibres to detrusor smooth muscle and an additional question was if there was also a preganglionic action. This study aimed to compare the frequency range of bladder contractile activation by pre- and postganglionic stimulation in pig and rat bladders and if sildenafil exerted additional preganglionic actions.METHODS: An arterially-perfused ex vivo pig bladder preparation was used for preganglionic (pelvic nerve) and mixed pre-and postganglionic (direct bladder wall) stimulation at 36°C and postganglionic mediated contractions achieved by field-stimulation of in vitro isolated detrusor strips. With rats, pelvic nerve stimulation was carried out in vivo and postganglionic stimulation also with isolated detrusor strips.RESULTS: All contractions were abolished by 2% lignocaine indicating they are nerve-mediated. Stimulation targets were verified with hexamethonium that completely abolished pelvic nerve responses by had no effect on detrusor strips; responses to mixed bladder wall stimulation were partially reduced. The frequency-dependence of contractile activation was similar whether by pre- or postganglionic stimulation in both pigs and rats. Sildenafil reduced contractions to preganglionic stimulation significantly more than to postganglionic stimulation. Mixed pre- and postganglionic stimulation were reduced by an intermediate extent.CONCLUSION: Intramural ganglia offer no frequency-dependent modulation under the experimental conditions used here and the sildenafil data are consistent with multiple sites of action underlying generation of bladder contractions. A translational aspect of these findings is discussed in terms of setting stimulation parameters for neuromodulation protocols.

Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.Легочная гипертензия (ЛГ) тяжелое и часто быстро прогрессирующее заболевание с фатальным исходом. Эндотелиальная дисфункция при ЛГ сопровождается снижением продукции оксида азота. После рассмотрения механизмов действия и доказательной базы специфической терапии ингибиторами фосфодиэстеразы 5 (иФДЭ-5) и стимуляторами растворимой гуанилатциклазы проводится обзор исследований по переключению с иФДЭ-5 на риоцигуат. Потенциальным преимуществом риоцигуата является независимость от эндогенного оксида азота и других (помимо ФДЭ-5) изоферментов фосфодиэстераз. Благоприятный профиль эффективности силденафила доказан для основных форм легочной артериальной гипертензии, риоцигуата для основных форм легочной артериальной гипертензии и хронической тромбоэмболической ЛГ. Клиническая эффективность замены иФДЭ-5 на риоцигуат показана в неконтролируемых исследованиях и рандомизированном контролируемом исследовании REPLACE. Возможность оптимизации терапии за счет переключения с иФДЭ-5 на риоцигуат закреплена в российских (класс и уровень доказательности B-3) и евразийских (класс и уровень доказательности IIb-B) клинических рекомендациях, а также в материалах Кельнского консенсуса экспертов. Дополнительным аргументом за переключение в условиях Российской Федерации служит меньшая стоимость по сравнению с комбинированной терапией. Согласно российским и евразийским рекомендациям по ЛГ и российской инструкции по применению риоцигуата его прием следует начинать не ранее чем через 24 ч после отмены силденафила.

Phosphodiesterase 5 (PDE5) is a clinically relevant biomarker and therapeutic target for many human pathologies, yet a noninvasive agent for the assessment of PDE5 expression has yet to be realized. Such agents would improve our understanding of the nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP)/PDE5 pathway in human pathologies and potentially lead to novel uses of PDE5 inhibitors to manage lung conditions like SARS-CoV-2-mediated pulmonary inflammatory responses. In this study, efforts were made to produce an 18F-labeled analogue of the PDE5 inhibitor tadalafil to visualize PDE5 expression in vivo with positron emission tomography (PET). However, during the late-stage fluorination step, quantitative epimerization of the tadalafil C12a stereocenter occurred, yielding a less active epi-isomer. In vivo dynamic microPET images in mice revealed that the epimerized radiotracer, [18F]epi-18, rapidly accumulated in the liver with negligible uptake in tissues of known PDE5 expression.

A feasible and cost effective reverse-phase high-performance thin layer chromatography (RP-HPTLC) based method was developed for the quantification of sildenafil (SLD) using eco-friendly EtOH:H2O (9.5:0.5 v/v) as mobile phase. SLD was subjected to stress conditions according to the International Conference on Harmonization (ICH) guidelines. The drug undergoes significant structural changes under oxidative stress condition to the N-oxide derivative. The oxidation product Sildenafil N-oxide (SDL N-oxide) designated in the European Pharmacopeia (EP) as impurity B was characterized utilizing 1D- and 2D-NMR as well as High Resolution Electrospray Ionization Mass Spectroscopy. The aphrodisiac potency of SDL N-oxide in comparison with SLD was evaluated in vivo using rats as experimental animal model. The evaluation based on the following parameters: mount, intromission and ejaculation latencies (ML, IL and EL, respectively), mounting and intromission frequencies (MF and IF, respectively), and postejaculatory interval (PEI). SLD N-oxide expressed similar aphrodisiac effect to SLD but with less potency. Molecular docking of SDL N-oxide along with the parent drug SLD, indicated a strong binding affinity and similar binding pattern within the active site of phosphodiesterase 5 (PDE5). However, the docking score of SLD N-oxide was slightly lower as compared to SLD in agreement with the biological study findings.

Phosphodiesterase 5 inhibitors (PDE5Is) and low-energy shock wave therapy (LESWT) have created a revolution in the treatment of erectile dysfunction (ED). However, they are not able to restore the actual changes in the penis. An emerging new therapy called platelet-rich plasma (PRP) is believed to be more beneficial in treating ED. The objective of this study is to evaluate and compare the efficacy of LESWT and PRP in treating ED. A total of sixty participants of pathological ED was included in the study and divided into two groups. Group A received the LESWT, whereas Group B received the PRP. The benefits were measured by the International Index of Erectile Function (IIEF), an erection hardness score (EHS) and Self-Esteem And Relationship (SEAR) questionnaires. The results of this analysis demonstrated a larger effect in treatment group B in percentage terms, but there were no statistical differences in the two groups. In the near future, PCP may be a new modality for treating ED, especially PDE5I non-respondents with organic ED. However, more extensive preclinical and applied research needs to be conducted.

A 46-year-old man who had undergone hematopoietic stem cell transplant twice because of acute lymphoblastic leukemia with recurrence presented with dyspnea, leading to a diagnosis of pulmonary arterial hypertension which was quickly and effectively treated with the phosphodiesterase type 5 inhibitor tadalafil. To our knowledge, pulmonary arterial hypertension related to hematologic malignancies requiring hematopoietic stem cell transplant is rarely reported. Importantly, the present case suggests that early diagnosis and treatment with a pulmonary vasodilator, such as tadalafil, can greatly decrease pulmonary vascular resistance in patients with severe pulmonary arterial hypertension after hematopoietic stem cell transplant and can then improve other symptoms. Accordingly, pulmonary vascular disease should be considered if respiratory symptoms develop following hematopoietic stem cell transplant, because treatment with pulmonary vasodilator may lead to significant improvement in pulmonary arterial hypertension.

The primary goals of medical expulsive therapy are to increase the rate of stone expulsion along the ureter to avoid ureteral obstruction and reduce ureteral colic and thus avoid the need for surgical and more invasive interventions. This review focussed on the findings from in vivo and in vitro animal and human studies that have investigated the pharmacological mechanisms controlling ureteral motility and their translation to current and potentially new clinically used drugs for increasing the rate of stone expulsion along the ureter. The complicated contractility profile of the ureter, which alters with age, tissue segment region, orientation and species contributes to the difficulty of interpreting studies on ureteral pharmacology, which translates to the complexity of discovering ideal drug targets for medical expulsive therapy. Nevertheless, the current drug classes clinically used for patients with stone lodgement include α1 -adrenoceptor antagonists, calcium channel blockers and NSAIDS, whilst there are promising targets for drug development that require further clinical investigations including the phosphodiesterase type 5 enzyme, β-adrenoceptors and 5-HT receptors.

Phosphodiesterase-5 inhibitors (PDE-5i, such as Sildenafil, Tadalafil and Vardenafil, mainly prescribed to treat erectile dysfunction) and their generic drug equivalents have been widely marketed and consumed in Korea. From the concentrations detected in wastewater, we could deduce that relatively large amounts of PDE-5i were consumed without a legal prescription. Thus, PDE-5i’s presence in the environment via sewage is unavoidable, and their environmental fate within a sewage treatment plant (STP) should be evaluated. In this study, we investigated the occurrence of three PDE-5i analogs in the influent and effluent of two STPs and the receiving water bodies. The PDE-5i concentration in total reached 62 ± 12 (STP#1) and 88 ± 37 ng L−1 (STP#2) in the sewage influent; about 70% of it was Sildenafil in both STPs. However, they were hardly removed by the STPs as the removal efficiency of the STPs was less than 10% ± 5%. Therefore, the pharmaceuticals were detected in the receiving water (lower than 7 ng L−1as a total amount) and the concentration slightly increased downstream of the STPs. A simple mass balance model applied for the compounds in the STP effluent and receiving water bodies also confirmed that the discharged PDE-5i were quite persistent. Lastly, we identified temporal and regional patterns in the consumption of the drugs from daily variations of PDE-5i in the influent to these two STPs. For instance, the levels of PDE-5i in the sewage significantly increased on weekends (from Friday to Saturday), and especially in the area where adult-entertainment businesses are common. We estimated that the amount of PDE-5i consumption in this area was 31% higher than that in the area with fewer nightlife spots. Considering that they are pharmaceutically active and resistant to treatment processes within an STP, it is advised that a regular monitoring and management program for PDE-5i should be developed to prevent the discharge of the pharmaceuticals into the water environment.

Phosphodiesterase type 5 inhibitors such as sildenafil citrate and tadalafil are well known for the treatment of erectile dysfunction. However, their use in the presence of pulmonary hypertension can cause ophthalmologic side effects, including non-arteritic optic ischemic neuropathy, chorioretinopathy, glaucoma, and optic atrophy. The present review aimed to identify these visual side effects and provide recommendations. We identified articles published from January 2000 to March 2019 on diseases arising from the management of sexual dysfunction in urology or pulmonary hypertension in pneumonia that could cause pathologic alterations in eye structure based on a literature search of the MEDLINE electronic database using keywords for the most common adverse effects and different kinds of phosphodiesterase 5 inhibitors. After applying the exclusion criteria, we selected 36 of the 77 articles initially identified to write the narrative review and added 20 additional articles to completely describe the pathological entities. Phosphodiesterase type 5 inhibitors can cause side effects in the eye including ocular surface abnormalities, increased intraocular pressure and glaucoma, uveitis, non-arteritic ischemic neuropathy, chorioretinopathy, retinal occlusion, and visual field changes. There is an increased need for well-performed studies to better understand these side effects, which are common due to the wide use of sildenafil.

Purpose Phosphodiesterase type 5 (PDE5) inhibitors are effective treatments for erectile dysfunction, and several recent studies have reported positive effects of PDE5 inhibitors on semen parameters as well. However, the data are still controversial. We investigated the effect of PDE5 inhibitors on sperm function by analyzing sperm motility and acrosome reaction. Materials and methods This study included young healthy men who underwent fertility evaluation; 32 cases were finally included. Men were excluded if they used a PDE5 inhibitor within 2 weeks or if they had insufficient semen volume (≤2 mL), leukocytospermia, or a genitourinary infection. Changes in sperm motility and acrosome reaction were determined after in vitro exposure to the maximal semen concentration of oral intake of sildenafil (100 mg) or tadalafil (20 mg). Results Mean age of the participants was 35.4±4.9 years, mean sperm concentration was 68.7±32.4 ×10⁶/mL, and mean sperm motility was 50.38%±8.41%. All three groups (control, sildenafil, tadalafil) experienced trends of decreased average sperm motility over time, but these changes were not significant. There were no significant differences between the three groups in the acrosome reaction after 120 minutes of drug exposure, either. The maximal semen concentration of oral intake of sildenafil (100 mg) or tadalafil (20 mg) did not substantially affect sperm motility or acrosome reaction. Conclusions Our results suggest that on-demand use of a PDE5 inhibitor is safe and useful for the male partner of an infertile couple; however, further studies are warranted for daily PDE5 inhibitor use.

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.

Objectives Sickle cell disease related pulmonary hypertension (SCD-PH) is a complex disorder with multifactorial contributory mechanisms. Previous trials have evaluated the efficacy of pulmonary arterial hypertension (PAH) therapies in SCD-PH with mixed results. We hypothesized that a subset of patients with right heart catheterization (RHC) confirmed disease may benefit from PAH therapy. Methods We performed a retrospective chart review of patients with SCD-PH diagnosed by RHC who were treated with phosphodiesterase 5 inhibitor (PDE5-I) therapy for ≥4 months between 2008-2019 at two institutions. Results Thirty-six patients were included in the analysis. The median age (IQR) upon PDE5-I initiation was 47.5 years (35 to 51.5 years); 58% were female and twenty-nine (81%) had HbSS disease. Of these, 53% of patients had a history of acute chest syndrome, 42% had a history of venous thromboembolism and 38% had imaging consistent with chronic thromboembolic PH. Patients were treated for a median duration of 25 months (IQR 13-60 months). Use of PDE5-I was associated with a significant improvement in symptoms as assessed by NYHA Class (p=0.002). Conclusions In SCD patients with PH defined by RHC, PDE5-I therapy was tolerated long-term and may improve physical activity.

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.

The pathophysiologies of metabolic syndrome (MS) and overactive bladder (OAB) might overlap. Using fructose-fed rats (FFRs) as a rodent model of MS we investigated the effects of tadalafil (a phosphodiesterase type 5 inhibitor) on the dysregulated insulin signalling in the bladder mucosa and bladder overactivity. Micturition behaviour was evaluated. Concentration–response curves on detrusor relaxation to insulin stimulation were examined. Expression and phosphorylation of proteins in the insulin signalling pathway were evaluated by Western blotting. Levels of detrusor cGMP and urinary nitrite and nitrate (NOx) were measured. We observed FFRs exhibited metabolic traits of MS, bladder overactivity, and impaired insulin-activated detrusor relaxation in organ bath study. A high-fructose diet also impeded insulin signalling, reflected by overexpression of IRS1/pIRS1Ser307 and pIRS2Ser731 and downregulation of PI3K/pPI3KTyr508, AKT/pAKTSer473, and eNOS/peNOSSer1177 in the bladder mucosa, alongside decreased urinary NOx and detrusor cGMP levels. Tadalafil treatment restored the reduced level of mucosal peNOS, urinary NOx, and detrusor cGMP, improved the insulin-activated detrusor relaxation, and ameliorated bladder overactivity in FFRs. These results suggest tadalafil may ameliorate MS-associated bladder overactivity by restoring insulin-activated detrusor relaxation via molecular mechanisms that are associated with preservation of IR/IRS/PI3K/AKT/eNOS pathway in the bladder mucosa and cGMP production in the bladder detrusor.

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

The viability of cutaneous flaps and grafts is dependent on adequate circulation and perfusion. Smoking, excessive tension or pressure, arterial insufficiency, and venous congestion are factors that can contribute to flap failure due to poor perfusion. Early identification of tissue ischemia and its intervention can improve flap survival. Tadalafil is a phosphodiesterase-5 (PDE5) inhibitor that increases blood flow by vasodilation of the peripheral vasculature as well as inhibition of platelet aggregation. Although current indications for tadalafil by the US Food and Drug Administration are for erectile dysfunction and pulmonary hypertension,1 its mechanism of action is theoretically beneficial in increasing blood perfusion in patients who are at risk of flap or graft ischemia due to poor circulation. The following case series presents the successful off-label use of tadalafil in preventing tissue ischemia in high-risk patients and treating patients with early signs of tissue necrosis.

Objectives To assess the efficacy of an endothelin receptor antagonist (ERA) and phosphodiesterase type5 inhibitors (PDE5is) for treating SSc-related digital ulcers (DUs). Methods This prospective, multicentre, observational cohort study recruited patients with active SSc-related DUs from 13 medical centres in South Korea. The primary outcome was time to cardinal ulcer (CU) healing. A secondary outcome was time to new DU occurrence. Patients were followed up 4, 8, 12 and 24 weeks after treatment initiation. Results Sixty-three patients were analysed. Their mean age was 49.9 years (s.d. 11.4) and 49 were female. Twenty-eight had limited SSc. Forty-nine patients received ERA, 11 received a PDE5i (9 sildenafil, 1 udenafil and 1 tadalafil) and 3 received other medication. The hazard ratio (HR) for time to CU healing in the ERA group vs the PDE5i group was 0.75 (95% CI 0.35, 1.64; P = 0.47) in an unadjusted model and 0.80 (95% CI 0.36, 1.78; P = 0.59) in a model adjusted for age, sex, use of calcium channel blockers (CCBs), total DU number and initial CU area. The HR for new DU development in the ERA group vs the PDE5i group was 0.39 (95% CI 0.16, 0.93; P = 0.03) in an unadjusted model and 0.32 (95% CI 0.13, 0.81; P = 0.02) in an adjusted model. No patients receiving CCBs developed new DUs at 24 weeks. Conclusion Time to CU healing is comparable for ERA and PDE5i. ERAs are more effective in reducing new DU occurrence than PDE5is. CCBs may be effective as a background medication.

BACKGROUND In recent years, phosphodiesterase type 5 (PDE5) inhibitors have been proposed for relieving the ureteral stent-related symptoms. We conducted a meta-analysis to assess the efficacy and safety of PDE5 inhibitors in the treatment of ureteral stent-related symptoms. METHODS Randomized controlled trials (RCTs) that reported on the effectiveness of PDE5 inhibitors on ureteral stent-related symptoms were identified and collected from Medline, Embase, and Cochrane Library databases. RESULTS Four RCTs involving 352 patients were included. Following treatment with PDE5 inhibitors for 1 week, significant improvement of urinary symptoms (P

Accumulated evidence shows that the cAMP and cGMP signaling pathway plays an important role in memory function and neuronal plasticity. Phosphodiesterase 5 (PDE5) is a hopeful therapeutic target in AD (Alzheimer disease), and PDE5 inhibition may be a good therapeutic strategy for the treatment of AD. In the present study, the four-day bilateral intra-hippocampal infusion of H-89 as a protein kinase AII inhibitor (10 µM/side) and intra-peritoneal injections of tadalafil (20 mg/kg) and scopolamine (0.5 mg/kg) alone and also on combination on spatial learning in Morris water maze (MWM) were investigated. DMSO and saline were used as controls for H-89 and other mentioned drugs, respectively. Rats were trained for 4 days; each day included one block of four trials. Post- training probe trial tests were performed on day 5. Administration of H-89 and scopolamine led to a significant impairment in spatial learning compared to their related controls. But, combination of tadalafil/H-89 or tadalafil/scopolamine reversed H-89 or scopolamine- induced spatial learning deficits in MWM. Taken together, these results showed the probable regulatory effects of cGMP on cholinergic and cAMP/PKA signaling pathways in co-administrations of these mentioned drugs on spatial learning in MWM.

Introduction The recent global outbreak of coronavirus disease 2019 (COVID-19) has become a pandemic with a lot of sufferers. Excessive inflammation, exaggerated immune response, with ultimate apoptosis contribute to COVID-19 pathology that progress to acute lung acute respiratory distress. Objective To shed a light on the likely benefits of the oral phosphodiesterase 5 (PDE5) inhibitor adjuvant role in combating COVID-19 infection. Methods A literature review was performed in the PubMed/Medline database, Scopus, Cochrane Library, EMBASE, Academic Search Complete, Google Scholar, and CINAHL databases using the keywords COVID-19; phosphodiesterase-5 inhibitors; cytokine storm; respiratory distress. Results Despite the worsening trends of COVID-19, still no drugs are validated to have significant clinical efficacy in the treatment of patients with COVID-19 in large-scale studies. While the progress toward a curative agent and/or vaccine is certainly hopeful, the principal limiting factor in such public health emergencies is always the time. Therefore, a preexisting licensed therapeutic(s) might offer a reprieve to the healthcare systems operating at the edge of capacity. In this context, the innovation of oral PDE5 inhibitors with their valuable effects on erection have provided a breakthrough in the treatment of erectile dysfunction and opened new fields of clinical application for this class of drugs. Oral PDE5 inhibitors have been demonstrated to possess many beneficial useful additional implications with acknowledged anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties. These properties have been elucidated through the nitric oxide/soluble guanylyl cyclase/cyclic guanylate monophosphate pathway in addition to the emerged hemeoxygenase-1 enzyme as well as hydrogen sulfide pathways. These properties could support repurposing oral PDE5 inhibitors' potential adjuvant use in targeting different aspects of COVID-19 infection. Conclusion Oral PDE5 inhibitors retain several acknowledged off-labeled useful implications with anti-inflammatory, antioxidant, immune response regulation, and antiapoptotic properties. These properties may support repurposing oral PDE5 inhibitors' potential adjuvant use in the protocols combating COVID-19 manifestations. Mostafa T. Could Oral Phosphodiesterase 5 Inhibitors Have a Potential Adjuvant Role in Combating Coronavirus Disease 2019 Infection? Sex Med Rev 2021;9:15–22.

Background Radical prostatectomy for prostate cancer can not only induce cavernous nerve injury (CNI), but also causes cavernous hypoxia and cavernous structural changes, which lead to a poor response to phosphodiesterase 5 inhibitors. Aim To investigate the therapeutic effect of oral administration of LM11A-31, a small molecule p75 neurotrophin receptor (p75NTR) ligand and proNGF antagonist, in a mouse model of bilateral CNI, which mimics nerve injury–induced erectile dysfunction after radical prostatectomy. Methods 8-week-old male C57BL/6 mice were divided into sham operation and CNI groups. Each group was divided into 2 subgroups: phosphate-buffered saline and LM11A-31 (50 mg/kg/day) being administered once daily starting 3 days before CNI via oral gavage. 2 weeks after CNI, we measured erectile function by electrical stimulation of the bilateral cavernous nerve. The penis was harvested for histologic examination and Western blot analysis. The major pelvic ganglia was harvested and cultured for assays of ex vivo neurite outgrowth. Outcomes Intracavernous pressure, neurovascular regeneration in the penis, in vivo or ex vivo functional evaluation, and cell survival signaling were measured. Results Erectile function was decreased in the CNI group (44% of the sham operation group), while administration of LM11A-31 led to a significant improvement of erectile function (70% of the sham operation group) in association with increased neurovascular content, including cavernous endothelial cells, pericytes, and neuronal processes. Immunohistochemical and Western blot analyses showed significantly increased p75NTR expression in the dorsal nerve of CNI mice, which was attenuated by LM11A-31 treatment. Protein expression of active PI3K, AKT, and endothelial nitric oxide synthase was increased, and cell death and c-Jun N-terminal kinase signaling was significantly attenuated after LM11A-31 treatment. Furthermore, LM11A-31 promoted neurite sprouting in cultured major pelvic ganglia after lipopolysaccharide exposure. Clinical Implications LM11A-31 may be used as a strategy to treat erectile dysfunction after radical prostatectomy or in men with neurovascular diseases. Strengths & Limitations Unlike biological therapeutics, such as proteins, gene therapies, or stem cells, the clinical application of LM11A-31 would likely be relatively less complex and low cost. Our study has some limitations. Future studies will assess the optimal dosing and duration of the compound. Given its plasma half-life of approximately 1 hour, it is possible that dosing more than once per day will provide added efficacy. Conclusion Specific inhibition of the proNGF-p75NTR degenerative signaling via oral administration of LM11A-31 represents a novel therapeutic strategy for erectile dysfunction induced by nerve injury. Yin GN, Ock J, Limanjaya A, et al. Oral Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Improves Erectile Function in a Mouse Model of Cavernous Nerve Injury. J Sex Med 2021;18:17–28.

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.

The Eriobotrya japonica leaves have the activity to relax the smooth muscle in the respiratory tract. However, the mechanism of action due to that activity has never been carried out. This study aims to determine the relaxation effects of E. japonica leaves extract in the isolated trachea of the guinea pigs through the inhibition of the histamine-1 (H-1) receptor and the phosphodiesterase-5 (PDE-5) enzyme. The determination of the relaxation effects was carried out by using histamine to contract smooth muscle within the tracheal tract, followed by adding cumulative concentrations of extract. Michaelis-Menten kinetics equation was used to determine the antagonist type of extract toward H-1 receptor. The understanding of mechanism of action of the extract toward PDE-5 enzyme was performed by incubating the smooth muscle using sildenafil. The percentage value of responses, originated from the relaxation effect of the extract toward the trachea was analyzed by using the t-independent test. The result showed that the extract was able to relax the smooth muscle, which was contracted by histamine, and there was a positive correlation between concentration and relaxation effect (P < 0.05; r = 0.973). The extract also antagonized the histamine as a noncompetitive antagonist. The incubation within the trachea with sildenafil demonstrated equal relaxation effect, produced by the extract. It can be concluded that E. japonica extract had relaxation effect within the isolated trachea as antagonist noncompetitive toward H-1 receptor and inhibitor of the PDE-5 enzyme.

Sildenafil, approved two decades ago, is the inhibitor of phosphodiesterase 5 (PDE5). First of all, it was designated for angina pectoris, but soon it showed a wonderful efficacy in erectile dysfunction (ED) and then pulmonary arterial hypertension (PAH). Due to the distribution of phosphodiesterase (PDE) in almost all organs, maybe it effects other diseases. Hence, a great number of investigations began to understand the role of PDEi in different organs. Preliminary research on sildenafil in cell culture and animal models has yielded promising results. Soon, a greater number of animal researches and clinical trials joined them. The results disclosed sildenafil can have beneficial effects in each organ such as heart, liver, kidney, brain, and intestines. Furthermore, it has significantly improved the prognosis of organ ischemia in various animal models. Clinical trials in several diseases, such as recurrent spontaneous miscarriage, fatty liver disease, bronchopulmonary dysplasia (BPD), heart failure, and premature ejaculation (PE) brought promising results. Although some clinical trials are available on the effects of sildenafil on various diseases, further studies on humans are needed to consolidate the ultimate effects of sildenafil. The aim of this review was to describe the effects of sildenafil on each organ and explain its mechanisms of action. Further, other PDE inhibitors such as tadalafil and vardenafil have been briefly discussed in parts of this review.

The article is devoted to topical issues of management of patients with pulmonary arterial hypertension and strategies for switching to riociguat therapy in patients with insufficient clinical response against the background of phosphodiesterase type 5 (PDE-5) inhibitors. The role of the NO metabolic pathway in the development of pulmonary arterial hypertension (PAH) was shown. From the standpoint of pathogenesis, the importance of the effect of medication on this pathway through soluble guanylate cyclase (sGC) has been assessed. The effects of the drug riociguat, the only member of the sGC stimulant class approved for the treatment of PAH, are associated with a dual mechanism of action: riociguat sensitizes the sGC enzyme to endogenous NO by stabilizing the NO-sGC bond, and also directly stimulates the latter through another site of the bond, regardless of NO. The favorable efficacy and safety profile of riociguat has been demonstrated in the PATENT-1,2 studies. During therapy, patients showed an improvement in exercise tolerance, functional class, and a number of other indicators. Studies that indicate the feasibility of using a change in therapy in clinical practice are reviewed. In particular, the article provides a detailed analysis of the REPLACE study. It demonstrated a significantly greater likelihood of achieving clinical improvement and a significant decrease in the rate of development of clinical deterioration when switching patients with PAH from PDE-5 inhibitors to riociguat. This therapy was well tolerated and can be considered as a strategy for managing patients at intermediate risk with insufficient patient response to PDE-5 inhibitors. In conclusion, the need to plan the need for specific therapy for pulmonary arterial hypertension in the region is noted in order to rapidly escalate therapy to achieve a low risk of mortality in these patients.

Currently, treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is focused on three signaling pathways: the NO pathway, the endothelin pathway, and the prostacyclin pathway. Riociguat is the only representative of stimulators of the soluble guanylate cyclase (sGC) class that is approved for the treatment of PAH and inoperable and persistent/recurrent CTEPH. The review presents data from clinical trials showing a positive effect of riociguat on the functional and hemodynamic profile of patients with PAH and CTEPH. In recent years there has been much discussion about the possibility of optimizing therapy by switching to drugs that affect a single pathogenesis target. Thus, sGC stimulants have obvious advantages over phosphodiesterase type 5 (PDE-5) inhibitors, including the ability of riociguat to exert pharmacological effects (due to a NO-independent mechanism of action) even in conditions of reduced NO production. Switching from PDE-5 to riociguat may be safe and appropriate, according to clinical trials presented in the review. In accordance with the guidelines for the diagnosis and treatment of pulmonary hypertension of the Eurasian Association of cardiologists from 2019, this strategy is approved when PDE5 therapy is ineffective in patients with PAH FC III (WHO).В настоящее время лечение легочной артериальной гипертензии (ЛАГ) и хронической тромбоэмболической легочной гипертензии (ХТЭЛГ) сосредоточено на трех сигнальных путях: путь оксида азота (NO), путь эндотелина и путь простациклина. Риоцигуат является единственным представителем класса стимуляторов растворимой гуанилатциклазы, который одобрен для лечения ЛАГ и неоперабельной и персистирующей/рецидивирующей ХТЭЛГ. В обзоре приведены данные клинических исследований, показывающие положительное влияние риоцигуата на функциональный и гемодинамический профиль пациентов с ЛАГ и ХТЭЛГ. В течение последних лет широко обсуждается вопрос о возможности оптимизации терапии за счет замены препаратов, которые воздействуют на одну мишень патогенеза. Так, у стимуляторов растворимой гуанилатциклазы есть очевидные преимущества перед ингибиторами фосфодиэстеразы типа 5 (ИФДЭ-5), среди которых способность риоцигуата оказывать фармакологические эффекты (за счет NO-независимого механизма действия) даже в условиях сниженной продукции NO. Перевод с ИФДЭ-5 на риоцигуат может быть безопасным и целесообразным, согласно данным исследований, представленных в обзоре. В соответствии с клиническими рекомендациями по диагностике и лечению легочной гипертензии Евразийской ассоциации кардиологов от 2019 г. эта стратегия одобрена при неэффективности терапии ИФДЭ-5 у пациентов с ЛАГ III функционального класса.

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.

Purpose To assess the prevalence and potential indications of PDE5 inhibitor use among pregnant and reproductive-age women in the United States. Methods We identified women 15 to 50 years with a livebirth from January 2001 through March 2018 in Sentinel Database. We assessed the prevalence of PDE5 inhibitor use prior to and during pregnancy by trimester, identified potential on- and off-label indications using predefined diagnosis codes recorded within 90 days before the estimated last menstrual period through delivery. Separately, we used data from IQVIA's National Prescription Audit and Total Patient Tracker to estimate the dispensed prescriptions for PDE5 inhibitors and the number of patients with PDE5 inhibitor prescriptions. Results We identified approximately 3.3 million pregnancies during 2001 to 2018, 96 of which had PDE5 inhibitor use during pregnancy. Prevalence of PDE5 inhibitor use was 2.61, 0.62, and 0.62 per 100, 000 live-born pregnancies during the first, second, or third trimesters, respectively. Among women exposed to a PDE5 inhibitor from 90 days before conception to the end of pregnancy, 25.0%, 31.1%, and 15.5% had a diagnosis code for fetal growth restriction, preeclampsia, and pulmonary arterial hypertension. In IQVIA data, an estimated 223, 000 prescriptions from July 2015 through June 2018 and 58, 000 women received prescriptions for PDE5 inhibitors in 2017, of whom approximately 15, 000 (26%) were aged 15 to 50 years. Conclusion We found a low prevalence of PDE5 inhibitor use in pregnant and reproductive-age women. Given the very low prevalence of use and the inconsistency of neonatal mortality data across STRIDER centers, the risk to public health is low at present.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKAy mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule-1, and monocyte chemoattractant protein-1 levels, as well as that of renal pro-fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor-beta (TGF-β). Moreover, compound A significantly suppressed TGF-β-induced pro-fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms.

Background Testosterone (T) deficiency is associated with erectile dysfunction (ED). The relaxant response of T on the corporal smooth muscle through a non-genomic pathway has been reported; however, the in vitro modulating effects of T on human corpus cavernosum (HCC) have not been studied. Objectives To compare the effects of various concentrations of T on nitric oxide (NO)-dependent and nitric oxide-independent relaxation in organ bath studies and elucidate its mode of action, specifically targeting the cavernous NO/cyclic guanosine monophosphate (cGMP) pathway. Materials and methods Human corpus cavernosum (HCC) samples were obtained from men undergoing penile prosthesis implantation (n = 9). After phenylephrine (Phe) precontraction, the effects of various relaxant drugs of HCC strips were performed using organ bath at low (150 ng/dL), eugonadal (400 ng/dL), and hypergonadal (600 ng/dL) T concentrations. The penile tissue measurements of endothelial nitric oxide synthase (eNOS), neuronal (n)NOS, and phosphodiesterase type 5 (PDE5) were evaluated via immunostaining, Western blot, cGMP and nitrite/nitrate (NOx) assays. Results Relaxation responses to ACh and EFS in isolated HCC strips were significantly increased at all T levels compared with untreated tissues. The sildenafil-induced relaxant response was significantly increased at both eugonadal and hypergonadal T levels. Normal and high levels of T are accompanied by increased eNOS, nNOS, cGMP, and NOx levels, along with reduced PDE5 protein expression. Conclusion This study reveals an important role of short-term and modulatory effects of different concentrations of T in HCC. T positively regulates functional activities, inhibition of PDE5 expression, and formation of cGMP and NOx in HCC. These results demonstrate that T indirectly contributes to HCC relaxation via downstream effects on nNOS, eNOS, and cGMP and by inhibiting PDE5. This action provides a rationale for normalizing T levels in hypogonadal men with ED, especially when PDE5 inhibitors are ineffective. T replacement therapy may improve erectile function by modulating endothelial function in hypogonadal men.

Low-intensity shockwave therapy (Li-ESWT) has been shown to be an effective and safe treatment for vasculogenic erectile dysfunction (ED). We aim to evaluate the effectiveness and safety of LiESWT in treating patients affected from vasculogenic ED who did not respond to oral treatment with Phosphodiesterase 5 inhibitors (PDE5-i). It is a multicentric open-label prospective study, in a cohort of patients non-responders to PDE-5i. Li-ESWT was performed in an outpatient setting by using the following schedule: 3000 shockwaves with an energy of 0.25 mJ/mm2 and a frequency of 4–6 Hz, twice a week for 3 weeks. International Index of Erectile Function, Erection Hardness Score and Sexual Quality of Life-Male questionnaires, and penile doppler ultrasound (PDU) are the outcome measurements. The Student t-test or Wilcoxon signed-rank test were applied to compare variables, with results considered statistically significant at p < 0.05. 106 (97.2%) completed treatment and performed follow-up visit after 4 weeks. At follow up visit, the mean IIEF-EF increased by 8.6 points (13.47 ± 4.61 vs 22.07 ± 5.27; p < 0.0001). A clinically significant improvement of IIEF-EF was achieved in 75 patients (70.7%). An EHS score ≥ 3, sufficient for a full intercourse, was reported by 72 patients (67.9%) at follow-up visit. 37 (34.9%) patients reported a full rigid penis (EHS = 4) after treatment. Li-ESWT treatment was also able to improve quality of life (SQOL-M: 45.56 ± 8.00 vs 55.31 ± 9.56; p < 0.0001). Li-ESWT significantly increased mean PSV (27.79 ± 5.50 vs 41.66 ± 8.59; p < 0.0001) and decreased mean EDV (5.66 ± 2.03 vs 1.93 ± 2.11; p < 0.0001) in PDU. Combination of Li-ESWT and PDE5-i represents an effective and safe treatment for patients affected from ED who do not respond to first line oral therapy.

Pulmonary Hypertension due to left heart disease is the most common type of Pulmonary Hypertension. Morbidity and mortality significantly increase once Pulmonary Hypertension is present. Treatment is aimed toward optimizing the underlying condition. Targeted therapy has been evaluated in small studies with mixed results. The goal of this systematic review is to identify the possible benefit and safety of Phosphodiesterase 5 inhibitors in Pulmonary Hypertension due to left heart disease with elevated pulmonary vascular resistance, diagnosed by right heart catheterization. Electronic searches using MEDLINE/PREMEDLINE, EMBASE, and The Cochrane Library were searched on 21 October 2018. Randomized clinical trials comparing Phosphodiesterase 5 inhibitors versus placebo in patients with proven Pulmonary Hypertension by right heart catheterization secondary to left heart disease (both heart failure with reduced ejection fraction and with preserved ejection fraction) and reported pulmonary vascular resistance were included. We identified 436 potentially relevant studies. After reviewing the titles and abstracts to exclude irrelevant articles, five randomized clinical trials were considered for the study. Sildenafil was well tolerated among all studies. Sildenafil was found to improve hemodynamics, exercise capacity, and quality of life in patients with elevated pulmonary vascular resistance. Phosphodiesterase 5 inhibitors therapy in patients with proven Pulmonary Hypertension due to left heart disease and elevated pulmonary vascular resistance by right heart catheterization may improve the quality of life, exercise capacity, and pulmonary hemodynamics. Further prospective randomized controlled studies are needed to confirm.

Aim To evaluate the efficacy and safety of combination therapy with 1-blocker and phosphodiesterase type 5 inhibitor (PDE5) in patients with benign prostatic hyperplasia (BPH) and erectile dysfunction (ED). Materials and methods The observational multicenter program involving 18 medical institutions in Moscow included 315 men aged 40-65 years with BPH and ED. The inclusion criteria were a total IPSS score more than 8 points, QoL score of more than 3 points and clinical manifestations of ED ( less or equal 20 points on the IIEF-5 score). All patients received combined pharmacotherapy with Alfuprost MP 10 mg/day and Viatail 50 mg/day (if necessary, the dose was increased to 100 mg/day) for 3 months. Results The combination therapy showed a high clinical efficiency and a favorable safety profile. Lower urinary tract symptoms improved by more than 60%, QoL increased by 64% and erectile function improved in more than 80% of patients. At the end of treatment, the average patient satisfaction score on the Likert scale was 4.2 (high and very high satisfaction), while doctors satisfaction with the clinical response of patients to the treatment was 4.35 points, which also corresponds to high and very high efficacy of therapy. Conclusion Combination of Alfuprost MP 10 mg/day and Viatail 50 mg/day (100 mg, if necessary) can be considered as one of the best options for non-surgical treatment of patients with BPH and ED.

TPN729 is a novel phosphodiesterase 5 (PDE5) inhibitor used to treat erectile dysfunction in men. Our previous study shows that the plasma exposure of metabolite M3 (N-dealkylation of TPN729) in humans is much higher than that of TPN729. In this study, we compared its metabolism and pharmacokinetics in different species and explored the contribution of its main metabolite M3 to pharmacological effect. We conducted a combinatory approach of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolite identification, and examined pharmacokinetic profiles in monkeys, dogs, and rats following TPN729 administration. A remarkable species difference was observed in the relative abundance of major metabolite M3: i.e., the plasma exposure of M3 was 7.6-fold higher than that of TPN729 in humans, and 3.5-, 1.2-, 1.1-fold in monkeys, dogs, and rats, respectively. We incubated liver S9 and liver microsomes with TPN729 and CYP3A inhibitors, and demonstrated that CYP3A was responsible for TPN729 metabolism and M3 formation in humans. The inhibitory activity of M3 on PDE5 was 0.78-fold that of TPN729 (The IC(50) values of TPN729 and M3 for PDE5A were 6.17 ± 0.48 and 7.94 ± 0.07 nM, respectively.). The plasma protein binding rates of TPN729 and M3 in humans were 92.7% and 98.7%, respectively. It was astonishing that the catalyzing capability of CYP3A4 in M3 formation exhibited seven-fold disparity between different species. M3 was an active metabolite, and its pharmacological contribution was equal to that of TPN729 in humans. These findings provide new insights into the limitation and selection of animal model for predicting the clinical pharmacokinetics of drug candidates metabolized by CYP3A4.

Abusive chronic alcohol consumption can cause metabolic and functional derangements in the heart and is a risk factor for development of non-ischemic cardiomyopathy. microRNA 214 (miR-214) is a molecular sensor of stress signals that negatively impacts cell survival. Considering cardioprotective and microRNA modulatory effects of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, we investigated the impact of chronic alcohol consumption on cardiac expression of miR-214 and its anti-apoptotic protein target, Bcl-2 and whether sildenafil attenuates such changes. Adult male FVB mice received unlimited access to either normal liquid diet (control), alcohol diet (35% daily calories intake), or alcohol + sildenafil (1 mg/kg/day, p.o.) for 14 weeks (n = 6-7/group). The alcohol-fed groups with or without sildenafil had increased total diet consumption and lower body weight as compared with controls. Echocardiography-assessed left ventricular function was unaltered by 14-week alcohol intake. Alcohol-fed group had 2.6-fold increase in miR-214 and significant decrease in Bcl-2 expression, along with enhanced phosphorylation of ERK1/2 and cleavage of PARP (marker of apoptotic DNA damage) in the heart. Co-ingestion with sildenafil blunted the alcohol-induced increase in miR-214, ERK1/2 phosphorylation, and maintained Bcl-2 and decreased PARP cleavage levels. In conclusion, chronic alcohol consumption triggers miR-214-mediated pro-apoptotic signaling in the heart, which was prevented by co-treatment with sildenafil. Thus, PDE5 inhibition may serve as a novel protective strategy against cardiac apoptosis due to chronic alcohol abuse.

The lucrative market of herbal remedies spurs rampant adulteration, particularly with pharmaceutical drugs and their unapproved analogues. A comprehensive screening strategy is, therefore, warranted to detect these adulterants and, accordingly, to safeguard public health. This study uses the data-dependent acquisition of liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS) to screen phosphodiesterase 5 (PDE5) inhibitors in herbal remedies using suspected-target and non-targeted strategies. For the suspected-target screening, we used a library comprising 95 PDE5 inhibitors. For the non-targeted screening, we adopted top-down and bottom-up approaches to flag novel PDE5 inhibitor analogues based on common fragmentation patterns. LC-QTOF-MS was optimised and validated for capsule and tablet dosage forms using 23 target analytes, selected to represent different groups of PDE5 inhibitors. The method exhibited excellent specificity and linearity with limit of detection and limit of quantification of

Background: Phosphodiesterase enzyme inhibitors (PDEIs) are most commonly prescribed by urologists for the treatment of erectile dysfunction. They are also gaining popularity as a treatment for lower urinary tract symptoms, based on their effect on smooth muscles – either vascular smooth muscles or smooth muscles in the urinary tract. For vascular smooth muscles, they cause vasodilation, enhanced microcirculatory haemodynamics through inhibition of platelet aggregation and adhesion, induction of apoptosis of adhesion fibroblasts and a reduction in the scarring process. Methodology: We reviewed articles published in English and indexed in the PubMed, Embase and Google Scholar databases, and consulted textbooks. Key search terms used were: urethral stricture, anti-fibrotic, scar-modulating agent, PDEIs, urethral scarring and urethroplasty. We created a synopsis of relevant articles, including original research studies and reviews. Level of evidence: Not applicable.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome type III (CP/CPPS) is associated with pelvic pain, sexual dysfunction and irritative voiding. Sustained symptom relief has proven difficult with alpha blockers, antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs). Phosphodiesterase type 5 (PDE5) inhibitors (PDE5is) have the potential to alleviate bladder urgency, relax the pelvic floor, and correct underlying erectile dysfunction; however, few studies have investigated the application of PDE5i’s to CP/CPPS. The purpose of this study was to assess the effect of long-term PDE5i therapy on symptoms among patients with diagnosed CP/CPPS. METHODS: A group of patients older than 18 years diagnosed with CP/CPPS presenting from 2009 to 2018 were followed prospectively while they were being prescribed off-label PDE5i therapy for symptoms. National Institute of Health chronic prostatitis symptom index (CPSI) scores before PDE5i therapy initiation and after at least 3 months were utilized to assess impact on symptoms. RESULTS: A total of 25 patients (mean age 44.4±12.9 years) met study criteria. The mean duration of PDE5i therapy was 1.3±1.6 years. Continued use of daily PDE5is was associated with significant decreases in total CPSI, pain, urinary symptom and quality of life scores [total CPSI: −12.8, standard deviation (SD) 9.5; pain: −6.1, SD 4.1; urinary symptoms: −2.4, SD 2.1; quality of life: −4.5, SD 3.9; P

Objective: The purpose of this work was to investigate the effect of phosphodiesterase type 5 (PDE-5) inhibitor sildenafil citrate (SC) on the level of brain hippocampal neurophysiological parameters (inhibitory and excitatory neurotransmitters), oxidant/antioxidant status, minerals, and anxiety-like behavior using albino male rats. Materials and methods: A total of 24 albino male rats were allocated to three separate groups (each one had eight rats): control and SC 5 and 10 mg/kg treatments via i.p. infusion every 3 days for 12 injections. For the behavior of anxiety evaluation, the elevated plus maze test was conducted 1 day after the last treatment, and then all the rats were killed. For serum separation, the blood samples were taken, and hippocampus was dissected from the brain and stored frozen until analysis. Results: Both doses of sildenafil significantly improved brain hippocampal neurotransmitter [nor­epinephrine, serotonin (5-hydroxytryptamine), and gamma-aminobutyric acid] values accompa­nied by a decreased dopamine level. Interestingly, the SC higher given dose (10 mg/kg) increased the malondialdehyde level with the reduction of the antioxidant parameters [reduced glutathione (GSH) level, catalase (CAT), and superoxide dismutase (SOD) activities] although the lower dose of SC did not cause oxidative stress. Serum and brain hippocampal K, Cu, and Se concentrations were also increased with SC treatments. Moreover, the test of elevated plus maze revealed an anxiolytic impact of sildenafil. Conclusion: It was concluded that SC improved the parameters of some hippocampal neurotrans­mitters and minerals accompanied by anxiolytic impact with the test of elevated plus maze, with a state of oxidative stress revealed with the higher dose of SC which was not recorded with the lower dose. Adv. Vet. Anim. Res., 7(2): 281-289, June 2020

Introduction: Priapism is prolonged penile erection in the absence of sexual arousal or desire and is a devastating condition affecting millions of patients with sickle cell disease (SCD) globally. Available drug treatments for SCD-related priapism remain limited and have been primarily reactive rather than preventive. Hence, there is an unmet need for new drug targets and pharmacologic therapies.Areas covered: We examine the molecular mechanisms underlying SCD-associated priapism evaluated mostly in animal models. In mouse models of SCD, molecular defects of priapism operating at the cavernous tissue level include reduced tonic NO/cGMP signaling, elevated oxidative/nitrosative stress, vascular adhesion molecule derangements, excessive adenosine and opiorphin signaling, dysregulated vasoconstrictive RhoA/ROCK signaling, and testosterone deficiency. We discuss the consequences of downregulated cGMP-dependent phosphodiesterase type 5 (PDE5) activity in response to these molecular signaling derangements, as the main effector mechanism causing unrestrained cavernous tissue relaxation that results in priapism.Expert opinion: Basic science studies are crucial for understanding the underlying pathophysiology of SCD-associated priapism. Understanding the molecular mechanisms could unearth new therapeutic targets for this condition based on these mechanisms. Treatment options should aim to improve deranged erection physiology regulatory signaling to prevent priapism and potentially restore or preserve erectile function.

Treatment of erectile dysfunction is associated with inhibition of Phosphodiesterase 5 enzyme. This study deals with the evaluation of Pterin-6-carboxylic acid inhibitory activity on phosphodiesterase 5 (PDB ID: 4OEW) using in silico docking studies. Pterin-6-carboxylic acid from Baphia nitida was isolated using GC-MS and docked into PDE5 active site. The docking result showed that pterin-6-carboxylic acid bind to the active site of phosphodiesterase 5 with the binding energy value of -7.1 and 2.05A° - 2.23A° when compared with other compound found in the plant. Moreso, docking analysis with the ligand identified specific residues such as: Ile 778, Phe 820, Gln 817, Ser 815 and Gln 775 within the binding pocket which played an important role in the ligand binding affinity to the protein. Result from our In silico studies hypothesized that pterin-6-carboxylic acid can be an inhibitory agent for PDE5 protein which could be a potential drug candidate for the treatment of erectile dysfunction.

Patients with metabolic syndrome (MetS) often exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and/or bioavailability. Since phosphodiesterase 5 (PDE5) inhibitors restore NO signaling, we hypothesized that chronic treatment with long-acting PDE5 inhibitor tadalafil may enhance plasma NO levels and reduce cardiac dysfunction following ischemia/reperfusion (I/R) injury in C57BL/6NCrl-Leprdb−lb/Crl mice with MetS phenotypes. Adult male MetS mice were randomized to receive vehicle solvent or tadalafil (1 mg/kg,i.p.) daily for 28 days and C57BL/6NCrl mice served as healthy wild-type controls. After 28 days, cardiac function was assessed by echocardiography and hearts from a subset of mice were isolated and subjected to 30 min of global ischemia followed by 60 min of reperfusion (I/R) in ex vivo Langendorff mode. Body weight, blood lipids, and glucose levels were elevated in MetS mice as compared with wild-type controls. The dyslipidemia in MetS was ameliorated following tadalafil treatment. Although left ventricular (LV) systolic function was minimally altered in the MetS mice, there was a significant diastolic dysfunction as indicated by reduction in the ratio of peak velocity of early to late filling of the mitral inflow, which was significantly improved by tadalafil treatment. Post-ischemic cardiac function, heart rate, and coronary flow decreased significantly in MetS mice compared to wild-type controls, but preserved by tadalafil treatment. Myocardial infarct size was significantly smaller following I/R, which was associated with higher plasma levels of nitrate and nitrite in the tadalafil-treated MetS mice. In conclusion, tadalafil induces significant cardioprotective effects as shown by improvement of LV diastolic function, lipid profile, and reduced infarct size following I/R. Tadalafil treatment enhanced NO production, which may have contributed to the cardioprotective effects.

Aims To evaluate the impacts of hydrogen sulfide (H2 S) donor, sodium hydrogen sulfide (NaHS), and phosphodiesterase type-5 inhibitor (PDE5i), tadalafil per se and their combination treatment on partial bladder outlet obstruction (PBOO)-induced erectile dysfunction (ED). Methods Sprague-Dawley rats were equally divided into five groups: (a) sham-operated control; (b) PBOO; (c) PBOO-treated with NaHS (5.6 mg/kg/day, ip); (d) PBOO-treated with tadalafil (2 mg/kg/day, oral); and (e) PBOO-treated with combination of NaHS and tadalafil. The obstruction was created by urethral ligation for 6 weeks. In vivo erectile responses, in vitro relaxant and contractile responses in penile tissue as well as protein expression of nitric oxide synthases (NOS), H2 S synthesis enzymes, oxidative stress, hypoxia, fibrosis markers, and the smooth muscle/collagen ratio and apoptosis were analyzed. Results Combined treatment entirely returned increased bladder mass, reduced erectile responses, relaxation responses to acetylcholine, and electrical field stimulation in obstructed rats, while partial amelioration was observed after mono-treatment. Decreased neuronal NOS and 3-mercaptopiruvate transferase enzyme expressions in penile tissue from obstructed rats were also entirely restored by the combined treatment. Mono-treatment partially improved increased hypoxia, oxidative stress, fibrosis markers, decreased smooth muscle mass, and H2 S levels, while combined therapy completely recovered. Conclusions The combination therapy with H2 S donor and PDE5i had positive effects on erectile responses through the improvement of ischemia-induced morphological and functional penile alterations in obstruction. H2 S and NO may likely play a synergistic role in the regulation of erectile function and have constructive effects on clinical outcomes in male patients with ED and benign prostatic hyperplasia/lower urinary tract symptoms.

Background While phosphodiesterase type-5 inhibitors (PDE5Is) are highly effective for the treatment of erectile dysfunction (ED) and well tolerated, updated data on prescription patterns have been limited in real-world settings. Aim To describe men in the United States who are prescribed PDE5Is for ED treatment and to evaluate patterns of initiation, switching, and treatment overlap. Methods This retrospective claims study used MarketScan Commercial and Medicare Supplement Databases from January 1, 2010, to December 31, 2015, to identify initial PDE5I claims (index date) for sildenafil, tadalafil, and/or vardenafil. Adults aged ≥18 years with ED were identified between July 1, 2010, and December 31, 2014, allowing for a 6-month preindex and 12-month follow-up period from the index date. Outcomes Outcomes included patient demographics and treatment-related patterns after treatment initiation. Results A total of 106,206 identified patients met all inclusion criteria. Of these, 51,694, 40,193, and 14,319 had initial claims for sildenafil, tadalafil, and vardenafil, respectively. Mean age was 50.35 years, and comorbidities included dyslipidemia (44.17%), hypertension (43.09%), diabetes (15.32%), and depression (10.61%). More patients (48.67%) initiated on sildenafil than tadalafil (37.85%) or vardenafil (13.48%). Rate of switching was lower in the 60 days after the end of day supply of the initial prescription in the sildenafil cohort (2.71%) compared with the tadalafil (2.81%) and vardenafil (3.88%) cohorts (P Clinical Implications These findings provide insight into updated patterns of PDE5I prescriptions in the United States and may aid in clinical decision-making. Strengths & Limitations Strengths include the large sample size, long data coverage period, and the real-world nature of the study. Limitations include the retrospective study design, use of data collected with a primary focus of claims, and lack of further details regarding reasons that drive switching. Actual rates of ED and impact on prescription patterns may be underestimated because the claims database only captured patients electing to visit a health-care provider. Conclusion Among men with ED in the United States, rates of switching and treatment overlap were low for all PDE5Is but were found to be the lowest for sildenafil compared with tadalafil and vardenafil.