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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.

Aims There have been few reports on whether long-term oral phosphodiesterase 5 inhibitor administration can ameliorate bladder changes due to bladder outlet obstruction (BOO). Therefore, we clarified the chronological changes of the bladder using male BOO rats and evaluated the effects of tadalafil on these changes. Methods Eight-week-old male Sprague-Dawley rats were used. BOO was created by placing a polyethylene catheter around the urethra. Then, the rats were orally treated with a vehicle, or tadalafil 2 or 10 mg/kg until each evaluation period. Cystometric measurements were performed and the degree of fibrosis in the smooth muscle layer was evaluated at 2, 4, and 16 weeks. Results In BOO rats, a significant increase in the number of non-voiding contractions (NVCs) and a shortened intercontraction interval (ICI) were observed in the earlier phase (2 and 4 weeks) compared to Sham rats. In the chronic phase (16 weeks), markedly increased residual urine volume and an extended ICI were observed accompanied by enhanced smooth muscle fibrosis. These results indicated that the bladder in BOO rats represented the overactive phenotype in the earlier phase and changed into the underactive phenotype in the chronic phase. Even in Sham rats, an increased number of NVCs and enhanced fibrosis were observed with time. Tadalafil administration significantly prevented these bladder changes in both BOO and Sham rats. Conclusions Long-term oral administration of tadalafil can prevent functional and histological changes in the BOO rat bladder. This agent is also effective for the bladder functional change even in non-obstructed rats.

Introduction Erectile dysfunction is defined as the inability to achieve and maintain an erection to satisfactorily complete intercourse. Treatment depends on the cause and includes phosphodiesterase 5 inhibitor medications, penile pumps, implants, and surgery. Low-intensity shockwave therapy has been shown to be effective and safe for the treatment of erectile dysfunction. Objective We explored the role of low-intensity radial shockwave therapy for erectile dysfunction treatment in a dermatology and/or medical aesthetic practice setting. Materials and methods A literature review was conducted on radial low-intensity shockwave technology in use for erectile rejuvenation to explore its positioning, safety, efficacy, tolerability, subject satisfaction, and usability in a dermatology and/or medical aesthetic setting. Results Low-intensity shockwave therapy was shown to be effective in subjects with organic erectile dysfunction, and the treatment effect was maintained for up to 2 years post-treatment. The treatment is reported to be safe and well-tolerated and have little downtime. Many dermatologists use low-intensity shockwave therapy for the treatment of cellulite and other conditions. This type of treatment is now available for erectile dysfunction and seems an attractive and safe option for subjects with organic vascular erectile dysfunction. Conclusions Studies and clinical experience suggest that male erectile rejuvenation using low-intensity radial shockwave therapy seems an attractive option. The treatment can be safely, and effectively, delivered by trained staff as part of the total package that is available to men in a dermatology and/or medical aesthetic practice.

BACKGROUND AND PURPOSE: Pulmonary arterial hypertension (PAH) is an incurable, incapacitating disorder resulting from increased pulmonary vascular resistance, pulmonary arterial remodeling and right ventricular failure. In pre-clinical models, combination of a phosphodiesterase 5 inhibitor (PDE5i) with a neprilysin inhibitor augments natriuretic peptide bioactivity, promotes cyclic GMP signaling, and reverses the structural and hemodynamic deficits that characterize PAH. Herein, we conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of repurposing the neprilysin inhibitor, racecadotril, in PAH. EXPERIMENTAL APPROACH: 21 PAH patients stable on PDE5i therapy were recruited. Acute hemodynamic and biochemical changes following a single dose of racecadotril or matching placebo were determined; this was followed by a 14 day safety and efficacy evaluation. The primary endpoint in both steps was circulating atrial natriuretic peptide (ANP) concentration (Δmax ), with secondary outcomes including pulmonary and systemic hemodynamics plus mechanistic biomarkers. KEY RESULTS: Acute administration of racecadotril (100mg) resulted in a 79% (95%CI, +6,+203) increase in the plasma ANP concentration and a 106% (+28,+229) increase in plasma cyclic GMP levels, with a concomitant 14% (-24,-3) fall in pulmonary vascular resistance. Racecadotril (100mg; tid) treatment for 14 days resulted in a 19% (-18,+72) rise in plasma ANP concentration. Neither acute (-16%,-28,+1) nor chronic (-4%, -21,+16) administration of racecadotril resulted in a significant drop in MABP or any serious adverse effects. CONCLUSIONS AND IMPLICATIONS: This Phase IIa evaluation provides proof-of-principle evidence that neprilysin inhibitors may have therapeutic utility in PAH and warrants a larger-scale prospective trial.

Background Experimental autoimmune prostatitis (EAP) and prostatitis induced by 17β-estradiol treatment combined with castration (hormone/castration-induced prostatitis; HCP) are the most commonly used rodent models of nonbacterial prostatitis. We studied the effect of the phosphodiesterase 5 inhibitor tadalafil on chronic pelvic pain in two such models in rats. Methods EAP was induced by intradermal injection of rat prostate antigen and complete Freund's adjuvant on Days 0 and 28. HCP was induced by castration followed by daily subcutaneous injection of 17β-estradiol for 30 days. On Day 42 after antigen injection in the EAP model and Day 30 after castration in the HCP model, we investigated voiding behavior, pelvic pain (measured by applying von Frey filaments to the lower abdomen), and inflammatory changes, including changes in histopathology and IL-1β, CCL2, and CCL3 mRNA levels. We investigated the effect of repeated administration of tadalafil on chronic pelvic pain in both models. Results In the EAP model, we observed inflammation in the ventral prostate, while in the HCP model, we observed inflammation in the lateral lobe of the prostate. Neither model showed any change in voiding behavior. As well as in the EAP model, in which chronic pelvic pain was observed, we found for the first time that HCP led to a significant increase in chronic pelvic pain. Repeated treatment with tadalafil attenuated the chronic pelvic pain in both models. Conclusions Chronic pelvic pain was induced in both EAP and HCP models. Tadalafil significantly attenuated the chronic pelvic pain in both models.

Phosphodiesterase 5 inhibitors are widely used to treat erectile dysfunction and lower urinary tract symptoms with benign prostatic hyperplasia. Recent studies have indicated the renoprotective effects of this class of compounds. Whether renoprotection depends on blood pressure reduction remains controversial. In this study, we investigated the renoprotective effects of the phosphodiesterase 5 inhibitor, tadalafil, in a rat model of high‐salt induced kidney injury with hypertension. Dahl salt‐sensitive rats were fed a normal diet, high‐salt (8% sodium chloride) diet, or high‐salt diet with oral administration of either low‐ or high‐dose tadalafil (1 and 10 mg kg−1 day−1, respectively). Serum creatinine, urinary protein, and blood pressure were measured at baseline and after 8 weeks, at which point the rats were examined for glomerular injury and fibrosis. PAI1 mRNA levels were also evaluated. After 8 weeks, blood pressure, serum creatinine, and urinary protein levels were significantly higher in the high‐salt group than those in the normal‐salt group. Serum creatinine and urinary protein were significantly lower in both tadalafil groups than those in the high‐salt group, while only high‐dose tadalafil affected blood pressure. In addition, glomerulosclerosis and α‐smooth muscle actin expression significantly decreased in both tadalafil treatment groups. PAI1 mRNA increased significantly in the high‐salt group but decreased in both tadalafil‐treated groups. Our results indicated that both low‐ and high‐dose tadalafil prevented fibrosis and glomerular injury in a chronic kidney disease rat model. Mechanistically, these effects may be associated with PAI1 expression and glomerular structure protection., A PDE5 inhibitor, Tadalafil is renoprotective by preventing glomerular injury and fibrosis from high blood pressure. This study suggest that Inhibition of PDE5 might be effective to delay the CKD progression.

Regorafenib is approved for the treatment of colorectal cancer and hepatocellular carcinoma. In the trial NCT02466802, we have discovered that regorafenib can be safely combined with the phosphodiesterase 5 inhibitor sildenafil in advanced solid tumor patients. The present studies determined whether the approved ERBB1/2/4 and RAS downregulating drug neratinib, could enhance the lethality of [regorafenib + sildenafil]. Neratinib enhanced [regorafenib + sildenafil] lethality in a greater than additive fashion in colon cancer cells. The drug combination reduced the expression of mutant K-RAS and of multiple histone deacetylase (HDAC) proteins that required autophagosome formation. It caused green fluorescent protein or red fluorescent protein-tagged forms of K-RAS V12 to localize into large intracellular vesicles. Compared with [regorafenib + sildenafil], the three-drug combination caused greater and more prolonged activation of the ATM-AMPK-ULK-1 pathway and caused a greater suppression and prolonged inactivation of mammalian target of rapamycin, AKT, and p70 S6K. Approximately 70% of enhanced lethality caused by neratinib required ataxia-telangiectasia-mutated (ATM)-AMP-dependent protein kinase (AMPK) signaling whereas knockdown of Beclin1, ATG5, FADD, and CD95 completely prevented the elevated killing effect. Exposure of cells to [regorafenib + sildenafil] reduced the expression of the checkpoint immunotherapy biomarkers programmed death-ligand 1, ornithine decarboxylase, and indoleamine 2,3-dioxygenase-1 and increased the expression of major histocompatibility complex A (MHCA), which also required autophagosome formation. Knockdown of specific HDAC proteins recapitulated the effects observed using chemical agents. In vivo, using mouse cancer models, neratinib significantly enhanced the antitumor efficacy of [regorafenib + sildenafil]. Our data support performing a new three drug Phase I trial combining regorafenib, sildenafil, and neratinib.

Background and purpose Inhibition of PDE5 improves synaptic plasticity and memory via enhancing cGMP expression, thus activating the cGMP/cAMP response element binding protein (CREB) signalling pathway. This study investigated the effects of a PDE5 inhibitor on scopolamine-induced cognitive dysfunction, using memory-related behavioural tests and biochemical assays. Experimental approach In mice were pretreated with PDE5 inhibitor, amnesia was induced by scopolamine. The learning and memory abilities of mice were tested using the Morris water maze test, the Y-maze test, the passive avoidance test and the novel object recognition test in sequence. Expression of memory-related bio-molecules and oxidative stress parameters in brain tissue were measured using Western blot and spectrophotometry respectively. Key results KJH-1002, a novel and potent inhibitor of PDE5 (IC50 0.059 ± 0.04 nmol·L-1 ), was synthesized. In the behavioural tests, it markedly improved the memory performance impaired by scopolamine, indicating a restoration of cognitive function in the mice. Moreover, KJH-1002 increased cGMP levels in the cortex and the scopolamine-reduced expression of phosphorylated CREB, Levels of ERK 1/2, Akt and brain-derived neurotrophic factor in the cortex and hippocampus were restored by KJH-1002 treatment. In addition, KJH-1002 administration increased the activities of SOD, glutathione peroxidase and glutathione reductase, and decreased the level of malondialdehyde. Conclusion and implications KJH-1002 restored cognitive function in scopolamine-induced amnesia mice by activating the cGMP/CREB signalling pathway and attenuating oxidative stress. The beneficial effects of KJH-1002 on cognition indicate its potential as a therapeutic candidate for Alzheimer's disease.

Purpose The objective of the study was to determine the risk of sudden sensorineural hearing loss (SNHL) associated with use of phosphodiesterase type 5 (PDE5) inhibitors. Methods We conducted a retrospective cohort study in the MarketScan Commercial Claims and Encounters Database including adult men who initiated a PDE5 inhibitor (n = 377,722) and 1,957,233 nonusers between 1998 and 2007. Periods of drug exposure were assessed on a weekly basis based on pharmacy billing records, assuming use of 1 dose per week (current use). Incident sudden SNHL was defined based on inpatient or outpatient visits with International Classification of Diseases, Ninth Revision, Clinical Modification codes 389.1x, 389.2x, or 388.2 plus ≥2 procedure codes for audiometric hearing testing within ±30 days of sudden SNHL diagnosis. We used age- and propensity score-adjusted Cox proportional hazards model to evaluate the risk of sudden SNHL during periods of current or recent use compared with that of nonuse. We conducted sensitivity analyses by varying the assumed drug utilization frequency and sudden SNHL case definition. Results We evaluated 1233 sudden SNHL cases, resulting in an incidence of 4.35, 5.58, and 2.38 per 10,000 person-years for current, recent, and nonuse of PDE5 inhibitors, respectively. Compared with nonuse, the adjusted hazard ratio was 1.25 (1.01-1.55) for current use with a risk difference of 1.97 (1.12-2.82) per 10,000 person-years. For recent use, the adjusted hazard ratio was 1.60 (1.33-1.94) and risk difference was 3.19 (2.24-4.14). Estimates were consistent across the sensitivity analyses. Conclusions Use of PDE5 inhibitors is associated with a small but significantly increased risk of sudden SNHL.

Background Pulmonary hypertension (PH) is an important contributor of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). Treatment options are limited, but sildenafil might improve oxygenation and PH in neonates with CDH. Objective Aim of this study is to assess effects of intravenous sildenafil on oxygenation and PH in neonates with CDH. Methods A retrospective chart review was performed in all neonates with CDH born in our institution between September 2012 and December 2014. Indication for sildenafil was an OI > 15, PH > 2/3 systemic pressure, or a difference in pre- and postductal oxygen saturation (≥8%). A sildenafil bolus was administered followed by a maintenance infusion of 1.6 mg/kg/d. Primary outcome was improved oxygenation after starting sildenafil. Patients were compared according to improvement in oxygenation (responder vs non-responder). Results A total of 26 of 44 neonates were treated with intravenous sildenafil and in all sildenafil were initiated within the first 24 h of life (median age 3.1 h). Improved oxygenation was observed in 11 infants (42.3%). Among the 15 non-responders (57.6%) ECMO was started in 13 and two infants died without ECMO. Vasopressor support increased significantly during the first hours after commencing sildenafil in responders and non-responders. Echocardiographic indices demonstrated an effect on pulmonary arterial pressure within the first 24 h after starting sildenafil. Conclusions Treatment of neonates with intravenous sildenafil during the first day of life was associated with acute improvement in oxygenation in more than 40% of patients. However, a significant increase in vasopressor support was observed.

A series of novel pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized and evaluated for their anti-phosphodiesterase-5 (PDE-5) activity. A total of 28 compounds, containing alkyl and aryl groups at the 1-N and 3-C positions on the pyrazole ring, and also bearing different alkyl substituents on the piperazine ring were synthesized. Four compounds (4d, 5d, 6d, and 5o) were found to have better inhibitory activity against PDE-5 (IC50

OBJECTIVE To investigate the effects of tadalafil on storage and voiding function in treatment-naive patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia, based on a urodynamic study. METHODS This was an open-labeled, single-center, prospective study. A total of 80 untreated outpatients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia received tadalafil 5 mg/day for 12 weeks. Subjective symptoms and objective findings on voiding and storage function obtained through urodynamic studies, including cystometry and pressure flow study, were evaluated before and after treatment. RESULTS A total of 71 patients with a mean age of 70.2 years and a mean prostate volume of 45.6 mL were included in the analysis. In the International Prostate Symptom Score and Overactive Bladder Symptom Score, mean total scores significantly improved from 18.2 to 13.4 (P < 0.001) and 6.5 to 4.7 (P < 0.001), respectively, after treatment. Mean maximum bladder capacity significantly increased by approximately 35 mL (P < 0.001). Detrusor overactivity disappeared in 15 (39.5%) of 38 patients with detrusor overactivity at baseline (P < 0.001). Mean maximum flow rate on pressure flow study significantly increased from 7.1 to 9.1 mL/s (P < 0.001) and mean bladder outlet obstruction index significantly decreased from 61.3 to 47.1 (P < 0.001). CONCLUSIONS Treatment with tadalafil 5 mg once daily effectively relieves lower urinary tract symptoms based on objective improvement of storage and voiding function, such as detrusor overactivity and bladder outlet obstruction, in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

Objectives Phosphodiesterase-5 (PDE-5) inhibitors induces vasodilation in several organs by blocking cyclic GMP (guanosine monophosphate) degradation. However, the existence of alternative mechanism of action in case of an impaired nitric oxide (NO) system remains controversial. Previous studies suggested that decreased NO bioavailability may result in the down-regulation of klotho expression, but the relationship between klotho and NO remains obscure. Therefore, we investigated whether a PDE-5 inhibitor could preserve epithelial mesenchymal transition (EMT) and relationship exists between the NO and renal klotho expression. Materials and methods 10 weeks SD rats (N=24, 200 g, male) were divided (N=6) into four groups, which received: A LSD, L-NAME 1 mg/mL in drinking water, udenafil 5 mg/kg subcutaneously and both for 4 weeks. Urine nitrate/nitrite, NGAL (Neutrophil gelatinase-associated lipocalin), and cGMP were measured using ELISA. Kidney was subjected to evaluate PCNA (proliferative cell nuclear antigen), α-SMA (smooth muscle cell antigen), E-cadherin, and klotho expression. Results Urine cGMP decreased after treatment of PDE-5 inhibitor compared with control due to blocking degradation of cGMP (p

Pulmonary hypertension (PH) is a life-threatening lung disorder with towering prevalence and risk for future has been gradually rising worldwide. Even, no specific medications are available for pulmonary hypertension; various classes of treatment based upon the origin and magnitude of hypertension are still used for the treatment of PH. Consideration of molecular or signaling modulation is the imperative approach that can offer a new notion for prevalent pharmacotherapeutic agents. Instead of concurrent targets, including endothelin receptor antagonists (ETA/ETB), phosphodiesterase 5 inhibitor (PDF-5), calcium channel blockers, anticoagulants, diuretics and long acting prostacyclin analogue, recent scientific reports revealed the numerous potential alternative therapeutic approaches that can significantly target the pathological signaling alteration associated with PH. Understanding precise molecular cascade involved in PH can be useful for designing preclinical animal experiments and human clinical trials to evaluate target specific novel therapeutic interventions for the treatment of PH. In this review, we discussed the possible molecular signaling involved in the pathogenesis of PH and detailed account of the current status of medications employed for the treatment of PH. Moreover, the newly identified potential target sites and alternative approaches for treating the PH have been discussed. This article is protected by copyright. All rights reserved

Patients with pulmonary arterial hypertension associated with connective tissue disease (PAH-PAH-CTD) such as systemic sclerosis (SSc) have a poorer response to treatment and increased mortality compared with patients with idiopathic PAH. Current treatment options for PAH-CTD include prostanoids, phosphodiesterase type-5 inhibitors (PDE-5i), endothelin receptor antagonists, and the soluble guanylate cyclase stimulator riociguat. In this case series, we describe three patients with PAH-CTD related to limited scleroderma who were switched from a PDE-5i to riociguat due to insufficient clinical response. The switch to riociguat was associated with an improvement in respiratory and hemodynamic parameters and a favorable tolerability profile. These cases demonstrate that switching to riociguat is a therapeutic option in patients with PAH-CTD who have not achieved a satisfactory clinical response to a PDE-5i.

For severe pre-eclampsia (PE) with fetal growth restriction (FGR), the only effective treatment is early delivery of the placenta. Clinicians are often forced to end the pregnancy because of maternal indications. We report a case of severe PE with FGR in which the PE was temporarily improved and pregnancy successfully prolonged with tadalafil, a phosphodiesterase 5 inhibitor. A 35-year-old primigravid woman presented at 27 3/7 weeks of gestation with severe PE and FGR. After commencing tadalafil administration, biochemical and angiogenic markers improved. Thereafter, hypertension and proteinuria temporarily improved. Importantly, the pregnancy was prolonged by 14 days after the initiation of tadalafil administration. Tadalafil may be a novel treatment for severe PE with FGR to prolong pregnancy.

Objectives Effect of tadalafil on lower urinary tract symptoms (LUTS), erectile function and quality of life (QoL) were prospectively evaluated in patients with benign prostatic hyperplasia (BPH) at multicenter. Methods Eligible men were ≥40 years who had no treatment with alpha-blocker for BPH, with total International Prostate Symptom Score (IPSS) ≥8, IPSS-QOL ≥2 and prostate volume ≥20 mL. Data were collected on age, body mass index (BMI), and prostate specific antigen (PSA). Patients were asked to complete a self-reported questionnaire regarding the IPSS, Overactive Bladder Symptom Score (OABSS), International Index of Erectile Function 5 (IIEF5), and Medical Outcome Study 8-Item Short-Form Health Survey (SF-8). These measures were assessed at baseline, 4-, 8-, 12-week of tadalafil treatment. In addition, uroflowmetry was also performed at baseline, and 12-week end point visit. Results Thirty five patients with mean age 67.3 years, mean BMI 23.6 kg/m2, mean prostate volume 36 mL, and mean PSA 3.4 ng/mL were enrolled. Treatment with tadalafil significantly improved IPSS total score, IPSS voiding subscore, IPSS storage subscore, OABSS and IPSS-QoL score after 4 weeks and these improvements were maintained for 12-week treatment period. IIEF5 score and general health in SF-8 are significantly improved with the treatment of tadalafil. However, maximum flow rate and postvoiding residual volume were not significantly changed. There were not any serious adverse events. Conclusions These results indicate that tadalafil 5 mg once daily would be effective and well tolerated treatment in Japanese men with BPH-LUTS.

Oxidative stress is a major cause of cellular injury in a variety of human diseases including neurodegenerative disorders. Thus, removal of excessive reactive oxygen species (ROS) or suppression of ROS generation may be effective in preventing oxidative stress-induced cell death. This study was designed to investigate the effect of icariside II (ICS II), a novel phosphodiesterase 5 inhibitor, on hydrogen peroxide (H2 O2 )-induced death of highly differentiated rat neuronal PC12 cells, and to further examine the underlying mechanisms. We found that ICS II pre-treatment significantly abrogated H2 O2 -induced PC12 cell death as demonstrated by the increase of the number of metabolically active cells and decrease of intracellular lactate dehydrogenase (LDH) release. Furthermore, ICS II inhibited H2 O2 -induced cell death through attenuating intracellular ROS production, mitochondrial impairment, and activating glycogen synthase kinase-3β (GSK-3β) as demonstrated by reduced intracellular and mitochondrial ROS levels, restored mitochondrial membrane potential (MMP), decreased p-tyr216-GSK-3β level and increased p-ser9-GSK-3β level respectively. The GSK-3β inhibitor SB216763 abrogated H2 O2 -induced cell death. Moreover, ICS II significantly inhibited H2 O2 -induced autophagy by the reducing autophagosomes number and the LC3-II/LC3-I ratio, down-regulating Beclin-1 expression, and up-regulating p62/SQSTM1 and HSP60 expression. The autophagy inhibitor 3-methyl adenine (3-MA) blocked H2 O2 -induced cell death. Altogether, this study demonstrated that ICS II may alleviate oxidative stress-induced autophagy in PC12 cells, and the underlying mechanisms are related to its antioxidant activity functioning via ROS/GSK-3β/mitochondrial signalling pathways.

OBJECTIVE To perform a randomized control trial (RCT) assessing the effect of phosphodiesterase 5 inhibitor (PDE5i) used prior to hilar clamping during robot assisted partial nephrectomy (RAPN) for renoprotection. MATERIALS AND METHODS We performed an institutional review board approved, placebo controlled, double blinded RCT evaluating a single 100 mg oral dose of sildenafil immediately prior to RAPN. Primary end point was accrual, participation and retention of patients with secondary endpoints assessing post-operative renal functional outcomes and safety. Exclusion criteria included history of coronary artery disease, solitary kidney, suspected benign pathology, PDE5i intolerance or pregnant females. RESULTS Of 40 eligible consecutive patients undergoing RPN between 9/2013 and 12/2014, 30 (75%) were randomized to treatment and there was 100% participation and retention. The groups were well matched for all measured comorbidities. Intraoperative outcomes including warm ischemia time (median 15 vs. 16.5 min, P = 0.29) were similar. Change in eGFR demonstrated similar decrease between sildenafil versus placebo at 1 day (-8% vs. -10%, P = 0.53), 2 days (-9% vs. -9%, P = 0.77), and 1 month (-4% vs. -6%, P = 0.31) following RAPN. Intermediate follow up (median 183 days) demonstrated similar results (-8% vs. -1%, P = 0.16) between the two cohorts. Safety profiles were similar between the two cohorts without any adverse reactions to the sildenafil. CONCLUSIONS Successful retention of patients was achieved in this RCT. The secondary outcome of renoprotection was not identified. J. Surg. Oncol. 2016;114:785-788. © 2016 2016 Wiley Periodicals, Inc.

Our aim was to identify relevant literature supporting the use of phosphodiesterase-5 (PDE5) inhibitors in patients with persistent pulmonary hypertension with signs of postprocedural right ventricular (RV) dysfunction following left ventricular assist device (LVAD) implantation. We searched MEDLINE, SCOPUS, and Web of Science from inception through November 27, 2014 for citations evaluating patients with end-stage heart failure necessitating LVAD, continuous and pulsatile, who received a PDE5 inhibitor to prevent RV failure. Outcomes of interest included changes in mean pulmonary artery pressure, pulmonary vascular resistance, central venous pressure, cardiac index, and mean arterial pressure. Results are presented qualitatively. Four citations (n = 83 patients) were included. These included a single case report, two retrospective case series, and a prospective open-label study with a historical control. All four studies utilized the PDE5 inhibitor sildenafil with various doses for up to 3 months. Sildenafil routinely reduced mean pulmonary artery pressures as soon as 90 min after administration. Reductions in pulmonary vascular resistance were also seen shortly after the procedure and maintained through 12-15 weeks. While one study saw improvements in postoperative central venous pressures, another did not. Evidence supporting PDE5 inhibitor use to attenuate RV failure in patients requiring an LVAD is weak.

Aims To investigate the effect of the phosphodiesterase 5 (PDE5) inhibitor Tadalafil on bladder blood flow and bladder function in a rat model of partial bladder outlet obstruction (BOO). Methods Female 14–15-week-old Sprague–Dawley rats were divided into three groups. BOO was surgically induced in rats by placing a rubber ring around the urethra. BOO rats were administered daily oral Tadalafil (BOO-Tadalafil) or vehicle (BOO-Vehicle), while sham-operated animals were treated with vehicle (Sham). On the 14th day after surgery, micturition behavior was recorded for 24 hr by using a metabolic cage. On the 15th day after surgery, bladder blood flow and bladder weight were measured. The expression of PDE5 mRNA in the vesical and iliac arteries of intact rats was measured by reverse transcriptase-polymerase chain reaction. Results BOO led to a significant decrease in bladder blood flow and a significant increase in bladder weight. These changes were partially suppressed by Tadalafil treatment. The number of micturitions in the BOO group was significantly increased and the average micturition volume was significantly decreased, without affecting the total micturition volume. Repeated Tadalafil treatment markedly inhibited the increase in micturition frequency and the decrease in average micturition volume. PDE5 mRNA was expressed in the vesical and iliac arteries. Conclusion Tadalafil suppressed the reduction in bladder blood flow caused by BOO in rats and improved urinary function. This action of Tadalafil may contribute to its amelioration of bladder function. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc.

Right ventricular (RV) function immediately after left ventricular assist device (LVAD) implantation is a crucial prognostic factor. RV failure is linked to increased mortality and worse outcome. A phosphodiesterase 5 inhibitor, sildenafil, was shown to decrease pulmonary vascular resistance and pulmonary artery pressure post-LVAD. We report on a series of heart failure patients, and the effect of sildenafil on the incidence of RV failure after LVAD implantation. We retrospectively analyzed the data of end-stage heart failure patients who underwent LVAD implantation with pulmonary hypertension and RV dysfunction prior to surgery. Patients were divided into two groups; group 1: patients who received sildenafil perioperatively, and group 2: patients who did not receive sildenafil. Hemodynamic and echographic data were collected before and after surgery. Fourteen patients were included, 8 patients in group 1 and 6 in group 2. Sildenafil was administered with a mean dose of 56.2 ± 9.4 mg in group 1 and was able to significantly reduce right heart failure incidence, and to demonstrate a significant reduction in pulmonary vascular resistance, pulmonary artery pressure, transpulmonary gradient, and a significant increase in cardiac output. In conclusion, sildenafil seems to have a promising role perioperatively in preventing acute RV failure postsurgery in patients with RV dysfunction and pulmonary hypertension, requiring LVAD therapy.

Aims Increased indiscriminate use of pulmonary artery hypertension-targeted drugs has been observed in patients with pulmonary hypertension (PH) secondary to heart failure. We performed a meta-analysis to evaluate the chronic effects of using phosphodiesterase 5 (PDE5) inhibitors to treat patients with PH secondary to chronic systolic heart failure. Methods and results PubMed, EMBASE, and the Cochrane Library were searched up to October 2013 for randomized controlled trials (RCTs) assessing PDE5 inhibitor treatments in PH patients secondary to chronic heart failure. Six RCTs involving 206 chronic systolic heart failure patients with PH complications were included. Sildenafil was used in all trials. Sildenafil treatment resulted in fewer hospital admissions compared with the placebo treatment (3.15% vs. 12.20%; risk ratio 0.29; 95% confidence interval 0.11–0.77). Various haemodynamic parameters were improved with additional sildenafil treatment, including reduced mean pulmonary artery pressure [weighted mean difference (WMD) −5.71 mmHg, P

Reductions in skeletal muscle function occur during the course of healthy aging as well as with bed rest or diverse diseases such as cancer, muscular dystrophy, and heart failure. However, there are no accepted pharmacologic therapies to improve impaired skeletal muscle function. Nitric oxide may influence skeletal muscle function through effects on excitation-contraction coupling, myofibrillar function, perfusion, and metabolism. Here we show that augmentation of nitric oxide-cyclic guanosine monophosphate signaling by short-term daily administration of the phosphodiesterase 5 inhibitor sildenafil increases protein synthesis, alters protein expression and nitrosylation, and reduces fatigue in human skeletal muscle. These findings suggest that phosphodiesterase 5 inhibitors represent viable pharmacologic interventions to improve muscle function.

(−)-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors.

TAKE HOME MESSAGE: The administration of phosphodiesterase 5 inhibitor commencing at the time of castration might preserve erectile function. OBJECTIVE: To determine if sildenafil citrate treatment could improve erectile function after castration. To determine if sildenafil citrate treatment reduces collagenisation and apoptosis in erectile tissue after castration. MATERIALS AND METHODS: In all, 60 Sprague-Dawley rats were studied; the rats were divided into the following groups: sham - no orchidectomy (S), control - orchidectomy only (O) and treatment - orchidectomy plus sildenafil treatment (V), with 10 rats per group. Erectile haemodynamics assessment was done at 7 days (S7, O7, V7) and at 28 days (S28, O28, V28) yielding a total of six groupings. Functional assessment measured the mean maximum intracavernosal pressure-mean arterial pressure (ICP/MAP) ratio. TUNEL assay was used to define apoptotic indices (AIs) and Masson's trichrome staining was used to evaluate smooth muscle-collagen (SM-C) ratios. RESULTS: The S28 group had the highest and the O7 group the lowest ICP/MAP ratio, at a mean (sd) of 70 (6)% and 36 (6)%, respectively. Both treatment groups, V7 [42 (12)%] and V28 [49 (13)%] showed statistically significant improvements over their corresponding control groups: O7 [36 (6)%] and O28 [37 (9)%] (P < 0.05). However, ICP/MAP values for V7 and V28 remained significantly below the S28 group (P < 0.001). There were no significant differences in ICP/MAP values between the 28-day and 7-day ICP/MAP ratios within each group (S, O, V). There were no significant differences in SM-C ratio between the O and V groups (O7 vs V7, P = 0.45; O28 vs V28, P = 0.16). There were no significant differences in AIs between the O and V groups (O7 vs V7, P = 0.54; O28 vs V28, P = 0.8). CONCLUSIONS: Daily treatment with sildenafil improved erectile function in rats after castration. ICP/MAP ratios increased significantly in the treatment groups compared with the control groups with the greatest erectile function occurring 28 days from administration. In this series of experiments the improved erectile function recovery with sildenafil after surgical castration cannot be explained by smooth muscle protection and decreased collagenisation. The improved erectile function with sildenafil after surgical castration cannot be explained by reduced apoptosis in erectile tissue.

Aims Congestive heart failure (CHF) is associated with impaired renal function. Previously, we have demonstrated that rats with decompensated CHF exhibited exaggerated sensitivity to the adverse renal effects of increased increased intra-abdominal pressure (IAP) as compared with normal controls. This study tested whether phosphodiesterase 5 (PDE5) inhibition protects against the adverse renal effects of increased IAP in rats with CHF. Methods and results Following baseline periods, rats with compensated and decompensated CHF induced by the placement of an aorto-caval fistula (ACF), rats with myocardial infarction (MI) induced by left anterior descending (LAD) artery ligation, and sham controls were subjected to consecutive IAPs: 7, 10, or 14 mmHg. Urine flow (V), Na+ excretion (UNaV), glomerular filtration rate (GFR), and renal plasma flow (RPF) were determined. The effects of pre-treatment with tadalafil on the adverse renal effects of IAP were examined in rats with decompensated CHF and MI. Elevation of IAP to 10 and 14 mmHg produced linear reductions in these parameters. Basal renal function and haemodynamics were lower in CHF rats. Decompensated CHF rats and MI rats that were subjected to 10 and 14 mmHg exhibited exaggerated declines in V, UNaV, GFR, and RPF. In contrast, no adverse renal effects were observed in rats with compensated CHF subjected to IAP. Pre-treatment of decompensated CHF rats and MI rats with tadalafil ameliorated the adverse renal effects of high IAP. Conclusion Decompensated CHF and MI rats are vulnerable to the adverse renal effects of IAP. Tadalafil abolishes IAP-induced renal dysfunction, supporting a therapeutic role for PDE5 inhibition in CHF associated with ascites.

What's known on the subject? and What does the study add? Tadalafil, a phosphodiesterase type 5 inhibitor, might be effective for not only erectile dysfunction but also lower urinary tract symptoms (LUTS). One of the mechanisms of tadalafil on LUTS is added in the study. OBJECTIVE • To determine if tadalafil, a phosphodiesterase type 5 inhibitor, decreases afferent nerve activity from the bladder with and without chemical stimulation by intravesical acrolein instillation. MATERIALS AND METHODS • Female Sprague-Dawley rats were used. Under urethane anaesthesia, single afferent fibres of the nerve primarily originating from the bladder were identified by electrical stimulation of the pelvic nerve and by bladder distension, and classified by conduction velocity as Aδ- or C-fibres. After measuring the baseline single afferent activities (SAA) during constant filling, two experiments were performed. • First, tadalafil was administrated intravenously (i.v.) at three doses, 0.01, 0.03 and 0.1 mg/kg cumulatively and SAA were repeatedly studied after each administration. • Second, in the presence of vehicle or tadalafil (0.1 mg/kg) i.v., the effect of intravesical instillation of acrolein (0.003%) was studied. RESULTS • In all, 39 single units were isolated (Aδ-fibres 21; C-fibres, 18) in 25 rats. • Tadalafil dose-dependently decreased SAA of both Aδ- and C-fibres during saline instillation. Intravesical acrolein facilitated SAA of both fibres after vehicle administration. • Pretreatment with tadalafil significantly inhibited the acrolein-induced hyperactivity of both fibres. CONCLUSION • Our study shows, using selective unifibre potential measurement, that systemic administration of tadalafil reduces mechanosensitive afferent activities of both Aδ- and C-fibres elicited by bladder distension in the rat, and also that tadalafil has an inhibitory effect on the increased activities of both fibres induced by intravesical acrolein instillation.

Background: Viagra and PDE-5 inhibitors use has mushroomed since its launch over a decade ago. A growing body of evidence indicates significant morbidity associated with the side effect profile of this class of drug. Hearing loss associated with PDE-5 inhibitor use has recently been reported, but few studies have evaluated the causal link. Aim: To review and scrutinise the current literature on the subject and propose possible physiologic mechanisms and to investigate the global reporting of this side effect. Methods and Materials: Pharmacovigilance agencies around North America, Europe, and Australasia were contacted requesting reports of hearing loss associated with PDE-5 inhibitors. Reports were scrutinised to exclude those where others causes of hearing loss existed. Results: Forty-seven cases of sensorineural hearing loss with a temporal association with PDE-5 inhibitor ingestion were obtained from both published literature and pharmacovigilance agencies. Cases had a mean age 56.6 years, male-to-female ratio of 7:1. Eighty-eight percent of reports were unilateral with an even left/right distribution. Hearing loss occurred within 24 hours of ingestion of PDE-5 inhibitor in 66.7% (n = 18) of cases. Sildenafil accounted for over 50% of cases. Conclusion: There is increasing evidence that PDE-5 inhibitors may induce sensorineural hearing loss via plausible physiological mechanisms. There needs to be more awareness of this disabling side effect among healthcare professionals responsible for prescribing this drug.

BACKGROUND AND PURPOSE 8-Nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP), formed nitric oxide (NO)-dependently, is a physiological second messenger, yet little is known about its role in the pathophysiology of vascular diseases. To study the pharmacological activity of 8-nitro-cGMP in diabetic mice, we compared its effects on vascular reactivity of aortas from non-diabetic and diabetic mice. EXPERIMENTAL APPROACH Vascular tension recording was performed in thoracic aortic rings from wild-type (C57BL/6), non-diabetic db/+ and obese/diabetic db/db mice. Endothelial NO synthase (eNOS) uncoupling and superoxide were tested by Western blot and dihydroethidium fluorescence respectively. KEY RESULTS 8-Nitro-cGMP, at concentrations up to 10 µM, enhanced phenylephrine-induced contractions in aortas from C57BL/6 and db/+ mice, but not from db/db mice. This enhancement was not observed with 8-bromo-cGMP. Pretreatment of aortas from C57BL/6 and db/+ mice with l-NAME (100 µM), superoxide dismutase (100 U·mL−1) or tiron (1 mM), abolished 8-nitro-cGMP-induced enhancement of the phenylephrine contraction. In 8-nitro-cGMP (10 µM)-treated C57BL/6 aortas, eNOS dimer/monomer ratio was significantly decreased and vascular superoxide production increased, suggesting that 8-nitro-cGMP-induced superoxide production via eNOS uncoupling may mediate the enhancement of the phenylephrine contraction. At higher concentrations (>10 µM), 8-nitro-cGMP produced relaxation of the phenylephrine-contracted aortas from C57BL/6, db/+ and db/db mice. The 8-nitro-cGMP-induced relaxation in db/db mouse aortas was found to be resistant to a phosphodiesterase 5 inhibitor, zaprinast (1 µM). CONCLUSIONS AND IMPLICATIONS The vasodilator effect of 8-nitro-cGMP may contribute to amelioration of the vascular endothelial dysfunction in diabetic mice, representing a novel pharmacological approach to prevent the complications associated with diabetes.

Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)< 5th percentile] and either the gestational age was

BACKGROUND It is well established that the pathogenesis of diabetic nephropathy is associated with abnormalities of renal nitric oxide (NO) generation. Many of the biological actions of NO are mediated by cGMP, which is rapidly degraded by phosphodiesterases. In this study, we evaluated the renoprotective effects of sildenafil (SIL), an inhibitor of phosphodiesterase-5, in type 2 diabetic rats. METHODS Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a non-insulin-dependent diabetes model, and Long-Evans Tokushima Otsuka rats, a non-diabetic control, were treated with either SIL (2.5 mg·kg−1 in drinking water) or undosed water for 28 weeks, starting at 30 weeks of age. RESULTS Sildenafil treatment significantly decreased albuminuria, attenuated glomerular hyperfiltration and resulted in a decrease in glomerular hypertrophy, in addition to a reduced glomerulosclerosis score and a dramatic decrease in the number of glomerular and tubulointerstitial proliferating cell nuclear antigen-positive cells in OLETF rats. This was accompanied by a significant reduction in renal cortical mRNA levels of collagen types I and III. The increased mRNA levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitors of MMPs (TIMP)-1 and TIMP-2 in the OLETF rats were significantly or partially attenuated by SIL treatment. CONCLUSIONS This study suggests that SIL attenuated diabetic nephropathy due to its potent antiproliferative effects and its regulatory effects on extracellular matrix. This latter effect is thought to be a result of its ability to affect the balance between MMPs and their inhibitors.

The effect of unripe Rubus coreanus extract on rabbit penile corpus cavernosum (PCC) was evaluated. Penises were obtained from healthy male New Zealand white rabbits (2.5–3.0 kg). The pre-contracted penis with phenylephrine (Phe, 10 μm) was treated with various concentrations of an extract of unripe R. coreanus (0.5, 1, 2, 3 and 4 mg/mL). The change in penile tension was recorded, cyclic nucleotides in the perfusate and the PCC were measured by radioimmunoassay, and the expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) in the perfused PCC were measured by western blotting. The interaction between unripe R. coreanus and sildenafil was also evaluated. The PCC relaxation induced by the extracts of R. coreanus was in a concentration-dependent manner and enhanced sildenafil-induced PCC relaxation. The perfusion of penile cavernous tissue with the unripe R. coreanus extract increased cGMP and cAMP in the tissue and in the perfusate and the expression of eNOS and nNOS in the tissue. The unripe R. coreanus extract exerts a relaxing effect on penile cavernous tissue in part by activating the NO-cGMP system and it may improve erectile dysfunction (ED), which does not completely respond to sildenafil citrate. Copyright © 2011 John Wiley & Sons, Ltd.

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Phosphodiesterase type-5 (PDE5) inhibitors (tadalafil, vardenafil, and sildenafil) are well-known treatment options for men with erectile dysfunction and should be taken before anticipated sexual activity. Tadalafil is also approved for once daily use in men with erectile dysfunction. Recent 12-week studies in men with benign prostatic hyperplasia (BPH) have shown once daily use of tadalafil significantly reduced their urinary symptoms. This article is the first to report the long-term safety and maintenance of efficacy for once-daily use of tadalafil in men with urinary symptoms secondary to BPH. OBJECTIVE • To evaluate the 1-year safety of 5 mg of tadalafil once daily in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTS); efficacy measures were included to evaluate the maintenance of efficacy after an additional year of treatment. PATIENTS AND METHODS • In total, 427 men who completed a 12-week, placebo-controlled, dose- finding study assessing once-daily tadalafil (2.5, 5, 10 or 20 mg) or placebo elected to continue into the open-label extension period. Safety and efficacy parameters were assessed after 1 month and every 3 months. RESULTS • In total, 299 patients (69.9%) completed the 1-year, open-label extension period. Treatment-emergent adverse events (TEAEs) were reported by 57.6% of patients, with most TEAEs being mild (44%) or moderate (45%) in severity; the most common TEAEs (≥2%) were dyspepsia, gastro-oesophageal reflux disease, back pain, headache, sinusitis, hypertension and cough. Twenty-two patients (5.2%) discontinued as a result of AEs. During the open-label extension period, mean prostate-specific antigen increased from 1.6 ± 1.3 ng/mL to 1.8 ± 1.4 ng/mL. • Mean post-void residual volume was 61.1 ± 60.4 mL at study entry and 42.2 ± 64.1 mL after the open-label extension period. Changes in the total International Prostate Symptom Score (IPSS), IPSS irritative and obstructive subscores, IPSS health-related quality of life and BPH Impact Index were maintained after 1 year. In sexually-active patients with erectile dysfunction, improvements in the International Index of Erectile Function–Erectile Function domain were maintained after 1 year. CONCLUSION • In men with BPH-LUTS, 5 mg of tadalafil once daily during 1 year of treatment was well tolerated and efficacy changes were maintained.

Please cite this paper as: Pellicer B, Herraiz S, Cauli O, Rodrigo R, Asensi M, Cortijo J, Serra V, Morcillo E, Felipo V, Simon C, Pellicer A. Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats. BJOG 2011;118:615–623. Objective To determine the effects of chronic administration of sildenafil citrateon healthy pregnant rats. Design In vivo animal experimental study. Setting Fundacion IVI–Instituto Universitario IVI, Valencia, Spain. Sample Pregnant and non-pregnant Wistarrats exposed to chronic administration of sildenafil. Methods Placental cross-barrier and feto-maternal relationship levels, maternal blood pressure, and haemodymamic effects on uterine arteries were evaluated. The effect of growth on weight and fetal tissues, and on perinatal outcome, was investigated. Main outcome measures Maternal blood pressure, blood viscosity, vascular indices of uterine arteries and fetal ductus venosus, plasmatic levels of sildenafil, embryo/fetal and litter weights, perinatal/postnatal survival rates. Results Sildenafil citrate crossed the placenta. The maternal and fetal levels of sildenafil, and its metabolite desmethyl-sildenafil, demonstrated a positive linear correlation in treated pregnant animals versus controls; a selective maternal hypotensive effect without changes in uterine vascular resistance was noted on days E8 and E11 (embryonic day). The lower pulsatility index of the ductus venosus on day E18 suggests fetal overflow at the end of the pregnancy. Effects on offspring were placental and liver enlargement, and increased fetal weight gain in the second half of pregnancy (irrespective of liver enlargement) and at birth. Perinatal and postnatal survival rates in the sildenafil group remained unaltered. No haemodynamic effects were evident in non-pregnant animals. Conclusions In normotensive rats, sildenafil appears to have a selective effect at the onset of pregnancy, implying increased fetal blood supply, and increased fetal weight, and placental and liver enlargement, but no increased perinatal mortality.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Pulmonary arterial hypertension (PAH) is a rare syndrome of dyspnoea and fatigue due to an increase in pulmonary vascular resistance. Although the disease remains incurable, targeted therapies have been shown to be beneficial to patients. Oral sildenafil (20 mg three times daily) is a phosphodiesterase type 5 inhibitor with proven efficacy on exercise capacity, symptoms and pulmonary haemodynamics in patients with PAH. WHAT THIS STUDY ADDS It is advisable that chronic therapies for PAH, including oral sildenafil, not be interrupted. However, patients may not be able to take their medication because of an intervening illness or a requirement to undergo general anaesthesia, preventing oral drug administration. This study demonstrates that an intravenous bolus of 10 mg sildenafil in stable patients with PAH is safe, well tolerated and maintains plasma levels to preserve drug exposure. AIMS To assess pharmacokinetics and pharmacodynamics of a 10 mg intravenous sildenafil bolus in pulmonary arterial hypertension (PAH) patients stabilized on 20 mg sildenafil orally three times daily. METHODS Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS After an acute increase, plasma concentrations stabilized within the range reported previously for a 20 mg oral tablet. At 0.5 h, mean ± SD changes from baseline were −8.4 ± 11.7 mmHg (systolic pressure), −2.6 ± 7.3 mmHg (diastolic pressure) and −3.5 ± 10.4 beats min−1 (heart rate). There was no symptomatic hypotension. CONCLUSIONS Although further research is warranted, a 10 mg sildenafil intravenous bolus appears to provide similar exposure, tolerability and safety to the 20 mg tablet.

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? There is a positive effect of PDE5 inhibitors on several aspects of the men’s sex lives, chiefly erectile function, personal self-esteem, and satisfaction from their sex lives. To our knowledge, our study is the first study to evaluate the effects of PDE5 inhibitors on erectile variables simultaneously in a laboratory setting. In the present study, significant penile rigidities were obtained with PDE5 inhibitors in a short period, with no sexual stimulation, in laboratory conditions. Our findings might support the use of PDE5 inhibitors in the men who need penile rehabilitation. OBJECTIVE To investigate the effects of phosphodiesterase type 5 (PDE5) inhibitors on erectile variables during a period with no sexual stimulation in a laboratory setting double-blind study. PATIENTS AND METHODS In all, 80 men without erectile dysfunction (ED) but with lifelong premature ejaculation (PE) were included in the study. The men were divided equally in to four groups and received either placebo, vardenafil (10 mg), sildenafil (50 mg) or tadalafil (20 mg) in a double-blind study design. The men attended the laboratory following 3 days of sexual abstinence and placebo or one of the PDE5 inhibitors was ingested after ≥2 h of fasting and non-smoking. The men were then immediately placed in a silent room and real-time penile rigidity and tumescence monitoring with Rigiscan Plus (Rigiscan Plus® System, Osbon Medical Systems, Augusta, GA, USA) began. The men read some magazines or newspapers that contained no sexually stimulating material for 1.5 h. There was no interaction between the men and observer during the test period. Times to first measured and total durations of base and tip rigidities, and also total and per minute rigidity were evaluated. RESULTS The recorded base and/or tip rigidity ratios were 40% (eight of 20), 71% (12/17), 47% (nine of 19) and 70% (14/20) in men who took placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.126). The ratio of men who could obtain ≥60% base and/or tip rigidities were 10% (two of 20), 41% (seven of 17), 26% (five of 19) and 55% (11/20) in placebo, sildenafil, tadalafil and vardenafil groups, respectively (P < 0.05). The median time to first measured base rigidity was 58.0, 21.5, 54.5 and 57 min with placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0032). The median total duration of recorded base rigidity was 4.0, 27.5, 10.0 and 11.5 min in men who took placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.013). The median total base rigidity (area under the curve) was 72.8, 699.0, 360.5 and 553.0 with placebo, sildenafil, tadalafil and vardenafil, respectively (P= 0.016). CONCLUSIONS Significant penile rigidities were obtained with PDE5 inhibitors during the short test period, with no sexual stimulation, in laboratory conditions. This finding might support the use of PDE5 inhibitors in men who need penile rehabilitation.

OBJECTIVES To explore the possible role of of 8-isoprostane F2α (8-IPF2α) in the aetiology of erectile dysfunction (ED), as the over-production of superoxide (O2-) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase results in the formation of 8-IPF2α in vascular tissue, which has similar properties to thromboxane A2 (TXA2). TXA2 is vasoconstrictor and up-regulates the expression of NADPH oxidase and phosphodiesterase type 5 (PDE5). MATERIALS AND METHODS Cavernosal vascular smooth muscle cells (CVSMCs) were incubated with 8-IPF2α or the TXA2 analogue, U46619, ±sildenafil, iloprost (a stable prostacyclin [PGI2] analogue) or the nitric oxide (NO) donor NONOate for 16 h. The formation of O2- was then measured, PDE5 expression assessed using Western blotting and PGI2 and 8-IPF2α formation measured using enzyme-linked immunoassays. RESULTS 8-IPF2α promoted the formation of O2-, an effect inhibited by apocynin (an NADPH oxidase inhibitor) and up-regulated the expression of PDE5. Under identical incubation conditions, 8-IPF2α induced an increase in the formation of 8-IPF2α but reduced the formation of PGI2. All, these effects were reversed by sildenafil, iloprost, NONOate and picotamide. CONCLUSIONS These data show that O2- derived from NADPH oxidase influences the relative balance of PGI2 and 8-IPF2α in CVSMCs, which in turn alters the degree of PDE5 expression. This is a novel pathogenic mechanism underlying ED and a novel mechanism of action of sildenafil.

To evaluate the efficacy of sildenafil in the treatment of neurogenic erectile dysfunction (ED) secondary to upper motor neuron (UMN) and lower motor neuron (LMN) spinal cord injury (SCI). After taking consents 105 patients suffering from ED were enrolled in this prospective study. Seventy-two patients had signs and symptoms of UMN and 33 patients had signs and symptoms of LMN or mixed (UMN and LMN) spinal cord injuries. The patients took 50-100 mg sildenafil or placebo tablet at least 45 min before sexual intercourse. Based on a IIEF questionnaire, success in achieving erection adequate for sexual intercourse was compared between sildenafil and placebo groups in UMN and non-UMN spinal cord injuries. In patients with UMN disease, sildenafil was effective in 82% of patients and its efficacy was statistically higher than placebo (82 vs. 25%, p < 0.05). Twenty-eight per cent of patients with non-UMN disease had a favourable response to sildenafil that was not statistically different from placebo. Sildenafil seems more effective in the treatment of neurogenic ED secondary to UMN spinal cord injury compared with that secondary to LMN injury. Actually, its efficacy on LMN injuries does not seem different from placebo and administration of this treatment may not be effective in spinal cord injury which has caused LMN symptoms.

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Phosphodiesterase type 5 inhibitors (PDE 5Is) improve erectile function and lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH), however the exact effects on prostate tissue and its underlying mechanisms remain unclear. PDE 5Is enhanced the production of cyclic nucleotides in the plasma and prostate, and the distribution of PDE 5Is in the prostate was higher than in the plasma. OBJECTIVE • To evaluate the impact and distribution of a single phosphodiesterase type 5 inhibitor (PDE5 I) dose (udenafil or tadalafil) in prostate tissue and plasma in patients with benign prostatic hyperplasia (BPH). PATIENTS AND METHODS • Thirty BPH patients complaining of erectile dysfunction along with moderate-to-severe lower urinary tract symptoms (LUTS) who underwent transurethral resection of the prostate (TURP) were enrolled in the present study. • The patients were randomly divided into the three groups: group 1, TURP without PDE5 Is; group 2, 200 mg of udenafil given 1 h before TURP; and group 3, 20 mg of tadalafil given 1 h before TURP. • We evaluated the concentrations of PDE5-I, cAMP and cGMP in prostate tissues and plasma, and calculated the prostate tissue-to-plasma (T/P) ratio. RESULTS • The concentration of udenafil in prostate tissue and plasma was 2028.6 ± 360.8 ng/g and 463.7 ± 39.1 ng/mL, respectively, and the resulting T/P ratio was 4.4. The tadalafil concentration in prostate tissue and plasma was 385.7 ± 83.8 ng/g and 305.8 ± 41.1 ng/mL, respectively, and the T/P ratio was 1.3. • Udenafil and tadalafil significantly increased the cAMP and cGMP levels in plasma and prostate tissues. CONCLUSIONS • Udenafil and tadalafil significantly increased cAMP and cGMP levels and were more highly distributed in the prostate than plasma. The T/P ratio of udenafil was higher than tadalafil. • These findings may help in the assessment of the feasibility of using PDE5 Is to concurrently treat both LUTS and erectile dysfunction.

SUMMARY Background: It has been demonstrated that sildenafil is effective in patients with pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH in adults with congenital heart disease (CHD) has been less investigated. Objective: In this prospective, open-label, uncontrolled and multicenter study, 60 patients with PAH related to CHD received oral sildenafil (75 mg/day) for 12 weeks. The enrolled patients underwent six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of the 12 weeks. The primary end point was the changes in exercise capacity assessed by SMWT; the secondary end point included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening (defined as death, transplantation, and rehospitalization for PAH). Drug safety and tolerability were also examined. Results: Oral sidenafil significantly increased SMWT distances (422.94 ± 76.95 m vs. 371.99 ± 78.73 m, P < 0.0001). There was also remarkable improvement in Borg dyspnea score (2.1 ± 1.32 vs. 2.57 ± 1.42, P= 0.0307). Moreover, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also discovered (mean pulmonary artery pressure, P= 0.0002; cardiac index, P < 0.0001; pulmonary vascular resistance, P < 0.0001). Side effects in this study were mild and consistent with reported studies. None of the enrolled patients experienced significant clinical worsening. Conclusions: This study confirmed and extended previous studies. It suggested that oral sildenafil was safe and effective for the treatment of adult patients with CHD-related PAH.

Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE To examine the early use of phosphodiesterase-5 inhibitor (PDE-5i; sildenafil citrate) in preventing subsequent erectile dysfunction (ED) after (monotherapy) prostate brachytherapy (PB, an accepted option for Gleason 6 or low-volume Gleason 7 prostate cancer), as PB is currently being offered more frequently in younger patients, and ED can be a side-effect often within the first 12 months after treatment. PATIENTS AND METHODS We examined a single-surgeon series of 69 patients who had been treated with PB from 2002 to 2005. All patients had a follow-up of ≥1 year; prospectively, and patients had baseline, 6- and 12-month assessments using the Sexual Health Inventory for Men (SHIM) and International Index of Erectile Function (IIEF)-6 scores. The 69 patients were divided into early treatment with PDE-5i (31) and not treated with PDE-5i (38), and their SHIM and IIEF-6 scores were compared at baseline, 6 and 12 months. Daily sildenafil (25–50 mg) was given immediately after PB for 12 months. Overall, for the entire group, the mean prostate-specific antigen (PSA) level was 6.8 ng/mL; 78% had Gleason 6 cancer and 20% had Gleason 7 (3 + 4) cancer. The mean age in the early PDE-5i group was 64.8 years, and was 66.0 years in the no-PDE-5i group. The mean radiation dose in the early PDE-5i group was 50.2 Gy, and 43.9 Gy in the other group (P= 0.08). RESULTS In the no-PDE-5i group, the mean baseline SHIM score of 17.1 decreased rapidly to 9.1 at 6 months (P= 0.01) and stayed at 9.3 at 12 months (P= 0.01). In the early PDE-5i group, the mean baseline SHIM score of 21.8 decreased slightly to 17.6 at 6 months (P= 0.2), and was maintained at 17.9 at 12 months (P= 0.2). Using the Wilcoxon rank-sum test, the 6- and 12-month SHIM scores in the two groups (P < 0.001). The IIEF-6 questionnaire confirmed the SHIM analysis. CONCLUSIONS After PB patients had a significant decline in SHIM/IIEF-6 scores at 6 and 12 months. Our results indicate a 50% decrease in the quality of their erections. This provides an opportunity to initiate early intervention with PDE-5i or perhaps vacuum constriction devices or intraurethral alprostadil. In this study, the early use of PDE-5i after PB maintained erectile function at both 6 and 12 months.

Pulmonary hypertension is a group of diseases comprising vascular constriction and obstructive changes of the pulmonary vasculature. Phosphodiesterase type 5 inhibitors, for example, sildenafil, can alleviate vascular remodeling in the monocrotaline pulmonary hypertension model in rats. We investigate the mechanisms of sildenafil on the pulmonary vascular remodeling of pulmonary hypertension induced by monocrotaline (MCT) in rats. Thirty Sprague-Dawley rats (weighing 200-220 g) were administered with MCT abdominal cavity injection or equivalent volume of normal saline (NS) (which were treated as C group n = 10) to induce pulmonary hypertension model. Fourteen days later, 20 MCT treated rats were randomly fed with sildenafil (25mg/kg/day) or placebo as S, P group (10 rats for each group), respectively. Another 6 weeks later, mean pulmonary artery pressure (mPAP), index of right ventricular hypertrophy (RV/LV+S) of all animals were measured under general anesthesia. Pulmonary tissue was collected to investigate pathological features of pulmonary arteries and to measure protein expression of ERK(1)/ERK(2) and MKP1. After 6 weeks, there were significant elevated mPAP and RV/LV+S in both P and S groups. The ratio of wall thickness to vessel diameter in pulmonary arteries with diameters

Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVE To determine, by post hoc analysis, the effects of tadalafil (a long-acting phosphodiesterase 5 inhibitor) on peak urinary flow (Qmax), bladder capacity, voiding efficiency and the obstructive symptoms of benign prostatic hyperplasia (BPH) in men with lower urinary tract symptoms secondary to BPH (BPH-LUTS), compared with placebo. PATIENTS AND METHODS After a 4-week placebo run-in period, 1058 men with BPH-LUTS were randomly allocated to receive once daily treatment with placebo or tadalafil (2.5, 5, 10, or 20 mg) for 12 weeks. Uroflowmetry, postvoid residual volume (PVR), and BPH symptom score measurements were assessed throughout the trial. RESULTS Increases in Qmax were numerically greater for tadalafil (2.5, 5, 10, and 20 mg with percentage changes of 15%, 16%, 17%, 22%, respectively) vs placebo (12%), but did not reach statistical significance. Age, baseline Qmax, erectile dysfunction history, sexual activity, and previous α-blocker therapy significantly influenced the Qmax response. Tadalafil was not associated with significant changes in PVR. Tadalafil had its greatest effects on bladder capacity and voiding efficiency in men with a Qmax of

Summary Purpose: The goal of the present study was to evaluate the effects of sildenafil on the threshold for electrically induced seizures in mice. In addition, interactions between sildenafil and classical and second-generation antiepileptic drugs (AEDs), that is, carbamazepine (CBZ), phenobarbital (PB), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC) were evaluated. Methods: Two electroconvulsive tests were used: maximal electroshock seizure threshold (MEST) and maximal electroshock seizure (MES) tests in mice. Acute adverse effects of the studied combinations were investigated in the chimney test, step-through passive avoidance task, and grip-strength test. Total brain and free plasma concentrations of AEDs were also determined. Results: Sildenafil raised the threshold for electroconvulsions in a dose-dependent manner. It also increased the anticonvulsant activity of CBZ, VPA, and TPM in the MES test, whereas the activity of the remaining AEDs was not significantly changed. Sildenafil increased total brain and free (protein unbound) plasma CBZ concentrations and total brain VPA concentration. Neither sildenafil nor its coadministration with the studied AEDs affected motor coordination and long-term memory in mice. Interestingly, sildenafil dose-dependently enhanced the skeletal muscle strength in mice, although combinations of sildenafil with AEDs were ineffective in this respect. Conclusions: Sildenafil significantly raised the threshold for electroconvulsions in mice without any impairment of motor performance and long-term memory, but it enhanced muscle strength. Treatment of patients on CBZ or VPA with sildenafil may not be recommended due to pharmacokinetic interactions. Coadministration of sildenafil with other AEDs, especially with TPM, seems to be a reasonable choice.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Endothelin-A receptor antagonists (ETRAs) and phosphodiesterase-type 5 inhibitors are approved monotherapies for the treatment of pulmonary arterial hypertension; combining agents from these two drug classes could be beneficial. • There is a significant pharmacokinetic (PK) interaction between the ETRA bosentan and the phosphodiesterase-type 5 inhibitor sildenafil. • This study assessed whether the ETRA sitaxentan similarly impacts the PK of sildenafil. WHAT THIS STUDY ADDS • This study demonstrates that sitaxentan has little effect on sildenafil PK and pharmacodynamics and that no dose adjustment of either agent is required upon co-administration of sildenafil with sitaxentan. AIMS This study evaluated the effects of sitaxentan on the pharmacodynamic [systemic blood pressure (BP)] and pharmacokinetic (PK) parameters of sildenafil in healthy volunteers. METHODS Healthy subjects (18–60 years, n= 24) were randomized into two sequence groups. Group 1 received sitaxentan sodium 100 mg daily (7 days), followed by placebo (7 days). Group 2 received placebo (7 days), followed by sitaxentan sodium 100 mg (7 days). On day 7 of each treatment period, participants received sildenafil 100 mg. PK parameters and BP were analysed on day 7 in each treatment period. RESULTS Sildenafil exposure was slightly higher [AUC∞ geometric mean ratio (GMR), 128%] when co-administered with sitaxentan 100 mg vs. placebo, demonstrating a weak, but statistically significant interaction (90% confidence interval 115.5%, 141.2%). The mean maximum positive (Emax+) and maximum negative (Emax–) changes from baseline in both systolic and diastolic BP were comparable for sitaxentan and placebo (range 4.8–7.3 mmHg) with three of four geometric mean ratios falling within the equivalence window, suggesting that the drug interaction was not clinically significant. Adverse events were similar between sitaxentan 100 mg (39%) and placebo (30%). No deaths or serious adverse events occurred during the study. CONCLUSION The dose of sildenafil does not need to be adjusted when co-administered with sitaxentan.

Study Type – Aetiology (case control) Level of Evidence 3b OBJECTIVE To evaluate the effect of N(G)-nitro-l-arginine methyl ester (L-NAME)-induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)-5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L-NAME induces NO-deficient HT. MATERIALS AND METHODS Thirty-six adult Sprague-Dawley male rats were divided into three groups, i.e. a control, L-NAME-HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil-treated L-NAME-HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L-NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ-bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme-linked immunosorbent assay. RESULTS The erectile response was diminished in the HT group. Nitrergic and endothelium-dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L-NAME-treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels. CONCLUSIONS Sildenafil treatment did not correct the ED in L-NAME-treated HT rats. Under sustained high blood pressure, up-regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium-dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT.