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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.

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

Background Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Research Question Which factors determine the outcome of PH in COPD? Study Design and Methods We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). Results The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Interpretation Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. Trial Registry ClinicalTrials.gov; No.: NCT01347216 ; URL: www.clinicaltrials.gov

To investigate the efficacy and safety of vibegron add-on therapy in men with persistent storage symptoms receiving α-1 blockers or PDE5 inhibitor for benign prostatic hyperplasia and then determine the independent factors affecting the efficacy of vibegron.Vibegron 50 mg was administered for 12 weeks to 42 patients (72.0 ± 8.2 years) with persistent storage symptoms who had taken α-1 blockers (22 patients) or PDE5 inhibitor (20 patients). The primary endpoint was change in the overactive Bladder (OAB) Symptom Score from baseline to end of treatment. The secondary endpoints were changes in each question of several questionnaires, maximum flow rate and residual urine volume. Finally, independent factors affecting the efficacy of vibegron were investigated.Total OAB Symptom Score was significantly decreased (6.21 ± 3.12 vs 4.38 ± 2.46; P.001). Although each score of several questionnaires, especially for storage symptoms, improved significantly, no significant improvement was found in stress incontinence, straining, bladder pain and urethral pain in the Core Lower Urinary Tract Symptom score. Maximum flow rate and residual urine volume did not change, and no patient discontinued vibegron because of adverse events. Multiple regression analysis showed that OAB Symptom Score, Core Lower Urinary Tract Symptom score, prostate volume and monotherapy with α-1 blocker were independent factors affecting the efficacy of vibegron.Add-on therapy of vibegron to monotherapy with α-1 blockers or PDE5 inhibitor for patients with benign prostatic hyperplasia and persistent storage symptoms was effective and safe.

Purpose Radiation therapy (RT) is widely used in the treatment of cancer. Unfortunately, RT alone is insufficient to control the disease in most cases, as regrowth after irradiation still occur. Thus, it would be meaningful to explore the underlying mechanism of tumor regrowth after irradiation. Myeloid-derived suppressor cells (MDSCs) contribute to the immunosuppressive tumor microenvironment and hinder the therapeutic efficacy of RT. However, it is unclear whether MDSCs-mediated immune suppression contributes to local relapse after irradiation. In this article, we tried to figure out how MDSCs sabotage the therapeutic effect of RT, and tried to determine the potential synergistic effect of combination between targeting MDSCs and RT. Methods and Materials A syngeneic murine model of Lewis lung cancer was used. The abundance of tumor infiltrating MDSCs and tumor growth after irradiation was assessed. The percentage and functional state of CD8+ T cells were measured by flow cytometry, with or without polymorphonuclear (PMN)-MDSCs depletion. Arginase 1 (ARG1) expression and activity of MDSCs were examined by hematoxylin and eosin staining and flow cytometry. ARG1 inhibitor and phosphodiesterase 5 inhibitor sildenafil were administered after RT to figure out the underlying mechanism of MDSCs-mediated immunosuppression. Results We demonstrated that irradiation recruited MDSCs, especially the polymorphonuclear subset, into the tumor microenvironment. PMN-MDSCs inhibited the CD8+ T cell response by elevating ARG1 expression. Selective depletion of PMN-MDSCs or inhibition on ARG1 promoted the infiltration and activation of intratumoral CD8+ T cells, and delayed tumor regrowth after irradiation. We showed that sildenafil reduced the accumulation and ARG1 expression of PMN-MDSCs after irradiation, thus abrogating the MDSCs-mediated immunosuppression. Conclusions Our results have suggested that PMN-MDSCs participate in the irradiation-induced immune suppression through ARG1 activation. We have also found that sildenafil has the potential to facilitate antitumor immunity, which provides a new alternative to delay tumor recurrence after RT.

Summary Erectile dysfunction varied by country, affecting between 20 to 40% of men aged 60 and 69 and more than 50% of men aged over 75. Our objective was to evaluate the habits of urologists in 2018 and also evaluate the need for additional, objective tools to aid physicians when providing care. A questionnaire was sent from the French Urology Association to 1158 physicians between November and December 2018. In all, 177 urologists (15.28%) took part in the study. Only 22% of urologists regularly used a questionnaire, such as the IIEF-5. When faced with erection problems, 56.5% of them did not carry out systematic cardiology evaluations. More than half of urologists requested fasting glucose, lipid and total testosterone levels. Twenty-seven percent did not carry out additional tests. First line treatment included a phosphodiesterase 5 inhibitor in 81% of cases. Two thirds of urologists (78%) rated themselves as being correctly trained in the area of erectile dysfunction. However, only 49% systematically inquired about erection problems when faced with benign prostatic hyperplasia and 65% thought that erectile dysfunction was not treated optimally. Despite existing recommendations, only half of urologists carry out a cardiac evaluation when a finding of erectile dysfunction is made. One third of urologists do not request additional testing. Greater training, along with the use of an objective diagnostic tool could help urologists to optimise the care they provide for patients suffering from erectile dysfunction, allowing them to keep working within current guidelines. Level of evidence 3.

Using genetically engineered mice lacking estrogen receptor-α non-nuclear signaling, this study demonstrated that estrogen receptor-α non-nuclear signaling activated myocardial cyclic guanosine monophosphate-dependent protein kinase G and conferred protection against cardiac remodeling induced by pressure overload. This pathway was indispensable to the therapeutic efficacy of cyclic guanosine monophosphate-phosphodiesterase 5 inhibition but not to that of soluble guanylate cyclase stimulation. These results might partially explain the equivocal results of phosphodiesterase 5 inhibitor efficacy and also provide the molecular basis for the advantage of using a soluble guanylate cyclase simulator as a new therapeutic option in post-menopausal women. This study also highlighted the need for female-specific therapeutic strategies for heart failure.

Background Acute mesenteric ischemia carries a significant morbidity. Measures to improve blood flow parameters to the intestine may ameliorate the disease. Sildenafil, a phosphodiesterase 5 inhibitor, increases cyclic guanosine monophosphate and has been shown to prevent the effects of ischemia when given before injury. However, its effects as a rescue agent have not been established. We therefore hypothesized that sildenafil, when given as a rescue agent for intestinal ischemia, would improve mesenteric perfusion, limit intestinal epithelial injury, and decrease intestinal leukocyte chemoattractants. Methods Eight to 12 wk-old-male C57BL/6J mice underwent laparotomy and temporary occlusion of the superior mesenteric artery for 60 min. Following ischemia, reperfusion was permitted, and before closing the abdomen, sildenafil was injected intraperitoneally in a variety of concentrations. After 24 h, reperfusion was reassessed. Animals were euthanized and intestines evaluated for histologic injury and leukocyte chemoattractants. Results Postischemic administration of sildenafil did not improve mesenteric perfusion following intestinal ischemia and reperfusion injury. However, sildenafil did improve histologic injury scores in dose ranges of 0.01 to 10 mg/kg. No difference was noted in histological injury with 100 mg/kg dose, and all members of the 1000 mg/kg group died within 24 h of injury. Epithelial protection was not facilitated by the leukocyte chemoattractants Regulated on Activation, Normal T Cell Expressed, and Secreted, macrophage inflammatory protein 1 alpha, monocyte chemoattractant protein, neutrophil activating protein, or granulocyte colony stimulating factor. Conclusions Administration of sildenafil following intestinal ischemia may limit intestinal mucosal injury but does not appear to alter mesenteric perfusion or leukocyte chemoattractant influx. Type Basic science. Level of evidence N/A.

Sildenafil is a phosphodiesterase 5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Proconvulsant effect is a serious adverse event associated with sildenafil use. Here, we investigated the possible proconvulsant effects of sildenafil in pilocarpine (PILO)-induced seizures model, which mimics some aspects of temporal lobe epilepsy. We also evaluated sildenafil’s effects on hippocampal markers related to PILO-induced seizure, for instance, acetylcholinesterase (AChE) activity, oxidative stress and nitric oxide (NO) markers, namely nitrite, inducible NO synthase (iNOS) and neuronal NOS (nNOS). The influences of muscarinic receptors blockade on sildenafil proconvulsant effects and brain nitrite levels were also evaluated. Male mice were submitted to single or repeated (7 days) sildenafil administration (2.5, 5, 10 and 20 mg/kg). Thirty minutes later, PILO was injected and mice were further evaluated for 1 h for seizure activity. Sildenafil induced a dose- and time-progressive proconvulsant effect in PILO-induced seizures. Sildenafil also potentiated the inhibitory effect of PILO in AChE activity and induced a further increase in nitrite levels and pro-oxidative markers, mainly in the hippocampus. Repeated sildenafil treatment also increased the hippocampal expression of iNOS and nNOS isoforms, while the blockade of muscarinic receptors attenuated both sildenafil-induced proconvulsant effect and brain nitrite changes. Our data firstly demonstrated the proconvulsant effect of sildenafil in PILO-model of seizures. This effect seems to be related to an increased cholinergic-nitrergic tone and pro-oxidative brain changes. Also, our findings advert to caution in using sildenafil for patients suffering from neurological conditions that reduces seizure threshold, such as epilepsy.

The phosphodiesterase-5 inhibitor sildenafil was developed for the treatment of pulmonary hypertension. The authors investigated the efficacy and safety of sildenafil in the early postoperative period after mitral valve surgery in patients with pulmonary hypertension.A double-blind, placebo-controlled randomized trial was performed.The trial was performed in a single tertiary referral center.Fifty consecutive patients who experienced pulmonary hypertension and underwent mitral valve surgery.Patients were randomly assigned to the following 2 groups: 25 patients received 20 mg sildenafil every 8 hours, and the remaining 25 patients received placebo during the same period. Hemodynamic parameters were studied by using a pulmonary artery catheter at baseline and every 6 hours up to 36 hours.Patients who received sildenafil showed a decrease in mean pulmonary pressure, from 32 ± 7 mmHg at baseline to 26 ± 3 mmHg after 36 hours, whereas no change was seen in patients who received placebo (mean pulmonary pressure 34 ± 6 mmHg at baseline and 35 ± 5 mmHg after 36 h) (p0.001). No significant changes in systemic hemodynamic and oxygenation were observed. Patients who received sildenafil compared with those who received placebo had a median mechanical lung ventilation time of 16 (10-31) hours versus 19 (13-41) hours (p = 0.431), intensive care unit stay of 74 (44-106) hours versus 91 (66-141) hours (p = 0.410), and a total hospitalization stay of 7 (5-10) days versus 11 (7-15) days (p = 0.009).The immediate postoperative administration of sildenafil after mitral valve surgery is safe. Sildenafil demonstrates a favorable decreasing effect on pulmonary vascular pressure without systemic hypotension and ventilation-perfusion mismatch.

BACKGROUND: Erectile dysfunction(ED) is common in patients with chronic liver disease(CLD). Although it significantly worsens the quality of life, caregivers and researchers often neglect it. AIM: Evaluating the prevalence of ED in patients with CLD, associated factors, and response to therapy with tadalafil, a phosphodiesterase-5 inhibitor. METHODS: A total of 60 males with Child-Pugh score between 5 and 10 and no overt hepatic encephalopathy were studied. ED was assessed based on the 15-question International Index of Erectile Function (IIEF) questionnaire. Patients were classified as ED+ if score was

To examine the relationship between phosphodiesterase 5 inhibitor drugs (PDE5i) and skin cancers in a large-scale study of Veterans.This was a retrospective database review using the Department of Veterans Affairs Informatics and Computing Infrastructure database. Veterans Affairs Informatics and Computing Infrastructure was searched 19 years for Veterans who received PDE5i treatment of erectile dysfunction. A non-PDE5i group of Veterans was selected for comparison analysis. Follow-up time, outpatient clinic visits and incidence of malignant melanoma (MM), and basal cell carcinoma (BCC) were measured in both groups.A total of 2.55 million Veterans were included in this study (1.27 million in each group). Mean age of the PDE5i group and non-PDE5i group was 59.2 years (standard deviation [SD] ± 10.8) and 58.7 (SD ± 10.8), respectively. Mean follow-up time for the PDE5i group was 8.9 years (SD ± 4.2) and 8.5 years (SD ± 4.3) for non-PDE5i group. Odds ratio for malignant melanoma and BCC in the PDE5i group was 1.25 (confidence interval 95%, 1.22-1.28, P.0001) and 1.49 (confidence interval 95%, 1.46-1.51, P.0001), respectively. PDE5i users showed more mean outpatient visits/year (8.9 SD ± 9.50) compared to non-PDE5i users (5.9 SD ± 10.0; P.0001).Veterans prescribed PDE5is to treat erectile show a minimal increased risk of MM and a greater risk of BCC compared to non-PDE5i users. PDE5i users visited outpatient VA clinics at a higher rate than non-PDE5i users in this study. These findings suggest confounding variables are likely involved in the relationship between skin cancers and PDE5i use. PDE5i drugs remain a safe treatment for erectile dysfunction.

Nitric oxide has been proven to play an important role in nociception, accordingly, its promoters, phosphodiesterase inhibitors have been investigated as pain response modulators. Aiming to evaluate the central antinociceptive effect of tadalafil, a phosphodiesterase 5 inhibitor, and to determine its EC50, tail flick and hot plate tests were employed. On the other hand, tadalafil antinociceptive peripheral effect was assessed through acetic acid-induced writhing model. Formalin test was used to appraise both non-inflammatory and inflammatory pain responses. In order to elaborate the involvement of opioid receptors and nitric oxide/cyclic guanosine monophosphate/potassium-ATP pathway in tadalafil-induced analgesia, mice were pretreated with naloxone, l-nitro-arginine-methyl-ester (l-NAME), methylene blue, and glibenclamide. The results illustrated that tadalafil had a significant antinociceptive effect in the tail flick, hot plate, acetic acid-induced writhing and formalin tests indicating the involvement of peripheral and central analgesic mechanisms. Moreover, tadalafil mechanism of action involved several receptors and mediators, specifically NO/cGMP pathway and opioid receptors. In the formalin test, naloxone significantly blocked the effect of tadalafil in the first phase and partially in the second phase which is an inflammatory pain-dependent aspect. l-NAME, methylene blue and glibenclamide partially blocked the effect of tadalafil in the first phase and enhanced its effect in the second phase which is related to nitric oxide role in the inflammatory process. As a conclusion, tadalafil possesses a potential analgesic effect via the involvement of opioid and nitric oxide pathways.

Background Recent guidelines recommend riociguat, a soluble guanylate cyclase (sGC) stimulator, and the type 5 phosphodiesterase inhibitor (PDE5i) tadalafil or sildenafil as treatments for pulmonary arterial hypertension. We compared the safety profiles of sildenafil, tadalafil, and riociguat in pulmonary hypertension. Methods We combined two approaches. First, we performed a meta-analysis of safety data extracted from randomized controlled trials. Second, we conducted a disproportionality analysis of data from VigiBase, the World Health Organization's global database of individual case safety reports, to compare the safety profiles with real-life data. Results In the meta-analysis, a significant difference between the three drugs was only detected for gastrointestinal disorders, in disfavor of riociguat ( P Conclusions The safety profiles of PDE5is and sGC stimulators significantly differ in pulmonary hypertension. Accordingly, there is a safety rationale in switching between PDE5is and sGC stimulators because of their different side effects. Trial Registry PROSPERO; No.: CRD42016051986; URL: https://www.crd.york.ac.uk/prospero/.

Purpose This network meta-analysis (NMA) is designed to compare the efficacy and tolerability of various therapies and combinations for pulmonary arterial hypertension (PAH). Method We conducted a systematic search in databases PubMed, Embase, and Cochrane Library. Treatment efficacy and tolerability were compared by synthesizing direct and indirect evidence. The surface under the curve ranking area was utilized to rank multiple interventions. Result A total of 43 randomized clinical trials were included in our NMA. With regard to efficacy outcomes, including 6 min walking distance (6MWD), functional class amelioration (FCA), death, clinical worsening (CW), pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), cardiac index (CI), and mean right atrial pressure (mRAP), endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitor (PDE-5Is), ERA combined with PDE-5Is (EAP), and prostacyclin analogs (PGI) combined with ERA (PAE) performed better than others. Meanwhile PAP and PGE demonstrated better than others in tolerability. Overall, EAP and PAE showed good efficacy and were well-tolerated among all therapies. Conclusion Overall, we recommend EAP as the optimal choice for patients with PAH in clinical practice and PAE as suboptimal in view of their desirable performance in efficacy. Most of the combination therapies performed better than monotherapies.

Endothelin receptor antagonists (ERA) have been recognised as effective therapy for pulmonary arterial hypertension in congenital heart disease (CHD-PH), and Eisenmenger syndrome (ES) since The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (Breathe 5) study. A new dual receptor antagonist - Macitentan - is currently undergoing trials to determine its efficacy in simple ES. To date there is little information on this therapy in CHD and we report our first experience, some with more complex diseases.Data was collected prospectively from September 2014. Patients with CHD-PH were started on or converted to macitentan if they required therapy with phosphodiesterase 5 inhibitor (PDE5i) or if there was insufficient response or a reaction to bosentan, especially those with trisomy 21. Patients were seen approximately three months after starting therapy to assess echocardiography, six minute walk test, clinical response and tolerability. All patients underwent monthly liver tests initially, but this was reduced to three-monthly in Q4 2015.Fifteen patients with CHD-PH (eight male, seven female) were started on macitentan, median (range) age 38 (23-61) years, and eight patients with Down's syndrome. Eight patients had complex CHD with one having unoperated double inlet left ventricle with ventriculo-arterial discordance, one had double outlet right ventricle and six with complete atrio-ventricular septal defect. Six patients were ERA naïve and nine patients changed from bosentan to macitentan in order to achieve improved drug-drug interaction. Median length of time of treatment with macitentan is 289 (0-694) days to date. One discontinued due to rash and feeling unwell; one was unable to comply with medication due to learning difficulties and one died soon after commencing rescue therapy. This last patient was functional class IV with oxygen saturation of 67% at rest, with right heart failure and was unable to perform a walk test before commencing therapy. All patients who remained on therapy had significant increase in six minute walk test from median 286 (120-426) to 360m (150-450)(p0.05), most notably in those treatment naïve. Functional class median remained at 3 but the range was reduced (1-3). Resting oxygen saturations improved from median 83 range (77-95%) at rest to 91 (77-96%) and at end walk from 78 (48-90%) to 79 (62-96%). Tricuspid regurgitant peak Doppler derived pressure drop did not change (as expected) at 4.6 (4.3-5.5)m/s. There were no episodes of liver dysfunction.The introduction of this new therapy has been simple and mostly well tolerated in our sick group of patients. With the usual reservations concerning the open-label nature of our observations, macitentan has good signals regarding oxygen saturations and encouraging signals relating to efficacy.

Background Riociguat, the first approved drug for patients with chronic thromboembolic pulmonary hypertension (CTEPH), is a soluble guanylate cyclase (sGC) Stimulator. It directly stimulates sGC independently of nitric oxide (NO) and increases sGC sensitivity for NO. The safety and efficacy of transitioning from a phosphodiesterase 5 inhibitor (PDE5i) to riociguat is unknown. Methods and results Twenty-three patients were prospectively enrolled: 8 symptomatic patients with inadequate clinical responses to PDE5i were changed to riociguat (transitioned group); 15 started riociguat anew (new or add-on group). We analyzed the change from baseline to 6–12 months of riociguat treatment for the 6-minute walk distance (6MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), partial pressure of oxygen in arterial blood (PaO2), brain natriuretic peptide (BNP), World Health Organization (WHO) functional class, safety and adverse events. The mPAP, BNP and WHO functional class significantly improved in total. In the transitioned group, BNP significantly decreased by −116.5±188.6pg/ml ( P =0.0156). The 6MWD, mPAP, PVR, CI, and PaO2 improved but not significantly. The baseline condition was significantly more severe in the transitioned than in the new or add-on group. No patients discontinued riociguat. Relatively rapid transitioning from PDE5i to riociguat was safe under careful observation. Conclusions Transitioning to riociguat may be safe and effective in CTEPH patients with inadequate clinical responses to PDE5i.

Background We conducted a systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacologic interventions for pulmonary arterial hypertension (PAH). Methods MEDLINE, the Cochrane Register, EMBASE, CINAHL, and clinicaltrials.gov were searched (January 1, 1990 to March 3, 2016). Randomized controlled trials (RCTs) studying the approved pharmacologic agents endothelin receptor antagonists (ERA), phosphodiesterase inhibitors (PDE5i), the oral/inhaled (PO/INH) and IV/subcutaneous (SC) prostanoids, and riociguat and selexipag, alone or in combination, for pulmonary arterial hypertension (PAH) and reporting at least one efficacy outcome were selected. Results Thirty-one RCTs with 6,565 patients were selected. In network meta-analysis, when compared with a median placebo rate of 14.5%, clinical worsening was estimated at 2.8% with riociguat (risk ratio [RR], 0.19; 95% CI, 0.05-0.76); at 3.9% with ERA + PDE5i (RR, 0.27; 95% CI, 0.14-0.52), and at 5.7% with PDE5i (RR, 0.39; 95% CI, 0.24-0.62). For improvement in functional status, when compared with 16.2% in the placebo group, improvement in at least one New York Heart Association/World Health Organization (NYHA/WHO) functional class was estimated at 81.8% with IV/SC prostanoids (RR, 5.06; 95% CI, 2.3211.04), at 28.3% with ERA + PDE5i (RR, 1.75; 95% CI, 1.05-2.92), and at 25.2% with ERA (RR, 1.56; 95% CI, 1.22-2.00). Differences in mortality were not significant. Adverse events leading to discontinuation of therapy were highest with the PO/INH prostanoids (RR, 2.92; 95% CI, 1.68-5.06) and selexipag (RR, 2.06; 95% CI, 1.04-3.88) compared with placebo. Conclusions Currently approved pharmacologic agents have varying effects on morbidity and functional status in patients with PAH. Future comparative effectiveness trials are warranted with a focus on a patient-centered approach to therapy. Registration PROSPERO CRD42016036803

In this work, we examined some mechanisms involved in the hypotension caused by Lachesis muta (South American bushmaster) venom in anesthetized rats. Venom (1.5 mg/kg, i.v.) caused immediate hypotension that was maximal after 5 min and gradually returned to baseline over 60 min. Pretreatment of rats with the non-selective nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) did not attenuate the early phase of venom-induced hypotension, but abolished the recovery phase and resulted in rapid death; a similar effect was observed with the soluble guanylate cyclase (sGC) inhibitor ODQ. In contrast, the hemodynamic responses to venom were not attenuated by the non-selective NOS inhibitor NG-monomethyl-L-arginine, the inducible NOS inhibitor aminoguanidine, the phosphodiesterase 5 inhibitor sildenafil, the adenylate cyclase (AC) inhibitor SQ-22.536, the non-selective muscarinic receptor antagonist atropine, the bradykinin B2 receptor antagonist HOE-140 and the non-selective cyclooxygenase inhibitor indomethacin. Preincubation of venom with the PLA2 inhibitor pBPB had no effect on the immediate hypotension but tended to improve the recovery phase. Neither AEBSF (a serine proteinase inhibitor) nor EDTA (a metalloproteinase inhibitor) prevented the venom-induced hypotension, but AEBSF and not EDTA protected against the lethality of a high dose (3.0 mg/kg, i.v.). There were no marked changes in the ECG parameters with the various treatments, except with L-NAME and ODQ that increased the RR interval. Pulmonary thrombus formation was markedly enhanced by L-NAME and ODQ, and to a lesser extent by pBPB, especially in small vessels, whereas AEBSF and EDTA inhibited thrombus formation. Venom relaxed phenylephrine-precontracted thoracic aorta and pulmonary artery in vitro, with the latter being more sensitive. The relaxation was endothelium-dependent and was inhibited by ODQ but not by H-89, a protein kinase A (PKA) inhibitor. Together, these findings indicate involvement of the NO/sGC/cGMP, but not the AC/cAMP/PKA signaling pathway, in the hemodynamic responses to L. muta venom in rats. Muscarinic mechanisms, kinins and arachidonic acid metabolites are apparently not involved.

Purpose Medical combination therapy of pulmonary arterial hypertension (PAH) may alleviate the drawbacks of monotherapy by avoiding drug tolerance and by increasing effectiveness, as shown by the combination of ambrisentan and tadalafil (AMBITION trial). The present ex-vivo study evaluated the combination of the endothelin receptor antagonists (ERA) macitentan and bosentan with the phosphodiesterase-5 (PDE-5) inhibitor vardenafil in pulmonary arteries from patients suffering from terminal lung disease as a model of PAH. Methods Segments of the pulmonary vessels were excised from resected lungs of patients requiring lung transplantation (LTX). Contraction of pulmonary arteries (PA) was elicited by consecutive dose-response curves of endothelin-1 (ET-1) followed by norepinephrine (NE) to allow inhibition by different pathways. Forces were measured isometrically in an organ bath in the presence and absence of ERA and PDE-5 inhibitors and their combination. Results PA of 38 patients were examined between October 2016 and November 2019. Bosentan (1E-7 M) and macitentan (1E-8 M, 3E-8 M, 1E-7 M) inhibited ET-1 induced contractions, whereas vardenafil (1E-6 M, 3E-6 M, 1E-5 M) inhibited only the NE induced part of the contractions. Vardenafil enhanced bosentan-induced inhibition of vasoconstriction in a dose-dependent fashion. Combination effects exceeded single bosentan at 3E-6 M and 1E-5 M vardenafil, and they exceeded single vardenafil at the lower vardenafil concentrations. Macitentan showed a more pronounced inhibition than bosentan regardless of the lower concentrations. Accordingly, combination effects with vardenafil resembled those of macitentan alone. Conclusions Macitentan and bosentan were potent antagonists of vasoconstriction in PA of LTX patients. The benefit of drug combinations was demonstrated at selected concentrations only owing to a narrow therapeutic range of vardenafil in this ex-vivo model. These results suggest the utility of drug combinations other than the established pair of ambrisentan and tadalafil in PAH treatment but also make a case for a further assessment of vasodilator properties of drugs complementing ERA.

Background Presence of pulmonary hypertension (PH) and right ventricular dysfunction worsens prognosis in patients with chronic heart failure (CHF). Preclinical and clinical studies suggest a role for the impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in both PH and CHF. Hence, we examined the effects of the NO–sGC–cGMP pathway modulation by the PDE5 inhibitor sildenafil or sGC stimulator riociguat on pulmonary hemodynamics and heart function in a murine model of secondary PH induced by transverse aortic constriction. Methods C57Bl/6N mice were subjected to transverse aortic constriction (TAC) for 6weeks to induce left heart failure and secondary PH and were subsequently treated with either sildenafil (100mg/kg/day) or riociguat (10mg/kg/day) or placebo for 2weeks. Results Six weeks after surgery, TAC induced significant left ventricular hypertrophy and dysfunction associated with development of PH. Treatment with riociguat and sildenafil neither reduced left ventricular hypertrophy nor improved its function. However, both sildenafil and riociguat ameliorated PH, reduced pulmonary vascular remodeling and improved right ventricular function. Conclusions Thus, modulation of the NO–sGC–cGMP pathway by the PDE5 inhibitor sildenafil or sGC stimulator riociguat exerts direct beneficial effects on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PH due to left heart disease and these drugs may offer a new therapeutic option for therapy of this condition.

Background The therapeutic potential of phosphodiesterase-5 inhibitor PF-03049423 was evaluated in a phase 2, multicenter, randomized, double-blind, placebo-controlled study of subjects with acute ischemic stroke (Clinical Trial Registration Information: http://www.clinicaltrials.gov , unique identifier: NCT01208233; http://www.clinicaltrialsregister.eu , EudraCT number: 2010-021414-32). Materials and Methods Subjects (N = 70) received PF-03049423 6 mg (or placebo, N = 67) once daily, orally, commencing between 24 and 78 hours of stroke onset, and continuing for 90 days. Postbaseline efficacy assessments were performed on Days 7, 14, 30, 60, and 90. Modified Rankin Scale (mRS), Barthel Index, National Institutes of Health Stroke Scale, Box and Blocks Test, Hand-Grip Strength Test, 10-Meter Walk Test, Repeatable Battery Assessment of Neuropsychological Status Naming and Coding Subtests, Line Cancellation Test, and Recognition Memory Test were administered to evaluate poststroke recovery. The primary endpoint was the mRS responder rate (score 0-2 at Day 90). The study included a planned interim analysis of efficacy data. Results The primary efficacy analysis using logistic regression showed no statistically significant difference between PF-03049423 6 mg and placebo (responder rate of 42.6% and 46.2%, respectively). Although PF-03049423 showed a satisfactory safety and tolerability profile, no signal of efficacy emerged from any of the outcome measures. Conclusions PF-03049423 showed no therapeutic potential for acute ischemic stroke.

Pulmonary arterial hypertension (PAH) secondary to pulmonary Langerhans cell histiocytosis (PLCH) is known to be a relatively common complication and is associated with a poor prognosis. However, the optimal therapeutic approach for these cases remains to be established. A 57-year-old man visited our hospital because of a progressive dry cough. A thoracic computed tomography examination showed a combination of diffuse thick-walled cysts and reticulonodular shadows that were predominant in bilateral upper lobes of the lungs. He was diagnosed as having PLCH based on the results of video-assisted thoracoscopic lung biopsies. During a 3-year clinical course, his condition deteriorated despite smoking cessation. A systemic evaluation demonstrated precapillary PAH caused by PLCH (PAH-PLCH), and treatment with tadalafil, a phosphodiesterase-5 inhibitor, was started. During a 50-month period of treatment with tadalafil, improvements in his dyspnea, 6-min walking distance, and hemodynamics were maintained without either overt hypoxemia or pulmonary edema. We considered that tadalafil therapy may be a useful option in the treatment of patients with PAH-PLCH.

Purpose Late right heart failure (LRHF) is a major cause of morbidity after LVAD. Phosphodiesterase-5 inhibitors (PDE5i) are often used for post-LVAD right heart dysfunction, but their impact on LRHF is unknown. Methods We identified adult patients from the INTERMACS registry undergoing continuous-flow LVAD (CFLVAD) after 2012 and stratified them by use of PDE5i at 1 month. Early RHF (ERHF) was defined as the need for RVAD within 1 month or inotropes for > 2 weeks. Among patients surviving > 1 month after discharge from the index LVAD implant, LRHF was defined as any of the following: death from RHF, need for RVAD or inotropes, re-hospitalization for RHF or volume overload , or fulfilling INTERMACS criteria of documentation and manifestation of RHF. Freedom from LRHF was compared with the Kaplan-Meier method and Cox proportional hazards modeling. Results Among 9627 CFLVAD patients surviving >1 month after discharge, 2463 (26%) were treated with PDE5i at 1 month. Patients on PDE5i were more likely to require >2 weeks of inotropic support (27% vs 14%), be INTERMACS Profile 1 or 2 (52% vs 46%), and have higher pulmonary vascular resistance (2.8 vs 2.2 WU), p Conclusion Irrespective of ERHF, post-implant PDE5i use is associated with an increased risk of LRHF after LVAD. Further studies are required to determine if selective pulmonary vasodilator therapy has a role in preventing LRHF after LVAD.

Lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) are associated with erectile dysfunction. Alpha-1-adrenoceptor antagonists are effective drugs for treating symptomatic BPH. Clinical data show improvements in LUTS by phosphodiesterase 5 inhibitors. This study aimed to evaluate effects of silodosin, a highly selective α1A-adrenoceptor antagonist, alone or in combination with the phosphodiesterase 5 inhibitor tadalafil on contractions of isolated human and rat prostates. In organbath studies, effects of increasing concentrations of silodosin (1 nM-1 μM) and tadalafil (100 nM-100 μM) on contractions by electrical field stimulation or phenylephrine of human and rat prostate strip preparations were investigated. The combination silodosin and tadalafil reduced electrically-induced contractions of human prostate preparations better than single drugs alone. At any frequencies (1-32 Hz), inhibitory effects of combined therapy (P-values vs single drug) in human tissue were 26-42% (1 nM silodosin+100 nM tadalafil; P

Hesperidin (4'-methoxy-7-O-rutinosyl-3',5-dihydroxyflavanone), a naturally occurring flavanone glycoside, was previously shown to produce an antidepressant-like effect with modultation of the serotonergic 5-HT1A and kappa-opioid receptors. In this study, the signaling mechanisms underlying their antidepressant-like effects were further evaluated by investigating in acute and chronic treatments. Results showed that chronic treatment of hesperidin or hesperitin (0.1, 0.3 and 1mg/kg, intraperitoneal, i.p.) have an antidepressant-like effect in the mouse tail suspension test (TST) without modified the locomotor activity in the open field test. Pretreatment with l-arginine (a nitric oxide (NO) precursor), sildenafil (a phosphodiesterase 5 inhibitor) or S-nitroso-N-acetyl-penicillamine (a NO donor) significantly reversed the reduction in immobility time elicited by acute treatment with hesperidin (0.3mg/kg) in the TST. Hesperidin (0.01mg/kg, a sub-effective dose in acute treatment) produced an additive antidepressant-like effect with N(G)-nitro-l-arginine (an inhibitor of nitric oxide synthase (NOS)) or 7-nitroindazole (a neuronal NOS inhibitor) in the TST. Pretreatment of animals with methylene blue (an inhibitor of NOS/soluble guanylate cyclase (sGC)) or ODQ (a specific inhibitor sGS) caused an additive effect with hesperidin in the TST. Hesperidin in the acute (1mg/kg) and chronic (0.1, 0.3 and 1mg/kg) treatments caused a significant decrease in nitrate/nitrite (NOX) levels in the hippocampus of mice. Chronic treatment with hesperidin (0.3 and 1mg/kg) also resulted in an increase in hippocampal brain-derived neurotrophic factor (BDNF) levels. These results demonstrated that the antidepressant-like effect of hesperidin is likely mediated by inhibition of l-arginine-NO-cGMP pathway and by increased of the BDNF levels in hippocampus.

Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC₅₀ of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2Å resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors.

Context Erectile dysfunction (ED) is considered a vascular impairment that shares many risk factors with cardiovascular disease (CVD). A correlation between ED and CVD has been hypothesized, and ED has been proposed as an early marker of symptomatic CVD. Objective To analyze the relationship between ED and CVD, evaluating the pathophysiologic links between these conditions, and to identify which patients would benefit from cardiologic assessment when presenting with ED. Evidence acquisition A systematic literature review searching Medline, Embase, and Web of Science databases was performed. The search strategy included the terms erectile dysfunction, cardiovascular disease, coronary artery disease, risk factors, pathophysiology, atherosclerosis, low androgen levels, inflammation, screening, and phosphodiesterase type 5 inhibitors alone or in combination. We limited our search to studies published between January 2005 and May 2013. Evidence synthesis Several studies reported an association between ED and CVD. The link between these conditions might reside in the interaction between androgens, chronic inflammation, and cardiovascular risk factors that determines endothelial dysfunction and atherosclerosis, resulting in disorders of penile and coronary circulation. Because penile artery size is smaller compared with coronary arteries, the same level of endothelial dysfunction causes a more significant reduction of blood flow in erectile tissues compared with that in coronary circulation. Thus ED could be an indicator of systemic endothelial dysfunction. From a clinical standpoint, because ED may precede CVD, it can be used as an early marker to identify men at higher risk of CVD events. ED patients at high risk of CVD should undergo detailed cardiologic assessment and receive intensive treatment of risk factors. Conclusions ED and CVD should be regarded as two different manifestations of the same systemic disorder. ED usually precedes CVD onset, and it might be considered an early marker of symptomatic CVD. © 2013 European Association of Urology.

Background To evaluate the effects of Tadalafil, a phosphodiesterase 5 enzyme inhibitor, on Escherichia coli –induced renal damage in an acute pyelonephritis (PN) rat model. Methods Experimental PN was induced in 32 Wistar rats, and four groups were formed: group 1 (no treatment), group 2 (antibiotic), group 3 (Tadalafil), and group 4 (antibiotic + Tadalafil). Antibiotic was given on days 3 to 8, and Tadalafil was administered between days 0 and 28 of bacterial inoculation. Half of the rats were killed on the ninth day (early period) and histopathological parameters, immunohistochemical renal fibrosis markers, and oxidant/antioxidant system activities were evaluated. The rest of the rats were killed at the sixth week of the study and evaluated for histopathological parameters and renal fibrosis markers. Results Inflammatory activity was significantly milder in rats treated with antibiotic + Tadalafil versus no treatment group both in the early and late periods. In the late period, interstitial fibrosis or tubular atrophy was lower in the antibiotic + Tadalafil group versus the no treatment and antibiotic groups, and in Tadalafil versus antibiotic group. Tadalafil administration significantly reduced renal malondialdehyde and nitric oxide levels and enhanced superoxide dismutase and catalase activities. In addition, circulating tumor necrosis factor α, interleukin 1β was greatly reduced in Tadalafil group versus the no treatment group. Conclusions We have provided the first evidence that phosphodiesterase 5 enzyme inhibitor Tadalafil ameliorates circulating inflammatory cytokines, reverses oxidant/antioxidant dysfunction and eventually possesses an overall protective effect on renal tissue from Escherichia coli –induced PN-related kidney injury. Phophodieterase 5 inhibitor might be a novel therapeutic target for PN.

The senescence accelerated mouse-prone 8 (SAMP8) strain of mice is an experimental model of accelerated senescence that also shares several pathological features with Alzheimer's disease. Among them, cognitive impairments and abnormal hyperphosphorylation of tau are ameliorated by the phosphodiesterase 5 inhibitor sildenafil, possibly through the modulation of Cdk5/p25 and Akt/GSK-3β pathways. Here we studied the implication of protein phosphatase 2A (PP2A) and c-Jun N-terminal kinase (JNK) in the therapeutic effects of sildenafil. Results demonstrated that there were no differences in hippocampal PP2A protein levels or activity (measured by its inactive isoform phopho-PP2A Y307) when we compared 6-month old SAMP8 mice and age-matched control, SAMR1 mice, treated with saline or sildenafil (7.5 mg/kg i.p. for 4 weeks). However, this same treatment of sildenafil, that had been shown to reverse the cognitive impairment and tau hyperphosphorylation in this animal model, also reversed the increased levels of activated JNK (p-JNK) found in the hippocampus of SAMP8 mice. Moreover, the administration of the JNK inhibitor, D -JNKI-1 (0.2 mg/kg i.p. for 3 weeks) also ameliorated the cognitive deficits shown by SAMP8 mice in the Morris water maze and decreased hippocampal levels of phospho-c-Jun(Ser73). When phosphorylated tau (AT8 epitope) was analyzed a significant reduction was observed in the hippocampus of D-JNKI-1 treated SAMP8 mice, providing a plausible explanation for the attenuation of cognitive decline shown by these animals. These findings suggest the involvement of the JNK pathway on tau pathology and cognitive deficits shown by 6-month old SAMP8 mice. They also point to the modulation of this kinase to be among the mechanisms responsible for the beneficial effects shown by sildenafil.

Vardenafil, a phosphodiesterase-5 inhibitor, is approved for the therapy of erectile dysfunction. However, in contrast to Sildenafil and Tadalafil, little is known about its effects on pulmonary hypertension. Four weeks after monocrotaline-administration rats exhibited a significant increase in right ventricular pressure (RVSP, 94mmHg vs. 25mmHg; p=0.001) right ventricular weight (right ventricle/left ventricle+septum, 59 vs. 23; p=0.001) and pulmonary vascular remodeling (medial wall area 104% vs. 66%; p0.05) as compared to controls, with a corresponding reduction in exercise capacity (% from baseline value: 67%; p0.05). Vardenafil treatment resulted in decreased RVSP (56mmHg vs. 95mmHg; p=0.008), right ventricular weight (41 vs. 59; p=0.013), pulmonary vascular remodeling (medial wall area 64% vs. 104%; p0.05) and a significant better exercise capacity (% from baseline value: 84% vs. 67%; p0.05) compared to monocrotaline only treated animals. In conclusion, Vardenafil exerts beneficial effects on monocrotaline-induced pulmonary hypertension in rats. Whether it is a treatment option for patients with pulmonary hypertension needs to be elucidated.

Phosphodiesterase type 5 (PDE5) mediates the degradation of cGMP in a variety of tissues including brain. Recent studies have demonstrated the importance of the nitric oxide/cGMP/cAMP-responsive element-binding protein (CREB) pathway to the process of learning and memory. Thus, PDE5 inhibitors (PDE5Is) are thought to be promising new therapeutic agents for the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by memory loss. To explore this possibility, a series of quinoline derivatives were synthesized and evaluated. We found that compound 7a selectively inhibits PDE5 with an IC50 of 0.27 nM and readily crosses the blood brain barrier. In an in vivo mouse model of AD, compound 7a rescues synaptic and memory defects. Quinoline-based, CNS-permeant PDE5Is have potential for AD therapeutic development.

Guanosine is an extracellular signaling molecule implicated in the modulation of glutamatergic transmission and neuroprotection. The present study evaluated the antidepressant-like effect of guanosine in the forced swimming test (FST) and in the tail suspension test (TST) in mice. The contribution of NMDA receptors as well as l-arginine-NO-cGMP and PI3K-mTOR pathways to this effect was also investigated. Guanosine administered orally produced an antidepressant-like effect in the FST (0.5-5 mg/kg) and TST (0.05-0.5 mg/kg). The anti-immobility effect of guanosine in the TST was prevented by the treatment of mice with NMDA (0.1 pmol/site, i.c.v.), d-serine (30 μg/site, i.c.v., a co-agonist of NMDA receptors), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase), sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor), LY294002 (10 μg/site, i.c.v., a reversible PI3K inhibitor), wortmannin (0.1 μg/site, i.c.v., an irreversible PI3K inhibitor) or rapamycin (0.2 nmol/site, i.c.v., a selective mTOR inhibitor). In addition, the administration of ketamine (0.1 mg/kg, i.p., a NMDA receptor antagonist), MK-801 (0.001 mg/kg, i.p., another NMDA receptor antagonist), 7-nitroindazole (50 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of guanosine (0.01 mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. None of the treatments affected locomotor activity. Altogether, results firstly indicate that guanosine exerts an antidepressant-like effect that seems to be mediated through an interaction with NMDA receptors, l-arginine-NO-cGMP and PI3K-mTOR pathways.

The airway epithelium provides important barrier and host defense functions. Recent studies reveal that nitrite is an endocrine reservoir of nitric oxide (NO) bioactivity that is converted to NO by enzymatic reductases along the physiological oxygen gradient. Nitrite signaling has been described as NO dependent activation mediated by reactions with deoxygenated redox active hemoproteins, such as hemoglobin, myoglobin, neuroglobin, xanthine oxidoreductase (XO) and NO synthase at low pH and oxygen tension. However, nitrite can also be readily oxidized to nitrogen dioxide (NO(2)·) via heme peroxidase reactions, suggesting the existence of alternative oxidative signaling pathways for nitrite under normoxic conditions. In the present study, we examined normoxic signaling effects of sodium nitrite on airway epithelial cell wound healing. In an in vitro scratch injury model under normoxia, we exposed cultured monolayers of human airway epithelial cells to various concentrations of sodium nitrite and compared responses to NO donor. We found sodium nitrite potently enhanced airway epithelium wound healing at physiological concentrations (from 1 μM). The effect of nitrite was blocked by the NO and NO(2)· scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO). Interestingly, nitrite treatment did not increase cyclic guanosine monophosphate (cGMP) levels under these normoxic conditions, even in the presence of a phosphodiesterase 5 inhibitor, suggesting cGMP independent signaling. Consistent with an oxidative signaling pathway requiring hydrogen peroxide (H(2)O(2))/heme-peroxidase/NO(2)· signaling, the effects of nitrite were potentiated by superoxide dismutase (SOD) and low concentration H(2)O(2), whereas inhibited completely by catalase, followed by downstream extracellular-signal-regulated kinase (ERK) 1/2 activation. Our data represent the first description of normoxic nitrite signaling on lung epithelial cell proliferation and wound healing and suggest novel oxidative signaling pathways involving nitrite-H(2)O(2) reactions, possibly via the intermediary, NO(2)·.

Clinical and preclinical data reported that ascorbic acid has antidepressant properties. The present study was designed to investigate the participation of l -arginine–NO–cGMP pathway in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST) in mice. The antidepressant-like effect of ascorbic acid (1 mg/kg, p.o.) in the TST was prevented by the pre-treatment of mice with NMDA (0.1 pmol/site, i.c.v.), l -arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor). The administration of MK-801 (0.001 mg/kg, i.p), 7-nitroindazole (25 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of ascorbic acid (0.1 mg/kg, p.o.) reduced the immobility time in the TST test when compared with either drug alone. None of the results in the TST appears to be due to a nonspecific locomotor effect. Our findings provide evidence that the effect of ascorbic acid in the TST involve an interaction with NMDA receptors and l -arginine–NO–cGMP pathway, contributing to the understanding of the mechanisms underlying the antidepressant-like effect of this vitamin.

A sildenafil analogue was detected and isolated from a health supplement claimed for human use. The structure of this new analogue was elucidated using LC–UV, LC–Orbitrap-MS, IR spectroscopy, 1D and 2D NMR. It was characterized as dithio-desmethylcarbodenafil containing 2 thiocarbonyl groups instead of 2 carbonyl groups, and 4-methyl substitution, on the piperazine ring, rather than 4-ethyl substitution, when compared to sildenafil.

Pharmaceutical counterfeiting is a permanently growing problem. Control laboratories are constantly analysing counterfeit medicines. In industrialised countries, one of the main counterfeited class of medicines are erectile dysfunction drugs. This paper describes the development and validation of a fast method to detect and quantify the three authorised phosphodiesterase type 5 inhibitors and five analogues. The method is based on the use of a sub-2 microns polar-embedded column with a gradient using acetonitrile as organic modifier and 10 mM ammonium formate buffer (pH 3.5) as aqueous component of the mobile phase. The separation was achieved in less than 4.5 min. The method has also been compared to the registered HPLC method for the assay of Viagra® which was considered as the reference method. The method is also compatible with on-line coupling mass spectrometry and will significantly reduce analysis times and solvent consumption.

Tadalafil is a phosphodiesterase-5 (PDE-5) inhibitor that was approved by the US Food and Drug Administration (FDA) in 2009 for the treatment of pulmonary arterial hypertension (PAH).The purpose of this review is to evaluate the pharmacology, pharmacokinetic properties, clinical efficacy, adverse effects, drug interactions, and dosage and administration of tadalafil in patients with PAH.A literature search of MEDLINE and International Pharmaceutical Abstracts (1960 through September 5, 2010) was conducted with the search terms tadalafil, pulmonary arterial hypertension, and phosphodiesterase-5 inhibitor. Data found from orignial research and case series published in English were screened for relevancy to pharmacology, pharmacokinetics, clinical efficacy and safety, and tolerability. Relevant articles from the bibliographies of the identified published articles were also obtained. Unpublished data and posters were obtained from the manufacturer of tadalafil and the FDA Web site.By selectively inhibiting PDE-5, tadalafil causes nitric oxide-mediated vasodilation in the pulmonary vasculature. Tadalafil has a greater affinity (10,000-fold) for PDE-5 compared with the other PDE inhibitors and has a t(½) of 17.5 hours. In a controlled clinical study in patients with PAH, patients receiving tadalafil in a total daily dose of 40 mg had significant improvements in their 6-minute walk distance (33 m from baseline) and time to clinical worsening compared with those receiving placebo (both, P0.05). Tadalafil had adverse effects similar to placebo, with headache being the most commonly reported (42%).In the small number of studies available, tadalafil was effective and well tolerated when used to treat patients with PAH. Compared with placebo, tadalafil was associated with significant improvements in exercise capacity and reduced time to clinical worsening (68% relative risk reduction; P = 0.038). There is limited evidence comparing tadalafil with sildenafil and vardenafil, and the studies are limited by short treatment durations.

OBJECTIVES: We investigated the influence of sildenafil on cardiac contractility and diastolic relaxation and examined the distribution of phosphodiesterase-5 in the hearts of hypertensive rats that were treated with by NG-nitro-L-arginine methyl ester (L-NAME). METHODS: Male Wistar rats were treated with L-NAME and/or sildenafil for eight weeks. The Langendorff method was used to examine the effects of sildenafil on cardiac contractility and diastolic relaxation. The presence and location of phosphodiesterase-5 and phosphodiesterase-3 were assessed by immunohistochemistry, and cGMP plasma levels were measured by ELISA. RESULTS: In isolated hearts, sildenafil prevented the reduction of diastolic relaxation (dP/dt) that was induced by L-NAME. In addition, phosphodiesterase-5 immunoreactivity was localized in the intercalated discs between the myocardial cells. The staining intensity was reduced by L-NAME, and sildenafil treatment abolished this reduction. Consistent with these results, the plasma levels of cGMP were decreased in the L-NAME-treated rats but not in rats that were treated with L-NAME + sildenafil. CONCLUSION: The sildenafil-induced attenuation of the deleterious hemodynamic and cardiac morphological effects of L-NAME in cardiac myocytes is mediated (at least in part) by the inhibition of phosphodiesterase-5.

Previous studies in rats have suggested a causal relationship between progressive pulmonary inflammation and lung fibrosis induced by crystalline silica particles. We report here that, in NMRI mice, the lung response to silica particles is accompanied by a mild and non progressive pulmonary inflammation which is dispensable for the development of lung fibrosis. We found that glucocorticoid (dexamethasone) dramatically reduced lung injury, cellular inflammation and pro-inflammatory cytokine expression (TNF-α, IL-1β and KC) but had no significant effect on silica-induced lung fibrosis and expression of the fibrogenic and suppressive cytokines TGF-β and IL-10 in mice. Other anti-inflammatory molecules such as the COX inhibitor piroxicam or the phosphodiesterase 5 inhibitor sildenafil also reduced lung inflammation without modifying collagen, TGF-β or IL-10 lung content. Our findings indicate that the development of lung fibrosis in silica-treated NMRI mice is not driven by inflammatory lung responses and suggest that suppressive cytokines may represent critical fibrotic factors and potential therapeutic targets in silicosis.

OBJECTIVES To evaluate the efficacy and safety of tadalafil in men with treatment-emergent sexual dysfunction due to serotonin reuptake inhibitors. METHODS The present prospective, double-blind, 12-week study, randomized in a 1:1 ratio to tadalafil 20 mg or placebo taken on demand, included 50 men. The efficacy measures were the changes in total and domain scores of the International Index of Erectile Function questionnaire, Sexual Encounter Profile diary questions 2-6, and the Global Assessment questions (GAQs) 1 and 2. The safety analyses included the evaluation of adverse events, vital signs, serum chemistry results, and electrocardiography findings. RESULTS For the patients who took tadalafil 20 mg, the net median score change from baseline to the endpoint compared with placebo was 26 for the 15-item International Index of Erectile Function; 10, 4, 4, 3, and 3 for the erectile function, intercourse satisfaction, overall satisfaction, orgasmic function, and sexual desire domains; and 3 and 5 points for "yes" responses to the Sexual Encounter Profile 2 and Sexual Encounter Profile 3 questions, respectively. All comparisons between tadalafil and placebo were significant (P < .001). At the endpoint, 92% of the tadalafil group responded affirmatively to both GAQs 1 and 2 compared with 8% of the placebo group (P < .001, for each). In the safety measures, no clinically significant changes attributable to tadalafil use were found. CONCLUSIONS Tadalafil 20-mg treatment significantly improved sexual function in patients who were taking serotonin reuptake inhibitors for depression, with mild to moderate, well-tolerable adverse events.

Excessive activation of microglial cells has been implicated in various neuroinflammation. The present study showed that sildenafil, a PDE5 inhibitor, significantly suppressed NO, interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) production induced by LPS in microglial cells through decreasing the protein and/or mRNA expressions of inducible NO synthase (iNOS), IL-1β and TNF-α in a concentration-dependent manner. Sildenafil also blocked IκBα phosphorylation and degradation, inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK). Moreover, the increase of the expression of gp91phox, a critical and catalytic subunit of NADPH oxidase, and the levels of intracellular reactive oxygen species (iROS) induced by LPS were markedly inhibited by sildenafil. In summary, these data suggest that sildenafil exerts its in vitro anti-inflammatory effect in LPS-activated N9 microglial cells by blocking nuclear factor-κB (NF-κB) and MAPKs activation, which may be partly due to its potent down-regulation of the NADPH-derived iROS production.

In this review we identify whether problems encountered in urology, such as erectile dysfunction, have a bearing on general health, in particular cardiovascular health. Testosterone, traditionally regarded as the hormone subserving male reproductive and sexual functioning, appears to have a much wider role. Recent findings show that testosterone is involved in the metabolic control of glucose and lipids, of strength of bone and muscle, and psychological aspects such as mood and energy. Serum testosterone levels decline with ageing, free testosterone levels more so than total testosterone. At least 10 publications have shown that low testosterone levels are associated with an increased risk of death. The metabolic syndrome is a clustering of risk factors predisposing to diabetes mellitus type 2, atherosclerosis, and cardiovascular morbidity and mortality. There is a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels are associated with an increased risk of type 2 diabetes mellitus, dramatically illustrated by androgen deprivation in men with prostate carcinoma. Lower total testosterone and sex hormone-binding globulin levels predict a higher incidence of the metabolic syndrome. Administration of testosterone to hypogonadal men reverses part of the unfavourable risk profile for the development of diabetes and atherosclerosis, thus also improving risk factors for erectile dysfunction. We conclude that urologists diagnosing and treating erectile problems are in a unique position to include general aspects of men’s health in their work, and thus contribute to general health and to cardiovascular health in particular.

A 63-year-old woman developed consecutive visual loss in the presence of chronic renal failure on hemodyalisis, arterial hypertension, and pulmonary hypertension treated with sildenafil. Temporal artery biopsy was negative for giant cell arteritis. Bilateral, consecutive non-arteritic ischemic optic neuropathy was diagnosed. The implications and potential risk of sildenafil use in women are discussed.