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

Eisenmenger syndrome (ES) is the most severe form of pulmonary arterial hypertension (PAH) associated with congenital heart disease. It is an extremely devastating condition with a serious impact on patients' life. Classical therapy of ES remains directed to avoid complications, such as erythrocytosis, treatment of congestive heart failure, prevention of infection, and secondary haematological abnormalities such as iron deficiency and coagulation disorders. However, the only effective treatment is heart–lung transplantation; still, morbidity and mortality after transplantation remain substantially high. Furthermore, waiting lists for heart–lung transplantation are long. Recent studies examining the use of advanced medical treatment in patients with ES have shown that it may have beneficial effects in patients with ES; however, additional studies need to be done to confirm its efficacy and appropriate clinical use. A 41-year-old female admitted to the Hospital of Lithuanian University of Health Sciences due to progressive dyspnea on minimal effort, heart failure symptoms leading to NYHA functional class III-IV. After clinical and instrumental investigations, ES secondary to unrepaired patent ductus arteriosus with severe PAH was diagnosed. Treatment with sildenafil was initiated together with the standard pharmacological therapy, and the patient was added to the waiting list for the heart and lung transplantation. After 24 months of stable condition, her clinical status deteriorated, and combination therapy (sildenafil and ambrisentan) was initiated. Clinical symptoms and exercise capacity improved, and she has been stable for 4 years thereafter. Our experience of the management of an adult patient with ES showed the benefits of treatment with advanced therapy with pulmonary vasodilators that improved the patient's quality of life and delayed the need for heart and lung transplantation.

Eisenmenger syndrome (ES) is the most severe form of pulmonary arterial hypertension (PAH) associated with congenital heart disease. It is an extremely devastating condition with a serious impact on patients' life. Classical therapy of ES remains directed to avoid complications, such as erythrocytosis, treatment of congestive heart failure, prevention of infection, and secondary haematological abnormalities such as iron deficiency and coagulation disorders. However, the only effective treatment is heart–lung transplantation; still, morbidity and mortality after transplantation remain substantially high. Furthermore, waiting lists for heart–lung transplantation are long. Recent studies examining the use of advanced medical treatment in patients with ES have shown that it may have beneficial effects in patients with ES; however, additional studies need to be done to confirm its efficacy and appropriate clinical use. A 41-year-old female admitted to the Hospital of Lithuanian University of Health Sciences due to progressive dyspnea on minimal effort, heart failure symptoms leading to NYHA functional class III-IV. After clinical and instrumental investigations, ES secondary to unrepaired patent ductus arteriosus with severe PAH was diagnosed. Treatment with sildenafil was initiated together with the standard pharmacological therapy, and the patient was added to the waiting list for the heart and lung transplantation. After 24 months of stable condition, her clinical status deteriorated, and combination therapy (sildenafil and ambrisentan) was initiated. Clinical symptoms and exercise capacity improved, and she has been stable for 4 years thereafter. Our experience of the management of an adult patient with ES showed the benefits of treatment with advanced therapy with pulmonary vasodilators that improved the patient's quality of life and delayed the need for heart and lung transplantation. [ABSTRACT FROM AUTHOR]

Ferraz MMD, Quintella SL, Parcial ALN, Ferraz MR. The effects of sildenafil citrate and L-NAME on male rat sexual behaviour. PHARMACOL BIOCHEM BEHAV. Erectile dysfunction (ED) affects up to 50% of men between 40 and 70 years of age. Significant advances in the pharmacological treatment of ED occurred in recent years, most notably the introduction of the first oral selective phosphodiesterase type-5 inhibitor, sildenafil. This study investigated the effectiveness of chronic oral treatment with L-NAME in rats as an experimental model of erectile dysfunction to evaluate new pharmacological agents that affect the sexual response. The effects of chronic oral L-NAME treatment, separately or in combination with sildenafil, on the sexual behaviour of male rats were evaluated. Filtered water was used as a control. Acute administration of L-NAME did not alter the sexual response compared with control, but sildenafil administration facilitated sexual behaviour after acute and chronic administration. Chronic L-NAME treatment inhibited motivational and consummatory measures of male rat sexual behaviour. Sildenafil prevented the inhibitory effects of L-NAME. The present results confirm that chronic oral treatment with a nitric oxide synthase inhibitor may be a relevant peripheral ED model to evaluate the effects of drugs on erectile function of male rats. [ABSTRACT FROM AUTHOR]

The present study was undertaken to determine the effect of a phosphodiesterase (PDE) type-5 (cyclic guanosine monophosphate-specific) inhibitor, sildenafil, on capacitation and penetration of boar spermatozoa in a basic chemically defined medium (adenosine- and theophylline-free PGM-tac4). When ejaculated spermatozoa were cultured for 90 minutes in the absence or presence of sildenafil at 2.5 mM, the inhibitor significantly increased the percentage of capacitated/acrosome-reacted spermatozoa, as a result of the chlortetracycline assay. When fresh spermatozoa were co-cultured with oocytes in the presence of sildenafil at a different concentration (0, 2.5, 25, or 250 μM), higher sildenafil concentrations (25 and 250 μM) significantly resulted in higher sperm penetration rates. When oocytes matured in vitro were co-cultured with spermatozoa in the presence of 25 μM sildenafil or 25 mM caffeine benzoate for 8 hours, the incidence of penetrated oocytes did not differ between two groups, whereas the incidence of monospermic oocytes in penetrated one was significantly higher in the presence of sildenafil. Immunocytochemical analysis reported the presence of PDE type-5 on the acrosome region of boar spermatozoa. These results report that regulation of cyclic guanosine monophosphate-specific PDE type-5 by sildenafil somehow can increase the penetrability of boar spermatozoa in vitro . [ABSTRACT FROM AUTHOR]

Over the past 20 years, great progress has been made in the treatment of pulmonary arterial hypertension (PAH). Available therapies target one of three principal pathways: the endothelin (ET), nitric oxide (NO) or the prostacyclin (PGI2) pathway. Evidence shows that current drugs, used either as monotherapy or in different combinations, can improve exercise capacity, clinical symptoms, hemodynamics and even survival in PAH. Unfortunately, the disease remains incurable and the prognosis of the disease is still poor. However, existing and novel potent antiproliferative therapies are being explored, and new agents targeting different and/or additional pathways are likely to become available to clinicians in the near future. Promising candidates include tyrosine kinase antagonists (e.g. imatinib); soluble guanylate cyclase stimulators (riociguat); an oral analog of prostacyclin (selexipag); and a tissue targeting endothelin receptor antagonist (macitentan). Phase II or III trials have either been completed or are underway to evaluate the safety and efficacy of these various therapies. [ABSTRACT FROM AUTHOR]

The article looks at the effects of tadalafil on dopaminergic neurons of gerbils as part of its evaluation as a potential cerebral ischemia treatment. The study was performed on 40 adult Mongolian gerbils, where they were organized into groups provided with different dosages of the drug including 0.1, 1, and 10 milligrams per kilogram. Results that tadalafil reduced thyrosine hydroxylase expression and boosted dopamine D2 receptor expression, enabling treatment of cerebral ischemia.

Vardenafil hydrochloride (HCl) is a potent and selective phosphodiesterase type-5 (PDE-5) inhibitor that enhances nitric oxide (NO)-mediated relaxation of human corpus cavernosum and NO-induced rabbit penile erection, and enhances erectile function in patients. In the present study, the effect of vardenafil on nitric oxide synthase (NOS) and neuronal NOS expressions in the paraventricular nucleus (PVN) of rats without sexual stimulation was investigated using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry and neuronal NOS (nNOS) immunohistochemistry and western blot analysis. The present results showed that NOS and nNOS expression in the PVN was increased by vardenafil treatment as the dose- and duration-dependently without sexual stimulation. The phosphodiesterase type-5 inhibitor, vardenafil, augmented NOS expression in the brain without sexual stimulation. The present study suggests that sexual behaviour can be directly modulated by neurotransmitters such as nitric oxide. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: We aimed to determine the effects of sildenafil and vardenafil in human umbilical artery preparation taken from pre-eclamptic or normal pregnant women, and also to investigate the underlying mechanisms in these effects. Study design: Fifteen pregnant women with pre-eclampsia and 15 healthy pregnant women were involved. Relaxation responses of sildenafil and vardenafil in the presence and absence of nitric oxide synthase inhibitor, N-[omega]-nitro-l-arginine methyl ester (l-NAME), and soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), were compared between the pre-eclampsia group and the control group. Results: Sildenafil induced relaxation responses were significantly attenuated in the presence of pre-eclampsia, l-NAME and QDO. Similarly, pre-eclampsia, l-NAME or ODQ incubation also shifted vardenafil-induced relaxation responses rightward. However, in all set of experiments a maximal relaxation response was achieved by vardenafil unlike sildenafil. In conclusion vardenafil seems to relax human umbilical artery stronger than sildenafil in both pre-eclamptic and normal pregnancies. Conclusion: These data indicate that vardenafil might affect vascular responsiveness of human umbilical artery through the involvement of NO/cGMP-dependent and independent pathways while sildenafil-induced responses were seemed to be completely NO/cGMP-dependent. Further investigations are needed to clarify the mechanisms. [Copyright &y& Elsevier]

Abstract: Early adverse experiences resulting from maternal separation may lead to neuronal cell death and eventually cause memory impairment. Maternal separation has been used to create a valid animal model of early life stress and a depression-like syndrome. The phosphodiesterase (PDE)-5 inhibitor, tadalafil (Cialis), is a widely prescribed agent for the treatment of erectile dysfunction. In this study, we investigated the effects of tadalafil on apoptosis and cell proliferation in the hippocampal dentate gyrus of rat pups following maternal separation. Specifically, the immobility time in the forced swim test was increased in the maternal-separated rat pups, and tadalafil treatment decreased the immobility time. The rat pups in the maternal separation group had deceased memory function compared to the rat pups in the maternal care group, and tadalafil treatment increased memory function of the rat pups in the maternal separation group. Apoptotic cell death in the hippocampal dentate gyrus was significantly increased in the maternal-separated rat pups, and tadalafil treatment suppressed maternal separation-induced apoptosis. In contrast, cell proliferation in the dentate gyrus was significantly decreased in the maternal-separated rat pups, and taldalafil treatment increased cell proliferation. The present results suggest that tadalafil improves depressive symptoms and alleviates memory impairment by suppressing apoptotic neuronal cell death and enhancing cell proliferation in maternal-separated rat pups. [ABSTRACT FROM AUTHOR]

Abstract: In order to assess the role of nitric oxide/cyclicGMP signaling pathway in the anticonvulsant effect of benzodiazepines, we studied the potential interaction of a phosphodiesterase type 5 inhibitor, sildenafil with the effect of diazepam on a mouse model of clonic seizures induced by intravenous infusion of GABA antagonist, pentylenetetrazole (PTZ). Administration of sildenafil (10mg/kg; per se effective on seizure threshold) could abolish the anticonvulsive effect of diazepam, and a subeffective dose (5mg/kg), when added to NO precursor l-arginine (50mg/kg) could cause the same effect. Conversely, subeffective doses of diazepam (0.02mg/kg) and NO synthase inhibitor N(omega)-nitro-l-arginine methyl ester (L-NAME, 5mg/kg), administered together, reversed the proconvulsive effect of sildenafil. Our findings indicate that the enhancement of NO/cGMP signaling pathway by sildenafil attenuates the anticonvulsant effect of the benzodiazepine prototype, diazepam. This suggests that the effects of facilitating GABAA-mediated inhibition and modulating NO pathways are additive and there might be a role for NO pathway in benzodiazepine effect against PTZ-induced seizures in mice. [Copyright &y& Elsevier]

Premature ejaculation (PE) is thought to be the most common male sexual dysfunction; however, the prevalence of lifelong (LL)-PE is relatively low. The aim of this study was to investigate the effects of on-demand vardenafil (10 mg) to modify the intravaginal ejaculatory latency time (IELT) in men with LL-PE without erectile dysfunction. Forty-two men (18–35 years) were enrolled in a 16-week, double-blind, placebo-controlled, cross-over study. Primary end point was the modification from baseline of IELT assessed by stopwatch technique; secondary end points were post-ejaculatory refractory time (PERT) and variations of scores at the Index of Premature Ejaculation questionnaire. The changes in geometric mean IELT were superior after taking vardenafil (0.6±0.3 vs 4.5±1.1 min, P<0.01), compared with placebo (0.7±0.3 vs 0.9±1.0 min, ns). PERT dropped significantly after vardenafil (16.7±2.0 vs 4.3±0.9 min, P<0.001), compared with placebo (15.3±2.2 vs 15.8±2.3 min). Patients who took vardenafil (vs placebo) reported significantly (P<0.01) increased ejaculatory control (6±2 vs 16±2), improved overall sexual satisfaction (7±2 vs 15±1) and distress (4±1 vs 8±1) scores, respectively. Multiple regression analysis (r2=0.86) for IELT by the number of attempts at sexual intercourse showed significant differences between the slopes of lines for placebo and vardenafil (P<0.0001). The most common adverse events for vardenafil (vs placebo) were headache (10 vs 3%), flushing (12 vs 0%) and dyspepsia (10 vs 0%), which tended to disappear over the time. In conclusion, in our study, vardenafil increased IELT and reduced PERT in men with LL-PE. Besides, improvements in confidence, perception of ejaculatory control and overall sexual satisfaction were reported.International Journal of Impotence Research (2009) 21, 221–227; doi:10.1038/ijir.2009.21; published online 28 May 2009 [ABSTRACT FROM AUTHOR]

Abstract: Context: Erectile dysfunction (ED) is often the manifestation of a generalized vascular disorder characterized by endothelial dysfunction. Reduced biological activity of endothelium-derived nitric oxide links human atherosclerosis to ED and underscores the role of an altered endothelium in the pathogenesis of both conditions. Objective: This review will provide an update on clinical data available on drugs promoting endothelial health and repair with regard to sexual medicine. Evidence acquisition: A comprehensive evaluation of available published data in full-length papers, identified in MedLine up to February 2008, was performed. Evidence synthesis: Evidence indicates that angiotensin-converting-enzyme inhibitors, sartanes, statins, vitamins (C and E), and L-arginine are all effective drugs for improving endothelial dysfunction in clinical studies; real benefits of dietary vitamin supplements and nutraceuticals are questionable. Growing evidence suggests that continued use of phosphodiesterase type 5 inhibitors as well as adjunctive testosterone replacement in deficiency syndromes may be beneficial and may synergistically improve endothelial function in selected subjects. Conclusions: Endothelially active drugs may serve as active treatment for both general and sexual health in men with increased cardiovascular risk. Further controlled studies are necessary to establish the real cost-effectiveness of such therapies and their impact on outcomes for patients. [Copyright &y& Elsevier]

Abstract: Background: To date, no data have been available from large, well-designed trials comparing on demand and nightly dosing of phosphodiesterase type 5 (PDE5) inhibitors on recovery of erectile function in postprostatectomy patients with erectile dysfunction (ED). Objective: To investigate the effect of early postoperative dosing with vardenafil, administered either nightly or on demand, compared with placebo on recovery of erectile function in men with ED following bilateral nerve-sparing radical prostatectomy (NSRP) surgery. Design, setting, and participants: A randomised, double-blind, double-dummy, multicentre, parallel group study conducted at 87 centres across Europe, Canada, South Africa, and the United States. For inclusion, patients had to be scheduled to undergo bilateral NSRP within 1 mo of screening and have a normal International Index of Erectile Function erectile function domain (IIEF-EF) score of ≥26 at screening. A total of 628 men, aged 18–64 yr, were randomised to treatment. Study design consisted of a 9-mo double-blind treatment period, a 2-mo single-blind washout period, and an optional 2-mo open-label period. Intervention: Patients received placebo, nightly vardenafil, or on demand vardenafil. Measurements: Primary outcome measure was the percentage of subjects with an IIEF-EF score of ≥22 after the 2-mo washout period. Secondary variables included mean per-patient success rates for Sexual Encounter Profile (SEP) questions 2 and 3. Results and limitations: No statistically significant differences were observed among treatment groups in the proportion of patients with an IIEF-EF score of ≥22 or in SEP3 success rates after the washout period. On-demand vardenafil treatment resulted in significantly greater IIEF-EF scores and better SEP3 response rates than placebo over the entire treatment period. Conclusions: In this study of men with ED following bilateral NSRP, vardenafil was efficacious when used on demand, supporting a paradigm shift towards on demand dosing with PDE5 inhibitors in this patient group. Trial registration: European clinical trials database (EudraCT; available at http://eudract.emea.europa.eu/). Trial registration number: 11336. [Copyright &y& Elsevier]

To investigate the therapeutic effect of androgen on hypogonadal patients unresponsive to sildenafil alone. In total, 32 hypogonadal patients with erectile dysfunction (ED), initially had an inadequate response to sildenafil (100 mg). Oral testosterone undecanoate (Restandol®, 80 mg, bid or tid) alone was supplied for 2 months, and if patients could not achieve a satisfactory erection, combined use of testosterone and sildenafil was continued thereafter. Total testosterone (TT), free testosterone (FT), and the parameters of the International Index of Erectile Function (IIEF), International Prostate Symptom Score (IPSS), and uroflow rate (UFR) were assessed. Eleven patients (34.3%) achieved satisfactory erectile function after testosterone replacement only. Another 12 (37.5%) patients experienced satisfactory intercourse after combined therapy. Serum TT and FT levels significantly increased after the use of testosterone alone (415±163 vs 220±101 ng/dl, P<0.01; 10.4±4.6 vs 5.1±1.9 ng/dl; P<0.01, respectively) and the combined use of testosterone and sildenafil (498±178 vs 220±101 ng/dl, P<0.01; 11.7±4.6 vs 5.1±1.9 ng/dl, P<0.001, respectively); as did the IIEF score (14.8±6.8 vs 12.6±7.5, P<0.01, 17.5±5.2 vs 12.6±7.5, P<0.001, respectively). However, no statistical differences were demonstrated for IPSS or UFR. In conclusions, one-third of hypogonadal patients with ED who failed to respond to sildenafil, responded to testosterone alone, another third responded to sildenafil again after normalization of testosterone. So, in hypogonadal patients with ED, androgen supplementation is first-line therapy. If patients are unresponsive to androgen alone or sildenafil alone, combined use may improve erectile function and enhance the therapeutic effect of PDE-5 inhibitors.International Journal of Impotence Research (2006) 18, 400–404. doi:10.1038/sj.ijir.3901446; published online 5 January 2006 [ABSTRACT FROM AUTHOR]

Objective: To explore the clinical value of phosphodiesterase type-5 inhibitors (PDE-5i) combined with RigiScan-based audiovisual sexual stimulation (AVSS) test in comparison with that of nocturnal penile tumescence (NPT) test in evaluation of erectile function., Methods: A total of 166 ED patients, aged 21－63 (mean 31) years, with a disease course of 3 months to 10 years (mean 14 months), underwent NPT test or PDE-5i + RigiScan-based AVSS test from 2017 to 2018. We compared the results of the diagnostic strategies. Normal NPT patterns were presumed to indicate psychogenic and abnormal ones to indicate organic ED., Results: Compared with the results of NPT test, no statistically significant difference was observed in the accuracy rate between Viagra + AVSS test and Cialis + AVSS test (P > 0.05). PDE-5i + RigiScan-based AVSS test achieved a sensitivity of 78.9% and a specificity of 90.7% in the diagnosis of psychogenic ED and an overall accuracy rate of 81.9%. According to the results of PDE-5i + RigiScan-based AVSS test, the patients fell into a normal and an abnormal erection group, with significant differences between the two groups in age, disease course, IIEF-5 score and maintenance time of penile tip rigidity ≥60% (P < 0.05). ROC curve analysis indicated that PDE-5i + RigiScan-based AVSS test accurately manifested the erectile function of the patients., Conclusions: Compared with NPT test, PDE -5i combined with RigiScan-based AVSS test is simple, inexpensive, practical and with a high sensitivity and specificity, and therefore can be used as the first-choice strategy for etiological diagnosis of ED.

Objective: To investigate that short-term treatment of sildenafil can induce browning of subcutaneous white adipose tissue (sWAT) in human adults., Design: A randomized, double-blinded, placebo-controlled, parallel group trial., Methods: Sixteen eligibility overweight male subjects were recruited, comparing 100mg/day sildenafil versus an identical placebo therapy for 7days. sWAT samples were collected from subjects before and after 7-day sildenafil or placebo interventions., Results: The results showed that multilocular UCP1-positive adipocytes existed in sWAT samples from subjects after sildenafil treatment. Compared to before treatment in both group as well as after treatment in placebo, sildenafil significantly decreased adipocyte size, increased the expressions of UCP1 protein and mRNA, mitochondrial density, and leak respiratory capacity in sWAT (p<0.05). Sildenafil also increased plasma cyclic guanosine-3',5'-monophosphate (cGMP) and catecholamine concentrations (p<0.05), and consequently activated the expressions of vasodilator-stimulated phosphoprotein (VASP) and p70 ribosomal S6 kinase 1 (S6K1) (p<0.05). Sildenafil did not activate typical brown fat., Conclusions: The current findings demonstrate that sildenafil can induce browning of sWAT in human, and this action may be through cGMP-dependent protein kinase I and mechanistic/mammalian target of rapamycin (mTOR) signaling pathways. Sldenafil may be a promising treatment for metabolic disease., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To investigate factors associated with demographic/clinical characteristics and drug selection in patients with erectile dysfunction (ED). The prevalence of ED is increasing worldwide. Studies have shown that ED is associated with age, lifestyle and comorbidities. However, the factors associated with patient characteristics as well as drug selection are incompletely understood., Setting: A tertiary medical centre in Kuala Lumpur, Malaysia., Participants: A total of 219 patients (range 23-80 years) who had received phosphodiesterase type-5 (PDE-5) inhibitors as ED treatment were evaluated., Inclusion Criteria: Adult patients aged ≥18 years, diagnosed with ED, and prescribed with sildenafil, tadalafil or vardenafil., Exclusion Criteria: Patients diagnosed with ED but who did not receive any PDE-5 inhibitor, or those with missing data., Primary and Secondary Outcome Measures: Factors associated with demographic and clinical characteristics as well as drug selection were assessed., Results: Ischaemic heart disease (p=0.025), benign prostatic hyperplasia (p<0.001), obesity (p=0.005), lower urinary tract symptoms (LUTS) (p=0.006) and α-blockers (p<0.001) were significantly associated with elderly patients with ED. Additionally, LUTS (p=0.038) and α-blockers (p=0.008) were significantly associated with the selection of PDE-5 inhibitor., Conclusions: These data showed that elderly patients with ED were significantly associated with comorbidities and α-blockers, whereas LUTS and α blockers were associated with drug selection., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)