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In a trial, patients with moderate to severely advanced idiopathic pulmonary fibrosis were treated with nintedanib plus sildenafil or nintedanib alone, with the goal of decreasing IPF symptoms. There were no between-group differences in any of three symptom measures.

BackgroundPatients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH.ObjectiveTo explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial.MethodsThis was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response).ResultsIn the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups.ConclusionsThis post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy.Trial registration number NCT01178073, post results.

Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. To determine whether sildenafil reduces perinatal mortality or major morbidity. This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. ClinicalTrials.gov Identifier: NCT02277132.

Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events. To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH. In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks. At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min(-1)·m(-2); P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (-5.3 mm Hg, P = 0.047; -4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012-0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events. Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.

Abstract Context Erectile function is important for life satisfaction and often impaired in men with obstructive sleep apnea (OSA). Uncontrolled studies show that treating OSA with continuous positive airway pressure (CPAP) improves erectile function. Phosphodiesterase type 5 inhibitors (e.g., vardenafil) are the first-line therapy for erectile dysfunction (ED), but may worsen OSA. Objective To assess the effects of CPAP and vardenafil on ED. Design Sixty-one men with moderate-to-severe OSA and ED were randomized to 12 weeks of CPAP or sham CPAP, and 10 mg daily vardenafil or placebo in a two-by-two factorial design. Main Outcome Measures International Index of Erectile Function (primary end point), treatment and relationship satisfaction, sleep-related erections, sexual function, endothelial function, arterial stiffness, quality of life, and sleep-disordered breathing. Results CPAP increased the frequency of sleep-related erections, overall sexual satisfaction, and arterial stiffness but did not change erectile function or treatment or relationship satisfaction. Vardenafil did not alter erectile function, endothelial function, arterial stiffness, or sleep-disordered breathing, but did improve overall self-esteem and relationship satisfaction, other aspects of sexual function, and treatment satisfaction. Adherent CPAP improved erectile function, sexual desire, overall sexual, self-esteem, relationship, and treatment satisfaction, as well as sleepiness, and quality of life. Adherent vardenafil use did not consistently change nocturnal erection quality. Conclusion CPAP improves overall sexual satisfaction, sleep-related erections, and arterial stiffness. Low-dose daily vardenafil improves certain aspects of sexual function and did not worsen OSA. Adherent CPAP or vardenafil use further improves ED and quality of life. This randomized controlled study investigating the effect of CPAP and a PDE-5 inhibitor on erectile function highlights the importance of identifying erectile dysfunction in patients with OSA.

Background Acute exacerbation of idiopathic pulmonary fibrosis has become an important outcome measure in clinical trials. This study aimed to explore the concept of suspected acute exacerbation as an outcome measure. Methods Three investigators retrospectively reviewed subjects enrolled in the Sildenafil Trial of Exercise Performance in IPF who experienced a respiratory serious adverse event during the course of the study. Events were classified as definite acute exacerbation, suspected acute exacerbation, or other, according to established criteria. Results Thirty-five events were identified. Four were classified as definite acute exacerbation, fourteen as suspected acute exacerbation, and seventeen as other. Definite and suspected acute exacerbations were clinically indistinguishable. Both were most common in the winter and spring months and were associated with a high risk of disease progression and short-term mortality. Conclusions In this study one half of respiratory serious adverse events were attributed to definite or suspected acute exacerbations. Suspected acute exacerbations are clinically indistinguishable from definite acute exacerbations and represent clinically meaningful events. Clinical trialists should consider capturing both definite and suspected acute exacerbations as outcome measures.

Multiple phase III randomized controlled trials (RCTs) for pharmacologic interventions in traumatic brain injury (TBI) have failed despite promising results in experimental models. The heterogeneity of TBI, in terms of pathomechanisms and impacted brain structures, likely contributes to these failures. Biomarkers have been recommended to identify patients with relevant pathology (predictive biomarkers) and confirm target engagement and monitor therapy response (pharmacodynamic biomarkers). Our group focuses on traumatic cerebrovascular injury as an understudied endophenotype of TBI and is validating a predictive and pharmacodynamic imaging biomarker (cerebrovascular reactivity; CVR) in moderate-severe TBI. We aim to extend these studies to milder forms of TBI to determine the optimal dose of sildenafil for maximal improvement in CVR. We will conduct a phase II dose-finding study involving 160 chronic TBI patients (mostly mild) using three doses of sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor. The study measures baseline CVR and evaluates the effect of escalating sildenafil doses on CVR improvement. A 4-week trial of thrice daily sildenafil will assess safety, tolerability, and clinical efficacy. This dual-site 4-year study, funded by the Department of Defense and registered in ClinicalTrials.gov (NCT05782244), plans to launch in June 2023. Biomarker-informed RCTs are essential for developing effective TBI interventions, relying on an understanding of underlying pathomechanisms. Traumatic microvascular injury (TMVI) is an attractive mechanism which can be targeted by vaso-active drugs such as PDE-5 inhibitors. CVR is a potential predictive and pharmacodynamic biomarker for targeted interventions aimed at TMVI. (Trial registration: NCT05782244, ClinicalTrials.gov).

Abstract Context Vascular dysfunction is a common feature in end-organ complications of type 2 diabetes mellitus (T2DM). The endothelium-specific receptor tyrosine kinase Tie2 and its ligand, angiopoietin-1 (Ang1), participate in the processes of vessel repair, renewal, and maturation. However, their dysregulation in T2DM has seldom been investigated. Objectives To examine the relationship between angiogenic Tie2-expressing monocytes (TEMs) and Ang1, and their pharmacological modulation by the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, in T2DM and in db/db mouse model. Design and Setting Randomized, double-blind, placebo-controlled study. Patients and Intervention db/db male mice were randomly assigned to receive 8 weeks of sildenafil or vehicle. Diabetic men were randomly assigned to receive 4 weeks of sildenafil or placebo. Main Outcomes and Measures Peripheral blood cells were investigated by flow cytometry to quantify inflammatory myeloid CD11b+ Gr1+ cells and proangiogenic TEMs in mice and classical CD14++CD16neg monocytes and proangiogenic TEMs in humans at baseline and after treatment. In vitro human tube formation assay was used to test serum angiogenic potential. Results We show that TEMs and Ang1 are defective in mouse and human models of diabetes and are normalized by PDE5i treatment. Serum angiogenic properties are impaired in diabetes because they do not support the in vitro formation of capillary-like structures, but they are reestablished by in vivo PDE5i treatment. Conclusions Restoring a more physiological Tie2-Ang1 axis with sildenafil reestablishes serum angiogenic properties in diabetes, promoting angiogenic homeostasis. Tie2-expressing monocytes and Ang-1 are novel biomarkers linking chronic inflammation to vascular repair impairment in diabetes; their expression can be modulated by PDE5i.

Udenafil is an oral phosphodiesterase-5 inhibitor approved for the treatment of erectile dysfunction. In a multicenter, placebo-controlled, randomized Phase IIa study, the reduction of pulmonary vascular resistance index was greater with a 50-mg baseline dose of udenafil than with the 100-mg dose, the cardiac index did not decrease at most points, and the safety was excellent, suggesting that 50-mg udenafil could be used in a Phase IIb trial. In this 16-week, double-blind, placebo-controlled study, 63 patients with pulmonary arterial hypertension were randomized to receive 50-mg udenafil or a placebo BID. The primary efficacy end point was the 6-min walking distance. The secondary efficacy end points were the Borg dyspnea score and time to clinical worsening. Patients who completed the 16-week study could participate in a long-term extension study. : In terms of the difference between the baseline and 16-week 6-min walking distance in both groups, the mean placebo-corrected treatment effect was 25 (58) m (P = 0.0873). Among the patients with a history of endothelin receptor antagonist therapy, the treatment effect at week 16 between the udenafil and placebo groups was 34 (60) m (P = 0.0460). However, there were no significant differences in the Borg dyspnea score and time to clinical worsening between groups. The safety profile and adverse effects of udenafil were similar to those of typical phosphodiesterase-5 inhibitors seen in previous studies. Udenafil has a favorable safety profile and improves exercise capacity in patients with pulmonary arterial hypertension. ClinicalTrials.gov identifier: NCT01553721.

Sildenafil and tadalafil are efficacious and well tolerated in Chinese men with erectile dysfunction （ED）. Recent study results indicate that men with ED in China who were naive to phosphodiesterase inhibitor type 5 （PDE5） therapy prefer tadalafil 20-mg （on-demand） versus sildenafil 100-mg （on-demand）. Differences in psychosocial outcomes may help to explain treatment preference in favor of tadalafih This open-label, randomized, crossover study compared psychosocial outcomes and drug attribute choices between tadalafil and sildenafil in Chinese men with ED na＇（ve to PDE5 inhibitor therapy. Eligible patients were randomized to sequential 20-mg tadalafU/lOO-mg sildenafil （n = 190） or 100-mg sildenafil/20-mg tadalafil （n = 193） for 8 weeks each and were asked which treatment they preferred to take for the 8-week extension phase. Psychosocial outcomes were assessed using the Psychological and Interpersonal Relationship Scale （PAIRS）, Drug Attributes Questionnaire （DRAQ）, and Sexual Life Quality Questionnaire （SLQQ）. When taking tadalafil versus sildenafil, men had a higher mean endpoint score on the PAIRS Spontaneity Domain （tadalafil = 2.86 vs sildenafil = 2.72; P 〈 0.001）, and a lower mean endpoint score on the Time Concerns Domain （tadalafil = 2.41 vs sildenafil = 2.55; P 〈 0.001）. A numerical increase in the Sexual Self-Confidence Domain was observed when taking tadalafil versus sildenafil （tadalafil -- 2.76 vs sildenafil = 2.72; P= 0.102）. The most frequently chosen drug attributes explaining treatment preference were able to get an erection long after having drug, and ability to get an erection every time. SLQQ results were comparable between treatment groups. These psychosocial outcomes may explain why more Chinese men preferred tadalafil versus sildenafil for the treatment of ED in this clinical trial.