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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.

Background Congenital diaphragmatic hernia is an orphan disease with high neonatal mortality and significant morbidity. An important cause for this is pulmonary hypertension, for which no effective postnatal therapy is available to date. An innovative strategy aiming at treating or preventing pulmonary hypertension more effectively is urgently needed. Prenatal sildenafil administration to expectant mothers prevented fetal and neonatal vascular changes leading to pulmonary hypertension in several animal models, and is, therefore, a promising approach. Before transferring this antenatal medical approach to the clinic, more information is needed on transplacental transfer and safety of sildenafil in humans. Methods This is a randomized, investigator-blinded, double-armed, parallel-group, phase I/IIb study with as a primary objective to measure the in-vivo transplacental transfer of sildenafil in women in the second and early third trimester of pregnancy (sub-study 1; weeks: 20.0–32.6) and at term (sub-study 2; weeks: 36.6–40). Participants will be randomized to two different sildenafil doses: 25 or 75 mg. In sub-study 1, a single dose of the investigational product will be administered to women undergoing termination of pregnancy, and maternal and fetal blood samples will be collected for determination of sildenafil concentrations. In sub-study 2, sildenafil will be administered three times daily from 3 days before planned delivery until actual delivery, following which maternal and umbilical cord samples will be collected. Proxies of maternal and fetal tolerance as well as markers of fetal pulmonary vasodilation will also be measured. Discussion This is the first study evaluating in-vivo transplacental passage of sildenafil in humans. Trial registration EU Clinical Trials Register 2016–002619-17, validated on 12 August 2016. Trial sponsor: UZ Leuven, Herestraat 49, 3000 Leuven.

Background The management of severe persistent pulmonary hypertension (PPHN) can be very challenging in many resource-limited centers without access to inhaled nitric oxide or extracorporeal membrane oxygenation. Objectives The current study aimed to investigate the efficacy of oral sildenafil and intravenous milrinone infusion and compare the effects of these drugs in combination versus as monotherapy in neonates with PPHN. Methods A double-blind randomized controlled trial was conducted in which neonates with PPHN were divided into three groups of 20 patients each: group 1 received oral sildenafil starting at 0.5 mg/kg every 6 h to a target maintenance dose of 2 mg/kg every 6 h; group 2 received intravenous milrinone 0.5 g/kg/min as a continuous infusion; and group 3 received both oral sildenafil and intravenous milrinone. Results Post-treatment pulmonary artery systolic pressure was significantly lower in group 3 than in groups 1 and 2, which both received monotherapy (p = 0.031). The oxygenation index also decreased significantly in the dual-therapy group (p = 0.002) compared with the monotherapy groups. Combined use of both drugs demonstrated a beneficial synergistic effect with better outcomes and reduced mortality. Conclusion Dual therapy using sildenafil and milrinone was superior to monotherapy with either drug in neonates with severe PPHN and is recommended for use in resource-constrained settings. Registration Pan African Clinical Trial Registry identifier number PACTR201902691230243.

Background Sildenafil is the drug of choice for neonatal pulmonary hypertension in developing countries where inhaled nitric oxide is not available. Available as oral and intravenous preparation – no study has been done in the past to compare the two forms. Each has its own benefits – but requires comparison in terms of efficacy and safety. This study was done to compare the efficacy of oral versus intravenous (IV) sildenafil in infants with mild to moderate pulmonary hypertension. Methods An open labelled randomized trial was conducted in a neonatal intensive care unit of urban tertiary hospital in western India between February 2019 to December 2020. Infants born after 34 weeks of gestation with Pulmonary arterial pressure (PAP) > 25 mm Hg measured by echocardiography, within 72 h of birth, were enrolled for the study. Participants were randomly assigned to receive sildenafil either orally or by intravenous route. Primary outcome was the time taken for PAP to decrease below 25 mm Hg. Secondary outcomes were time taken for oxygenation index to decrease by 25%, duration of invasive and non-invasive mechanical ventilation, nasal oxygen, hospital stay, time to achieve full feeds, mortality, and side effects. Results Forty patients were enrolled. The baseline characteristics of neonates in both groups were similar except for APGAR scores at 1 min and 5 min, with oral group having lower score [MEDIAN (IQR) 5.00 (4.00- 7.00) and 7.00 (6.00- 8.00)] compared to IV group [MEDIAN (IQR) 7.00 (6.00–8.00) and 9.00 (8.00–9.00)] respectively. Time taken for PAP to decrease below 25 mm was not statistically different between the oral and intravenous groups. Systemic hypotension occurred in 4 neonates of the intravenous group but none in the oral group. Conclusion Oral and intravenous sildenafil had equal efficacy at reducing PAP in neonatal pulmonary hypertension, albeit intravenous sildenafil use was associated with a greater complication rate. Trial registration Trial was registered in the clinical trials registry of India [ CTRI/2019/04/018781 ][25/04/2019].

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.

Background Intraoperative blood loss (IBL) is the major concern in hepatectomy, which was closely relating to the central venous pressure (CVP). The controlled low central venous pressure (CLCVP) technique is moderately required for minimizing hemorrhage during hepatectomy nowadays. Nevertheless, an excessive reduction in CVP might give rise to the jeopardy of inadequate perfusion of vital organs. Sildenafil, being a first-line pharmaceutical for treating pulmonary hypertension, its mechanism of action lies in diminishing pulmonary vascular resistance (PVR) by dilating pulmonary arteries, and thereby alleviating the afterload of the right ventricle. We initially postulate that administration of sildenafil citrate in combination with intermittent Pringle’s maneuver (IPM) can exert a notable impact in efficaciously reducing intraoperative blood loss (IBL), enhancing the surgical field of vision, and augmenting the safety of the operation. Methods This research constitutes a double-blind, randomized, controlled trial. All patients fulfilling the criteria for open or laparoscopic hepatectomy will be randomly allocated to the sildenafil (S) group and the placebo (C) group via the block randomization approach. All surgeons, anesthesiologists, and outcome assessors will remain oblivious to the patient’s group details. The primary outcome is the intraoperative blood loss (IBL). Secondary outcomes include the classification of the surgical field, the cumulative consumption of nitroglycerine, hemodynamic parameters, blood gas analysis, coagulation function (comprising thromboelastogram (TEG), activated partial thromboplastin time (APTT), and prothrombin time (PT)), intraoperative urine output, adverse events in the recovery room (hypotension, hypoxemia and hematuria), biochemical markers (total bilirubin, total albumin, alanine aminotransferase, aspartate aminotransferase, creatinine, urea nitrogen), complete blood count (Hb, Plt, and Hct), cardiac function (brain natriuretic peptide, creatine kinase isoenzyme, troponin), postoperative hospital stay and indwelling time of drainage tube, and postoperative complications. These parameters will be comprehensively compared and analyzed in-depth through appropriate statistical means. Discussion This trial evaluated the influence of administration of sildenafil citrate combined with IPM on IBL and surgical results during open or laparoscopic hepatectomy, as well as its safety and feasibility. It is expected to provide an innovative management optimization plan for reducing the bleeding in hepatectomy, and to provide empirical support for the potential value of sildenafil citrate or sildenafil-like drugs in improving the safety and quality of perioperative hepatectomy patients. Trial registration This trial was registered on June 25, 2024, in the US Clinical Trials Registry ( https://register.clinicaltrials.gov ), with the ClinicalTrial.gov Identifier: NCT06237751. The protocol version is V1.0 (20,231,114).

Background Access to inhaled nitric oxide (iNO) is limited in low resource settings due to non-availability and high cost. There is a need for research on low-cost alternative therapies for management of persistent pulmonary hypertension of the newborn (PPHN). We aimed to compare oral sildenafil and bosentan as monotherapy in the treatment of neonates with PPHN. Study design In this single-centre open-label randomized controlled trial (RCT), term and late preterm neonates with PPHN, defined as pulmonary arterial systolic pressure (PASP) > 35 mmHg and requiring fraction of inspired oxygen (FiO 2 ) > 0.21, were randomized to receive oral sildenafil and bosentan. The primary outcome was reduction of PASP by 25% within 48 h after start of drug. Results Thirty-six neonates were analyzed (18 in each group). Initial PASPs were similar in both groups. The median (IQR) time for the primary outcome (PASP to reduce by 25% within 48 h) was 36 (24–48) h and 96 (48–120) h in sildenafil and bosentan groups respectively ( p  = 0.008). There was also a higher need to add other pulmonary vasodilators in bosentan group as compared to sildenafil group ( p  = 0.006). Conclusion Sildenafil was associated with quicker reduction of PASP and FiO 2 in neonates with PPHN, as compared to bosentan. Large multicentre blinded trials to assess efficacy and safety of bosentan in comparison with other pulmonary vasodilators would help to get a clearer understanding of its role in the management of PPHN, particularly for use in resource-limited settings that lack iNO. Clinical trial registration: https://ctri.nic.in/Clinicaltrials/rmaindet.php? trialid=63997&EncHid=39716.16132&modid=1&compid=19[CTRI/2022/06/043328].

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.

Despite its established inter-individual variability, sildenafil has been the subject of only a few pharmacogenetic investigations, with limited data regarding the genetic modulators of its pharmacokinetics. We conducted a pharmacogenetic sub-study of patients randomized to sildenafil (n=85) in the RELAX trial, which investigated the impact of high-dose sildenafil in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). In the overall population, the CYP3A4 inferred phenotype appeared associated with the dose-adjusted peak concentrations of sildenafil at week 12 and week 24 (adjusted P=0.045 for repeated measures analysis), although this P-value did not meet our corrected significance threshold of 0.0167. In the more homogeneous Caucasian subgroup, this association was significant (adjusted P=0.0165 for repeated measures). Hence, CYP3A4 inferred phenotype is associated with peak sildenafil dose-adjusted concentrations in patients with HFpEF receiving high doses of sildenafil. The clinical impact of this association requires further investigation.

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.