Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension.
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ABSTRACT:
SUBMITTER: Wirostko BM
PROVIDER: S-EPMC3283528 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The burden associated with frequent injections of current intravitreal (IVT) therapeutics may be reduced by long-acting delivery strategies. Binding to serum albumin has been shown to extend the ocular half-life in rabbits, however, the underlying molecular mechanisms and translational relevance remain unclear. The aim of this work was to characterize the in vitro and in vivo formation of complexes between human serum albumin (HSA) and an antigen-binding fragment of a rabbit antibody linked to an anti-HSA nanobody (FabA). The ocular and systemic pharmacokinetics of 3H-labeled FabA (0.05 mg/eye IVT) co-formulated with HSA (1 and 15 nmol/eye) were assessed in Dutch belted rabbits. Next, FabA was incubated in vitreous samples from cynomolgus monkeys and human donors (healthy and diseased) supplemented with species-specific serum albumin. Finally, the FabA-albumin complexes formed in vitro and in vivo were analyzed by radio-size exclusion chromatography. A 3-fold increase in FabA vitreal exposure and half-life was observed in rabbits co-administered with 15 nmol HSA compared to 1 nmol and a control arm. The different pharmacokinetic behavior was explained with the formation of higher molecular weight FabA-albumin complexes. The analysis of vitreous samples revealed the existence of predominantly 1:1 complexes at endogenous or low concentrations of supplemented albumin. A shift towards 1:2 complexes was observed with increasing albumin concentrations. Overall, these results suggest that endogenous vitreal albumin concentrations are insufficient for half-life extension and warrant supplementation in the dosing formulation.
| S-EPMC7559355 | biostudies-literature
Project description:BACKGROUND:This study assessed whether i.v. sildenafil citrate prevented acute kidney injury in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS:In a double-blind RCT, adults at increased risk of acute kidney injury undergoing cardiac surgery in a single UK tertiary centre were randomised to receive sildenafil citrate 12.5 mg kg-1 i.v. over 150 min or dextrose 5% at the commencement of surgery. The primary outcome was serum creatinine measured at six post-randomisation time points. The primary analysis used a linear mixed-effects model adjusted for the stratification variables, baseline estimated glomerular filtration rate, and surgical procedure. Secondary outcomes considered clinical events and potential disease mechanisms. Effect estimates were expressed as mean differences (MDs) or odds ratios with 95% confidence intervals. RESULTS:The analysis population comprised eligible randomised patients that underwent valve surgery or combined coronary artery bypass graft and valve surgery, with cardiopulmonary bypass, between May 2015 and June 2018. There were 60 subjects in the sildenafil group and 69 in the placebo control group. The difference between groups in creatinine concentration was not statistically significant (MD: 0.88 ?mol L-1 [-5.82, 7.59]). There was a statistically significant increase in multiple organ dysfunction scores in the sildenafil group (MD: 0.54 [0.02, 1.07]; P=0.044). Secondary outcomes, and biomarkers of kidney injury, endothelial function, and inflammatory cell activation, were not significantly different between the groups. CONCLUSIONS:These results do not support the use of i.v. sildenafil citrate for kidney protection in adult cardiac surgery. CLINICAL TRIAL REGISTRATION:ISRCTN18386427.
| S-EPMC7271663 | biostudies-literature
Project description:In a previous study, 6-minute walk distance (6MWD) improvement with sildenafil was not dose dependent at the 3 doses tested (20, 40, and 80 mg 3 times daily [TID]). This study assessed whether lower doses were less effective than the approved 20-mg TID dosage.Treatment-naive patients with pulmonary arterial hypertension were randomized to 12 weeks of double-blind sildenafil 1, 5, or 20 mg TID; 12 weeks of open-label sildenafil 20 mg TID followed. Changes from baseline in 6-minute walk distance (6MWD) for sildenafil 1 or 5 mg versus 20 mg TID were compared using a Williams test. Hemodynamics, functional class, and biomarkers were assessed.The study was prematurely terminated for non-safety reasons, with 129 of 219 planned patients treated. At week 12, 6MWD change from baseline was significantly greater for sildenafil 20 versus 1 mg (P?=?0.011) but not versus 5 mg. At week 24, 6MWD increases from baseline were larger in those initially randomized to 20 versus 5 or 1 mg (74 vs 50 and 47 m, respectively). At week 12, changes in hemodynamic parameters were generally small and variable between treatment groups; odds ratios for improvement in functional class were not statistically significantly different. Improvements in B-type natriuretic peptide levels were significantly greater with sildenafil 20 versus 1 but not 5 mg.Sildenafil 20 mg TID appeared to be more effective than 1 mg TID for improving 6MWD; sildenafil 5 mg TID appeared to have similar clinical and hemodynamic effects as 20 mg TID.ClinicalTrials.gov NCT00430716 (Registration date: January 31, 2007).
| S-EPMC5322647 | biostudies-literature
Project description:OBJECTIVE:To study the effect of sildenafil citrate on spontaneous passage of distal ureteric stones (DUS). PATIENTS AND METHODS:This was a randomised double-blinded placebo-controlled study of 100 patients with DUS. Inclusion criteria were: male, age 18-65 years, normal renal function, and a single radiopaque unilateral DUS of 5-10 mm. Patients were randomly allocated into two equal groups, one that received placebo and the other that received 50 mg sildenafil citrate once daily. Both investigators and patients were masked to the type of treatment. Patients self-administered the medication until spontaneous passage of the DUS. In patients where there was uncontrolled pain, fever, an increase in serum creatinine of >1.8 mg/dL, progressive hydronephrosis or no further progress after 4 weeks, a decision was taken for further treatment. RESULTS:In all, 47 and 49 patients were available for analysis in both the placebo and sildenafil citrate groups; respectively. Both groups were comparable for age and stone characteristics. Spontaneous expulsion occurred in 19 of 47 patients (40.4%) in the placebo group and in 33 of 49 (67.3%) in the sildenafil citrate group (P = 0.014). The mean time to stone expulsion was significantly shorter in the sildenafil citrate group (P < 0.001). A multivariable Cox proportional hazards model showed that receiving sildenafil citrate was the only independent factor that had a significant impact on stone passage with a hazard ratio of 2.7 (95% confidence interval 1.5-4.8; P < 0.001). CONCLUSION:Sildenafil citrate enhances spontaneous passage of 5-10 mm DUS.
| S-EPMC4767793 | biostudies-literature
Project description:The aim of our study was to determine whether sildenafil citrate influences the production of Th1- (TNF-α, INF-γ) or Th2-type (TGF-β, IL-10) cytokines by lymphocytes of healthy men. Sildenafil citrate (SC) is a selective blocker of phosphodiesterase 5, by competing for the binding site with cGMP. It was reported that a higher risk of sexually transmitted diseases (STD) could be correlated with a recreational use of sildenafil, especially when combined with another drug. While behavioral causes of these findings are understood, it is worth considering other causes of that phenomenon that might rely on the influence of sildenafil on the immune system. Material and Methods. Peripheral blood mononuclear cells (PBMCs) were isolated from 27 healthy men donors and cultured in the presence of SC at a concentration of 400 ng/ml. The first set of research was performed on cells stimulated, for at least 4 hours, by incubation with phorbol myristate acetate (PMA), ionomycin, and Golgi-Stop. Subsequently, we determined cytokine production in cells stimulated with phytohemagglutinin (PHA) for 12 hours in the presence of Golgi-Stop. Flow cytometry immunophenotyping of PBMC was performed towards the surface marker of T cells: CD3 and intracellular cytokine expression: TNF-α, IFN-γ, TGF-β, and IL-10. Our findings show that SC significantly decreased the percentage of T cells producing TNF-α and displayed tendency to decrease IFN-γ, when stimulated with PMA. Frequent usage of SC might strengthen this effect. That could partially explain the impaired immune response to the pathogens of men using the drug.
| S-EPMC6930755 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a life-threatening disease of varied etiologies. Although PAH has no curative treatment, a greater understanding of pathophysiology, technological advances resulting in early diagnosis, and the availability of several newer drugs have improved the outlook for patients with PAH. Sildenafil is one of the therapeutic agents used extensively in the treatment of PAH in children, as an off-label drug. In 2012, the United States Food and Drug Administration (USFDA) issued a warning regarding the of use high-dose sildenafil in children with PAH. This has led to a peculiar situation where there is a paucity of approved therapies for the management of PAH in children and the use of the most extensively used drug being discouraged by the regulator. This article provides a review of the use of sildenafil in the treatment of PAH in children.
| S-EPMC4943407 | biostudies-other
Project description:BackgroundPulmonary hypertension is a deadly complication of bronchopulmonary dysplasia, the most common pulmonary morbidity of prematurity. Despite these catastrophic consequences, no evidence-based therapies are available for the prevention of pulmonary hypertension in this population. Sildenafil is a potent pulmonary vasodilator approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults. Preclinical models suggest a beneficial effect of sildenafil on premature lungs through improved alveolarization and preserved vascular development. Sildenafil may therefore prevent the development of pulmonary hypertension associated with lung disease of prematurity by reducing pulmonary vascular remodeling and lowering pulmonary vascular resistance; however, clinical trial evidence is needed. The present study, supported by the National Institutes of Health's National Heart Lung and Blood Institute, will generate safety, pharmacokinetics, and preliminary effectiveness data on sildenafil in a population of premature infants with severe bronchopulmonary dysplasia at risk for pulmonary hypertension.MethodsWe have designed a multicenter, randomized, placebo-controlled, sequential dose-escalating, double-masked, safety trial of sildenafil in premature infants with severe bronchopulmonary dysplasia. We will randomize 120 premature infants <?29?weeks gestational age with severe bronchopulmonary dysplasia at 32-40?weeks postmenstrual age in a dose-escalating approach 3:1 (sildenafil: placebo) sequentially into each of 3 cohorts at ~?30 clinical sites. Participants will receive up to 34?days of study drug, followed by 28?days of safety monitoring. The primary outcome will be safety as determined by incidence of hypotension. Secondary outcomes will include pharmacokinetics and preliminary effectiveness of sildenafil based on presence or absence of pulmonary hypertension diagnosed by echocardiography at the end of treatment period.DiscussionSildenafil is a promising intervention to prevent the development of pulmonary hypertension in premature infants with bronchopulmonary dysplasia. Clinical trials of sildenafil specifically designed for premature infants are urgently needed. The current study will make substantial contributions to scientific knowledge of the safety of sildenafil in premature infants at risk for pulmonary hypertension. Results from the study will be used by investigators to inform the design of a pivotal efficacy trial.Trial registrationClinicalTrials.gov NCT04447989 . Registered 25 June 2020.
| S-EPMC7735412 | biostudies-literature
Project description:The aim of this study was to determine whether masked hypertension (MHT) and white coat hypertension (WCHT) could be related to increased arterial stiffness and to identify the best office cutoff values of office BP for the diagnosis of MHT and WCHT. A total of 542 consecutive patients (50.2% male, age 42.5 ± 26.2 years) were included in the study. Patients were never treated before for hypertension. Patients were classified as true normotensives (44%), true hypertensives (30%), WC hypertensives (19%), and masked hypertensives (7%). Carotid-femoral pulse wave velocity (c-f PWV) was 9.91 ± 0.20 m/s in true normotension, 10.26 ± 0.27 m/s in WCHT, 11.28 ± 0.47 m/s in MHT, and 11.86 ± 0.23 m/s in true hypertension after adjustment for age and sex. Decision limits yielding 65% sensitivity were 130 mm Hg for office systolic BP with 72% specificity for the diagnosis of MHT. The optimal cutoff value of 80 mm Hg for office diastolic BP provides 60% sensitivity and 68% specificity. Decision limits yielding 63% sensitivity were 150 mm Hg for office systolic BP with 72% specificity for the diagnosis of WCHT. The optimal cutoff value of 95 mm Hg for office diastolic BP provides 75% sensitivity and 51% specificity. The presence of MHT should be taken into account when increased c-f PWV is detected in the absence of office hypertension. The optimal office BP of 130/80 mm Hg provides the best sensitivity and specificity for the diagnosis of MHT. As regards the diagnosis of WCHT, the cutoff value of 150/95 mm Hg seems to provide the best option.
| S-EPMC8030454 | biostudies-literature
Project description:BACKGROUND: Men with erectile dysfunction (ED) often have low self-esteem, confidence, and sexual relationship satisfaction. OBJECTIVE: We evaluated the impact of sildenafil citrate and its generalizability across cultures on self-esteem, confidence, and sexual relationship satisfaction in men with ED using the Self-Esteem And Relationship (SEAR) questionnaire. DESIGN: Pooled analysis of 2 double-blind, placebo-controlled, flexible-dose trials of sildenafil with identical protocols: 1 was conducted in the United States and the other in Mexico, Brazil, Australia, and Japan. PATIENTS: Men > or = 18 years old with ED. MEASUREMENTS: The impact of treatment on psychosocial factors associated with ED was determined by patient responses to the SEAR questionnaire. Erectile function was determined using the International Index of Erectile Function (IIEF) and a global efficacy question. Successful sexual intercourse attempts were derived from event logs of sexual activity. Treatment effect sizes were calculated for all study outcomes. RESULTS: Compared with patients who received placebo (n = 274), patients who received sildenafil (n = 279) reported significantly greater improvements (P < .0001) in self-esteem, confidence, sexual relationship satisfaction, and in all sexual function domains of the IIEF. Treatment effect sizes were large (range, 0.7 to 1.2) for all SEAR components, and improvement in psychosocial measures showed moderate to high correlations (range, 0.50 to 0.83, P < .0001) with improvement in erectile function, percentage of successful intercourse attempts, and global efficacy. CONCLUSIONS: In men with ED from 5 different nations, sildenafil produced substantial improvements in self-esteem, confidence, and sexual relationship satisfaction. Improvements in these psychosocial factors were observed crossculturally and correlated significantly and tangibly with improvements in erectile function.
| S-EPMC1831645 | biostudies-other
Project description:Purpose To evaluate the long-term safety of latanoprost benzalkonium chloride (BAK)-free vs currently marketed latanoprost 0.005% ophthalmic solution containing BAK (referred to as reference), to treat open-angle glaucoma (OAG) or ocular hypertension (OHT). Patients and Methods This phase 3, multicenter, open-label, nonrandomized, single group assignment, safety study included patients who previously completed a phase 3 noninferiority study. Patients self-administered 1 drop of latanoprost BAK-free nightly for 36 weeks in the affected eye(s). Intraocular pressure (IOP), visual acuity (VA), and slit lamp biomicroscopy were assessed predose at baseline and Days 28, 56, 84, 112, 140, and 168; dilated ophthalmoscopy and visual field (VF) at baseline and Day 168. Adverse events (AEs) were recorded throughout the study. Results A total of 161 patients who previously received latanoprost BAK-free (n = 80) or reference (n = 81) were enrolled. Latanoprost BAK-free maintained lowered IOP for both the study and nonstudy eye in all patients relative to baseline throughout the study. Clinically significant retinal or optic nerve changes were identified in 5 patients (1 mild-to-moderate change, prior latanoprost BAK-free; 4 mild changes, prior reference). No clinically important changes were identified for VA, slit lamp biomicroscopy, and VF measurements. Ocular AEs occurred in 66 (82.5%) vs 74 (91.4%) patients on prior latanoprost BAK-free and reference, respectively; the most frequent being eye pain (50.0% vs 64.2%) and ocular hyperemia (47.5% vs 54.3%). Most AEs were mild. There were 5 serious systemic AEs in 5 patients (n = 3, prior latanoprost BAK-free; n = 2, prior reference); all were considered unrelated or not likely related to treatment. One patient (prior reference) discontinued due to follicular conjunctivitis. There were no deaths or serious ocular AEs. Conclusion Latanoprost BAK-free was well tolerated. These findings support the chronic use of latanoprost BAK-free to treat OAG or OHT. Clinical Trial Registration Number NCT00945958.
| S-EPMC9309311 | biostudies-literature