Sildenafil Therapy Research Articles

Association of FOXO3A Polymorphisms with Hematocrit, LDH and Longevity in Patients with Sickle Cell Anemia from CSSCD, Walk-Phasst, and PUSH Clinical Trials

BackgroundThe FOXO3A genotype is strongly associated with longevity in humans. It encodes a transcription factor that appears to regulate anti-oxidant genes during erythroid differentiation in mice, resulting in a hemolytic anemia. The gene has also been implicated in the regulation of fetal hemoglobin expression in children with sickle cell disease. We performed a gene-wide association study to identify and replicate variants of FOXO3A that might be associated with seven biomarkers in patients with sickle cell anemia.Methods1198 patients from the Cooperative Study of Sickle Cell Disease (CSSCD) study, 308 patients from the Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (walk-PHaSST) study, and 220 patients from the Pulmonary Hypertension and the Hypoxic Response in Sickle Cell Disease (PUSH) study were analyzed. Biomarkers included hematocrit, reticulocyte count, fetal hemoglobin (HbF), serum levels of lactate dehydrogenase (LDH), aspartate aminotransferase and bilirubin, and the calculated hemolytic component, each appropriately transformed to achieve normality. A total of 189 single nucleotide polymorphisms (SNP) that were either genotyped or imputed (quality r2 > 0.9) were used. Association between each biomarker and SNP was tested using linear regression assuming an additive genetic model, adjusted for age and sex. None of the patients in the CSSCD were treated with hydroxyurea at the time of measurements of the biomarker variables. In the Walk-PHaSST and PUSH, we first examined whether there was a significant association between the biomarker and treatment effect of hydroxyurea; if there was a significant treatment effect, then we looked at potential SNP-by-treatment interaction. For those with significant interactions, only patients without hydroxyurea treatment were included in the analysis. The genetic analysis results from the three studies were then combined to produce meta-analyzed results. Finally, a survival analysis using Cox regression was performed to model age at death in a subset of 54 patients in the CSSCD.ResultsAmong the seven biomarkers, hematocrit showed the most robust enrichment of associations with FOXO3A SNPs. Eight of the 16 published variants had meta-analyzed p-value <0.05. Of those, six had a consistent direction of effects across all three cohorts. Overall, there were 8 loci with 34 SNPs that had meta-analyzed p<0.05 in hematocrit. The most significantly associated SNP (rs6911407; meta-analyzed Beta=-0.0127, meta-analyzed p=0.0013) is one previously associated with human longevity. LDH was most significantly associated with variant rs12206094 (meta-analyzed Beta=0.0256, meta-analyzed p=0.0072), another SNP previously associated with human longevity. Four of the allelic variants associated with LDH were also associated with hematocrit in the appropriate direction. There were also some evidence of enrichment of associations with reticulocyte counts (2 loci with 22 SNPs), HbF (1 locus with 11 SNPs; 10 SNP associations overlapped with reticulocyte count in the appropriate direction), and hemolytic component (2 loci with 8 SNPs); however, the strengths of associations in these biomarkers were marginal (0.01<p<0.05). The survival analysis revealed one locus significantly associated with age at death in the CSSCD patients (rs2802297; p=0.028).ConclusionFOXO3A genetic polymorphisms are associated with hematocrit and serum LDH in this meta-analysis of patients with sickle cell anemia, with less robust associations with fetal hemoglobin level and reticulocyte count. Our genetic findings are biologically consistent with published knockout mouse data indicating that FOXO3A regulates red cell antioxidant capacity and hemolytic severity. Our observation of fetal hemoglobin association with FOXO3A helps to validate previously presented results from Sheehan and colleagues. Parallel to well-documented results in the general population, we find preliminarily that a FOXO3A allelic variant predicts longevity in patients with sickle cell anemia. FOXO3A appears to play a significant role in phenotypic variation in sickle cell anemia. DisclosuresNo relevant conflicts of interest to declare.

Effects of Two Different Dosages of Sildenafil on Patients With Erectile Dysfunction.

To investigate the effects of two different dosages of sildenafil on patients with erectile dysfunction (ED), a total of 3,674 patients with ED were recruited to answer questionnaires designed specifically for this study. There were 977 patients in the 50 mg group and there were 2,697 patients in the 100 mg group. Both 50 mg and 100 mg of sildenafil therapy increased the ED patients' average monthly frequency of sexual intercourse, improved erectile function state in self-assessment, and elevated sexual satisfaction and enjoyment. Despite a higher rate of concomitant diseases, patients in the higher dosage of sildenafil group had a better outcome in the average monthly frequency of sexual intercourse and sexual enjoyment compared with those in the lower dosage. Such a study might be helpful for health care providers to choose sildenafil dosage for patients with ED.

Editorial: Pediatric Pulmonary Hypertension.

Editorial: Pediatric Pulmonary Hypertension.

Assessment of short term effects of sildenafil therapy in patients with secondary pulmonary hypertension

Assessment of short term effects of sildenafil therapy in patients with secondary pulmonary hypertension

Assessment of short term effects of sildenafil therapy in patients with secondary pulmonary hypertension

Assessment of short term effects of sildenafil therapy in patients with secondary pulmonary hypertension

Sildenafil reduces signs of oxidative stress in pulmonary arterial hypertension: Evaluation by fatty acid composition, level of hydroxynonenal and heart rate variability

Pulmonary arterial hypertension (PAH) is a rare multifactorial disease with an unfavorable prognosis. Sildenafil therapy can improve functional capacity and pulmonary hemodynamics in PAH patients. Nowadays, it is increasingly recognized that the effects of sildenafil are pleiotropic and may also involve changes of the pro-/antioxidant balance, lipid peroxidation and autonomic control. In present study we aimed to assess the effects of sildenafil on the fatty acids (FAs) status, level of hydroxynonenal (HNE) and heart rate variability (HRV) in PAH patients. Patients with PAH were characterized by an increase in HNE and changes in the FAs composition with elevation of linoleic, oleic, docosahexanoic acids in phospholipids as well as reduced HRV with sympathetic predominance. Sildenafil therapy improved exercise capacity and pulmonary hemodynamics and reduced NT-proBNP level in PAH. Antioxidant and anti-inflammatory effects of sildenafil were noted from the significant lowering of HNE level and reduction of the phopholipid derived oleic, linoleic, docosahexanoic, docosapentanoic FAs. That was also associated with some improvement of HRV on account of the activation of the neurohumoral regulatory component. Incomplete recovery of the functional metabolic disorders in PAH patients may be assumed from the persistent increase in free FAs, reduced HRV with the sympathetic predominance in the spectral structure after treatment comparing to control group. The possibilities to improve PAH treatment efficacy through mild stimulation of free radical reactions and formation of hormetic reaction in the context of improved NO signaling are discussed.

Abstract 14023: Insulin-like Growth Factor-binding Protein 7 as a Biomarker of Diastolic Dysfunction and Functional Capacity: Results From the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction (RELAX) Trial

Introduction: Insulin-like growth factor-binding protein 7 (IGFBP7) was previously found to be associated with diastolic function in heart failure (HF) with reduced ejection fraction (EF), but it is unclear whether such associations exist in HF with preserved EF (HFpEF), where diastolic function is of pivotal importance. Hypotheses: Baseline (BL) and change (Δ) in IGFBP7 will be significantly associated and correlated with BL and Δ in diastolic indices as well as peak oxygen consumption (VO2 max ) in patients with HFpEF. IGFBP7 will decrease with sildenafil therapy. Methods: At BL and 6 months (6M), IGFBP7, imaging studies, and VO2 max were obtained and compared in 160 HFpEF patients randomized to sildenafil or placebo. Results: Patients with supramedian BL IGFBP7 concentrations (&gt;219 ng/mL) were more likely to be older, to have more congestion and worse renal function, and to have elevated concentrations of several emerging or established HF biomarkers including amino-terminal pro-B-type natriuretic peptide, cystatin C, and highly sensitive troponin (all P&lt;0.05). Higher BL IGFBP7 was correlated with indices of worse diastolic function, including higher E velocity (ρ=0.395, P&lt;0.001), E/e’ (ρ=0.398, P&lt;0.001), left atrial volume index (ρ=0.386, P&lt;0.001), right ventricular systolic pressure (RVSP; ρ=0.413, P&lt;0.001), and transmitral E/A (ρ=0.258, P=0.006). IGFBP7 was also inversely correlated with aortic distensability (ρ= -0.301, P=0.02). There was no association or correlation with measures of systolic function. Notably, in analyses adjusted for respective baseline variables, ΔIGFBP7 was significantly correlated with Δ in E (ρ=0.114), E/A (ρ=0.225), E/e’ (ρ=0.174), and RVSP (ρ=0.282; all P&lt;0.03). Elevated BL IGFBP7 was associated with lower BL VO2 max (13.2 versus 11.1 mL/min/kg; P&lt;0.001) and ΔIGFBP7 was inversely correlated with ΔVO2 max (ρ=-0.19, P=0.01). Subjects receiving sildenafil had a decrease in IGFBP7 over 6M in contrast to placebo-treated patients (median ΔIGFBP7 -1.5 versus +13.6 ng/mL; P&lt;0.001). Conclusions: In patients with HFpEF, concentrations of IGFBP7 have unique relationships with measures of diastolic dysfunction and VO2 max . Rise in IGFBP7 may reflect worsening diastology and deteriorating VO2 max .

Sildenafil and retinopathy of prematurity risk in very low birth weight infants.

ObjectiveTo examine the effect of sildenafil therapy on development of severe retinopathy of prematurity (ROP) requiring surgical intervention in premature infants.Study DesignWe identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care units from 2003–2012 and who received an ophthalmologic exam. We matched each infant exposed to sildenafil prior to first eye exam to three non-exposed infants using propensity scoring to control for differences in baseline infant characteristics. We evaluated the association between sildenafil exposure and development of severe ROP using conditional logistic regression.ResultOf the 57815 infants meeting inclusion criteria, 88 were exposed to sildenafil. We matched 81/88 (92%) sildenafil-exposed with 243 non-exposed infants. There was no difference in the proportion of infants who developed severe ROP in the sildenafil-exposed vs. non-exposed groups (17/81 [21%] vs. 38/243 [16%], P=0.27). On adjusted analysis, there was no difference in severe ROP in the sildenafil-exposed versus non-exposed infants (odds ratio=1.46, 95% confidence interval=0.76–2.82, P=0.26).ConclusionWe did not observe an association between risk of severe ROP and sildenafil exposure prior to first eye exam in this cohort of premature infants.

Sildenafil treatment attenuates ventricular remodeling in an experimental model of aortic regurgitation.

BackgroundCurrently there is no reliable medical treatment for aortic regurgitation (AR).MethodsThirty-nine Sprague–Dawley rats underwent creation of AR or sham operation. Treated rats were assigned to early or late institution of sildenafil therapy (100 mg/kg/day) for a total of 10 weeks. Treatment–effects were measured by serial echocardiography, invasive hemodynamic measurements, and tissue analysis.ResultsRats assigned to early treatment developed less remodeling than untreated rats. Thus, left ventricular (LV) dilation was blunted by sildenafil with end–systolic diameter being significantly smaller (6.6 ± 0.4 vs. 7.7 ± 0.4 mm, respectively, p < 0.05). Also, LV wall thickness was significantly decreased in treated rats compared to controls (2.23 ± 0.08 vs. 2.16 ± 0.05 mm, p < 0.01). Fractional shortening was improved by treatment (p < 0.05). Myocardial fibrosis was borderline decreased by treatment (p = 0.09). Akt was increased in treated compared to controls (p < 0.05).ConclusionSildenafil slightly inhibits LV remodeling and improves fractional shortening in rats with AR when treatment is initiated early.

Effect of Treatment With Sildenafil (A Phosphodiesterase-5 Inhibitor) on Cognitive Functions and Health-Related Quality of Life in Patients With Cirrhosis Who Have Minimal Hepatic Encephalopathy

Introduction: Patients with minimal hepatic encephalopathy (MHE) have cognitive impairment. Animal studies have shown that the learning impairment is the result of alteration in Glutamate-nitric oxide-cyclical guanosine monophosphate pathway (Glu-NO-cGMP). Enhancement of cGMP levels with phosphodiesterase 5 inhibitors (sildenafil) has been shown to restore cognitive function in rats with MHE (Eur J Neurosci 2007;25:2103-2111). We performed this study to assess the efficacy and safety of sildenafil in improvement of cognition and health-related quality of life (HRQOL) in patients with MHE. Methods: A prospective, open label, interventional study was conducted in randomly divided 50 male patients (age, 18-70 yr); 25(52%) patients received treatment with sildenafil (MHE-S), while 24(48%) did not (MHE-NS). All patients in both groups were analyzed for - cognition by psychometric hepatic encephalopathy score (PHES), HRQOL by sickness impact profile (SIP), liver disease severity by Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores, and ammonia and interleukin (IL)-6 levels at inclusion into the study and after 4 weeks of follow-up. Results: There was no significant difference in change in PHES (ΔPHES) between 2 visits in both groups [MHS-S, mean (95% CI) 1.57 (0.54-2.60); MHE-NS, 1.66 (0.44-2.89); P=0.73]. There was also no significant difference in change in SIP (ΔSIP) between 2 visits in MHE-S group as compared to the MHE-NS group [MHS-S, 1.89 (0.36-3.41); MHE-NS, 3.50 (1.12-5.86); P=0.28]. There was no significant change in ammonia levels (μmol/dL) in MHE-S group [baseline, 149.3(129.1-169.6 versus 4 week, 136.8 (118.9-154.7); P=0.13), while there was significant increase in MHE-NS group [baseline, 119.5 (105.0-134.0) versus 4 week, 136.81(118.9-154.7); P=0.01). There was no significant change in IL-6 levels (ng/mL) in MHE-S (P=0.68) and MHE-NS groups (P=0.66). There was also no significant change in CTP and MELD scores in MHE-S and MHE-NS groups (P=NS). Patients in MHE-S group had higher incidence of flushing as compared to the MHE-NS (χ2 = 8.55, P=0.003). However, there were no major side effects noted during the study period. Conclusion: This study did not show improvement in cognitive and HRQOL parameters, ammonia and IL-6 levels and liver disease severity as measured by CTP and MELD scores with sildenafil therapy in cirrhotic patients with MHE. Sildenafil use in cirrhotic patients is safe. (ClinicalTrials.gov Identifier: NCT02028429).

Acute resolution of pulmonary alveolar infiltrates in 10 dogs with pulmonary hypertension treated with sildenafil citrate: 2005–2014

ObjectiveTo describe clinical canine patients with naturally occurring pulmonary hypertension and radiographic pulmonary alveolar infiltrates before and after treatment with sildenafil. AnimalsTen client-owned dogs. MethodsA retrospective analysis of dogs with echocardiographically-determined pulmonary hypertension and pulmonary alveolar infiltrates on thoracic radiographs was performed before (PRE) and after (POST) sildenafil therapy. Clinical scores, pulmonary alveolar infiltrate scores and tricuspid regurgitation gradients were analyzed PRE and POST sildenafil. ResultsPulmonary alveolar infiltrates associated with pulmonary hypertension developed in a diffusely patchy distribution (10/10). Sixty percent of dogs had a suspected diagnosis of interstitial pulmonary fibrosis as the etiology of pulmonary hypertension. Median PRE clinical score was 4 (range: 3–4) compared to POST score of 0 (0–2) (p = 0.005). Median alveolar infiltrate score PRE was 10 (5–12) compared to POST score of 4 (0–6) (p = 0.006). Median tricuspid regurgitation gradient PRE was 83 mmHg (57–196) compared to 55 mmHg POST (33–151) (p = 0.002). ConclusionsA subset of dogs with moderate to severe pulmonary hypertension present with diffuse, patchy alveolar infiltrates consistent with non-cardiogenic pulmonary edema. The typical clinical presentation is acute dyspnea and syncope, often in conjunction with heart murmurs suggestive of valvular insufficiency. This constellation of signs may lead to an initial misdiagnosis of congestive heart failure or pneumonia; however, these dogs clinically and radiographically improve with the initiation of sildenafil.

Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

Intravascular hemolysis and hemoglobinuria are associated with sickle cell nephropathy. ApoL1 is involved in cell-free hemoglobin scavenging through association with haptoglobin-related protein. APOL1 G1/G2 variants are the strongest genetic predictors of kidney disease in the general African-American population. A single report associated APOL1 G1/G2 with sickle cell nephropathy. In 221 patients with sickle cell disease at the University of Illinois at Chicago, we replicated the finding of an association of APOL1 G1/G2 with proteinuria, specifically with urine albumin concentration (β=1.1, P=0.003), observed an even stronger association with hemoglobinuria (OR=2.5, P=4.3×10(-6)), and also replicated the finding of an association with hemoglobinuria in 487 patients from the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy study (OR=2.6, P=0.003). In 25 University of Illinois sickle cell disease patients, concentrations of urine kidney injury molecule-1 correlated with urine cell-free hemoglobin concentrations (r=0.59, P=0.002). Exposing human proximal tubular cells to increasing cell-free hemoglobin led to increasing concentrations of supernatant kidney injury molecule-1 (P=0.01), reduced viability (P=0.01) and induction of HMOX1 and SOD2. HMOX1 rs743811 associated with chronic kidney disease stage (OR=3.0, P=0.0001) in the University of Illinois cohort and end-stage renal disease (OR=10.0, P=0.0003) in the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy cohort. Longer HMOX1 GT-tandem repeats (>25) were associated with lower estimated glomerular filtration rate in the University of Illinois cohort (P=0.01). Our findings point to an association of APOL1 G1/G2 with kidney disease in sickle cell disease, possibly through increased risk of hemoglobinuria, and associations of HMOX1 variants with kidney disease, possibly through reduced protection of the kidney from hemoglobin-mediated toxicity.

Efficacy of inhaled nitric oxide combined with oral sildenafil on persistent pulmonary hypertension in the newborn infants

Objective To evaluate the effects of inhaled nitric oxide(iNO) combined with oral sildenafil therapy in the newborn infants with persistent pulmonary hypertension(PPHN). Methods Forty-six neonates with PPHN were devided into group A(n=23) and group B(n=23). The combined treatment of iNO and oral sildenafil was used in group A, and iNO was used in group B. During the therapy, the following factors were monitored: blood gas analysis, systolic blood pressure(SBP), systolic pulmonary artery pressure(SPAP), inspired oxygen fraction(FiO2), iNO concentration, iNO duration, ventilation time and hospital stay.The effective rate, mortality and the risk of pneumothorax, intraventricular hemorrhage, pulmonary hemorrhage, bronchopulmonary dysplasia were compared between the two groups.All patients were treated in the same neonatal unit and received the same standard therapy throughout the study period. Results The effective rates of group A and group B were 87.0%(20/23) and 78.3%(18/23) respectively.There was no significant difference between the two groups(χ2=0.15, P>0.05). The levels of SPAP/SBP decreased significantly, and the levels of PaO2/FiO2 rised significantly at baseline 30 min, 6 h and after the treatment.But there were no significant differences between the two groups(P>0.05). In group A, the iNO concentration stared at ≤15×10-6 for 14 infants, >15×10-6 for 6 infants, which were lower than those in the group B(χ2=6.71, P<0.05). The iNO would be stopped when the concentration reached 40×10-6 without any sign of improvement.Compared to group B, the duration of iNO[(57.3±27.8)h vs.(87.7±47.0) h], the ventilation time[(94.44±31.88)h vs.(123.20±47.43) h], and the time of hospital stay[(14.55±3.19) d vs.(18.78±4.60) d]in group A were shorter(P<0.05), whereas the mortality and the incidence of pneumothorax, intraventricular hemorrhage, pulmonary hemorrhage and bronchopulmonary dysplasia had not significantly differences between the two groups. Conclusion The effects of iNO combined with oral sildenafil in the newborn infants with PPHN was same compared to iNO.But it can effectively reduced the iNO concentration and shorten the duration of iNO, the ventilation time and the hospital stay without augmentation of risk of mortality, pneumothorax, intraventricular hemorrhage, pulmonary hemorrhage, bronchopulmonary dysplasia in neonatal patients. Key words: Nitric oxide; Sildenafil; Persistent pulmonary hypertension; Newborn

Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension.

The safety and efficacy of adding bosentan to sildenafil in pulmonary arterial hypertension (PAH) patients was investigated.In this prospective, double-blind, event-driven trial, symptomatic PAH patients receiving stable sildenafil (≥20 mg three times daily) for ≥3 months were randomised (1:1) to placebo or bosentan (125 mg twice daily). The composite primary end-point was the time to the first morbidity/mortality event, defined as all-cause death, hospitalisation for PAH worsening or intravenous prostanoid initiation, atrial septostomy, lung transplant, or PAH worsening. Secondary/exploratory end-points included change in 6-min walk distance and World Health Organization functional class at 16 weeks, change in N-terminal pro-brain natriuretic peptide (NT-proBNP) over time, and all-cause death.Overall, 334 PAH patients were randomised to placebo (n=175) or bosentan (n=159). A primary end-point event occurred in 51.4% of patients randomised to placebo and 42.8% to bosentan (hazard ratio 0.83, 97.31% CI 0.58-1.19; p=0.2508). The mean between-treatment difference in 6-min walk distance at 16 weeks was +21.8 m (95% CI +5.9-37.8 m; p=0.0106). Except for NT-proBNP, no difference was observed for any other end-point. The safety profile of bosentan added to sildenafil was consistent with the known bosentan safety profile.In COMPASS-2, adding bosentan to stable sildenafil therapy was not superior to sildenafil monotherapy in delaying the time to the first morbidity/mortality event.

Clinical case: combination therapy with iloprost and sildenafil in the treatment of idiopathic pulmonary hypertension

Idiopathic pulmonary arterial hypertension is a rare disease with unknown etiology, characterized by progressive increase in pulmonary vessel resistance, right heart failure. Combined pathogenetic therapy using leads to depression of disease progression, repeated hospitalization, improvement in disease prognosis in patients with III-IV functional class (WHO).The patient with diagnosis of idiopathic pulmonary arterial hypertension, verified by right heart catheterization method, functional class III (WHO) was treated by anticoagulants, diuretics. There were observed the negative dynamic with right heart chambers dilation, appearing of heart failure signs during the treatment with phosphodiesterase type 5-inhibitor sildenafil. After adding an inhaled form of prostanoids-iloprost to sildenafil therapy there was achieved the significant improvement of the functional and hemodynamic status. Reduction in dyspnoea level, improvement in physical activity tolerance and disease prognosis were reached.

Resveratrol and sildenafil synergistically improve diabetes-associated erectile dysfunction in streptozotocin-induced diabetic rats.

Despite effective control of blood glucose levels in diabetic patients, complaints of diabetes-associated erectile dysfunction (ED) persist. Resveratrol has been indicated to possess anti-diabetic effects and therapeutic potential for ED. This study was conducted to observe the effect of resveratrol alone or in combination with sildenafil on ED in streptozotocin (STZ)-induced diabetic rats. Among 58 adult male STZ-induced (60 mg/kg) diabetic Sprague-Dawley rats, 48 STZ-induced diabetic rats were randomized equally to four groups: untreated diabetic rats, resveratrol (25mg/kg), sildenafil (5mg/kg) or resveratrol (25mg/kg) plus sildenafil (5mg/kg) through oral gavage for 8 weeks. Additionally, 12 age-matched rats were chosen as controls. Intracavernous pressure (ICP) and mean arterial blood pressure (MAP) were used to measure erectile function. The cavernous level of cyclic guanosine monophosphate (cGMP), protein and mRNA of endothelial NO synthase (eNOS), neuronal NOS (nNOS), and phosphodiesterase-5 (PDE5) was measured. Treatment with either resveratrol or sildenafil improved ICP/MAP compared to the untreated diabetic rats (P<0.05). Treatment with resveratrol increased nNOS and eNOS expression, inhibited PDE5 expression, and increased the cavernous cGMP level compared to the untreated diabetic rats. Resveratrol significantly decreased superoxide anion and ROS production. Two-way ANOVA indicated that resveratrol in combination with sildenafil therapy had a significant synergistic effect in improving ICP/MAP and cavernous cGMP levels. Resveratrol improves diabetes-associated ED in rats. Combination therapies with resveratrol and sildenafil have a synergistic effect in improving ED. The mechanisms might be attributed to its anti-oxidative properties and NO-cGMP signaling pathway upregulation.

Caution is recommended prior to sildenafil use in vascular anomalies.

Since publication of a single case report of lymphatic malformation improvement during sildenafil therapy for pulmonary hypertension, sildenafil use has propagated across multiple vascular anomalies diagnoses. Vascular anomalies are rare conditions, often with poor long-term outcomes from available therapies, making these patients vulnerable to novel therapy use. We have retrospectively reviewed 14 children with vascular anomalies treated with sildenafil. None of these patients reported improvement of disease while on treatment and some reported side effects including infections and bleeding. Pending more convincing prospective data, we recommend caution prior to sildenafil use for vascular anomalies.

Sildenafil therapy in bronchopulmonary dysplasia-associated pulmonary hypertension: a retrospective study of efficacy and safety.

Bronchopulmonary dysplasia (BPD) is associated with a high incidence of pulmonary artery hypertension (PAH) and is frequently treated with sildenafil. The objective was to investigate the echocardiographic and clinical efficacy and safety of sildenafil in this setting. The hypothesis was that treatment would result in significant echocardiographic and clinical improvements. This was a retrospective study of the cohort of infants who were born between 2004 and 2012 and administered sildenafil as in-patients for BPD-associated PAH. Medical records and archived echocardiographic data were reviewed. Twenty-two infants fulfilled the inclusion criteria and had a mean (±SD) gestation age and birth weight of 25.6 (±1.3) weeks and 631 (±181) g, respectively. Six (27 %) infants died before discharge (predominantly due to respiratory failure; in three of them, a concomitant viral respiratory infection was thought to be an aggravating factor). Amongst survivors, no mortality was noted up to 1 year follow-up. Significant improvement in echocardiographic markers of pulmonary hypertension was noted in the echocardiogram performed 27.5 days (interquartile range 24, 31) post-initiation of therapy, two thirds showing ≥20 % decline in the right ventricular systolic pressure. Left ventricular fractional shortening did not alter significantly. At initiation, all infants had 'severe' BPD. The fraction of inspired oxygen (FiO2) decreased significantly from 0.57 (SE ± 0.05) to 0.42 (SE ± 0.03) (p = 0.02), and no significant alteration was noted over the timeframe in mean pCO2 (64.4 ± 3.3 to 63.2 ± 3.3 mmHg). The number of infants needing endotracheal intubation and mechanical ventilation decreased (from 3 to 1) over the same time. No serious adverse effects were noted. Sildenafil therapy was associated with a significant improvement in the echocardiographic markers of PAH and a reduction in FiO2. The medication was well tolerated.

Traffic Light: prognosis-based eligibility for clinical trials of hematopoietic SCT in adults with sickle cell anemia.

Estimating prognosis in sickle cell anemia (SCA) assumes greater importance as intensive treatments, such as hematopoietic SCT (HSCT), are being tested. Here we estimate the mortality risk from the walk-PHaSST (Sildenafil Therapy for Pulmonary Hypertension and Sickle Cell Disease) trial of homozygous SCA patients with suspected pulmonary hypertension (19/468 deaths; 10 centers in the US and UK). Parallel investigations were also undertaken in the Cooperative Study of Sickle Cell Disease (CSCCD) and a contemporary urban sickle cell disease population (Case Western Reserve University-University Hospitals (CWRU-UH), Cleveland, OH, USA). One- and two-value positive predictive values for 2-year mortality (from study entry) are calculated using factors that include demographics, laboratory values and clinical evaluations. We define high-, intermediate-, and low-risk SCA as > 15%, 10-15% and < 10% 2-year mortality. In walk-PHaSST, no single factor qualifies as high-risk SCA, although several combinations of two factors (that is, both age > 35 years and history of chronic transfusion) do. Either elevated white blood cell count (> 13.5 × 10(3) cells/mcL, 7/70 deaths) or elevated Tricuspid Regurgitant Jet Velocity (⩾ 3.0 m/s, 8/67 deaths) was individually associated with intermediate-risk disease, as were many two-factor combinations. N-terminal pro-brain natriuretic peptide > 160 ng/L, lactate dehydrogenase > 600 IU/L, history of chronic transfusion, sepsis or age > 35 years are individually associated with low-risk SCA, as are many two-factor combinations. SCA risk was integrated with estimated donor type-associated risk from HSCT to form 'Traffic Light' eligibility criteria for clinical trials of HSCT. This method is adaptable to evolutions in clinical care.

Reported sildenafil side effects in pediatric pulmonary hypertension patients.

Background: Sildenafil, a phosphodiestase type 5 inhibitor, was approved in 2005 for the treatment of pulmonary arterial hypertension (PAH) in adults and is commonly used off-label for pediatric patients. Little is known, however, about sildenafil’s side effects in this population.Methods: Single institution, longitudinal survey-based study performed in an outpatient pediatric cardiology clinic. Pediatric patients on sildenafil [alone or in combination with other pulmonary hypertension (PH) therapies] completed questionnaires regarding frequency of vascular, gastrointestinal, neurologic, and hematologic side effects.Results: Between January 2011 and May 2014, 66 pediatric patients with PH on sildenafil filled out 214 surveys, 32 patients (96 surveys) on monotherapy, and 43 patients (118 surveys) on sildenafil plus an endothelin receptor antagonist (ERA) (bosentan or ambrisentan) and/or a prostacyclin (epoprostenol or treprostinil). Overall, 30% of respondents identified at least one side effect. For all patients on sildenafil, incidence of side effects by system was 37% gastrointestinal, 35% vascular, and 22% neurologic. For patients on sildenafil monotherapy, incidence of side effects by system was 24% gastrointestinal, 21% vascular, and 18% neurologic compared to patients on combination therapy who reported an incidence of 48% gastrointestinal, 45% vascular, and 25% neurologic.Conclusion: Incidence of vascular, gastrointestinal, and neurologic side effect in pediatric patients on sildenafil therapy for PAH was 30%. Side effects were more common in patients on combination therapy with an ERA and/or prostacyclin than in patients on sildenafil monotherapy.