Sildenafil in pediatric pulmonary arterial hypertension.
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ABSTRACT:
SUBMITTER: Dhariwal AK
PROVIDER: S-EPMC4943407 | biostudies-other | 2015 Jul-Sep
REPOSITORIES: biostudies-other
Publications
Sildenafil in pediatric pulmonary arterial hypertension.
Dhariwal A K AK Bavdekar S B SB
Journal of postgraduate medicine 20150701 3
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 (USF ...[more]
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Project description:Elevated serum creatinine (sCr) and low estimated glomerular filtration rate (eGFR) are associated with poor outcomes in patients with pulmonary arterial hypertension (PAH) whereas sildenafil treatment improves PAH outcomes. This post hoc analysis assessed the effect of sildenafil on kidney function and links with clinical outcomes including 6-min walk distance, functional class, time to clinical worsening and survival.Patients with PAH received placebo or sildenafil 20, 40 or 80 mg three times daily in the SUPER-1 study and open-label sildenafil titrated to 80 mg three times daily (as tolerated) in the extension study.Baseline characteristics were similar among groups (n = 277). PAH was mostly idiopathic (63%) and functional class II (39%) or III (58%). From baseline to week 12, kidney function improved (increased eGFR, decreased sCr) with sildenafil and worsened with placebo. In univariate logistic regression, improved kidney function was associated with significantly improved exercise and functional class (odds ratios 1.17 [95% CI 1.01, 1.36] and 1.21 [95% CI 1.03, 1.41], respectively, for sCr and 0.97 [95% CI 0.94, 0.99] and 0.97 [95% CI 0.94, 0.99] for eGFR, all P < 0.05). In patients who maintained or improved kidney function, time to worsening was significantly delayed (P < 0.02 for both kidney parameters). Observed trends towards improved survival were not significant. Patients with eGFR <60 (vs. ?60) ml min(-1) 1.73 m(-2) appeared to have worse survival.Sildenafil treatment was associated with improved kidney function in patients with PAH, which was in turn associated with improved exercise capacity and functional class, a reduced risk of clinical worsening, and a trend towards reduced mortality.
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Project description:BackgroundDapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), can reduce cardiovascular events and mortality in patients with heart failure. A number of mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors. The purpose of this study was to determine whether dapagliflozin can improve pulmonary vascular remodelling and the efficacy of dapagliflozin as an add-on therapy to sildenafil in rats with pulmonary arterial hypertension (PAH).MethodsA monocrotaline (MCT)-induced PAH rat model was used in our study. MCT-injected rats were randomly divided into four groups and treated for 3 weeks with daily per os treatment with vehicle, dapagliflozin (1 mg/kg/day), sildenafil (25 mg/kg/day), or a combination of dapagliflozin (1 mg/kg/day) and sildenafil (25 mg/kg/day). Haemodynamic measurements, histological analysis, enzyme-linked immunosorbent assay and western blotting analysis were employed to detect the changes in PAH rats after treatments.ResultsDapagliflozin significantly attenuated MCT-induced increases in right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in PAH rats. Dapagliflozin effectively decreased the thickening of pulmonary artery media and decreased the muscularization of pulmonary arterioles in PAH rats. Moreover, dapagliflozin attenuated nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation in lung tissues and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) in plasma. However, dapagliflozin as an add-on therapy to sildenafil in rats with PAH did not show a more pronounced beneficial effect on right ventricular systolic pressure and pulmonary vascular remodelling in MCT rats than sildenafil alone.ConclusionsDapagliflozin reduces right ventricular systolic pressure and pulmonary vascular remodelling in a rat model of PAH. However, combination therapy with dapagliflozin and sildenafil was not more effective than monotherapy with sildenafil in PAH rats.
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Project description:Microarray analysis of peripheral blood mononuclear (PBMC) cells in pulmonary arterial hypertension. Keywords = mononuclear cells Keywords = gene microarray Keywords = pulmonary arterial hypertension Keywords = Herpesvirus Keywords = biomarker Keywords: other
2003-11-15 | GSE703 | GEO
Project description:Purpose of reviewPediatric pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. Herein we review the diagnosis and classification for pediatric PAH and detail the current therapeutic options available for use in the pediatric PAH population.Recent findingsClassification and treatment of pediatric PAH is guided by adult criteria and treatment algorithms, yet the distribution of factors contributing to PAH in children differs significantly from that seen in adults. It is necessary to understand these differences in order to appropriately tailor therapy to the needs of the child or adolescent. An expanding array of targeted PAH drugs are now approved for use in adults, and many of these drugs are used "off-label" to treat children and adolescents with PAH. Use of these novel therapies has coincided with marked improvement in outcomes, suggesting significant benefit. However, because most of these drugs have not been studied in rigorous randomized, controlled trials in children, it is critical that physicians understand their mechanisms of action, potential benefits, and safety profiles. Pediatric PAH outcomes have improved substantially in the modern era, coinciding with the "off-label" use of targeted PAH drugs in children and adolescents. Ideally, care should be provided at centers with specialized expertise in the diagnosis and treatment of pediatric PAH by providers who understand the appropriate diagnostic algorithms, classification schemes, and treatment approaches.
| S-EPMC7373343 | biostudies-literature