lu-208075 and Anemia--Sickle-Cell

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive pulmonary vasculopathy with ensuing right heart failure if left untreated. In the 1980's, prior to the current treatment era, idiopathic pulmonary arterial hypertension (IPAH) carried a poor prognosis with a 10 month median survival for children after diagnosis. However, in 1995 continuous intravenous epoprostenol was approved for the treatment of severe PAH, improving hemodynamics, quality of life, exercise capacity, functional class and survival. In the past decade there have been further advances in the treatment of PAH; however, there is still no cure. While much of the groundbreaking clinical research has been performed in adults, children have also seen the benefits of PAH novel therapies. The target population among pediatric patients is expanding with the recent recognition of pulmonary hypertension as a risk factor for sickle cell disease patients. With rapid advances, navigating the literature becomes challenging. A comprehensive review of the most recent literature over the past year on available and emerging novel therapies as well as an approach to target pediatric populations provides insights into the management of pediatric PAH patients.

Topics: Anemia, Sickle Cell; Antihypertensive Agents; Child; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Pyridazines

The objective of this study is to determine if ambrisentan (ET. Male 12-week-old humanized sickle mice (HbSS) and their genetic controls (HbAA) were treated with vehicle, HU, ambrisentan, or HU with ambrisentan for 2 weeks and renal structure and function were assessed.. Vehicle treated HbSS mice exhibited significant proteinuria compared to vehicle treated HbAA mice. HbSS mice also displayed significantly elevated plasma ET-1 concentrations and decreased urine osmolality compared to HbAA controls. Proteinuria was significantly lower in both HU and ambrisentan treated animals compared to vehicle treated HbSS mice; however, there was no additional improvement in HbSS mice treated with combined ambrisentan and HU. The combination of HU and ambrisentan resulted in significantly lower KIM-1 excretion, glomerular injury, and interstitial inflammation than HU alone.. These findings indicate that HU and ET

Topics: Anemia, Sickle Cell; Animals; Antisickling Agents; Disease Models, Animal; Drug Therapy, Combination; Endothelin A Receptor Antagonists; Humans; Hydroxyurea; Kidney Diseases; Male; Mice; Phenylpropionates; Pyridazines

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ET

Topics: Anemia, Sickle Cell; Animals; Disease Models, Animal; Endothelin A Receptor Antagonists; Female; Humans; Kidney Diseases; Male; Mice; Phenylpropionates; Pyridazines; Time Factors

Pulmonary Hypertension is a serious complication of sickle cell disease (SCD), with high morbidity and mortality. Endothelin (ET)-1, a potent vasoconstrictor elevated in SCD, acts through the ET receptors (ETR), ETR-A and ETR-B. Bosentan and ambrisentan are ETR blockers used in primary pulmonary hypertension. We report on the use of ETR blocking agents in a cohort of 14 high-risk SCD adult patients with pulmonary hypertension. Patients underwent right heart catheterization, 6-min walk test, echocardiogram, physical examination and blood work-up before starting ETR blockers. Eight patients received ETR blockers as initial therapy; six patients were already taking sildenafil. Over more than 6 months of therapy, sequential measurements of 6-min walk distance increased significantly (baseline 357 +/- 22 to 398 +/- 18 m at 5-6 months, P < 0.05). Downward trends were observed for amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity. Pulmonary artery mean pressures decreased in three patients that had repeat right heart catheterization (44-38 mmHg). Adverse events were: increased serum alanine aminotransferase (2), peripheral oedema (4), rash (1), headache (3), decreased haemoglobin (2). Therapy was stopped in two patients who were switched then to the other ETR blocker agent. These data suggest preliminary evidence for the benefit of bosentan and ambrisentan in pulmonary hypertension in SCD.

Topics: Adult; Anemia, Sickle Cell; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Evaluation; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Test; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Piperazines; Purines; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome