beraprost and Familial-Primary-Pulmonary-Hypertension

To investigate the efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH).. In this open-label, uncontrolled, dose-escalation study, 25 Japanese patients with PAH were scheduled to receive 5 mg of ambrisentan once daily for the first 12 weeks, and 10 mg once daily for an additional 12 weeks. The primary endpoint was improvement in exercise capacity from baseline which was indicated by 6-minute walk distance; the secondary endpoints included World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, and cardiopulmonary hemodynamics.. NCT00540436.. At week 24, improvements were noted in all endpoints, with no clinically significant elevation of serum aminotransferase level. Pharmacokinetics in these Japanese patients was similar to that of non-Japanese populations, suggesting that once-daily dosing is appropriate in Japanese patients. Ambrisentan was generally well tolerated. No new safety signals were identified.. This study lacked a control group and was insufficiently powered to reach definitive conclusions on the efficacy of ambrisentan.. Ambrisentan is considered as safe and effective for Japanese adults with PAH.

Topics: Adult; Aged; Antihypertensive Agents; Asian People; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Platelet Aggregation Inhibitors; Pyridazines; Treatment Outcome

The heterozygous loss of function mutations in the Type II bone morphogenetic protein receptor (BMPR-II), a member of the transforming growth factor (TGF-β) receptor family, underlies the majority of familial cases of pulmonary arterial hypertension (PAH). The TGF-β1 pathway is activated in PAH, and inhibitors of TGF-β1 signaling prevent the development and progression of PAH in experimental models. However, the effects of currently used therapies on the TGF-β pathway remain unknown. Prostacyclin analogs comprise the first line of treatment for clinical PAH. We hypothesized that these agents effectively decrease the activity of the TGF-β1 pathway. Beraprost sodium (BPS), a prostacyclin analog, selectively inhibits proliferation in a dose-dependent manner in murine primary pulmonary arterial smooth muscle cells (PASMCs) harboring a pathogenic BMPR2 nonsense mutation in both the presence and absence of TGF-β1 stimulation. Our study demonstrates that this agent inhibits TGF-β1-induced SMAD-dependent and SMAD-independent signaling via a protein kinase A-dependent pathway by reducing the phosphorylation of SMADs 2 and 3 and p38 mitogen-activated protein kinase proteins. Finally, in a monocrotaline-induced rat model of PAH, which is associated with increased TGF-β signaling, this study confirms that treprostinil, a stable prostacyclin analog, inhibits the TGF-β pathway by reducing SMAD3 phosphorylation. Taken together, these data suggest that prostacyclin analogs inhibit dysregulated TGF-β signaling in vitro and in vivo, and reduce BMPR-II-mediated proliferation defects in mutant mice PASMCs.

Topics: Animals; Bone Morphogenetic Protein Receptors, Type II; Cell Proliferation; Codon, Nonsense; Epoprostenol; Familial Primary Pulmonary Hypertension; HEK293 Cells; Humans; Hypertension, Pulmonary; Lung; Male; MAP Kinase Signaling System; Mice; Monocrotaline; Myocytes, Smooth Muscle; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Smad3 Protein; Transforming Growth Factor beta1

Topics: Adult; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Kartagener Syndrome; Male; Treatment Outcome; Vasodilator Agents

Although endothelin receptor antagonists (ERAs) and phosphodiesterase type 5 (PDE5) inhibitors have become the most commonly used treatments for pulmonary arterial hypertension (PAH) since their introduction in 2005, it remains unknown whether these medications play a significant role in the survival of Japanese patients with PAH.. The cardiac catheterization and survival data of 103 PAH patients were retrospectively reviewed. A comparison of survival benefits with regard to the type of PAH was completed in PAH patients diagnosed between 2005 and 2012 and those diagnosed between 1983 and 2004 and in patients undergoing treatment with ERAs and/or PDE5 inhibitors and those being treated with conventional therapy and/or oral beraprost. Although pulmonary vascular resistance (PVR) at baseline differed, the more recent group showed better survival rates compared with those observed in the early group (5-year survival: 70.1% vs. 44.8) (p<0.05). In addition, the survival of PAH patients treated with ERAs and/or PDE5 inhibitors was superior to that of the patients treated without these medications (5- and 8-year survival: 77.8% and 66.7% vs. 39.0% and 37.0%, respectively) (p<0.05), especially in patient with idiopathic and heritable PAH.. Superior survival rates are observed in patients with idiopathic and heritable PAH after introduction of ERAs and PDE5 inhibitors, and the use of these drugs provides benefits for survival.

Topics: Adolescent; Adult; Aged; Endothelin Receptor Antagonists; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Retrospective Studies; Time Factors; Young Adult

Severe pulmonary hypertension in chronic obstructive pulmonary disease (COPD) is referred to as 'disproportionate' because the elevated pulmonary artery pressure does not match the degree of air flow limitation. We report a 41-year-old man presenting with early-onset pulmonary emphysema and pulmonary hypertension with a mean pressure of 74 mmHg. Continuous intravenous epoprostenol led to marked hemodynamic improvement, and epoprostenol was successfully replaced with bosentan. The patient has been followed for 3 years without exacerbation. This is the first report demonstrating the long-term efficacy of specific drugs for pulmonary arterial hypertension in disproportionate pulmonary hypertension in COPD.

Topics: Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Male; Pulmonary Emphysema; Sulfonamides; Vasodilator Agents