beraprost and Heart-Failure

The purpose of this study was to assess the efficacy and safety of beraprost sodium, an orally active prostacyclin analogue, in New York Heart Association (NYHA) functional class II and III patients with pulmonary arterial hypertension (PAH).. Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous infusion of prostacyclin has been proven effective. However, this treatment is associated with serious complications arising from the complex delivery system.. In this double-blind, placebo-controlled study, 130 patients with PAH were randomized to the maximal tolerated dose of beraprost (median dose 80 microg four times a day) or to placebo for 12 weeks. The primary end point was the change in exercise capacity assessed by the 6-min walk test. Secondary end points included changes in Borg dyspnea index, cardiopulmonary hemodynamics and NYHA functional class.. Patients treated with beraprost improved exercise capacity and symptoms. The difference between treatment groups in the mean change of 6-min walking distance at week 12 was 25.1 m (95% confidence interval [CI]: 1.8 to 48.3, p = 0.036). The difference in the mean change of Borg dyspnea index was -0.94 (95% CI: -1.63 to -0.24, p = 0.009). In the sub-group of patients with primary pulmonary hypertension, the difference in the mean change of 6-min walking distance was 46.1 m (95% CI: 3.0 to 89.3, p = 0.035). Cardiopulmonary hemodynamics and NYHA functional class had no statistically significant changes. Drug-related adverse events were common in the titration phase and decreased in the maintenance period.. Beraprost improves exercise capacity and symptoms in NYHA functional class II and III patients with PAH and, in particular, in those with primary pulmonary hypertension.

Topics: Administration, Oral; Adult; Double-Blind Method; Dyspnea; Epoprostenol; Exercise Tolerance; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Treatment Outcome; Vasodilator Agents

BACKGROUND To explore the efficacy of beraprost sodium combined with sildenafil and its effects on the vascular endothelial function and inflammation in left heart failure patients complicated with pulmonary arterial hypertension. MATERIAL AND METHODS A total of 80 patients with left heart failure complicated with pulmonary arterial hypertension was enrolled as the subjects of this study and assigned into an observation group (n=40) and a control group (n=40) using a random number table. The changes in pulmonary arterial hypertension-associated indicators at 3 months after treatment and the alterations in the levels of cardiac function-associated biochemical indicator brain natriuretic peptide (BNP), inflammatory factor tumor necrosis factor alpha (TNF-alpha), and mean pulmonary arterial pressure during treatment were compared between the 2 groups. RESULTS At 3 months after treatment, the pulmonary arterial hypertension-associated indicators human urotensin II and calcitonin gene-related peptide in the observation group were lower and higher, respectively, than those in control group. Moreover, the observation group had significantly lower BNP and TNF-alpha levels and mean pulmonary arterial pressure than the control group. After intervention, the echocardiographic parameters left ventricular ejection fraction (LVEF), cardiac output (CO), and stroke volume (SV) in both groups were significantly higher than those before intervention, and the observation group had significantly higher LVEF, SV, and CO than the control group after intervention. CONCLUSIONS Beraprost sodium combined with sildenafil for left heart failure complicated with pulmonary arterial hypertension can effectively improve pulmonary arterial hypertension, alleviate left heart failure, and reduce inflammatory responses, thereby achieving better clinical efficacy in patients.

Topics: Aged; Aged, 80 and over; Echocardiography; Endothelial Cells; Epoprostenol; Exercise Tolerance; Female; Heart Failure; Humans; Inflammation; Male; Middle Aged; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Ventricular Function, Right

It was hypothesized that a serial stimulation of vascular cyclooxygenase-2 (COX-2) with subsequent activation of endothelial nitric oxide synthase (eNOS) is responsible for decrease in blood pressure, cardiac performance, and vascular reactivity in endotoxemia caused by LPS. The hypothesis was tested in catheterized, conscious, freely moving, wild-type mice and mice (C57BL/6J background) with targeted deletion of COX-2 and eNOS that were given an intravenous LPS bolus (2 mg/kg, 055:B5). In vitro studies were performed on murine aorta rings. LPS caused a concomitant decrease in mean arterial blood pressure (MAP) and heart rate (HR) that was significant after 3 h and was sustained throughout the experiment (8 h). The LPS-induced changes in MAP and HR were not different from control in COX-2(-/-) and eNOS(-/-) mice. A prostacyclin receptor antagonist (BR5064) blocked the hypotensive effect of a prostacyclin agonist (beraprost), but did not attenuate the LPS-induced decrease in MAP and HR. LPS decreased eNOS and neuronal NOS mRNA abundances in several organs, while inducible NOS mRNA was enhanced. In aortic rings, LPS suppressed α(1)-adrenoceptor-mediated vascular tone. Inhibition of COX-2 activity (NS 398), disruption of COX-2, endothelium removal, or eNOS deletion (eNOS(-/-)) did not improve vascular reactivity after LPS, while the NO synthase blockers 1400W and N(G)-nitro-l-arginine methyl ester prevented loss of tone. COX-2 and eNOS activities are not necessary for LPS-induced decreases in blood pressure, heart rate, and vascular reactivity. Inducible NOS activity appears crucial. COX-2 and eNOS are not obvious therapeutic targets for cardiovascular rescue during gram-negative endotoxemic shock.

Topics: Animals; Aorta; Blood Pressure; Cyclooxygenase 2; Epoprostenol; Gene Expression Regulation; Heart Failure; Heart Rate; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Receptors, Adrenergic; Receptors, Epoprostenol; RNA; Time Factors

A 49-year-old woman suffering from rapidly progressing right-sided heart failure assessed as World Health Organization functional class (WHO-FC) IV is described. After treatment with oxygen and diuretics, she was in WHO-FC III on admission to our hospital, as confirmed by her poor exercise tolerance in cardiopulmonary exercise testing. Upon detailed examination, she was diagnosed as having idiopathic pulmonary arterial hypertension (IPAH). Right heart catheterization (RHC) revealed severe pulmonary hypertension (mPAP = 65 mmHg) with a markedly decreased cardiac index (CI = 1.0 L/minute/m(2)), and an acute vasoreactivity test with nitric oxide inhalation did not show any response. Due to her severe condition, we decided to attempt oral combination therapy consisting of bosentan, tadalafil, and beraprost, prescribed in the same order and titrated up to their maximum respective doses, instead of intravenous (IV) epoprostenol therapy. Her clinical symptoms improved day by day, and the hemodynamic parameters recovered to nearly normal ranges about 6 months after initiation of the combination therapy. Initial/programmed oral combination therapy for severe IPAH patients is not yet fully established, and there is less evidence concerning its efficacy than IV epoprostenol therapy. However, it has tremendous advantages for PAH patients when they respond well. It is very important to further identify what types of PAH patients will respond to this oral combination therapy and should be treated with it as the first-line therapy.

Topics: Administration, Oral; Antihypertensive Agents; Bosentan; Carbolines; Cardiac Output; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Echocardiography; Electrocardiography; Epoprostenol; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Middle Aged; Sulfonamides; Tadalafil; Vasodilator Agents

Beraprost sodium (BPS) is an orally active prostacyclin analogue. The effects of BPS on the heart, including coronary circulation improvement, myocardial and vascular protection and anti-fibrosis effect on myocardium interstitium, have previously been demonstrated. However, the effects of BPS on hemodynamics, cardiac function and myocardial contractility in patients in the hypertrophic phase have not been clarified. Therefore, in the present study, the effects of BPS under long-term administration were investigated using the hypertension model of salt-sensitive Dahl rats. Six-week-old Dahl rats were divided into three groups, an 8% high salt diet group treated with BPS (BPS group), an untreated 8% high salt diet group (HHF group) and an untreated 0.3% low salt diet group (Control group), and observations were conducted until 17 weeks of age. In the BPS and HHF groups, the survival rates after 11 weeks of high salt diet intake were 87.5% and 47.1%, respectively (p<0.05). At 17 weeks of age, the atrial systolic peak velocity/early diastolic peak velocity and heart weight index of the BPS group decreased significantly compared with the HHF group (p<0.05). The HHF group exhibited significantly more severe myocardial fibrosis mainly in the endocardial layer of the left and right ventricles compared with the BPS and Control groups (p<0.05). In the present study, long-term BPS administration preserved diastolic function and prevented myocardial interstitial fibrosis in the non-compensatory phase. The results of the present study suggest that BPS is effective for treatment of hypertensive cardiac hypertrophy.

Topics: Animals; Cardiomyopathies; Drug Administration Schedule; Endocardium; Epoprostenol; Fibrosis; Heart Failure; Heart Function Tests; Heart Ventricles; Longevity; Rats; Rats, Inbred Dahl; Vasodilator Agents

Pimobendan, an oral inotropic drug with phosphodiesterase III-inhibitory activity, induces cAMP-dependent relaxation of vascular smooth muscle in the pulmonary artery, as well as in the systemic cardiovascular system. We report here a patient with severe primary pulmonary hypertension (PPH), who had developed right heart failure (New York Heart Association functional class IV) despite uptitrated intravenous epoprostenol, and who was treated with extremely low-dose (0.625-1.25 mg daily) pimobendan as an adjunct to prostacyclin therapy. The combination therapy of low-dose pimobendan, prostacyclin, intravenous epoprostenol and oral beraprost has been continued for over 2 years without occurrence of fatal arrhythmia, and her six-minute walk test has exceeded 400 m. We suggest that low-dose pimobendan may enhance the hemodynamic effect of prostacyclin in severe PPH.

Topics: Adult; Drug Therapy, Combination; Epoprostenol; Female; Heart Failure; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Prostaglandins I; Pyridazines