beraprost and Hypertension--Pulmonary

Prostacyclin is produced in vascular endothelial cells and acts via the IP prostacyclin receptor to cause vasodilation and inhibit smooth muscle cell proliferation and platelet aggregation. Prostacyclin production is reduced in pulmonary arterial hypertension (PAH), and drugs targeting the prostacyclin pathway are one of the pharmacotherapeutic options for PAH. Areas covered: The prostacyclin pathway and drugs that target it are discussed, including synthetic prostacyclin (epoprostenol), prostacyclin analogs (iloprost, treprostinil, beraprost) and selective prostacyclin IP receptor agonists (selexipag). An overview of the development of these therapies, from the earlier agents requiring parenteral administration, through inhaled formulations, to oral products, is provided, together with a summary of data from key clinical trials and registries. Expert commentary: Synthetic prostacyclin and prostacyclin analogs are beneficial for patients with PAH, but they tend to be underused, in part due to the difficulties associated with the administration of parenteral and inhaled formulations. Oral prostacyclin analogs have some limitations with regard to efficacy. The newest agent targeting the prostacyclin pathway, the selective prostacyclin receptor agonist selexipag, is administered orally, and has been shown to reduce a composite morbidity/mortality endpoint. Ongoing studies will help clarify how best to use it in the management of PAH.

Topics: Acetamides; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazines; Receptors, Epoprostenol

Prostacyclin pathway medications have been shown to be highly efficacious in the treatment of pulmonary arterial hypertension (PAH) through multiple prospective clinical trials and more than two decades of clinical experience. The strongest support for prostacyclin use in PAH management is with parenteral administration. Numerous risks and limitations of parenteral delivery systems as well as significant patient burdens restrict widespread parenteral use. Highly effective and tolerable oral prostacyclin preparations to manage PAH have long been sought. We review the development of the oral prostacyclin agents beraprost, treprostinil, and selexipag and including current indications and limitations. Research into new approaches to the management of PAH, expanding indications for existing agents, and development of novel agents are also discussed.. Two oral prostacyclin pathway medications, oral treprostinil and selexipag, were FDA approved in December 2013 and 2015, respectively. Current guidelines recommend use of selexipag in WHO-FC II and III (class 1, level B recommendation) and oral treprostinil in WHO-FC III (class 2b, level B recommendation). The use of these medications is challenging due to complexity in dosing and their side effect profiles which limit patient tolerability and acceptance. There is a promising role for oral prostacyclin pathway medications in patients with PAH. Future investigations are underway of alternative dose regimens and transitioning from parenteral therapies in order to improve efficacy and tolerability.

Topics: Acetamides; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazines

Prostacyclin analogs, such as epoprostenol, treprostinil, iloprost, and beraprost, have long been used for pulmonary arterial hypertension (PAH) treatment, yet their relative efficiency remains disputed. Eligible randomized controlled trials (RCTs) involving the 4 therapies mentioned above were retrieved from PubMed, Embase, and Cochrane (up to August 1, 2015). Odds ratios (ORs) were estimated for dichotomous data (mortality, functional class (FC) amelioration, and discontinuation); standardized mean differences (SMDs) with 95% confidence intervals (CIs) were estimated for continuous data (6-min walk distance [6-MWD]). Patients taking epoprostenol were anticipated to demonstrate more expedient 6-MWD than those taking placebo when network meta-analysis (NMA) was implemented (SMD = 52.19; 95% CI: 24.28-113.39), the trend of which was identical with that of pairwise meta-analysis (SMD = 69.28; 95% CI: 10.43-128.98). Nonetheless, the prominent advantages of treprostinil over placebo (SMD = 30.15; 95% CI: 19.29-40.01) in 6-MWD could not be replicated by NMA. Furthermore, direct and indirect (NMA) comparisons also differed in FC amelioration. For example, the superiority of epoprostenol over placebo as evident with the use of NMA (OR = 42.79; 95% CI: 10.63-301.98) could not be confirmed by pairwise meta-analysis. As suggested by indirect comparisons among 4 prostanoids, epoprostenol appears to result in remarkably favorable FC amelioration comparing to other regimens (all P < 0.05). Participants taking beraprost were more probable to withdraw in comparison with those administrated with iloprost (OR = 10.07; 95% CI: 1.47-160.65). Taking mortality, FC amelioration, discontinuation, and 6-MWD into account, epoprostenol could be recommended as an alternative treatment for patients with moderate/advanced PAH.

Topics: Antihypertensive Agents; Arterial Pressure; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Randomized Controlled Trials as Topic

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Carbolines; Endothelin Receptor Antagonists; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Tadalafil; Vascular Resistance; Vasodilator Agents

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Bosentan; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Mice; Molecular Targeted Therapy; Piperazines; Protein Kinase Inhibitors; Purines; Rats; rho-Associated Kinases; Signal Transduction; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance

Some patients with chronic obstructive pulmonary disease (COPD) have pulmonary hypertension (PH) that adversely affects survival. We performed a systematic review and meta-analysis to assess whether PH-specific therapies have an effect for stable COPD. Data sources were Medline, EMBASE, Cochrane Central Register of Controlled Trials, Korea med and references from relevant publications. Randomized prospective trials that compared PH specific therapy in COPD for more than 6 weeks with placebo were included. The outcomes were the exercise capacity and adverse events. Four randomized controlled trials involving 109 subjects were included in the analysis. Two trials involved bosentan, one sildenafil and one beraprost. The studies varied in duration of treatment from 3 to 18 months. In a pooled analysis of four trials, exercise-capacity was not significantly improved with PH-specific treatment for COPD (risk ratio, -5.1; 95% CI, -13.0 to 2.8). COPD with overt PH significantly improved the exercise capacity (mean difference, 111.6; 95% CI, 63.3 to 159.9) but COPD with PH unknown did not (mean difference, 26.6; 95% CI, -24.3 to 77.5). There was no significant difference in hypoxemia (mean difference, 2.6; 95% CI, -3.7 to 8.8). PH specific treatments have a significant effect in improving exercise capacity in COPD with overt PH.

Topics: Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Databases, Factual; Epoprostenol; Humans; Hypertension, Pulmonary; Hypoxia; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Surveys and Questionnaires

It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.

Topics: Acetamides; Animals; Antihypertensive Agents; Benzamides; Clinical Trials as Topic; Drugs, Investigational; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epoprostenol; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Lisuride; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Serotonin Antagonists; Sulfonamides

Prostacyclin has vasoprotective effects such as vasodilation and antiplatelet aggregatory activity. A relative deficiency of prostacyclin contributes to the pathogenesis of cardiovascular disease including pulmonary artery disease (PAH). Inconvenient intravenous dosing of prostacyclin led to the development of more stable, an orally active analogue: beraprost. It is a chemically stable prostacyclin analogue owing to its cyclo-pentabenzofuranyl structure and produces strong vasodilation and inhibition of platelet aggregation. To date, beraprost has been used in the treatment of PAH and peripheral arterial disease (PAD). Recently, we have shown that beraprost induces neovascularization in ischemic myocardium by enhancement of bone marrow cell mobilization. Interestingly, meta-analysis of clinical studies for PAD has shown that repeated administration of beraprost decreases the number of cardiovascular events. These results suggest that oral administration of beraprost has beneficial effects on cardiovascular disease. Orally active prostacyclin analogues, are promising drugs for the treatment of cardiovascular disease.

Topics: Administration, Oral; Cardiovascular Diseases; Epoprostenol; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Myocardial Ischemia; Neovascularization, Physiologic; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors; Treatment Outcome; Vasodilator Agents

Beraprost sodium (BPS) is a stable orally active prostacyclin analogue with vasodilatory and anti-platelet effects, and has been widely used as therapeutics for pulmonary artery hypertension and chronic arterial obstruction. In order to elucidate its effects on endothelium, we first examined the short-term effects of BPS on nitric oxide (NO) production and endothelial NO synthase (eNOS) activation using bovine aortic endothelial cells. Short-term treatment of BPS induced NO production as well as eNOS phosphorylation at Ser-1179 mediated via cAMP/protein kinase A (PKA) pathway. The effects of BPS on capillary-like tube formation were next determined using human umbilical vein ECs (HUVECs)/normal human dermal fibroblasts co-culture system. BPS was observed to induce capillary-like tube formation mediated via cAMP/PKA pathway, but not via NO generation. Finally, we performed DNA microarray analyses using RNA extracted from BPS treated HUVECs. Interestingly, BPS up-regulated several genes involved in angiogenesis, anti-atherosclerosis, and endothelial function, while down-regulated several genes involved in atherosclerosis. Our data therefore indicate that BPS may be useful not only for patients with pulmonary artery hypertension and chronic arterial obstruction, but also for general atherosclerotic patients complicated with endothelial dysfunction. Further studies are needed to clarify molecular mechanisms of these BPS effects including the involvement of peroxisome proliferator-activated receptor-delta.

Topics: Animals; Arterial Occlusive Diseases; Atherosclerosis; Cardiovascular Diseases; Endothelium, Vascular; Epoprostenol; Gene Expression Regulation; Humans; Hypertension, Pulmonary; Neovascularization, Physiologic; Nitric Oxide; Nitric Oxide Synthase Type III; Platelet Aggregation Inhibitors; Signal Transduction; Vasodilator Agents

Among the most commonly used therapies to treat pulmonary arterial hypertension (PAH) are the prostanoids. Epoprostenol, a relatively effective therapy for PAH, has its limitations, which are largely attributable to its pharmacokinetic properties and its requirement for intravenous administration. The development of an equally effective oral prostanoid would be an important advance in the PAH armamentarium. An early generation oral prostanoid, beraprost, was previously demonstrated to have modest, transient clinical benefits, but at the cost of a high proportion of intolerable side effects. TRK-100STP is a newer generation oral prostanoid currently under clinical investigation.

Topics: Antihypertensive Agents; Drug Discovery; Epoprostenol; Humans; Hypertension, Pulmonary; Prostaglandins; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Topics: Animals; Delayed-Action Preparations; Epoprostenol; Humans; Hypertension, Pulmonary; Rats; Vasodilator Agents

Pulmonary arterial hypertension is a progressive disease marked by increased pulmonary artery resistance leading to right heart failure and has very high mortality. Survival rates have somewhat improved in recent years due to the development of new drugs and early diagnosis. This review aims to summarize the current therapeutic approach to pulmonary arterial hypertension and share our experience at our center.

Topics: Antihypertensive Agents; Diltiazem; Disease Progression; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nifedipine; Turkey; Vasodilator Agents

Epoprostenol (prostacyclin) has been shown to improve survival in pulmonary arterial hypertension. However, this therapy needs continuous intravenous administration devises because of its short half-life. Recently, an orally active prostacyclin analogue, beraprost sodium, and its drug delivery system have been developed in Japan. Beraprost sodium improves pulmonary hemodynamics in patients with pulmonary arterial hypertension. In addition, we have developed ONO-1301, a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. Subcutaneous administration of ONO-1301 markedly attenuated monocrotaline-induced pulmonary hypertension and improved survival in rats. These prostacycline derivates may be promising for the treatment of pulmonary arterial hypertension.

Topics: Epoprostenol; Humans; Hypertension, Pulmonary; Pyridines

Epoprostenol and the structurally related compounds treprostinil, iloprost, and beraprost are collectively referred to as prostanoids. The discovery of epoprostenol in 1976 and unequivocal demonstration of its efficacy in 1996 dramatically altered the approach to therapy for pulmonary arterial hypertension (PAH). Development of prostanoids available through multiple routes of administration and the discovery and development of other agents acting through alternative pathways continue to expand the array of therapeutic options. The use of prostanoids in combination with other PAH drugs and for treating pulmonary hypertensive disorders outside of the PAH classification are areas of ongoing research.

Topics: Antihypertensive Agents; Chronic Disease; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Prostaglandins; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome

This review assesses the available evidence supporting the use of drug combinations for the management of the various forms of pulmonary arterial hypertension (PAH). Ongoing and forthcoming randomized trials evaluating this strategy are also highlighted. Furthermore, new types of agents to treat PAH in the future are explored.

Topics: Adrenomedullin; Angiopoietin-1; Antihypertensive Agents; Benzamides; Bosentan; Drug Therapy, Combination; Eicosanoids; Epoprostenol; Genetic Therapy; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Intracellular Signaling Peptides and Proteins; Piperazines; Platelet Aggregation Inhibitors; Prostaglandins; Protein Serine-Threonine Kinases; Purines; Pyrimidines; rho-Associated Kinases; Serotonin; Serotonin Plasma Membrane Transport Proteins; Sildenafil Citrate; Sulfonamides; Sulfones; Vasoactive Intestinal Peptide; Vasodilator Agents

Topics: Anticoagulants; Calcium Channel Blockers; Cardiac Catheterization; Echocardiography; Epoprostenol; Humans; Hypertension, Pulmonary; Life Style; Oxygen Inhalation Therapy; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vasoconstriction and progressive remodelling of the pulmonary arterial wall leading to right ventricular failure and death. Idiopathic PAH (IPAH) and PAH associated with congenital heart defects account for the majority of paediatric patients with PAH. During the last few decades, several pharmacological approaches have been introduced, including calcium channel-blockers (CCBs), prostacyclin analogues, endothelin receptor antagonists and, most recently, phosphodiesterase inhibitors. This paper reviews the treatment options available to children with a special focus on the initial experience with bosentan. Although CCBs have been shown to increase survival in IPAH, the beneficial effect appears to be limited to a small number of patients, defined as 'responders' to the vasoreactivity testing. With the availability of prostacyclin (intravenous epoprostenol) and then prostacyclin analogues, the treatment options have increased markedly and particularly in patients who have not responded to conventional therapy. Although epoprostenol has been shown to be efficacious in PAH, the drug is not ideal owing to serious complications arising from the invasive mode of application, particularly in children. Phosphodiesterase-5 inhibitors have also shown beneficial effects. Targeting the endothelin (ET) system with the oral, dual ET(A)/ET(B) receptor antagonist, bosentan has been demonstrated to improve the cardiopulmonary haemodynamics, exercise capacity, quality-of-life and survival in adult patients with PAH. Specific ET(A) antagonists may also present the same beneficial profile. Recent experience with bosentan in paediatric patients with PAH indicates that the results obtained in adult patients may be extrapolated to children, thus offering a safe and effective therapy that is easy to administer.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Child; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Phosphodiesterase Inhibitors; Receptors, Endothelin; Sulfonamides; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and smooth muscle cell proliferation of the pulmonary arterioles, as well as in situ thrombosis of the small pulmonary arteries. Prostacyclin is involved in PAH vascular remodeling. It is unclear if decreased prostacyclin in the lungs is a cause or a consequence of PAH, but the relative lack of prostacyclin and its positive effects on the pulmonary vascular bed support the theory that long-term prostacyclin replacement is effective. Current therapies based on evidence-based medicine include epoprostenol, treprostinil, iloprost, and beraprost, each with limitations based on the drugs' inherent properties and administration route. Treatment of PAH by inhibiting multiple pathways concurrently may produce additive benefit. Because prostacyclin therapy is not curative and does not normalize pulmonary hemodynamics in the majority of cases, combining a prostacyclin with other PAH agents may be a promising approach.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Vasodilator Agents

The improved understanding of the pathophysiology of pulmonary vascular diseases over the last decade has brought with it significant changes in disease management. Newer therapies have targeted the cardinal features of pulmonary hypertension, which include pulmonary vasoconstriction and vascular remodelling. In addition to prostacyclin, which had been the mainstay of therapy until recently, other available drugs include other prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase inhibitors. This review will discuss some of the evidence for their use and will look towards the future in the search of treatments that may ultimately modify and even reverse the disease process.

Topics: Adult; Antihypertensive Agents; Arginine; Bosentan; Child; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Nitric Oxide; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors; Sulfonamides

Pulmonary arterial hypertension (PAH) is one of the main causes of death in patients with systemic sclerosis (SSc), particularly in its limited forms.. Survival with conventional treatment associated with Epoprostenol is two times less in SSc patients than in idiopathic PAH. WHO recommendations (annually heart echoscreening) must be applied in all patients with SSc. Conventional therapy associates anticoagulation, to avoid excessive exertion, pregnancy, warm baths, no pressurised flights. Calcium-channel blockers give long term survival in patients with positive acute vasodilatator test with nitric oxide (NO) but these patients are very rare in SSc. Diuretics are very useful in treating right heart insufficiency. Randomized control trials in PAH have demonstrated the short term efficacy of i.v. epoprostenol, nebulized iloprost, oral beraprost and oral bosentan, a dual endothelin-1 receptor antagonist. Results in SSc are very limited except for i.v. epoprostenol. Long-term efficacy in terms of survival has been demonstrated in non randomized studies for i.v. epoprostenol and oral bosentan in patients with idiopathic and familial PAH. Atrial septostomy and lung transplantation could be an alternative to treatment, even in SSc patients, in case of refractory evolution.. Randomized control trials with sildenafil and selective endothelin-1 receptor antagonists are ongoing.

Topics: Antihypertensive Agents; Bosentan; Calcium; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Scleroderma, Systemic; Sulfonamides

Pulmonary arterial hypertension (PAH) is associated with changes in vascular tone as well as vascular structure, with the relative contribution of each dependent upon the etiology of the increased vascular resistance. Prostacyclin treatment has markedly improved both the therapeutic options and the prognosis of PAH. The beneficial effect of prostacyclin in PAH is linked to the powerful vasodilating capacity and, even more importantly, to the inhibition of platelet aggregation, smooth muscle proliferation and antiinflammatory actions. Since prostacyclin has a very short plasma half-life, continuous intravenous administration via a portable infusion pump must be carried out. Because of the complexity of the delivery and the associated complications, intravenous prostacyclin (epoprostenol) therapy is restricted to patients with late NYHA Class III and Class IV and thus alternative modes of delivery in less advanced PAH are desirable. Recent clinical studies with more stable prostacyclin analogs such as subcutaneously delivered treprostinil, orally active beraprost and aerosolized iloprost have demonstrated beneficial effects of each of these prostanoids, especially in NYHA Class II and III patients and, therefore, these agents should be considered first for prostanoid therapy in the early stages of PAH. Prostaglandins may be more effective in conjunction with endothelin receptor antagonists or phosphodiesterase inhibitors and an increasing number of studies are now addressing the combined efficiency and safety of these combinations. This update will focus on the current development status of PAH therapy with prostacyclin and its analogs. Special attention will be accorded to the selection of patients for prostanoid therapy, therapy monitoring and improvement of therapeutic efficacy by addition of other new therapeutic agents to prostaglandins. Survival benefits and special aspects of bridging-to-transplant therapy are also important aspects of the review.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Pulmonary Circulation; Treatment Outcome

To review the epidemiology, pathophysiology, clinical symptoms, and diagnostic workup of primary pulmonary hypertension (PPH) and to discuss the available data on the current and emerging therapies being used to treat this disorder.. Primary and review articles were identified with a MEDLINE search (1966-December 2001) and through secondary sources.. All articles identified from the data sources were evaluated and all information deemed relevant was included in this review.. In the absence of a definable cause, PPH is a disorder classified by a progressive increase in pulmonary vascular resistance and mean pulmonary artery pressure. A relatively rare condition, PPH has an annual incidence of 1-2 cases per million people, slightly higher in women than men. The prognosis is poor, with a mean survival time of 2.8 years after diagnosis if untreated. Vasoconstriction, vascular remodeling, and thrombosis are hallmarks of the disease process. Anticoagulation and vasodilators are the most commonly employed treatment options, showing benefits in clinical outcomes, hemodynamic parameters, and mortality. Several new vasodilators are being evaluated for the treatment of PPH. Bosentan was recently approved as the first oral agent for the treatment of PPH. Iloprost, treprostinil, and beraprost are investigational agents in Phase III studies.. Until additional studies and experience with these agents become available, calcium-channel blockers (CCBs) remain the first option for therapy. For patients not responding to CCBs, therapeutic options will now include epoprostenol and bosentan. Since there are no comparison trials between these 2 agents, therapeutic decisions should be based on patient-specific concerns. Clinical data and experience support the use of epoprostenol; however, in patients at risk or considered unsuitable candidates, bosentan may become a preferred option. Additional studies are warranted to address the potential therapeutic benefits of combination therapy and long-term benefits of agents to treat PPH.

Topics: Anti-Inflammatory Agents; Anticoagulants; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Vasodilator Agents

Past medical therapy for pulmonary arterial hypertension included the use of calcium-channel antagonists in acute vasoreactive subjects and oral anticoagulants and continuous intravenous administration of epoprostenol in the more severe cases. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in >1,100 patients. Except for terbogrel, all compounds improved the mean exercise capacity by different degrees, as assessed by the 6-min walk test. In the evaluation of the clinical relevance of exercise capacity improvements, additional elements need to be considered, such as baseline functional class and concomitant favourable effects on combined clinical events (including hospitalisations, mortality and rescue therapies), quality of life and haemodynamics. No trials have shown effects on mortality, as the study protocols were not designed for assessing this end-point. Each new compound presents side-effects that are unpredictable in the individual patient and require appropriate attention upon treatment initiation and maintenance. These new therapeutic options will be available in the near future and will allow tailoring of the most appropriate treatment to the single patient, according to an individualised benefit-to-risk ratio.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Prognosis; Pyridines; Randomized Controlled Trials as Topic; Severity of Illness Index; Survival Rate; Treatment Outcome; Vasodilator Agents

Beraprost sodium (beraprost) is a stable, orally active prostacyclin analogue with vasodilatory, antiplatelet and cytoprotective effects. Beraprost acts by binding to prostacyclin membrane receptors ultimately inhibiting the release of Ca2+ from intracellular storage sites. This reduction in the influx of Ca2+ has been postulated to cause relaxation of the smooth muscle cells and vasodilation. Data from a large, randomised, double-blind, multicentre study indicated that beraprost was as efficacious as ticlopidine in the treatment of patients with peripheral arterial disease (Buerger's disease and arteriosclerosis obliterans). Most patients receiving beraprost exhibited reduction of ulcer size, reported improvement of granulation appearance of the tissue and showed improvement of pain at rest and sensation of cold in the extremities. In a large pivotal clinical trial in patients with intermittent claudication, beraprost treatment was associated with statistically significant increases in pain-free and absolute walking distances compared with those in patients receiving placebo. Statistically significant differences in the incidence of critical cardiovascular events among both treatment groups were not observed but patients receiving beraprost were more likely to be satisfied with changes in their quality of life. However, while preliminary unpublished data from a large, phase III, placebo-controlled study in the US suggested a trend toward fewer critical cardiovascular events (no specific data presented), this study did not confirm the positive results from the European phase III trial and statistical significance was not achieved in the study's endpoints relating to exercise. A series of small, noncomparative clinical trials of patients with the rare condition of pulmonary arterial hypertension (PAH) demonstrated that substantial reductions of pulmonary arterial pressure and resistance, increase of cardiac output, and increase of exercise capacity appeared to be associated with beraprost therapy; however, these data are very limited and in most instances are not fully published. Beraprost is a well tolerated agent. Overall, the main adverse events include headache, hot flushes, diarrhoea and nausea. However, patients with PAH showed higher incidence of adverse events than those with peripheral arterial disease.. Beraprost, an orally administered PGI2 analogue, is generally well tolerated and appears to be an effective agent in the treatment of patients with Buerger's disease and arteriosclerosis obliterans. Comparative data from a large randomised trial indicated that the drug appears as effective as ticlopidine in patients with these conditions. In patients with intermittent claudication, significant benefits of beraprost compared with placebo were reported in a randomised clinical trial; however, the use of beraprost in these patients is not supported by recent preliminary unpublished data from a large, phase III, placebo-controlled study. Limited data suggest some efficacy with long-term beraprost treatment of patients with PAH, where options are few and where oral administration of the drug could be a considerable advantage over intravenous prostacyclin (PGI2) therapy. Additional well-designed and, where possible, large trials with active comparators are necessary to define more precisely the place of beraprost in the treatment of patients with PAH, Buerger's disease and arteriosclerosis obliterans.

Topics: Animals; Epoprostenol; Humans; Hypertension, Pulmonary; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors

SEVERITY AND TREATMENT: The management of primitive pulmonary hypertension starts by the evaluation of its severity, based on the New York Heart Association's (NYHA) functional classification and right cardiac catheterization data. Hemodynamic criteria of poor prognosis are: an increase in right atrial pressure > 10 mm Hg, a decrease in cardiac output (cardiac index < 2.2 l/min/m2), an increase in pulmonary vascular resistance > to 20 mm Hg/l/min/m2, and saturation of the oxygen content in venous blood < 63%. These prognostic data will condition treatment. CALCIUM CHANNEL BLOCKERS: Are the only vasodilators that have demonstrated efficacy in primitive pulmonary hypertension (PPH). However, only 20% of patients respond to calcium blockers. To determine a positive response to these agents, a carbon monoxide inhalation test is required during right cardiac catheterization. Prescription of calcium channel blockers to non-responders is often responsible for adverse events, from enhanced dyspnoea to sudden death. Continuous intravenous infusion of epoprostenol has considerably improved the prognosis of PPH and related pulmonary hypertension (PH). Despite the constraints, such treatment should be proposed to NYHA functional class III and IV patients not responding to carbon monoxide tests, until new, equally efficient products have been launched on the market. If epoprostenol fails or provokes severe side effects, pulmonary or cardio-pulmonary transplantation should be envisaged.

Topics: Administration, Oral; Adult; Algorithms; Anticoagulants; Antihypertensive Agents; Calcium Channel Blockers; Cardiac Catheterization; Clinical Trials as Topic; Diuretics; Epoprostenol; Female; Heart Atria; Heart Septum; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Lung Transplantation; Male; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Survival Analysis; Vasodilator Agents

Prostacyclin is an endogeneous eicosanoid synthesized by vascular endothelial cells, and has potent inhibitory effects on platelet adhesion/aggregation and vasoconstriction. However, its therapeutic use is restricted by its extremely short half-life. Beraprost sodium (beraprost) is the first orally active prostacyclin analogue developed by TORAY Industries, Inc. Beraprost possesses a phenol moiety instead of the exo-enol ether moiety, which is the cause of the instability of prostacyclin, and has a modified omega-side chain that contributes to dissociating antiplatelet action from adverse reactions. In 1992, beraprost was approved as a drug for chronic arterial occlusion. Beraprost is now widely used clinically as "Dorner" or "Procylin". The indication for "primary pulmonary hypertension" was also approved in 1999. Recently in Europe, a placebo controlled trial named "Beraprost et Claudication Intermittent-2 (BERCI-2)" was performed, and it was reported that beraprost improved the walking distances of the patients. Beraprost has a variety of biological activities such as antiplatelet effects, vasodilation effects, antiproliferative effects on vascular smooth muscle cells, cytoprotective effects on endothelial cells and inhibitory effects on the production of inflammatory cytokines. On the basis of basic and clinical research, it has been suggested that beraprost is also effective for many intractable diseases. We expect that the relationship between reduced prostacyclin level and these diseases would be clarified and the beneficial effects of beraprost would be demonstrated by controlled clinical trials in the future.

Topics: Administration, Oral; Animals; Arterial Occlusive Diseases; Chronic Disease; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Platelet Aggregation Inhibitors; Vasodilator Agents

Prostacyclin is a substance produced by endothelial cells that induces vasodilation and inhibition of platelet aggregation and of vascular cell migration and proliferation. A dysregulation of the prostacyclin metabolic pathways has been shown in patients with pulmonary arterial hypertension. The clinical use of prostacyclin has been made possible by the synthesis of stable analogues that possesses different pharmacokinetic properties but share similar pharmacodynamic effects. The greatest experience has been collected with intravenous epoprostenol while other compounds like subcutaneous UT-15, inhaled iloprost and oral beraprost are currently in different stages of clinical development. Although favorable results have been reported for each compound, different benefit-to-side effects profiles characterize the various modalities of the administration.

Topics: Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Vasodilation; Vasodilator Agents

Advances in the understanding of the molecular and cellular pathogeneses of PPH have led clinicians beyond simple pulmonary vasodilation as the only treatment for PPH and to a realization that what were previously believed to be irreversible vascular lesions may, in fact, be reversible. The development of agents that target the known endothelial and nonendothelial defects in patients with PPH is well underway. Clinicians are witnessing an exciting new era for physicians and patients dealing with this disease.

Topics: Animals; Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelins; Endothelium, Vascular; Epoprostenol; Humans; Hypertension, Pulmonary; Nitric Oxide; Vasodilator Agents

Distal-type chronic thromboembolic pulmonary hypertension (CTEPH) is a fatal disease for which a new therapeutic strategy needs to be developed. We examined the effects of percutaneous transluminal pulmonary angioplasty (PTPA).. We prospectively enrolled 12 patients with distal-type CTEPH. After stabilizing their condition with pulmonary vasodilators, we then performed PTPA, which markedly improved pulmonary hemodynamics and pulmonary artery structure, as confirmed by angiography and optical coherence tomography, and also significantly improved their long-term prognosis compared with 39 historical controls.. PTPA is a promising therapeutic option for distal-type CTEPH.

Topics: Aged; Angioplasty; Antihypertensive Agents; Bosentan; Chronic Disease; Combined Modality Therapy; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Prognosis; Prospective Studies; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

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

Sildenafil and beraprost, as orally available pulmonary vasodilators, are used increasingly to treat pulmonary hypertension (PH). An evaluation was made, in patients with PH undergoing valvular heart surgery, as to whether preoperative combined oral sildenafil and beraprost treatment could induce synergistic and prolonged pulmonary vasodilation, or result in a loss of pulmonary selectivity.. Fifty patients scheduled for valvular heart surgery with a mean pulmonary arterial pressure (PAP) > 30 mmHg were randomly assigned to receive either 50 mg oral sildenafil + 40 microg beraprost, or a placebo, 15 min before the induction of anesthesia. Hemodynamic variables were measured intraoperatively.. The treatment group had a significantly lower systemic vascular resistance index at 60 min after medication. No other significant intergroup differences in hemodynamic variables were observed. In addition, significantly more patients in the treatment group required vasopressor therapy. In both groups, the PAP was significantly reduced by general anesthesia, and almost normalized after valvular heart surgery.. Preoperative oral sildenafil and beraprost treatment resulted in a loss of pulmonary selectivity, and did not provide any additional pulmonary vasodilation or favorable perioperative hemodynamics in patients with PH undergoing valvular heart surgery.

Topics: Adult; Aged; Anesthesia, General; Blood Pressure; Comorbidity; Drug Therapy, Combination; Epoprostenol; Female; Heart Valve Diseases; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Preoperative Care; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

The long-acting beraprost preparation TRK-100STP is formulated to provide sustained release of an orally active prostacyclin derivative to maintain the optimal plasma concentration for a longer period of time compared with the currently used conventional beraprost sodium. In the present study, we evaluated the efficacy of this newly developed formulation for pulmonary arterial hypertension (PAH).An open-label, 12-week multicenter clinical trial was performed in 46 patients with PAH. They were initially treated with 120 microg of TRK-100STP divided into 60 microg twice daily, followed by a stepwise increase to 360 microg given as 180 microg twice daily. The 6-minute walking distance showed a significant increase by 33.4+/-66.0 m (95% confidence interval [CI], 13.4 to 53.5) from the baseline measurement. Mean pulmonary artery pressure, total pulmonary vascular resistance, and pulmonary vascular resistance decreased by -2.8+/-5.5 mmHg (95% CI, -4.6 to -1.0), by -0.92+/-2.63 mmHg*L(-1)*min (95% CI, -1.78 to -0.05), and by -0.89+/-2.81 mmHg*L(-1)*min (95% CI, -1.84 to 0.06), respectively, from the baseline measurements. A higher efficacy was observed in patients with a maximum tolerated dose of 360 microg daily than those of 240 microg daily or less.Treatment with TRK-100STP for a 12-week period improved the exercise capacity, mean pulmonary artery pressure, and total pulmonary vascular resistance. TRK-100STP was effective for Japanese patients with PAH.

Topics: Administration, Oral; Adult; Aged; Cohort Studies; Delayed-Action Preparations; Drug Administration Schedule; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Japan; Male; Middle Aged; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Young Adult

Oral prostacyclin analogs can improve the prognosis of patients with mild to moderate pulmonary arterial hypertension (PAH), but because they often provoke adverse effects, such as flushing and dizziness, administering the optimal dose can be difficult.. In the present study, a novel long-acting oral beraprost (TRK-100STP: 0-360 mug/day for 12 weeks) was administered to 4 patients with mild to moderate PAH. The patients tolerated the drug well with mild adverse manifestations and negligible effects on the systemic circulation. In contrast, pulmonary vascular resistance decreased by 27+/-12% and the 6-min walk test distance increased by 11+/-11%.. TRK-100STP is a novel option in the medical management of patients with PAH.

Topics: Administration, Oral; Adult; Blood Circulation; Dose-Response Relationship, Drug; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pilot Projects; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive disease with a bad prognosis. Prostanoids are well established in the medical treatment of this disease. Treatment of patients with progressive disease despite prostanoids remains a therapeutic challenge. In this study, we examined the effect of adding bosentan, an endothelin antagonist, to existing prostanoid therapy on exercise capacity (6-min walking distance [6MWD]) and right ventricular (RV) function (Tei index) in patients with progressive pulmonary hypertension.. Prospective, nonrandomized, open-label study.. University hospital.. Sixteen patients with pulmonary hypertension (PAH, n = 10; pulmonary hypertension due to other cause, n = 6) with progressive disease receiving either beraprost (n = 3), inhaled iloprost (n = 10), or iloprost IV (n = 3).. Combination therapy with bosentan (final dosage, 125 mg bid) was initiated following an interval of 3-months minimum of unchanged prostanoid therapy.. Tei index, 6MWD, and New York Heart Association (NYHA) functional class were assessed prior to the initiation of combination therapy (baseline), at 6 months after initiation of combination therapy, and every 3 months thereafter. Two patients were followed up for 6 months only; all remaining patients reached a mean follow-up period (+/- SD) of 13.5 +/- 5.0 months (range, 9 to 22 months). 6MWD increased by 42.5 +/- 66 m at 6 months and 44.6 +/- 66 m at the last follow-up (both time points vs baseline, p < 0.001), and Tei index improved by -0.13 +/- 0.08 at 6 months and - 0.13 +/- 0.11 at the last follow-up (both time points vs baseline, p < 0.001). All patients reported subjective improvements. Nine of 16 patients exhibited improvement in NYHA functional class at 6 months. No side effects occurred that required dose adjustment or discontinuation of the study medication.. Bosentan administered to patients with progressive pulmonary hypertension receiving prostanoids resulted in an increased exercise capacity and an improved RV function. Bosentan therefore appears to be well suited for combination therapy with prostanoids in selected patients pending results of ongoing randomized trials.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Prostaglandins; Sulfonamides; Ultrasonography; Vasodilator Agents

Earlier studies have shown that administration of beraprost sodium (BPS), an orally active prostacyclin analogue, improves hemodynamics in patients with primary pulmonary hypertension (PH), but it is not known whether BPS has beneficial effects in secondary precapillary PH. The present study investigated the hemodynamic and hormonal parameters of 18 patients with secondary precapillary PH (8 patients with chronic thromboembolic PH, 7 with collagen vascular disease, and 3 with residual PH after surgery for atrial septal defect). Hemodynamics were repeatedly measured by right heart catheterization. Treatment with BPS improved New York Heart Association (NYHA) functional class in 10 of the 18 patients and significantly decreased pulmonary vascular resistance by 17% (12.9+/-1.1 to 10.7+/-1.2 Wood units, p<0.01). Circulating brain natriuretic peptide and uric acid significantly decreased from 246+/-61 to 215+/-65 pg/ml and from 6.5+/-0.6 to 5.3+/-0.3 mg/dl, respectively. In summary, BPS therapy improved NYHA functional class, hemodynamics, and hormonal parameters in patients with secondary precapillary PH. Thus, oral administration of BPS may be a new therapeutic strategy for the treatment of secondary precapillary PH.

Topics: Administration, Oral; Capillaries; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Thromboembolism; Vascular Diseases; Vasodilator Agents

This study investigated whether treatment with beraprost sodium (BPS), an orally active prostacyclin analog, improves hemodynamics and survival in patients with peripheral-vessel chronic thromboembolic pulmonary hypertension (CTEPH), for which there is no surgical option.. Oral administration of BPS has been shown to improve the hemodynamics and prognosis in patients with primary pulmonary hypertension; however, whether BPS has beneficial effects in CTEPH remains unknown.. Forty-three patients with peripheral-vessel CTEPH were classified into two groups: patients treated with BPS (BPS group, n = 20) and those without BPS (conventional group, n = 23). Baseline demographic and hemodynamic data did not significantly differ between the two groups.. BPS therapy improved New York Heart Association functional class in 10 patients (50%) and significantly decreased total pulmonary resistance from 18 +/- 6 to 15 +/- 8 Wood units (p < 0.05) [mean +/- SD]. Sixteen patients died of cardiopulmonary causes in the conventional group during a mean follow-up period of 58 +/- 45 months. In contrast, only three patients died of cardiopulmonary causes in the BPS group during a mean follow-up period of 44 +/- 30 months. The absence of BPS therapy, elevated total pulmonary resistance, heart rate, and age were independently related to the mortality by Cox proportional hazard analysis. The 1-year, 3-year, and 5-year survival rates for the BPS group were 100%, 85%, and 76%, respectively, compared to 87%, 60%, and 46% in the conventional group.. This preliminary study suggests that oral administration of BPS may improve hemodynamics and survival in patients with peripheral-vessel CTEPH, for which there is no surgical option.

Topics: Administration, Oral; Chronic Disease; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Vasodilator Agents

The purpose of this study was to assess the safety and efficacy of the oral prostacyclin analogue beraprost sodium during a 12-month double-blind, randomized, placebo-controlled trial in patients with pulmonary arterial hypertension (PAH).. Pulmonary arterial hypertension is a progressive disease that ultimately causes right heart failure and death. Despite the risks from its delivery system, continuous intravenous epoprostenol remains the most efficacious treatment currently available.. A total of 116 patients with World Health Organization (WHO) functional class II or III primary pulmonary hypertension or PAH related to either collagen vascular diseases or congenital systemic to pulmonary shunts were enrolled. Patients were randomized to receive the maximal tolerated dose of beraprost sodium (median dose 120 microg four times a day) or placebo for 12 months. The primary end point was disease progression; i.e., death, transplantation, epoprostenol rescue, or >25% decrease in peak oxygen consumption (VO(2)). Secondary end points included exercise capacity assessed by 6-min walk test and peak VO(2), Borg dyspnea score, hemodynamics, symptoms of PAH, and quality of life.. Patients treated with beraprost exhibited less evidence of disease progression at six months (p = 0.002), but this effect was not evident at either shorter or longer follow-up intervals. Similarly, beraprost-treated patients had improved 6-min walk distance at 3 months by 22 m from baseline and at 6 months by 31 m (p = 0.010 and 0.016, respectively) compared with placebo, but not at either 9 or 12 months. Drug-related adverse events were common and were related to the disease and/or expected prostacyclin adverse events.. These data suggest that beneficial effects may occur during early phases of treatment with beraprost in WHO functional class II or III patients but that this effect attenuates with time.

Topics: Administration, Oral; Adult; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epoprostenol; Exercise Tolerance; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Quality of Life; Severity of Illness Index; Tablets; Time Factors; Vasodilator Agents

Primary pulmonary hypertension (PPH) is a life-threatening disease. Nonparenteral prostanoids, i.e. aerosolised iloprost or oral beraprost sodium show beneficial therapeutic effects but are not sufficiently active in all patients with this devastating disease. The purpose of the present study was to determine whether the endothelin-receptor antagonist bosentan is safe and effective in patients with PPH already receiving nonparenteral prostanoids. The effect of bosentan as add-on medication was studied in 20 patients with PPH, who received either inhaled iloprost (n=9) or oral beraprost (n=11) for a median period of 16+/-13 months, by means of the 6-min walk test and cardiopulmonary exercise testing. After 3 months of administration of bosentan in addition to prostanoids, the walking distance in the 6-min walk test increased by 58+/-43 m. Cardiopulmonary exercise testing revealed an increase in maximal oxygen consumption from 11.0+/-2.3 to 13.8+/-3.6 mL x kg(-1) x min(-1) accompanied by significant improvements in anaerobic threshold, oxygen pulse and minute ventilation/carbon dioxide production slope. Peak systolic blood pressure increased from 120+/-17 to 139+/-21 mmHg. Combination treatment was well tolerated by all patients. It is concluded that the addition of the endothelin-receptor antagonist bosentan to inhaled iloprost or oral beraprost therapy appears to be safe for patients with primary pulmonary hypertension, resulting in a marked increase in exercise capacity. Therefore, rigorous studies should address whether combination treatment is more effective than either therapeutic intervention alone.

Topics: Administration, Inhalation; Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Pilot Projects; Sulfonamides; Treatment Outcome; Vasodilator Agents

Although long-term prostacyclin(PGI2) therapy in patients with severe pulmonary hypertension (PH)reduces pulmonary vascular resistance (PVR), there have been no reports on its therapeutic effects in patients with mild PH. We investigated the chronic effect of beraprost sodium (BPS), an oral PGI2 analog, in children with mild PH.. We studied 20 patients who were destined for a Fontan procedure with a mean pulmonary arterial pressure(PAP) of>20 mmHg and/or PVR of>3.0 Wood units. Both the PAP and the PVR in these cases were too high for patients to undergo a successful Fontan procedure. Seven patients received BPS (PG group) and 13 did not (control group). All patients underwent repeat cardiac catheterization to examine pulmonary hemodynamics.. In the PG group, the pulmonary-to-systemic flow ratio (Qp/Qs) did not change after BPS administration(1.1 +/- 0.6 vs 1.3 +/- 0.9);however, the mean PAP decreased significantly (25.3 +/- 8.2 vs 19.9 +/- 6.5 mmHg; P < 0.05),as did PVR (3.7 +/- 1.3 vs 2.3 +/- 0.9 Wood units; P < 0.05), whereas the pulmonary artery (PA) index increased significantly (312 +/- 136 vs 375 +/- 165; P < 0.05). In the control group, the mean PAP decreased significantly (24.9 +/- 4.7 vs 19.8 +/- 6.3 mmHg; P < 0.05)and the PA index increased significantly (295 +/- 72 vs 362 +/- 114; P < 0.05). No significant changes in Qp/Qs (1.5 +/- 0.8 vs 1.4 +/- 0.6)or PVR (2.9 +/- 1.3 vs 2.5 +/- 0.8 Wood units) were observed.. We conclude that long-term BPS administration probably reduces PVR in potential candidates for a Fontan procedure with mild PH. This treatment would reduce the risks associated with the Fontan procedure and would also improve its outcome.

Topics: Adolescent; Child; Child, Preschool; Contraindications; Epoprostenol; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Pulmonary Circulation; Vascular Resistance; Vasodilator Agents

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

To evaluate the effects of one year's treatment with beraprost, an orally active prostacyclin analogue, in patients with severe pulmonary hypertension.. 13 patients with severe pulmonary hypertension. This was primary in nine, thromboembolic in three, and caused by Eisenmenger syndrome in one.. All patients underwent right heart catheterisation. Mean (SD) right atrial pressure was 5 (3) mm Hg, mean pulmonary artery pressure was 48 (12) mm Hg, cardiac index was 2.6 (0.8) l/min/m(2), and mixed venous oxygen saturation was 68 (7)%. Beraprost was started at the dose of 20 microgram three to four times a day (1 microgram/kg/day), increasing after one month to 40 microgram three to four times a day (2 microgram/kg/day), with further increases of 20 microgram three to four times a day in case of clinical deterioration.. New York Heart Association (NYHA) functional class, exercise capacity measured by distance walked in six minutes, and systolic pulmonary pressure (by echocardiography) were evaluated at baseline, after one month's treatment, and then every three months for a year.. After the first month of treatment, NYHA class decreased from 3.4 (0.7) to 2.9 (0.7) (p < 0.05), the six minute walking distance increased from 213 (64) to 276 (101) m (p < 0.05), and systolic pulmonary artery pressure decreased from 93 (15) to 85 (18) mm Hg (NS). One patient died after 40 days from refractory right heart failure, and another was lost for follow up at six months. The 11 remaining patients had persistent improvements in functional class and exercise capacity and a significant decrease in systolic pulmonary artery pressure in the period from 1-12 months. Side effects were minor.. Oral administration of beraprost may result in long lasting clinical and haemodynamic improvements in patients with severe pulmonary hypertension.

Topics: Administration, Oral; Adolescent; Adult; Blood Pressure; Child; Eisenmenger Complex; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Long-Term Care; Male; Middle Aged; Prospective Studies; Thromboembolism; Vasodilator Agents

This study sought to investigate the effect of beraprost sodium (BPS), an orally active prostacyclin analogue, on the survival of outpatients with primary pulmonary hypertension (PPH).. Continuous intravenous administration of epoprostenol (prostacyclin) has been shown to improve survival in PPH. However, the effect of oral BPS on survival in PPH remains unknown.. Fifty-eight consecutive patients with PPH who could be discharged after the first diagnostic catheterization for PPH were retrospectively divided into two groups: patients treated with BPS (BPS group, n = 24) and those without BPS (conventional group, n = 34). The baseline demographic and hemodynamic data did not significantly differ between the two.. Twenty-seven patients died of cardiopulmonary causes in the conventional group during a mean follow-up period of 44 +/- 45 months. In contrast, only 4 patients died of cardiopulmonary causes in the BPS group during a mean follow-up period of 30 +/- 20 months. In a subsample (n = 15) of patients in the BPS group, mean pulmonary arterial pressure and total pulmonary resistance significantly decreased, respectively, by 13% and 25% during a mean follow-up period of 53 days. Among the variables previously known to be associated with the mortality in PPH, the absence of BPS therapy and the reduced cardiac output were independently related to the mortality by a multivariate Cox proportional hazards regression analysis (both p < 0.05). The Kaplan-Meier survival curves demonstrated that the one-, two- and three-year survival rates for the BPS group were 96%, 86% and 76%, respectively, as compared with 77%, 47% and 44%, respectively, in the conventional group (log-rank test, p < 0.05).. The oral administration of BPS may have beneficial effects on the survival of outpatients with PPH as compared with conventional therapy alone.

Topics: Administration, Oral; Adult; Cause of Death; Dose-Response Relationship, Drug; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Retrospective Studies; Survival Rate; Vasodilator Agents

Topics: Administration, Oral; Adult; Epoprostenol; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged; Vasodilator Agents

Prostacyclin (PGI2) is a bioactive substance produced by vascular endothelial cells, which exerts powerful vasodilative and anti-platelet actions. Patients with pulmonary hypertension have an imbalance between vasodilative PGI2 and vasoconstrictive thromboxane B2 (TXB2). Treatment with vasodilative agents is essential for such patients. Continuous intravenous infusion of PGI2 is an effective treatment of primary pulmonary hypertension in terms of exercise capacity and survival rate. We tested a new stable PGI2 analogue, beraprost sodium (Procyclin, Dornar) suitable for oral administration, in patients with primary and secondary pulmonary hypertension. A short-term study of cardiac catheterization in four patients with primary pulmonary hypertension showed a 15 +/- 12% reduction in mean pulmonary artery pressure in three of the four patients, and a 24 +/- 22% decrease in pulmonary vascular resistance in all four patients. Cardiac index increased by 27 +/- 14% in three of the four patients. Among three patients with secondary pulmonary hypertension, there was a 7% reduction in pulmonary artery pressure in one patient, and a 24 +/- 14% decrease in pulmonary vascular resistance in all three patients. In a long-term study (23 +/- 11 months), NYHA functional class improved from 3.0 +/- 0.7 to 2.4 +/- 0.5 in two of the five patients with primary pulmonary hypertension. Although the radiographic cardiothoracic ratio was not significantly improved, cardiac index increased by 78 +/- 60% in four of the five patients. Only two patients, one with primary and one with secondary pulmonary hypertension, died during the long-term follow-up period. Plasma TXB2/6-keto prostaglandin F1 alpha ratio decreased from 8.1 +/- 8.7 to 1.5 +/- 0.4. The optimal dose remains uncertain, but the initial dosage of 40-60 micrograms/day given in three to four doses for adult patients is considered to be acceptable. Side effects such as flushing face, headache, vomiting, and nausea were mild and resolved when the dose was reduced. Oral PGI2, beraprost, appears to be an effective and possibly adequate substitute for intravenous vasodilators in pulmonary hypertension for both short- and long-term management.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infant; Male; Middle Aged; Platelet Aggregation Inhibitors; Pulmonary Circulation; Pulmonary Wedge Pressure; Thromboxane B2; Time Factors; Vascular Resistance; Vasodilator Agents

This study aims to assess the cost-effectiveness and budget impact of adopting sildenafil to the benefits package for the indication of pulmonary arterial hypertension (PAH), compared to beraprost.. Based on a societal perspective, a model-based economic evaluation was performed using local and international data to quantify the potential costs and health-related outcomes in terms of life years (LYs) and quality-adjusted life years (QALYs).. The economic model calculated the incremental cost-effectiveness ratio (ICER) per QALY gained for using sildenafil as first-line therapy compared to beraprost for the patient in functional class (FC) II and III, i.e. USD 3098 and USD 2827, respectively. The results indicated that in spite of sildenafil being more expensive than beraprost, generic sildenafil could potentially be a good value for money since ICER per QALY is below one times gross domestic product (GDP) per capita in Indonesia. Furthermore, budget impact analysis estimated that the incremental budget needed within 5 years for including sildenafil compared to beraprost for PAH patients starting in FC II and FC III was USD 436,775 and USD 3.6 million, respectively.. Compared to beraprost, sildenafil would be preferable for the treatment of PAH patients in FC II and FC III in Indonesia. The additional budget for adopting sildenafil compared to beraprost as the treatment of PAH in the benefits package was estimated at around USD 4.0 million.

Topics: Budgets; Cost-Benefit Analysis; Epoprostenol; Humans; Hypertension, Pulmonary; Indonesia; Sildenafil Citrate; Vasodilator Agents

Beraprost is used to treat peripheral chronic arterial occlusive disease. However, the efficacy and safety of beraprost in patients with pulmonary hypertension (PH) due to left ventricular systolic dysfunction (PH-HFrEF) remains unknown. The primary objective of this study was to determine the effects of beraprost on PH-HFrEF.We prospectively recruited patients with PH-HFrEF as determined by echocardiography and right cardiac catheterization. Beraprost sodium was given orally (1 μg/kg/d) added to the usual treatment, and patients were evaluated at 1-year follow-up.Twenty-five patients were recruited with baseline systolic pulmonary artery pressure (PAP) of 49.5 ± 10.8 mm Hg. Systolic PAP results at 3, 6, 9, and 12 months were 39.1 ± 8.1, 30.4 ± 5.2, 27.7 ± 3.0, and 27.0 ± 4.7 mm Hg, respectively, which were all significantly lower than systolic PAP at baseline (P < .05). Left ventricular ejection fraction results at 6 months (43.5 ± 7.0%), 9 months (47.0 ± 5.5%), and 12 months (48.2 ± 4.8%) were significantly higher than at baseline (34.7 ± 9.2%) (P < .05). Six-minute walking distance at 3 months (282.8 ± 80.6 m), 6 months (367.1 ± 81.2 m), 9 months (389.8 ± 87.1 m), and 12 months (395.7 ± 83.4 m) increased with time, and all were significantly higher than baseline (190.1 ± 75.5 m) (P < .05). One patient developed atrial fibrillation and recovered to sinus rhythm after intravenous administration of amiodarone. There were no instances of cardiac-related death, severe bleeding, or severe impairment of liver function.Routine oral administration of beraprost sodium added to the usual treatment may improve cardiopulmonary hemodynamics and exercise capacityin patients with PH-HFrEF.

Topics: Administration, Oral; Aged; Echocardiography; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Pilot Projects; Prospective Studies; Pulmonary Wedge Pressure; Systole; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Left; Walking

Beraprost is a prostacyclin analogue and IP receptor agonist which is approved to treat pulmonary arterial hypertension (PAH) in Asia. The beraprost-314d isomer (esuberaprost) is one of four stereoisomers contained within the racemic mixture of beraprost. The pharmacological profile of esuberaprost is now evaluated to determine how stereoisomer separation affects its potency and mode of action in functional assays.. Vascular tone was assessed using wire myography in rat and human distal pulmonary arteries (PAs) pre-contracted with U46619 (100 nM). HEK-293 cells stably expressing the human IP receptor (HEK-293-IP) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients were used to assess cyclic AMP (cAMP) generation and cell proliferation, respectively.. Esuberaprost relaxed rat PAs with a 5-fold greater potency compared with beraprost, and effects were strongly inhibited by RO3244794 (IP receptor antagonist) or L-NAME (NO synthase inhibitor). Esuberaprost caused EP. Stereoisomer separation of beraprost has a significant effect on the pharmacology of the individual isomer, esuberaprost, identified in vitro as a highly potent prostanoid IP receptor agonist.

Topics: Animals; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Epoprostenol; Female; HEK293 Cells; Humans; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Vasodilation; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease characterized by elevated pulmonary vascular resistance, which results in right-heart failure. We present a case of interferon (IFN)-α-induced PAH developed after living donor liver transplantation. Although IFN is categorized as a "possible" risk factor for PAH in the current international classification, it is still under recognized. Moreover, the prognosis of IFN-induced PAH is poor in the limited number of published cases. In our case, we achieved good outcome by the withdrawal of IFN and administration of combination therapy using tadalafil, beraprost, and treprostinil. Since IFN is an important treatment option in current medical therapy, its contribution to the pathogenesis of PAH should be taken into consideration. In conclusion, our case suggests the importance of PAH screening in patients treated with IFN.

Topics: Antihypertensive Agents; Arterial Pressure; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Immunologic Factors; Interferon-alpha; Liver Transplantation; Living Donors; Male; Middle Aged; Pulmonary Artery; Tadalafil; Treatment Outcome

This study aims to compare the lifetime costs and health outcomes of both first-line and sequential combination treatments with standard treatment for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) (PAH-CHD) patients.. A cost-utility analysis was performed using a Markov model based on a societal perspective. One-way and probabilistic sensitivity analyses were performed to investigate the effect of parameter uncertainty.. As first-line treatments, both beraprost (incremental cost-effectiveness ratio (ICER) = 192,752 and 201,308 Thai baht (THB) per quality-adjusted life year (QALY) gained) and sildenafil (ICER = 249,770 and 226,802 THB per QALY gained) seemed cost-effective for PAH-CHD patients aged ≤30 years in functional classes II and III, respectively, while no treatment was cost-effective for the sequential combination therapy.. Sildenafil should be included in the National Drug List of Essential Medicines as the first-line treatment for PAH-CHD, and its price per dose should be negotiated to be reduced by 43-57%.

Topics: Adult; Budgets; Cost-Benefit Analysis; Drug Costs; Drugs, Essential; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Markov Chains; Quality-Adjusted Life Years; Sildenafil Citrate; Thailand; Vasodilator Agents

Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.

Topics: Adolescent; Adult; Animals; Cell Hypoxia; Cell Proliferation; Child; Disease Models, Animal; Drug Delivery Systems; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Myocytes, Smooth Muscle; Nanoparticles; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Time Factors; Young Adult

Prostaglandin I2 (PGI2) and its analogues (such as beraprost sodium, BPS) are beneficial for the treatment of pulmonary arterial hypertension (PAH). The encapsulation of BPS in nanoparticles to provide sustained release and targeting abilities would improve both the therapeutic effect of BPS on PAH and the quality of life of patients treated with this drug. BPS was encapsulated into nanoparticles prepared from a poly(lactic acid) homopolymer and monomethoxy poly(ethyleneglycol)-poly(lactide) block copolymer. The accumulation of nanoparticles in damaged pulmonary arteries was examined using fluorescence-emitting rhodamine S-encapsulated nanoparticles. The monocrotaline-induced PAH rat model and the hypoxia-induced mouse model were used to examine the pharmacological activity of BPS-encapsulated nanoparticles. A nanoparticle, named BPS-NP, was selected among various types of BPS-encapsulated nanoparticles tested; this was based on the sustained release profile in vitro and blood clearance profile in vivo. Fluorescence-emitting rhodamine S-encapsulated nanoparticles were prepared in a similar manner to that of BPS-NP, and showed accumulation and prolonged residence in monocrotaline-damaged pulmonary peripheral arteries. Intravenous administration of BPS-NP (once per week, 20μg/kg) protected against monocrotaline-induced pulmonary arterial remodeling and right ventricular hypertrophy. The extent of this protection was similar to that observed with oral administration (once per day, 100μg/kg) of BPS alone. The once per week intravenous administration of BPS-NP (20μg/kg) also exhibited an ameliorative effect on hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy. The beneficial effects of BPS-NP on PAH animal models seem to be mediated by its sustained release and tissue targeting profiles. BPS-NP may be useful for the treatment of PAH patients due to reduced dosages and frequency of BPS administration.

Topics: Animals; Capillary Permeability; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Epoprostenol; Hypertension, Pulmonary; Lactic Acid; Male; Mice, Inbred C57BL; Monocrotaline; Nanoparticles; Polyesters; Polyethylene Glycols; Polymers; Pulmonary Artery; Rats, Wistar; Rhodamines

Therapeutic strategies for pulmonary arterial hypertension (PAH) associated with atrial septal defect (ASD) remain a matter of debate.. We identified 5 outpatients who had been diagnosed with ASD-PAH and undergone ASD closure in combination with targeted therapy with certified PAH drugs. We assessed changes in hemodynamic parameters and exercise capacity. The combination of ASD closure and targeted therapy significantly increased systemic blood flow (Qs) from the baseline (from 3.3 ± 0.6 L/minute to 4.2 ± 1.0 L/minute, P < 0.05) with a significant improvement in the World Health Organization Functional Class (WHO-FC; from 2.8 ± 0.4 to 1.6 ± 0.5, P < 0.05). The hemodynamic data before and after ASD closure without targeted therapy showed further elevation of pulmonary vascular resistance shortly after ASD closure (678 dyne · s/cm(5) to 926 dyne · s/cm(5)) in 1 case, as well as after a long time since ASD closure (491.0 ± 53.7 dyne · s/cm(5) to 1045.0 ± 217.8 dyne · s/cm(5)) in 2 cases. This worsening was reversed after the targeted therapy, accompanied by an increase in Qs and an improvement in WHO-FC in all cases.. Targeted therapy should be added to ASD closure in adult patients with ASD-PAH.

Topics: Adult; Antihypertensive Agents; Atrial Septum; Bosentan; Cardiac Catheterization; Cardiac Surgical Procedures; Disease Management; Epoprostenol; Exercise Tolerance; Female; Heart Septal Defects, Atrial; Hemodynamics; Humans; Hypertension, Pulmonary; Japan; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sulfonamides; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Recent vasodilating drugs have improved prognosis of Pulmonary arterial hypertension (PAH). Some reports describe the merits of combination therapies for PAH, and this study evaluated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5i) combination therapy, using sildenafil and tadalafil, for multi-drug-resistant PAH.. We retrospectively analyzed 7 consecutive refractory patients with PAH administered either sildenafil 60 mg or tadalafil 40 mg as well as both ERA and prostanoid as combination therapies. All were started on the dual PDE5i (sildenafil and tadalafil at maximum dose).. Treatment was generally well tolerated without severe adverse events. On completion of the study, the seven patients received right heart catheterization and the 6-minute walk test (6WMT) 9.6 ± 1.4 months after initiation of the dual PDE5i therapy, showing significant improvements in hemodynamic parameters and exercise tolerance. Mean pulmonary arterial pressure and pulmonary vascular resistance decreased from 47.9 ± 9.7 to 41.7 ± 9.2 mmHg (P = 0.004) and 9.3 ± 2.7 to 6.7 ± 2.9 mmHg (P = 0.018), respectively. Cardiac index and 6MWT also increased from 2.8 ± 0.9 to 3.1 ± 0.8 L/min/m(2) (P = 0.026) and 353 ± 60 to 382 ± 62 m (P = 0.014), respectively.. The findings support dual PDE5i therapy as a new treatment option for refractory PAH.

Topics: Adult; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Middle Aged; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pilot Projects; Prostaglandins; Pulmonary Wedge Pressure; Pyridazines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Tadalafil; Treatment Outcome; Vascular Resistance; Young Adult

Beraprost was developed as the first oral prostacyclin analog to treat patients with pulmonary arterial hypertension (PAH). Although this drug demonstrates improvements in the patient's exercise capacity and symptoms, it carries a weak recommendation in the PAH evidence-based treatment algorithm due to a lack of durability of effects. However, this therapy remains a major treatment method in Japan due to its availability and inexpensive cost. The purpose of this study was to elucidate whether this drug exhibits durable effects on sustained overall survival.. A comparison of survival benefits was completed among patients undergoing treatment with beraprost (n=35) or conventional therapy (n=44). In addition, the estimated survival calculated using the equation developed by the National Institutes of Health Registry was used for the analysis.. Although no significant differences were observed between the two groups using the Kaplan-Meier survival curve, a statistical difference was observed between the patients receiving high-dose beraprost therapy (>120 μg) and those receiving conventional therapy (5- and 10-year survival: 71.1% and 49.4% vs. 37.7% and 21.2%, respectively; p=0.0466). Moreover, the cumulative survival rates in the patients receiving beraprost were slightly better than the estimated survival rates. In the PAH patients with connective tissue diseases, a tendency towards better survival outcomes was observed in the group treated with beraprost.. This study suggests the survival benefits of high-dose beraprost therapy for patients with PAH. The retrospective nature of this study, however, makes it difficult to conclude definitively that beraprost exerts significant beneficial effects on survival.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Pulmonary Wedge Pressure; Retrospective Studies; Survival Rate; Time Factors; Treatment Outcome; Vasodilator Agents; Young Adult

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

Right ventricular (RV) dysfunction, caused by severe pulmonary hypertension (PH), is associated with high mortality because of RV failure. However, some patients can suffer from sudden cardiac death (SCD). We hypothesized that severe PH can cause RV arrhythmogenesis, leading to SCD. We sought to investigate arrhythmogenesis in PH. Optical mapping analysis (OMP) with an electrophysiological study (EPS) and pathological examination were performed in a monocrotaline (MCT)-induced rat PH model. Rats were injected with MCT (60 mg/kg), and OMP was performed in isolated Langendorff-perfused hearts. OMP revealed abnormal RV conduction delays and abnormal patterns, along with elevated RV pressure. In addition, impaired action potential duration dispersion (APDd), an index of myocardial repolarization instability, was observed only in the RVs with severe PH. The EPS demonstrated that lethal arrhythmias were induced by burst pacing to the RV when deteriorated APDd became evident. This arrhythmogenesis was inhibited by combination treatment with sildenafil and beraprost (SIL + BERA). RT-PCR showed an mRNA up-regulation of Type I collagen and down-regulation of connexin-43 in the RV at 5 weeks after MCT injection. Pathological examination revealed pulmonary vascular remodeling and RV hypertrophy with interstitial fibrosis, which was substantially reduced by SIL + BERA. Immunohistochemistry also revealed connexin-43 degradation in the RVs with severe PH. In contrast, connexin-43 was well preserved, and no lethal arrhythmias were induced by burst pacing to the RV in the absence of PH after SIL + BERA. In conclusion, RV electrical remodeling, including impaired APDd, causes arrhythmogenesis in severe PH, potentially associated with SCD attributable to PH.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Collagen Type I; Connexin 43; Death, Sudden, Cardiac; Drug Therapy, Combination; Epoprostenol; Gene Expression Regulation; Heart; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Organ Culture Techniques; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Right; Ventricular Remodeling; Voltage-Sensitive Dye Imaging

To explore the protective effects of beraprost plus simvastatin on monocrotaline-induced pulmonary arterial hypertension in rats.. Forty male Sprague-Dawley rats were allocated to control (C), untreated pulmonary arterial hypertension (P), beraprost (B), simvastatin (S) and combination groups (Com) (n = 8 each). Normal saline was injected subcutaneously into group C and then there was no other intervention for 21 days. Group P, B, S and Com rats received subcutaneous injections of monocrotaline (MCT, 60 mg/kg) and then isovolumetric normal saline, beraprost (100 µg·kg(-1)·d(-1)), simvastatin (2 mg·kg(-1)·d(-1)) and beraprost (100 µg·kg(-1)·d(-1)) plus simvastatin (2 mg·kg(-1)·d(-1)) by daily gastric lavage for 21 days. At Day 22, heart rate (HR), mean arterial pressure (MAP) and mean pulmonary pressure (mPAP) were detected and right heart ventricular hypertrophy index (RVHI) was calculated. The histopathology changes and tunica media thickness percentage of pulmonary arteries (WT%) were evaluated by pulmonary tissue staining. The results were analyzed statistically.. The differences of HR and MAP were not significant among 5 groups (all P > 0.05). The levels of mPAP, RVHI and WT% in group B ((27.4 ± 3.7) mm Hg, 0.35 ± 0.03, 26.7% ± 2.4%), group S ((29.9 ± 4.4) mm Hg, 0.36 ± 0.03, 28.2% ± 1.9%) and group Com ((23.1 ± 3.9) mm Hg, 0.32 ± 0.03, 17.4% ± 3.3%) were lower than those in group P ((35.4 ± 5.7) mm Hg, 0.41 ± 0.05, 42.8% ± 5.9%) (all P < 0.05).. The combined use of beraprost and simvastatin may delay the increase of mPAP and remodeling of pulmonary vessels and inhibit right ventricular hypertrophy in pulmonary arterial hypertension rats. Its efficacy is superior to that of monotherapy.

Topics: Animals; Drug Therapy, Combination; Epoprostenol; Hypertension, Pulmonary; Male; Monocrotaline; Rats; Rats, Sprague-Dawley; Simvastatin

To elucidate left ventricular function in pulmonary hypertension, we measured parameters of left ventricular as well as right ventricular function by echocardiography in 11 patients with pulmonary hypertension (idiopathic pulmonary artery hypertension in 4, chronic thromboembolic pulmonary hypertension in 5, and other pulmonary hypertension in 2). The percent change in these parameters 6 months after treatment with pulmonary artery vasodilators (beraprost in 8 and sildenafil in 3) was assessed. There was a correlation between the relative change in right ventricular systolic pressure (RVSP) and the relative changes in left ventricular outflow tract velocity-time integral (r = -0.730, P = 0.011) and mitral valve velocity-time integral (r = -0.621, P = 0.041). However, there was no correlation between the relative change in RVSP and the relative changes in left ventricular ejection fraction, left ventricular diastolic dimension, and systolic blood pressure. The relative change in RVSP was also correlated with the relative change in early diastolic myocardial velocity at the medial mitral annulus (r = -0.675, P = 0.023). Reduction of RVSP by pulmonary artery vasodilators might increase left ventricular preload, leading to an increase in stroke volume. Right ventricular load reduction might improve left ventricular diastolic function in patients with pulmonary hypertension, possibly through altered interventricular septal performance.

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Blood Pressure; Diastole; Echocardiography, Doppler; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Linear Models; Male; Middle Aged; Mitral Valve; Piperazines; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Systole; Time Factors; Treatment Outcome; Vasodilator Agents; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right; Ventricular Function, Left; Ventricular Function, Right; Ventricular Pressure

The development of right ventricular (RV) dysfunction in pulmonary hypertension (PH) patients is associated with adverse outcome, so that the assessment of RV function has become increasingly important in the management of such patients. The present objective was to test the hypothesis that RV free-wall longitudinal speckle-tracking strain (RV-free), an independent echocardiographic predictor of hemodynamic RV performance, can predict long-term outcome.. Forty-two PH patients were studied. RV-free was calculated by averaging the 3 regional peak systolic strains for the RV free wall. For comparison, tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, RV index of myocardial performance, and tissue Doppler-derived tricuspid lateral annular systolic velocity were also studied. Long-term follow-up was performed for 4 years after adding PH-specific drugs. Receiver operating characteristic curve analysis identified RV-free ≤ 19.4% as the best predictor of cardiovascular events with 90% sensitivity, 69% specificity, and area under the curve of 0.819 (P=0.0001). Furthermore, the Kaplan-Meier curve indicated that patients with RV-free >19.4% experienced fewer cardiovascular events than those with RV-free ≤ 19.4% (log-rank P=0.0008). Importantly, the co-occurrence of RV-free ≤ 19.4% and TAPSE <16 mm was associated with the highest frequency of cardiovascular events.. RV-free may serve as a non-invasive predictor of cardiovascular events for PH patients. Combining RV-free with TAPSE may be more effective for predicting long-term cardiovascular events.

Topics: Aged; Antihypertensive Agents; Bosentan; Echocardiography, Doppler; Epoprostenol; Female; Follow-Up Studies; Heart Ventricles; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Longitudinal Studies; Male; Middle Aged; Predictive Value of Tests; Prognosis; ROC Curve; Sensitivity and Specificity; Sulfonamides; Vasodilator Agents; Ventricular Dysfunction, Right

Pulmonary hypertension (PH) is an infrequently reported complication after hematopoietic stem cell transplantation, and its etiology and therapeutic strategies, especially in infants, remain unclear. We report a case of severe PH that developed in an infant with acute leukemia following administration of busulfan as a preconditioner for cord blood transplantation; the case was successfully treated with sildenafil and beraprost, which to our knowledge is the first reported successful use of this regimen in PH following transplantation for infantile leukemia. From a review of all previous reports, use of busulfan in infants may raise the risk of developing PH, and unlike definitive pulmonary veno-occlusive disease, PH in this subgroup may be reversible by early detection and treatment.

Topics: Cord Blood Stem Cell Transplantation; Echocardiography; Epoprostenol; Humans; Hypertension, Pulmonary; Infant; Leukemia; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

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

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

Selective right pulmonary arteriography and 3-dimensional computed tomography revealed multiple severe stenoses of the peripheral pulmonary artery associated with poststenotic aneurysms in a 65-year-old woman. She was referred to the hospital for evaluation of dry cough, gradually increasing dyspnea and multiple nodular shadows on a chest radiograph. Echocardiography and cardiac catheterization showed severe pulmonary hypertension, though other structural heart diseases or well-characterized congenital syndromes were ruled out. She was diagnosed as isolated peripheral pulmonary artery branch stenosis. Recent advances in CT technology enable a less-invasive assessment of pulmonary artery, and can be useful in the management of pulmonary arterial hypertension.

Topics: Aged; Aneurysm; Arterial Occlusive Diseases; Cardiac Catheterization; Constriction, Pathologic; Cough; Dyspnea; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Imaging, Three-Dimensional; Oxygen Inhalation Therapy; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Ultrasonography; Vasodilator Agents; Warfarin

Portopulmonary hypertension is a complication of chronic liver disease, which has significant effects on survival and prognosis. Although the pathogenesis of pulmonary arterial hypertension has been well known, portopulmonary hypertension is often underestimated in patients with chronic liver disease. Every clinician who manages patients with chronic liver disease complaining of dyspnea should consider portopulmonary hypertension because this disorder requires special treatment. Herein, a 40-year-old woman with liver cirrhosis who complained of dyspnea on exercise is presented. She was diagnosed with portopulmonary hypertension by echocardiography and right-heart catheterization. Beraprost was used to reduce the pulmonary arterial pressure and improve the symptoms. Her symptoms were improved after 2 weeks, and improved symptoms and reduced pulmonary arterial pressure were sustained for 18 months.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Cardiac Catheterization; Dyspnea; Echocardiography, Doppler; Epoprostenol; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Liver Cirrhosis; Time Factors; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a rare complication of glycogen storage disease (GSD), and several cases with a poor outcome have been reported. A 17-year-old boy, who was diagnosed with GSD at 1 year of age, complained of shortness of breath on exertion, and was diagnosed with PAH based on the echocardiographic findings. Beraprost sodium (BPS) was started, and his symptoms improved after 3 months of treatment. Eighteen months later, he experienced frequent episodes of syncope. Because increasing the dose of BPS was ineffective, he was admitted to hospital. The echocardiogram showed marked elevation of the right ventricular pressure and low cardiac output, and his symptoms deteriorated despite continuous infusion of olprinone hydrochloride. Because a single dose of sildenafil increased his cardiac output, treatment with 25 mg sildenafil twice daily was started. His symptoms gradually ameliorated, and 3 weeks later he left the hospital. Two months after starting sildenafil, the cardiac index and the serous B-type natriuretic peptide concentration had become normal. Sildenafil may be effective in patients with secondary PAH and in patients who have developed tolerance to BPS.

Topics: Administration, Oral; Adolescent; Antihypertensive Agents; Drug Tolerance; Echocardiography; Electrocardiography; Epoprostenol; Glycogen Storage Disease Type I; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Natriuretic Peptide, Brain; Piperazines; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfones; Syncope; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is often associated with congenital heart disease (CHD). Acute administration of beraprost reduces pulmonary vascular resistance in patients with idiopathic PAH and PAH associated with CHD; however, little is known about whether or not long-term treatment with oral beraprost benefits these patients. We report the case of a patient suffering from severe PAH associated with large patent ductus arteriosus (PDA), who was considered to be ineligible for PDA closure using a conventional treatment strategy. Eventually, long-term administration of oral beraprost ameliorated the degree of PAH and the patient subsequently underwent successful closure of the PDA.

Topics: Child, Preschool; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male

Beraprost sodium (BPS), a chemically stable and orally active prostacyclin analogue used for the treatment of chronic occlusive disease and primary pulmonary hypertension, was investigated in terms of its drug-drug interaction mediated by cytochrome P450. In a metabolic enzyme characterization study using P450-expressing insect cell microsomes, beraprost (BP) was slightly metabolized in the presence of CYP2C8, but not metabolized by the other P450 isoforms (CYP1A2, [corrected] CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11) at a concentration of 20 microM. These results suggest that none of the P450 isoforms is a major metabolic enzyme of BP. In a P450 induction study using human hepatocytes, BP did not induce any P450 isoform (CYP1A2, CYP2C9, CYP2C19, and CYP3A4) at concentrations of 1-100 microM. Furthermore, in a P450 inhibition study using human liver microsomes, BP did not inhibit any P450 isoform (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations of 0.05-1 microM. Therefore it is concluded that BP is not involved in drug-drug interaction mediated by P450 isoforms.

Topics: Antihypertensive Agents; Arterial Occlusive Diseases; Chronic Disease; Cytochrome P-450 Enzyme System; Drug Interactions; Epoprostenol; Humans; Hypertension, Pulmonary; In Vitro Techniques; Isoenzymes; Microsomes, Liver; Platelet Aggregation Inhibitors

A 33-year-old-man had severe secondary pulmonary hypertension due to perivalvular leakage at the aortic and mitral positions after aortic and mitral valve replacement. Preoperative cardiac catheterization revealed pulmonary artery pressure of 105/45 mmHg and pulmonary vascular resistance of 929 dynes.s.cm(-5) To save the patient, we performed aortic and mitral valve re-replacement, and tricuspid annuloplasty. After surgery, selective pulmonary vasodilators, beraprost sodium, inhaled nitric oxide, and intravenous prostaglandin (PG) I(2) were administered because of persistent severe pulmonary hypertension. Cardiac catheterization on postoperative day 58 showed that the pulmonary artery pressure and pulmonary vascular resistance had decreased to 40/20 mmHg and 87.7 dynes x s x cm(-5), respectively The simultaneous use of inhaled nitric oxide, intravenous PGI(2), and oral beraprost sodium might be useful for treating postoperative persistent pulmonary hypertension.

Topics: Administration, Inhalation; Administration, Oral; Adult; Antihypertensive Agents; Aortic Valve Insufficiency; Blood Pressure; Cardiac Catheterization; Combined Modality Therapy; Device Removal; Drug Therapy, Combination; Epoprostenol; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Mitral Valve Insufficiency; Nitric Oxide; Pulmonary Circulation; Reoperation; Severity of Illness Index; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Topics: Calcium Channel Blockers; Epoprostenol; Exercise Therapy; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Meta-Analysis as Topic; Research Design

We report a 16-year-old man with severe heart failure due to idiopathic pulmonary arterial hypertension (IPAH). The patient was initially treated with a combination of beraprost, a prostacyclin analog, and sarpogrelate, a serotonin receptor inhibitor. However, he was unresponsive to the treatment. We then changed the treatment to sildenafil, and his condition dramatically improved. Sildenafil has an immediate pulmonary vasodilator effect in patients already receiving vasodilators for IPAH.

Topics: Adolescent; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Serotonin Antagonists; Sildenafil Citrate; Succinates; Sulfones; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is commonly associated with CREST (Calcinosis, Raynaud phenomenon, Esophageal motility disorders, Sclerodactyly, and Telangiectasia) syndrome. Sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of PAH. However, little is known about the long-term hemodynamic effects of sildenafil, and the potential role of sildenafil in long-term combination with beraprost, an oral prostacyclin analogue, remains unclear. We therefore examined the hemodynamic effect of oral sildenafil alone and when coadministered with beraprost in a patient with PAH associated with CREST syndrome. Traces of the acute hemodynamic effects of beraprost (20 microg) disappeared after 2 hours. In contrast, the acute hemodynamic effects of sildenafil (50 mg) produced a greater reduction in PAP (31%) and PVR (40%), and these effects also disappeared after 5 hours. After 1 month of combination therapy of sildenafil (25 mg) twice daily and beraprost (20 microg) 3 times daily, the fall in pulmonary artery pressure and pulmonary vascular resistance was sustained (31% in both). Furthermore, the patient had significantly improved her 3-minute walk test and NYHA function class without significant adverse effects at the reported doses. The findings indicate that oral sildenafil is a potent pulmonary vasodilator that appears to act synergistically with oral beraprost to cause sustained pulmonary vasodilatation in a patient with PAH associated with CREST syndrome.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; CREST Syndrome; Cryoprotective Agents; Drug Therapy, Combination; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have previously demonstrated that long-term inhibition of Rho-kinase, an effector of the small GTPase Rho, ameliorates monocrotaline-induced PH in rats and hypoxia-induced PH in mice. We also have reported that prostacyclin and its oral analogue, beraprost sodium (BPS), may lack direct inhibitory effect on Rho-kinase in vitro, suggesting that combination therapy with a Rho-kinase inhibitor and BPS is effective for the treatment of PH. In this study, we addressed this point in monocrotaline-induced PH model in rats. Male Sprague-Dawley rats were given a subcutaneous injection of monocrotaline (60 mg/kg). They were maintained with or without the treatment with a Rho-kinase inhibitor, fasudil (30 mg/kg/day), BPS (200 microg/kg/day), or a combination of both drugs for 3 weeks. The combination therapy, when compared with each monotherapy, showed significantly more improvement in PH, right ventricular hypertrophy, and pulmonary medial thickness without any adverse effects. Plasma concentrations of fasudil were not affected by BPS. These results suggest that combination therapy with a Rho-kinase inhibitor and prostacyclin exerts further beneficial effects on PH.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Epoprostenol; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Protein Kinase Inhibitors; Pulmonary Artery; Random Allocation; Rats; Rats, Sprague-Dawley; Vasodilator Agents

To study whether there is any difference in the clinical characteristics between the two patterns of perfusion lung scan of idiopathic pulmonary arterial hypertension (normal vs. diffuse, multiple ill-defined defects) and whether the perfusion lung scan patterns of these patients would predict the effect of long-term use of beraprost sodium.. We evaluated 27 patients who used beraprost sodium for over 3 months, and noted a diffuse patchy pattern in 13 cases and a normal pattern in the remaining 14 cases. We judged that beraprost sodium was effective when at least two of the following conditions were met: improvement in symptom of dyspnea, more than 10% decrease in peak velocity of tricuspid valve regurgitation by echocardiography (Vmax), or more than 10% increase in 6-min walking distance.. At baseline there was no difference between the two groups in dyspnea, hemodynamic parameters, and 6-min walking distance. After the use of beraprost sodium, the normal group showed improvement in dyspnea, 6-min walking distance, and Vmax. But the diffuse patchy group showed no improvement. The use of beraprost sodium in the normal group was effective in 10 out of 14 cases, but was effective in only two out of 13 cases in the diffuse patchy group.. Perfusion lung scan pattern in patients with idiopathic pulmonary arterial hypertension is a useful prognostic indicator of the response to beraprost sodium.

Topics: Adolescent; Adult; Blood Pressure; Cardiac Output; Dyspnea; Echocardiography, Doppler; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Lung; Male; Perfusion; Prognosis; Pulmonary Artery; Radionuclide Imaging; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Prostanoids are a well-established therapy for pulmonary arterial hypertension (PAH), and observational studies suggest their efficacy even in chronic thromboembolic pulmonary hypertension (CTEPH) patients.. To compare the effects of 6 months of treatment with beraprost, an orally-active prostacyclin analog, in patients with distal CTEPH and PAH.. Case-control study.. Sixteen patients with severe pulmonary hypertension (NYHA II-IV), eight with distal CTEPH matched with eight patients with idiopathic PAH for similar effort tolerance.. All patients were in stable clinical and hemodynamic condition for 3 months with maximal standard therapy. During the titration phase (4 weeks) beraprost was increased to maximal tolerated dose (mean daily dosage: CTEPH 275 +/- 47 microg, PAH 277 +/- 47 microg) in adjunction of standard therapy, patients were followed-up for 6 months.. World Heart Organization (WHO) functional class, exercise capacity measured by distance walked in 6 min, and systolic pulmonary pressure (echocardiography), were evaluated at baseline, and at 1-, 3- and 6-month interval.. At 6 months WHO class decreased significantly in both groups (CTEPH from 2.7 +/- 0.6 to 2.0 +/- 0.24, p < 0.05; PAH from 3.0 +/- 0.26 to 2.1 +/- 0.25, p < 0.05), similarly the 6-min walk distance increased significantly from baseline (CTEPH from 312 +/- 31 to 373 +/- 29 m, p < 0.003; PAH from 303 +/- 31 to 347 +/- 29, p < 0.0003). Systolic pulmonary artery pressure showed a trend toward lower value (CTEPH from 85 +/- 7 m to 81 +/- 6 mm Hg, p = NS; PAH from 89 +/- 7 to 82 +/- 5, p = NS). During the observation period we did not have any death. The drug was well-tolerated with minor side-effects.. In patients with CTEPH beraprost had similar mid-term clinical and hemodynamic improvements than in patients with PAH.

Topics: Adult; Case-Control Studies; Chronic Disease; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Thromboembolism; Treatment Outcome

A 70-year-old man with a past history of lung resection for early stage lung cancer was admitted to our hospital because of worsening exertional dyspnea. Right heart catheterization revealed severe pulmonary arterial hypertension (PAH) with pulmonary vascular resistance of 1671.64 dyne.sec.cm(-5). The patient was treated with sildenafil added to an oral prostacyclin analog, beraprost, and long term oxygen therapy. His exertional dyspnea continued to improve until his sudden death following nasal bleeding. Autopsy revealed marked thickening of pulmonary arteriolar walls, but no recurrence of lung cancer, significant pulmonary embolism or pulmonary parenchymal disease. His PAH could not be explained by the mild airway obstruction or sleep apnea syndrome, and unrelated pulmonary vascular disease was suspected.

Topics: Aged; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Neoplasms; Male; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Piperazines; Pneumonectomy; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance

Primary pulmonary hypertension continues to be a fatal disease. We have recently demonstrated that long-term inhibition of Rho-kinase, an effector of the small GTPase Rho, is effective for the treatment of pulmonary hypertension (PH) in rats and humans. Prostacyclin has been clinically used for the treatment of PH with moderate success. However, it remains to be examined whether Rho-kinase inhibition is involved in its beneficial effects on PH. In an ELISA assay, neither prostacyclin nor its oral analogue, beraprost sodium, inhibited Rho-kinase even at higher concentrations (10(-7) to 10(-5) M, 100 to 10,000 times higher than their clinical concentrations), whereas specific Rho-kinase inhibitors, fasudil and hydroxyfasudil, markedly (approximately 95%) inhibited the Rho-kinase activity at 10(-5) M (near their clinical concentrations). Beraprost sodium did not significantly suppress serotonin-induced vascular smooth muscle cell (VSMC) contractions or Rho-kinase activity of the rat aorta without endothelium, as evaluated by the extent of phosphorylation of the ERM family, a substrate of Rho-kinase, whereas hydroxyfasudil markedly suppressed the VSMC contractions and Rho-kinase activity. These results indicate that prostacyclin lacks direct inhibitory effect on Rho-kinase and suggest that combination therapy with prostacyclin and a Rho-kinase inhibitor could exert further beneficial effects on PH.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Hypertension, Pulmonary; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Male; Platelet Aggregation Inhibitors; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; rho-Associated Kinases; Serotonin

Although sildenafil, an oral phosphodiesterase type-5 inhibitor, may offer benefits in the pharmacological management of pulmonary hypertension (PH), safety and effectiveness have not been studied during coadministration with beraprost, an oral prostacyclin analogue. To address this issue, we administered oral beraprost (40 microg) on day 1 and beraprost (40 microg) plus sildenafil (25 mg) on days 2 to 6 patients with moderate to severe PH. Although sildenafil plus beraprost produced transient flushing in 2 of 6 patients, systemic hemodynamics and arterial and venous gas analyses were similar in comparisons between the 2 treatment groups. In contrast, sildenafil plus beraprost therapy resulted in a 2.2-fold greater reduction in mean pulmonary arterial pressure and a 1.6-fold greater reduction in pulmonary vascular resistance compared with beraprost alone, and reductions in these parameters persisted longer with combination therapy than with beraprost alone. Addition of oral sildenafil to beraprost appears to represent a safe and effective therapeutic option, at least in the acute phase, for patients with pulmonary hypertension.

Topics: Administration, Oral; Aged; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones

10 years ago a now 49-year-old woman with Render-Osler-Weber disease showed unspecific symptoms of nausea, and general unwellness. Pulmonary manifestation of the disease was accompanied by pulmonary hypertension.. Teleangiectasia of the tongue and pharynx as well as of the mucosa of mouth and nose were observed. Fixed-splitting of the second heart sound with accentuated pulmonary component and a 2/6 systolic murmur over the tricuspid valve were heard. In addition, a murmur was heard dorsal over the right lung's lower lobe. Apart from minor oedema of both ankles, the physical status was not remarkable. Echocardiography showed dilatation of the right ventricle and a minor regurgitation of the tricuspid valve. The computed tomography showed dilatation of the pulmonary arteries as well as an arteriovenous malformation in the right lower lobe. Right-heart catheterisation revealed elevated pulmonary pressure. THERAPY AND FOLLOW-UP: Initial treatment with a calcium channel blocker proved insufficient and was changed to inhalative, and later to oral prostanoids. Under this treatment the cardiopulmonary state was stabilised, but episodes of epistaxis were increased. Two years after readjustment of the medication to a dual endothelin receptor antagonist, the cardiopulmonary state remains stable without significant haemorrhagic complications.. Prostanoid treatment in patients with Render-Osler-Weber disease and additional pulmonary hypertension can lead to an increased risk of haemorrhagic complications. Treatment with newer medications, such as endothelin receptor antagonists, seems indicated as successfully illustrated in our case.

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Diuretics; Endothelin Receptor Antagonists; Epistaxis; Epoprostenol; Female; Furosemide; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Nifedipine; Pedigree; Phenprocoumon; Pyridines; Sulfonamides; Telangiectasia, Hereditary Hemorrhagic; Treatment Failure; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a recognized complication of congenital heart disease. Despite differences in etiology and pathophysiology, successful therapy for idiopathic PAH may benefit in patients with congenital heart disease. We theorized that combination of oral and aerosolization prostacyclin will benefit this group of patients in long-term.. The study design was single group and open label study with intention to treat for patients with congenital heart disease with pulmonary artery (PA pressure) more than 50% of systemic pressure. All patients were given a combination of orally given beraprost sodium and inhalation of iloprost for 12 months. Data were collected prospectively consisting of functional class, O2 saturation, 6-minute walk test and right ventricular systolic pressure (RVSP).. There were 23 patients with an average right ventricular systolic pressure (+/- SD) of 94.8 +/- 14.5 mmHg and with average age of 27.8 +/- 14.9 years (2.5 to 50 years). The average oxygen saturation was 87.9 +/- 7 %. There were 12 patients with post surgical repair or cardiac catheterization interventional procedure and 11 with and Eisenmenger's syndrome. There were significant improvement of 6-minute-walk test from an average of 268 +/- 70 meters to 308 +/- 57 meters at the end of 12 months. The functional class of patients was also improving. However, there were no significant different in oxygen saturation.. Combination therapy of oral and inhalation of aerosolized vasodilators is a fascinating concept in the therapy of pulmonary hypertension. Treated patients showed an improvement in exercise capacity and right ventricular systolic pressure without a worsening in oxygen saturation.

Topics: Administration, Inhalation; Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Epoprostenol; Exercise Test; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Middle Aged; Oxygen; Vasodilator Agents; Ventricular Pressure

Sildenafil, an oral phosphodiesterase type-5 inhibitor, has vasodilatory effects through a cyclic guanosine 3', 5'-monophosphate-dependent mechanism, whereas beraprost, an oral prostacyclin analog, induces vasorelaxation through a cAMP-dependent mechanism. We investigated whether the combination of oral sildenafil and beraprost is superior to each drug alone in the treatment of pulmonary hypertension. Rats were randomized to receive repeated administration of saline, sildenafil, beraprost, or both of these drugs twice a day for 3 weeks. Three weeks after monocrotaline (MCT) injection, there was significant development of pulmonary hypertension. The increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight were significantly attenuated in the Sildenafil and Beraprost groups. Combination therapy with sildenafil and beraprost had additive effects on increases in plasma cAMP and cyclic guanosine 3', 5'-monophosphate levels, resulting in further improvement in pulmonary hemodynamics compared with treatment with each drug alone. Unlike MCT rats given saline, sildenafil, or beraprost alone, all rats treated with both drugs remained alive during 6-week follow-up. These results suggest that combination therapy with oral sildenafil and beraprost attenuates the development of MCT-induced pulmonary hypertension compared with treatment with each drug alone.

Topics: Administration, Oral; Analysis of Variance; Animals; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Male; Piperazines; Probability; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Survival Rate; Vascular Patency; Vasodilator Agents

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Epoprostenol; Hypertension, Pulmonary; Male; Piperazines; Purines; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Sildenafil Citrate; Sulfones; Treatment Outcome

Topics: Epoprostenol; Humans; Hypertension, Pulmonary; Nitric Oxide; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

The course of 12-year-old, homozygotic twins with primary pulmonary hypertension (PPH) treated with different vasoactive agents, beraprost vs epoprostenol, is described.. Clinical, exercise, and hemodynamic assessments were made at baseline, and at 9 months and 24 months of treatment.. Twin A had a rapid improvement with epoprostenol. In contrast, twin B, initially treated with beraprost, had progressive worsening with subsequent improvement on epoprostenol.. Epoprostenol was efficacious for identical twins with PPH. A 9-month delay in initiating epoprostenol for twin B did not appear to have irreversible short-term detrimental effects.

Topics: Antihypertensive Agents; Child; Diseases in Twins; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Twins, Monozygotic; Vasodilator Agents

Beraprost sodium (BPS)--an orally active prostacyclin analogue--improves haemodynamic parameters and quality of life in group of patients with pulmonary arterial hypertension. Effect of long-term therapy with BPS is not well defined. This study assesses influence of long-term therapy with BPS on the survival of patients with precapillary pulmonary hypertension. Studied group consisted of 25 patients with precapillary PH (18 F, 7M, aged 34 +/- 13,9 years). Sixteen patients were diagnosed with primary PH, 3 pts had PH associated with connective tissue disease, 5 pts developed PH in course of congenital systemic to pulmonary shunt, and 1 patient suffered from inoperable chronic thromboembolic PH. At time of diagnosis 15 pts presented exercise impairment of WHO class II and 10 pts were in functional class III. All studied subjects had complete hemodynamic assessment of right heart and obtained values were used for estimation of hypothetic survival using prognostic equation proposed by D'Alonzo et al. On follow-up period patients received BPS in the highest tolerated dose (80-480 mg daily). During a follow-up period (mean: 22 months) 7 patients died. Cumulative survival rate BPS group was significantly higher in BPS group comparing to hypothetical survival at 6 months (96% (95% CI: 88-104%) vs 73% (95% CI: 67-78%), p = 0.02) and 12 months (94% (95% CI: 84-104%) vs 65% (58-71%), p = 0.01), respectively. At 18 and 24 months differences between BPS virtual and hypothetical survival were not statistically significant. There was no correlation between survival and maximal achieved dose of BPS. These results suggest, that BPS improves prognosis of patients with precapillary PH during 12 months after initiation of therapy. Later effect of BPS seems to decrease, requiring changing or intensification of therapy.

Topics: Adolescent; Adult; Aged; Drug Administration Schedule; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Platelet Aggregation Inhibitors; Survival Analysis; Thromboembolism; Vasodilator Agents

To investigate whether the combination of an oral endothelin (ET)-A receptor antagonist and an oral prostacyclin(PGI2) analogue is superior to the single use of each drug alone for treating pulmonary hypertension(PH).. Treatment with intravenous PGI2 or an ET-A receptor antagonist was effective for PH; however, the effect of both administrations is unclear.. We administered the oral ET-A receptor antagonist TA-0201 and/or the oral PGI2 analogue beraprost sodium(BPS) to monocrotaline-induced PH rats for 19 days in the following groups: normal rats with vehicle treatment (Control group), PH rats with vehicle treatment (PH group), PH rats with TA-0201 treatment (PH + TA group), PH rats with BPS treatment (PH + BPS group), and PH rats with TA-0201 and BPS treatment (PH + TA + BPS group).. Right ventricular systolic pressure and Pp/Ps were markedly higher in the PH group than in the Control group. The increased right ventricular systolic pressure and Pp/Ps were significantly and comparably depressed in the PH + TA group and PH + BPS group; it was more greatly depressed in the PH + TA + BPS group than in the groups with each drug alone. The indices of right ventricular hypertrophy showed the same tendency as the increase in right ventricular systolic pressure in the five groups. The expression of beta-myosin heavy chain mRNA in right ventricle was markedly augmented in the PH group; the enhancement was inhibited in the PH + TA + BPS group to the greatest degree. Medial wall thickness of the pulmonary artery was markedly increased in the PH group; the increase was depressed in PH + TA + BPS group. Combined treatment also ameliorated PH even if it started from the post-onset of PH.. The combination of an oral ET-A receptor antagonist and an oral PGI2 analogue is superior to the single use of each drug alone in inhibiting the progression of PH.

Topics: Administration, Oral; Animals; Drug Synergism; Endothelin Receptor Antagonists; Endothelins; Epoprostenol; Hypertension, Pulmonary; Rats; Vasodilator Agents

Topics: Administration, Oral; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Exercise Tolerance; Hemodynamics; Humans; Hypertension, Pulmonary; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterised by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and death. A dysregulation of prostacyclin metabolic pathways has been demonstrated in patients with PAH and in experimental models. Recently, therapy with continuous intravenous prostacyclin (epoprostenol) has been shown to improve symptoms and prognosis in New York Heart Association (NYHA) functional class III and IV patients with different types of PAH. However, epoprostenol administration requires invasive methods with a permanent intravenous catheter and is associated with several side effects and potentially serious complications. Other modes of prostacyclin therapies are being considered using stable prostacyclin analogues administered by inhalation (iloprost), subcutaneously (treprostinil) or orally (beraprost). Over the last years, different multicenter international double-blind trials have demonstrated the efficacy of those novel prostacyclin analogues in PAH compared to conventional therapy promising a better future for these patients.

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; 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

Topics: Down Syndrome; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Vasodilator Agents

To investigate the effect of beraprost sodium, an orally active prostacyclin analogue, on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension.. Symptom limited cardiopulmonary exercise testing was performed before and 3 (1) months (mean (SEM)) after beraprost treatment in 30 patients with precapillary pulmonary hypertension (14 with primary pulmonary hypertension and 16 with chronic thromboembolic pulmonary hypertension).. Long term treatment with beraprost resulted in significant increases (mean (SEM)) in peak workload (87 (4) W to 97 (5) W, p < 0.001) and peak oxygen consumption (peak VO2, 14.9 (0.7) ml/kg/min to 16.8 (0.7) ml/kg/min, p < 0.001). Beraprost decreased the ventilatory response to carbon dioxide production during exercise (VE-VCO2 slope, 42 (2) to 37 (1), p < 0.001). No significant difference in the responses of these variables to beraprost treatment was observed between patients with primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension.. Oral administration of beraprost sodium may improve exercise capacity and ventilatory efficiency in patients with both primary and chronic thromboembolic pulmonary hypertension.

Topics: Administration, Oral; Adult; Epoprostenol; Exercise; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Platelet Aggregation Inhibitors; Pulmonary Embolism; Respiration

We sought to investigate whether the combination of an oral endothelin (ET)A receptor antagonist and an oral prostacyclin (PGI(2)) analogue is superior to the single use of each drug alone for treating pulmonary hypertension (PH).. Treatment with intravenous PGI(2) or an ET(A) receptor antagonist was effective for PH; however, the effect of both agents is unclear.. We administered the oral ET(A) receptor antagonist TA-0201 and/or the oral PGI(2) analogue beraprost sodium (BPS) to rats with monocrotaline-induced PH for 19 days. The groups were: normal rats with vehicle treatment (Control group), PH rats with vehicle treatment (PH group), PH rats with TA-0201 treatment (PH + TA group), PH rats with BPS treatment (PH + BPS group) and PH rats with TA-0201 and BPS treatment (PH + TA + BPS group).. Right ventricular (RV) systolic pressure and the ratio of RV systolic pressure to systemic systolic blood pressure (Pp/Ps) were markedly higher in the PH group than in the Control group. The increased RV systolic pressure and Pp/Ps were significantly and comparably depressed in the PH + TA and PH + BPS groups; it was more greatly depressed in the PH + TA + BPS group than in the groups with each drug alone. The indexes of RV hypertrophy showed the same tendency as the increase in RV systolic pressure among the five groups. The expression of beta-myosin heavy chain messenger ribonucleic acid in the RV was markedly augmented in the PH group; the enhancement was inhibited in the PH + TA + BPS group to the greatest degree. Medial wall thickness of the pulmonary artery was markedly increased in the PH group; the increase was depressed in the PH + TA + BPS group. Combined treatment also ameliorated PH, even if it started after the onset of PH.. The combination of an oral ETA receptor antagonist and an oral PGI(2) analogue is superior to the single use of each drug alone in inhibiting the progression of PH.

Topics: Administration, Oral; Animals; Drug Therapy, Combination; Echocardiography; Endothelin Receptor Antagonists; Epoprostenol; Hypertension, Pulmonary; Male; Pyrimidines; Rats; Rats, Wistar; Sulfonamides; Vasodilator Agents; Ventricular Function, Right; Ventricular Pressure

Inhaled PGI2 has been reported to elicit pulmonary vasodilation, but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain. We designed this study to address the in vivo effectiveness of inhaled Beraprost, a stable PGI2 analogue, on pulmonary vascular tone during hypoxic exposure in normoxic (N) and chronically hypoxic (CH) rats. Pulmonary vasodilation was observed by low-dose inhaled Beraprost in N rats, but not in CH rats. It was not until higher doses of Beraprost were given that pulmonary vasodilation was obtained in CH rats. When the agent was continuously administered by an intravascular route at the inhaled dose, it elicited no vasodilation in N rats. On the contrary, it elicited profound vasodilation in CH rats, although a concomitant systemic hypotension was observed. The PGI2 receptor mRNA expression was unchanged in the lungs of CH rats compared with that of N rats. We conclude that low doses of aerosolized Beraprost may reduce pulmonary vascular tone in rats without preexisting lung diseases. In contrast, when hypoxic pulmonary hypertension is present, the threshold of Beraprost inhalation was elevated to provoke pulmonary vasodilation.

Topics: Administration, Inhalation; Animals; Chronic Disease; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Injections, Intravenous; Male; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Receptors, Prostaglandin; RNA, Messenger

Acute hemodynamic effects of beraprost sodium were tested in a canine vasoconstrictive pulmonary hypertension model induced by the continuous infusion of U-46619, a thromboxane A(2)mimetic. The effects of beraprost were compared with those of prostaglandin E(1), nitroglycerin and nifedipine. Beraprost and nitroglycerin decreased pulmonary arterial pressure. On the other hand, prostaglandin E(1)and nifedipine increased pulmonary arterial pressure. All drugs except nitroglycerin increased cardiac output and decreased pulmonary vascular resistance. Beraprost was selective to pulmonary circulation, while nitroglycerin, prostaglandin E(1), and nifedipine showed poor selectivity for the pulmonary vasculature. These results suggest that the vasodilative effect of beraprost is the most selective for the pulmonary circulation among these four vasodilators.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alprostadil; Animals; Antihypertensive Agents; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Epoprostenol; Humans; Hypertension, Pulmonary; Male; Nifedipine; Nitroglycerin; Oxygen; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

Topics: Aged; CREST Syndrome; Disease Progression; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Platelet Aggregation Inhibitors; Vasodilator Agents

This study investigated whether plasma levels of adrenomedullin, a potent vasodilating endogenous neurohumoral mediator, are useful for assessing the severity of primary pulmonary hypertension.. Seventeen pediatric patients with primary pulmonary hypertension (eight girls, nine boys, mean age 12 +/- 4 years) were enrolled in this study. Thirteen patients in New York Heart Association (NYHA) classes III and IV had been treated with long-term continuous intravenous prostacyclin (PGI2) infusion therapy, and four patients in classes I and II had received beraprost sodium, an oral PGI2 analogue. Blood samples were taken from all patients at the first visit. Plasma levels of atrial and brain natriuretic peptide (ANP, BNP) and endothelin-1, and mature-type adrenomedullin were measured. The relationships were investigated between neurohumoral mediator levels and NYHA class, pulmonary hemodynamics, and exercise capacity assessed by 6-minute walk test. The changes in neurohumoral mediator levels at 1 month, 3 months, and 6 to 12 months were also evaluated in 11 survivors with long-term PGI2 treatment.. All neurohumoral mediator levels were positively correlated with severity of NYHA class. Patients in class IV demonstrated significantly elevated neurohumoral mediator levels, except endothelin-1, in comparison with patients in classes I-III. Neurohumoral mediator levels had a significant negative correlation with exercise capacity. Stepwise regression analysis revealed that the BNP to ANP ratio (BNP/ANP) was the most powerful independent factor for total pulmonary resistance (r = 0.85, p = 0.0071) and cardiac index (r = 0.84, p = 0.009). Adrenomedullin was significantly correlated with BNP (r = 0.53, p = 0.03), endothelin-1 (r = 0.66, p = 0.006), and BNP/ANP (r = 0.73, p = 0.0009). ANP and BNP decreased from 196 +/- 213 and 494 +/- 361 pg/ml at baseline to 74 +/- 47 and 153 +/- 133 pg/ml at 1 month, respectively. There was an apparent re-increase in both ANP (187 +/- 194 pg/ml) and BNP (466 +/- 621 pg/ml) at 3 months, regardless of improvement in NYHA class and exercise capacity after long-term PGI2 treatment. In contrast, adrenomedullin decreased from 3.0 +/- 2.2 (baseline) to 1.7 +/- 0.7 fmol/ml at 1 month and 1.6 +/- 0.5 fmol/ml at 3 months. Adrenomedullin was slightly increased at 6-12 months (2.1 +/- 0.9 fmol/ml) without statistical significance. There was a significant relationship between the changes in adrenomedullin at 3 months compared to values at initiation of PGI2 therapy and the changes in mean pulmonary arterial pressure (r = 0.97, p = 0.0041).. Plasma levels of neurohumoral mediators are useful for assessing the severity of primary pulmonary hypertension. In particular, adrenomedullin was valuable for evaluating both cardiac performance and pulmonary hemodynamics after long-term treatment with PGI2 in patients with primary pulmonary hypertension.

Topics: Adolescent; Adrenomedullin; Antihypertensive Agents; Atrial Natriuretic Factor; Child; Child, Preschool; Endothelin-1; Epoprostenol; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Natriuretic Peptide, Brain; Peptides

Pulmonary hypertension (PH) has a poor prognosis and is a drug-resistant disease. Recently, it has been reported that continuous intravenous prostacyclin (PGI2) administration is effective for PH. In this study, we compared the effects of chronic treatment with an endothelin-A- (ETA) receptor antagonist with an oral PGI2 analog on PH in rats. We administered the ETA-receptor antagonist TA-0201 or beraprost sodium (BPS), which is an orally active PGI2 analog, to monocrotaline- (MCT) induced PH rats. Each drug was given orally for 19 days. The rats were divided into the following four groups: (1) normal rats with vehicle (control); (2) PH rats with vehicle treatment (PH + vehicle); (3) PH rats with TA-0201 treatment (0.5 mg/kg/day) (PH + TA-0201); (4) PH rats with BPS treatment (100 microg/kg/day) (PH + BPS). Nineteen days after MCT injection, Pp/Ps [the ratio of right ventricular (RV) systolic pressure to systemic systolic blood pressure) and the ratio of the RV weight to the body weight (RV/BW), indicators of PH and RV hypertrophy. were markedly higher in the PH + vehicle group than in the control (healthy) group. The increase in Pp/Ps and RV/BW was significantly depressed in the PH + TA-0201 group and PH + BPS group to a similar extent. The expression of beta-myosin heavy chain (MHC) mRNA, a molecular marker for cardiac hypertrophy, in the RV was greatly increased in the PH + vehicle group and this increase was inhibited in the PH + TA-0201 group and PH + BPS group to a similar effect. In conclusion, treatment with an ETA-receptor antagonist or an oral PGI2 analog is comparably effective in the prevention of progression of PH and RV hypertrophy.

Topics: Administration, Oral; Animals; Endothelin Receptor Antagonists; Epoprostenol; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Pyrimidines; Rats; Rats, Wistar; Receptor, Endothelin A; Sulfonamides

A 65-year-old woman was admitted to our hospital because of exertional dyspnea in 1987. A diagnosis of primary pulmonary hypertension was confirmed by right heart catheterization. She had received conventional therapy in the outpatient clinic. She was readmitted with the deterioration of exertional dyspnea in 1995. Stabilization of pulmonary hemodynamics, while not achieved with conventional therapy, was achieved with additive administration of an oral prostacyclin (PGI2) analogue, beraprost sodium.

Topics: Administration, Oral; Aged; Cardiac Catheterization; Echocardiography; Epoprostenol; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Vasodilator Agents

Abnormal biosynthesis of thromboxane and prostacyclin has been implicated in patients with primary pulmonary hypertension and secondary pulmonary hypertension associated with congenital heart disease, and could be involved in the pathogenesis of pulmonary vascular disease. The chronic effects of an oral prostacyclin analogue, beraprost sodium, on thromboxane and prostacyclin biosynthesis and on pulmonary circulation were investigated in 15 children with pulmonary hypertension. The plasma concentrations of thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured, as was the urinary excretion of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, which are stable metabolites of thromboxane A2 and prostacyclin, respectively. In patients with pulmonary hypertension, the plasma concentration of thromboxane B2 and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha were greater than in healthy controls: 210 +/- 49 versus 28 +/- 4 pg/mL (P < 0.05) and 32.6 +/- 8.9 versus 5.7 +/- 1.8 (P < 0.01), respectively. After 3 months of administration of beraprost, the plasma concentration of thromboxane B2 and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha were reduced significantly: 210 +/- 49 to 98 +/- 26 pg/mL (P < 0.01) and 32.6 +/- 8.9 to 18.0 +/- 6.7 (P < 0.05), respectively. In contrast, the plasma concentrations of 6-keto-prostaglandin F1 alpha in patients were slightly but not significantly higher than in controls, and did not change significantly after administration of beraprost. The concentrations of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha in urine correlated significantly with thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively, in plasma. Beraprost improved the imbalance of thromboxane and prostacyclin biosynthesis and has a potential efficacy for preventing the progressive development of pathological changes in pulmonary vasculature.

Topics: Child; Child, Preschool; Epoprostenol; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Platelet Aggregation Inhibitors; Prostaglandins F; Thromboxane A2; Thromboxane B2; Vasodilator Agents

The hemodynamic effects of acute oral administration of a newly-developed prostacyclin analogue (beraprost sodium; 1-2 micrograms/kg), inhaled nitric oxide (NO; 20 ppm) and tolazoline hydrochloride (1 mg/kg) were measured in 17 children (mean age 1 year and 9 months) with pulmonary hypertension complicating congenital heart disease or primary pulmonary hypertension. Beraprost, NO and tolazoline achieved approximately equivalent reductions in pulmonary vascular resistance (20%, 26% and 18%, p < 0.05), but the greatest percentage decrease of pulmonary to systemic resistance ratio was obtained after administration of NO (33%, p < 0.05). Furthermore, combined administration of beraprost and NO produced the maximum effect of pulmonary vasodilation without adverse effects (49%). Beraprost appears to be an effective and available substitute for NO and tolazoline in screening for pulmonary vasodilator responsiveness. The combined use of beraprost and NO may provide an alternative treatment for pulmonary hypertension in children without serious complications.

Topics: Administration, Inhalation; Administration, Oral; Child, Preschool; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Nitric Oxide; Pulmonary Circulation; Tolazoline; Vascular Resistance; Vasodilator Agents

Combined administration of inhaled nitric oxide and beraprost sodium resulted in a more intense decrease in pulmonary vascular resistance than nitric oxide given alone (mean -33% vs -45%, p <0.05), without serious systemic hypotension. Combined therapy with nitric oxide and beraprost sodium is highly desirable in treating primary and secondary pulmonary hypertension in children.

Topics: Child; Child, Preschool; Cyclic AMP; Cyclic GMP; Drug Synergism; Epoprostenol; Humans; Hypertension, Pulmonary; Infant; Lung; Nitric Oxide; Vascular Resistance; Vasodilation; Vasodilator Agents

Experimental pulmonary hypertension (PH) was induced by a single injection of monocrotaline (MCT), a pyrrolizidine alkaloid extracted from Crotalaria spectabilis. The effect of beraprost sodium, a stable prostacyclin analogue, on the development of MCT-induced PH in rats was studied. Chronic administration of beraprost sodium at a dose of 30 micrograms/kg/day initiated on the same day as MCT injection decreased the degree of PH determined by weight ratio of right ventricular free wall to that of left ventricle plus septum depending on the duration of administration. Although the injection of prostaglandin E1 (PGE1) at a dose of 200 micrograms/kg/day initiated 1 week after MCT injection did not decrease the degree of PH significantly, beraprost sodium administration at doses of 30 and 100 micrograms/kg/day decreased the degree of PH significantly. The cytoprotective effect of beraprost sodium against endothelial cell (EC) damage is believed to be involved in inhibiting development of PH in MCT-injected rats. The amounts of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) produced by alveolar macrophages decreased in accordance with the inhibiting effect of beraprost sodium on development of PH, indicating that beraprost sodium inhibited the development of PH in MCT-injected rats not only through its effect of vasodilation and anti-platelet aggregation in pulmonary circulation but also through its antiinflammatory effects.

Topics: Alprostadil; Animals; Endothelium, Vascular; Epoprostenol; Hypertension, Pulmonary; Interleukin-1; Interleukin-6; Male; Mice; Monocrotaline; Platelet Aggregation Inhibitors; Poisons; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Vasodilator Agents

In 4 patients with primary pulmonary hypertension, there was a -24% +/- 20% decrease in pulmonary vascular resistance, a significant increase of cardiac index by +27 +/- 14% in all 4 patients; a -15 +/- 12% decrease in pulmonary artery pressure in 3 patients; and in 3 patients with 12% secondary pulmonary hypertension, there was a -24 +/- 14% decrease in pulmonary vascular resistance. Beraprost appears to be effective as a new pulmonary vasodilative agent.

Topics: Adult; Child; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Male; Middle Aged; Platelet Aggregation Inhibitors; Treatment Outcome; Vasodilator Agents

To determine whether beraprost sodium (beraprost) can cause pulmonary vasodilation in chronic hypoxic pulmonary hypertension, we measured the hemodynamic effects of intravenous beraprost, a stable and orally active agent with a PGI2-like structure, in chronic hypoxic (H) and normoxic (N) rats. During anesthesia baseline pulmonary artery pressure (PAP) was 32.0 +/- 1.0 in H rats and 18.0 +/- 0.4 mmHg in N rats. Intravenous beraprost (20 micrograms/kg) elicited acute pulmonary vasodilation by 17.7 +/- 4.6% (5.6 +/- 1.4 mmHg) in H rats and by 16.8 +/- 2.1% (3.0 +/- 0.6 mmHg) in N rats, which indicates that the relative degree of acute pulmonary vasodilation caused by beraprost was similar in H and N rats. Thirty minutes after the drug was injected, PAP had not returned to baseline levels in either H or N rats, and it was lower in H rats (90 +/- 2%) than in N rats (95 +/- 2%). Lungs were isolated and perfused with saline, and those from H rats and N rats showed similar pulmonary vasodilator responses to 2 and 20 micrograms/kg beraprost. These results indicate that although beraprost caused a similar degree of acute pulmonary vasodilation in H and N rats, in H rats the response lasted longer. Thus PGI2 derivatives may be useful as vasodilators in some patients with primary and secondary pulmonary hypertension.

Topics: Animals; Blood Pressure; Epoprostenol; Female; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Male; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Vasodilation

A 24-year-old woman was admitted to our hospital because of pulmonary hypertension. Five years earlier, she had been given a diagnosis of systemic lupus erythematosus. The pulmonary hypertension was believed to have been caused by pulmonary vasculitis, because pulmonary angiography, nuclear perfusion scans, and axial magnetic resonance imaging of the pulmonary artery showed no evidence of pulmonary thromboembolism. Steroids, a calcium antagonist, and home oxygen therapy did not reduce the patient's pulmonary hypertension. The level of thromboxane B2, a stable metabolite of thromboxane A2, in the pulmonary artery was abnormally high (140 pg/ml). This suggested that vasoconstriction of the pulmonary artery and microthrombosis would cause continuous pulmonary hypertension. Beraprost sodium (120 micrograms/day, p.o.) was administered. This analogue of prostaglandin I2 is a potent relaxer of vascular smooth muscle, and it inhibits platelet aggregation. The pulmonary artery pressure was normal eight months after the start of therapy with beraprost sodium.

Topics: Adult; Depression, Chemical; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Platelet Aggregation Inhibitors; Pulmonary Artery; Pulmonary Wedge Pressure; Time Factors

Rats were fed on distilled water (DW) or DW containing beraprost sodium (BPS). BPS concentration was 1.5 or 3.0 mu/ml in DW for the low BPS groups and 6.0 or 10.0 mu/ml in DW for the high BPS group. Monocrotaline (MCT) was subcutaneously given (60 mg/kg), and saline was injected as control. Data were analyzed among the following groups; Groups (Saline + DW), (Saline + Low BPS), (MCT + DW), (MCT + Low BPS) and (MCT + High BPS). Three weeks later, pulmonary (Ppa) and systemic (Psa) arterial pressure were measured under anesthesia. MCT caused significant elevation of Ppa [18.3 +/- 0.6 cmH2O for Group (Saline + DW) vs. 27.2 +/- 1.2 cmH2O for Group (MCT + DW), p < 0.001, mean +/- S.E.] and Ppa was significantly and dose-dependently suppressed by BPS; Group (MCT + DW) vs. Groups (MCT + Low BPS), 23.4 +/- 0.7 cmH2O and (MCT + High BPS), 22.5 +/- 0.5 cmH2O, p < 0.05, mean +/- S.E.). Psa was not lowered dose-dependently by BPS. We conclude that oral beraprost sodium suppresses pulmonary hypertension produced by monocrotaline in rat.

Topics: Administration, Oral; Animals; Blood Pressure; Dose-Response Relationship, Drug; Epoprostenol; Hypertension, Pulmonary; Injections, Subcutaneous; Monocrotaline; Platelet Aggregation Inhibitors; Rats; Rats, Wistar