iloprost and beraprost

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

Peripheral arterial disease (PAD) is a common cause of morbidity in the general population. While numerous studies have established the efficacy of prostanoids in PAD stages III and IV, the question of the role of prostanoids as an alternative or additive treatment in patients suffering from intermittent claudication (PAD II) has not yet been clearly answered. This is an update of a Cochrane Review first published in 2004.. To determine the effects of prostanoids in patients with intermittent claudication (IC) Fontaine stage II.. For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched January 2013) and CENTRAL (2012, Issue 12). Clinical trials databases were searched for details of ongoing or unpublished studies. In addition, reference lists of relevant articles were checked.. Randomised clinical trials of prostanoids versus placebo or alternative ('control') treatment in people with intermittent claudication were considered for inclusion.. Two authors independently assessed trial quality and extracted data. Primary outcomes included pain-free walking distance (PFWD) and maximum walking distance (MWD), presented as mean change in walking distance during the course of the trial (% improvement) and as final walking distance (that is walking distance, in metres, after treatment) for the prostanoid and control groups.. Eighteen trials with a total of 2773 patients were included (16 in the original review and a further two in this update). As the majority of trials did not report standard deviations for the primary PFWD and MWD outcomes, it was often not possible to test for the statistical significance of any improvements in walking distance between groups. The quality of individual trials was variable and usually unclear due to insufficient reporting information. Comparison between trials was hampered by the use of different treadmill testing protocols, including different walking speeds and gradients. Such limitations in the data and the trial heterogeneity meant it was not possible to meaningfully pool results by meta-analysis.Four trials compared prostaglandin E1 (PGE1) with placebo; individual trials showed significant increases in walking distances with administration of PGE1 and in several trials the walking capacity remained increased after termination of treatment. Compared with pentoxifylline, PGE1 was associated with a higher final PFWD and MWD but these results were based on final walking distances rather than changes in walking distance from baseline. When PGE1 was compared with other treatments including laevadosin, naftidrofuryl and L-arginine, improvements in walking distances over time were observed for both PGE1 and the alternative treatment, but it was not possible from the data available to analyse statistically whether or not one treatment was more effective than the other.Six studies compared various preparations of prostacyclins (PGI2) with placebo. In one study using three different dosages of iloprost, PFWD and MWD appeared to increase in a dose-dependent manner; iloprost was associated with headache, pain, nausea and diarrhoea, leading to a higher rate of treatment withdrawal. Of three studies using beraprost sodium, one showed an improvement in PFWD and MWD compared with placebo while two showed no significant benefit. Beraprost sodium was associated with an increased incidence of drug-related adverse events. Of two studies on taprostene, the results of one in particular must be interpreted with caution due to an imbalance in walking capacity at baseline.Comprehensive, high quality data on outcomes such as quality of life, ankle brachial index, venous occlusion plethysmography and haemorrheological parameters were lacking.. Whilst results from some individual studies suggested a beneficial effect of PGE1, the quality of these studies and of the overall evidence available is insufficient to determine whether or not patients with intermittent claudication derive clinically meaningful benefit from the administration of prostanoids. Further well-conducted randomised, double blinded trials with a sufficient number of participants to provide statistical power are required to answer this question.

Topics: Alprostadil; Epoprostenol; Humans; Iloprost; Intermittent Claudication; Prostaglandins; Randomized Controlled Trials as Topic

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 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

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

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 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

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

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

Prostacyclin (PGI2) and its mimetics (iloprost, treprostinil, beraprost and MRE-269) are potent vasodilators (via IP-receptor activation) and a major therapeutic intervention for pulmonary hypertension (PH). These PGI2 mimetics have anti-proliferative and potent vasodilator effects on pulmonary vessels. We compared the relaxant effects induced by these recognized IP-agonists in isolated human pulmonary arteries (HPA) and veins (HPV). In addition, using selective antagonists, the possible activation of other prostanoid relaxant receptors (DP, EP4) was investigated. Iloprost and treprostinil were the more potent relaxant agonists when both vessels were analyzed. HPA were significantly more sensitive to iloprost than to treprostinil, pEC50 values: 7.94±0.06 (n=23) and 6.73±0.08 (n=33), respectively. In contrast, in HPV these agonists were equipotent. The relaxations induced by treprostinil were completely or partially inhibited by IP-antagonists in HPA or HPV, respectively. The effects of the IP-agonists were not significantly modified by the EP4 antagonist. Finally, DP-antagonists inhibited the relaxations induced by treprostinil in HPV, suggesting that the DP-receptor plays a role in treprostinil-induced relaxation in the HPV. These data suggest that iloprost and treprostinil should be the most effective clinically available agonists to decrease pulmonary vascular resistance and to prevent oedema formation (by similar decrease in HPA and HPV resistance) in PH patients.

Topics: Acetates; Aged; Drug Evaluation, Preclinical; Epoprostenol; Female; Humans; Iloprost; In Vitro Techniques; Inhibitory Concentration 50; Male; Middle Aged; Molecular Mimicry; Pulmonary Artery; Pulmonary Veins; Pyrazines; Receptors, Epoprostenol; Receptors, Immunologic; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP4 Subtype; Vasodilation; Vasodilator Agents

Among pleiotropic effects, the capacity of prostaglandin I(2) (PGI(2)) analogues to affect adaptive immunity remains poorly characterised. The purpose of this study was to assess whether PGI(2) analogues could affect T helper (Th) cell responses in patients with systemic sclerosis (SSc) and healthy donors (HD).. Peripheral blood mononuclear cells (PBMC) were obtained from 33 patients with SSc and 29 HD. Cytokine levels in PBMC and monocyte/CD4 T cell cultures were quantified by immunoassays. The frequencies of interleukin (IL)-17A, IL-22, interferon γ (IFNγ) and IL-4-producing CD4 T cells were assessed by multiparametric flow cytometry. Selective receptor antagonists, cytokine blocking antibodies and signalling protein inhibitors were used to identify the receptors and signalling pathways mediating PGI(2) analogue effects.. Th17 and Th22 cells were more abundant in individuals with SSc than in HD. PGI(2) analogues (iloprost, treprostinil and beraprost) significantly increased IL-17A and IL-22 in vitro while decreasing IFNγ production both in SSc and HD PBMC. These effects relied on the specific expansion of Th17 and Th22 and inhibition of Th1 cells. The enhanced Th17 cell responses depended on increased IL-23 production by monocytes, involved the IP prostacyclin receptor and required protein kinase A activation. Importantly, in vivo administration of iloprost in individuals with SSc presenting with digital ulcers resulted in a significant increase in the frequency of Th17 cells.. These findings demonstrate that PGI(2) analogues affect Th cell differentiation/expansion programmes, favouring Th17 and inhibiting Th1 cell responses in SSc. The impact of these changes on the disease course needs to be taken into consideration and further exploited to improve SSc.

Topics: Adaptive Immunity; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Cell Proliferation; Cells, Cultured; Cyclic AMP-Dependent Protein Kinases; Epoprostenol; Female; Humans; Iloprost; Interferon-gamma; Interleukin-17; Interleukin-22; Interleukin-23 Subunit p19; Interleukins; Male; Middle Aged; Monocytes; Platelet Aggregation Inhibitors; Scleroderma, Systemic; Th1 Cells; Th17 Cells; Young Adult

Although prostanoids are known to be involved in regulation of the spontaneous beating rate of cultured neonatal rat cardiomyocytes, the various subtypes of prostanoid receptors have not been investigated in detail. In our experiments, prostaglandin (PG)F(2α) and prostanoid FP receptor agonists (fluprostenol, latanoprost and cloprostenol) produced a decrease in the beating rate. Two prostanoid IP receptor agonists (iloprost and beraprost) induced first a marked drop in the beating rate and then definitive abrogation of beating. In contrast, the prostanoid DP receptor agonists (PGD(2) and BW245C) and TP receptor agonists (U-46619) produced increases in the beating rate. Sulprostone (a prostanoid EP(1) and EP(3) receptor agonist) induced marked increases in the beating rate, which were suppressed by SC-19220 (a selective prostanoid EP(1) antagonist). Butaprost (a selective prostanoid EP(2) receptor agonist), misoprostol (a prostanoid EP(2) and EP(3) receptor agonist), 11-deoxy-PGE(1) (a prostanoid EP(2), EP(3) and EP(4) receptor agonist) did not alter the beating rate. Our results strongly suggest that prostanoid EP(1) receptors are involved in positive regulation of the beating rate. Prostanoid EP(1) receptor expression was confirmed by western blotting with a selective antibody. Hence, neonatal rat cardiomyocytes express both prostanoid IP and FP receptors (which negatively regulate the spontaneous beating rate) and prostanoid TP, DP(1) and EP(1) receptors (which positively regulate the spontaneous beating rate).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blotting, Western; Cells, Cultured; Cloprostenol; Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Hydantoins; Iloprost; Latanoprost; Myocytes, Cardiac; Prostaglandin D2; Prostaglandins F, Synthetic; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Thromboxane

Although treatment for asthma control has improved a lot recently, refractory asthma is still a challenge for clinicians. Evidence revealed that anti-tumor necrosis factor (TNF)-α therapy may have potential in treating refractory asthma. Recently in an animal model, prostaglandin I(2) (PGI(2)) analogues can suppress the cardinal feature of asthma. However, whether PGI(2) analogues can regulate TNF-α expression in monocytes and the mechanism is not well-known.. The human monocytes were pretreated with beraprost, iloprost and treprostinil, three PGI(2) analogues, before stimulation with lipopolysaccharide (LPS). TNF-α concentration of the cell supernatants was measured by ELISA. Intracellular signaling was investigated by Western blot.. PGI(2) analogues suppressed LPS-induced TNF-α expression in THP-1 cells. CAY10449, an I prostanoid receptor antagonist, could reverse these effects. Beraprost increased intracellular cAMP level in THP1 cells. Forskolin, an adenylyl cyclase activator, could confer similar effect. LPS-induced TNF-α expression in THP-1 cells could be reversed by mitogen-activator protein kinase (MAPK)-p38, extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) inhibitors. Western blot revealed that beraprost suppressed MAPK phospho-p38, phosphor-JNK and phosphor-ERK expression.. PGI(2) analogues suppressed LPS-induced TNF-α expression in THP-1 cells via the IP receptor-cAMP and the MAPK pathways. PGI(2) analogues may have potentiality to treat asthma.

Topics: Animals; Antihypertensive Agents; Cell Line; Epoprostenol; Humans; Iloprost; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Monocytes; PPAR gamma; Tumor Necrosis Factor-alpha; Vasodilator Agents

Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is an orally available prostacyclin (PGI(2)) receptor (IP receptor) agonist that is chemically distinct from PGI(2) and is in clinical development for the treatment of pulmonary arterial hypertension. Selexipag is highly selective for the human IP receptor in vitro, whereas analogs of PGI(2) can activate prostanoid receptors other than the IP receptor. The goal of this study was to determine the impact of selectivity for the IP receptor on gastric function by measuring 1) contraction of rat gastric fundus ex vivo and 2) the rates of gastric emptying and intestinal transport in response to selexipag in comparison with other PGI(2) analogs. The rat gastric fundus expresses mRNA encoding multiple prostanoid receptors to different levels: prostaglandin E receptor 1 (EP(1)) > prostaglandin E receptor 3 (EP(3)), IP receptor > prostaglandin D(2) receptor 1, thromboxane receptor. Selexipag and metabolite {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) did not contract gastric fundus at concentrations up to 10(-3) M. In contrast, the PGI(2) analogs iloprost and beraprost evoked concentration-dependent contraction of gastric fundus. Contraction to treprostinil was observed at high concentration (10(-4) M). Contraction to all PGI(2) analogs was mediated via activation of EP(3) receptors, although EP(1) receptors also contributed to the contraction of gastric fundus to iloprost and beraprost. Antagonism of IP receptors did not affect responses. Oral selexipag did not significantly alter gastric function in vivo, as measured by rates of stomach emptying and intestinal transport, whereas beraprost slowed gastrointestinal transport. The high functional selectivity of selexipag and ACT-333679 for the IP receptor precludes a stimulatory action on gastric smooth muscle and may help minimize gastric side effects such as nausea and vomiting.

Topics: Acetamides; Animals; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Gastric Emptying; Gastrointestinal Transit; Humans; Iloprost; Male; Muscle Contraction; Pulmonary Artery; Pyrazines; Rats; Receptors, Epoprostenol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach

Prostacyclin is a short-lived metabolite of arachidonic acid that is produced by several cells in the lung and prominently by endothelial cells. It increases intracellular cAMP levels activating downstream signaling thus regulating vascular mesenchymal cell functions. The alveolar wall contains a rich capillary network as well as a population of mesenchymal cells, i.e., fibroblasts. The current study evaluated the hypothesis that prostacyclin may mediate signaling between endothelial and mesenchymal cells in the alveolar wall by assessing the ability of prostacyclin analogs to modulate fibroblast release of VEGF. To accomplish this study, human lung fibroblasts were cultured in routine culture on plastic support and in three-dimensional collagen gels with or without three prostacyclin analogs, carbaprostacyclin, iloprost, and beraprost, and the production of VEGF was evaluated by ELISA and quantitative real-time PCR. Iloprost and beraprost significantly stimulated VEGF mRNA levels and protein release in a concentration-dependent manner. These effects were blocked by the adenylate cyclase inhibitor SQ-22536 and by the protein kinase A (PKA) inhibitor KT-5720 and were reproduced by a direct PKA activator but not by an activator of exchange protein directly activated by cAMP (Epac), indicating that cAMP-activated PKA signaling mediated the effect. Since VEGF serves to maintain the pulmonary microvasculature, the current study suggests that prostacyclin is part of a bidirectional signaling network between the mesenchymal and vascular cells of the alveolar wall. Prostacyclin analogs, therefore, have the potential to modulate the maintenance of the pulmonary microcirculation by driving the production of VEGF from lung fibroblasts.

Topics: Adenine; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Adult; Carbazoles; Cell Culture Techniques; Cells, Cultured; Epoprostenol; Fibroblasts; Humans; Iloprost; Lung; Prostaglandins I; Pyrroles; RNA, Messenger; Stimulation, Chemical; Vascular Endothelial Growth Factor A

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

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

Primary pulmonary hypertension is characterized by increased pulmonary vascular resistance and smooth muscle proliferation. Stable analogs are increasingly being used to treat this disease, although no data exists comparing their effects on proliferation. We therefore investigated the antiproliferative activity of several prostacyclin (PGI(2)) analogs on human pulmonary arterial smooth muscle cells, including UT-15 and iloprost, analogs that have recently completed successful clinical trials. Serum-induced proliferation, as assessed by [(3)H]thymidine incorporation (30 h) or cell number (48 h), was significantly inhibited with a 10-fold difference in potency, ranking in effectiveness UT-15 > iloprost > cicaprost > beraprost. Effects were reversed by the adenylyl cyclase inhibitor, 2,5'dideoxyadenosine (DDA) but not SQ22536. Intracellular cyclic AMP (cAMP) was elevated by all analogs and inhibited by DDA, although SQ22536 was a highly variable inhibitor, suggesting that different pathways might mediate cAMP generation. UT-15 produced a significantly larger and more sustained increase in cAMP compared with other analogs, with iloprost being the weakest elevator. Thus, PGI(2) analogs potently inhibit proliferation of human pulmonary artery, probably via a cAMP-dependent pathway, although cAMP elevation in itself is not a good predictor of antiproliferative potency.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Cell Division; Cells, Cultured; Cyclic AMP; Enzyme Inhibitors; Epoprostenol; Humans; Iloprost; Molecular Structure; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Pulmonary Artery