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American Journal of Respiratory and... Mar 2020Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. To evaluate the... (Clinical Trial)
Clinical Trial
Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).
Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Double-Blind Method; Epoprostenol; Female; Humans; Male; Middle Aged; Placebos; Pulmonary Arterial Hypertension; Young Adult
PubMed: 31765604
DOI: 10.1164/rccm.201908-1640OC -
Acta Medica Okayama 2015Pulmonary arterial hypertension (PAH) is characterized by elevation of pulmonary artery pressure caused by pulmonary vasoconstriction and vascular remodeling, which... (Review)
Review
Pulmonary arterial hypertension (PAH) is characterized by elevation of pulmonary artery pressure caused by pulmonary vasoconstriction and vascular remodeling, which leads to right heart failure and death. Epoprostenol (prostaglandin I2) has a potent short-acting vasodilator property, and intravenous continuous epoprostenol is therefore used for treatment of PAH. Here we review evidence for the usefulness of intravenous continuous epoprostenol therapy in patients with PAH. Epoprostenol therapy is effective in idiopathic PAH patients and in patients with PAH associated with connective tissue disease, portal hypertension or congenital heart diseases, but it is not effective in patients with pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis. High-dose epoprostenol therapy markedly improved hemodynamics in some patients with PAH, possibly due to reverse remodeling of pulmonary arteries. This therapy has several side effects and complications such as headache, hypotension and catheter-related infections. Intravenous continuous epoprostenol is an effective treatment, but there are still some problems to be resolved.
Topics: Antihypertensive Agents; Connective Tissue Diseases; Epoprostenol; Humans; Hypertension, Pulmonary
PubMed: 26101188
DOI: 10.18926/AMO/53519 -
European Respiratory Review : An... Jan 2017Epoprostenol was the first therapy to be approved for the treatment of pulmonary arterial hypertension (PAH). In the 20 years since the introduction of this... (Review)
Review
Epoprostenol was the first therapy to be approved for the treatment of pulmonary arterial hypertension (PAH). In the 20 years since the introduction of this prostacyclin analogue, the outlook for patients with PAH has improved, with survival rates now double those from the era before the development of disease-specific treatments. Today, there are a large amount of data on the clinical role of prostacyclin treatments and a body of evidence attesting the efficacy of epoprostenol in improving exercise capacity, key haemodynamic parameters and PAH symptoms, as well as in reducing mortality. The place of epoprostenol in the therapeutic management of PAH continues to evolve, with the development of new formulations and use in combination with other drug classes. In this review, we provide a historical perspective on the first 20 years of epoprostenol, a therapy that led to evidence-based study of PAH-specific treatments and the subsequent expansion of treatment options for PAH.
Topics: Antihypertensive Agents; Arterial Pressure; Drug Compounding; Drug Therapy, Combination; Epoprostenol; Exercise Tolerance; Humans; Hypertension, Pulmonary; Pulmonary Artery; Recovery of Function; Time Factors; Treatment Outcome; Vasodilator Agents
PubMed: 28096285
DOI: 10.1183/16000617.0055-2016 -
Journal of the Royal Society of Medicine Apr 1983
Topics: Animals; Cardiovascular Diseases; Dogs; Epoprostenol; Hemoperfusion; Humans; Prostaglandins; Thrombosis
PubMed: 6341583
DOI: 10.1177/014107688307600401 -
The Cochrane Database of Systematic... Mar 2016Buerger's disease (thromboangiitis obliterans) is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Buerger's disease (thromboangiitis obliterans) is a non-atherosclerotic, segmental inflammatory pathology that most commonly affects the small and medium sized arteries, veins, and nerves in the upper and lower extremities. The etiology is unknown, but involves hereditary susceptibility, tobacco exposure, immune and coagulation responses. In many cases, there is no possibility of revascularization to improve the condition. Pharmacological treatment is an option for patients with severe complications, such as ischaemic ulcers or rest pain.
OBJECTIVES
To assess the effectiveness of any pharmacological agent (intravenous or oral) compared with placebo or any other pharmacological agent in patients with Buerger's disease.
SEARCH METHODS
The Cochrane Vascular Trials Search Co-ordinator searched their Specialised Register (last searched in April 2015) and the Cochrane Register of Studies (Issue 3, 2015). The review authors searched trial registers and the European grey literature; screened reference lists of relevant studies, and contacted study authors and major pharmaceutical companies.
SELECTION CRITERIA
Randomised controlled trials (RCTs) involving pharmacological agents used in the treatment of Buerger's disease.
DATA COLLECTION AND ANALYSIS
Two review authors, independently assessed the studies, extracted data and performed data analysis.
MAIN RESULTS
Five randomised controlled trials (total 602 participants) compared prostacyclin analogue with placebo, aspirin, or a prostaglandin analogue, and folic acid with placebo. No studies assessed other pharmacological agents such as cilostazol, clopidogrel and pentoxifylline or compared oral versus intravenous prostanoid.Compared with aspirin, intravenous prostacyclin analogue iloprost improved ulcer healing (risk ratio (RR) 2.65; 95% confidence interval (CI) 1.15 to 6.11; 98 participants; one study; moderate quality evidence), and helped to eradicate rest pain after 28 days (RR 2.28; 95% CI 1.48 to 3.52; 133 participants; one study; moderate quality evidence), although amputation rates were similar six months after treatment (RR 0.32; 95% CI 0.09 to 1.15; 95 participants; one study; moderate quality evidence). When comparing prostacyclin (iloprost and clinprost) with prostaglandin (alprostadil) analogues, ulcer healing was similar (RR 1.13; 95% CI 0.76 to 1.69; 89 participants; two studies; I² = 0%; very low quality evidence), as was the eradication of rest pain after 28 days (RR 1.57; 95% CI 0.72 to 3.44; 38 participants; one study; low quality evidence), while amputation rates were not measured. Compared with placebo, the effects of oral prostacyclin analogue iloprost were similar for: healing ischaemic ulcers (iloprost 200 mcg: RR 1.11; 95% CI 0.54 to 2.29; 133 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 0.90; 95% CI 0.42 to 1.93; 135 participants; one study; moderate quality evidence), eradication of rest pain after eight weeks (iloprost 200 mcg: RR 1.14; 95% CI 0.79 to 1.63; 207 participants; one study; moderate quality evidence, and iloprost 400 mcg: RR 1.11; 95% CI 0.77 to 1.59; 201 participants; one study; moderate quality evidence), and amputation rates after six months (iloprost 200 mcg: RR 0.54; 95% CI 0.19 to 1.56; 209 participants; one study, and iloprost 400 mcg: RR 0.42; 95% CI 0.13 to 1.31; 213 participants; one study). When comparing folic acid with placebo in patients with Buerger's disease and hyperhomocysteinaemia, pain scores were similar, there were no new cases of amputation in either group, and ulcer healing was not assessed (very low quality evidence).Treatment side effects such as headaches, flushing or nausea were not associated with treatment interruptions or more serious consequences. Outcomes such as amputation-free survival, walking distance or pain-free walking distance, and ankle brachial index were not assessed by any study.Overall, the quality of the evidence was very low to moderate, with few studies, small numbers of participants, variation in severity of disease of participants between studies and missing information regarding for example baseline tobacco exposure.
AUTHORS' CONCLUSIONS
Moderate quality evidence suggests that intravenous iloprost (prostacyclin analogue) is more effective than aspirin for eradicating rest pain and healing ischaemic ulcers in Buerger's disease, but oral iloprost is not more effective than placebo. Verylow and low quality evidence suggests there is no difference between prostacyclin (iloprost and clinprost) and the prostaglandin analogue alprostadil for healing ulcers and relieving pain respectively in severe Buerger's disease. Very-low quality evidence suggests there is no difference in pain scores and amputation rates between folic acid and placebo, in people with Buerger's disease and hyperhomocysteinaemia. High quality trials assessing the effectiveness of pharmacological agents (intravenous or oral) in people with Buerger's disease are needed.
Topics: Adult; Alprostadil; Amputation, Surgical; Aspirin; Epoprostenol; Humans; Iloprost; Male; Middle Aged; Prostaglandins; Randomized Controlled Trials as Topic; Thromboangiitis Obliterans; Ulcer
PubMed: 26967103
DOI: 10.1002/14651858.CD011033.pub3 -
Clinical Cardiology Nov 1997The endothelium releases factors that control vascular relaxation and contraction, thrombogenesis and fibrinolysis, and platelet activation and inhibition. Maintaining... (Review)
Review
The endothelium releases factors that control vascular relaxation and contraction, thrombogenesis and fibrinolysis, and platelet activation and inhibition. Maintaining the functional integrity of the endothelium, therefore, is critical for the preservation of blood flow and the prevention of thrombosis. This article reviews the primary endothelium-dependent substances that promote either relaxation (e.g., nitric oxide, prostacyclin) or contraction (e.g., endothelin) of blood vessels, including their physiology, mechanism of effect, and role in endothelial dysfunction. Risk factors for cardiovascular disease, such as hypertension, hypercholesterolemia, diabetes, vascular aging, and estrogen deficiency, are discussed in terms of their contributions to endothelial dysfunction, which may be the initial step in atherogenesis.
Topics: Animals; Cardiovascular Diseases; Endothelins; Endothelium, Vascular; Epoprostenol; Humans; Muscle, Smooth, Vascular; Nitric Oxide; Vasoconstriction; Vasodilation
PubMed: 9422846
DOI: No ID Found -
American Journal of Respiratory and... Dec 2023
Topics: Humans; Epoprostenol; Pulmonary Arterial Hypertension; T-Lymphocytes, Regulatory; Familial Primary Pulmonary Hypertension; Antihypertensive Agents; Treatment Outcome
PubMed: 37774405
DOI: 10.1164/rccm.202308-1347LE -
Advances in Therapy Sep 2022Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The... (Review)
Review
Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The targeting of fibroblasts and myofibroblasts with antifibrotic treatments is a potential therapeutic target for these potentially fatal diseases. Treprostinil is unique among the prostacyclin mimetics in that it has distinct actions at additional prostaglandin receptors. Preclinical and clinical evidence suggests that treprostinil has antifibrotic effects through the activation of the prostaglandin E receptor 2 (EP), the prostaglandin D receptor 1 (DP), and peroxisome proliferator-activated receptors (PPAR). In vivo studies of EP and the DP have found that administration of treprostinil resulted in a reduction in cell proliferation, reduced collagen secretion and synthesis, and reduced lung inflammation and fibrosis. In vitro and in vivo studies of PPARβ and PPARγ demonstrated that treprostinil inhibited fibroblast proliferation in a dose-dependent manner. Clinical data from a post hoc analysis of the INCREASE trial found that inhaled treprostinil improved forced vital capacity in the overall population as well as in idiopathic interstitial pneumonia and idiopathic pulmonary fibrosis subgroups. These preclinical and clinical findings suggest a dual benefit of treprostinil through the amelioration of both lung fibrosis and pulmonary hypertension.
Topics: Epoprostenol; Fibrosis; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis
PubMed: 35781186
DOI: 10.1007/s12325-022-02229-8 -
American Journal of Physiology. Lung... Jun 2022Inhalational prostacyclins act as strong vasodilators, potentially improving oxygenation by reducing shunt fraction and ventilation-perfusion mismatch. As prostacyclin...
Inhalational prostacyclins act as strong vasodilators, potentially improving oxygenation by reducing shunt fraction and ventilation-perfusion mismatch. As prostacyclin receptors are known to be present on human erythrocytes, possible direct effects on hemoglobin oxygen transport were further explored by examining the sole in vitro influence of prostacyclins on hemoglobin oxygen (Hb-O) affinity. Venous blood samples from 20 healthy volunteers were exposed in vitro to supramaximal doses of epoprostenol, iloprost, and compared with control. By high-throughput measurements, hemoglobin oxygen dissociation curves (ODCs) were derived. Hb-O affinity, expressed by P50 and Hill coefficient, was determined and analyzed for three subgroups: males ( = 10), females not taking oral contraceptives ( = 4), and females taking oral contraceptives ( = 6). Epoprostenol significantly decreased P50 in all (males, females without contraceptives, and females taking oral contraceptives) [27.5 (26.4-28.6) mmHg (control) vs. 24.2 (22.7-25.3) mmHg; < 0.001. median (interquartile range, IQR)] thereby increasing Hb-O affinity. Inversely, iloprost only showed significant effects in females taking oral contraceptives where P50 was markedly increased and therefore Hb-O affinity decreased [28.4 (27.9-28.9) mmHg (control) vs. 34.4 (32.2-36.0) mmHg; < 0.001]. Prostacyclin-receptor stimulation and subsequent cAMP-mediated ATP release from erythrocytes are discussed as a possible underlying mechanism for the effect of epoprostenol on Hb-O affinity. The reason for the sex hormone-modified iloprost effect remains unclear. Being aware of potentially differing effects on Hb-O affinity might help select the right prostacyclin (epoprostenol vs. iloprost) depending on the patient and the underlying disease (e.g., acute respiratory distress syndrome vs. peripheral arterial disease).
Topics: Contraceptives, Oral; Epoprostenol; Female; Hemoglobins; Humans; Iloprost; Male; Oxygen; Prostaglandins I
PubMed: 35503651
DOI: 10.1152/ajplung.00084.2022 -
Vascular Health and Risk Management 2015The release of endogenous prostacyclin (PGI2) is depressed in patients with pulmonary arterial hypertension (PAH). PGI2 replacement therapy by epoprostenol infusion is... (Review)
Review
The release of endogenous prostacyclin (PGI2) is depressed in patients with pulmonary arterial hypertension (PAH). PGI2 replacement therapy by epoprostenol infusion is one of the best treatments available for PAH. Here, we provide an overview of the current clinical data for epoprostenol. Epoprostenol treatment improves symptoms, exercise capacity, and hemodynamics, and is the only treatment that has been shown to reduce mortality in patients with idiopathic PAH (IPAH) in randomized clinical trials. We have reported that high-dose epoprostenol therapy (>40 ng/kg/min) also results in marked hemodynamic improvement in some patients with IPAH. High-dose epoprostenol has a pro-apoptotic effect on PAH-PASMCs via the IP receptor and upregulation of Fas ligand (FasL) in vitro. However, long-term intravenous administration of epoprostenol is sometimes associated with catheter-related infections and leads to considerable inconvenience for the patient. In the future, the development of new routes of administration or the development of powerful PGI2 analogs, IP-receptor agonists, and gene and cell-based therapy enhancing PGI2 production with new routes of administration is required.
Topics: Antihypertensive Agents; Apoptosis; Epoprostenol; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Treatment Outcome
PubMed: 25999730
DOI: 10.2147/VHRM.S50368