u-62840 and Familial-Primary-Pulmonary-Hypertension

Pulmonary arterial hypertension is a progressive pulmonary vascular disease, which can cause right heart failure and even death in severe cases. Treprostinil is a stable prostacyclin analogue and a powerful drug for dilating pulmonary vessels. It can be administered in different ways, with a long half-life, good stability and is suited for diverse types of PAH. It is approved for the treatment of Group 1 PAH, but some studies show that treprostinil is effective in patients with Group 3 or Group 4 PAH. Therefore, this article will review the progress of evidence-based medicine evidence of traprostanil in the treatment of type 1, 3 and 4 pulmonary hypertension.. 肺动脉高压是一种进行性加重的肺血管疾病，严重时可引起右心衰竭进而导致患者死亡。曲前列尼尔是一种稳定的前列环素类似物，可强效扩张肺血管，可通过多种途径给药，且半衰期长，稳定性好，治疗范围广。目前临床上被批准用于1型肺动脉高压，但有文献报道曲前列尼尔在3、4型肺动脉高压患者中也有一定疗效。本文就曲前列尼尔治疗1、3、4型肺动脉高压循证医学证据的进展进行综述。.

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary

Pediatric pulmonary hypertension (PAH) is a rare disease that carries a poor prognosis if left untreated. Although there are published guidelines for the treatment of children with pulmonary hypertension, due to the limited number of robust pediatric clinical trials, recommendations are often based on limited data or clinical experience. Furthermore, many practical aspects of care, particularly for the pediatric patient, are learned through experience and best navigated with a multidisciplinary team. While newer PAH therapies have been approved for adults, there is still limited but expanding experience in pediatrics. This new information will help improve the targets of goal-oriented therapy. Lastly, this review highlights practical aspects in the use of the different therapies available for the treatment of pediatric pulmonary hypertension.

Topics: Adolescent; Adult; Bosentan; Calcium Channel Blockers; Child; Child, Preschool; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Infant; Infant, Newborn; Phenotype; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Prognosis; Pulmonary Arterial Hypertension; Pyridazines; Pyrimidines; Receptors, Endothelin; Sildenafil Citrate; Sulfonamides; Tadalafil; Young Adult

Since continuous IV epoprostenol was approved in the U.S., parenteral prostanoid therapy has remained the gold standard for the treatment of patients with advanced pulmonary arterial hypertension (PAH). Prostanoid agents can be administered as continuous intravenous infusions, as continuous subcutaneous infusions and by intermittent nebulization therapy. This article presents data from clinical trials of available prostanoid agents, and their varied routes of administration. The varied routes of administration allow for the incremental use of this class of agents in advanced PAH, and if PAH progresses. Prostanoids will remain a major component of PAH therapy for the foreseeable future.

Topics: Administration, Inhalation; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by increasing pulmonary vascular resistance leading to right ventricular failure and death. Treprostinil is a stable prostacyclin analog approved for the treatment of PAH to improve exercise capacity. In the setting of PAH, the major pharmacological actions of treprostinil include vasodilatation of the pulmonary and systemic vascular beds, inhibition of platelet aggregation and inhibition of smooth muscle cell proliferation. Treprostinil therapy may be delivered via parenteral (subcutaneous and intravenous) or inhaled routes of administration, with oral tablets in the later stages of clinical development. In clinical trials, treprostinil has been shown to improve clinical status, functional class, exercise capacity and quality of life. Common side effects of treprostinil therapy include headache, flushing, jaw pain, diarrhea, and for subcutaneous administration, infusion site pain or reaction. This article provides an overview of treprostinil therapy for the treatment of PAH with a focus on the available efficacy and safety data for parenteral, inhaled and oral administration.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Infusions, Parenteral

Pulmonary arterial hypertension, part of the larger spectrum of disorders causing pulmonary hypertension, is a complex and progressive disease of multiple etiologies that ultimately leads to vascular remodeling, right-sided heart failure, and death. Advances in treatment over the past 15 to 20 years have dramatically reduced the morbidity and mortality of the disease, but often have significant drawbacks. Of the more recently approved therapies, the prostaglandin analogs have been shown to have the greatest therapeutic benefit but are also the most difficult to administer, many being given as continuous intravenous infusions in the ambulatory setting. After a case presentation highlighting some of the challenges that accompany treatment with these agents, this article reviews the diagnosis and classification of pulmonary hypertension and pulmonary arterial hypertension and gives a brief overview of the various other pharmacologic agents used in its treatment. A more comprehensive review of the biochemistry of prostaglandins and the pharmacology and clinical use of this class of drugs follows. Recommended treatment guidelines are also discussed.

Topics: Ambulatory Care; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Middle Aged; Practice Guidelines as Topic; Prostaglandins

Pulmonary arterial hypertension (PAH) is a life-threatening disease which, if untreated, leads to right ventricular failure and often death. Several effective therapies are now available for PAH, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs. The prostacyclin analog treprostinil has proven efficacious when delivered by subcutaneous or intravenous infusion, and most recently by inhalation. Inhaled treprostinil has been shown to be 64%-72% bioavailable in healthy volunteers. Pilot clinical studies have elucidated the acute hemodynamic effects and relative pulmonary selectivity of this agent, as well as established target dosing in PAH and nonoperable chronic thromboembolic PAH. Likewise, chronically administered inhaled treprostinil resulted in clinical and hemodynamic improvement. Both pilot studies confirmed a satisfactory safety profile in patients with PAH. The pivotal Phase III trial, TRIUMPH-I, demonstrated the efficacy and safety of inhaled treprostinil (target dose of 54 μg four times daily) in PAH patients added to background therapies of bosentan or sildenafil, as assessed by improvements in the primary endpoint, peak six-minute walk distance (median placebo-corrected treatment effect of 20 m), as well as select secondary endpoints. Inhaled treprostinil is approved by the US Food and Drug Administration for patients with World Health Organization Group I PAH to improve exercise ability. Studies establishing effectiveness included predominately patients with New York Heart Association functional class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

Topics: Administration, Inhalation; Antihypertensive Agents; Clinical Trials as Topic; Drug Approval; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; United States; United States Food and Drug Administration

This paper provides an overview of the current state of pharmacotherapy in children with pulmonary arterial hypertension (PAH) and a brief introduction to the potentially novel pharmacologic targets for PAH. Currently, 3 classes of drugs including prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase-5 inhibitors are approved for the treatment of PAH in children, which has led to improved hemodynamics, increased exercise capacity and prolonged survival. Despite these improvements, there is still a need to carry out well-designed, randomized, controlled studies with larger samples. In addition, novel drugs targeting other molecular pathways should be developed.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Bosentan; Calcium Channel Blockers; Child; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Iloprost; Sulfonamides

Treprostinil is a prostacyclin derivative approved for the treatment of pulmonary arterial hypertension by intravenous, subcutaneous and inhalational administration. Unlike its precursor epoprostenol, treprostinil is chemically stable at room temperature and neutral pH, and its plasma half-life is longer. In addition to promoting smooth muscle relaxation in the pulmonary vasculature, treprostinil has suppressive effects on platelet aggregation, smooth muscle proliferation and inflammation. A Phase III study, investigating the addition of inhaled treprostinil to oral bosentan or sildenafil, confirmed significant improvements in exercise capacity and quality of life. This review examines the pharmacodynamics, pharmacokinetics, clinical efficacy and safety of inhaled treprostinil for use in pulmonary arterial hypertension.

Topics: Administration, Inhalation; Antihypertensive Agents; Blood Pressure; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Artery; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a chronic condition of elevated pulmonary arterial pressures with associated increases in pulmonary vascular resistance leading to right ventricular failure, which was almost uniformly fatal prior to the introduction of pulmonary hypertension specific therapy. Systemic prostacyclin analogs are the first PAH-specific therapies to be made available and are typically recommended as first-line therapy for subjects with severe disease. Treprostinil is a newer prostacyclin analog similar to epoprostenol in its mechanism of action and relative efficacy with the advantage of a longer half life in human serum and room temperature stability. It is unique in that it is available in multiple formulations for alternative routes of delivery, including subcutaneous, intravenous and inhalational routes. Additionally, oral treprostinil is currently under investigation. Both subcutaneous and intravenous forms of treprostinil have demonstrated efficacy in short-term clinical trials and are currently approved for use in subjects with PAH and New York Heart Association functional class (NYHA FC) II-IV symptoms in the USA and for subjects with NYHA FC III and IV in Europe. Inhaled treprostinil has also demonstrated efficacy in short-term clinical trials primarily as add-on therapy and is currently approved for use in subjects with PAH and NYHA FC III-IV symptoms in the USA and Europe. The different formulations of treprostinil have significantly increased the treatment options and opportunities for treatment of patients with PAH.

Topics: Antihypertensive Agents; Drug Approval; Drug Delivery Systems; Drug Stability; Drug Storage; Epoprostenol; Europe; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; United States

Treprostinil is a synthetic prostacyclin analogue with antiplatelet and vasodilatory properties. It is the only prostacyclin analogue with different options of delivery, i.e. subcutaneous, intravenous, inhaled or oral. Subcutaneous treprostinil has been shown in short- and long-term studies to improve exercise capacity, functional class, haemodynamics and survival in patients with pulmonary arterial hypertension (PAH). Pain at the infusion site has been a major drawback of subcutaneous treprostinil, hampering dose titration, and ultimately leading to increased discontinuation rates. The additional clinical interest in treprostinil as an alternative intravenous prostacyclin has developed due to its favourable properties, including longer half-life, chemical stability, the possibility of intravenous infusion without the need for ice packs, and easy drug preparation. Intravenous treprostinil improves exercise capacity, functional class and haemodynamics in patients with PAH, over the period of 12 weeks. If patients are switched to intravenous treprostinil, they usually need to double the dose to attain the same efficacy. Whether the effect of intravenous treprostinil remains clinically relevant beyond 12 weeks is not known, and a longer follow-up would be required to investigate this. Inhaled treprostinil is an efficacious treatment in PAH patients who are moderately symptomatic on background oral therapy. Oral treprostinil on top of background therapy did not lead to an improvement in 6-minute walking distance after 16 weeks of treatment.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Familial Primary Pulmonary Hypertension; Half-Life; Humans; Hypertension, Pulmonary; Injections, Intravenous; Injections, Subcutaneous; Treatment Outcome

Inhaled treprostinil sodium, a prostacyclin analog, is the most recent agent to receive FDA approval for the treatment of a fatal orphan disease: pulmonary arterial hypertension (PAH).. This article first reviews the data supporting the use of infusion prostacyclin and treprostinil as treatments for PAH. The authors then review inhaled treprostinil sodium: the compound and its properties, initial clinical evidence supporting its use and the pivotal data that support a role for inhaled treprostinil sodium in the treatment of patients with PAH. A broad PubMed literature search was done to identify the most current data on the use of treprostinil for PAH. Inhaled treprostinil received FDA approval to improve exercise tolerance in 2009, following the publication of several studies demonstrating its safety and its beneficial effect on hemodynamics, exercise capacity and quality-of-life measures.. Inhaled treprostinil seems to have a similar efficacy profile as inhaled iloprost, although the demonstrated trough effect on exercise tolerance with treprostinil is an advantage. Perhaps more importantly, the longer half-life makes treprostinil more convenient with four-times-daily dosing. As compared with iloprost, inhaled treprostinil has practical advantages for patients (less frequent dosing, shorter inhalation times, once-daily preparation of the drug delivery device, and easier routine maintenance of the nebulizer), but direct comparisons about efficacy or durability of the treatment effect cannot be made in the absence of carefully controlled trials.

Topics: Administration, Inhalation; Antihypertensive Agents; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prevalence

Pulmonary arterial hypertension is a progressive disease characterized by vascular proliferation and vasoconstriction of the small pulmonary arteries that eventually leads to right-sided heart failure and death. Patients often initially have symptoms such as shortness of breath, fatigue, and edema; later in the disease, presyncope and syncope are common. Patients with progressive pulmonary arterial hypertension despite oral therapy and/or with severe disease typically require treatment with a prostanoid. Inhaled treprostinil (Tyvaso) is a prostacyclin analog indicated for the treatment of pulmonary arterial hypertension to increase walk distance in patients with symptoms classified as New York Heart Association functional class III. Inhaled treprostinil was approved by the Food and Drug Administration in July 2009. This article provides a brief overview of the pathophysiology of pulmonary arterial hypertension and reviews the mechanism of action, key clinical data, and the practical management of inhaled treprostinil in patients with pulmonary arterial hypertension.

Topics: Administration, Inhalation; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Medical Illustration; Randomized Controlled Trials as Topic; Treatment Outcome

Multiple conditions result in development of pulmonary hypertension. Pulmonary arterial hypertension (PAH) is the subclassification of pulmonary hypertension, in which known or unknown underlying conditions lead to similar intrinsic alterations in the pulmonary vasculature. PAH is a progressive condition characterized by restricted blood flow through the pulmonary circulation leading to poor survival in the absence of effective therapy. Over the last two decades, new therapeutic agents have substantially improved the course and prognosis for PAH patients. Three available classes of drugs, ie, prostacyclins, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors provide multiple options for treatment of PAH. Endothelin receptor antagonists and phosphodiesterase-5 inhibitors are administered orally, whereas prostacyclin therapies are delivered by continuous intravenous or subcutaneous infusion, or as aerosols by nebulization. Because of the risks and inconveniences associated with administration, prostacyclins are typically reserved for patients with more advanced disease or progression despite oral therapy. Inhaled administration may be a safer and easier route for prostacyclin administration. Treprostinil is a prostacyclin analog that has been demonstrated to be effective when administered by continuous subcutaneous or intravenous infusion, and more recently by nebulization.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary

The aim of this study is to evaluate the effects of treprostinil injection on the control of pulmonary blood pressure in children with congenital heart disease (CHD) complicated by severe pulmonary arterial hypertension (PAH).. Eighty children with CHD complicated by severe pulmonary arterial hypertension admitted to our hospital from January 2015 to June 2018 were selected and randomly divided into a control group (N.=40) and a treatment group (N.=40). Based on standard treatment, the treatment group was intravenously infused with 8-12 ng/kg·min treprostinil, while the control group received the same dose of normal saline. Hemodynamic parameters such as BP, AP, P and SpO2% were monitored before anesthesia induction (T0), before cardiopulmonary bypass (T1), 1 h after cardiopulmonary bypass (T2) and at the end of cardiopulmonary bypass (T3). Pulmonary arterial pressure parameters (PASP, PADP and PAMP) were measured at T1, T2 and T3 by transesophageal echocardiography.. For the treatment group, the HR values at T2 and T3 were lower than that at T0 (P<0.05). For the control group, HR at T3 was lower than that at T0 (P<0.05). HR at T3 of the treatment group was lower than that of the control group (P<0.05). SpO2 of the treatment group was higher than that of the control group at T3 (P<0.05). At T2 and T3, PASP, PADP and PAMP of both groups were lower than those before surgery (P<0.05), and the values of the treatment group were lower than those of the control group (P<0.05).. Treprostinil can improve cardiac function and reduce pulmonary circulation resistance in PAH children.

Topics: Antihypertensive Agents; Child; Epoprostenol; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension

The clinical impact of pulmonary capillary wedge pressure (PCWP) on long-term mortality among patients with pulmonary arterial hypertension (PAH) has been incompletely reported, particularly in relation to concomitant treprostinil administration. The goal of this study was to assess the impact of PCWP on long-term mortality in PAH patients treated with parenteral treprostinil.. We studied a cohort of 743 patients with PAH treated with parenteral treprostinil therapy. The long-term all-cause mortality was compared in patients with baseline mean PCWP≤8mmHg, 811mmHg over 4-year follow-up.. Of the 743 patients studied, 280 patients (37.7%) had a baseline mean PCWP ≤ 8mmHg, 233 patients (31.4%) had a mean PCWP of >8mmHg and ≤11mmHg, and 230 patients (31.0%) had a mean PCWP >11mmHg. While patients with higher PCWP had higher mean right atrial and PA pressures, no difference was noted in cardiac output and pulmonary vascular resistance (PVR). All-cause mortality was similar between patients with PCWP≤8mmHg, 811mmHg at 1 year (10.4% vs 9.9% vs 10.0%, p=0.980) and 4 years (16.8% vs 21.9% vs 19.2%, p=0.353) respectively. In multivariate analysis, PCWP was not independently predictive of 4-year all-cause mortality [HR 1.00, 95%CI 0.95-1.05, p=0.98 (permmHg)]. Predictors of 4-year mortality included older age [HR 1.02, 95%CI 1.00-1.03, p=0.0091 (per year)], non-​Caucasian race, and higher PVR [HR 1.06, 95% CI 1.04-1.08, p<0.0001 (per Woods Unit)].. In this study of patients with PAH receiving parenteral treprostinil, PCWP was not associated with long-term all-cause mortality. Further studies examining prognostic indicators in patients with PAH optimised on guideline-based therapies are warranted.

Topics: Adult; Antihypertensive Agents; Cause of Death; Dose-Response Relationship, Drug; Double-Blind Method; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Middle Aged; Prognosis; Pulmonary Wedge Pressure; Survival Rate; Time Factors; United States; Vascular Resistance

Topics: Antihypertensive Agents; Case-Control Studies; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hyperthermia, Induced; Iontophoresis; Laser-Doppler Flowmetry; Male; Microcirculation; Microvessels; Skin; Vascular Diseases

Treprostinil is a stable prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) as parenteral or inhaled therapy. Treprostinil diolamine, a sustained-release oral formulation of treprostinil, was studied to determine whether it could provide a more convenient prostacyclin treatment option for patients with less severe PAH. The objective of this study was to evaluate the efficacy and safety of oral treprostinil in patients with PAH receiving stable background endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE-5I) therapy, or both.. A 16-week, multicenter, double-blind, placebo-controlled study in 310 patients with PAH compared bid administration of oral treprostinil (n = 157) with placebo (n = 153). The primary end point was change in 6-min walk distance at week 16. Secondary efficacy end points were World Health Organization functional class, Borg dyspnea score, dyspnea-fatigue index, signs and symptoms of PAH, and clinical worsening.. One hundred thirty-two patients (84%) receiving oral treprostinil and 138 (90%) receiving placebo completed the study. The mean ± SD dose of oral treprostinil at week 16 was 3.1 ± 1.9 mg bid. The Hodges-Lehmann placebo-corrected median difference in 6MWD at week 16 was 10.0 m (95% CI, -2 to 22 m; P = .089). There were no significant changes in secondary end points. The most common adverse events associated with oral treprostinil were headache (71%), diarrhea (55%), nausea (46%), flushing (35%), and jaw pain (25%).. The addition of oral treprostinil to background ERA and PDE-5I therapy did not result in a statistically significant improvement in exercise capacity. Side effects were common but tolerated by most subjects.. ClinicalTrials.gov; No.: NCT00887978; URL: www.clinicaltrials.gov.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Time Factors; Treatment Outcome; Vasodilator Agents; Young Adult

Intravenous (IV) epoprostenol has been the mainstay of therapy in advanced pulmonary arterial hypertension (PAH). Continuous IV treprostinil has several potential advantages over IV epoprostenol; however, there has been a lack of published long-term efficacy and safety data on IV treprostinil in PAH.. We conducted a 48-week, multicenter, prospective, open-label, uncontrolled, study of continuous IV treprostinil in 16 patients on no prior PAH specific therapy at baseline (de novo), or 31 patients transitioned at baseline from IV epoprostenol (transition). The primary end point was change in exercise capacity assessed by the 6-minute walk distance (6MWD) test.. In de novo patients, IV treprostinil increased the mean ± standard error 6MWD by 125 m from 332 ± 21 m at baseline to 457 ± 26 m at Week 48. There were also improvements in the secondary end points of Naughton-Balke treadmill time, Borg Dyspnea Score, and hemodynamics at Week 48 compared with baseline. In 23 patients transitioned from IV epoprostenol with 48-week follow-up data, 6MWD, hemodynamic measures, and World Health Organization functional class at Week 48 were all stable compared with baseline. Side effects were generally mild and consistent with those reported with prostacyclin treatment. During the study, 5 patients died of causes not considered related to the therapy, and 7 discontinued due to adverse events.. In this open-label trial, continuous IV treprostinil for 1 year appears to be safe and effective in de novo PAH patients and those transitioned from IV epoprostenol.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure; Child; Endpoint Determination; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Outcome Assessment, Health Care; Prospective Studies; Treatment Outcome; Walking; Young Adult

Inhaled treprostinil is a prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) that may provide a more convenient treatment option for patients receiving inhaled iloprost while maintaining the clinical benefit of inhaled prostacyclin therapy.. In this open-label safety study, 73 PAH patients were enrolled with primarily World Health Organization Class II (56%) or III (42%) symptoms. At baseline, most patients (93%) were receiving 5 μg of iloprost per dose but 38% of patients reported a dosing frequency below the labeled rate of 6-9 times daily. Patients initiated inhaled treprostinil at 3 breaths four times daily (qid) at the immediate next scheduled iloprost dose. The primary objective was to assess the safety of rapid transition from iloprost to inhaled treprostinil; clinical status and quality of life were also assessed.. Most patients (84%) achieved the target treprostinil dose of 9 breaths qid and remained on study until transition to commercial therapy (89%). The most frequent adverse events (AEs) were cough (74%), headache (44%), and nausea (30%), and five patients prematurely discontinued study drug due to AE (n = 3), disease progression (n = 1), or death (n = 1). At week 12, the time spent on daily treatment activities was reduced compared to baseline, with a mean total savings of 1.4 h per day. Improvements were also observed at week 12 for 6-min walk distance (+16.0; P < 0.001), N-terminal pro-B-type natriuretic peptide (-74 pg/mL; P = 0.001), and the Cambridge Pulmonary Hypertension Outcome Review (all domains P < 0.001).. Pulmonary arterial hypertension patients can be safely transitioned from inhaled iloprost to inhaled treprostinil while maintaining clinical status.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Antihypertensive Agents; Arterial Pressure; Drug Administration Schedule; Drug Substitution; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Iloprost; Male; Middle Aged; Prospective Studies; Pulmonary Artery; Quality of Life; Time Factors; Treatment Outcome; United States; Vasodilation; Vasodilator Agents; Young Adult

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease with no cure. Parenteral and inhaled prostacyclin analogue therapies are effective for the treatment of PAH, but complicated administration requirements can limit the use of these therapies in patients with less severe disease. This study was designed to evaluate the safety and efficacy of the oral prostacyclin analogue treprostinil diolamine as initial treatment for de novo PAH.. Three hundred forty-nine patients (intent-to-treat population) not receiving endothelin receptor antagonist or phosphodiesterase type-5 inhibitor background therapy were randomized (treprostinil, n=233; placebo, n=116). The primary analysis population (modified intent-to-treat) included 228 patients (treprostinil, n=151; placebo, n=77) with access to 0.25-mg treprostinil tablets at randomization. The primary end point was change from baseline in 6-minute walk distance at week 12. Secondary end points included Borg dyspnea index, clinical worsening, and symptoms of PAH. The week 12 treatment effect for 6-minute walk distance (modified intent-to-treat population) was 23.0 m (P=0.0125). For the intent-to-treat population, 6-minute walk distance improvements were observed at peak (26.0 m; P=0.0001) and trough (17.0 m; P=0.0025) plasma study drug concentrations. Other than an improvement in the combined 6-minute walk distance/Borg dyspnea score, there were no significant changes in secondary end points. Oral treprostinil therapy was generally well tolerated; the most common adverse events (intent-to-treat) were headache (69%), nausea (39%), diarrhea (37%), and pain in jaw (25%).. Oral treprostinil improves exercise capacity in PAH patients not receiving other treatment. Oral treprostinil could provide a convenient, first-line prostacyclin treatment option for PAH patients not requiring more intensive therapy.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00325403.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Child; Dyspnea; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Incidence; International Cooperation; Longitudinal Studies; Male; Middle Aged; Treatment Outcome; Walking; Young Adult

Pulmonary arterial hypertension (PAH) is a progressive vascular disease that ultimately leads to right ventricular failure and death. Treprostinil diolamine is an oral prostacyclin analogue; sustained release tablets of oral treprostinil are currently being evaluated for efficacy and safety as a potential therapy in patients with PAH. Previous attempts at developing an oral prostanoid have been limited by rapid absorption and short plasma half-life; thus, the aim of this study was to characterize the pharmacokinetic profile of treprostinil diolamine in PAH patients after chronic dosing. The study enrolled 74 PAH patients who had been taking treprostinil diolamine for a minimum of 4 weeks (range: 0.5-16 mg). We collected plasma samples over 12 hours and estimated pharmacokinetic parameters using noncompartmental methods. Seventy patients had complete data. After chronic twice-daily oral dosing of treprostinil diolamine, mean area under the curve (AUC0-12) of treprostinil increased from 5244 to 20,4086 pg·hr-·mL- and mean maximum observed plasma concentration (Cmax) increased from 1383 to 33588 pg/mL. The apparent clearance (CL/F) was similar across all doses, indicating a linear dose-exposure relationship after twice-daily dosing. We conclude that twice-daily oral treprostinil provides sustained and proportional treprostinil concentrations over a wide range of doses during chronic administration to PAH patients.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Area Under Curve; Biological Availability; Dose-Response Relationship, Drug; Double-Blind Method; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Tablets; Treatment Outcome; Young Adult

Infused and inhaled treprostinil are effective for treatment of pulmonary arterial hypertension (PAH), although their administration routes have limitations. This study assessed the efficacy and safety of bid oral sustained-release treprostinil in the treatment of PAH with a concomitant endothelin receptor antagonist (ERA) and/or phosphodiesterase type 5 inhibitor.. A 16-week, multicenter, double-blind, placebo-controlled study was conducted in 350 patients with PAH randomized to placebo or oral treprostinil. All patients were stable on background ERA, PDE-5 inhibitor, or both. Primary end point was Hodges-Lehmann placebo-corrected median difference in change from baseline 6-min walk distance (6MWD) at week 16. Secondary end points included time to clinical worsening, change in World Health Organization functional class, Borg dyspnea score, and dyspnea fatigue index score.. Thirty-nine patients (22%) receiving oral treprostinil and 24 patients (14%) receiving placebo discontinued the study. Placebo-corrected median difference in change from baseline 6MWD at week 16 was 11 m (P = .07). Improvements in dyspnea fatigue index score (P = .01) and combined 6MWD and Borg dyspnea score (P = .01) were observed with oral treprostinil vs placebo treatment. Patients who achieved a week-16 bid oral treprostinil dose of 1.25 to 3.25 mg and 3.5 to 16 mg experienced a greater change in 6MWD (18 m and 34 m, respectively) than patients who achieved a bid dose of < 1 mg or discontinued because of adverse events (4 m).. The primary end point of improvement in 6MWD at week 16 did not achieve significance. This study enhanced understanding of oral treprostinil titration and dosing, which has set the stage for additional studies.. ClinicalTrials.gov; No.: NCT00325442; URL: www.clinicaltrials.gov.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Walking; Young Adult

The introduction of prostanoid therapy has revolutionized the treatment of pulmonary arterial hypertension (PAH). However, continuous intravenous prostacyclin infusion poses significant risks and challenges, particularly in children. Inhaled treprostinil has been shown to be safe and efficacious in adults. This study describes the safety and efficacy of inhaled treprostinil in children with PAH. A retrospective analysis of 29 children treated with inhaled treprostinil for ≥6 weeks was performed. Effects of inhaled treprostinil on exercise capacity, functional class, and echocardiographic and hemodynamic data were evaluated. Adverse events were documented. Patients received 3 to 9 breaths (6 μg/breath) of inhaled treprostinil 4 times/day. All were receiving background PAH therapy; 12 had previously received parenteral prostanoid. Inhaled treprostinil was discontinued in 4 patients because of symptoms including cough and bronchospasm (n = 3) and progression of PAH (n = 1). Mild side effects including cough (n = 9) and sore throat (n = 6) did not require discontinuation of therapy. World Health Organization functional class improved in 19 and was unchanged in 10; exercise capacity significantly improved with the 6-minute walk distance, improving on follow-up from 455.7 ± 71.5 to 498 ± 70 m (p = 0.01) and peak oxygen consumption increasing from 25.5 ± 10.2 to 27.4 ± 10 (p = 0.04). In conclusion, inhaled treprostinil was associated with improvement in exercise capacity and World Health Organization functional class when added to background targeted PAH therapy in children and had an acceptable safety profile. Based on these early data, further study of inhaled treprostinil appears warranted in pediatric patients with PAH.

Topics: Administration, Inhalation; Adolescent; Antihypertensive Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Nebulizers and Vaporizers; Pulmonary Wedge Pressure; Retrospective Studies; Treatment Outcome; Young Adult

Pulmonary vasodilators in general and prostacyclin therapy in particular, have markedly improved the outcome of patients with pulmonary arterial hypertension (PAH). As endothelial dysfunction is a key feature of PAH, and as endothelial progenitor cells (EPC) may contribute to vascular repair in PAH, we suspected that prostacyclin therapy might enhance EPC numbers and functions. In the present study, objectives were to determine whether EPC may contribute to vasodilator treatment efficacy in PAH.. We quantified CD34+ cells, CFU-Hill and ECFC (endothelial colony forming cells) in peripheral blood from children with idiopathic PAH (n = 27) or PAH secondary to congenital heart disease (n = 52). CD34+ were enumerated by flow cytometry, CFU-Hill and ECFC by a culture assay. ECFC grown ex vivo were tested for their angiogenic capacities before and after prostacyclin analog therapy (subcutaneous treprostinil).. ECFC counts were significantly enhanced in the 8 children treated with treprostinil, while no change was observed in children receiving oral therapy with endothelin antagonists and/or PDE5 inhibitors. CD34+ cell and CFU-Hill counts were unaffected. ECFC from patients treated with treprostinil had a hyperproliferative phenotype and showed enhanced angiogenic potential in a nude mouse preclinical model of limb ischemia.. ECFC may partly mediate the clinical benefits of prostanoids in pulmonary arterial hypertension.

Topics: Animals; Antihypertensive Agents; Cell Count; Cell Separation; Child; Colony-Forming Units Assay; Endothelial Cells; Epoprostenol; Familial Primary Pulmonary Hypertension; Hematopoietic Stem Cells; Humans; Hypertension, Pulmonary; Mice; Neovascularization, Physiologic; Stem Cells

Because of the challenges associated with conducting large survival studies of patients with pulmonary arterial hypertension (PAH), we analyzed the surrogate markers predictive of long-term survival in a large cohort of patients treated with subcutaneous treprostinil.. A retrospective review was conducted using data from a total of 811 patients with New York Heart Association Functional Class (NYHA FC) II to IV PAH, who were treated with subcutaneous treprostinil. Patient baseline disease and on-treatment parameters were analyzed by uni- and multivariate analyses for predictive value of 3-year survival with PAH.. Among the baseline disease-related factors analyzed, there was a significantly higher risk of death (p < 0.001) associated with connective tissue disease-associated PAH relative to idiopathic PAH (hazard ratio for death [HR] 1.93), NYHA FC IV vs III (HR 2.31), pulmonary vascular resistance index (PVRI) >30 vs ≤16 mm Hg/liter/min/m(2) (HR 2.44) and mixed venous oxygen saturation (SVO(2)) ≤55% vs >55%. The 6-minute walk distance (6MWD) of ≤295 m after 12 weeks of treprostinil treatment was associated with reduced survival at 3 years (58%). A ≥20-m increase from baseline in 6MWD was associated with greater survival (80%) vs smaller walk increments (69%; p = 0.039). Treprostinil dose of ≥40 ng/kg/min (p < 0.001) and every 10-ng/kg/min dose increase (p = 0.009) resulted in improved long-term survival. In a multivariate analysis, only SVO(2), 6MWD and treprostinil dose were significant on-treatment predictors (p < 0.02) of survival.. Disease etiology, baseline factors (NYHA FC, PVRI and SVO(2)) and on-treatment factors (6MWD, SVO(2) and treprostinil dose) were predictors of survival in this study and may be used to aid in treatment optimization.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Middle Aged; Multivariate Analysis; Prognosis; Retrospective Studies; Survival Rate; Treatment Outcome; Vascular Resistance; Young Adult

Pulmonary arterial hypertension (PAH) is a progressive and inevitably fatal disease characterized by the progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling, which lead to right-sided heart failure and premature death. Many of the genetically modified mouse models do not develop severe PH and occlusive vascular remodeling.

Topics: Animals; Familial Primary Pulmonary Hypertension; Heart Failure; Hypertension, Pulmonary; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; Pulmonary Arterial Hypertension; Pulmonary Artery; Sildenafil Citrate; Vascular Remodeling; Vasodilator Agents

Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil.. ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions.. Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging.. Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients.

Topics: Administration, Oral; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prospective Studies; Pulmonary Arterial Hypertension; Registries

Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint.. EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension.. Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16.. Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction.. Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil.

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Treatment Outcome

Current guidelines recommend treatment with parenteral prostacyclin analogs in patients with severe pulmonary arterial hypertension (PAH), who have insufficient response to treatment. Real-life data are sought to help physicians in treatment decisions and clinical care of patients.. This study analyzed safety, clinical effects, and long-term outcomes of subcutaneous (sc) and/or intravenous (iv) treprostinil via different pump systems in consecutive patients with PAH.. Thirty-seven patients with severe progressive PAH despite dual combination therapy (20 female, mean age: 52.3 ± 15 years, mean pulmonary vascular resistance: 12.1 ± 5.1 WU) were initiated with add-on treprostinil sc and were routinely clinically assessed. Changes in clinical parameters, adverse events, and outcome were analyzed retrospectively.. In 24 of 37 patients, treprostinil administration was continued iv via implantation of LENUS Pro® pump after 3 ± 1.3 months, 6 patients continued with sc therapy, and 7 discontinued treatment. After 3, 6, 9, and 12 months of treprostinil treatment, patients showed a significant improvement in mean 6-min walk distance and tricuspid annular plane systolic excursion compared to baseline. In 8 of the 24 patients, iv pumps required surgical revision. During a mean follow-up of 2.82 ± 1.95 years, 12 patients died, four received lung transplantation. Transplant-free survival after 1, 2, and 3 years was 85.7%, 69.2%, and 65.3%, respectively.. sc treprostinil as add-on to double combination treatment significantly improved exercise capacity and right heart function. In most patients, treprostinil could be continued via more tolerable iv administration approach (LENUS Pro® pump), showing reasonable overall survival with respect to the severity of PAH.

Topics: Adult; Aged; Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Arterial Hypertension; Retrospective Studies; Treatment Outcome

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Pulmonary Arterial Hypertension; T-Lymphocytes, Regulatory; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a fatal disease caused by the progressive remodeling of pulmonary arteries (PAs). Treprostinil (TPS) is a tricyclic benzidine prostacyclin clinically used for PAH treatment. However, due to low bioavailability, short half-times, and severe systemic side effects, TPS efficacy remains limited.. In this study, glucuronic acid (GlcA)-modified liposomes were developed to improve the site-specific delivery of TPS to pulmonary arterial smooth muscle cells (PASMCs) by targeting the glucose transporter-1 (GLUT-1) in vitro and in vivo.. Non-GlcA-modified and GlcA-modified liposomes encapsulating TPS were 106 ± 1.12 nm in diameter. The drug encapsulation efficiency (EE) was 92%. Data from rat PASMCs showed that GlcA-liposomes enhanced the inhibitory effects of TPS on PASMC proliferation and migration by suppressing growth factor expression, including transforming growth factor-ß1 (TGF-ß1), connective tissue growth factor (CTGF), and cAMP, which was possibly mediated by the cAMP-C/EBP-α p42-p21 signaling pathway. In PAH model rats, GlcA-modified liposomes significantly improved TPS bioavailability and sustained its release over time. Most importantly, the selective inhibition of pulmonary arterial pressure, rather than systemic arterial pressure, indicated the increased pulmonary-specific accumulation of TPS. Of the three TPS formulations, TPS-loaded GlcA-modified liposomes exhibited the most potent activity by inhibiting PA remodeling and muscularization, decreasing PA medial thickening, suppressing collagen deposition in PAs, and attenuating right ventricle hypertrophy (RVH) in sugen-5416-induced PAH rats.. The GLUT-1-targeted delivery of TPS increased pulmonary specificity and enhanced TPS anti-PAH activities in vivo and in vitro.

Topics: Animals; Cell Proliferation; Epoprostenol; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Liposomes; Myocytes, Smooth Muscle; Pulmonary Arterial Hypertension; Pulmonary Artery; Rats; Vascular Remodeling

Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity.. Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients.. GWAS identified three loci for association with P < 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures.. The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Genome-Wide Association Study; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Topics: Double-Blind Method; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Pulmonary Arterial Hypertension

Topics: Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) results from pulmonary vascular disease and may eventually lead to right heart failure and death. Vasodilator therapy has greatly improved PAH prognosis. Circulating microvesicles are considered as surrogate markers of endothelial and hematopoietic cell activation.. Thus, our purpose was to determine if MVs are upregulated in pediatric PAH such as reported in adult patients, and to analyze the impact of vasodilator therapies on MV count and function.. Population study consisted of 26 patients of median age 6.09 years, with Congenital Heart Disease (CHD) and elevated pulmonary vascular resistance (CHD-PAH) or idiopathic PAH (iPAH).. Compared to healthy controls, all circulating MV subpopulations were found higher in untreated PAH patients. No significant differences of annexin-V+ total MV, endothelial, or leukocyte derived-MV counts were found between untreated patients and those receiving oral vasodilator therapies. Conversely, platelet MVs were significantly lower in the group treated with SC-treprostinil compared with both untreated PAH and oral therapy groups (P = 0.01), and exhibited a significant decrease of phospholipid procoagulant activity. Control samples treated in vitro with treprostinil at therapeutic concentrations showed as expected a significant decrease of platelet aggregation but also a reduced spontaneous MV generation.. Our results suggest that treprostinil, besides vasodilation, might exert its beneficial effect through an inhibition of platelet activation, resulting in a decreased number and procoagulant activity of circulating MVs.

Topics: Adolescent; Adult; Antihypertensive Agents; Cell-Derived Microparticles; Child; Child, Preschool; Coagulants; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Lung; Male; Pulmonary Arterial Hypertension; Pulmonary Circulation; Vasodilator Agents; Young Adult

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prognosis; Treatment Outcome

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Prognosis; Treatment Outcome

Treprostinil is applied for pulmonary arterial hypertension (PAH) therapy. However, the mechanism by which the drug achieves its beneficial effects in PAH vessels is not fully understood. This study investigated the effects of treprostinil on PDGF-BB induced remodelling parameters in isolated human pulmonary arterial smooth muscle cells (PASMC) of four PAH patients. The production of TGF-β1, CTGF, collagen type-I and -IV, and of fibronectin were determined by ELISA and PCR. The role of cAMP was determined by ELISA and di-deoxyadenosine treatment. Proliferation was determined by direct cell count. Treprostinil increased cAMP levels dose and time dependently, which was not affected by PDGF-BB. Treprostinil significantly reduced PDGF-BB induced secretion of TGF-β1 and CTGF, both was counteracted when cAMP generation was blocked. Similarly, the PDGF-BB induced proliferation of PASMC was dose dependently reduced by treprostinil through signalling via cAMP-C/EBP-α p42 -p21(WAf1/Cip1). In regards to extracellular matrix remodelling, treprostinil significantly reduced PDGF-BB-TGF-β1-CTGF induced synthesis and deposition of collagen type I and fibronectin, in a cAMP sensitive manner. In contrast, the deposition of collagen IV was not affected. The data suggest that this action of treprostinil in vessel wall remodelling may benefit patients with PAH and may reduce arterial wall remodelling.

Topics: Adult; Becaplermin; CCAAT-Enhancer-Binding Proteins; Cell Proliferation; Collagen Type I; Collagen Type IV; Connective Tissue Growth Factor; Cyclic AMP; Epoprostenol; Extracellular Matrix; Familial Primary Pulmonary Hypertension; Female; Fibronectins; Gene Expression Regulation; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase 1; Myocytes, Smooth Muscle; Pulmonary Artery; Signal Transduction; Transforming Growth Factor beta1; Vascular Remodeling

Anticoagulation is a common treatment modality in patients with pulmonary arterial hypertension (PAH). Further studies are needed to appropriately assess the risk/benefit ratio of anticoagulation, particularly in PAH patients receiving PAH-specific therapies.. We use observational long-term data on PAH patients treated with subcutaneous (SQ) treprostinil from a large open-label study. Patients were followed for up to 4 years. The use of warfarin and bleeding events were recorded.. At total of 860 patients (age [mean±SD] 46±15 years, 76% female, 83% Caucasian, 49% idiopathic PAH, and 76% New York Heart Association [NYHA] functional class III) were included. All patients received SQ treprostinil (15% also other pulmonary hypertension [PH]-therapies) and 590 (69%) received warfarin during the study. The proportions of women, African American, and idiopathic pulmonary hypertension (IPAH) patients were higher in the group receiving warfarin. A higher proportion of patients with congenital heart disease and portopulmonary hypertension did not receive warfarin. There were no differences in unadjusted long-term survival between PAH patients receiving warfarin or not (log-rank test, P value=.69), even when only considering idiopathic PAH (P=.32). In addition, no difference was found in adjusted long-term survival both in PAH (P=.84) and idiopathic PAH patients (P=.44) based on the use of warfarin. Furthermore, no survival difference based on the use of warfarin were noted between propensity score-matched PAH patients (P=.37).. Long-term anticoagulation with warfarin was not associated with any significant effect on survival in PAH or idiopathic PAH patients treated with SQ treprostinil.

Topics: Adult; Anticoagulants; Antihypertensive Agents; Chi-Square Distribution; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Hemorrhage; Humans; Infusions, Subcutaneous; Kaplan-Meier Estimate; Male; Middle Aged; Propensity Score; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Warfarin

In this report, we describe the first successful case of transition from subcutaneous administration of treprostinil to selexipag in a patient with severe pulmonary arterial hypertension (PAH), by evaluating hemodynamic changes and exercise tolerance.. A 38-year-old female with idiopathic PAH (IPAH) had received initial triple combination therapy (macitentan PO, tadalafil PO, and treprostinil SC) and achieved excellent improvement in hemodynamics. Afterwards, due to the development of side effects from subcutaneous administration, we replaced treprostinil therapy with oral selexipag, resulting in stable hemodynamic parameters and exercise capacities.. We report the first case of successful replacement of treprostinil (20.1 ng/kg/min) with selexipag (1600 μg BID) as a component of triple combination therapy, which provides incentive to perform a larger, prospective exchange study.

Topics: Acetamides; Adult; Antihypertensive Agents; Drug Therapy, Combination; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Prospective Studies; Pyrazines; Pyrimidines; Sulfonamides

Topics: Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary

Parenteral prostanoids are effective treatment for pulmonary arterial hypertension, but long-term pump infusion systems have significant delivery-related safety and convenience limitations.. Subjects with a favorable risk profile transitioned from parenteral to oral treprostinil using a protocol-driven titration during 5 days of inpatient observation. Baseline and Week 24 assessments included 6-minute walk distance, echocardiogram, right heart catheterization, pharmacokinetics, treatment satisfaction and quality of life. Thirty-three subjects (76% female, mean age 50 years) enrolled; 85% were using subcutaneous treprostinil with a median dose of 57 (range 25 to 111) ng/kg/min. Participants were using background, approved non-prostanoid therapy, including 9 on 2 oral therapies; baseline right atrial pressure and cardiac output were in the normal range. All 33 subjects transitioned to oral treprostinil therapy within 4 weeks, but 2 transitioned back to parenteral drug before Week 24. At Week 24, subjects were taking a median total daily dose of 44 (15 to 75) mg, with 25 of 31 using a 3-times-daily regimen at 7- to 9-hour intervals.. The 6-minute walk distance was preserved (median +17 m [-98 to 95 m]) at its baseline of 446 m. Hemodynamic variables, including pulmonary vascular resistance, were similar at Week 24 except for mixed venous saturation, which dropped from a median of 71% to 68% (p < 0.001). Overall quality of life and treatment satisfaction measures did not change; however, mood-related symptom and treatment convenience subscores improved. Common adverse effects included headache, nausea, flushing and diarrhea.. Lower risk patients managed on parenteral treprostinil may be candidates for transition to a more convenient, oral form of the drug.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Infusions, Parenteral; Infusions, Subcutaneous; Male; Middle Aged; Patient Selection; Prostaglandins; Quality of Life; Retrospective Studies; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome; Vascular Resistance; Young Adult

Hemodynamic differentiation between pulmonary arterial hypertension (PAH) and postcapillary pulmonary hypertension (PH) is important because treatment options are strikingly different for the two disease subsets. Whereas patients with PAH can be treated effectively with targeted therapies, their use in postcapillary PH is currently not recommended. Our aim was to establish an algorithm to identify patients who are likely to experience a significant hemodynamic treatment response.. We determined hemodynamic cutoffs to discriminate between idiopathic PAH and postcapillary PH in a large database of 4,363 stable patients undergoing first diagnostic right and left heart catheterizations. In a second step, we performed a patient-level pooled analysis of four randomized, placebo-controlled trials including 541 patients with PAH who received treprostinil or placebo, to validate hemodynamic cutoffs with regard to treatment response.. Receiver operating characteristic analysis identified mean pulmonary arterial wedge pressure (mPAWP) < 12 mm Hg and diastolic pulmonary vascular pressure gradient (DPG) ≥ 7 mm Hg as the best hemodynamic discriminators between idiopathic PAH and postcapillary PH. In our treatment study, only patients with mPAWP < 12 mm Hg, DPG > 20 mm Hg or a combination of both had a significant placebo-corrected improvement in hemodynamics.. mPAWP < 12 mm Hg and DPG > 20 mm Hg identify patients with PAH who are likely to have significant hemodynamic improvement with prostacyclin treatment.

Topics: Adult; Aged; Antihypertensive Agents; Cardiac Catheterization; Cohort Studies; Databases, Factual; Diagnosis, Differential; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Proportional Hazards Models; Pulmonary Circulation; Pulmonary Wedge Pressure; Retrospective Studies; ROC Curve; Vascular Resistance

Pulmonary arterial hypertension (PAH) associated with chronic lung disease of infancy can be a life-threatening disease affecting an increasing number of former premature infants. There is a need for improved delivery of targeted PAH therapies for this subgroup of patients who have severe and persistent PAH despite standard respiratory care for chronic lung disease. Currently infants who have severe PAH despite oral or inhaled therapy receive continuous intravenous prostanoid therapy (mostly epoprostenol), which is complicated because of the need for central venous access and associated catheter-related complications. We present a series of 5 infants who were successfully treated with a continuous infusion of subcutaneous treprostinil, which is a longer-acting prostanoid with similar hemodynamic effects. There were improvements in echocardiographic assessment of right ventricular function and estimated pulmonary hypertension, and in respiratory support required within weeks of therapy. Unlike commonly in adults, these 5 infants had no instances of severe site erythema, bleeding, bruising, or infection. In our experience with 5 former extremely preterm infants who had PAH associated with chronic lung disease, subcutaneous treprostinil was safe, efficacious, and well tolerated. We believe that subcutaneous treprostinil can be beneficial in a select group of former premature infants who have chronic lung disease and severe pulmonary arterial hypertension who have not responded adequately to conservative therapies.

Topics: Antihypertensive Agents; Chronic Disease; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Infant; Infusions, Subcutaneous; Lung Diseases; Male

Pulmonary arterial hypertension (PAH) is a rare yet progressive and life-threatening condition that, despite the availability of FDA-approved therapies, remains incurable. Prostacyclin analogues are a mainstay of therapy for patients with PAH, but in spite of demonstrated improvements in survival, exercise capacity and hemodynamics, these agents have been limited by poor pharmacokinetics and complex administration requirements. Treprostinil diolamine (Orenitram™; United Therapeutics) is a novel oral formulation that joins the approved parenteral and inhaled formulations (Remodulin® and Tyvaso®; United Therapeutics). It displays similar pharmacokinetic properties, while offering the potential for improved patient compliance through the convenience of oral dosing. Following the demonstration of improved exercise capacity as monotherapy in patients with de novo PAH (FREEDOM-M), treprostinil diolamine was recently approved by the FDA for the treatment of patients with WHO group 1 PAH and continues to be evaluated in a number of clinical trials in this patient population.

Topics: Administration, Oral; Antihypertensive Agents; Drug Interactions; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Medication Adherence

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

Medical treatment of pulmonary arterial hypertension (PAH) is increasingly common. Prostacyclins were introduced in the early 90s, and treprostinil is one of the most frequently used drugs of this class today, owing to its long half-life and to the possibility to administer the molecule through several routes. Treprostinil is considered a safe drug and is associated with a significant improvement of exercise capacity, especially in patients with idiopathic PAH (iPAH). Systemic sclerosis-associated PAH (sc-PAH) correlates to a worse prognosis compared with that of iPAH. Despite these considerations, safety data on treprostinil are still limited and mainly derived from randomised controlled trials and retrospective studies with relatively small and heterogeneous cohorts of patients with PAH. We report the occurrence of a severe intra-abdominal bleeding during treprostinil infusion in a patient with sc-PAH.

Topics: Adult; Angiography; Antihypertensive Agents; Combined Modality Therapy; Epoprostenol; Familial Primary Pulmonary Hypertension; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Hypertension, Pulmonary; Male; Sigmoidoscopy; Tomography, X-Ray Computed

Pediatric patients with severe pulmonary arterial hypertension (PAH) are treated with intravenous epoprostenol or intravenous or subcutaneous treprostinil. Little is known about longitudinal hemodynamics and outcomes of epoprostenol, treprostinil, and transitions from epoprostenol to treprostinil.. This was retrospective study of 77 pediatric patients (47 idiopathic PAH, 24 congenital heart disease-PAH) receiving epoprostenol or treprostinil from 1992 to 2010 at 2 centers. Outcomes were defined as living vs dead/transplant.. Mean age at baseline was 7.7 ± 5.2 years, with follow-up of 4.3 ± 3.4 years. Thirty-seven patients were treated with epoprostenol, 20 with treprostinil, and 20 were transitioned from epoprostenol to treprostinil. Mean pulmonary-to-systemic vascular resistance ratio (Rp/Rs) for epoprostenol was 1.0 ± 0.4, 0.8 ± 0.4, 0.8 ± 0.4, 1.0 ± 0.4, and 1.2 ± 0.4, respectively, at baseline, 1, 2, 3, and 4 years. For treprostinil, Rp/Rs was 0.9 ± 0.3, 0.7 ± 0.3, 0.5 ± 0.2, (p < 0.01 vs baseline), and 1.1 ± 0.2, respectively, at baseline, 1, 2, and 3 to 4 years, respectively. There were similar changes in mean pulmonary artery pressure and pulmonary vascular resistance index. The Rp/Rs 1 year after epoprostenol to treprostinil transition increased from 0.6 to 0.8 (n = 7). Changes not statistically significant unless noted. Eight patients died or received a transplant within 2 years of baseline; compared with the rest of the cohort, mean baseline Rp/Rs, right atrial pressure, and pulmonary vascular resistance index were significantly worse in this group. Thirty-nine patients remain on prostanoids, 17 are off, 16 died, and 5 received heart-lung transplant. Kaplan-Meier 5-year transplant-free survival was 70% (95% confidence interval, 56%-80%).. There was improvement in Rp/Rs on both therapies at 1 to 2 years that was not sustained. The 5-year transplant-free survival was better than in similar adult studies.

Topics: Administration, Intravenous; Adolescent; Antihypertensive Agents; Blood Pressure; Child; Child, Preschool; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Subcutaneous; Longitudinal Studies; Male; Prostaglandins; Retrospective Studies; Survival Rate; Treatment Outcome; Vascular Resistance

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male

Pulmonary hypertension is defined by 25 mmHg pressure at rest, and 35 mmHg pressure at exercise, in the pulmonary arteries. Hypertension either primary or secondary. The exact prevalence of all types of pulmonary hypertension is not yet known. We present a case of a 58-year-old female patient suffering from CREST syndrome, Raynaud's syndrome, esophageal motility impairment, and severe pulmonary hypertension who had previously obtained a specially developed implantable pump, named Lenus Pro(®), to facilitate continuous parenteral treatment of pulmonary arterial hypertension with treprostinil. Treprostinil is a prostanoid derivative with very stable physiochemical properties which allows subcutaneous treatment of pulmonary arterial hypertension in the outpatient. Treprostinil is normally dosed individually in a range of 0.6 to 50 ng/kg/minute. In the underlying case, a dose of more than 100 mg given over 1 minute is equivalent to a 1000 fold overdose. The patient's critical condition required installment of a central venous access, full monitoring, sedation, oxygen nasal tube, fluid balance, and parenteral nutrition. The patient could be hemodynamically stabilized within 24 hours after the overdose. After 6 days of recovery, the patient left the hospital with no remaining health impairment.

Topics: Antihypertensive Agents; Drug Overdose; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Middle Aged

The Tyvaso Inhalation System is a hand-held nebulizer system used to administer treprostinil, an approved therapy for pulmonary arterial hypertension. Our goal was to establish an in vitro method for delivering a standard dose of treprostinil through a ventilator circuit and artificial airway.. An AeroTech II jet nebulizer (continuous air flow at 10 L/min; Biodex Medical Systems) was placed in the ventilator circuit with a test lung. Two ventilators were tested, the Dräger Evita 2 Dura (Dräger Medical GmbH) and Avea (CareFusion), without humidity. Delivered dose was defined by capturing radiolabeled particles exiting the endotracheal tube with a filter (Pari) and measuring radioactivity. Particle distributions were measured distal to the endotracheal tube by cascade impaction. We hypothesized that drug delivery would be determined by the number of breaths needed, such that the complete time of inspiration totaled 29 sec (e.g., number of breaths needed=29 sec/TI, where TI is the inspiratory time of an average breath read from the ventilator display).. Nebulizer output was linear for 6 min, and the standard prescribed target dose of 54 μg (3.1% of full ampule) was delivered in 29 sec. Using our TI algorithm to control delivery, the mean inhaled dose±SD was 72.2±16.5 μg (range 47.2-98.6; n=23). Dräger delivered higher doses than Avea. Effects of mode, breathing pattern, and positive-end expiratory pressures were not significant. The mass median aerodynamic diameter and fine particle fraction were 0.71±0.015 and 0.997±0.0006, respectively.. Using the algorithm, it was possible to deliver aerosolized treprostinil, at controlled doses, via mechanical ventilation over a wide range of controlled breathing patterns. The conditions of nebulization must be precisely followed (one full ampule per treatment, use of the AeroTech II nebulizer, continuous nebulization using an external flow of 10 L/min, bypass of the humidifier or removal of in-line heat and moisture exchanger, and treatment completed in 6 min or less).

Topics: Administration, Inhalation; Aerosols; Algorithms; Antihypertensive Agents; Drug Delivery Systems; Drug Dosage Calculations; Epoprostenol; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Inhalation; Models, Anatomic; Nebulizers and Vaporizers; Positive-Pressure Respiration; Respiration, Artificial; Time Factors; Ventilators, Mechanical

Pulmonary vasodilators in general and prostacyclin analogues in particular have improved the outcome of patients with pulmonary arterial hypertension (PAH). Endothelial dysfunction is a key feature of PAH and we previously described that circulating endothelial cell (CEC) level could be used as a biomarker of endothelial dysfunction in PAH. We now hypothesized that an efficient PAH-specific vasodilator therapy might decrease CEC level.. CECs were prospectively quantified by immunomagnetic separation with mAb CD146-coated beads in peripheral blood from children with idiopathic PAH (iPAH, n = 30) or PAH secondary to congenital heart disease (PAH-CHD, n = 30): before, after treatment and during follow up. Controls were 23 children with reversible PAH. Oral treatment with endothelin receptor antagonists (ERA) and/or phosphodiesterase 5 inhibitors (PDE5) significantly reduced CEC counts in children. In 10 children with refractory PAH despite oral combination therapy, subcutaneous (SC) treprostinil was added and we observed a significant decrease in CEC counts during the first month of such treatment. CECs were quantified during a 6 to 36 month-follow-up after initiation of SC treprostinil and we found that CEC counts changed over time, with rising counts always preceding clinical deterioration.. CECs might be useful as a biomarker during follow-up of pediatric iPAH and PAH-CHD to assess response to treatment and to anticipate clinical worsening.

Topics: Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Case-Control Studies; Child; Child, Preschool; Drug Resistance; Endothelial Cells; Endothelin Receptor Antagonists; Endothelium, Vascular; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Immunomagnetic Separation; Infant; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Severity of Illness Index; Vascular Resistance; Vasodilator Agents; Young Adult

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.

Topics: Aminorex; Antihypertensive Agents; Appetite Depressants; Bosentan; Dasatinib; Epoprostenol; Familial Primary Pulmonary Hypertension; Fenfluramine; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Iloprost; Phenylpropionates; Piperazines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridazines; Pyrimidines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Thiazoles; Vasodilator Agents

Acute pulmonary vasodilator testing (AVT) is essential to determining the initial therapy for children with pulmonary arterial hypertension (PAH). This study aimed to report the initial experience with inhaled treprostinil used for AVT in children with PAH and to evaluate the hemodynamic change after inhaled treprostinil compared with inhaled nitric oxide. This prospective cohort study was designed for 13 children who underwent AVT with inhaled treprostinil or oxygen plus inhaled nitric oxide (iNO) during catheterization. Inhaled treprostinil was delivered during cardiac catheterization by adapting the Optineb ultrasonic nebulizer via either a flow-inflating bag or the manual mode of the anesthesia system. The median age of the patients was 10 years (range 4-17 years). The etiologies of PAH included idiopathic PAH and associated PAH. All the patients tolerated inhaled treprostinil without marked clinical worsening and received six or nine breaths (36 or 54 μg) of treprostinil. The median of the total treprostinil doses was 1.53 μg/kg (range 0.71-2.89 μg/kg). Inhaled treprostinil was administrated via an endotracheal tube (n = 8), anesthesia mask (n = 3), or laryngeal mask airway (n = 2). Inhaled nitric oxide (iNO) and inhaled treprostinil significantly decreased the mean pulmonary artery pressure and the pulmonary vascular resistance index compared with baseline. Three adverse events were reported after inhaled treprostinil, including cough and mild to moderate hypotension with higher doses. All adverse events resolved without any intervention. This study report is the first to describe the use of inhaled treprostinil for AVT in children with PAH. In this small pediatric cohort, inhaled treprostinil was effectively delivered and well tolerated and may be useful for AVT.

Topics: Administration, Inhalation; Adolescent; Antihypertensive Agents; Child; Child, Preschool; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Oxygen; Prospective Studies; Statistics, Nonparametric

Topics: Antihypertensive Agents; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male

Treprostinil is a prostacyclin analogue approved for the treatment of pulmonary arterial hypertension (PAH). It is commonly administered through a central venous catheter (CVC). Treprostinil is associated with the incidence of Gram-negative bacterial bloodstream infections (BSI), a susceptibility that has been associated with a diluent used for treprostinil. We report the case of a 14-year-old boy with idiopathic PAH on continuous intravenous treprostinil therapy who presented with fever and fatigue. A blood culture drawn from his CVC was positive for the rare Gram-negative organism Chryseomonas luteola. The patient made a complete recovery with antibacterial treatment. This is the only documented case of a C. luteola BSI in a PAH patient receiving continuous intravenous treprostinil. We recommend maintaining a high index of suspicion for both common and rare Gram-negative pathogens and the early administration of appropriate antibiotic therapy in this population. The use of an alternate diluent solution, such as Sterile Diluent for Flolan, further decreases the infection risk.

Topics: Adolescent; Anti-Bacterial Agents; Antihypertensive Agents; Bacteremia; Blood; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Male; Pseudomonas; Pseudomonas Infections; Treatment Outcome

Treprostinil is a synthetic analog of prostacyclin, which is used for treatment of pulmonary arterial hypertension (PAH). Continuous subcutaneous administration of treprostinil has been proven in randomized controlled trials to improve quality of life, hemodynamics, and 5-year survival in patients with PAH. The efficacy of treprostinil has been attributed to its vasodilatory and antiplatelet effects. Unfortunately, the efficacy of treprostinil in the treatment of PAH is rapidly reversed upon cessation of the continuous infusion. Furthermore, cases of patients rapidly declining or succumbing to disease progression upon cessation of treprostinil have raised significant concern regarding discontinuation of this medication. To date, there are no reports of emergency craniotomies performed in the setting of continuous subcutaneous infusion of treprostinil. The authors report a case of a patient with PAH, treated with continuous administration of subcutaneous treprostinil as well as warfarin, who developed an acute subdural hematoma (SDH). Despite adequate INR (international normalized ratio) correction, the patient eventually underwent an emergency craniotomy for evacuation of the SDH while on continuous treprostinil administration. This case highlights the neurosurgical dilemma regarding the appropriate management of acute SDHs in patients receiving continuous treprostinil infusion.

Topics: Aged; Antihypertensive Agents; Craniotomy; Disease Management; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Hematoma, Subdural, Acute; Humans; Hypertension, Pulmonary; Infusions, Subcutaneous; Treatment Outcome

Recent studies have reported an increase in catheter-related bloodstream infections (BSIs) and gram-negative BSIs among patients with pulmonary arterial hypertension treated with IV treprostinil. One possible explanation is the neutral pH of the treprostinil diluent compared with the basic pH of epoprostenol. We hypothesized that administering IV treprostinil with epoprostenol diluent will lower the rate of gram-negative BSI.. We prospectively enrolled patients treated with IV treprostinil and changed the diluent from native diluent to epoprostenol diluent. We compared the incidence of BSI and gram-negative BSI between those receiving IV treprostinil with epoprostenol diluent (n = 25) and those actively receiving IV epoprostenol (n = 61), as well as with a cohort of patients who received IV treprostinil in native diluent (n = 34). Incidence rates of BSI were expressed as a fraction of 1,000 medicine treatment days.. There were similar rates of BSI in those treated with treprostinil with epoprostenol diluent and those treated with epoprostenol (0.32 of 1,000 vs 0.40 of 1,000; P = .79). Also, there were similar rates of gram-negative BSI in these two cohorts (0.08 of 1,000 vs 0.20 of 1,000; P = .46). BSI rates were not statistically different between those treated with treprostinil with epoprostenol diluent and those treated with treprostinil (0.32 of 1,000 vs 0.90 of 1,000; P = .06). However, gram-negative BSIs were significantly lower in patients treated with treprostinil with epoprostenol diluent than in those treated with treprostinil (0.08 of 1,000 vs 0.71 of 1,000, respectively; P = .01).. Patients treated with treprostinil with epoprostenol diluent have a lower incidence of gram-negative BSI than do those treated with treprostinil and a similar rate to those treated with epoprostenol. Changing the diluent of treprostinil to epoprostenol diluent, in combination with the use of water-tight seals throughout the delivery system, appears to be an effective safety measure.

Topics: Antihypertensive Agents; Bacteremia; Catheter-Related Infections; Catheterization, Peripheral; Catheters; Dose-Response Relationship, Drug; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Gram-Negative Bacterial Infections; Humans; Hydrogen-Ion Concentration; Hypertension, Pulmonary; Illinois; Incidence; Injections, Intravenous; Male; Middle Aged; Prognosis; Prospective Studies; Risk Factors

Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary pressures and chronic right heart failure. Therapies for moderate and severe PAH include subcutaneous (SQ) and intravenous (IV) prostanoids that improve symptoms and quality of life. However, treatment compliance can be limited by severe side effects and complications related to methods of drug administration. Inhaled prostanoids, which offer the advantage of direct delivery of the drug to the pulmonary circulation without need for invasive approaches, may serve as an alternative for patients unable to tolerate SQ/IV therapy. In this retrospective cohort study we collected clinical, hemodynamic, and functional data from 18 clinically stable patients with World Health Organization group I PAH seen in 6 large national PAH centers before and after transitioning to inhaled treprostinil from IV/SQ prostanoids. Before transition 15 patients had been receiving IV or SQ treprostinil (mean dose 73 ng/kg/min) and 3 patients had been on IV epoprostenol (mean dose 10 ng/kg/min) for an average duration of 113 ± 80 months. Although most patients who transitioned to inhaled treprostinil demonstrated no statistically significant worsening of hemodynamics or 6-minute walk distance, a minority demonstrated worsening of New York Heart Association functional class over a 7-month period. In conclusion, although transition of patients from IV/SQ prostanoids to inhaled treprostinil appears to be well tolerated in clinically stable patients, they should remain closely monitored for signs of clinical decompensation.

Topics: Administration, Inhalation; Adult; Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Prostaglandins; Pulmonary Wedge Pressure; Retrospective Studies; Treatment Outcome

An excessive risk for bacteremia has recently been reported in patients with pulmonary arterial hypertension (PAH) treated with intravenous treprostinil. We aimed to assess this association in a cohort of patients from a Spanish referral center.. We performed a retrospective cohort study that included 55 patients diagnosed with PAH who received a continuous intravenous infusion of a prostanoid (epoprostenol or treprostinil) for ≥1month at our center between January 1991 and December 2011. The risk factors associated with the incidence of bacteremia were analyzed with the log-rank test.. After a total follow-up of 64,453 treatment days, we found 12 episodes of bacteremia: Staphylococcus aureus (5 episodes), non-fermenting gram-negative bacilli (4 episodes), other gram-positive cocci (2 episodes), and Enterobacter cloacae (one episode). The incidence of bacteremia was 0.118 episodes per 1,000 treatment days in patients receiving epoprostenol versus 0.938 episodes per 1,000 treatment-days in patients receiving treprostinil (P=.0037). All episodes of bacteremia due to Gram-negative bacilli were diagnosed in patients on treprostinil. In the univariate analysis the treatment with intravenous treprostinil was associated with the incidence of bacteremia (hazard ratio: 4.09; 95% confidence interval: 1.24-14.53), although the low number of events prevented us from performing a multivariate analysis.. Therapy with intravenous treprostinil is associated with a higher risk for bacteremia, especially due to non-fermenting Gram-negative bacilli. This association should be taken in consideration when choosing empirical antibiotic therapy for patients with PAH and sepsis.

Topics: Adult; Antihypertensive Agents; Bacteremia; Cohort Studies; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Gram-Negative Bacteria; Humans; Hypertension, Pulmonary; Incidence; Infusions, Intravenous; Male; Middle Aged; Retrospective Studies

Topics: Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase 5 Inhibitors; Sulfonamides

Treprostinil is an intravenous prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH). Few studies have compared the pharmacodynamics and effectiveness of treprostinil and epoprostenol in patients with high-risk PAH.. Case series of patients with PAH admitted to a Medical Intensive Care Unit for transition from epoprostenol to intravenous treprostinil for refractory class III-IV functional symptoms or right heart failure. Mixed linear models were used for comparisons between repeated hemodynamic measurements.. Five of fourteen patients treated with intravenous treprostinil during the study period underwent transition to epoprostenol. Two had PAH associated with systemic sclerosis, three had idiopathic PAH. Pulmonary arterial pressures (PAP) and pulmonary vascular resistance significantly increased within 1 h after discontinuation of treprostinil in all subjects. Mean PAPs immediately prior to discontinuation of treprostinil (53.4 ± 7.5 mmHg) were significantly lower than the values 1 h after discontinuation (63.6 ± 9.6 mmHg, p = 0.026), but were significantly higher than the values following transition to epoprostenol (45.4 ± 5.5, p = 0.0493); 4/5 subjects had short-term clinical follow-up data available; all improved in functional class. No subject experienced adverse events during the transition.. High-risk PAH patients with an inadequate response to treprostinil may have significant clinical and hemodynamic response to epoprostenol. Following discontinuation of treprostinil in these patients, the hemodynamic effects of discontinuation were seen in substantially shorter time than what is known to be the pharmacokinetic terminal half-life.

Topics: Adult; Aged; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Intravenous; Male; Middle Aged

Fibrocytes comprise a recently described cell type of blood-derived, fibroblast-like cells that are recruited from the circulation to sites of wound repair, vascular remodeling, or fibrotic tissue remodeling. We recently showed that the stable prostacyclin analogue treprostinil, a clinically approved drug for pulmonary arterial hypertension (PAH), significantly reduced the recruitment of fibrocytes to sites of vascular remodeling in experimental hypoxic pulmonary hypertension. Here we report on the molecular mechanism underlying the inhibitory action of treprostinil on the adhesion and differentiation of human fibrocytes. Human fibrocytes expressed the prostanoid receptors, prostaglandin I (IP) receptors and prostaglandin E subtype receptors (EP2 and EP4). The generation of intracellular cyclic adenosine monophosphate (cAMP) by treprostinil reduced the expression of the integrins CD49 and CD29 when freshly isolated human peripheral blood mononuclear cells were treated with treprostinil. Cell-matrix adhesion was significantly impaired by treatment with treprostinil. We present evidence for a treprostinil/cAMP-induced downstream suppression of extracellular regulated kinase (ERK) that is transmitted via a protein kinase A-independent pathway through Rap proteins, which sequester Ras. The resulting dephosphorylated state of c-Raf limits the activity of ERK. The cell-matrix adhesion assay with the ERK inhibitor further confirmed that the adhesion of fibrocytes was impaired. Thus our data suggest that treprostinil inhibits the adhesion and differentiation of fibrocytes by limiting the activity of ERK via the cAMP-Rap axis.

Topics: Cell Adhesion; Cell Differentiation; Cells, Cultured; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Epoprostenol; Extracellular Matrix; Extracellular Signal-Regulated MAP Kinases; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Integrin alpha5; Integrin beta1; Leukocytes, Mononuclear; Mutation; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-raf; rap1 GTP-Binding Proteins; ras Proteins; Receptors, Prostaglandin; Signal Transduction; Time Factors; Transfection

In the past 5-10 years, drug treatment of idiopathic pulmonary arterial hypertension has evolved considerably. Experience and results from use of such updated treatment in Norway has not been reported.. 32 patients newly diagnosed with idiopathic pulmonary arterial hypertension, were consecutively assessed with respect to hemodynamics and physical capacity. The results after three months were compared with those after 12 months. Observed survival was compared with estimated survival from the time when only conventional treatment was available.. The patients (78% women) were 42 ± 14 years, had dyspnea in NYHA class 2.9 ± 0.4 and a maximal oxygen uptake of 12.0 ± 3.9 ml/kg/min (37 ± 13% of the expected). Updated treatment led to significantly improved hemodynamics and physical capacity, which persisted during follow-up. During 43 ± 31 months follow-up, seven patients died while two underwent bilateral lung transplantation. Observed transplantation-free survival was 81% after one, two and three years, while that for estimated transplantation-free survival was 70%, 58% and 49% respectively.. Treatment of idiopathic pulmonary arterial hypertension with updated treatment improves hemodynamics and thereby symptoms. Mortality remains high, but is probably lower than it was when only conventional treatment was available.

Topics: Adult; Airway Resistance; Antihypertensive Agents; Bosentan; Epoprostenol; Familial Primary Pulmonary Hypertension; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Lung Volume Measurements; Male; Middle Aged; Oxygen Consumption; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Administration, Inhalation; Adolescent; Drug Overdose; Epoprostenol; Erythema; Facial Dermatoses; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Male; Skin Absorption

Pulmonary arterial hypertension (PAH) is a rare and severe condition characterised by a progressive increase in pulmonary vascular resistance. Two decades ago patients with idiopathic PAH were defined as the people from the kingdom of near- -dead because of poor survival. The progress in treatment of PAH was made, however the disease is still severe and not curable. We present a 26 year-old male patient diagnosed with idiopathic PAH. The clinical course was complicated by progressive worsening, hemoptysis and thrombocytopenia. Treatment with treprostinil and bronchial artery embolisation was started, resulting in symptomatic and functional improvement.

Topics: Adult; Antihypertensive Agents; Embolization, Therapeutic; Epoprostenol; Familial Primary Pulmonary Hypertension; Hemoptysis; Humans; Hypertension, Pulmonary; Male; Thrombocytopenia; Treatment Outcome