u-62840 and Hypertension--Pulmonary

Here, we summarize the results from the INCREASE study, originally published in the. A total of 326 participants took part in the study. Half the participants took inhaled treprostinil and the other half took placebo. After 16 weeks, the INCREASE study showed that participants with PH-ILD who took inhaled treprostinil could walk around 31 meters (102 feet) further than the participants who took placebo. Participants taking inhaled treprostinil also had a decrease in NT-proBNP, which is a protein found in the blood. Lower NT-proBNP levels suggest that the heart is functioning better compared with higher levels. Participants taking inhaled treprostinil showed a decrease of NT-proBNP of 15% compared to a 46% increase in participants taking placebo. More participants taking placebo had worsening of their PH-ILD (33%) compared to participants taking inhaled treprostinil (∼23%). The most common side effects reported in the study were cough, headache and shortness of breath.. In the INCREASE study, on average, people with PH-ILD taking inhaled treprostinil, were able to be more active and had less chance of their PH-ILD getting worse, compared to placebo. Based on inhaled treprostinil showing positive results in most people with PH-ILD in this study, the drug has been approved in the USA for the treatment of PH-ILD.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary

Interstitial lung diseases (ILD) encompasses a heterogeneous group of parenchymal lung diseases characterized by variable amounts of inflammation and fibrosis. The targeting of fibroblasts and myofibroblasts with antifibrotic treatments is a potential therapeutic target for these potentially fatal diseases. Treprostinil is unique among the prostacyclin mimetics in that it has distinct actions at additional prostaglandin receptors. Preclinical and clinical evidence suggests that treprostinil has antifibrotic effects through the activation of the prostaglandin E receptor 2 (EP

Topics: Epoprostenol; Fibrosis; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis

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

Add-on therapy with prostacyclin in pediatric refractory pulmonary hypertension (PH) poses a challenge, especially when considering continuous intravenous administration in younger children. A search for alternate routes of drug delivery has led to the clinical investigation of stable and long-acting prostacyclin analogues, such as subcutaneous treprostinil. We reported 2 pediatric cases of PH treated with subcutaneous treprostinil and reviewed the literature on treprostinil use in children.. The literature review used 3 electronic databases and a combination of terms (treprostinil, pediatric, PH, prostanoid, etc). We also searched for pediatric clinical trials on treprostinil registered on international clinical trial registries.. The reported cases highlighted the multifactorial nature of PH in pediatrics: a female child with a giant omphalocele, and intracardiac and extracardiac shunts; and a male premature child with a congenital diaphragmatic hernia and long-term PH. The literature review identified 19 studies reporting treprostinil use in 421 children with various types of PH (groups 1 and 3). Subcutaneous treprostinil was the most administered formulation, at a mean dose of 40 ng/kg/min. Overall, 12 clinical trials on treprostinil for children with PH were registered on the clinical trial registries. Most authors concluded that subcutaneous treprostinil was effective, well tolerated, and represented an alternative to intravenous epoprostenol.. Subcutaneous treprostinil may be a useful adjunct in the therapeutic algorithm for children with severe PH, refractory to oral drugs, and after a complete check-up for all PH etiologies.

Topics: Antihypertensive Agents; Arterial Pressure; Child; Child, Preschool; Drug Therapy, Combination; Epoprostenol; Female; Gestational Age; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Infant, Premature; Infusions, Subcutaneous; Male; Pulmonary Artery; Treatment Outcome

Despite progress over the past 30 years, pulmonary arterial hypertension remains a condition with high morbidity and mortality. Pharmacological and technological advances have shifted the approach to treating pulmonary arterial hypertension. Recent developments revolve heavily around novel routes of drug administration and delivery. In 2009, inhaled treprostinil was approved followed by oral treprostinil in 2013 providing patients with more convenient routes of administration compared with the parenteral alternatives. We are on the cusp of having the first fully implantable infusion pump for continuous intravenous treprostinil delivery. In 2019, generic treprostinil was approved, making the medication much more affordable for patients. In this review, we discuss in detail the recent developments surrounding both traditional and novel treprostinil products.

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

Despite worse outcomes associated with the development of pulmonary hypertension in chronic lung disease, there are no approved treatments for this population. The present review summarizes the recent clinical trials in World Symposium on Pulmonary Hypertension (WSPH) Group 3 pulmonary hypertension, with a particular focus on the study of pulmonary arterial hypertension (PAH)-targeted therapy.. Multiple recent randomized controlled trials have studied a host of PAH-specific medications in the treatment of WSPH Group 3 pulmonary hypertension, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins. In pulmonary hypertension associated with chronic obstructive lung disease (PH-COPD) and with interstitial lung disease (PH-ILD), most trials have shown conflicting or negative results, although they have been limited by variable patient populations and small sample sizes. Recent large-scale trial data demonstrate that inhaled treprostinil is associated with improved outcomes in the PH-ILD population.. Although most PAH medications have not shown consistent benefit in the WSPH Group 3 population, recent work suggests that inhaled treprostinil has an important role in the treatment of PH-ILD. Efforts are ongoing to evaluate the efficacy of other medications, identify optimal treatment candidates, and define clinically meaningful endpoints in WSPH Group 3 pulmonary hypertension.

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

The present review provides an update on treatment of chronic thromboembolic pulmonary hypertension (CTEPH), a rare form of pulmonary hypertension characterized by precapillary pulmonary hemodynamic parameters with chronic thrombotic occlusion of the pulmonary vasculature.. Pulmonary thromboendarectomy (PTE) remains the recommended treatment for patients with surgically accessible disease. Recent data suggest that patients preoperatively bridged with medical therapy may have improved outcomes but further research is needed. Riociguat improves hemodynamics, right ventricular function, quality of life, and functional capacity and is the drug of choice for patients with inoperable/persistent disease. Recently published data suggest that endothelin receptor blockers and treprostinil may also have a role in medical management of this patient population. A growing body of evidence indicates that in experienced centers balloon pulmonary angioplasty (BPA) may be a well tolerated and effective adjunct to pharmacological treatment for patients with inoperable disease affecting subsegmental vasculature.. Untreated CTEPH carries significant morbidity and mortality. Recent publications provide a wealth of data on safety and efficacy of BPA for inoperable subsegmental disease, but its precise fit in the treatment algorithm, both pharmacological and procedural, requires further investigation. PTE remains the procedure of choice for surgically accessible disease.

Topics: Angioplasty, Balloon; Anticoagulants; Antihypertensive Agents; Chronic Disease; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Vasodilator Agents

Treprostinil diolamine is the first oral dosage preparation of a prostacyclin analogue for use in treatment naive pulmonary arterial hypertension (PAH). This case series and review of the available literature describes the experience of patients with PAH receiving treprostinil by intravenous (IV), subcutaneous (SQ), or inhalation route who were transitioned to treprostinil diolamine. At our institution, 3 patients were transitioned to treprostinil diolamine who received treprostinil administered by each of the alternative routes: IV, SQ, and inhalation. All patients tolerated the transition without significant worsening of disease end points. In the literature, 5 additional reports representing 48 patients were transitioned to treprostinil diolamine from an alternate route of administration. A majority (92%) of patients were hospitalized during the cross-titration phase and tolerated the transition without changes in disease markers or significant adverse effect. Six (13%) patients required reinitiation of parenteral therapy due to clinical decline. The most common dosing frequency utilized for treprostinil diolamine was 3 times per day. In patients with stable PAH receiving parenteral or inhaled treprostinil, a transition to treprostinil diolamine was a safe approach in a highly select population meeting clinical end points. Additional studies are required to further describe this clinical strategy before accepted in clinical practice.

Topics: Administration, Inhalation; Administration, Oral; Adult; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Parenteral; Middle Aged

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by unresolved thrombi in the pulmonary arteries and microvasculopathy in nonoccluded areas. If left untreated, progressive pulmonary hypertension will induce right heart failure and, finally, death. Currently, pulmonary endarterectomy (PEA) remains the only method that has the potential to cure CTEPH. Unfortunately, up to 40% of patients are ineligible for this procedure for various reasons. In recent years, refined balloon pulmonary angioplasty (BPA) has become an alternative option for inoperable CTEPH patients, and it may be another curative treatment in the future, particularly in combination with prior PEA. Nevertheless, 23% of patients still suffer from persistent PH after BPA. Given that CTEPH shares many similarities with idiopathic pulmonary arterial hypertension (PAH), targeted drugs developed for PAH are also attractive options for CTEPH, especially for inoperable or persistent/recurrent CTEPH patients. To date, riociguat, macitentan, and subcutaneous treprostinil are the only drugs proven by randomized control trials to be capable of improving the exercise capacity (6-min walking distance) of CTEPH patients. In this review, we summarize the achievements and unresolved problems of PAH-targeted therapy for CTEPH over the last decade.

Topics: Adult; Aged; Angioplasty, Balloon; Antihypertensive Agents; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Epoprostenol; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Molecular Targeted Therapy; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; Walk Test

Pulmonary arterial hypertension (PAH) is a rare, but severe and life-threatening disease characterized by vasoconstriction and remodeling of the pulmonary arterioles, leading to progressive increase in pulmonary vascular resistance and ultimately to right-heart failure. In the last two decades, significant progress in treatment of PAH has been made, with currently 12 drugs approved for targeted therapy. Among these, the stable prostacyclin analogues iloprost and treprostinil have been repurposed for inhalation. The paper highlights the development of the two drugs emphasizing the rationale and advantages of the inhalative approach. Despite substantial advances in the specific, mainly vasodilatory PAH therapy, disease progression is mostly inevitable and mortality remains unacceptably high. Thus, introduction of new drugs targeting the cancer-like remodeling of the diseased pulmonary arteries is urgently needed. Inhalation offers pulmonary selectivity and will hopefully pioneer the repurposing of novel highly potent drugs for effective aerosol therapy of PAH.

Topics: Administration, Inhalation; Antihypertensive Agents; Drug Repositioning; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost

Although many studies have reported on the cost-effectiveness of bosentan for treating pulmonary arterial hypertension (PAH), a systematic review of economic evaluations of bosentan is currently lacking. Objective evaluation of current pharmacoeconomic evidence can assist decision makers in determining the appropriate place in therapy of a new medication.. Systematic literature searches were conducted in English-language databases (MEDLINE, EMBASE, EconLit databases, and the Cochrane Library) and Chinese-language databases (China National Knowledge Infrastructure, WanFang Data, and Chongqing VIP) to identify studies assessing the cost-effectiveness of bosentan for PAH treatments.. A total of 8 published studies were selected for inclusion. Among them were two studies comparing bosentan with epoprostenol and treprostinil. Both results indicated that bosentan was more cost-effective than epoprostenol, while the results of bosentan and treprostinil were not consistent. Four studies compared bosentan with other endothelin receptor antagonists, which indicated ambrisentan might be the drug of choice for its economic advantages and improved safety profile. Only two economic evaluations provided data to compare bosentan versus sildenafil, and the results favored the use of sildenafil in PAH patients. Four studies compared bosentan with conventional, supportive, or palliative therapy, and whether bosentan was cost-effective was uncertain.. Bosentan may represent a more cost-effective option compared with epoprostenol and conventional or palliative therapy. There was unanimous agreement that bosentan was not a cost-effective front-line therapy compared with sildenafil and other endothelin receptor antagonists. However, high-quality cost-effectiveness analyses that utilize long-term follow-up data and have no conflicts of interest are still needed.

Topics: Antihypertensive Agents; Bosentan; Cost-Benefit Analysis; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Phenylpropionates; Pyridazines; Sildenafil Citrate; Vasodilator Agents

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

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

Pulmonary arterial hypertension (PAH) is a rare disease resulting in progressive remodeling of the pulmonary vasculature and eventual right ventricular failure. Despite the development of 13 therapies for PAH since 2000, the use of continuously infused prostanoids retains a special role. Infused medications present unique challenges, and the search for an efficacious oral prostanoid culminated in the FDA approval of oral treprostinil - a first in class oral prostanoid medication approved to treat pulmonary arterial hypertension (PAH). Areas covered: In this discussion, we review the pharmacologic properties of oral treprostinil, and discuss three original major registration studies that resulted in the approval and widespread use of the drug. We also review several post-approval analyses and transitional studies. We discuss administration issues including side effects, transitioning, cost, and comparative analysis with selexipag. Expert opinion: Though the prospects of harnessing the benefits of continuously infused prostanoid therapy in a pill form are tantalizing, the gap in efficacy between oral and infused treatment is substantial. Major side effects and exorbitant cost are further barriers to broad uptake. Competition from oral prostaglandin receptor agonist selexipag challenges the commercial success of oral treprostinil. The long-term viability of oral treprostinil rests largely on the outcome of the long-term event-driven study of the molecule added to background approved ERA or PDE5 inhibitor monotherapy.

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Clinical Trials as Topic; Drug Approval; Epoprostenol; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pyrazines; Receptors, Prostaglandin; Treatment Outcome

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

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

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

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

Treprostinil is available in three different formulations and four different routes of administration: Remodulin

Topics: Antihypertensive Agents; Area Under Curve; Circadian Rhythm; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Interactions; Epoprostenol; Hypertension, Pulmonary; Maximum Tolerated Dose; Metabolic Clearance Rate

The approval of oral treprostinil is a landmark event in the treatment of pulmonary arterial hypertension. Nineteen years after epoprostenol was approved we now have an oral prostanoid available in the USA. Although the current data in prostanoid naïve patients are unimpressive, emerging data suggest that in carefully selected patients oral treprostinil may be able to replace continuously infused treprostinil; however, many hurdles exist for this new medication including overcoming a complex side effect profile, astronomical cost and perhaps other entrants into the oral prostanoid space.

Topics: Administration, Oral; Antihypertensive Agents; Clinical Trials, Phase III as Topic; Epoprostenol; Ethanolamines; Humans; Hypertension, Pulmonary; Pulmonary Artery; Randomized Controlled Trials as Topic

The inhaled route has a number of attractive features for treatment of pulmonary hypertension, including delivery of drug directly to the target organ, thus enhancing pulmonary specificity and reducing systemic adverse effects. It can also improve ventilation/perfusion matching by dilating vessels supplying ventilated regions, thus improving gas exchange. Furthermore, it can achieve higher local drug concentrations at a lower overall dose, potentially reducing drug cost. Accordingly, a number of inhaled agents have been developed to treat pulmonary hypertension. Most in current use are prostacyclins, including epoprostenol, which has been cleared for intravenous applications but is used off-label in acute care settings as a continuously nebulized medication. Aerosolized iloprost and treprostinil are both prostacyclins that have been cleared by the FDA to treat pulmonary arterial hypertension (PAH). Both require frequent administration (6 and 4 times daily, respectively), and both have a tendency to cause airway symptoms, including cough and wheeze, which can lead to intolerance. These agents cannot be used to substitute for the infused routes of prostacyclin because they do not permit delivery of medication at high doses. Inhaled nitric oxide (INO) is cleared for the treatment of primary pulmonary hypertension in newborns. It is also used off-label to test acute vasoreactivity in PAH during right-heart catheterization and to treat acute right-heart failure in hospitalized patients. In addition, some studies on long-term application of INO either have been recently completed with results pending or are under consideration. In the future, because of its inherent advantages in targeting the lung, the inhaled route is likely to be tested using a variety of small molecules that show promise as PAH therapies.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Bronchodilator Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Infant, Newborn; Nitric Oxide; Off-Label Use; Prostaglandins I; Vasodilator Agents

This review summarizes current information on the first oral prostanoid approved for treatment of pulmonary arterial hypertension, treprostinil diolamine , which, similar to other prostacyclin analogs, vasodilates, impacts remodeling (antiproliferative), reduces endothelial cell dysfunction, inhibits platelet aggregation (antithrombotic) and increases right heart inotropy.. From a pharmacological point of view, it appears that with sustained blood concentrations for 8 - 10 h after a single dose, twice or thrice daily dosing is possible. This review discusses three randomized trials of oral treprostinil that have been completed (FREEDOM-M, FREEDOM-C, FREEDOM-C2). FREEDOM-C and -C2 evaluated oral treprostinil in patients on stable background therapy; FREEDOM-M evaluated oral treprostinil as monotherapy. In FREEDOM-M, the primary end point (6-minute walk distance; 6MWD) was attained, but was not reached in either FREEDOM-C trial. As such, the FDA did not grant approval. Thus, another clinical trial (FREEDOM-EV) is underway: oral treprostinil in patients on background therapy evaluating co-primary end points: i) change in 6MWD; and ii) occurrence of predetermined events. In the interim, oral treprostinil was approved in December 2013.. The use and future of oral treprostinil is not clear. This will depend on the ability to titrate the drug to high levels with acceptable tolerance, on the results of FREEDOM-EV trial and on the impact of selexipag and other oral prostanoids being developed.

Topics: Administration, Oral; Antihypertensive Agents; Drug Approval; Epoprostenol; Humans; Hypertension, Pulmonary; Randomized Controlled Trials as Topic; Treatment Outcome

Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance ultimately resulting in progressive right heart failure. Although new specific treatments have demonstrated improvements in various end points including morbidity/mortality, prognosis remains unfavorable with an on-treatment yearly mortality rate of 10%. Due to complex delivery systems, the use of parenteral prostanoids has been limited to patients with advanced disease. While inhaled prostanoids have had little effect, an oral prostacyclin analog is a desired initial treatment for PAH patients. To that end, UT-15C was synthesized as a sustained-release tablet. FREEDOM-M in treatment-naïve PAH patients resulted in significant improvements of 6-min walk distance supporting the use of oral treprostinil as initial monotherapy in PAH patients with class II or III symptoms. A further study targeting patients on combination treatments is currently exploring a morbidity/mortality end point in a large patient population.

Topics: Animals; Antihypertensive Agents; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Treatment Outcome

The usual differential diagnoses of nocturnal events in children include parasomnias, nocturnal seizures, nocturnal reflux (Sandifer syndrome), hypnic jerks, periodic limb movements of sleep, and sleep disordered breathing. We report a previously healthy young girl who presented to the sleep clinic for evaluation of nocturnal events which were diagnosed as medically refractory nocturnal seizures. It was not until a syncopal event occurred in the daytime, which prompted referral for cardiac evaluation, the diagnosis of idiopathic pulmonary arterial hyper-tension (IPAH) was made. Sleep physicians should consider IPAH in the differential diagnosis of nocturnal events in children.

Topics: Carbolines; Cardiac Output, Low; Child, Preschool; Diagnosis, Differential; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Oxygen Inhalation Therapy; Parasomnias; Seizures; Severity of Illness Index; Sleep Apnea Syndromes; Tadalafil; Treatment Outcome; Warfarin

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

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Withholding Treatment

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

Pulmonary arterial hypertension (PAH) is considered an orphan disease. Prostacyclins are the keystone for PAH treatment. Choosing between the three available prostacyclin therapies could be complicated because there are no comparison studies, so the final decision must be driven by factors such as efficacy, administration route, safety profile and economic aspects.. This study provides a cost-effectiveness and cost-utility comparison of initiating prostacyclin therapy with three different treatment alternatives (inhaled iloprost [ILO], intravenous epoprostenol [EPO] and subcutaneous treprostinil [TRE]) for patients with PAH. The goal of this work is to help physicians with their therapeutic decision-making.. A Markov model was built to simulate a patient cohort with class III PAH according to the classification of the New York Heart Association (NYHA). Four health states corresponding with the NYHA classes plus death were allowed for patients in the model. Changing the treatment was possible when patients worsened from functional class III to IV. The time horizon was 3 years, allowing patients to transition between health states on a 12-week cycle basis. The study perspective was that of the National Health System (NHS) [only direct medical costs were included]. Unitary costs were obtained from the Drug Catalogue and e-Salud Database in 2009 and are given in euros (€). Data on health resources and treatment pathways were informed by a four-member expert panel. Efficacy was obtained from pivotal clinical trials of ILO, EPO and TRE, the latter used in Spain as a foreign medication. Utilities for each health state were obtained from the literature. The final efficacy measure was life-years gained (LYG), and utilities were used to obtain quality-adjusted life-years (QALYs). Costs and effects were discounted at a 3% rate. To check for the robustness of the results, sensitivity analyses were performed.. At the end of the 3 years, in the base case of the deterministic analysis, initiating prostacyclin therapy with iloprost was the less costly strategy (€132,840), followed by treprostinil (€359,869) and epoprostenol (€429,775). Epoprostenol has shown the best efficacy results with 2.73 LYG and 1.78 QALY, followed by iloprost (2.69 LYG and 1.74 QALY) and treprostinil (2.69 LYG and 1.73 QALY). Incremental cost-effectiveness ratios (ICER) and cost-utility ratios (ICUR) of epoprostenol versus iloprost and treprostinil were much above the €30,000 per LYG or QALY threshold commonly used in Spain. Iloprost was dominant compared with treprostinil. In the probabilistic analysis, epoprostenol, when compared with iloprost, was a dominant strategy in 15% of the simulations, but it was not a cost-effective option in 83% of the cases. When compared with treprostinil, epoprostenol was dominant in 43% of the simulations. Iloprost was dominant compared with treprostinil in 45% of the cases and it was a cost-effective alternative in 39% of the simulations.. Initiating prostacyclin treatment with iloprost in patients with PAH, functional class III of the NYHA, is the less costly alternative for the NHS in Spain, with a good efficacy profile when compared with the other alternatives.

Topics: Antihypertensive Agents; Computer Simulation; Cost-Benefit Analysis; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Markov Chains; Models, Economic; Prostaglandins I; Quality-Adjusted Life Years; Spain; Vasodilator Agents

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

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

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

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 is a safe and well-tolerated approved pharmaceutical for the treatment of pulmonary arterial hypertension. In a series of open-label studies and in the pivotal trial with 253 patients, this long-acting prostacyclin analogue demonstrated pronounced pulmonary selectivity of vasodilatory effects, improved physical capacity and excellent tolerability and safety following aerosol administration. For efficient treatment, only four daily inhalations of treprostinil are necessary compared with six to nine in iloprost aerosol therapy. This review describes in detail the development of inhaled treprostinil, starting with intravenous epoprostenol followed by inhaled iloprost and subcutaneous treprostinil, all three representing well-established and widely approved prostanoid therapies for pulmonary hypertension. In order to circumvent the drawbacks of intravenous epoprostenol, stable prostacyclin analogues with similar pharmacological properties have been investigated. In addition, alternative routes of administration have been proposed and evaluated, mainly inhaled and subcutaneous delivery. The concept of inhaled treprostinil was to combine the pulmonary selectivity of an aerosolized vasodilator with the long-acting effects of a stable prostacyclin analogue. Pulmonary arterial hypertension remains, however, a severe, life-threatening disease, in spite of the enormous progress in specific drug therapy over the last decade. Therefore, further improvement of drug therapy will be essential, with clear potential for inhaled treprostinil: a reduction of inhalation frequency and duration would markedly improve quality of life and compliance, and a longer-lasting local prostanoid effect might further enhance the efficacy of inhaled treprostinil. The advantageous pharmacological properties of treprostinil offer the opportunity to establish a convenient metered dose inhaler as a delivery system, to combine inhaled treprostinil with available or future drugs for pulmonary arterial hypertension, or to develop sustained release formulations of treprostinil suitable for inhalation based on liposomes or biodegradable nanoparticles.

Topics: Administration, Inhalation; Antihypertensive Agents; Drug Design; Epoprostenol; Humans; Hypertension, Pulmonary; Medication Adherence; Quality of Life

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

Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. However, with the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients.. We performed a systematic literature search of MEDLINE and EMBASE databases for RCTs of PAH-specific therapy published between January 1980 and May 2009. Articles were selected if they contained a placebo comparator and described hemodynamic changes from baseline. We applied the weighted mean change in hemodynamic variables to the equation developed by the National Institutes of Health (NIH) Registry to estimate long-term survival with each therapy.. Ten RCTs involving 1,635 patients met the inclusion criteria. Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil. 77.6% of patients were female and the mean (SD) age was 46.5 +/- 4.9 years. 55.5% of patients had idiopathic PAH (iPAH), 23.9% PAH related to connective tissue disease, and 18.2% PAH related to congenital heart disease. Based on the effects observed in short-term trials and, relative to placebo, all analyzed therapies improved survival. The estimated 1-year survival was 78.4%, 77.8%, 76.1%, 75.8%, 75.2%, and 74.1% for epoprostenol, bosentan, treprostinil, sitaxentan, sildenafil, and beraprost, respectively. These estimates are considerably lower than the 1-year observed survival reported in several open-label and registry studies with PAH-specific therapies: 88% - 97%.. When applied to the NIH Registry equation, hemodynamic changes from baseline appear to underestimate the survival benefits observed with long-term PAH therapy.

Topics: Adult; Aged; Antihypertensive Agents; Bosentan; Cohort Studies; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Isoxazoles; Male; Middle Aged; Piperazines; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Time Factors; Treatment Outcome

The prostacyclins-prostanoids were one of the first medications used to treat pulmonary arterial hypertension (PAH). Three prostanoids have been developed to treat PAH: epoprostenol, treprostinil, and iloprost. In the acute setting, experience is growing, using the inhaled forms of these three medications. Inhalation may improve ventilation/perfusion matching, whereas in the intravenous form these medications may cause nonselective pulmonary vasodilation and may worsen ventilation/perfusion matching. Currently, there are no universal recommendations for dosing delivery of inhaled prostanoids to intubated patients in the intensive care unit setting.

Topics: Administration, Inhalation; Antihypertensive Agents; Child; Critical Care; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost

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

Treprostinil (Remodulin) is a new therapy for pulmonary hypertension. A multidisciplinary plan for safely managing the drug is described, and includes a flow chart to guide practice through high-risk issues.

Topics: Academic Medical Centers; Antihypertensive Agents; Drug Monitoring; Epoprostenol; Equipment Design; Equipment Failure; Humans; Hypertension, Pulmonary; Infusion Pumps; Infusions, Intravenous; Nursing Assessment; Nursing Records; Patient Care Planning; Patient Care Team; Patient Education as Topic; Safety Management; Severity of Illness Index; Southwestern United States; Total Quality Management

Treprostinil is a stable, long-acting prostacyclin analogue which can be administered as a continuous subcutaneous infusion using a portable miniature delivery system. Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor prognosis. Side effects include facial flush, headache, jaw pain, abdominal cramping, and diarrhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and infusion site pain which may make further treatment impossible in 7%-10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting efficacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2-3 times those given subcutaneously, appear to be needed to obtain the same efficacy. Preliminary results of a randomized controlled trial of inhaled treprostinil on top of bosentan and sildenafil therapies have shown significance on the primary endpoint, which was exercise capacity as assessed by the distance walked in 6 minutes. Trials of oral formulations of treprostinil have been initiated.

Topics: Administration, Cutaneous; Antihypertensive Agents; Chronic Disease; Epoprostenol; Exercise Test; Exercise Tolerance; Humans; Hypertension, Pulmonary; Thromboembolism

Pulmonary arterial hypertension (PAH) is a progressive disease marked by vasoconstriction and vascular remodeling within pulmonary arteries leading to right heart failure and death. Significant advances in understanding the pathobiology of the disease have identified three key pathways involved in progression of this disease, which are the endothelin pathway, the prostacyclin pathway, and the nitric oxide/cyclic guanosine monophosphate pathway. Echocardiogram is the best screening tool to obtain an estimation of the pulmonary artery systolic pressure but right heart catheterization remains the standard by which the diagnosis is made. There are currently six FDA approved therapies for PAH. The mechanistic rationale, evidence behind their use and side effect considerations in utilizing these therapies in PAH patients will be the focus of this review.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Disease Progression; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelium, Vascular; Epoprostenol; Heart Failure; Humans; Hypertension, Pulmonary; Iloprost; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Prognosis; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Vasoconstriction

Pulmonary hypertension (PH) is a severely disabling disorder characterized by sustained elevations of pulmonary arterial pressure, ultimately leading to right-heart failure and death. Pulmonary arterial hypertension (PAH) usually occurs in the absence of an evident cause (idiopathic PAH) or may be associated with connective tissue disease, HIV infection, congenital heart disease, chronic liver disease or result from the use of toxic agents and anorexigens.. Intravenous epoprostenol has been widely used in patients with PAH, leading to long-term clinical benefits and improved survival. Epoprostenol has to be delivered through a permanently implanted Intravenous catheter. This may expose patients to potentially life-threatening complications. Thus, more stable compounds and alternative modes of prostacyclin delivery have been sought.. Treprostinil sodium is a stable prostacyclin analogue, sharing pharmacologic actions similar to epoprostenol with comparable haemodynamic effects. Treprostinil is chemically stable at room temperature and has a long half-life (2 - 4 h), making this drug suitable for subcutaneous administration, with practical benefits in avoiding the risk of line infection and thrombosis, and cardiovascular reactions due to abrupt drug discontinuation.

Topics: Administration, Inhalation; Antihypertensive Agents; Clinical Trials as Topic; Drug Stability; Epoprostenol; Humans; Hypertension, Pulmonary; Injections, Intravenous; Injections, Subcutaneous

Pulmonary arterial hypertension is a group of diseases which forms a small subset of those with elevated pulmonary artery pressure (pulmonary hypertension). The recent development of selective pulmonary vasodilator has lead to a substantial resurgence of interest in what have been previously regarded as rare and incurable diseases. This review aims to describe the spectrum of pulmonary vascular diseases, the evolving understanding as to pathogenesis, the evolving evidence of efficacy for drug therapies, trying to put this into a contemporary Australian context. Several key pathogenic pathways may be involved: prostacycline, Nitric Oxide-cGMP-phosphodiesterase 5 and endothelin- all of which are exploited for therapeutic benefit by newly available drug therapies. A recently modified classification system reasserts the importance of precise diagnosis. The cardinal symptom of exertional dyspnea warrants careful evaluation in an attempt to prevent (frequently occurring) substantial delay in diagnosis. Echocardiogram is the cornerstone of screening for pulmonary arterial hypertension; however, a detailed evaluation including a carefully performed right heart catheterisation with sufficient data to allow calculation of pulmonary vascular resistance is key to accurate diagnosis. These new approaches to therapy are already substantially improving quality of life and prognosis.

Topics: Adolescent; Adult; Aged; Arterioles; Australia; Bosentan; Cardiac Catheterization; Diagnostic Imaging; Disease Progression; Dyspnea; Endothelin A Receptor Antagonists; Epoprostenol; Exercise Test; Female; Forecasting; Heart-Lung Transplantation; Humans; Hypertension, Pulmonary; Iloprost; Lung Transplantation; Male; Middle Aged; Nitric Oxide; Piperazines; Prognosis; Pulmonary Artery; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Sulfones; Vascular Resistance; Vasodilator Agents; Ventricular Dysfunction, Right

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

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

Topics: Activities of Daily Living; Antihypertensive Agents; Critical Care; Drug Monitoring; Epoprostenol; Exercise Test; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Nurse's Role; Nursing Assessment; Patient Education as Topic; Practice Guidelines as Topic; Safety; Severity of Illness Index

Evidence-based therapies and guidelines for pulmonary arterial hypertension are critiqued.. Morbidity and mortality in pulmonary arterial hypertension reflects failure of right ventricular compensation for increased afterload caused by obstructive pulmonary arterial remodeling. This predominantly reflects excessive proliferation/impaired apoptosis of smooth muscle and endothelial cells, rather than vasoconstriction. To exclude confounding effects of cardiac output and left ventricular end-diastolic pressure, the diagnosis of pulmonary arterial hypertension should require a pulmonary vascular resistance >3 Wood-units, not simply a mean pulmonary arterial pressure >25 mmHg. A 'positive' response (20% fall in pulmonary arterial pressure/pulmonary vascular resistance PAP/PVR) to acute, selective, pulmonary vasodilators (e.g. inhaled nitric oxide), occurs in 20% of patients, portends a favorable prognosis and justifies a trial of calcium channel blockers. Randomized controlled trials support treatment of NYHA class III pulmonary arterial hypertension with oral endothelin antagonists or phosphodiesterase-5 inhibitors. Prostacyclin analogues (inhaled/subcutaneous) are useful adjunctive therapies. Intravenous epoprostenol remains the therapeutic mainstay for class IV PAH. Emerging antiproliferative-proapoptotic therapies that merit investigator-initiated clinical trials include: statins, Imatinib, NONO-ates, anti-survivin, potassium channel modulation, and dichloroacetate.. The diagnostic criteria for pulmonary arterial hypertension should be revised to include PVR. Sildenafil's efficacy and price recommend it as a first-line oral therapy. New pulmonary arterial hypertension-regression therapies and therapeutic combinations offer the potential for cure of pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Benzamides; Bosentan; Calcium Channel Blockers; Comorbidity; Dichloroacetic Acid; Drug Therapy, Combination; Epoprostenol; Evidence-Based Medicine; Fluoxetine; Humans; Hypertension, Pulmonary; Iloprost; Imatinib Mesylate; Isoxazoles; Phosphodiesterase Inhibitors; Piperazines; Prostaglandins, Synthetic; Pulmonary Artery; Purines; Pyrimidines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Simvastatin; Sulfonamides; Sulfones; Thiophenes; Vasodilator Agents

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

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

Pulmonary Arterial Hypertension includes a heterogeneous group of disorders with a common genetic, pathological and hemodinamyc origin. It is characterized by a high pulmonary artery pressure due to a primary vascular disease, as a consequence of genetic and environmental factors. The common pathway is a vascular imbalance towards vasoconstriction and proliferation inside the small vessels. According to the World Health Organization, 2003, Pulmonary Arterial Hypertension is classified as idiopathic, familiar or associated to connective tissue diseases, HIV, drugs, porto-pulmonary hypertension, congenital intracardiac shunts and others. The diagnosis is based in hemodynamics. Echocardiogram is a non invasive and right ventricular catheterization is an invasive diagnostic tool. Follow up is based on a clinical and functional assessment through functional class classification, dyspnea scores and 6-minute walking test. The prognosis is historically devastating but new therapies are changing the natural history of the disease. New treatments have demonstrated improvement in symptoms, hemodynamic profiles and survival. Intravenous, subcutaneous or inhaled prostanoids such as Epoprostenol, Treprostinil or Iloprost respectively have been approved for Pulmonary Arterial Hypertension treatment as well as oral endothelial receptor blockers. They are all considered first line treatments for arterial pulmonary hypertensive patients with even better benefits than lung transplantation. Phosphodiesterase inhibitors (Sildenafil), have been recently approved for the treatment of pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Phosphodiesterase Inhibitors; Piperazines; Platelet Aggregation Inhibitors; Prognosis; Purines; Sildenafil Citrate; Sulfones

Pulmonary arterial hypertension (PAH) is a serious complication of systemic sclerosis (SSc) and a leading cause of death in patients with it. Recent publications suggest that a prevalence of 10-15% is likely. The prognosis remains poor compared to that of idiopathic PAH. WHO recommends annual echocardiography for PAH screening of patients with SSc. Right heart catheterization is necessary to confirm the diagnosis. Nevertheless, more than half of all SSc patients have symptoms classified as WHO functional class III or IV at diagnosis. Prostacyclin therapy, delivered via continuous intravenous infusion (epoprostenol), has been demonstrated to be effective in patients with severe PAH (both idiopathic and scleroderma-related). Prostacyclin analogs (such as treprostinil and iloprost) are other options. Bosentan is the first endothelin receptor antagonist approved in the EU for the treatment of PAH, both idiopathic and related to connective tissue diseases such as scleroderma, in patients in WHO functional class III. Sildenafil by its selective inhibition of phosphodiesterase type 5 is also effective against both types of PAH. It too is now approved in the EU for this purpose in patients in WHO functional class III, but we do not yet have any information about its long-term effects in scleroderma.

Topics: Algorithms; Antihypertensive Agents; Bosentan; Cardiac Catheterization; Cohort Studies; Echocardiography, Doppler; Epoprostenol; European Union; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prevalence; Prognosis; Purines; Randomized Controlled Trials as Topic; Scleroderma, Systemic; Sildenafil Citrate; Sulfonamides; Sulfones; Time Factors; Vasodilator Agents; World Health Organization

Primary pulmonary hypertension (PPH) is progressive, resulting in right ventricular failure. Pulmonary hypertension can be idiopathic or associated with other conditions. Prostacyclin is a potent vasodilator and inhibitor of platelet aggregation, and can be given orally, subcutaneously, intravenously or inhaled via a nebuliser.. To determine the efficacy of prostacyclin or one of its analogues in idiopathic primary pulmonary hypertension.. Electronic searches were carried out with pre-specified terms. Searches were current as of July 2004.. Two reviewers selected randomised controlled trials (RCTs) involving adults with pulmonary hypertension for inclusion.. Study quality was assessed and data extracted independently by two reviewers. Outcomes were analysed as continuous and dichotomous outcomes. We sub-grouped data where possible by aetiology of PH (PPH, PH secondary to connective tissue disorder or mixed populations).. Nine RCTs of mixed duration (3 days-52 weeks), recruiting 1175 participants were included (NYHA functional classes II-IV). Intravenous prostacyclin versus usual care (four studies): There were significant improvements in exercise capacity of around 90 metres, cardiopulmonary haemodynamics and NYHA functional class over 3 days-12 weeks. Effects were consistent in primary and secondary pulmonary hypertension. Oral prostacyclin versus placebo (two studies): Short-term data (3-6 months) indicated that there was a significant improvement in exercise capacity, but data from one study of 52 weeks reported no significant difference at 12 months. No significant differences were observed for any other outcome. Subcutaneous treprostinil versus placebo (two studies, 8-12 weeks):One large study reported a significant median improvement in exercise capacity of around 16 metres. Cardiopulmonary haemodynamics and symptom scores favoured treprostinil. Infusion site pain and withdrawals due to adverse events were more frequent with treprostinil. Inhaled prostacyclin versus placebo (one study, 12 weeks):There was a significant increase in exercise capacity of approximately 36 metres. Treatment led to better symptom scores and functional class status than with placebo. Subgroup analyses reported by individual studies showed a better exercise capacity in participants with PPH, than those participants with PH secondary to other diseases. Side effects and adverse events were common in the studies.. There is evidence that intravenous prostacyclin in addition to conventional therapy at tolerable doses optimised by titration, can confer some short-term benefits (up to 12 weeks of treatment) in exercise capacity, NYHA functional class and cardiopulmonary haemodynamics. There is also some evidence that patients with more severe disease based upon NYHA functional class showed a greater response to treatment.

Topics: Adult; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Randomized Controlled Trials as Topic

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

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

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

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

Primary pulmonary hypertension is a rare disease of the pulmonary vasculature manifested by dyspnea on exertion, syncope, and signs and symptoms of right heart failure. In the absence of adequate treatment, primary pulmonary hypertension has a grave prognosis, with a median survival of 2.8 years. Pulmonary arterial hypertension develops in association with known risk factors and predisposing clinical conditions, and shares many clinical, pathological and therapeutic characteristics with primary pulmonary hypertension. Therapeutic choices in pulmonary arterial hypertension depend on the etiology of the disease, severity of functional impairment and hemodynamic response following acute vasodilator administration during right heart catheterization. Agents currently approved for the specific treatment of pulmonary arterial hypertension are continuous intravenous epoprostenol, subcutaneous treprostinil and oral bosentan. A small group of patients who demonstrate true acute vasoreactivity at right heart catheterization may be chronically treated with oral calcium channel blockers. In addition, most patients with pulmonary hypertension receive conventional treatment, represented by anticoagulants, diuretics, inotropic medication or oxygen supplementation. Treatment of pulmonary arterial hypertension has significantly altered the natural course of the disease, with pronounced symptomatic, functional and survival benefit. Current clinical research focuses on the discovery of new targets of therapy and the use of a combination treatment approach, which will offer hope and valuable insight into the pathogenetic basis of this devastating illness.

Topics: Algorithms; Antihypertensive Agents; Bosentan; Calcium Channel Blockers; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Platelet Aggregation Inhibitors; Sulfonamides

Topics: Administration, Oral; Anticoagulants; Antihypertensive Agents; Clinical Protocols; Critical Care; Drug Administration Schedule; Epoprostenol; Humans; Hypertension, Pulmonary; Infusion Pumps; Injections, Subcutaneous; Patient Education as Topic; Vasodilator Agents

Pulmonary arterial hypertension is a life-threatening disorder that refers to a group of diseases characterized by an abnormal elevation of the blood pressure within the pulmonary circulation due to a vasculopathy of the pulmonary microcirculation (1). If left untreated, the overall prognosis of pulmonary arterial hypertension is poor, with a 5-year survival rate of 34%. The most common cause of death is progressive right-sided heart failure (2). There is no pharmacologic cure for pulmonary arterial hypertension, and a team approach is required for the proper care of these patients (3). Treatment is directed at improving clinical symptoms, increasing exercise tolerance and extending survival. Until just a few years ago, standard treatment options for the treatment of pulmonary arterial hypertension were limited and included coumarin derivatives, calcium channel blockers, diuretics, digoxin and oxygen supplementation (4). In the last decade, the therapeutic options for pulmonary arterial hypertension have made considerable advances. In at least three major randomized controlled trials, the continuous intravenous infusion of epoprostenol, a synthetic salt of prostacyclin with potent vasodilatory ability, has been shown to improve exercise tolerance, hemodynamics, survival and quality of life in patients with New York Heart Association (NYHA) functional classes III and IV with either primary pulmonary hypertension or pulmonary arterial hypertension associated with scleroderma (5-9). Epoprostenol has now become a mainstay therapy in the long-term treatment of primary pulmonary hypertension or pulmonary arterial hypertension associated with scleroderma. Nevertheless, epoprostenol is far from an ideal form of therapy. Issues such as the short half-life of the drug, need for continuous central intravenous access and significant side effects have led to the development of more stable prostacyclin analogues as alternative therapies for primary pulmonary hypertension. These alternative therapies include iloprost (inhaled delivery) and treprostinil (subcutaneous delivery). As a result, the Food and Drug Administration (FDA) recently approved treprostinil for the treatment of pulmonary arterial hypertension in patients with NYHA classes II-IV. This review will offer a discussion of the basic pharmacology of treprostinil, its similarities to and differences from epoprostenol, the animal studies as well as the initial investigational studies leading to its FDA approval

Topics: Antihypertensive Agents; Endothelium, Vascular; Epoprostenol; Humans; Hypertension, Pulmonary; Lung; Randomized Controlled Trials as Topic

Treprostinil (Remodulin, United Therapeutics) is a stable, long-acting prostacyclin analog, which has been shown to improve clinical state, functional class, exercise capacity and quality of life in patients with pulmonary arterial hypertension, an uncommon disease with poor prognosis. The drug is administered as a continuous subcutaneous infusion using a portable miniature delivery system. Side effects include facial flush, headache, jaw pain, abdominal cramping and diarrhea. These are all typical of prostacyclin impregnation and manageable by symptom-directed dose adjustments. Infusion site pain, a more serious side effect, may limit the treatment in 10% of patients. Otherwise, treprostinil has an excellent safety profile and compares favorably with reference continuous intravenous epoprostenol (Flolan, GlaxoSmithKline) therapy. Treprostinil has a place in currently proposed treatment algorithms of pulmonary arterial hypertension.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Infusion Pumps; Infusions, Intravenous; Injections, Subcutaneous; Pilot Projects; Treatment Outcome

Prostanoids have played a prominent role in the treatment of pulmonary arterial hypertension (PAH). Several compounds and methods of administration have been studied: chronic intravenously infused epoprostenol, chronic subcutaneously infused treprostinil, inhaled iloprost, and oral beraprost. Chronic intravenous epoprostenol therapy has had a substantial impact on the clinical management of patients with severe PAH. It improves exercise capacity, hemodynamics, and survival in patients with idiopathic pulmonary arterial hypertension (IPAH). It also improves exercise capacity and hemodynamics in patients with PAH occurring in association with scleroderma. The complexity of epoprostenol therapy (chronic indwelling catheters, reconstitution of the drug, operation of the infusion pump, and others) has led to attempts to develop other prostanoids with simpler modes of delivery. Treprostinil, a stable prostacyclin analogue with a half-life of 3 h, has been developed for subcutaneous delivery. It has beneficial effects on exercise and hemodynamics, which depend somewhat on the dose achieved. This, in turn, is determined by the patient's ability to tolerate the drug's side effects, including pain and erythema at the infusion site. Inhaled iloprost therapy may provide selectivity of the hemodynamic effects to the lung vasculature, thus avoiding systemic side effects. In a randomized and controlled trial, iloprost resulted in improvement in a combined end point incorporating the New York Heart Association functional class, 6-min walk test, and deterioration or death. Beraprost is the first orally active prostacyclin analogue. In the first of two randomized controlled trials, beraprost increased exercise capacity in patients with IPAH, with no significant changes in subjects with associated conditions. Hemodynamics did not change significantly, and no difference in survival was detected between the two treatment groups. The second study showed that beraprost-treated patients had less disease progression at six months and confirmed the results of the previous trial. However, this improvement was no longer present at 9 or 12 months. In conclusion, though treatment with prostanoids is complicated by their generally short half-lives and complicated drug delivery systems, they continue to play an important role in the treatment of PAH.

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Prostaglandins; Pulmonary Artery; Vasodilator Agents

Pulmonary hypertension (PH) occurs frequently in parenchymal lung disease and is usually correlated with increased mortality. Thus, the treatment of PH in patients with lung disease has been an active area of interest. Secondary pulmonary hypertension (SPH), whether from parenchymal lung disease or other etiologies, is more common than primary pulmonary hypertension (PPH). In 2002, two new medications, oral bosentan and subcutaneous treprostinil, were released for the treatment of pulmonary arterial hypertension (PAH). These new agents are not restricted to use in PPH, as they are approved for use in PAH in general. It is reasonable to consider the use of these medications in select patients with SPH caused by parenchymal lung disease, although these groups have not yet been studied in clinical trials. The initial hemodynamic evaluation of SPH patients, the potential use of these new medications in the context of standard care, and the assessment of response to therapy are discussed in this update. A relevant case report is used to illustrate use of these new agents in SPH, and ongoing clinical trials are reviewed. The available treatment options for patients with SPH are rapidly improving.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Clinical Trials as Topic; Echocardiography; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Middle Aged; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

The management of pulmonary arterial hypertension (PAH) should aim to provide vasodilation of the pulmonary arteries, treat right ventricular failure, improve functional capacity and quality of life, and improve survival, if possible. Data from right heart catheterization and an estimation of vasoresponsiveness together guide treatment for PAH. The judicious use of calcium channel blockers, prostacyclin analogues, anticoagulation, and endothelin receptor antagonists forms the current basis of therapy. Three drugs-the prostacyclin analogues epoprostenol and treprostinil and the endothelin receptor antagonist bosentan-are currently approved for the primary treatment of PAH and have been clinically shown to improve outcomes. Coumarin derivatives, epoprostenol, and, in selected patients, calcium channel blockers are the only drugs associated with improved survival, and only epoprostenol has been shown to improve survival in a prospective randomized trial. Knowledge of the supportive therapies, indications for surgical intervention, and emerging drug therapies should provide the working armamentarium for clinicians treating this rare but devastating disease.

Topics: Antihypertensive Agents; Calcium Channel Blockers; Controlled Clinical Trials as Topic; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Platelet Aggregation Inhibitors; Quality of Life; Risk Factors; Vasodilator Agents; Vasomotor System; Ventricular Dysfunction, Right

Topics: Antihypertensive Agents; Bosentan; Epoprostenol; Humans; Hypertension, Pulmonary; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome

New therapies for pulmonary arterial hypertension (PAH) improve functional status, quality of life (QOL), and survival. Clinicians must chose between very different therapies without the availability of comparison studies. We constructed a "virtual" clinical trial to help inform these treatment choices.. We compare key outcomes related to survival, costs, and QOL using a Markov-type decision model to estimate the expected outcomes and costs for PAH patients treated for 1 year with bosentan and treprostinil compared to patients treated with epoprostenol, as well as patients treated with bosentan compared to those treated with treprostinil. The allowed transitions in the model were between World Health Organization functional class I to IV and death. Transition probabilities were based on observed transitions for bosentan. Treatment effect was estimated using 6-min walk data for treprostinil and epoprostenol. Utilities were calculated from estimated EuroQol health states. Cost was estimated from average wholesale price and Medicare reimbursement data. The effects of changing values of input variables on the key outcomes were calculated.. Treatment with bosentan compared to treatment with either epoprostenol or treprostinil was less costly and resulted in a greater gain in quality-adjusted life years (QALYs). Conversely, treprostinil was significantly more expensive than epoprostenol, without an appreciable gain in QALYs. These findings were not substantially affected by the reasonable adjustments of transition probabilities, utility values, or tachyphylaxis to epoprostenol.. Treatment with bosentan is more cost-effective than treatment with either treprostinil or epoprostenol. In addition, a net improvement in quality-adjusted survival may be expected.

Topics: Antihypertensive Agents; Bosentan; Decision Support Techniques; Epoprostenol; Fees, Pharmaceutical; Humans; Hypertension, Pulmonary; Markov Chains; Quality-Adjusted Life Years; Sulfonamides

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

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

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

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

Pulmonary artery hypertension is a life-threatening disease characterised by a pulmonary vasculopathy and progressive right ventricular failure. Major advances were made with the development of continuous intravenous epoprostenol (Flolan trade mark ) as a treatment modality. Nevertheless, it is far from ideal as treatment for this disease. Subcutaneous treprostinil has been FDA approved for the treatment of New York Heart Association Functional Class II - IV pulmonary artery hypertension. It is a longer acting subcutaneous prostacyclin analogue that offers an additional mode of therapy for this disease. A discussion of the pharmacology of this prostacyclin analogue as compared to its related compounds, the clinical studies which led to its approval, a review of some additional basic studies and the practical use of this drug in the treatment modalities for precapillary pulmonary artery hypertension in 2002 in light of other available therapies is discussed.

Topics: Animals; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Artery

United Therapeutics Corp (UTC) is developing treprostinil sodium (Remodulin, UT-15), a stable structural analog of prostacyclin, for the potential treatment of primary pulmonary (arterial) hypertension (PAH), peripheral vascular disease (PVD) and other cardiovascular conditions [327593], including critical limb ischemia (CLI) [412483]. In August 2000, UTC submitted the initial, non-clinical sections of an NDA for the treatment of pulmonary hypertension [378906]. Treprostinil, which had previously been designated as an Orphan Drug, was also awarded Priority Review status by the US FDA in October 2000 [385864], [386271]. In December 2000, UTC agreed with the FDA that the NDA for treprostinil did not need to be presented to the Cardiovascular and Renal Drugs Advisory Committee, which was expected to allow UTC and the FDA to work towards the 6-month Priority Review timeline [393888]. On August 9, 2001, the advisory committee recommended approval of treprostinil and UTC refiled the NDA on the same day [418682]. In February 2002, the FDA issued an approvable letter for treprostinil injection for the treatment of PAH. The FDA proposed drug labeling for PAH consistent with the treatment of both primary and secondary pulmonary hypertension in patients with New York Heart Association (NYHA) Class II-IV symptoms. The approvable letter also stated that the FDA intended to approve treprostinil with a requirement that UTC subsequently conduct a post-marketing controlled clinical trial to verify and further describe the drug's clinical benefit [439278]. In February 2001, UTC submitted a marketing authorization application (MAA) in France for approval of treprostinil for the treatment of PAH. Upon approval of the MAA, UTC planned to file for Mutual Recognition in other European countries and was also preparing similar submissions to non-European countries [391986], [397958]. By early 2001, phase II trials of treprostinil for the treatment of CLI were underway [412483]. In March 2001, the company was planning a phase III pivotal study in late-stage PVD by the end of 2001 [424180]. In April 2000, UTC was issued US-06054486 for the method of treating PVD with treprostinil [364130]. In February 2000, UTC entered into an agreement with Paladin Labs for the exclusive Canadian distribution of treprostinil for the remainder of clinical trials and after regulatory approvals [357302]. In November 2000, UTC and Antigen Pharmaceuticals entered into a strategic alliance for the distr

Topics: Cardiovascular Agents; Clinical Trials as Topic; Epoprostenol; Extremities; Humans; Hypertension, Pulmonary; Ischemia; Peripheral Vascular Diseases; Platelet Aggregation Inhibitors

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

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

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

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

Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resulting from ILD.. Do higher dosages of iTre have greater benefits in preventing clinical worsening and achieving clinical improvement?. Post hoc analysis of the INCREASE study, a 16-week double-blind, randomized, placebo-controlled trial of iTre in patients with PH resulting from ILD. Four groups were identified based on the number of breaths per session (bps; < 9 and ≥ 9 bps) of active drug or placebo attained at 4 weeks. Patients were evaluated for clinical worsening (15% decrease in 6-min walkdistance, cardiopulmonary hospitalization, lung transplantation, or death) or clinical improvement (15% increase in the six-minute walk distance with a concomitant 30% reduction in N-terminal prohormone of brain natriuretic peptide without any clinical worsening event).. At 4 weeks, 70 patients were at a dose of ≥ 9 bps (high-dosage group) and 79 patients were at a dose of < 9 bps (low-dosage group) in the iTre arm vs 86 patients in the high-dose group and 67 patients in the low-dose group in the placebo arm. Between weeks 4 and 16, 17.1% of patients in the high-dose treprostinil group and 22.8% in the low-dose treatment group experienced a clinical worsening event vs 33.7% and 34.3% of patients in the two placebo arms, respectively (P = .006). By week 16, 15.7% and 12.7% of patients in the high- and low-dose iTre groups, respectively, demonstrated clinical improvement vs 7% and 1.5% patients in the placebo arms (P = .003) INTERPRETATION: Higher dosages of iTre overall show greater benefit in terms of preventing clinical worsening and achieving clinical improvement. These data support the early initiation and uptitration of therapy to a dosage of at least 9 bps four times daily in patients with PH resulting from ILD.. ClinicalTrials.gov; No.: NCT02630316; URL: www.. gov.

Topics: Antihypertensive Agents; Double-Blind Method; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Treatment Outcome

The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD.. Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded.. At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and -19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL. These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT.

Topics: Aged; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Quality of Life; Treatment Outcome

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

No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear.. We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening.. A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea.. In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Double-Blind Method; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Least-Squares Analysis; Lung Diseases, Interstitial; Male; Middle Aged; Quality of Life; Walk Test

INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest.. In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316.. Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI -30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; -25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI -32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; -20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea.. In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study.. United Therapeutics Corporation.

Topics: Adolescent; Adult; Double-Blind Method; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Prospective Studies; Treatment Outcome; Vital Capacity

Treprostinil, a prostacyclin analogue, is effective for the treatment of pulmonary arterial hypertension. However, information is scarce regarding treprostinil for treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the efficacy and safety of subcutaneous treprostinil in this setting.. In this 24-week, randomised, double-blind controlled trial, we enrolled patients with CTEPH, classified as non-operable, or with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, in six European expert centres in Austria, Czech Republic, Germany, and Poland. Patients in WHO functional class III or IV with a 6-min walk distance of 150-400 m were randomly assigned at a 1:1 allocation ratio to continuous high-dose subcutaneous treprostinil (target dose around 30 ng/kg per min at week 12) or low-dose subcutaneous treprostinil (target dose around 3 ng/kg per min at week 12). The primary endpoint was the change from baseline in 6-min walk distance at week 24. All patients who received at least one dose of the study drug were included in the intention-to-treat efficacy and safety analyses based on assessment of adverse events. The trial was registered at ClinicalTrialsRegister.eu EudraCT number 2008-006441-10 and ClinicalTrials.gov, number NCT01416636.. From March 9, 2009, to June 9, 2016, 105 patients were enrolled with 53 (50%) patients randomly assigned to high-dose and 52 (50%) patients to low-dose subcutaneous treprostinil. At week 24, marginal mean 6-min walk distance improved by 44·98 m (95% CI 27·52 to 62·45) in the high-dose group, and by 4·29 m (95% CI -13·34 to 21·92) in the low-dose group (treatment effect 40·69 m, 95% CI 15·86 to 65·53, p=0·0016). 12 serious adverse events were reported in ten (19%) of 52 patients from the low-dose group and 16 serious adverse events were reported in nine (17%) of 53 patients from the high-dose group. The most common treatment-related adverse events in both groups were infusion site pain and other infusion site reactions.. Treatment with subcutaneous treprostinil was safe, and improved exercise capacity in patients with severe CTEPH. Subcutaneous treprostinil provides a parenteral treatment option for patients of WHO functional class III or IV and those who do not tolerate other therapies or need combination treatment.. SciPharm Sàrl.

Topics: Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Middle Aged; Pulmonary Embolism; Severity of Illness Index; Treatment Outcome; Walk Test

Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP₂ receptor, the role of which is unknown in PAH. We hypothesised that EP₂ receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP₂ receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP₂ (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP₂ receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP₂ receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP₂ receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP₂ receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH.

Topics: Adolescent; Adult; Cell Proliferation; Child; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Receptors, Prostaglandin E, EP2 Subtype; Second Messenger Systems; Up-Regulation

Adverse drug events (ADEs) with pulmonary vasodilator use in pulmonary arterial hypertension (PAH) are common. ADEs may contribute to worse quality of life; however, their relationship to prognosis is unknown. The objective of this study was to determine whether common ADEs after initiating subcutaneous treprostinil were associated with prognosis in PAH.. We assembled a retrospective cohort of participants from four clinical trials of treprostinil for PAH, including 908 participants who received subcutaneous treprostinil and 243 who received placebo at the time ADEs were ascertained. The occurrences of four common early ADEs (infusion reactions, headaches, jaw pain, or gastrointestinal side effects) were assessed during the eight weeks after starting the infusion. We used Cox proportional hazards to estimate associations between ADEs and mortality.. No ADEs related to placebo were associated with mortality. In participants who received treprostinil, infusion reactions, headaches, and jaw pain were not associated with mortality. Gastrointestinal side effects occurring during the first eight weeks following treprostinil infusion were associated with a 57% increase in the hazard of mortality (95% CI: 14-118%). This relationship was unchanged after adjusting for demographic differences and differences in baseline PAH severity.. Gastrointestinal ADEs after starting subcutaneous treprostinil were associated with an increased risk for mortality. Increased mortality was not observed with other early ADEs or with gastrointestinal symptoms in participants who were not receiving treprostinil at the time. This hypothesis-generating association suggests ADEs may identify different phenotypes in PAH.

Topics: Adult; Antihypertensive Agents; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Epoprostenol; Female; Gastrointestinal Diseases; Humans; Hypertension, Pulmonary; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Vasodilator Agents

Prostacyclins improve symptoms and survival in pulmonary arterial hypertension (PAH). In response to risks associated with external delivery systems, an implantable IV infusion system was developed. A multicenter, prospective, single-arm, clinical trial (DelIVery for PAH) was conducted to evaluate this system for treprostinil in PAH. This analysis describes the findings related to the implant procedure.. Patients (N = 64) with PAH (World Health Organization group 1) receiving stable IV treprostinil were enrolled. Patients were transitioned to a temporary peripheral IV infusion catheter prior to the procedure. System implantation was performed at 10 centers under general anesthesia or deep IV sedation by clinicians from various specialties. Central venous access was via the cephalic, subclavian, jugular, or axillary vein. Using an introducer and fluoroscopic guidance, the distal tip of the infusion catheter was placed at the superior caval-atrial junction. The catheter was tunneled from the venous access site to an abdominal subcutaneous pocket, where the pump was placed.. Of the 64 patients enrolled, four exited prior to implantation. All 60 implant procedures were successful. At baseline, all patients were receiving treprostinil via an external pump at a mean dose of 71.4 ± 27.8 ng/kg/min (range: 22-142 ng/kg/min). The implant averaged 102 ± 32 min (range: 47-184 min). Clinically significant implant procedure-related complications included one pneumothorax, two infections, and one episode of atrial fibrillation. There were three postimplantation catheter dislocations in two patients. Common implant-related events that were not complications included implant site pain (83%) and bruising (17%).. The procedure for inserting a fully implantable system for treprostinil was successfully performed, with few complications.. ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.

Topics: Antihypertensive Agents; Catheterization, Central Venous; Dose-Response Relationship, Drug; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Pulmonary Wedge Pressure; Treatment Outcome

The use of systemic prostanoids in severe pulmonary arterial hypertension (PAH) is often limited by patient/physician dissatisfaction with the delivery methods. Complications associated with external pump-delivered continuous therapy include IV catheter-related bloodstream infections and subcutaneous infusion site pain. We therefore investigated a fully implantable intravascular delivery system for treprostinil infusion.. A multicenter, prospective, single-arm, clinical trial (DelIVery for Pulmonary Arterial Hypertension) was conducted by using an implantable intravascular delivery system. The implanted pumps were refilled percutaneously at least every 12 weeks. The primary end point was the rate of catheter-related complications using the new model 10642 catheter compared with a predefined objective performance criterion of 2.5 per 1,000 patient-days based on the literature.. Patients (n = 60) with severe PAH (World Health Organization group 1) receiving a stable dose of IV treprostinil for at least 4 weeks received an implant device and were followed up for 12.1 ± 4.4 months. Six catheter-related complications occurred, corresponding to a complication rate of 0.27 per 1,000 patient-days. The 97.5% upper one-sided confidence bound of 0.59 was less than the predefined criterion of 2.5 per 1,000 patient-days (P < .0001). Plasma treprostinil levels at 1 week postimplantation were highly correlated with baseline levels (r = 0.91; P < .0001). The delivery system management time as reported by the patients was 2.5 ± 1.7 hours per week preimplantation, and this time decreased to 0.6 ± 0.8 hour per week at 6 months' postimplantation (P < .0001). All patients rated overall satisfaction with the implantable system as good, very good, or excellent at 6 weeks and 6 months. There were no catheter-related bloodstream infections or catheter occlusions.. The implantable intravascular delivery system delivered treprostinil to patients with PAH with a low rate of catheter-related complications and a high rate of patient satisfaction.. ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov.

Topics: Adult; Antihypertensive Agents; Catheter Obstruction; Catheter-Related Infections; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Male; Middle Aged; Outcome and Process Assessment, Health Care; Prospective Studies; United States

Subcutaneous treprostinil has dose-dependent beneficial effects in patients with severe pulmonary arterial hypertension, but adverse effects like infusion site pain can lead to treatment discontinuation.. The objective of this study was to evaluate safety, tolerability and clinical effects of a rapid up-titration dosing regimen of subcutaneous treprostinil using proactive infusion site pain management.. Effects of rapid up-titration dosing regimen on tolerability and clinical parameters were evaluated in this 16-week, open-label multi-centre study.. Thirty-nine patients with idiopathic or heritable pulmonary arterial hypertension on stable treatment with oral pulmonary arterial hypertension-approved drugs (90% on dual combination therapy) were included. Patients achieved a median treprostinil dosage of 35.7 ng/kg/min after 16 weeks. A good overall safety profile was demonstrated with 3 patients (8%) withdrawing due to infusion site pain, which occurred in 97% of patients. After 16 weeks, median 6-min walking distance, cardiac index, pulmonary vascular resistance, and tricuspid annular plane systolic excursion improved.. Rapid up-titration of subcutaneous treprostinil was well tolerated, achieving a clinically effective dose associated with improvement of exercise capacity and haemodynamics after 16 weeks. A rapid dose titration regimen and proactive infusion site pain management may improve the handling of this therapy and contribute to better treatment outcome.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Female; Germany; Humans; Hypertension, Pulmonary; Infusions, Subcutaneous; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Treatment Outcome; Tricuspid Valve; Vascular Resistance; Walk Test

Treprostinil sodium improves haemodynamics and symptoms in pulmonary arterial hypertension (PAH) patients, but its subcutaneous (s.c.) administration can produce severe local site pain, and lead to discontinuation of vital treatment. Treprostinil is a prostacyclin analogue which stimulates prostacyclin receptors in skin nociceptor terminals, resulting in pain and cutaneous hypersensitivity, for which current pain remedies have limited effect. Capsaicin 8% patch relieves neuropathic pain for 3 months after a single 60 min cutaneous application; we investigated whether its pre-application can reduce s.c. trepostinil-induced pain.. A single-centre, double-blind, randomized, placebo-controlled, crossover study was conducted to assess the safety and efficacy of a single capsaicin 8% patch pre-application for s.c. treprostinil pain in 11 PAH patients, relative to control patch with low-dose capsaicin 0.075% cream.. The primary efficacy endpoint, mean difference between the two treatment arms in an 11-point numerical pain rating scale from baseline to 2 weeks after patch applications, was significantly lower on the capsaicin 8% patch treatment arm [P=0.01, mean difference=-1.47 units, 95% credible interval (CI): -2. 59 to -0.38] in the patients who completed the study per protocol, although intention-to-treat analysis did not show significant difference (P=0.28). Heat pain thresholds were decreased (P=0.027, mean difference=5.43°C, 95% CI: 0.71-10.21) and laser Doppler flux increased (P=0.016, mean difference=370 units, 95% CI: 612 to 127.9) at the application site immediately after capsaicin 8% patch, confirming activity.. Further investigation of the efficacy of capsaicin 8% patch in this indication is warranted.

Topics: Adult; Aged; Antihypertensive Agents; Capsaicin; Double-Blind Method; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Subcutaneous; London; Male; Middle Aged; Pain; Sensory System Agents; Transdermal Patch; Treatment Outcome

Pulmonary hypertension (PH)-targeted therapy in the setting of pulmonary fibrosis (PF) is controversial; the main clinical concern is worsening of systemic hypoxaemia. We sought to determine the effects of gentle initiation and chronic administration of parenteral treprostinil on right heart function in patients with PF associated with an advanced PH phenotype.. Open-label, prospective analysis of patients with PF-PH referred for lung transplantation (LT). Advanced PH was defined as mean pulmonary artery pressure (mPAP) ≥35 mm Hg. We compared haemodynamics, Doppler echocardiography (DE), oxygenation, dyspnoea and quality of life indices, and 6 min walk distance (6MWD) before and 12 weeks after parenteral treprostinil.. 15 patients were recruited in the study. After therapy, there were significant improvements in right heart haemodynamics (right atrial pressure (9.5 ± 3.4 vs 6.0 ± 3.7); mPAP (47 ± 8 vs 38.9 ± 13.4); CI (2.3 ± 0.5 vs 2.7 ± 0.6); pulmonary vascular resistance (698 ± 278 vs 496 ± 229); transpulmonary gradient (34.7 ± 8.7 vs 28.5 ± 10.3); mvO2 (65 ± 7.2 vs 70.9 ± 7.4); and stroke volume index (29.2 ± 6.7 vs 33 ± 7.3)) and DE parameters reflecting right heart function (right ventricular (RV) end diastolic area (36.4 ± 5.2 vs 30.9 ± 8.2 cm(2)), left ventricular eccentricity index (1.7 ± 0.6 vs 1.3 ± 0.5), tricuspid annular planar systolic excursion (1.6 ± 0.5 vs 1.9 ± 0.2 cm)). These changes occurred without significant alteration in systemic oxygenation, heart rate, or mean systemic arterial pressure. In addition, improvements were seen in 6MWD (171 ± 93 vs 230 ± 114), 36-Item Short Form Health Survey Mental Component Summary aggregate (38 ± 11 vs 44.2 ± 10.7), University of California, San Diego Shortness of Breath Questionnaire (87 ± 17.1 vs 73.1 ± 21), and brain natriuretic peptide (558 ± 859 vs 228 ± 340).. PH-targeted therapy may improve right heart haemodynamics and echocardiographic function without affecting systemic oxygen saturation in an advanced PH phenotype associated with RV dysfunction in the setting of PF.

Topics: Aged; Antihypertensive Agents; Dyspnea; Echocardiography, Doppler; Epoprostenol; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Oxygen Consumption; Phenotype; Pilot Projects; Prospective Studies; Pulmonary Fibrosis; Quality of Life; Treatment Outcome; Ventricular Dysfunction, Right

Patient treatment satisfaction is likely to be a highly relevant outcome measure in pulmonary arterial hypertension (PAH), a condition for which the benefits of treatment must be weighed against frequent, undesirable side effects, inconvenience, and complications associated with therapy. In this study, we sought to evaluate the psychometric properties of a patient-reported treatment satisfaction measure and its relationship to quality of life (QoL) among patients transitioning from inhaled iloprost (iILO) to inhaled treprostinil (iTRE).. We studied treatment satisfaction among 66 subjects with PAH in a single-arm, open-label, multi-center trial of iTRE following transition from iILO. Treatment satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM, version 1.4) administered to subjects immediately before and 12 weeks after transition of inhaled therapy. The TSQM is comprised of 4 domains: effectiveness, side effects, convenience, and global satisfaction. Scores range from 0 to 100 with higher scores indicating greater satisfaction. Six-minute walk distance (6MWD), functional class, adverse events, drug administration time, and PAH-specific QoL (CAMPHOR) were concurrently assessed.. Domains of the TSQM demonstrated evidence of strong internal consistency at baseline and at 12 weeks (Cronbach α = 0.88-0.93). Transition from iILO to iTRE was associated with an improvement in 3 of 4 TSQM domains: effectiveness (+20 ± 21, p < 0.0001), side effects (0 ± 22, p = 0.97), convenience (+39 ± 26, p < 0.0001), and global satisfaction (+20 ± 24, p = 0.0005). Change in effectiveness scores correlated with change in 6MWD (r = 0.43, p = 0.0004) and side effects scores at 12 weeks correlated inversely with number of severity-weighted treatment-emergent adverse events (r = -0.44, p = 0.0002). In multiple regression models adjusted for baseline characteristics, changes in effectiveness and convenience satisfaction scores were significantly associated with improvement in PAH-specific QoL (p = 0.002 and p = 0.01).. The TSQM demonstrated acceptable performance characteristics in patients with PAH. Changes in treatment satisfaction resulting from transitioning from iILO to iTRE were associated with improvements in PAH-specific QoL.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Antihypertensive Agents; Drug Administration Schedule; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nebulizers and Vaporizers; Patient Satisfaction; Prospective Studies; Quality of Life; Surveys and Questionnaires; Treatment Outcome

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

Transition from intravenous (IV) epoprostenol to IV treprostinil in patients with pulmonary hypertension (PH) has traditionally been performed by gradually decreasing the epoprostenol dose while increasing the treprostinil dose. Preliminary data suggest that this transition can be performed more rapidly without the need for epoprostenol weaning. We conducted a single center, prospective clinical trial to assess the safety, efficacy, and treatment satisfaction of rapidly switching from epoprostenol to IV treprostinil.. This study included patients with PH who had rapidly transitioned from epoprostenol to IV treprostinil. Data collected included clinical status, adverse events, PH symptoms, and previously validated measures of quality of life and treatment satisfaction.. Ten patients were enrolled in this study. Exercise capacity measured by mean 6-min walk distance was maintained from baseline throughout follow-up. Severity of disease as assessed by WHO functional class was maintained or improved for the majority of patients. Adverse events were minimal during the transition, and all patients remained on IV treprostinil throughout the follow-up period. A favorable impact on quality of life and treatment satisfaction measures was observed by eight weeks following the transition from epoprostenol to IV treprostinil. Specifically, time spent on drug preparation activities decreased by 39.5% with treprostinil compared to epoprostenol.. Rapidly switching from epoprostenol to IV treprostinil can be achieved without safety concerns, with minimal patient monitoring and without the need for extended hospitalization, while favorably impacting on patients' quality of life.

Topics: Adult; Aged; Antihypertensive Agents; Drug Administration Schedule; Drug Substitution; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Patient Satisfaction; Prospective Studies; Quality of Life; Severity of Illness Index; Treatment Outcome; Walking

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

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of disease severity in pulmonary arterial hypertension (PAH). In this study we aimed to determine whether baseline NT-proBNP levels correlate with improvement in 6-minute walk distance (6MWD) in the pivotal randomized, placebo-controlled, double-blind study of the addition of inhaled treprostinil to oral therapy for PAH.. A post hoc analysis of data from the TRIUMPH-1 study was performed in patients who had assessments of NT-proBNP levels and baseline and Week 12 6MWD. Least-squares mean analysis was used to compare patients in the highest quartile of baseline NT-proBNP with those in lower quartiles with regard to change from baseline in 6MWD, stratified by treatment.. The NT-proBNP within-treatment median changes from baseline to Week 12 were +44 and -72 pg/ml, and the median changes in 6MWD from baseline to Week 12 were +5 and +40 m for the placebo (n = 94) and inhaled treprostinil (n = 84) groups, respectively. Baseline NT-proBNP levels demonstrated a strong interaction with treatment in predicting change from baseline for 6MWD (p < 0.01), indicating that, in the upper quartile (≥1,513.5 pg/ml), patients on inhaled treprostinil had a better response (+64 vs +32 m), whereas patients on placebo fared worse (-13 vs +20 m) when compared with the lower 3 quartiles (<1,513.5 pg/ml). Furthermore, least-squares mean difference in 6MWD between active and placebo groups was +67 and +16 m for the upper and lower 3 quartiles of NT-proBNP, respectively.. Greater improvement in 6MWD in actively treated patients with high levels of NT-proBNP enhances understanding of the robustness of clinical response to inhaled treprostinil in more advanced disease.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Antihypertensive Agents; Biomarkers; Double-Blind Method; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Severity of Illness Index; Time Factors; 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

Inhaled treprostinil improved functional capacity as add-on therapy in the short-term management of patients with pulmonary arterial hypertension (PAH). This study investigated the long-term effects of inhaled treprostinil in patients concurrently receiving oral background therapy.. A total of 206 patients (81% women) completing the 12-week double-blind phase of the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study transitioned into an open-label extension. Patients were assessed every 3 months for changes in 6-minute walk distance (6MWD), Borg dyspnea score, New York Heart Association (NYHA) functional class, quality of life (QOL) scores, and signs and symptoms of PAH.. Patients were primarily NYHA class III (86%), with a mean baseline 6MWD of 349 ± 81 meters. A median change in 6MWD of 28, 31, 32, and 18 meters in patients continuing therapy was observed at 6, 12, 18, and 24 months, respectively. This effect was more prominent in those patients originally allocated to active therapy in the double-blind phase. Survival rates for patients remaining on therapy were 97%, 94%, and 91% at 12, 18, and 24 months, respectively. In addition, 82%, 74%, and 69% of patients maintained treatment benefit as evidenced by lack of clinical worsening at 12, 18, and 24 months. The most common adverse events were known effects of prostanoid therapy (headache [34%], nausea [21%], and vomiting [10%]) or were due to the route of administration (cough [53%], pharyngolaryngeal pain [13%], and chest pain [13%]).. Long-term therapy with inhaled treprostinil demonstrated persistent benefit for PAH patients who remained on therapy for up to 24 months.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure; Bosentan; Double-Blind Method; Drug Therapy, Combination; Epoprostenol; Female; Headache; Humans; Hypertension, Pulmonary; Incidence; Longitudinal Studies; Male; Middle Aged; Nausea; Physical Endurance; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Young Adult

Pulmonary arterial hypertension (PAH) remains a poorly understood and frequently lethal disease with few treatment options.. We conducted a placebo-controlled trial of intravenous treprostinil, a prostacyclin analog, in treatment-naive PAH patients. During 12 weeks of treatment with treprostinil or placebo, we quantified 6-minute walk distance (6MW), clinical symptoms and 11 cytokines/growth factors.. Forty-two of 44 study patients had idiopathic/familial PAH in New York Heart Association (NYHA) Class III. Treprostinil increased 6MW by a placebo-corrected median of 83 meters (p = 0.008; mean increase 93 +/- 42 meters), reduced Borg score by a median 2.0 units (p = 0.02), and improved NYHA class by a median of 1.0 (p = 0.02). There was a trend toward improved survival with treprostinil (p = 0.051). Baseline plasma angiopoietin-2 (Ang-2), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and platelet-derived growth factor (PDGF) were elevated compared with reported normal ranges. Treatment with treprostinil was associated with decreased Ang-2 levels. Improvement in 6MW distance after treatment was associated with reductions in Ang-2 and MMP-9 levels. Most of the cytokines and growth factors studied were not abnormal with disease nor did they change with treatment.. We conclude that treprostinil treatment significantly improved exercise capacity, dyspnea and functional class. Several plasma proteins that might track disease were abnormal at baseline, and changes were associated with improved exercise capacity.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Biomarkers; Double-Blind Method; Epoprostenol; Exercise; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Physical Endurance; Severity of Illness Index; Treatment Outcome; Walking

This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension (PAH) patients receiving therapy with either bosentan or sildenafil.. There is no cure for PAH, despite effective treatments, and outcomes remain suboptimal. The addition of inhaled treprostinil, a long-acting prostacyclin analog, might be a safe and effective treatment addition to other PAH-specific oral therapies.. Two hundred thirty-five PAH patients with New York Heart Association (NYHA) functional class III (98%) or IV symptoms and a 6-min walk distance (6MWD) of 200 to 450 m while treated with bosentan (70%) or sildenafil were randomized to inhaled treprostinil (up to 54 mug) or inhaled placebo 4 times daily. The primary end point was peak 6MWD at 12 weeks. Secondary end points included time to clinical worsening, Borg Dyspnea Score, NYHA functional class, 12-week trough 6MWD, 6-week peak 6MWD, quality of life, and PAH signs and symptoms. The biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP) was assessed.. Twenty-three patients withdrew from the study prematurely (13 treprostinil, 10 placebo). The Hodges-Lehmann between-treatment median difference in change from baseline in peak 6MWD was 19 m at week 6 (p = 0.0001) and 20 m at week 12 (p = 0.0004). Hodges-Lehmann between-treatment median difference in change from baseline in trough 6MWD at week 12 was 14 m (p = 0.0066). Quality of life measures and NT-proBNP improved on active therapy. There were no improvements in other secondary end points, including time to clinical worsening, Borg Dyspnea Score, NYHA functional class, and PAH signs and symptoms. Inhaled treprostinil was safe and well-tolerated.. This trial demonstrates that, among PAH patients who remain symptomatic on bosentan or sildenafil, inhaled treprostinil improves exercise capacity and quality of life and is safe and well-tolerated. (TRIUMPH I: Double Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension; NCT00147199).

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents; Young Adult

The stable prostanoid analogue treprostinil is approved as continuous infusion for treatment of pulmonary arterial hypertension. Unique drug characteristics may render this prostanoid feasible for inhalation therapy with a metered dose inhaler.. Randomised open label investigation of acute haemodynamic effects, safety and tolerability of inhaled treprostinil delivered in seconds by a metered dose inhaler (MDI-TRE). Inhaled nitric oxide (NO) and MDI-TRE were applied once during right heart catheter investigation to 39 consecutive patients with pre-capillary pulmonary hypertension. Doses of 30 microg, 45 microg and 60 microg MDI-TRE were investigated in separate groups of patients. Haemodynamics and blood gases were measured for 2h following treprostinil application. Acute haemodynamic responses to NO and MDI-TRE were comparable. MDI-TRE significantly improved haemodynamics compared to placebo inhalation. MDI-TRE induced effects were comparable to a historical control group that inhaled treprostinil from an ultrasonic nebuliser. The 120 min area under the curve for PVR changes due to placebo, 30 microg, 45 microg or 60 microg MDI-TRE was 1114+/-998, -870+/-940, -2450+/-2070 and -2000+/-900 min*%. Reduction of systemic vascular resistance and pressure were not clinically relevant. No significant side effects were observed. No impact on ventilation/perfusion matching by treprostinil was demonstrated in 5 patients with pre-existing gas exchange limitations by use of the multiple inert gas elimination technique.. The application of inhaled treprostinil with a metered dose inhaler is feasible and well tolerated. It induced a sustained pulmonary selective vasodilatation.

Topics: Administration, Inhalation; Aged; Antihypertensive Agents; Area Under Curve; Dose-Response Relationship, Drug; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Metered Dose Inhalers; Middle Aged; Nitric Oxide; Vasodilation

Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension.. Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15microg; n=25 or 30microg; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5).. Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed.. The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Area Under Curve; Blood Pressure; Cough; Drug Synergism; Drug Therapy, Combination; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Fibrosis; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance

Subcutaneous treprostinil is an effective treatment for pulmonary arterial hypertension (PAH). A previous pivotal study indicated that infusion site pain was dose dependent and resulted in suboptimal dose escalation by week 12 and a reduced clinical benefit. We hypothesized that a rapid-escalation treprostinil dosing regimen would be as safe and effective as a slow-escalation dosing regimen.. Twenty-three patients received treprostinil to treat PH of various aetiologies and were randomized into two groups. Group 1 (11 patients: seven females and four males, aged 51.7 +/- 15.4 years) received a slow-escalation regimen, and group 2 (12 patients: ten females and two males, aged 51.3 +/- 16.7 years) were exposed to rapid dose escalation. The dose escalation, exercise capacity (a 6-minute walk test [6WT] or a shuttle walk test [SWT]), WHO classification, blood pressure, heart rate, respiration rate, baseline haemodynamics and adverse events were followed up for 12 weeks.. Baseline haemodynamics did not differ significantly between the treatment groups. At follow-up, the treprostinil dose reached 12.9 +/- 2.7 ng/kg/min in group 1 and 20.3 +/- 5.8 ng/kg/min in group 2 (p < 0.01). The patients' WHO classification improved significantly (p < 0.05), with no difference between the groups. Improvement of exercise capacity was greater in group 2 (6WT and SWT, p < 0.05). Infusion site pain occurred in 81.8% of group 1 and in 58.3% of group 2 (p < 0.05) patients. Other adverse events and changes in the heart rate, respiration rate and blood pressure were similar in both groups.. The rapid-dosing regimen is as safe and effective as the slow-escalation regimen and may be associated with even better clinical outcomes. Infusion site pain is not dose dependent.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Exercise Tolerance; Female; Follow-Up Studies; Heart Rate; Humans; Hypertension, Pulmonary; Infusions, Subcutaneous; Male; Middle Aged; Respiration; Young Adult

This study assessed the relationship between dose and plasma concentration following administration of treprostinil sodium infusion therapy in pulmonary arterial hypertension patients. This was a multicenter, open-label, multiple-cohort, steady-state, pharmacokinetic study in subjects with pulmonary arterial hypertension receiving treprostinil by continuous intravenous or subcutaneous infusion at doses between 10 and 125 ng/kg/min. A blood sample was obtained from each patient at steady state and analyzed via a liquid chromatography/tandem mass spectrometry method. Forty-nine subjects receiving treprostinil were enrolled. Treprostinil doses ranged from 12.1 to 125 ng/kg/min; treprostinil plasma concentrations ranged from 14.9 to 18 248 pg/mL. Linear regression analysis revealed a correlation between treprostinil dose and treprostinil plasma concentration with an R2 value of 0.561. Using a power model to assess dose proportionality, the estimated nonproportionality parameter was 0.641 (95% confidence interval: 0.083-1.199), reflecting consistency with dose proportionality. Subset linear regression analysis, which excluded 2 subjects with anomalous treprostinil plasma concentrations, increased the R2 value to 0.796. Using a power model to assess dose proportionality of this subset, the estimated nonproportionality parameter was 0.941 (95% confidence interval: 0.809-1.073). This study supports previous findings of linearity at lower doses up to 15 ng/kg/min and demonstrates linearity at treprostinil doses up to 125 ng/kg/min.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antihypertensive Agents; Calcium Channel Blockers; Chromatography, Liquid; Digoxin; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Injections, Subcutaneous; Male; Mass Spectrometry; Middle Aged; Oxygen; Phosphodiesterase 5 Inhibitors; Regression Analysis

Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension (PAH); however, chemical instability and a short half-life have caused limitations in its use. The chemically stable prostacyclin analogue treprostinil has a longer half-life, and improves hemodynamics and signs/symptoms of PAH. This study investigated the feasibility of transitioning patients with PAH from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol. Twelve PAH patients were enrolled in a 12 week prospective open label study. Patients were switched from intravenous epoprostenol to intravenous treprostinil (1:1 ng/kg/min) by a direct switch of the medication reservoir from epoprostenol to treprostinil. The dose of treprostinil was adjusted throughout the study to achieve a 2-fold increase of treprostinil compared with the baseline epoprostenol dose. Rapid transition to treprostinil was achieved without serious adverse events and, baseline clinical status was maintained over 12 weeks. The mean baseline epoprostenol dose was 28 +/- 14 ng/kg/min. At week 12, the mean treprostinil dose was 62 +/- 30 ng/kg/min. All patients reported less prostacyclin-related side effects with treprostinil and remained on treprostinil after study completion. Selected patients with PAH can be safely transitioned from intravenous epoprostenol to intravenous treprostinil using a rapid switch protocol.

Topics: Adolescent; Adult; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Prospective Studies

Chronic thromboembolic pulmonary hypertension (CTEPH) results from non-resolving pulmonary thromboemboli that are resistant to plasmatic anticoagulation. Because of a secondary pulmonary arteriopathy accompanying major vessel obstruction, the disorder may be a target for vasodilator therapy.. In an open-label uncontrolled study, we investigated the prostacyclin analog treprostinil given s.c. in patients with severe inoperable CTEPH.. Between September 1999 and September 2005, 25 patients were included if their World Health Organization (WHO) functional class was III or IV, if their six-minute walking distance (6-MWD)

Topics: Aged; Antihypertensive Agents; Cardiac Output; Case-Control Studies; Chronic Disease; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infusion Pumps; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Odds Ratio; Pain; Pain Measurement; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Pulmonary Embolism; Risk Assessment; Severity of Illness Index; Thromboembolism; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Walking

We determined the relative efficacy of subcutaneous (SC) treprostinil in stable World Health Organization class II and III patients transitioned from IV epoprostenol.. This was an 8-week, multicenter, randomized study in which patients were transitioned from IV epoprostenol to SC treprostinil or placebo over a period of up to 14 days and monitored carefully during and after the transition period for signs of deterioration. Patients with clinical deterioration were returned promptly to epoprostenol. Placebo or SC treprostinil doses were titrated in response to symptoms. Time to adjudicated clinical deterioration was compared between treatment groups, and exercise capacity, symptoms of disease, and safety were assessed throughout the study.. Twenty-two patients were enrolled and completed the study. Seven of 8 patients (88%) [corrected] withdrawn to placebo had clinical deterioration, while only 1 of 14 patients (7%) [corrected] withdrawn to SC treprostinil had clinical deterioration (p = 0.00023 based on a treatment comparison of time to deterioration). Analyses of exercise capacity and symptoms strongly supported the efficacy of SC treprostinil in epoprostenol-treated patients. Adverse events consisted of painful infusion site reactions and anticipated prostacyclin side effects.. SC treprostinil is effective in pulmonary arterial hypertension and prevents clinical deterioration and maintains functional status in patients transitioned from epoprostenol.

Topics: Adult; Antihypertensive Agents; Drug Administration Schedule; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Treatment Outcome

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5), and has been shown to improve 6-minute walk distance (SMWD) and World Health Organization (WHO) functional class in patients with idiopathic pulmonary arterial hypertension (iPAH) and PAH associated with connective tissue disease or with repaired congenital systemic-to-pulmonary shunts. Despite the efficacy of sildenafil in patients on conventional therapy with diuretics and anti-coagulants, little is known of the safety and efficacy of transitioning patients already established on parenteral prostanoid therapy to sildenafil.. We studied 14 patients on long-term subcutaneous treprostinil for PAH (from a cohort of 51 patients [27%]), who wished to discontinue treatment because of injection-site pain. The etiology of their PAH included iPAH (7 of 14), PAH secondary to scleroderma (2 of 14), thromboembolic disease (3 of 14) and PAH post-surgical correction of ventricular septal defect (2 of 14). Treprostinil was gradually weaned and all patients were started open-label with 50 mg sildenafil four times per day for 3 months. New York Heart Association (NYHA) functional class, SMWD, echocardiogram and quality-of-life (QOL) measures were determined at baseline and after 3 months of therapy with sildenafil.. Of 14 patients, 4 discontinued the transition because of deterioration during treprostinil withdrawal, despite the introduction of sildenafil. Replacement of chronic subcutaneous treprostinil with sildenafil was possible in 10 of 14 patients (71%), who demonstrated stable NYHA class (mean +/- SD: 3.1 +/- 0.3 at baseline to 2.6 +/- 0.8 at 3 months, p = 0.138), stable SMWD (434 +/- 83 m at baseline, 451 +/- 72 at 3 months, p = 0.23) and significantly improved QOL measures at 3 months.. The transition from subcutaneous treprostinil to sildenafil was safely achieved in most (71%), but not all, patients with pulmonary arterial hypertension of varied etiology. These patients had an improvement in both NYHA functional class and QOL, and maintained stable walk distances over a 3-month period on sildenafil therapy.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Drug-Related Side Effects and Adverse Reactions; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Middle Aged; Piperazines; Purines; Quality of Life; Sildenafil Citrate; Sulfones; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a life-threatening disease for which both continuous IV epoprostenol and continuous subcutaneous treprostinil have proven effective. With continuous IV treprostinil having potential advantages over both of the above therapies, we investigated the safety and efficacy of this regimen in patients with PAH.. We conducted a 12-week, prospective, open-label, uncontrolled, multicenter study of continuous IV treprostinil in 16 patients with PAH that was idiopathic (n = 8), related to connective tissue disease (n = 6), or related to congenital heart disease (n = 2). The primary end point was change from baseline to week 12 in exercise capacity assessed by the 6-min walk (6MW) test.. Continuous IV treprostinil increased 6MW distance (mean +/- SE) by 82 m from baseline (319 +/- 22 m) to week 12 (400 +/- 26 m) [n = 14; p = 0.001]. There were also significant improvements in the secondary end points of Naughton-Balke treadmill time (p = 0.007), Borg dyspnea score (p = 0.008), and hemodynamics (mean pulmonary artery pressure, p = 0.03; cardiac index, p = 0.002; pulmonary vascular resistance, p = 0.001) at week 12 compared with baseline. Side effects were mild and consistent with those reported with prostacyclin treatment. One death, unrelated to study drug, occurred during the 12-week study in a patient who received 3 days of treprostinil and died 2 weeks later.. Long-term IV infusion of treprostinil is safe and appears to be effective for the treatment of patients with PAH.

Topics: Adult; Antihypertensive Agents; Epoprostenol; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies

The aim of this long-term multicenter analysis was to investigate whether subcutaneously infused treprostinil could provide sustained improvements of exercise capacity and survival benefits in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Subcutaneous administration of the prostacyclin analog treprostinil is an effective treatment for PAH that, unlike epoprostenol, does not require the insertion of a permanent central venous catheter.. Multicenter retrospective study.. Three European university hospitals.. Ninety-nine patients with PAH and 23 patients with CTEPH in New York Heart Association (NYHA) classes II-IV were followed up for a mean of 26.2 +/- 17.2 months (+/- SE) [range, 3 to 57 months]. Long-term efficacy was assessed by 6-min walking distance (SMWD), Borg dyspnea score, and NYHA class. Clinical events were monitored to assess survival and event-free survival.. At 3 years, significant improvements from baseline were observed in mean SMWD (305 +/- 11 to 445 +/- 12 m, p = 0.0001), Borg dyspnea score (5.7 +/- 0.2 to 4.5 +/- 1, p = 0.0006), and NYHA class (3.20 +/- 0.04 to 2.1 +/- 0.1, p = 0.0001). These changes were observed under a mean dose of subcutaneously infused treprostinil at 40 +/- 2.6 ng/kg/min (range, 16 to 84 ng/kg/min). Subcutaneously infused treprostinil was well tolerated, and local pain at the subcutaneous site accounted for treatment interruption in only 5% of the cases. Survival was 88.6% and 70.6% at 1 year and 3 years, respectively. At the same time points, the event-free survival rates, defined as survival without hospitalization for clinical worsening, transition to IV epoprostenol, and need for combination therapy or atrial septostomy, were 83.2% and 69%, respectively.. Long-term subcutaneous therapy with treprostinil appears to continuously improve exercise tolerance and symptoms in patients with PAH and inoperable CTEPH. Moreover, treatment may provide a significant survival benefit.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Child; Drug Administration Schedule; Epoprostenol; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Infusions, Parenteral; Male; Middle Aged; Recovery of Function; Retrospective Studies; Survival Rate; Treatment Outcome

Pulmonary arterial hypertension (PAH) is fatal if untreated. Intravenous epoprostenol improves exercise capacity and haemodynamics in PAH, and increases survival in idiopathic PAH (IPAH). To evaluate the effects of subcutaneous (SC) treprostinil, a longer-acting prostacyclin analogue, followed by the addition of other PAH therapies if needed, 860 PAH patients treated with SC treprostinil for up to 4 yrs were followed. Survival is reported as Kaplan-Meier estimates. For 332 IPAH patients with baseline haemodynamics, observed survival is also compared with predicted survival using the National Institute of Health formula. Out of the 860 patients, 199 (23%) discontinued due to adverse events, 136 (16%) died, 117 (14%) discontinued due to deterioration, 29 (3%) withdrew consent and 11 (1%) underwent transplantation. In total, 97 patients (11%) switched from SC treprostinil to an alternative prostacyclin analogue; bosentan was added in 105 patients (12%) and sildenafil in 25 (3%). In conclusion, survival was 87-68% over 1-4 yrs for all 860 patients and 88-70% over 1-4 yrs with subcutaneous treprostinil monotherapy. For the idiopathic pulmonary arterial hypertension subset with baseline haemodynamics (n = 332), survival was 91-72% over 1-4 yrs. In contrast, predicted survival was 69-38% over 1-4 yrs. The safety profile for long-term subcutaneous treprostinil was consistent with previous short-term trials with no unexpected adverse events.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Child; Cohort Studies; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Iloprost; Injections, Subcutaneous; Male; Middle Aged; Placebos; Sulfonamides; Survival Rate; Treatment Outcome

This study evaluated the safety and efficacy of inhaled treprostinil as add-on therapy to oral bosentan in patients with pulmonary arterial hypertension (PAH).. The addition of a long-acting prostacyclin analogue via the inhaled route might be a safe and effective strategy to optimize therapy in PAH patients on bosentan.. Twelve patients with symptomatic PAH despite bosentan received either 30 microg of inhaled treprostinil 4 times daily (n = 6) or 45 microg 4 times daily (n = 6), via an ultrasonic nebulizer. Six-min walk distance (6MWD), functional class, and hemodynamics were assessed at baseline and 12 weeks.. One patient was excluded from analysis due to the subsequent finding of pulmonary capillary hemangiomatosis. In the remaining 11 patients, inhaled treprostinil was safe and well tolerated. Inhaled treprostinil was associated with an increase in 6MWD at 12 weeks (baseline 339 +/- 86, 12 week, 1 h post-inhalation 406 +/- 121 m, 67-m change, p = 0.01). An improvement in 6MWD of 49 m from baseline was noted during the trough period, just before inhalation of treprostinil (p = 0.009). The 6MWD improvement of at least 10% was noted in 1 of 6 patients receiving 30 microg versus 5 of 6 receiving 45 microg. Over 12 weeks, significant decreases were noted in mean pulmonary arterial pressure (-10%) and in pulmonary vascular resistance (-26%). Functional class improved from III to II in 9 of 11 patients.. This trial suggests that inhaled treprostinil is safe, well tolerated, and associated with significant improvements in exercise capacity, functional class, and pulmonary hemodynamics in symptomatic patients with PAH on bosentan.

Topics: Administration, Inhalation; Administration, Oral; Adult; Aged; Antihypertensive Agents; Blood Pressure; Bosentan; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Severity of Illness Index; Sulfonamides; Treatment Outcome; Vascular Resistance

This study sought to investigate the effects of inhaled treprostinil on pulmonary hemodynamics and gas exchange in severe pulmonary hypertension.. Inhaled iloprost therapy has a proven clinical efficacy in pulmonary arterial hypertension, but this therapy necessitates 6 to 9 inhalation sessions per day. Treprostinil has a longer plasma half-life and might provide favorable properties when applied by inhalation.. Three different studies were conducted on a total of 123 patients by means of right heart catheterization: 1) a randomized crossover-design study (44 patients), 2) a dose escalation study (31 patients), and 3) a study of reduction of inhalation time while keeping the dose fixed (48 patients). The primary end point was the change in pulmonary vascular resistance (PVR).. The mean pulmonary arterial pressure of the enrolled patients was approximately 50 mm Hg in all studies. In study 1, both treprostinil and iloprost at an inhaled dose of 7.5 mug displayed a comparable PVR decrease, with a significantly different time course (p < 0.001), treprostinil showing a more sustained effect on PVR (p < 0.0001) and fewer systemic side effects. In study 2, effects of inhalation were observed for 3 h. A near-maximal acute PVR decrease was observed at 30 mug treprostinil. In study 3, treprostinil was inhaled at increasing concentrations with a pulsed ultrasonic nebulizer, mimicking a metered dose inhaler. A dose of 15 mug treprostinil was inhaled with 18, 9, 3, 2 pulses, or 1 pulse, each mode achieving comparable, sustained pulmonary vasodilation without significant side effects.. Inhaled treprostinil exerts sustained pulmonary vasodilation with excellent tolerability at relatively low doses and may be inhaled in a few breaths.

Topics: Administration, Inhalation; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Humans; Hypertension, Pulmonary; Nebulizers and Vaporizers; Pilot Projects; Pulmonary Artery; Pulmonary Circulation; Severity of Illness Index; Single-Blind Method; Ultrasonics; Vascular Resistance; Vasodilation

We assessed the efficacy of bosentan in transitioning from prostacyclin infusions in patients with pulmonary arterial hypertension (PAH).. Twenty-two PAH patients were recruited from five PAH centers if they had been clinically stable while receiving therapy with IV epoprostenol or subcutaneous treprostinil for at least 3 months. Patients were observed in an open-label prospective trial while bosentan was added to therapy, and then epoprostenol or treprostinil were tapered after 2 months.. Ten of the 22 patients were transitioned off prostacyclin infusion therapy after a mean (+/- SEM) duration of 6.1 +/- 1.2 months. Of those patients, seven patients have continued not receiving prostacyclin infusion therapy for a mean duration of 17.7 +/- 5.3 months, with no significant changes in pulmonary artery (PA) pressure estimated by echocardiography, World Health Organization (WHO)/New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD), or Borg dyspnea score. The conditions of three patients deteriorated, necessitating the resumption of prostacyclin therapy, and two patients subsequently died. Twelve patients failed to transition or even lower the prostacylin infusion rate and had worsening of their WHO/NYHA functional class and estimated systolic PA pressures, and had a trend toward deterioration in their mean 6MWD (294 +/- 41 to 198 +/- 34 m, respectively; p = 0.2). Of these, two patients subsequently died. The baseline characteristics of those who transitioned successfully vs those who transitioned unsuccessfully were a lower prostacyclin infusion rate, and less severe elevations in the mean and estimated systolic PA pressures.. Transitioning from therapy with prostacyclin to bosentan is possible in some PAH patients, mainly in those receiving lower prostacyclin doses and having less pulmonary hypertension at baseline. Careful patient selection and close interim monitoring is needed because the conditions of patients can deteriorate, and they may not respond to the resumption of therapy with prostacyclin.

Topics: Administration, Oral; Adult; Aged; Antihypertensive Agents; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Lung; Middle Aged; Physical Endurance; Pilot Projects; Severity of Illness Index; Sulfonamides; Walking

Intravenous epoprostenol improves exercise capacity and survival in patients with pulmonary arterial hypertension. The prostacyclin analog treprostinil is also efficacious by subcutaneous infusion, is easier to administer, and has a longer half-life. With the demonstration of bioequivalence between subcutaneous and intravenous treprostinil, intravenous treprostinil may have an overall better risk-benefit profile than intravenous epoprostenol.. To evaluate the safety and efficacy of transitioning patients with pulmonary arterial hypertension from intravenous epoprostenol to intravenous treprostinil.. Patients enrolled in a 12-wk prospective open label study were switched from intravenous epoprostenol to intravenous treprostinil over 24 to 48 h. The intravenous treprostinil dose was adjusted to minimize symptoms/side effects.. Thirty-one patients (mean age, 43 yr; 22 women) were enrolled. Twenty-seven patients completed the protocol; 4 patients transitioned back to epoprostenol. Six-minute walk distance (n = 27; baseline, 438 +/- 16 m; Week 12, 439 +/- 16 m), Naughton-Balke treadmill test time (n = 26; baseline, 582 +/- 50 s; Week 12, 622 +/- 48 s), functional class, and Borg score were maintained with intravenous treprostinil at Week 12 versus intravenous epoprostenol before transition. At Week 12, mean pulmonary artery pressure increased 4 +/- 1 mm Hg (n = 27, p < 0.01), cardiac index decreased 0.4 +/- 0.1 L/min/m2 (n = 27, p = 0.01), and pulmonary vascular resistance increased 3 +/- 1 Wood units x m2 (n = 26, p < 0.01). No serious adverse events were attributed to treprostinil.. These data suggest that transition from intravenous epoprostenol to intravenous treprostinil is safe and effective; whether the hemodynamic differences associated with intravenous treprostinil are clinically important requires longer follow-up.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Child; Cross-Over Studies; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Treatment Outcome

Pulmonary arterial hypertension (PAH) is characterized by abnormalities in endothelial and smooth muscle cell function. Prostacyclin released by endothelial cells is a potent vasodilator by increasing cyclic adenosine monophosphate. Sildenafil, an inhibitor of phosphodiesterase-5, increases cyclic guanosine monophosphate in the lungs, producing vasodilation. To test for a therapeutic benefit of the combination of a prostacyclin analogue, subcutaneous treprostinil, and sildenafil, a proof-of-concept, open-label investigational trial was initiated. Subjects with PAH in World Health Organization (WHO) functional classes II to IV receiving subcutaneous treprostinil for > or =6 months were evaluated with an exercise treadmill test using the Naughton-Balke protocol at baseline and after 12 weeks. Sildenafil 50 mg 3 times daily was added to the treprostinil. Mean treadmill times in seconds were compared before and after 12 weeks of therapy. Nine subjects enrolled in the trial; 7 were women (mean age 35 years). At baseline, 3 subjects were in WHO functional class II and 6 subjects were in WHO functional class III. The mean treadmill time at baseline was 465 +/- 167 seconds and at 12 weeks was 656 +/- 205 seconds (42% improvement, p = 0.049). All patients had symptomatic improvement. In conclusion, this pilot study of subcutaneous treprostinil with sildenafil for PAH suggests additive beneficial effects.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Drug Therapy, Combination; Epoprostenol; Exercise Test; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Pilot Projects; Piperazines; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

To assess the efficacy and safety of continuous subcutaneous infusion of treprostinil, a stable prostacyclin analogue, for treating pulmonary arterial hypertension (PAH) in patients with connective tissue disease (CTD).. Two multicenter, randomized, double-blind, placebo-controlled, prospective trials of treprostinil vs placebo in 470 patients with PAH.. A subset of 90 patients with PAH and CTD, including systemic lupus erythematosus, diffuse scleroderma, limited scleroderma, and mixed CTD/overlap syndrome.. Patients received either treprostinil (initiated at 1.25 ng/kg/min, and titrated upward) or placebo via continuous subcutaneous infusion. The maximum dose of treprostinil allowed was 22.5 ng/kg/min.. Six-minute walk (6MW) distance and dyspnea-fatigue scores were determined at baseline, and at 6 weeks and 12 weeks. Hemodynamic measures were obtained at baseline and at 12 weeks.. At baseline, most patients had New York Heart Association class III symptoms. The mean baseline 6MW distance was 289 m (range, 60 to 448 m). The mean dose of treprostinil at week 12 was 8.4 ng/kg/min (range, 1.25 to 17.5 ng/kg/min). After 12 weeks, the change in cardiac index from baseline was + 0.2 +/- 0.08 L/min/m(2) in the treprostinil group and - 0.07 +/- 0.07 L/min/m(2) in the placebo group (p = 0.007). The pulmonary vascular resistance index decreased by 4 +/- 2 U x m(2) in the treprostinil group and increased by 1 +/- 1 U x m(2) in the placebo group (p = 0.006). The placebo-corrected median improvement from baseline in 6MW distance was 25 m in treprostinil-treated patients (p = 0.055); this improvement appeared to be dose related. Dyspnea fatigue scores also improved in the treprostinil group compared with the placebo group (p = 0.014). Adverse events included infusion site pain and typical side effects related to prostaglandins, and were tolerated by most patients.. Continuous subcutaneous infusion of treprostinil in patients with PAH associated with CTD improved exercise capacity, symptoms of PAH, and hemodynamics.

Topics: Adolescent; Adult; Aged; Child; Connective Tissue Diseases; Double-Blind Method; Epoprostenol; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Injections, Subcutaneous; Lupus Erythematosus, Systemic; Male; Middle Aged; Mixed Connective Tissue Disease; Prospective Studies; Scleroderma, Limited; Scleroderma, Systemic; Treatment Outcome; Walking

Intravenous epoprostenol is currently FDA approved for management of primary pulmonary hypertension, but it requires intravenous infusion and is associated with adverse effects. The objective of this study was to evaluate the effects of an epoprostenol analog, treprostinil, for management of pulmonary hypertension. Ten tertiary care academic institutions with pulmonary hypertension programs participated in these pilot trials. In the first trial, intravenous epoprostenol and intravenous treprostinil were compared. In the second trial, intravenous treprostinil and subcutaneous treprostinil were compared. In the third trial, subcutaneous treprostinil was compared with placebo infusion during an 8-week period. Intravenous epoprostenol and intravenous treprostinil resulted in a similar reduction in pulmonary vascular resistance acutely (22% and 20%, respectively). Intravenous treprostinil and subcutaneous treprostinil also demonstrated comparable short-term decrease in pulmonary vascular resistance (23% and 28%, respectively). The placebo-controlled 8-week trial demonstrated a mean improvement of 37 +/- 17 m as measured by the 6-minute walk distance in patients receiving treprostinil compared with a 6 +/- 28 m reduction in those receiving placebo. There were trends toward an improvement in cardiac index and pulmonary vascular resistance index in the treprostinil group. Subcutaneous treprostinil has favorable hemodynamic effects when given acutely and in the short term. Treprostinil can be given safely to an ambulatory patient with a novel subcutaneous delivery pump system.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Child; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Statistics, Nonparametric

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

To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic hernia-related pulmonary hypertension (CDH-PH).. A retrospective review of a single-center prospective registry at a quaternary care children's hospital. Patients included in the study had CDH-PH treated with treprostinil between April 2013 and September 2021. Assessed outcomes were brain-type natriuretic peptide levels and quantitative echocardiographic parameters collected at baseline, 1 week, 2 weeks, and 1 month after treprostinil initiation. Right ventricular (RV) function was assessed by tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain). Septal position and left ventricular (LV) compression were assessed by eccentricity index and M-mode Z-scores.. Fifty-one patients were included, with an average expected/observed lung-to-head ratio of 28.4 ± 9.0%. Most patients required extra-corporeal membrane oxygenation (n = 45, 88%). Survival to hospital discharge was 31/49 (63%). Treprostinil was initiated at a median age of 19 days with a median effective dose of 34 ng/kg/minute. Median baseline brain-type natriuretic peptide level decreased from 416.9 pg/mL to 120.5 pg/mL after 1 month. Treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score, RV global longitudinal strain, RV free wall strain, LV eccentricity index, and LV diastolic and systolic dimensions, reflecting less compression by the RV, regardless of ultimate patient survival. No serious adverse effects were recorded.. In neonates with CDH-PH, treprostinil administration is well tolerated and is associated with improved RV size and function.

Topics: Child; Epoprostenol; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Natriuretic Peptides; Ventricular Function, Right

Topics: Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Naphazoline; Treatment Outcome

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; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

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

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

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

Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH.. In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied.. In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure.. In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH.. United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).

Topics: Animals; Disease Models, Animal; Epoprostenol; Female; Hernias, Diaphragmatic, Congenital; Hypertension, Pulmonary; Lung; Lung Diseases; Phenotype; Pregnancy; Rats

To investigate the effect of treprostinil on the early postoperative prognosis of patients with severe left heart valvular disease combined with severe pulmonary hypertension (PAH).. A retrospective study including 55 patients with severe left heart valvular disease combined with severe PAH who underwent left heart valve replacement in our hospital between January 2019 and May 2019 was conducted. Patients were divided into two groups (treprostinil group and control group), and the clinical data of patients in the two groups were compared and analyzed.. Compared with the preoperative status, the mean postoperative pulmonary artery pressure (mPAP) in both groups was significantly lower. Compared with the control group, the treprostinil group had a significantly lower mPAP. Moreover, the postoperative mechanical ventilation time, intensive care unit (ICU) stay, and hospital stay of the treprostinil group were significantly shorter than those of the control group. There were no serious drug-related side effects in either group.. Treprostinil can improve the early postoperative prognosis of patients with severe left heart valvular disease combined with severe PAH undergoing prosthetic valve replacement.

Topics: Adult; Antihypertensive Agents; Arterial Pressure; Epoprostenol; Female; Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Recovery of Function; Retrospective Studies; Severity of Illness Index; Time Factors; Treatment Outcome

Limited data are available on the transition from subcutaneous to intravenous prostacyclin in precapillary pulmonary hypertension. We performed a retrospective analysis of all patients who were switched from subcutaneous to intravenous treprostinil with an implantable infusion pump. We included 85 consecutive, clinically stable patients (mean age 66 years and range 16-85), who had been treated with subcutaneous treprostinil for mean 9 months (range 1-78) before pump implantation. An interdisciplinary expert panel defined standards for this procedure before the first implantation. As the first patient experienced a significant hypotensive episode indicating treprostinil overdose postoperatively, the time span to stop subcutaneous treprostinil was reduced to 60 minutes for all following patients. No events associated with the switch from subcutaneous to intravenous treprostinil were observed during postoperative hospital stay in 84 (98.8%) patients. Taking into account a likely depot effect of subcutaneous treprostinil patients can safely be switched to the intravenous route by the implantation of an infusion pump.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Arterial Pressure; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Infusions, Intravenous; Infusions, Subcutaneous; Male; Middle Aged; Pulmonary Artery; Recovery of Function; Retrospective Studies; Treatment Outcome; Young Adult

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

Treprostinil, a prostacyclin analogue used in the treatment of pulmonary arterial hypertension (PAH), is available for administration by parenteral, oral, or inhaled routes. Transitioning between routes may be beneficial for appropriate patients; however, there is little published data on transitions between oral and inhaled treprostinil. We used a modified Delphi process to develop expert consensus recommendations on transitions between these formulations. Three questionnaires were used to develop statements about relevant aspects of transition management, which the panelists rated, using a Likert scale, from -5 (strongly disagree) to +5 (strongly agree). Eleven physicians with expertise in PAH treatment modalities, participated in the panel. Of the 492 statements evaluated, consensus was reached on 215 (43.7%). Key consensus recommendations included (1) accurately defining successful transition, as stable or improved PAH with good tolerability and adherence, and (2) patients with stable, low-risk PAH showing insufficient response or tolerability to their existing treprostinil therapy (and due to restrictions in up titration of dosing), as appropriate candidates for transitions between treprostinil formulations. Panelists did not reach consensus for an overall strategy for performing these transitions, mainly because of variability in their practice parameters. Consensus was also achieved on recommendations for adverse event management, including reassurance, administration of oral treprostinil 3 times daily with food, and dosing inhaled treprostinil at intervals ≥3 hours apart. The Delphi process aided in developing expert consensus recommendations that may provide clinically useful guidance for transitioning between treprostinil formulations. However, additional data from centers with high volumes of PAH patients undergoing treprostinil transitions would be optimal for defining more complete and robust strategies to facilitate successful transition.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Consensus; Delphi Technique; Epoprostenol; Humans; Hypertension, Pulmonary; Patient Selection

Topics: Epoprostenol; Humans; Hypertension; Hypertension, Pulmonary; Lung Diseases, Interstitial

Chronic thromboembolic pulmonary hypertension (CTEPH) involves non-resolving thromboemboli in the pulmonary arteries. Treatment for CTEPH includes lifelong anticoagulation and determination of patients who have disease which is operable versus inoperable. Pulmonary arterial hypertension (PAH) targeted therapies are oftentimes used as a bridge to pulmonary thromboendarterectomy (PTE), though riociguat is the only Food and Drug Administration (FDA)-approved therapy for CTEPH. There is a paucity of data regarding the efficacy of other PAH therapies, particularly as a bridge to PTE. Here, we present a case report of severe CTEPH related to ventriculoatrial shunt in which intravenous treprostinil was used as a bridge to PTE.

Topics: Chronic Disease; Endarterectomy; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

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

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Anti-Asthmatic Agents; Antibodies, Monoclonal, Humanized; Antihypertensive Agents; Asthma; COVID-19; COVID-19 Vaccines; Cytokines; Epoprostenol; Humans; Hypertension, Pulmonary; Infection Control; Injections, Subcutaneous; Intensive Care Units; Lung Diseases, Interstitial; Nursing Homes; Oxygen; Oxygen Inhalation Therapy; Respiratory Insufficiency; Symptom Flare Up; Thymic Stromal Lymphopoietin; Walk Test

Epoprostenol and treprostinil are prostacyclins indicated for the treatment of pulmonary arterial hypertension (PAH). Although there is literature describing the conversion of intravenous (IV) epoprostenol to IV treprostinil or IV treprostinil to oral treprostinil, there is little data on the direct conversion of IV epoprostenol to oral treprostinil. In this case, we describe the direct conversion of IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil.. A 39 year-old female with PAH was admitted for altered mental status and self-removal of her peripherally inserted central catheter (PICC) used for IV epoprostenol. Given the unplanned hospitalization, absence of a dedicated central line for IV prostacyclin therapy, and concern the patient may remove a future subcutaneous line, the patient was transitioned to oral treprostinil. Of note, despite triple PAH therapy, the patient was unable to reach a low risk group based on her prognostic risk assessment. A right heart catheterization four months prior found severe PAH with a pulmonary arterial pressure of 79/32 mmHg (mean, 49 mmHg) and pulmonary vascular resistance of 10.6 Wood units. To expedite the transition, the patient was directly converted from IV epoprostenol to oral treprostinil without an intermediary conversion to IV treprostinil. A target oral treprostinil dose of 5 mg TID was calculated based on 110% of the IV epoprostenol dose (19 ng/kg/min) utilizing the conversion recommended by the medication manufacturer. Every 8 hours, IV epoprostenol was decreased by 2 ng/kg/min and oral treprostinil was increased by 0.5 mg. The target oral treprostinil dose of 5 mg TID was reached 72 hours after conversion initiation. Three hours after the final titration, the patient was discharged home on room air.. In this case, rapid transition from IV epoprostenol to oral treprostinil was achieved in 72 hours without reported adverse effects.

Topics: Adult; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Treatment Outcome

Prostacyclin (PGI. To study the effect of 17β-estradiol (E2) on the PGI. Following E2-treatments of isolated HPA and cultured hPASMC, we measured: 6-keto-Prostaglandin F. Incubation with E2 (24/48 h, doses ≥ 10 nM) significantly increased the expression of PGIS in hPASMC derived from both PH (65-98%) and non-PH (21-33%) patients, whereas incubation with E2 (2 h, 0.1 and 1 µM) increased 6-keto-PGF. E2-treatment may help to restore the PGI

Topics: 6-Ketoprostaglandin F1 alpha; Antihypertensive Agents; Arachidonic Acid; Case-Control Studies; Cytochrome P-450 Enzyme System; Endothelial Cells; Endothelium, Vascular; Epoprostenol; Estradiol; Estrogens; Female; Humans; Hypertension, Pulmonary; Intramolecular Oxidoreductases; Male; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Vasodilation

Despite advantages in the treatment options of pulmonary arterial hypertension, continuous parenteral prostanoid administration, although often complicated by serious side effects, remains the treatment of choice for patients with advanced disease. The need of transitioning from one parenteral prostanoid agent to the other is often faced in the daily clinical practise. Up to today, there is no established transition protocol from subcutaneous treprostinil to intravenous epoprostenol.. A staggered approach to subcutaneous treprostinil down-titration with simultaneous epoprostenol up-titration is described. Subcutaneous treprostinil is down-titrated by 5 ng/kg/min every 5 h while intravenous epoprostenol is up-titrated by 2 ng/kg/min every 2 h.. The designed protocol was implemented in 4 patients with pulmonary arterial hypertension (3 women, median age 70.5 (range 38-79) years). Median starting subcutaneous treprostinil dose was 44.5 (range 37-100) ng/kg/min and median treprostinil down-titration time was 32.5 (range 25-85) hours. The median maximal epoprostenol dose was 36 (range 28-90) ng/kg/min, achieved in 36 (range 30-90) hours. Only mild prostanoid-related side effects were reported.. The proposed staggered transition protocol from subcutaneous treprostinil to intravenous epoprostenol was safe in a limited number of patients with pulmonary arterial hypertension.

Topics: Adult; Aged; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pulmonary Arterial Hypertension

Prostanoid treatment in patients with severe pulmonary arterial hypertension (PAH) has been proven safe and effective. Subcutaneous administration of treprostinil has side effects, which limits their use and acceptance. An implantable pump for continuous intravenous treprostinil infusion has been recently approved. We describe our experience with the implantable pump in three pediatric patients.. The LENUS pro pump was implanted in three adolescents with severe PAH, who were treated with tadalafil, ambrisentan, and subcutaneous treprostinil. The indication of the Lenus pro pump implantation was the local side effects of subcutaneous treprostinil (pain, inflammation, and local infection) that were not well tolerated and that severely decreased their quality of life. The pump was surgically implanted under general anesthesia.One patient, in functional class IV, suffered postoperative hemodynamic instability and small pneumothorax,  requiring an increase in treprostinil dose up to 85 ng/kg/min and a decrease 9 days after the pump implantation. The second patient who was discharged 4 days after surgery with treprostinil at 60 ng/kg/min reported improvement in his quality of life, but the dose requirement increased up to 92 ng/kg/min. After a 21-month follow-up, this patient received a lung transplant. The third patient presented a hematoma at the pump site with no other complications and had a follow-up of 9 months with an improvement in her quality of life.. Implantable pumps for continuous parenteral prostanoid infusion in pediatric patients are an alternative to external pumps, especially when familiar psychological or psychomotor issues hinder the use of external pumps.

Topics: Adolescent; Antihypertensive Agents; Child; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Lung Transplantation; Male; Quality of Life

Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.. Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

Topics: AMP-Activated Protein Kinases; Animals; Antihypertensive Agents; Diet, High-Fat; Epoprostenol; Heart; Heart Failure; Hyperglycemia; Hypertension, Pulmonary; Hypoglycemic Agents; Insulin Resistance; Male; Metabolic Syndrome; Metformin; Mice; Mice, Inbred C57BL; Obesity; Rats; Receptors, Leptin; Stroke Volume

Treprostinil, a prostacyclin analog, is a safe and effective therapy for children with PAH; however, the use of this agent in children with mild PVR elevations related to HF, including those with SV congenital heart disease awaiting HT, is understudied. We describe the hemodynamic and symptomatic changes in pediatric patients awaiting HT treated with treprostinil.. Single-center retrospective review of all patients was listed for HT who received treprostinil during the listing period. Changes in hemodynamic and functional indices between the baseline catheterization (prior to drug initiation), and prior to HT, and patient outcomes were analyzed.. Among 16/17 (94%) who survived to HT, 8 (50%) were female, and 10 (63%) had SV physiology. The median age at drug initiation was 9 (IQR: 1, 14) years. The median duration of therapy prior to HT was 253 (IQR: 148, 504) days. Treprostinil significantly decreased PVR (3.8 vs 3.1 WU, P = .03), while mLA or mPCW pressure did not change (11 vs 13 mm Hg, P = .9). HF symptoms improved in 9/15 (60%) patients without VAD support prior to drug initiation, including 4/10 (40%) who did not receive a VAD any point while awaiting HT.. Treprostinil may be used safely in patients with mild PAH awaiting HT, including those with SV disease. PVR falls without substantial increases in mLA/mPCW pressure. HF symptoms improve in some patients.

Topics: Adolescent; Antihypertensive Agents; Child; Child, Preschool; Drug Administration Schedule; Epoprostenol; Female; Heart Failure; Heart Transplantation; Humans; Hypertension, Pulmonary; Infant; Male; Patient Safety; Retrospective Studies; Severity of Illness Index; Treatment Outcome; Waiting Lists

A 14-year-old boy was receiving subcutaneous infusions of treprostinil for pulmonary artery hypertension. Because he had severe infusion site pain in the lower abdomen, we changed his infusion site to the upper buttocks, adding some analgesics. His pain improved gradually. This change may be an effective method for reducing infusion site pain in subcutaneous treprostinil therapy, particularly in children.

Topics: Adolescent; Antihypertensive Agents; Buttocks; Epoprostenol; Humans; Hypertension, Pulmonary; Male; Pulmonary Artery

Selexipag is an oral nonprostanoid IP prostacyclin receptor agonist that is indicated for treatment of pulmonary arterial hypertension (PAH). In patients with continued symptoms of PAH despite maximized oral therapy with selexipag and other oral therapies, a transition to parenteral prostacyclin may be warranted. There is a paucity of data regarding how to safely transition from oral selexipag to parenteral treprostinil. We describe rapid transition from oral selexipag to parenteral treprostinil in this case report.. A 65-year-old female with mixed-etiology PAH as result of pulmonary fibrosis related to polymyositis was admitted to the intensive care unit to be transitioned from selexipag to treprostinil due to dyspnea at rest despite therapy with selexipag 1,600 mg twice daily and macitentan 10 mg daily for 3 years. At baseline the patient required oxygen support (4 L/min) at rest to maintain oxygen saturation at or above 90%. Right heart catheterization performed 8 weeks prior to admission revealed severe PAH, with a pulmonary arterial pressure of 73/27 mm Hg and pulmonary vascular resistance of 10 Wood units. On the day of admission the patient was given selexipag 800 µg at 9 am and simultaneously started on intravenous (i.v.) treprostinil at a dose of 2 ng/kg/min. The treprostinil dose was increased by 2 ng/kg/min every 3 hours until a target dose of 22 ng/kg/min was achieved, at which point the patient had experienced dyspnea improvement. She experienced a mild headache and flushing during rapid treprostinil dose escalation. After 30 hours of i.v. treprostinil infusion, the patient was transitioned to subcutaneous treprostinil therapy and discharged.. In this case the patient was rapidly transitioned from oral selexipag to i.v. and then subcutaneous treprostinil therapy over a 30-hour period, with minimal adverse effects.

Topics: Acetamides; Administration, Intravenous; Administration, Oral; Aged; Antihypertensive Agents; Blood Pressure; Drug Substitution; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Pyrazines; Time Factors

A 50-year-old woman with a medical history significant for limited scleroderma (SSc) complicated by interstitial lung disease (ILD) and pulmonary arterial hypertension presented to our institution with acute on chronic shortness of breath. Ten years before presentation, she was diagnosed with SSc. Two years before presentation, she was found to have ILD, for which she was started on mycophenolate mofetil and low-dose prednisone. One year before presentation, she noted worsening dyspnea on exertion (New York Heart Association Functional Class III) and required supplemental oxygen, up to 5 L, despite findings of stable ILD on a maintenance dose of mycophenolate mofetil. A subsequent right heart catheterization showed findings consistent with severe pulmonary arterial hypertension: right atrial pressure of 19 mm Hg, pulmonary arterial pressure of 98/39 mm Hg with a mean pulmonary arterial pressure of 58 mm Hg, right ventricular pressure of 59/6 mm Hg, pulmonary arterial wedge pressure of 10 mm Hg, cardiac output of 4.2 L/min with a cardiac index of 2.7 L/min/m

Topics: Antihypertensive Agents; Dyspnea; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Middle Aged; Scleroderma, Limited

Topics: Epoprostenol; Heart Failure; Humans; Hyperglycemia; Hypertension, Pulmonary; Metformin; Stroke Volume

TREPROSTINIL IS A PROSTACYCLIN ANALOG USED FOR TREATMENT OF PULMONARY HYPERTENSION (PH) IN ADULTS AND CHILDREN, CURRENTLY AWAITING CLINICAL ASSESSMENT FOR USE IN NEONATES.: OBJECTIVES: WE AIMED TO INVESTIGATE THE USE OF TREPROSTINIL IN NEONATES WITH PH ON EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) SUPPORT AND MEASURE PLASMA CONCENTRATIONS OF THE DRUG.: METHODS: THIS IS A RETROSPECTIVE CASE-SERIES WITH PROSPECTIVELY COLLECTED BLOOD SAMPLES, CONDUCTED IN A QUATERNARY CARE NEONATAL INTENSIVE CARE UNIT. BRAIN NATRIURETIC PEPTIDE, CARDIAC FUNCTION ON DOPPLER ECHOCARDIOGRAPHY, AND THE OCCURRENCE OF ADVERSE EFFECTS WAS MONITORED. PLASMA CONCENTRATIONS WERE MEASURED USING HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY AND MASS SPECTROMETRY.: RESULTS: FOUR PATIENTS WITH PH REQUIRING ECMO THERAPY WERE STUDIED. TREPROSTINIL DOSES OF 20-58 NG/KG/MIN REACHED CONCENTRATIONS OF 0.99-4.39 NG/ML AND INDUCED CLINICAL IMPROVEMENT. INFUSION OF TREPROSTINIL WAS ASSOCIATED WITH IMPROVED RIGHT VENTRICULAR FUNCTION, REVERSED RIGHT-TO-LEFT SHUNTING THROUGH THE DUCTUS ARTERIOSUS, AND STABLE OR DECREASING NEED FOR VASOPRESSOR SUPPORT.. CONCLUSIONS: THIS IS THE FIRST STUDY TO REPORT CLINICALLY THERAPEUTIC TREPROSTINIL CONCENTRATIONS IN CIRCULATING PLASMA AFTER TREPROSTINIL ADMINISTRATION IN NEONATES ON ECMO, WITH ASSOCIATED CLINICAL IMPROVEMENT OF PH AND NO SIGNS OF HEMODYNAMIC INSTABILITY.

Topics: Antihypertensive Agents; Epoprostenol; Extracorporeal Membrane Oxygenation; Female; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Prospective Studies; Retrospective Studies

Topics: Epoprostenol; Heart Failure; Humans; Hyperglycemia; Hypertension, Pulmonary; Metformin; Stroke Volume

The aim of this study was to establish the effects of treprostinil in congenital diaphragmatic hernia (CDH) patients with persistent pulmonary hypertension (PHT) after 1 week of treatment. Drug effects were assessed by oxygenation index (OI), clinical end points, serial biochemical markers, and pre- and posttreatment echocardiogram. Treatment complications were also described.. This is a quasi-experimental study of neonates with PHT admitted to the NICU within 48 hours showing persistent clinical instability, receiving mechanical ventilation with FiO2 > 60%, milrinone therapy, and inhaled nitric oxide. Clinical data were compared before and after treprostinil treatment.. Treprostinil was well tolerated with satisfactory clinical response. Further studies are required to identify early responder subgroups.

Topics: Antihypertensive Agents; Echocardiography; Epoprostenol; Female; Hematoma; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Hypotension; Infant, Newborn; Male; Treatment Outcome

Pregnancy in patients with pulmonary hypertension is associated with increased risk of maternal and fetal death. Physiological changes during pregnancy, labor and the postpartum period may all lead to acute decompensation of chronic right heart failure with rapid progression to circulatory collapse. As such, guidelines discourage planned pregnancies in women suffering from pulmonary hypertension. There are, however, rare cases of pulmonary hypertension which have previously been undiagnosed and only become apparent during late stage pregnancy. These individuals require close monitoring and multidisciplinary management.. We describe the case of a 34-year-old female who presented with acute decompensation of previously undiagnosed pulmonary hypertension during the 30th week of her second pregnancy. Echocardiography and CT scan confirmed severe pulmonary hypertension and right heart failure with no new thromboembolic component. Following stabilization of cardiorespiratory parameters with high FiO. The case described is the first published report of previously undiagnosed pulmonary hypertension presenting with acute right heart failure in late pregnancy successfully managed by pharmacological therapy, noninvasive ventilation and a Cesarean performed under epidural anesthesia. The case illustrates that despite the challenges, acutely discovered right heart failure can be successfully managed with a comprehensive multidisciplinary treatment plan.

Topics: Adult; Antihypertensive Agents; Cesarean Section; Chronic Disease; Computed Tomography Angiography; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echocardiography; Endarterectomy; Epoprostenol; Female; Heparin, Low-Molecular-Weight; Humans; Hypertension, Pulmonary; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Diagnosis; Pulmonary Artery; Pulmonary Embolism; Pulmonary Wedge Pressure

Topics: Double-Blind Method; Epoprostenol; Humans; Hypertension, Pulmonary

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; Data Analysis; Epoprostenol; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary

Topics: Epoprostenol; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary

Topics: Acetamides; Administration, Oral; Cardiac Catheterization; Drug Substitution; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Pyrazines

Pulmonary hypertension is a common complication of bronchopulmonary dysplasia, with a high mortality rate. Despite the high incidence of pulmonary hypertension, there are few available treatments. Epoprostenol and treprostinil are prostaglandin I2 analogs that activate adenylate cyclase and increase cyclic adenosine monophosphate in the pulmonary arterial smooth muscle cells. Therefore, they may be an effective treatment for these patients. We report the use of prostaglandin I2 analogs in an extremely low birth weight preterm baby with severe bronchopulmonary dysplasia associated with pulmonary hypertension non-responding to inhaled nitric oxide and sildenafil. In our patient this treatment resulted in remarkable clinical and echocardiographic improvement, evident after a few weeks of treatment.. La hipertensión pulmonar es una complicación frecuente de la displasia broncopulmonar. A pesar de su alta incidencia, existen pocos tratamientos disponibles. El epoprostenol y el treprostinil son análogos de las prostaglandinas I2, que activan la adenilato ciclasa e incrementan el adenosín monofosfato cíclico en las células de la musculatura lisa de la arteria pulmonar y pueden resultar eficaces en el tratamiento de estos pacientes. Se presenta el caso de un prematuro de extremado bajo peso con hipertensión pulmonar secundaria a displasia broncopulmonar grave, no respondedora a óxido nítrico inhalado y sildenafilo, que fue tratado con análogos de prostaglandinas I2. En nuestro paciente, este tratamiento evidenció mejoría clínica y ecocardiográfica significativa tras varias semanas de tratamiento.

Topics: Antihypertensive Agents; Bronchopulmonary Dysplasia; Epoprostenol; Humans; Hypertension, Pulmonary; Infant, Extremely Low Birth Weight; Infant, Newborn; Male

Pulmonary arterial hypertension (PAH) is a progressive condition that can lead to right ventricular failure and death. Treprostinil is a prostacyclin analogue that has proven clinical efficacy in patients with PAH. Difficulties in the administration of inhaled and parenteral prostacyclins led to the development of extended-release treprostinil diolamine for oral use. Limited data exist on the transition to oral treprostinil. The purpose of this case series is to describe the transition from subcutaneous or inhaled treprostinil to oral treprostinil in the outpatient setting. With the current availability of oral prostacyclins and prostacyclins analogues, most transitions to oral therapy are done in the hospital setting resulting in increased cost and risk of hospital-acquired infections. Four patients on background phosphodiesterase type 5 therapy with baseline World Health Organization functional class (WHO FC) II PAH were transitioned at home. Three of the 4 patients were safely transitioned as outpatients and maintained WHO FC II status at 10 and 12 months. The fourth patient had worsening right heart failure and was admitted within 2 months of the transition and started back on parenteral prostacyclin therapy. The 6-minute walk distance (6MWD) increased in patients transitioning from inhaled therapy and decreased in the patient transitioning from subcutaneous therapy. The most common adverse event was nausea.

Topics: Administration, Inhalation; Administration, Oral; Aged, 80 and over; Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Female; Follow-Up Studies; Home Care Services; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Middle Aged; Retrospective Studies

PAH is a progressive life-threatening disease in children. While parenteral prostacyclin therapy improves survival in patients with severe PAH, central line-related complications are common. Our aim was to assess the efficacy, safety, and tolerability of subcutaneous treprostinil treatment in pediatric PAH patients. Eight patients were treated with subcutaneous treprostinil at the Pediatric Heart Center Budapest. Indications for subcutaneous treprostinil therapy were clinical worsening and/or echocardiographic progression or switch from intravenous to subcutaneous therapy. Following treprostinil initiation, clinical status improved or did not change in four of eight patients. Two patients were lost early during treprostinil therapy, parenteral treprostinil as a rescue therapy being insufficient in these cases. The final dose in long-term treated patients was between 60 and 100 ng/kg/min. Aside from thrombocytopenia, other severe side effects were not observed. Potts shunt was performed as palliative treatment in two cases. Three patients had successful lung transplantation, and one died while on the waiting list. Long-term subcutaneous treprostinil could be a safe and well-tolerated therapy in children with severe PAH even at higher doses. It may serve as an alternative to intravenous prostacyclin treatment allowing to avoid the potential complications of permanent central line placement.

Topics: Adolescent; Antihypertensive Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infant; Injections, Subcutaneous; Lung Transplantation; Male; Retrospective Studies; Treatment Outcome

Pulmonary hypertension (PH) in the setting of parenchymal lung disease adversely affects quality of life and survival. However, PH-specific drugs may result in ventilation/perfusion imbalance and currently, there are no approved PH treatments for this patient population. In the present retrospective study, data from 22 patients with PH associated with lung disease treated with inhaled treprostinil (iTre) and followed up clinically for at least 3 months are presented.. PH was defined by resting right heart catheterization as a mean pulmonary artery pressure (mPAP) ≥ 35 mmHg, or mPAP ≥ 25 mmHg associated with pulmonary vascular resistance ≥ 4 Woods Units. Follow-up evaluation was performed at the discretion of the attending physician.. From baseline to follow-up, we observed significant improvement in functional class (n = 22, functional class III-IV 82 vs. 59%, p = 0.041) and 6-min walk distance (n = 11, 243 ± 106 vs. 308 ± 109; p = 0.022), without a deleterious effect on resting peripheral oxygen saturation (n = 22, 92 ± 6 vs. 94 ± 4; p = 0.014). Most of the patients (86%, n = 19/22) were using long-term nasal supplemental oxygen at baseline. During follow-up, only one patient had increased supplemental oxygen requirement. The most common adverse events were cough, headache, and diarrhea. No severe adverse event was reported.. The results suggest that iTre is safe in patients with Group 3 PH and evidence of pulmonary vascular remodeling in terms of functional class, gas exchange, and exercise capacity. Additionally, iTre was well tolerated. The potential role of PH-specific drugs in Group 3 PH should be further assessed in larger prospective studies.

Topics: Administration, Inhalation; Aged; Antihypertensive Agents; Arterial Pressure; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Lung Diseases; Male; Middle Aged; Pulmonary Artery; Recovery of Function; Retrospective Studies; Time Factors; Treatment Outcome; Vascular Remodeling; Vascular Resistance

SMT-101, a novel, proprietary, water-resistant wearable infusion pump prefilled with a preset dosage of treprostinil, was designed to address many of the administration-related shortcomings of existing parenteral therapy for pulmonary arterial hypertension (PAH). The objective of the human factors (HF) program was to demonstrate that the SMT-101 system is safe and effective when used by patients with PAH, their caregivers, or healthcare providers.. The HF program for SMT-101 consisted of 8 studies (148 participants): an ethnographic study, an online survey of patients with PAH, 4 formative studies, a study of the instructions for use (IFU), and a summative study for validation. The pump and IFU were iteratively modified using observational data and participant feedback to inform subsequent improvements throughout the HF program to optimize safe use of SMT-101 before the final study.. The results of the summative study demonstrated that the design of the SMT-101 wearable, pre-filled infusion pump and IFU are safe and effective for use.. In accordance with regulatory guidelines, the usability and HF aspects of SMT-101 were developed and refined through a rigorous HF program in patients with PAH and healthcare providers, which culminated in a summative study that validated the usability and use-safety of SMT-101.

Topics: Adult; Aged; Antihypertensive Agents; Biomedical Engineering; Epoprostenol; Equipment Design; Ergonomics; Female; Humans; Hypertension, Pulmonary; Infusion Pumps; Male; Middle Aged; Surveys and Questionnaires

To assess the efficacy and safety of subcutaneous treprostinil in adult patients with congenital heart disease (CHD)-associated pulmonary arterial hypertension (PAH) after 12 months of treatment.. Consecutive adult patients with CHD-PAH received subcutaneous treprostinil to maximum tolerated doses in an observational study.. Advanced CHD-PAH patients with WHO class III or IV disease (n=32, age 40±10 years, 20 females) received treprostinil for suboptimal response to bosentan (n=12), WHO functional class IV disease (FC, n=7) or prior to bosentan approval (n=13). In the multivariate mixed model, mean increase in 6 min walk distance (6-MWD) from baseline to 12 months was 114 m (76; 152) (P<0.001). WHO FC improved significantly (P=0.001) and B-type brain natriuretic peptide decreased from 1259 (375; 2368) pg/mL to 380 (144; 1468) pg/mL (P=0.02). In those 14 patients who had haemodynamic data before and after initiation of treprostinil, pulmonary vascular resistance decreased significantly (from 18.4±11.1 to 12.6±7.9 Wood units, P=0.003). The most common adverse events were infusion-site erythema and pain. One patient stopped treatment because of intolerable infusion-site pain after 8 months of treatment. No other major treatment-related complications were observed. Five patients died during early follow-up, having experienced a decrease in their 6-MWD prior.. Subcutaneous treprostinil therapy is generally safe and effective for at least 12 months and may be used in CHD-related PAH class III and IV.

Topics: Adult; Antihypertensive Agents; Cohort Studies; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infusion Pumps; Infusions, Subcutaneous; Male; Natriuretic Peptide, Brain; Oxygen; Vascular Resistance; Walk Test

Continuous intravenous epoprostenol was the first treatment approved for pulmonary arterial hypertension (PAH) but administration through a central venous line carries risks of thrombosis and sepsis, particularly in children. We sought to evaluate the safety, efficacy and management of subcutaneous (SC) treprostinil in children with PAH.. Fifty-six children (median age 65, range 1-200 months) were treated with SC treprostinil. Clinical status, echocardiography, NT-proBNP, and site pain and infection were evaluated. Right heart catheterization was performed in 54 patients before starting SC treprostinil infusion and was repeated at 6 months in 31 patients.. Treatment was well tolerated in 79% of patients. Site pain resistant to simple analgesics occurred in 12 patients (21%), but could be managed in 9/12 children. At 6 months, 3 patients had died, 4 had received a Potts shunt and 1 underwent lung transplantation. Among the 48 treated patients, 40 (83%) showed significant improvement in WHO functional class, 6 minute walk distance, NT-proBNP and pulmonary vascular resistance (p < 0.01 for all parameters). At last follow-up (median 37 months), ten patients had died, 2 underwent a lung transplantation and 8 underwent a Potts shunt. In 30 of the 36 remaining treated patients, improvement of clinical status was sustained. No children developed sepsis and 12 had minor site infections.. Subcutaneous treprostinil infusion is an effective therapy without serious side effects in children with PAH. Site pain can be managed with simple analgesics in most children.

Topics: Adolescent; Analgesics; Antihypertensive Agents; Cardiac Catheterization; Child; Child, Preschool; Cohort Studies; Echocardiography; Epoprostenol; Female; France; Humans; Hypertension, Pulmonary; Infant; Infusions, Subcutaneous; Male; Natriuretic Peptide, Brain; Pain, Procedural; Peptide Fragments; Retrospective Studies; Severity of Illness Index; Treatment Outcome

A case of life-threatening cardiovascular collapse after inadvertent subcutaneous injection of undiluted treprostinil is reported.. A 29-year-old, 76-kg woman with group 1 pulmonary arterial hypertension managed with subcutaneous treprostinil infusion arrived at the emergency department (ED) with headache, nausea, vomiting, and a syncopal episode. Her vital signs were stable on presentation. Admission orders were placed, and the appropriate 3-mL syringe containing 7.5 mg of treprostinil intended for use with the patient's home microinfusion pump was sent from inpatient pharmacy to the ED. The order in the electronic medical record stated to administer treprostinil as a subcutaneous injection rather than an infusion. The patient's nurse transferred the 7.5 mg (3 mL) of undiluted treprostinil to a standard syringe and administered it as a single subcutaneous injection. Within minutes the patient experienced cardiovascular collapse, with a blood pressure nadir of 50/20 mm Hg. Aggressive resuscitation measures were immediately implemented. Initial management included fluids, bolus-dose vasopressors, multiple high-dose vasopressor infusions, ondansetron, acetaminophen, and loperamide. Hemodynamic stability was achieved, and vasopressors were discontinued 16 hours after the overdose event. Subcutaneous treprostinil was restarted at a reduced dose 12 hours after the overdose event and was adjusted to the patient's home dose 24 hours after the initial event. She was discharged in stable condition 30 hours after the overdose event.. A patient who received an inadvertent overdose of subcutaneous treprostinil experienced cardiovascular collapse requiring aggressive resuscitation measures. Successful management of the patient was largely supportive, including fluids, bolus-dose vasopressors, multiple high-dose vasopressor infusions, ondansetron, acetaminophen, and loperamide.

Topics: Adult; Antihypertensive Agents; Drug Overdose; Epoprostenol; Female; Fluid Therapy; Humans; Hypertension, Pulmonary; Infusion Pumps; Injections, Subcutaneous; Medical Errors; Resuscitation; Vasoconstrictor Agents

Parenteral prostanoids are considered the treatment of choice for patients with severe pulmonary arterial hypertension (PAH). Prognostic studies for patients treated in the modern era are limited.. In this retrospective cohort study, patients initiating IV epoprostenol or IV or subcutaneous (SC) treprostinil therapy for PAH from 2007 to 2016 at UT Southwestern and The Ohio State University were included. Transplant-free survival was assessed from the time of IV/SC therapy initiation and from the time of first follow-up. The utility of traditional prognostic measures was assessed by using categories (lower, intermediate, and higher risk) recommended in the 2015 European Society of Cardiology/European Respiratory Society guidelines for functional class, 6-min walk distance, brain natriuretic peptide or N-terminal pro-brain natriuretic peptide level, and hemodynamic results.. Patients with group 1 PAH receiving IV epoprostenol (n = 132), IV treprostinil (n = 25), or SC treprostinil (n = 38) were included. Survival from IV/SC prostanoid initiation was 84%, 77%, and 67% at 1, 2, and 3 years. Follow-up assessment was performed after a minimum of 90 days' therapy (mean, 356 ± 247 days) in 163 patients. After treatment with an IV/SC prostanoid, better functional class, 6-min walk distance, brain natriuretic peptide/N-terminal pro-brain natriuretic peptide level, and mixed venous O. In patients with PAH receiving treatment with a parenteral prostanoid, survival was significantly associated with the number of guideline-recommended lower risk and higher risk criteria achieved at first follow-up.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Biomarkers; Child; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome

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

To evaluate the effect of continuous treprostinil in infants with severe pulmonary hypertension associated with congenital diaphragmatic hernia (CDH) on specific markers of pulmonary hypertension severity and to report the safety and tolerability of treprostinil.. We conducted a retrospective cohort study of infants with CDH-associated pulmonary hypertension treated with treprostinil from January 2011 to September 2016. Severity of pulmonary hypertension was assessed by echocardiogram and serum B-type natriuretic peptide (BNP) by using time points before initiation and 24 hours, 1 week, and 1 month after treprostinil initiation. Fisher exact tests, Wilcoxon-rank sum tests, and mixed-effects models were used for analysis.. Seventeen patients were treated with treprostinil for a median of 54.5 days (IQR 44.3-110 days). Compared with the concurrent CDH population (n = 147), infants treated with treprostinil were more likely to require extracorporeal support (76.5% vs 25.2%, P < .0001), to have a longer hospital stay (144 vs 60 days, P < .0001), and to need longer mechanical ventilator support (76.5 vs 30.9 days, P < .0001). Following treprostinil initiation, there was a significant reduction in BNP at 1 week (1439 vs 393 pg/mL, P < .01) and 1 month (1439 vs 242 pg/mL, P = .01). Severity of pulmonary hypertension by echocardiogram improved at 1 month (OR 0.14, CI 95% 0.04-0.48, P = .002). Despite these improvements, overall mortality remained high (35%). There were no adverse events related to treprostinil, including no hypotension, hypoxia, or thrombocytopenia.. In this cohort, treprostinil use was associated with improved severity of pulmonary hypertension assessed by echocardiogram and decreased BNP, with no significant side effects.

Topics: Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Female; Follow-Up Studies; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Pulmonary Wedge Pressure; Registries; Retrospective Studies; Treatment Outcome

Treprostinil (TRE), a prostanoid analogue approved in the USA for the treatment of pulmonary arterial hypertension, requires continuous infusion or multiple dosing sessions per day for inhaled and oral routes of administration due to its short half-life. The inhaled drug is known to induce adverse systemic and local effects including headache, nausea, cough, and throat irritation which may be due at least in part to transiently high drug concentrations in the lungs and plasma immediately following administration [1]. To ameliorate these side effects and reduce dosing frequency we designed an inhaled slow-release TRE formulation. TRE was chemically modified to be an alkyl prodrug (TPD) which was then packaged into a lipid nanoparticle (LNP) carrier. Preclinical screening in a rat model of hypoxia-induced pulmonary vasoconstriction led to selection of a 16-carbon alkyl ester derivative of TRE. The TPD-LNP demonstrated approximately 10-fold lower TRE plasma C

Topics: Administration, Inhalation; Animals; Antihypertensive Agents; Delayed-Action Preparations; Disease Models, Animal; Dogs; Drug Compounding; Drug Evaluation, Preclinical; Epoprostenol; Half-Life; Humans; Hypertension, Pulmonary; Lipids; Lung; Macaca fascicularis; Male; Nanoparticles; Prodrugs; Rats; Rats, Sprague-Dawley; Vasodilation

Treprostinil, a potent vasodilator, is the treatment of choice for severe pulmonary arterial hypertension (PAH) during pregnancy. Its inhibition of platelet aggregation increases the risk of hemorrhage. In addition, anticoagulation therapy is widely used in pregnancy with PAH due to the hypercoagulable state. However, very little is known about the complications of anticoagulants' use in pregnancy with PAH.. A 27-year-old pregnant woman was admitted to the hospital at 32weeks with progressive dyspnea.. The pregnant was diagnosed with ventricular septal defect 12 years prior to presentation. Combining clinical manifestation with results of right heart catheterization (RHC) and echocardiography, it was consistent with severe World Health Organization (WHO) group I PAH.. Supportive treatment included supplemental oxygen, intravenous treprostinil, sildenafil and prophylactic anticoagulation.. Gastrointestinal bleeding is occurred in our patient when dalteparin were used in conjunction with treprostinil. Her care was further complicated refractory to usual conservative measures before delivery.. This case report illustrates the complexities that arise when prostacyclin therapies are combined with necessary anticoagulation in patients with PAH during pregnancy. More intention should play to the complications of anticoagulant in pregnancy with PAH during treprostinil therapy.

Topics: Adult; Anticoagulants; Antihypertensive Agents; Cardiovascular Agents; Dalteparin; Epoprostenol; Female; Gastrointestinal Hemorrhage; Humans; Hypertension, Pulmonary; Pregnancy; Pregnancy Complications, Cardiovascular; Sildenafil Citrate; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure and death. Parenteral prostaglandins (PGs), including treprostinil, a prostacyclin analogue, represent the most effective medical treatment for severe PAH. We investigated the effect of treprostinil on established severe PAH and underlying mechanisms using the rat SU5416 (SU, a VEGF receptor-2 inhibitor)-chronic hypoxia (Hx) model of PAH.. Male Sprague Dawley rats were injected with SU (20 mg·kg. At week 7, no difference in RVSP or RV hypertrophy was observed between vehicle and Trep-100; however, Trep-810 significantly reduced RVSP and RV hypertrophy. Trep-810 treatment significantly improved cardiac structure and function. Further, a short-term infusion of treprostinil in rats with established PAH at 4 weeks post-SU produced an acute, dose-dependent reduction in RVSP consistent with a vasodilator effect. However, chronic Trep-810 treatment did not alter media wall thickness, degree of vascular occlusion or total vessel count in the lungs.. Treprostinil exerts therapeutic benefits in PAH through decreased vascular resistance and improved cardiac structure and function; however, treprostinil treatment does not have direct impact vascular remodelling.

Topics: Angiogenesis Inhibitors; Animals; Antihypertensive Agents; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Indoles; Male; Protein Kinase Inhibitors; Pyrroles; Rats, Sprague-Dawley; Vascular Remodeling; Vasodilator Agents; Ventricular Function, Right

We examined safety and long-term outcomes of intravenous treprostinil administered via the implantable LENUS Pro pump in patients with severe pulmonary hypertension (PH).. Patients with PH undergoing pump implantation between December 2009 and October 2016 in German referral centers were retrospectively analyzed (end of follow-up: May 2017). The primary objective was to determine long-term safety of the implantable pump. Secondary end points were 3-year survival and prognostic relevance of pre-implantation hemodynamics.. We monitored 129 patients (120 with pulmonary arterial hypertension, 1 with PH due to lung diseases, and 8 with inoperable chronic thromboembolic PH) for 260 patient-years (median follow-up, 19 months; interquartile range, 11-34 months). There were 82 complications/peri-procedural events in 60 patients; of these, 57 were serious adverse events (0.60 per 1,000 treatment-days), including 2 periprocedural deaths due to right heart failure. The incidence of complications related to the pump, catheter, infection, and pump pocket per 1,000 treatment-days was 0.074, 0.264, 0.032 (3 local infections; no bloodstream infections), and 0.380, respectively. Three-year overall and transplant-free survival were 66.5% and 55.7%, respectively (39 patients died; 16 underwent lung transplantation). Baseline cardiac index independently predicted transplant-free survival (multivariate hazard ratio, 1.90; 95% confidence interval, 1.11-3.28; p = 0.019; n = 95).. Our data suggest that intravenous treprostinil via the LENUS Pro pump in advanced PH is associated with a very low risk of bloodstream infections, but other serious adverse events may occur. Therefore, this therapy needs standardization and should be offered in specialized PH centers only. Further technical advances of the pump system and prospective studies are needed.

Topics: Adult; Cause of Death; Chronic Disease; Epoprostenol; Equipment Failure; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Lung Transplantation; Male; Middle Aged; Risk Factors; Survival Rate; Treatment Outcome

Safe transition of patients with pulmonary arterial hypertension (PAH) from parenteral treprostinil to oral selexipag therapy in both inpatient and outpatient settings is described.. There is a paucity of published data on how to safely transition patients to oral therapy in the event of complications and problems during parenteral administration of prostacyclins, which can include bloodstream infections, injection-site pain (with use of subcutaneous treprostinil), infusion pump malfunction, and dosing errors due to incorrect dose preparation. This case series describes the transition of 4 patients with World Health Organization (WHO) group I PAH (WHO functional classes II-IV) from i.v. (. Four patients with WHO group I PAH who were not candidates for continued parenteral treprostinil therapy were safely transitioned to oral selexipag in both inpatient and outpatient settings.

Topics: Acetamides; Administration, Intravenous; Administration, Oral; Adult; Antihypertensive Agents; Drug Substitution; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Middle Aged; Pyrazines

We report a rare aetiology of vocal cord paralysis secondary to undiagnosed severe pulmonary hypertension from a de novo ACVRL1 variant identified by whole-genome sequencing. The patient had a partial response to intravenous treprostinil in addition to inhaled nitric oxide, bosentan, and sildenafil.

Topics: Activin Receptors, Type II; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Infant; Male; Mutation; Vocal Cord Paralysis

Prolonged pulmonary hypertension (PH) is highly predictive for pulmonary morbidity and death in infants with congenital diaphragmatic hernia (CDH).. To report the effects and tolerability of subcutaneous treprostinil in newborns with severe CDH and late life-threatening PH.. We recorded clinical and echocardiography data before and after starting subcutaneous treprostinil, on patients with severe CDH and late PH, refractory to inhaled nitric oxide and oral sildenafil.. 14 patients were treated with treprostinil (gestational age: 39.1±2.0weeks; birth weight: 3200±600g). Prior to treatment, the pre- and post-ductal SpO2 difference (Δ SpO2) was 14±10%. Treprostinil was initiated at a median age of 12days [5-157]. After starting treprostinil, ΔSpO2 decreased to 3% at day 7 (p<0.05), and the mean blood flow velocities in the right pulmonary arteries increased by 110% (p<0.05). 2 of the 14 patients died. At the age of follow up (12months to 3years), the 12 surviving infants were all weaned from respiratory support and discharged home.. The subcutaneous treprostinil improves pulmonary hemodynamics and outcomes in infants with CDH and life-threatening PH. We suggest that the treatment should be considered in infants with severe CDH and late PH.. Case series with no comparison group.. Level IV.

Topics: Antihypertensive Agents; Echocardiography; Epoprostenol; Female; Follow-Up Studies; Gestational Age; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Pulmonary Artery

Parenteral prostanoids infused via external pumps are well-established pulmonary arterial hypertension (PAH) treatments. However, local side-effects and systemic infections restrict their use. The purpose of this study was to investigate the safety of a fully implantable treprostinil infusion pump (LENUS Pro. Thirty patients with PAH undergoing pump implantation (with stable PAH therapy for ≥3 weeks pre-implantation) were included in this prospective, multicenter, observational study (NCT01979822). Primary endpoints were predefined adverse events (AEs) during implantation, in-hospital and/or during 6-month follow-up. Refill-related AEs were a secondary endpoint.. Twenty-nine patients completed 6-month follow-up (one underwent lung transplantation). During implantation, one pneumothorax (not requiring drainage) occurred. Four patients had an in-hospital AE (including one catheter revision). During 6-month follow-up, AEs were most frequent at the first refill (10); the most common AE was seroma around the pump. No infections occurred. One pump required replacement because of a defective septum caused by use of a non-approved refill needle (associated with extravasation). Apart from the extravasation, no refill-related AEs were recorded. Post hoc efficacy analyses showed significant improvements in functional class [number in functional class I/II/III/IV: 0/5/21/2 (baseline) versus 3/8/17/0 (6 months); p = 0.012] and 6-min walk distance (mean ± standard deviation: 407 ± 122 m versus 445 ± 127 m; n = 17; p = 0.014).. This study supports use of a fully implantable treprostinil infusion pump in patients with PAH requiring parenteral prostanoids. Refills should be performed by specialized healthcare professionals at patients' homes or at experienced centers using approved equipment.

Topics: Antihypertensive Agents; Epoprostenol; Exercise Tolerance; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Treatment Outcome

To determine the feasibility of delivering inhaled treprostinil during mechanical ventilation and spontaneous unassisted ventilation using the Tyvaso Inhalation System and the vibrating mesh nebulizer. We sought to compare differences in fine particle fraction, and absolute inhaled treprostinil mass delivered to neonatal, pediatric, and adult models affixed with a face mask, conventional, and high-frequency ventilation between Tyvaso Inhalation System and with different nebulizer locations between Tyvaso Inhalation System and vibrating mesh nebulizer.. Fine particle fraction was first determined via impaction with both the Tyvaso Inhalation System and vibrating mesh nebulizer. Next, a test lung configured with neonatal, pediatric, and adult mechanics and a filter to capture medication was attached to a realistic face model during spontaneous breathing or an endotracheal tube during conventional ventilation and high-frequency oscillator ventilator. Inhaled treprostinil was then nebulized with both the Tyvaso Inhalation System and vibrating mesh nebulizer, and the filter was analyzed via high-performance liquid chromatography. Testing was done in triplicate. Independent two-sample t tests were used to compare mean fine particle fraction and inhaled mass between devices. Analysis of variance with Tukey post hoc tests were used to compare within device differences.. Academic children's hospital aerosol research laboratory.. Fine particle fraction was not different between the Tyvaso Inhalation System and vibrating mesh nebulizer (0.78 ± 0.04 vs 0.77 ± 0.08, respectively; p = 0.79). The vibrating mesh nebulizer delivered the same or greater inhaled treprostinil than the Tyvaso Inhalation System in every simulated model and condition. When using the vibrating mesh nebulizer, delivery was highest when using high-frequency oscillator ventilator in the neonatal and pediatric models, and with the nebulizer in the distal position in the adult model.. The vibrating mesh nebulizer is a suitable alternative to the Tyvaso Inhalation System for inhaled treprostinil delivery. Fine particle fraction is similar between devices, and vibrating mesh nebulizer delivery meets or exceeds delivery of the Tyvaso Inhalation System. Delivery for infants and children during high-frequency oscillator ventilator with the vibrating mesh nebulizer may result in higher than expected dosages.

Topics: Administration, Inhalation; Adult; Aerosols; Antihypertensive Agents; Child; Child, Preschool; Combined Modality Therapy; Drug Delivery Systems; Epoprostenol; Feasibility Studies; Humans; Hypertension, Pulmonary; Infant, Newborn; Models, Anatomic; Nebulizers and Vaporizers; Particle Size; Respiration, Artificial; Vibration

Prostacyclin (PGI

Topics: Acetamides; Acetates; Animals; beta-Arrestins; Cell Proliferation; CHO Cells; Contractile Proteins; Cricetinae; Cricetulus; Cyclic AMP; Epoprostenol; Extracellular Matrix; Humans; Hypertension, Pulmonary; Iloprost; Male; Muscle Contraction; Muscle Relaxation; Pyrazines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Epoprostenol

Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when pulmonary emboli fail to resolve with anticoagulation. For patients with inoperable or residual CTEPH, riociguat is currently the only therapy approved by the United States Food and Drug Administration. However, some patients with CTEPH may require therapy beyond riociguat, such as intravenous prostacyclins, which can present significant administration challenges in patients with complex comorbid conditions. We describe a 42-year-old man with T12 paraplegia complicated by CTEPH (functional class IV with substantial right ventricular dysfunction) and severe pressure ulcers. In order to facilitate goals of care (hospital discharge to a skilled nursing facility where parenteral prostanoids could not be administered), he underwent rapid transition from intravenous treprostinil to oral selexipag in the form of a cross-taper over 6 days. The patient required readmission due to worsening symptoms and was transitioned back to intravenous treprostinil; he tolerated conversion to oral treprostinil for approximately 4 months, but it was subsequently discontinued due to nausea and modified goals of care. The patient underwent transition to hospice care 3 months later and eventually died from clinical deterioration. To our knowledge, this is the first report to describe transition from intravenous treprostinil to selexipag as well as conversion from parenteral treprostinil to oral treprostinil in a patient with CTEPH and illustrates the approaches to and potential issues with prostanoid transitions. Additional observations are necessary to better understand the relative roles of selexipag and oral treprostinil regarding comparative efficacy and tolerability.

Topics: Acetamides; Administration, Oral; Adult; Antihypertensive Agents; Chronic Disease; Epoprostenol; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Paraplegia; Pyrazines; Severity of Illness Index; Ventricular Dysfunction, Right

Topics: Aged; Antihypertensive Agents; Capsaicin; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Subcutaneous; Male; Middle Aged; Pain; Pain Management; Sensory System Agents; Severity of Illness Index; Transdermal Patch

Pulmonary arterial hypertension (PAH) is a rare and progressive disorder. Current treatment in the pediatric population includes phosphodiesterase 5 inhibitors (PDE-5i), endothelin receptor antagonists (ERA), and both inhaled and intravenous prostacyclin pathway agonists. As of December 22, 2015 the first oral prostacyclin pathway agonist, selexipag (Uptravi

Topics: Acetamides; Adolescent; Antihypertensive Agents; Child; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Pyrazines; Treatment Outcome; Walk Test; Young Adult

Subcutaneous treprostinil is a prostacyclin analogue used to treat pulmonary arterial hypertension (PAH). Due to local pain it can cause a deterioration of heart related quality of life (HRQoL) or even abandonment of treatment. The aim of this paper was to assess the feasibility of treatment with intravenous treprostinil administered by means of the Lenus Pro® implantable pump.. This was a retrospective, multi-center study involving 12 patients (8 females) with PAH treated with a subcutaneous infusion of treprostinil with intolerable pain at the infusion site. Clinical evaluation, including HRQoL assessment with SF-36 questionnaire was performed, before pump implantation and 2-9 months after. The median time of follow-up time was 14 months (4-29 months).. After implantation of the Lenus Pro® pump, no statistically significant changes were observed in the 6-min walking distance and NT-proBNP. After implantation 50% of patients were in II WHO functional class (33% before, p = 0,59). There was a significant improvement in HRQoL within the Physical Component Score (28 ± 7 vs 38 ± 8 pts., p < 0,001) and in specific domains of SF-36 form: physical role (31 ± 7 pts. vs. 41 ± 12 pts., p = 0,03), bodily pain (31 ± 12 vs. 50 ± 14 pts., p = 0,02), and vitality (37 ± 8 pts. vs. 50 ± 14 pts., p = 0,03). During the periprocedural period, one patient developed a recurrent haematoma at the implantation site. During follow-up in one patient, the drug delivering cannula slipped out of the subclavian vein, what required repositioning repeated twice, and in another patient an unexpected increase in the drug administration rate was observed.. In patients with PAH who do not tolerate subcutaneous infusion of treprostinil, the use of the Lenus Pro® implantable pump results in significant subjective improvement of vitality and physical aspect of the HRQoL with acceptable safety profile.

Topics: Administration, Intravenous; Adult; Aged; Antihypertensive Agents; Catheters, Indwelling; Epoprostenol; Equipment Failure; Female; Hematoma; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Quality of Life; Retrospective Studies; Walk Test

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

In patients with severe pulmonary arterial hypertension, subcutaneous or catheter-based intravenous application of prostanoids carries a risk of local side effects or systemic infections, which limits their use and acceptance. Recently, a fully implantable pump for continuous application of intravenous treprostinil was approved in Germany. However, surgery is a major risk for patients with severe pulmonary arterial hypertension. The purpose of this study was to investigate the safety of a fully implantable pump inserted under local or general anesthesia in patients with severe pulmonary hypertension.. All patients with pulmonary hypertension undergoing pump implantation for the continuous application of intravenous treprostinil were included from two German centers. Surgery was performed under local or general anesthesia according to the protocol of the recruiting center. Intra-operative safety and in-hospital complications were analyzed for the two different implantation regimens.. In total, 51 patients were included. No major intra-operative complications were recorded. During the observation period, two patients died of progressive right heart failure, and two patients required treatment in the intensive care unit for acute right heart decompensation and respiratory failure. In total, major complications occurred in 8 out of 51 patients.. Our observational study provides preliminary evidence supporting the procedural safety of a fully implantable pump inserted under local or general anesthesia for patients with severe pulmonary hypertension. The observation of major complications in a subset of patients requires extensive pre- and post-operative assessments. Future trials are required to provide further evidence for the long-term safety and efficacy of the pump using this approach.

Topics: Adult; Antihypertensive Agents; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Male; Middle Aged; Prospective Studies; Prostaglandins; Pulmonary Wedge Pressure; Retrospective Studies; Treatment Outcome

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

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

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

Topics: Antihypertensive Agents; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary

Pulmonary arterial hypertension (PAH) is a rare, progressive, fatal vascular disorder. Genetic predisposition plays vital roles in the development of PAH, with most mutations being identified in genes involved in the transforming growth factor beta (TGF-β) signaling pathways. Defects in the BMP9 gene have been documented in hereditary hemorrhagic telangiectasia (HHT), the most common inherited vascular disorder, which is occasionally associated with PAH. Selective enhancement of endothelial BMPR2 with BMP9 reverses pulmonary arterial hypertension.. We report the case of a 5-year-old Hispanic boy who was diagnosed with severe PAH and right heart failure at 3 years of age. During his stay in the pediatric intensive care unit, treatment was initiated with inhaled nitric oxide and intravenous epoprostenol; he subsequently was transitioned to treprostinil, sildenafil, and prophylactic enoxaparin. Now, two years later, the child is asymptomatic on sildenafil, bosentan, subcutaneous treprostinil, and warfarin. Genetic screening revealed a novel homozygous nonsense mutation in the BMP9 gene (c.76C > T; p.Gln26Ter). The child had no telangiectasias or arteriovenous malformations; family history also was negative. Subsequent parental testing showed both parents were heterozygous for the same mutation, indicating that the child inherited the BMP9 mutant allele from each parent.. To our knowledge, this is the first report of a BMP9 mutation in a patient with PAH. The homozygous nonsense mutation may account for the early onset and severity of PAH in this patient and also fit the 'two-hit' model we proposed previously. The absence of clinical symptoms for PAH in the parents may be due to incomplete penetrance or various expressivities of the BMP9 mutations. Our study expands the spectrum of phenotypes related to BMP9 mutations.

Topics: Anticoagulants; Antihypertensive Agents; Bosentan; Child, Preschool; Codon, Nonsense; Epoprostenol; Growth Differentiation Factor 2; Growth Differentiation Factors; Homozygote; Humans; Hypertension, Pulmonary; Male; Mexican Americans; Sildenafil Citrate; Sulfonamides; Vasodilator Agents; Warfarin

Pulmonary arterial hypertension (PAH) has emerging therapeutic options including prostacyclin analogs. Inhaled therapy offers advantages compared with alternative routes of administration. We aimed to determine the safety and tolerability of inhaled treprostinil (iTRE) titrated to target maintenance dose higher than the labeled dose for PAH. Our study included 80 consecutive patients (69% female, 70% White) followed at the Duke University Medical Center prescribed iTRE at dose >9 breaths (54 μg). Etiology of pulmonary hypertension was most frequently PAH (51%) or secondary to lung disease (35%). Median follow-up was 20.3 months (interquartile range 14.2-33.2). Most patients (91%) had titrated iTRE dose to 12 breaths (72 μg) four times daily. Common side effects reported with drug initiation were cough (41%), headache (28%), and throat irritation (8%); most of the side effects improved at follow-up. Overall, 25% patients discontinued iTRE: 9 transitioned to parenteral therapy, 4 had untolerable side effects, 3 died, and 4 had other reasons. Overall, iTRE taken at a higher dose than approved for use in PAH was safe and well-tolerated in our cohort of pulmonary hypertension patients.

Topics: Administration, Inhalation; Antihypertensive Agents; Cohort Studies; Dose-Response Relationship, Drug; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Retrospective Studies; Treatment Outcome

In recent years, the population of patients with pulmonary arterial hypertension (PAH) has changed dramatically, including more advanced age at diagnosis. We hypothesized that older patients have a distinct clinical profile with different disease characteristics and response to intervention.. All previously published treatment studies for PAH conducted by United Therapeutics including seven randomized, placebo-controlled trials and one extension study were included and analyzed to assess the association of age with various demographic, functional, hemodynamic, and outcome variables.. A total of 2,627 patients across three age groups were included: ≤ 50 (n = 1,438, 54.7%), 51 to 64 (n = 780, 29.7%), and ≥ 65 years (n = 409, 15.6%). In comparison with the youngest group, the oldest age group had higher proportions of connective tissue disease-associated etiology (range across the studies, 27%-49% vs 13%-21%), higher proportions of New York Heart Association Functional classes III and IV (74%-91% vs 57%-84%), shorter baseline 6-min walk distance (6MWD) (261-316 vs 335-371 m), better hemodynamic measurements including lower baseline mean pulmonary artery pressure (48-51 vs 58-63 mmHg), and smaller changes in 6MWD from baseline to endpoint (-5.6 to 24 vs 14-43 m). Age remained associated with change in 6MWD when adjusting for covariates in multivariate analyses.. For the first time, using data from large randomized controlled trials, this study characterizes the different phenotype and outcomes of older patients with PAH, which includes different disease etiology, diminished functional status, and decreased response to intervention. This may have significant implications for the management of this patient population and design of future therapy trials.

Topics: Age Factors; Aged; Antihypertensive Agents; Connective Tissue Diseases; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multivariate Analysis; Phenotype; Pulmonary Wedge Pressure; Randomized Controlled Trials as Topic; Tadalafil; Treatment Outcome; Vasodilator Agents; Walk Test

Topics: Adult; Antihypertensive Agents; Child, Preschool; Epoprostenol; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Male; Poland

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Cardiac Catheterization; Disease Progression; Dose-Response Relationship, Drug; Echocardiography; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Pulmonary Wedge Pressure; Severity of Illness Index; Still's Disease, Adult-Onset

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

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

Parenteral prostacyclin therapy for PAH has allowed for improvements in functional status, quality of life and mortality. Parenteral therapies however carry an increased risk of line-associated complications. Inhaled prostacyclins are an attractive alternative therapy; however, limited data exists supporting the safety and outcomes after transition.. We describe a retrospective observational analysis of adults with PAH who were transitioned from a parenteral prostacyclin to inhaled treprostinil at our institution. Endpoints include duration of transition, hospital length of stay, adverse effects during transition, and cardiopulmonary function post transition.. Eight patients were included, all of which were on triple therapy. Seven patients receiving intravenous prostacyclin therapy were transitioned in an ICU setting, while one patient was transitioned from subcutaneous treprostinil as an outpatient. The average ICU and hospital length of stay was 4.1 ± 0.7 days. Patient preference was the most common reason for transition (n = 5), followed by line complication (n = 2), and intolerance to parenteral therapy (n = 1). One adverse event was observed while initiating inhaled treprostinil that only required slowing of the transition process. On follow-up (19.6 ± 11.1 months) functional class did not change, and non-parametric test showed no change in 6MWD after transition (p = 0.62). One patient failed inhaled therapy necessitating transition back to intravenous therapy.. Transitioning patients from parenteral to inhaled prostacyclin therapy can be safely accomplished in specialized centers over a 48-72 h period. Patient preference was overwhelming the most prevalent reason for transition.

Topics: Administration, Inhalation; Administration, Intravenous; Adult; Aged; Antihypertensive Agents; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Intensive Care Units; Length of Stay; Male; Middle Aged; Patient Preference; Quality of Life; Retrospective Studies; Time Factors

Topics: Adult; Antihypertensive Agents; Catheterization, Central Venous; Epoprostenol; Equipment Design; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Infusions, Intravenous; Male

Neurofibromatosis type 1 (NF1) is a rare multisystem genetic disorder. During the course of the disease it can be rarely complicated with pulmonary hypertension (PH) which confers a dismal prognosis.. We describe the case of a 57-year-old female patient with NF1 complicated by severe precapillary PH despite dual disease-specific oral combination therapy. The patient was treated with initial atrial septostomy followed by administration of high-dose subcutaneous treprostinil with a favorable medium-term clinical and hemodynamic response.. PH secondary to NF1 may be successfully treated with the combination of atrial septostomy and PH targeted therapy in selected patients.

Topics: Antihypertensive Agents; Cardiac Surgical Procedures; Echocardiography; Epoprostenol; Female; Heart Atria; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Middle Aged; Neurofibromatosis 1; Prognosis; Ventricular Remodeling

Sarcoidosis is a pleomorphic disease that can present with pulmonary hypertension (PH). What little information is available about the association of these two diseases comes mainly from small series of patients scheduled for transplant. We present 4 cases of mild pulmonary involvement in whom right catheterisation was performed and PH-specific therapy was administered. After obtaining written consent, a genetic study was performed that showed mutations in PH-related genes in 3 of the patients. This is the first study of its kind to yield genetic information for this type of PH.

Topics: Bone Morphogenetic Protein Receptors, Type II; Bosentan; Disease Progression; Epoprostenol; Fatal Outcome; Female; Humans; Hypertension, Pulmonary; Kv1.5 Potassium Channel; Male; Middle Aged; Mutation; Phenylpropionates; Point Mutation; Pyridazines; Respiratory Function Tests; RNA, Messenger; Sarcoidosis; Sildenafil Citrate; Sulfonamides; Tadalafil; Treatment Outcome

Both prostacyclin analogs and phosphodiesterase 5 (PDE5) inhibitors are effective treatments for pulmonary arterial hypertension (PAH). In addition to direct effects on vascular smooth muscle, prostacyclin analogs increase cAMP levels and ATP release from healthy human erythrocytes. We hypothesized that UT-15C, an orally available form of the prostacyclin analog, treprostinil, would stimulate ATP release from erythrocytes of humans with PAH and that this release would be augmented by PDE5 inhibitors. Erythrocytes were isolated and the effect of UT-15C on cAMP levels and ATP release were measured in the presence and absence of the PDE5 inhibitors, zaprinast or tadalafil. In addition, the ability of a soluble guanylyl cyclase inhibitor to prevent the effects of tadalafil was determined. Erythrocytes of healthy humans and humans with PAH respond to UT-15C with increases in cAMP levels and ATP release. In both groups, UT-15C-induced ATP release was potentiated by zaprinast and tadalafil. The effect of tadalafil was prevented by pre-treatment with an inhibitor of soluble guanylyl cyclase in healthy human erythrocytes. Importantly, UT-15C-induced ATP release was greater in PAH erythrocytes than in healthy human erythrocytes in both the presence and the absence of PDE5 inhibitors. The finding that prostacyclin analogs and PDE5 inhibitors work synergistically to enhance release of the potent vasodilator ATP from PAH erythrocytes provides a new rationale for the co-administration of these drugs in this disease. Moreover, these results suggest that the erythrocyte is a novel target for future drug development for the treatment of PAH.

Topics: Adenosine Triphosphate; Adolescent; Adult; Aged; Antihypertensive Agents; Carbolines; Cyclic AMP; Drug Synergism; Epoprostenol; Erythrocytes; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Purinones; Tadalafil; Young Adult

The development of pulmonary hypertension (PH) in non-World Health Organization group I PH adversely affects exercise capacity. It is unclear whether pulmonary artery hypertension (PAH)-specific drugs improve pulmonary hemodynamics and exercise capacity in such patients.. We performed a retrospective chart review of consecutive patients with non-World Health Organization group I PH treated with PAH-specific therapy.. We identified 24 patients. The mean (standard deviation) age was 48 (14.8) years. Seventeen (71%) patients were women. The 6-minute walk distance improved significantly for the whole group in an initial follow-up period of 4.6 (2.3) months; however, the improvement was seen only in patients with obstructive sleep apnea (OSA) or severe PH and it was not sustained during a longer follow-up period of 11.5 (4.1) months, except in patients with OSA. PH was treated with a variety of PAH-specific drugs, including combination therapy in five patients.. The use of PAH-specific therapy in selected patients with PH secondary to lung diseases, OSA, or sarcoidosis may result in significant improvement in 6-minute walk distance, particularly in patients with OSA or severe PH.

Topics: Adult; Antihypertensive Agents; Cohort Studies; Endothelin Receptor Antagonists; Epoprostenol; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prostaglandins; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Retrospective Studies; Sarcoidosis; Severity of Illness Index; Sleep Apnea, Obstructive; Treatment Outcome; World Health Organization

In the past 18 months, the U.S. Food and Drug Administration approved macitentan, riociguat, and treprostinil as oral agents for the treatment of pulmonary arterial hypertension (PAH); riociguat also became the first agent approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). These new agents are welcome additional therapeutic options for PAH and CTEPH. However, their use can be complicated by potential drug interactions, adverse effects, dosing complexity, and cost. Macitentan, the newest endothelin receptor antagonist, showed significant benefits in a long-term event-driven trial of morbidity and mortality. Dosed once daily and with minimal liver toxicity, it has potential drug interactions with potent CYP 3A4 inhibitors and inducers, and can decrease hemoglobin levels. Riociguat is approved for PAH and clinically inoperable CTEPH to improve exercise capacity and functional status. Riociguat requires dose titration beginning with 1 mg up to 2.5 mg three times a day, as tolerated, and should be used with caution in patients with underlying risk factors for systemic hypotension. Oral treprostinil, approved to improve exercise capacity in PAH, is associated with gastrointestinal side effects and headaches that are often dose limiting. Doses can begin with 0.125 mg or 0.25 mg twice a day with gradual increases on up to a weekly basis, as tolerated. Thrice daily dosing and administration with a meal can improve tolerance. These newer agents represent advances, but their specific roles in relation to pre-existing therapies are undergoing further evaluation. Therefore, close collaboration with clinicians at centers with therapeutic expertise is highly recommended to optimize patient outcomes.

Topics: Administration, Oral; Antihypertensive Agents; Chronic Disease; Drug Approval; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Sulfonamides; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Drug Approval; Epoprostenol; Humans; Hypertension, Pulmonary; United States; United States Food and Drug Administration

Topics: Blood Transfusion; Bosentan; Diagnostic Imaging; Dobutamine; Ductus Arteriosus, Patent; Eisenmenger Complex; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging; Menorrhagia; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Tomography, X-Ray Computed; Vasodilator Agents; Young Adult

Pulmonary vasodilators and prostacyclin therapy in particular, have markedly improved the outcome of patients with pulmonary hypertension (PH). Endothelial dysfunction is a key feature of PH, and we previously reported that treprostinil therapy increases number and proliferative potential of endothelial colony forming cells (ECFC) isolated from PH patients' blood. In the present study, the objective was to determine how treprostinil contributes to the proangiogenic functions of ECFC. We examined the effect of treprostinil on ECFC obtained from cord blood in terms of colony numbers, proliferative and clonogenic properties in vitro, as well as in vivo vasculogenic properties. Surprisingly, treprostinil inhibited viability of cultured ECFC but did not modify their clonogenic properties or the endothelial differentiation potential from cord blood stem cells. Treprostinil treatment significantly increased the vessel-forming ability of ECFC combined with mesenchymal stem cells (MSC) in Matrigel implanted in nude mice. In vitro, ECFC proliferation was stimulated by conditioned media from treprostinil-pretreated MSC, and this effect was inhibited either by the use of VEGF-A blocking antibodies or siRNA VEGF-A in MSC. Silencing VEGF-A gene in MSC also blocked the pro-angiogenic effect of treprostinil in vivo. In conclusion, increased VEGF-A produced by MSC can account for the increased vessel formation observed during treprostinil treatment. The clinical relevance of these data was confirmed by the high level of VEGF-A detected in plasma from patients with paediatric PH who had been treated with treprostinil. Moreover, our results suggest that VEGF-A level in patients could be a surrogate biomarker of treprostinil efficacy.

Topics: Adolescent; Adult; Angiogenesis Inducing Agents; Animals; Antibodies; Antihypertensive Agents; Biomarkers; Cell Differentiation; Cell Lineage; Cell Proliferation; Cell Survival; Cells, Cultured; Child; Child, Preschool; Dose-Response Relationship, Drug; Endothelial Progenitor Cells; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infant; Male; Mesenchymal Stem Cells; Mice, Nude; Neovascularization, Physiologic; Paracrine Communication; RNA Interference; Signal Transduction; Transfection; Up-Regulation; Vascular Endothelial Growth Factor A; Young Adult

Pulmonary hypertension (PH) is a rapidly progressive disease that eventually leads to right heart failure and death. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-Rs) play an important role in the survival, migration, and proliferation of vascular smooth muscle cells. However, the association between serum TRAIL levels and PH is unknown. In this study, we assayed the serum soluble TRAIL (sTRAIL) levels in 78 patients with PH and 80 controls. The sTRAIL concentrations were elevated in the PH patients compared with the controls (138.76 ± 6.60 pg/mL vs. 80.14 ± 3.38 pg/mL, p < 0.0001). The presence of sTRAIL levels of >103 pg/mL could discriminate PH patients from healthy individuals, with a sensitivity of 75.6% and specificity of 81.2%. Moreover, elevated sTRAIL concentrations were associated with eventual pathological complications; this is consistent with the finding that sTRAIL levels decreased in patients who responded to treatment. In a hypoxia-induced PH mouse model, sTRAIL levels were significantly higher compared with those in normoxia mice, and clearly decreased when the mice were treated with treprostinil. The sTRAIL levels were positively correlated with right ventricular systolic pressure and the index of right ventricular hypertrophy. In conclusion, serum sTRAIL could be a biomarker for diagnosis and effective therapy for PH patients.

Topics: Animals; Case-Control Studies; Disease Models, Animal; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Hypoxia; Male; Mice; Mice, Inbred C57BL; Middle Aged; Prospective Studies; Sensitivity and Specificity; Severity of Illness Index; TNF-Related Apoptosis-Inducing Ligand

We describe 2 infants with congenital diaphragmatic hernia with severe pulmonary hypertension at 6 weeks. Treprostinil was used with rapid clinical improvement. Repeat cardiac catheterization showed dramatic improvement. Both infants were weaned off the drug, representing the first reports of successful short-term treprostinil use in neonates with congenital diaphragmatic hernia.

Topics: Antihypertensive Agents; Epoprostenol; Female; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn

Pulmonary hypertension (PH) presents a high risk for maternal mortality. The intravenous administration of treprostinil has demonstrated effectiveness for the treatment of PH, though documentations of its use during pregnancy are few. The authors present a 30-year-old gravid women with symptoms of PH at 23 weeks gestation. Treatment comprised of oxygen therapy, enoxaparin, and intravenous treprostinil from gestational week 25, following a successful elective cesarean section at 33 weeks gestation with favorable outcome. This report demonstrates the effectiveness of an intensive therapeutic protocol, including intravenous treprostinil, for the treatment of PH in pregnancy.

Topics: Adult; Anticoagulants; Antihypertensive Agents; Cesarean Section; Enoxaparin; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Oxygen Inhalation Therapy; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Trimester, Second

A 20-year-old man with pulmonary arterial hypertension secondary to systemic sclerosis was admitted to our hospital. Prior to admission, his PAH had been successfully managed with the use of tadalafil, ambrisentan and inhaled Tyvaso. Owing to respiratory failure from vocal cord paralysis, he underwent an emergent tracheotomy. The delivery of inhaled Tyvaso through a tracheostomy tube was explored. Post-tracheostomy, the patient continued his ability to self-administer the medication. His WHO functional classification, brain natriuretic peptide levels, and echocardiograms were not significantly different when Tyvaso was administered via tracheostomy compared with oral administration. This case report summarises the method used to deliver Tyvaso via a tracheostomy tube, which proved to be successful in this patient.

Topics: Administration, Inhalation; Administration, Oral; Adult; Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Male; Respiratory Insufficiency; Tracheostomy; Tracheotomy; Vocal Cord Paralysis; Young Adult

Topics: Antihypertensive Agents; Drug Eruptions; Eosinophilia; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Middle Aged; Skin

Prostacyclin analogs are Food and Drug Administration-approved therapies for the treatment of pulmonary arterial hypertension and can be administered by inhalational, intravenous (IV), or subcutaneous (SQ) routes. Because there are limited data to guide the transition between SQ to IV prostacyclin analogs, we describe our experience.. We performed a retrospective review of patients with pulmonary hypertension diagnosed by right heart catheterization, who underwent transition from SQ to IV prostacyclin analogs.. We included 7 patients with pulmonary arterial hypertension and 2 with chronic thromboembolic pulmonary hypertension in this retrospective study. Median (interquartile range) age was 54 (39-63) years, and 67% were women. The reasons for the SQ to IV switch were site pain (n = 6, 67%), major surgery (n = 2, 22%), and septic shock (n = 1, 11%). SQ treprostinil was converted to IV treprostinil (n = 5, 56%) or IV epoprostenol (n = 4, 44%). When SQ treprostinil was converted to IV treprostinil, the initial mean (range) dose decreased from 84.9 (36.5-167) to 70.8 (24-114) ng·kg⁻¹·min⁻¹. When SQ treprostinil was converted to IV epoprostenol, the dose decreased from 24.5 (17.5-30) to 13.3 (9-20) ng·kg⁻¹·min⁻¹. The patient transitioned from SQ to IV treprostinil in the context of septic shock died a month after hospitalization. No deteriorations were observed in the remaining patients during the first year.. Under careful monitoring, SQ treprostinil was transitioned to IV treprostinil or epoprostenol without complications. Dosing downadjustment was needed in some patients who were switched over from SQ to IV prostacyclin analogs.

Topics: Adult; Antihypertensive Agents; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Retrospective Studies; Shock, Septic; Thromboembolism

Topics: Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Pulmonary Fibrosis; Ventricular Dysfunction, Right

Inhaled treprostinil represents an attractive alternative to the other available prostacyclin formulations by obviating the use of continuous infusions and its associated risks. Published evidence describing the process of transition from infusion prostacyclin therapy to inhaled treprostinil is limited. The purpose of this report is to describe an inpatient protocol for transitioning patients with pulmonary arterial hypertension (PAH) from intravenous (IV) or subcutaneous (SQ) prostacyclin therapy to inhaled treprostinil.. A retrospective case cohort study was performed evaluating medical records of three patients undergoing transition from IV/SQ continuous infusion prostacyclin therapy to inhaled treprostinil. The transition protocol and clinical data were collected prospectively.. Haemodynamics, six-min walk distance (6MWD), World Health Organization (WHO) functional class, modified Borg Dyspnea Score and brain natriuretic peptide prior to and after transition remained similar. All patients were receiving concomitant oral PAH medications prior to and after conversion. Adverse effects during the change were mild. No patients discontinued inhaled treprostinil following transition. At long-term follow-up, functional class remained stable at WHO functional class II or better. Patient 1 and Patient 3 demonstrated stable to modest improvement in 6MWD, whereas Patient 2 had a slight decrease in 6MWD. The transition to inhaled treprostinil from IV/SQ infusion prostacyclin therapy appears to be safe in carefully selected patients.. Our report describes a standard method used to transition patients from IV/SQ infusion prostacyclin to inhaled treprostinil.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Cohort Studies; Drug Administration Schedule; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Injections, Subcutaneous; Middle Aged; Retrospective Studies

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

Malignant atrophic papulosis (Köhlmeier-Degos disease; MAP) is an uncommon endotheliopathy with pathological findings similar to the vascular lesions of systemic sclerosis. These two disorders can overlap. When associated with visceral lesions, MAP has been considered almost universally and rapidly fatal. A recent report described dramatic response to treatment with eculizumab, but disease progression after initial response to therapy has occurred.. We describe the clinical and pathologic findings in two patients, one with MAP and the other with MAP like lesions, who received treatment with subcutaneous treprostinil. One patient had an overlap syndrome with features of systemic lupus erythematosus (SLE) and scleroderma and severe pulmonary hypertension. She also had very extensive MAP like cutaneous lesions. There was no evidence of central nervous system (CNS) disease and laparoscopy revealed no visible MAP lesions on the serosa of the small bowel. The second patient had experienced life-threatening disease progression despite ongoing eculizumab therapy. During this treatment, he had developed CNS and bladder involvement with neurologic symptoms and gross hematuria.. Patient one was placed on therapy with treprostinil for her pulmonary hypertension, but in the months subsequent to initiation of treatment, dramatic and complete resolution of cutaneous MAP like lesions and disabling digital pain occurred. In patient two, therapy with treprostinil was temporally associated with clearing of hematuria, resolution of CNS symptoms and improvement in MRI findings.. Treprostinil may offer a second effective treatment approach to individuals with MAP or "rescue therapy" to those in whom eculizumab treatment has failed to maintain suppression of disease activity.

Topics: Adolescent; Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Male; Malignant Atrophic Papulosis; Scleroderma, Systemic

Intravenous (IV) prostacyclin (epoprostanol) and its analogs (iloprost and treprostinil) are effective in treating pulmonary artery hypertension (PAH). Although prostacyclins are available for inhaled and subcutaneous delivery, IV administration of prostacyclins, sometimes in combination with other agents, such as bosentan or sildenafil, is considered the most aggressive method to manage PAH. This report attempts to help clinicians determine when to initiate IV treatment of PAH and when to refer a patient with PAH to a center for treatment. IV prostacyclin therapy initiation is suggested when patients exhibit World Health Organization functional class IV symptoms. The Registry to EValuate Early And Long-term Pulmonary Arterial Hypertension disease management (REVEAL) risk calculator can help determine a patient's 1-year mortality with PAH and characterize the clinical course, treatment, and predictors of outcomes in patients with PAH. Referring physicians can screen their patients for PAH and refer even before the diagnosis has been confirmed so that the center can facilitate the diagnostic process and provide suggestions for initial therapy selection and provide other collaborative and supportive services. Alternatively, the physician can diagnose and initiate early therapy with a plan to involve the pulmonary hypertension center at the need for IV therapy or consideration for transplantation, working closely with the patient to ensure stability. Physicians and pulmonary centers must develop good methods of communication to ensure effective diagnosis and management.

Topics: Disease Management; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Piperazines; Platelet Aggregation Inhibitors; Purines; Referral and Consultation; Sildenafil Citrate; Sulfones; Vasodilator Agents

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

The prostacyclin analogues, iloprost and treprostinil are extensively used in treating pulmonary hypertension. Their binding profile and corresponding biochemical cellular responses on human prostanoid receptors expressed in cell lines, have now been compared. Iloprost had high binding affinity for EP1 and IP receptors (Ki 1.1 and 3.9 nM, respectively), low affinity for FP, EP3 or EP4 receptors, and very low affinity for EP2, DP1 or TP receptors. By contrast, treprostinil had high affinity for the DP1, EP2 and IP receptors (Ki 4.4, 3.6 and 32 nM, respectively), low affinity for EP1 and EP4 receptors and even lower affinity for EP3, FP and TP receptors. In functional assays, iloprost had similar high activity in elevating cyclic AMP levels in cells expressing the human IP receptor and stimulating calcium influx in cells expressing EP1 receptors (EC50 0.37 and 0.3 nM, respectively) with the rank order of activity on the other receptors comparable to the binding assays. As with binding studies, treprostinil elevated cyclic AMP with a similar high potency in cells expressing DP1, IP and EP2 receptors (EC50 0.6, 1.9 and 6.2 nM, respectively), but had low activity at the other receptors. Activation of IP, DP1 and EP2 receptors, as with treprostinil, can all result in vasodilatation of human pulmonary arteries. However, activation of EP1 receptors can provoke vasoconstriction, and hence may offset the IP-receptor mediated vasodilator effects of iloprost. Treprostinil may therefore differ from iloprost in its overall beneficial pulmonary vasorelaxant profile and other pharmacological actions, especially in diseases where the IP receptor is down-regulated.

Topics: Antihypertensive Agents; Binding, Competitive; Calcium; Cell Culture Techniques; Cyclic AMP; Epoprostenol; HEK293 Cells; Humans; Hypertension, Pulmonary; Iloprost; Radioligand Assay; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Prostaglandin E, EP2 Subtype; Transfection

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

Pregnancy in patients with pulmonary arterial hypertension (PAH) is associated with a maternal mortality of 30-50% despite modern treatment modalities. The majority of maternal deaths in PAH patients occur either during labor and delivery or within 1 month postpartum. Cardiovascular collapse is attributed to a mismatch between the physiologic limitations of PAH and the changes that occur with pregnancy and delivery. In the Unites States, there is no consensus on the management of PAH in pregnancy. Several case reports have been published describing improved maternal-fetal outcomes, likely due to new advanced PH therapies, earlier diagnosis of PAH, and an adoption of a multidisciplinary treatment approach. We present five cases of gravid PAH patients successfully managed at our institution with a description of our standardized multidisciplinary treatment approach.

Topics: Adult; Algorithms; Anticoagulants; Antihypertensive Agents; Bosentan; Enoxaparin; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Postnatal Care; Pregnancy; Pregnancy Complications, Cardiovascular; Prenatal Care; Sulfonamides; Young Adult

Oral drugs have made the treatment of pulmonary hypertension (PH) feasible in non-expert centers, which could delay patient access to prostanoid therapy.. Fifty-seven consecutive patients with precapillary PH received a prostanoid in our center. Data at prostanoid initiation included modality of center referral, medical history, New York Heart Association [NYHA] class, exercise capacity, echocardiographic parameters, and hemodynamics.. Overall survival at 1, 2, and 3 years was 85%, 69%, 55%, respectively. Non-survivors had worse NYHA class III/IV (17/12) than survivors (27/1; p < 0.01) and exercise capacity on 6-minute-walk distance (254 ± 114 vs 354 ± 91 meters; p < 0.01). Non-survivors were more frequently referred on oral therapy (83% vs 36%; p < 0.01) and had a higher rate of urgent prostanoid treatment (69% vs 17%; p < 0.0001). Multivariate analysis (hazard ratio [95% confidence interval]) found the independent prognostic factors were urgent prostanoid therapy (2.0 [1.1-3.9]) and NYHA class (3.5 [1.5-8.2]). Survivors had a significant response to prostanoid, improving NYHA class from 2.8 ± 0.4 to 2.3 ± 0.5 (p = 0.002), 6-minute walk distance from 354 ± 91 to 426 ± 82 meters (p = 0.0001), and pulmonary hemodynamics (pulmonary artery pressure from 56 ± 13 to 44 ± 18 mm Hg [p < 0.05]; cardiac index from 2.0 ± 1.2 to 3.1 ± 1.2 liters/min/m(2) [p = 0.002], and pulmonary vascular resistance from 17 ± 10 to 8 ± 6 WU [p = 0.001]).. Referral of patients on oral treatment to a tertiary PH center is delayed and significantly affects prognosis.

Topics: Adult; Aged; Epoprostenol; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Prostaglandins; Referral and Consultation; Retrospective Studies; Survival Rate; Time Factors; Treatment Outcome

Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patient sub-sets, and study durations. In addition, common practice is to start oral therapies ahead of the more potent and titratable prostanoid therapies, despite advanced disease states at diagnosis. The objectives of our prospective registry were to evaluate long-term effects on functional class, 6-minute walking distance, hemodynamics, and survival, and also long-term tolerability of first-line sub-cutaneous treprostinil, a prostacyclin analog, in patients with severe pulmonary hypertension.. Data were collected from patients with functional class III/IV pre-capillary pulmonary hypertension (Dana Point groups 1 and 4; mean right arterial pressure ≥ 10 mmHg, and/or cardiac index ≤ 2.2 liters/min/m(2)). Treprostinil dose adjustments were driven by clinical symptoms and side effects.. The study included 111 patients (1999 to 2010). Of these, 13 (12%) stopped treatment prematurely because of drug side effects, 11 (9.9%) underwent double lung transplantation, and 49 (44.1%) died of any cause (41 on treatment, 8 after early drug discontinuation). Overall survival rates at 1, 5, and 9 years were 84%, 53%, and 33%. In patients who were able to tolerate treatment > 6 months, survival rates were 57% at 9 years.. First-line treatment of severe pre-capillary pulmonary hypertension with sub-cutaneous treprostinil is safe and efficacious over many years. If up-titration beyond 6 months is tolerated, effective doses are reached and outcomes are good.

Topics: Adult; Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Longitudinal Studies; Male; Middle Aged; Patient Safety; Prospective Studies; Registries; Retrospective Studies; Severity of Illness Index; Survival Rate; Treatment Outcome

Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.. Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline.. CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%).. Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antihypertensive Agents; Dose-Response Relationship, Drug; Epoprostenol; Female; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Monocrotaline; Nitroprusside; Piperazines; Pulmonary Artery; Purines; Rats; Sildenafil Citrate; Smooth Muscle Myosins; Sulfones; Swine; Vascular Resistance; Vasoconstriction; Vasodilator Agents

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

To evaluate the rate of and potential risk factors for bloodstream infections (BSIs) using data from the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension [PAH] Disease Management) REGISTRY(®), which provides current information about patients with PAH.. Patients were enrolled from March 30, 2006, through December 8, 2009, and data on reported BSIs were collected through the third quarter of 2010. Bloodstream infection rates were calculated per 1000 patient-days of risk.. Of 3518 patients enrolled, 1146 patients received intravenous (IV) prostanoid therapy for more than 1 day (no BSI, n=1023; ≥1 BSI, n=123; total BSI episodes, n=166). Bloodstream infections rates were significantly increased in patients receiving IV treprostinil vs IV epoprostenol (0.36 vs 0.12 per 1000 treatment days; P<.001), primarily due to gram-negative organisms (0.20 vs 0.03 per 1000 treatment days; P<.001). Multivariate analysis adjusting for age, causes of PAH, and year of BSI found that treatment with IV treprostinil was associated with a 3.08-fold increase (95% confidence interval, 2.05-4.62; P<.001) in BSIs of any type and a 6.86-fold increase (95% confidence interval, 3.60-13.07; P<.001) in gram-negative BSIs compared with treatment with IV epoprostenol.. Compared with IV epoprostenol therapy, treatment with IV treprostinil is associated with a significantly higher rate of gram-negative BSIs; observed differences in BSI rate did not seem to be due to any other analyzed factors.. clinicaltrials.gov Identifier: NCT00370214.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Bacteremia; Chi-Square Distribution; Child; Cross Infection; Epoprostenol; Female; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Middle Aged; Prostaglandins; Registries; Risk Factors; Survival Rate; United States

{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI(2) analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP(3) receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP(3) receptor antagonist (2E)-3-(3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP(3) receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.

Topics: Acetamides; Acetates; Alprostadil; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Epoprostenol; Hypertension, Pulmonary; In Vitro Techniques; Male; Pulmonary Artery; Pyrazines; Rats; Rats, Wistar; Receptors, Epoprostenol; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Benzamides; Drug Therapy, Combination; Early Medical Intervention; Epoprostenol; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Piperazines; Pyrazines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

Topics: Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoprostenol; Equipment Design; Equipment Safety; Follow-Up Studies; Germany; Humans; Hypertension, Pulmonary; Infusion Pumps, Implantable; Infusions, Intravenous; Middle Aged; Prostaglandins; Sampling Studies; Severity of Illness Index; Treatment Outcome

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

To evaluate the efficacy and tolerability of subcutaneous (SC) treprostinil, a prostacyclin analogue, in young children with refractory pulmonary arterial hypertension.. Eight children (median age, 4 years) received SC treprostinil therapy after failure of combined oral treatment (n = 7) or because of severe complications with intravenous epoprostenol (n = 1). Treprostinil was delivered through an SC catheter at gradually increasing doses to an average of 40 ng/kg/min, depending on the presence of adverse effects.. Seven patients demonstrated early significant improvement (in functional class, hemodynamics, and/or 6-minute walk distance; P <.05), and 6 had a sustained good response. Site pain could be effectively managed in all but one child.. Treprostinil may be a potentially valuable rescue therapy in children with refractory pulmonary arterial hypertension, but further study in a larger number of patients is needed.

Topics: Antihypertensive Agents; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Infusions, Subcutaneous; Treatment Outcome

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

We describe the case of a 37-year-old female with severe pulmonary hypertension on intravenous Remodulin and Tracleer who experienced presyncope following a six-minute walk. A transthoracic echocardiogram, in addition to showing the usual findings of chronic pulmonary hypertension, also demonstrated a noticeable increase in both mitral annular systolic and early diastolic (E') velocities while performing the Valsalva maneuver. Most importantly, a significant increase in the propagation velocity to an almost perpendicular tilt was noted with Valsalva, resembling the propagation velocity profile that has only been previously described in cases of constrictive pericarditis. The clinical relevance of this finding and the pathophysiologic implications are reviewed and discussed.

Topics: Adult; Antihypertensive Agents; Bosentan; Constriction, Pathologic; Epoprostenol; Exercise Test; Female; Humans; Hypertension, Pulmonary; Sulfonamides; Ultrasonography; Valsalva Maneuver

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

Topics: Antihypertensive Agents; Bosentan; Epoprostenol; Humans; Hypertension, Pulmonary; Sulfonamides; Treatment Outcome

Epoprostenol and treprostinil are intravenous prostacyclin medications used to treat pulmonary arterial hypertension (PAH). This survey explored hospital policies regarding prostacyclin infusions, and investigated the type and frequency of errors that occurred in the inpatient setting.. Information on prostacyclin infusion policies and inpatient errors was obtained through detailed interviews with 18 PAH nurses, and through an electronic survey completed by 97 PAH clinicians.. The electronic survey respondents reported wide variability in prostacyclin infusion policies, including variability in the use of home vs hospital infusion pumps, and variability in the use and storage of back-up epoprostenol and treprostinil. Serious or potentially serious errors in medication administration were reported by 68% of survey respondents. The most common error types (reported by >or=25%), included: incorrect cassette placed in the pump; inaccurate pump programming; errant drug dosing; and inadvertent cessation of the pump. Nine errors, all at different centers, were believed to have contributed to patient death. In the separate interviews with the PAH nurses, 94% reported serious errors. These errors prompted many of the centers to implement policy changes in an attempt to reduce future errors, improve safety and optimize patient outcomes.. These findings suggest that prostacyclin infusion therapy is problematic and that an opportunity exists to improve safety. The development of standardized treatment guidelines should be considered.

Topics: Antihypertensive Agents; Data Collection; Epoprostenol; Humans; Hypertension, Pulmonary; Incidence; Inpatients; Interviews as Topic; Medication Errors; Policy; United States

Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH). Mutations lead to reduced Smad1/5-driven expression of inhibitor of DNA binding protein 1 (Id1) and loss of the growth suppressive effects of BMPs. The impact of existing PAH therapies on BMP signaling is lacking.. Because prostacyclin analogues are effective treatments for clinical PAH, we hypothesized that these agents enhance Smad1/Id1 signaling.. Iloprost alone induced Id1 expression in human pulmonary artery smooth muscle cells (PASMCs), an effect that was independent of Smad1/5 activation but dependent on a cAMP-responsive element in the Id1 promoter. In addition, iloprost and treprostinil enhanced BMP-induced phosphorylation of Smad1/5 and Id1 expression in a cAMP-dependent manner. The mechanism involved suppression of inhibitory Smad, Smad6. Furthermore, iloprost rescued the deficit in Smad1/5 phosphorylation and Id gene expression in PASMCs harboring mutations in BMPR-II and restored growth suppression to BMP4 in mutant PASMCs. We confirmed a critical role for Id1 in PASMC proliferation. Reduced expression of Id1 was observed in concentric intimal lesions of heritable PAH cases. In the monocrotaline rat model of PAH, associated with reduced BMPR-II expression, we confirmed that treprostinil inhibited smooth muscle cell proliferation and prevented progression of PAH while enhancing Smad1/5 phosphorylation and Id1 gene expression.. Prostacyclin analogues enhance Id1 expression in vitro and in vivo and restore deficient BMP signaling in BMPR-II mutant PASMCs.

Topics: Animals; Antihypertensive Agents; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type II; Cell Proliferation; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Inhibitor of Differentiation Protein 1; Male; Monocrotaline; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Phosphorylation; Promoter Regions, Genetic; Pulmonary Artery; Rats; Rats, Sprague-Dawley; RNA Interference; Smad Proteins; Smad1 Protein; Smad5 Protein; Smad6 Protein; Transfection; Up-Regulation

A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as "circulating fibrocytes". These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes. The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population. To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy. In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Blood Circulation; Blood Vessels; Bone Marrow Cells; Chimerism; Chronic Disease; Epoprostenol; Female; Fibroblasts; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Leukocytes, Mononuclear; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Pulmonary Artery

Prostacyclin analogs, used to treat idiopathic pulmonary arterial hypertension (IPAH), are assumed to work through prostacyclin (IP) receptors linked to cyclic AMP (cAMP) generation, although the potential to signal through peroxisome proliferator-activated receptor-γ (PPARγ) exists.. IP receptor and PPARγ expression may be depressed in IPAH. We wished to determine if pathways remain functional and if analogs continue to inhibit smooth muscle proliferation.. We used Western blotting to determine IP receptor expression in peripheral pulmonary arterial smooth muscle cells (PASMCs) from normal and IPAH lungs and immunohistochemistry to evaluate IP receptor and PPARγ expression in distal arteries.. Cell proliferation and cAMP assays assessed analog responses in human and mouse PASMCs and HEK-293 cells. Proliferative rates of IPAH cells were greater than normal human PASMCs. IP receptor protein levels were lower in PASMCs from patients with IPAH, but treprostinil reduced replication and treprostinil-induced cAMP elevation appeared normal. Responses to prostacyclin analogs were largely dependent on the IP receptor and cAMP in normal PASMCs, although in IP(-/-) receptor cells analogs inhibited growth in a cAMP-independent, PPARγ-dependent manner. In IPAH cells, antiproliferative responses to analogs were insensitive to IP receptor or adenylyl cyclase antagonists but were potentiated by a PPARγ agonist and inhibited (∼ 60%) by the PPARγ antagonist GW9662. This coincided with increased PPARγ expression in the medial layer of acinar arteries.. The antiproliferative effects of prostacyclin analogs are preserved in IPAH despite IP receptor down-regulation and abnormal coupling. PPARγ may represent a previously unrecognized pathway by which these agents inhibit smooth muscle proliferation.

Topics: Animals; Antihypertensive Agents; Blotting, Western; Cell Proliferation; Down-Regulation; Epoprostenol; HEK293 Cells; Humans; Hypertension, Pulmonary; Iloprost; Immunohistochemistry; Mice; Muscle, Smooth, Vascular; PPAR gamma; Prostaglandins, Synthetic; Receptors, Epoprostenol; Rosiglitazone; Thiazolidinediones; Vasodilator Agents

Treprostinil, which is available for subcutaneous (SC) and intravenous (IV) administration, has demonstrated efficacy in increasing exercise capacity, reducing signs and symptoms of pulmonary arterial hypertension (PAH), and improving cardiopulmonary hemodynamics in patients with PAH; however, the infusion site pain commonly experienced with SC treprostinil has limited its use. Prospective and observational clinical studies have shown that the dose of SC treprostinil can be escalated at a higher rate than described in early clinical trials to achieve symptom relief, in part because of favorable tolerability of treatment and the apparent dose independence of site pain. In addition, pain management protocols that include non-pharmacologic and pharmacologic (i.e., topical and systemic) approaches provide analgesic relief from infusion site pain. With experience, physicians and patients have recognized that some infusion sites are better than others, and the frequency of site rotation can be reduced to improve tolerability. Dosing to achieve rapid onset of efficacy and proactively managing infusion site pain enhance the likelihood for a patient with PAH to maintain and derive benefit from SC treprostinil therapy.

Topics: Antihypertensive Agents; Biological Availability; Dose-Response Relationship, Drug; Epoprostenol; Humans; Hypertension, Pulmonary; Infusions, Subcutaneous; Pain

It has been widely accepted that development of porto-pulmonary hypertension (POPH) is independent of the cause of portal hypertension. The degree of hepatic damage and liver function do not correlate with predisposition to POPH or its severity. However, portal hypertension has been confirmed as a prerequisite for developing pulmonary hypertension. Transthoracic echocardiography is the best screening test for the presence of POPH, but a diagnosis of POPH can be established only by right heart catheterization. Randomized controlled trials comparing the efficacy and safety of different pharmacologic strategies are lacking in patients with POPH. The general management includes diuretics and oxygen supplementation. Notably, moderate to severe POPH predisposes candidates for orthotopic liver transplantation to a higher risk of perioperative mortality. Vasomodulating pharmacologic agents are used in patients with moderate to severe POPH to decrease pulmonary arterial hypertension, thereby permitting liver transplantation to be performed safely. Epo-prostenol is the best-studied medication, and bosentan appears promising.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Epoprostenol; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Transplantation; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Treprostinil is a prostacyclin analog and has been used on idiopathic pulmonary arterial hypertension (PAH). There is only limited clinical experience using treprostinil to manage PAH in patients with end-stage liver disease (ESLD). We report three ESLD patients with PAH, who were treated with continuous intravenous treprostinil. A 59-year-old woman with ESLD secondary to alcoholic hepatitis had portopulmonary hypertension with mean pulmonary arterial pressure (mPAP) of 44 mmHg and transpulmonary gradient (TPG) of 23 mmHg. Treprostinil at 45 ng/kg/min for 6 months decreased mPAP to 23 (TPG to 8). A 53-year-old man had ESLD secondary to alcoholic hepatitis with PAH caused by multiple pulmonary embolisms (mPAP of 32 and TPG of 23). Treprostinil at 36 ng/kg/min for 3 months decreased mPAP to 23 and TPG to 14. Both patients underwent uneventful liver transplantation. A 48-year-old man had ESLD secondary to hepatitis C and portopulmonary hypertension with mPAP of 60 and TPG of 44. Two years after intravenous treprostinil at 106 ng/kg/min, his mPAP decreased to 44 and TPG to 30. These results demonstrate that for a selected group of ESLD patients with PAH, a continuous intravenous infusion of treprostinil appears to be safe and effective.

Topics: Antihypertensive Agents; Epoprostenol; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Liver Failure; Male; Middle Aged

The aim of our study was to describe the efficacy of addition of intravenous or subscutaneous prostanoids in idiopathic pulmonary arterial hypertension (PAH) patients deteriorating on bosentan or on bosentan-sildenafil.. PAH treatment at our hospital is standardized with first-line oral therapy in New York Heart Association class III patients followed by addition of prostanoids on clinical worsening.. Mean improvement in 6-minute walk distance after 4 months of prostanoids was 86 m (p < 0.01) in the bosentan group versus 41 m (p < 0.05) in the bosentan-sildenafil group, and these improvements persisted at long-term follow-up.. From these results we conclude that addition of subcutaneous or intravenous prostanoids can be efficacious in PAH deteriorating on oral therapy.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

This case study reports the effects of a treprostinil accidental overdose in a patient with pulmonary hypertension. Treprostinil is labeled for treatment of pulmonary hypertension with New York Heart Association (NYHA) Class II, III and IV symptoms. It is characterized as a long-acting prostacyclin analog that can be delivered by intravenous or subcutaneous continuous infusions. This pediatric case report describes a massive overdose without significant side effects, thus suggesting a beneficial therapeutic index in pediatric patients.

Topics: Antihypertensive Agents; Child; Drug Overdose; Epoprostenol; Female; Humans; Hypertension, Pulmonary

Intravenous prostanoids (epoprostenol and treprostinil) are effective therapies for pulmonary arterial hypertension but carry a risk of catheter-related bloodstream infection (CR-BSI). Prevention of CR-BSI during long-term use of indwelling central venous catheters is important.. To evaluate whether using a closed-hub system and waterproofing catheter hub connections reduces the rate of CR-BSI per 1,000 catheter-days.. Single-center open observational study (January 2003-December 2008).. Pediatric patients with pulmonary arterial hypertension who received intravenous prostanoids.. In July 2007, CR-BSI preventive measures were implemented, including the use of a closed-hub system and the waterproofing of catheter hub connections during showering. Rates of CR-BSI before and after implementing preventive measures were compared with respect to medication administered and type of bacterial infection.. Fifty patients received intravenous prostanoid therapy for a total of 41,840 catheter-days. The rate of CR-BSI during the study period was 0.51 infections per 1,000 catheter-days for epoprostenol and 1.38 infections per 1,000 catheter-days for treprostinil, which differed significantly (P < .01). CR-BSIs caused by gram-negative pathogens occurred more frequently with treprostinil than with epoprostenol (0.91 infections per 1,000 catheter-days vs 0.08 infections per 1,000 catheter-days; P < .01). Patients treated with treprostinil after the implemented changes had a significant decrease in CR-BSI rate (1.95 infections per 1,000 catheter-days vs 0.19 infections per 1,000 catheter-days; P < .01).. The closed-hub system and the maintenance of dry catheter hub connections significantly reduced the incidence of CR-BSI (particularly infections caused by gram-negative pathogens) in patients receiving intravenous treprostinil.

Topics: Antihypertensive Agents; Bacteremia; Catheterization, Central Venous; Catheters, Indwelling; Epoprostenol; Equipment Contamination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Hypertension, Pulmonary; Incidence; Infusions, Intravenous; Risk Reduction Behavior

The available therapies and prognosis of idiopathic pulmonary fibrosis remain relatively poor, and concurrent pulmonary hypertension further increases the risk of death and complications after lung transplantation. Limited data exist for the treatment of pulmonary hypertension associated with idiopathic pulmonary fibrosis. We describe a case where intravenous treprostinil was used to bridge an elderly patient with idiopathic pulmonary fibrosis with severe pulmonary hypertension to successful single-lung transplantation.

Topics: Aged; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Lung Transplantation; Piperazines; Purines; Sildenafil Citrate; Spirometry; Sulfones; Tomography, X-Ray Computed; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a severely disabling disorder characterized by sustained elevations of pulmonary vascular resistance, ultimately leading to right-heart failure and death. Intravenous epoprostenol has been widely used in patients with PAH, leading to long-term clinical benefits and improved survival. Epoprostenol has to be delivered through a permanently implanted intravenous catheter, with the potential of life-threatening complications. Thus, treprostinil, a stable prostacyclin analog suitable for subcutaneous administration, has been developed. Treprostinil is chemically stable at room temperature, has a long half-life (2-4 hours), and has similar pharmacologic properties with comparable hemodynamic effects as epoprostenol.A large, double-blind, placebo-controlled, multicenter, 12-week study confirmed the efficacy of subcutaneous treprostinil, by improving exercise capacity, Borg Dypnea Score (BDS), New York Heart Association (NYHA) class, and clinical signs and symptoms in patients with PAH. Subsequently, multiple observational studies reported the long-term effects of subcutaneous treprostinil. The long-term survival of patients treated with subcutaneous treprostinil was similar to that reported with intravenous epoprostenol. Pain at the infusion site has been a major drawback of subcutaneous treprostinil, hampering dose titration and leading to an 8-10% discontinuation rate. In addition, studies have examined the efficacy of intravenous treprostinil in the treatment of patients with PAH. An open-label study demonstrated that intravenous treprostinil improved exercise capacity, BDS, NYHA functional class, and hemodynamics at week 12 compared with baseline. Transitioning from intravenous epoprostenol to intravenous treprostinil is safe and effective. The dose of intravenous treprostinil has to be adjusted to approximately twice the dose of intravenous epoprostenol. Most patients have reported less severe adverse effects with intravenous treprostinil compared with intravenous epoprostenol. The assessment of the long-term efficacy and safety of continuous intravenous treprostinil requires further studies.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Epoprostenol; Humans; Hypertension, Pulmonary; Injections, Intravenous; Injections, Subcutaneous; Survival Rate

Long-term follow-up after transition to oral agents from parenteral prostanoid therapy has not been well characterized.. We reviewed our long-term experience after oral transitioning in patients with pulmonary hypertension. Patients were weaned off parenteral therapy based on a pre-determined outpatient protocol. Data were collected retrospectively after transition had taken place.. Twenty-one transitioned patients were identified. Fifteen patients (71.4%) were successfully transitioned (ST): 7 to bosentan, 5 to bosentan and sildenafil, and 3 to sildenafil. Six patients failed transition (FT). None of the patients in the FT group received sildenafil. Prior to transition attempt, patients in the ST group were treated with parenteral agents for a mean of 26 months vs. 16 months in the FT group (p=0.12). Maximal epoprostenol dose was low in both groups (ST 17.8 ng/kg/min vs. FT 14.5 ng/kg/min). Mean duration of oral therapy prior to transition was 11 months. After a mean follow-up of 24 months, most patients on both groups were able to maintain stable 6 min walk distance and hemodynamics. FT was not associated with short- or long-term adverse events.. Oral transition from parenteral prostanoid agents can be safely done in a selected group of patients. Most patients are able to maintain stable functional class and hemodynamics at long follow up regardless of success of transition attempt. Combination therapy with sildenafil appears to be associated with higher likelihood of successful transitioning.

Topics: Administration, Oral; Adult; Aged; Antihypertensive Agents; Bosentan; Chi-Square Distribution; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Parenteral; Male; Middle Aged; Piperazines; Prostaglandins; Purines; Retrospective Studies; Sildenafil Citrate; Statistics, Nonparametric; Sulfonamides; Sulfones; Treatment Outcome

We present a case of a 77-year-old female with distal chronic thromboembolic pulmonary hypertension. Diagnostic and therapeutic difficulties are discussed. Clinical and haemodynamic benefits resulting from treprostinil therapy added to continuous anticoagulation are shown.

Topics: Aged; Antihypertensive Agents; Chronic Disease; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Treatment Outcome

Treprostinil, a long-acting prostacyclin analog, diminished the symptoms of pulmonary arterial hypertension (PAH) in controlled 12-week clinical efficacy studies. This retrospective, single-center, open-label study was designed to assess the efficacy of long-term, subcutaneously administered, treprostinil-based therapy alone or in combination with bosentan for the treatment of moderate-to-severe PAH.. Thirty-eight patients with pulmonary hypertension treated with subcutaneous treprostinil were followed up for a mean (+/-SD) duration of 984+/-468 days (range, 165 to 1,847 days). Oral bosentan was added to the treprostinil regimen if patients remained in New York Heart Association (NYHA) functional class III or II with intolerable prostacyclin side effects that limited therapy. Hemodynamic studies, Borg dyspnea score evaluations, 6-min walk (6MW) tests, and NYHA functional class determinations were performed at approximately 6-month intervals.. Mean pulmonary artery pressure decreased from 59.7 to 50.5 mm Hg (p<0.001). Significant and sustained improvement in 6MW distance (p=0.022) and Borg dyspnea score (p=0.023) were observed. At the final observation, the mean dose of treprostinil was 37.8 ng/kg/min (range, 7.5 to 115 ng/kg/min). At baseline, 5% of patients were in NYHA functional class 2 or lower vs 58% at the last follow-up. Bosentan was added to the regimens of 19 patients. In those patients, significant additional improvement occurred in the pulmonary arterial pressure (p<0.001), 6MW distance (p=0.001), and Borg dyspnea scale (p=0.020) compared to baseline.. Long-term treatment with subcutaneous treprostinil-based therapy improved functional parameters and hemodynamics in patients with moderate-to-severe PAH. In patients requiring combination therapy, the addition of oral bosentan to treprostinil-based therapy was safe, well-tolerated, and associated with further clinical improvements.

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Blood Pressure; Bosentan; Drug Therapy, Combination; Dyspnea; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Sulfonamides

In September 2006, the Centers for Disease Control and Prevention was notified of cases of gram-negative bloodstream infection (BSI) occurring among outpatients who received an intravenous formulation of the prostanoid treprostinil. An investigation was conducted to determine rates of prostanoid-associated BSI in this patient population and possible risk factors for infection.. We performed a retrospective cohort study of patients who had received intravenous formulations of at least 1 of the 2 approved prostanoids (epoprostenol and treprostinil) from January 1, 2004, through late 2006. Chart reviews were conducted at 2 large centers for pulmonary arterial hypertension, and a survey of infection control practices was conducted at 1 center.. A total of 224 patients were given intravenous prostanoid treatment, corresponding to 146,093 treatment-days during the study period. Overall, there were 0.55 cases of BSI and 0.18 cases of BSI due to gram-negative organisms per 1,000 treatment-days. BSI rates were higher for patients who received intravenous treprostinil than for patients who received intravenous epoprostenol (1.13 vs. 0.42 BSIs per 1,000 treatment-days; P < .001), as were rates of BSI due to gram-negative organisms (0.81 vs. 0.04 BSIs per 1,000 treatment-days; P < .001). Adjusted hazard ratios for all BSIs and for BSIs due to gram-negative organisms were higher among patients given treatment with intravenous treprostinil. The survey identified no significant differences in medication-related infection control practices.. At 2 centers, BSI due to gram-negative pathogens was more common than previously reported and was more frequent among patients given treatment with intravenous treprostinil than among patients given treatment with intravenous epoprostenol. Whether similar results would be found at other centers for pulmonary arterial hypertension warrants further investigation. This investigation underscores the importance of surveillance and evaluation of healthcare-related adverse events in patients given treatment primarily as outpatients.

Topics: Adolescent; Adult; Antihypertensive Agents; Bacteremia; Catheters, Indwelling; Centers for Disease Control and Prevention, U.S.; Cohort Studies; Cross Infection; Epoprostenol; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Home Infusion Therapy; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Proportional Hazards Models; Prostaglandins; Retrospective Studies; Risk Factors; Surveys and Questionnaires; United States

Intravenous epoprostenol was the first agent approved by the United States Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). However, epoprostenol therapy carries the risks of a short half-life (<6 minutes) and side effects, including jaw pain, flushing, and headache. Recently, intravenous treprostinil has been studied, primarily in adults with PAH, and found to provide effective therapy. The effects of continuous intravenous treprostinil were retrospectively evaluated in 13 children with stable PAH who had been treated with epoprostenol for >1 year. Children were transitioned in the hospital over 24 hours using a rapid or slow strategy. The children were a mean age of 11 years (range 3 to 17) and were transitioned to treprostinil from August 2004 to August 2005. The baseline 6-minute walking distance was on average 516 +/- 115 m (n = 9) and did not change after transition. Patients were treated with treprostinil for 1.1 +/- 0.5 years. There were 2 deaths, and 2 patients transitioned to other therapy. Seven patients experienced > or =1 central-line infection. Despite a higher dose of treprostinil, the side effects were subjectively diminished. In conclusion, treprostinil provides an alternative therapy in children with PAH, with fewer side effects. However, evaluation regarding rates of infection requires further exploration.

Topics: Adolescent; Antihypertensive Agents; Child; Child, Preschool; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Male; Retrospective Studies; Treatment Outcome

Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by elevated pulmonary artery pressure and pulmonary vascular resistance. Continuous infusion of a prostanoid, which acts as a vasodilator and anti-proliferative agent, is indicated in the treatment of patients with severe PAH. Two prostanoids are approved for intravenous (IV) use in the United States: epoprostenol (epoprostenol sodium [brand name Flolan], Gilead, Foster City, California) and treprostinil (treprostinil sodium [brand name Remodulin], United Therapeutics, Silver Spring, Maryland). These drugs are administered to PAH patients at hundreds of treatment centers in the United States. In September 2006, CDC received a report from a PAH specialist of a suspected increase in the number of gram-negative bloodstream infections (BSIs) among PAH patients treated with IV treprostinil. CDC conducted a retrospective investigation with the assistance of several state health departments and the cooperation of seven PAH treatment centers to determine the relative rates of BSI in a sample of patients treated with IV treprostinil and IV epoprostenol during 2003--2006. This report describes the results of that investigation, which indicated that, based on combined data from seven separate PAH treatment centers, pooled mean rates of BSI (primarily gram-negative BSI) were significantly higher for patients on treprostinil than for those on epoprostenol. The results do not suggest intrinsic contamination of IV treprostinil as a cause of the infections; the difference in rates might have been caused by differences in preparation and storage of the two agents, differences in catheter care practices, or differences in the anti-inflammatory activity of the agents. Health-care providers who care for PAH patients should be aware of these findings. Further investigation is needed to determine the causes of the different infection rates at centers where this was observed and to determine whether such a difference exists in other PAH treatment centers.

Topics: Antihypertensive Agents; Catheters, Indwelling; Drug Contamination; Epoprostenol; Humans; Hypertension, Pulmonary; Infection Control; Infusions, Intravenous; Sepsis; United States

Topics: Administration, Intranasal; Administration, Oral; Animals; Bosentan; Drug Evaluation, Preclinical; Endothelin A Receptor Antagonists; Epoprostenol; Forecasting; Humans; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Isoxazoles; Life Expectancy; Lung Transplantation; Monocrotaline; Piperazines; Platelet-Derived Growth Factor; Purines; Randomized Controlled Trials as Topic; Rats; Sheep; Sildenafil Citrate; Sulfonamides; Sulfones; Thiophenes; Vasodilator Agents

Hereditary hemorrhagic telangiectasia (HHT) may be associated with pulmonary hypertension (PH). In the context that little attention has been given to long-term follow-up of such individuals, we report a patient with PH associated with HHT with special attention to clinical features and long-term response to therapy. To our knowledge, this case represents only the second with a 10-year follow-up reported and demonstrates that aggressive therapy can lead to long-term improvement in clinical parameters and survival.

Topics: Adult; Antihypertensive Agents; Cardiac Catheterization; Disease Progression; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Pulmonary Wedge Pressure; Respiratory Function Tests; Telangiectasia, Hereditary Hemorrhagic; Time Factors

Pulmonary arterial hypertension (PAH) is a serious primary illness of the pulmonary arterioles, characterised by progressive precapillary pulmonary hypertension. The conventional therapy for this condition is so-called specific pharmacotherapy, which addresses the key mechanisms in the pathophysiology of the illness, making use of drugs from the prostanoid group, endothelin receptor antagonists and phosphodiesterase inhibitors. Treprostinil is a stable analogue of prostacyclin, which can be administered subcutaneously, intravenously or by inhalation.. In the centre for pulmonary hypertension in the Second Internal Clinic of Cardiology and Angiology of 1st Faculty of Medicine, Charles University, and the General Teaching Hospital in Prague, 22 patients with PAH (idiopathic PAH, familial PAH, PAH associated with congenital heart disease and PAH associated with systemic connective tissue disease) were treated with trerpostinil, 18 patients with a continuous subcutaneous infusion and 4 patients with a continuous intravenous infusion. The indicators followed were the distance reached in a 6-minute walking test, functional capacity assessed by NYHA classification and mortality.. The patients for whom treprostinil treatment was indicated had an average pressure in the right atrium of 11.9 +/- 4.2 mm Hg, average pressure in the pulmonary artery of 56.8 +/- 10.7 mm Hg, a cardiac index of 1.78 +/- 0.25 l/min/m2 and a total pulmonary resistance of 16.26 +/- 4.48 WU. 15 patients were functionally NYHA III and 7 patients were NYHA IV. The average distance achieved in a 6-minute walk test before the start of treatment was 326 +/- 83 m. When treated with gradually increasing doses of treprostinil the distance achieved in the 6-minute walk test improved. After 6 months, the group that received subcutaneous treatment had extended their distance to 359 m, after 12 months it was 393 m, after 24 months 447 m and after 36 months 494 m. After 6 months, the group that received intravenous treatment had extended their distance to 473 m, which increased to 451 m after 12 months and 489 m after 24 months. Functional capacity also improved. In total 5 patients were unable to tolerate the subcutaneous infusion, of whom 3 were placed on intravenous treprostinil and 2 on oral bosentan. 7 of the patients died in the period examined (31.8%).. Treprostinil improves symptoms and hemodynamics for PAH patients and reduces mortality.

Topics: Adult; Aged; Antihypertensive Agents; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Infusion Pumps; Infusions, Intravenous; Male; Middle Aged; Pulmonary Circulation

Topics: Antihypertensive Agents; Drug Administration Schedule; Epoprostenol; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Injections, Subcutaneous; Research Design; Risk Assessment

Significant advances have been achieved over the past few decades regarding comprehension of the pathogenesis of pulmonary arterial hypertension (PAH). The development of new agents and use of existing drug therapies have targeted the underlying abnormalities and pathways leading to progression of PAH. Milrinone, a phosphodiesterase inhibitor, remains a therapeutic option. Unfortunately, intravenous administration of the drug in patients with PAH may be limited by systemic hypotension, especially in those already receiving prostanoid treatment. We describe a 42-year-old woman with acute decompensated idiopathic PAH who was given nebulized milrinone as a novel adjunctive therapy. She was acutely treated with intravenous treprostinil 2 ng/kg/minute and inhaled nitric oxide 20 ppm. However, increasing the treprostinil infusion rate or adding other therapies such as intravenous milrinone for acute symptomatic relief was limited by her hemodynamic instability, which required treatment with dobutamine, vasopressin, and epinephrine. Nebulized milrinone was added as salvage therapy for her acute PAH crisis. After 8 days of therapy, the patient's PAH symptoms improved without compromising her mean arterial pressure and heart rate. Nebulized milrinone in addition to inhaled nitric oxide and low-dose intravenous treprostinil may have played a major role in the acute management of her PAH crisis. Further studies are needed to assess the role of nebulized milrinone in patients with PAH.

Topics: Acute Disease; Administration, Inhalation; Adult; Antihypertensive Agents; Blood Pressure; Bronchodilator Agents; Drug Therapy, Combination; Epoprostenol; Female; Heart Rate; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Milrinone; Nebulizers and Vaporizers; Nitric Oxide; Phosphodiesterase Inhibitors; Salvage Therapy

To measure survival, haemodynamic function and functional class in patients with systemic sclerosis associated pulmonary arterial hypertension (SSc-PAH) in two treatment eras.. Six year longitudinal study of 92 consecutive patients with SSc-PAH diagnosed by cardiac catheterisation. Data were collected both prospectively and retrospectively. Patients were given basic treatment (diuretics, digoxin, oxygen and warfarin). Where clinically indicated, a prostanoid was used as advanced treatment (historical control group). From 2002, the range of treatments available expanded to include bosentan, which was generally the preferred treatment (current treatment era group). Survival was measured from the date of diagnosis of pulmonary hypertension by cardiac catheterisation. Six minute walking distance and haemodynamic function were measured at the time of diagnosis and at least one month after treatment was started.. The historical control group comprised 47 patients, all of whom received basic treatment; 27 of these were also treated with prostanoids. The current treatment era group comprised 45 patients, all of whom received bosentan as preferred treatment. Kaplan-Meier survival in the historical control group was 68% at one year and 47% at two years. Survival in the current treatment era group was 81% and 71% (p = 0.016) at one and two years, respectively. Pulmonary vascular resistance increased in the historical control group (by 147 dyn.s.cm(-5)), whereas in the current treatment era group, it remained stable over an average of nine months (decrease of 16 dyn x s x cm(-5), p < 0.006).. Survival of selected patients with SSc-PAH has improved in the current treatment era. In contrast to patients treated historically with basic drugs and prostanoids, patients treated in the current treatment era had improved survival associated with a lack of deterioration in cardiac haemodynamic function.

Topics: Antihypertensive Agents; Bosentan; Epoprostenol; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prognosis; Prostaglandins; Scleroderma, Systemic; Sulfonamides; Survival Analysis; Vasodilator Agents

Topics: Administration, Inhalation; Bronchodilator Agents; Drug Therapy, Combination; Epoprostenol; Humans; Hypertension, Pulmonary; Nitric Oxide; Vasodilator Agents

Topics: Antihypertensive Agents; Drug Labeling; Epoprostenol; Humans; Hypertension, Pulmonary; Information Storage and Retrieval; Infusions, Intravenous; Severity of Illness Index

Beneficial effects of treprostinil, a stable prostacyclin analogue, were demonstrated in patients with pulmonary arterial hypertension (PAH). Although regression of pulmonary vascular remodeling has been suggested as therapeutic mechanism, its mode of action remains unknown.. Flow-associated PAH was created in rats by injection of monocrotaline (60 mg/kg) combined with an abdominal aortocaval shunt. Subsequently, rats were treated with subcutaneous treprostinil (50 ng/kg/min, treated; n = 8) or saline (untreated; n = 9). A control group underwent sham-surgery (n = 8). Animals were sacrificed at symptoms of cardiac failure, together with their matched controls.. Dyspnea and weight loss determined the moment of sacrifice in 8/9 untreated animals (89%) versus in one of eight treated animals (13%; log-rank test survival curves; P = 0.02). Mean pulmonary arterial pressure increased in the model (42 +/- 2 mm Hg in untreated vs. 18 +/- 1 in controls; P < 0.01) and decreased by 8 mm Hg after therapy (34 +/- 3 mm Hg, P = 0.04 vs. untreated). No effects of treatment on right ventricular hypertrophy could be demonstrated. Quantitative morphometry of pre- and intra-acinar pulmonary arteries revealed no effects of treatment on vessel histopathology.. Treprostinil treatment improved clinical course and ameliorated symptoms of heart failure in a model of advanced PAH. However, beneficial effects were not associated with reversed structural remodelling of the pulmonary vasculature.

Topics: Animals; Blood Pressure; Disease Models, Animal; Epoprostenol; Hypertension, Pulmonary; Pulmonary Circulation; Rats; Rats, Wistar; Treatment Outcome

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Survival Rate; Treatment Outcome

To describe a successful transition process from subcutaneous treprostinil to intravenous epoprostenol after the failure of treprostinil in a patient with idiopathic pulmonary arterial hypertension and present an algorithm to achieve the conversion without significant adverse reactions.. A 25-year-old white female receiving subcutaneous treprostinil 97 ng/kg/min was admitted to the intensive care unit for transition from subcutaneous treprostinil to a target intravenous epoprostenol dose of 72 ng/kg/min via a staggered interval dose adjustment approach. The patient experienced facial flushing, hot flashes, and headache when dose adjustments of the drugs were made simultaneously; however, when dose adjustments were staggered, the adverse reactions did not occur and larger adjustments could be achieved.. This case demonstrates a suboptimal therapeutic response to treprostinil for the treatment of idiopathic pulmonary arterial hypertension. The transition of treprostinil to epoprostenol is rare; however, in the event therapy change is needed, dosing information is minimal. A staggered transition dosing regimen that accounts for the pharmacokinetic differences between epoprostenol and treprostinil was successfully used in this case.. The approach in this case demonstrates the success of staggered-interval dose adjustments to minimize supratherapeutic symptoms and coincides with the pharmacokinetic profile of the 2 medications.

Topics: Adult; Epoprostenol; Female; Headache; Hot Flashes; Humans; Hypertension, Pulmonary; Pulmonary Artery

Inhaled vasodilator therapy for pulmonary hypertension may decrease the systemic side effects commonly observed with systemic administration. Inhaled medications only reach ventilated areas of the lung, so local vasodilation may improve ventilation-perfusion matching and oxygenation. We compared the effects of intravenous vs. aerosolized treprostinil on pulmonary and systemic hemodynamics in an unanesthetized sheep model of sustained acute pulmonary hypertension. Acute, stable pulmonary hypertension was induced in instrumented unanesthetized sheep by infusing a PGH(2) analog, U-44069. The sheep were then administered identical doses of treprostinil either intravenously or by aerosol. Systemic and pulmonary hemodynamics were recorded during each administration. Both intravenous and aerosol delivery of treprostinil reduced pulmonary vascular resistance and pulmonary arterial pressure, but the effect was significantly greater with aerosol delivery (P < 0.05). Aerosol delivery of treprostinil had minimal effects on systemic hemodynamics, whereas intravenous delivery increased heart rate and cardiac output and decreased left atrial pressure and systemic blood pressure. Aerosol delivery of the prostacyclin analog treprostinil has a greater vasodilatory effect in the lung with minimal alterations in systemic hemodynamics compared with intravenous delivery of the drug. We speculate that this may result from treprostinil stimulated production of vasodilatory mediators from pulmonary epithelium.

Topics: Acute Disease; Administration, Inhalation; Aerosols; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Epoprostenol; Female; Hypertension, Pulmonary; Injections, Intravenous; Male; Pulmonary Circulation; Recovery of Function; Sheep; Treatment Outcome; Vasodilation

Topics: Adult; Antihypertensive Agents; Drug Combinations; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Piperazines; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Idiopathic pulmonary arterial hypertension (IPAH) is associated with substantial morbidity and mortality. Treprostinil was compared to epoprostenol for the economic impact of treating IPAH patients who failed or were not candidates for bosentan.. The model was a cost-minimization analysis, assuming clinical equivalence was achieved by proper dosing of both drugs, in terms of survival and surrogate measures. Two theoretical cohorts of 270 patients were treated with subcutaneous treprostinil and intravenous epoprostenol, and were evaluated over 3 years using a spreadsheet model. Annual survival rates were estimated for the cohorts so that at endpoint 114 (42%) patients survived in both groups. The model utilized resource valuation data for medication and supply costs from Medicare; hospital, consultation, surgical, and diagnostic procedural fees from North Carolina hospitals; and costs to treat adverse events from published sources. Costs were obtained from standard lists and were presented as 2003 US dollars, discounted at 3%. Sensitivity analyses were performed testing all model uncertainties.. In the base case analysis, treprostinil demonstrated savings of 22,701 US dollars and 37,433 US dollars per patient over 1- and 3-year time horizons, respectively. The greatest savings came from reduced or minimal hospitalizations attributed to the dose titration and treatment of adverse events, such as sepsis, associated with epoprostenol and its delivery system. Probabilistic sensitivity analyses resulted in average 3-year cost-savings of 41,051 US dollars (Standard Deviation = 13,902 US dollars) per patient.. By initiating and continuing treatment with treprostinil over a 3-year period, the economic burden associated with IPAH may be reduced compared to treatment with epoprostenol. The greatest saving with treprostinil was attributed to decreased sepsis.

Topics: Administration, Oral; Cost Savings; Economics, Pharmaceutical; Epoprostenol; Health Care Costs; Humans; Hypertension, Pulmonary; Monte Carlo Method; Multivariate Analysis

Topics: Aerosols; Animals; Epoprostenol; Hypertension, Pulmonary; Injections, Intravenous; Prostaglandin H2; Sheep

Prior to the availability of the oral endothelin antagonist bosentan, most patients with pulmonary arterial hypertension (PAH) were treated with continuously infused prostacyclins. Many patients receiving prostacyclins would have received bosentan if it had been available at the time of their diagnosis. Noninvasive criteria (symptoms, World Health Organization [WHO] functional class, 6-min walk test [6MWT] distances, and echocardiograms) are used to govern up-titration of prostacyclins and to assess response to bosentan. The purposes of this study were to see if some patients might be able to transition safely from prostacyclin to bosentan, and whether noninvasive criteria could be used to monitor this transition.. From January 2002 to July 2003, 23 stable patients with PAH attempted a transition from prostacyclin to bosentan over an 8-week period. 6MWT results, WHO class, and echocardiograms were recorded prior to transition and 1 month after successful transition. The transition was stopped and prostacyclin was resumed or up-titrated if any symptoms of PAH worsened.. Of 23 candidates (19 female and 4 male; age range, 17 to 73 years), 15 patients were transitioned to bosentan. Of these patients, four patients experienced worsening symptoms (range, 7 weeks to 12 months after cessation of prostacyclin) and resumed treatment with prostacyclin. Of the remaining 11 patients, 2 patients had liver function abnormalities 3 months and 10 months after transition to bosentan, respectively; 9 patients remained on bosentan 3 to 16 months after prostacyclin cessation. Patients failing transition and resuming prostacyclin returned to their pretransition functional baseline.. Nine of 23 carefully selected, stable patients with PAH receiving long-term prostacyclin were successfully transitioned to oral bosentan using noninvasive monitoring. No long-term adverse events were associated with failed transition attempts. Further studies need to be carried out to determine which patients are more likely to undergo the transition successfully.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antihypertensive Agents; Bosentan; Endothelin Receptor Antagonists; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Long-Term Care; Male; Middle Aged; Substance Withdrawal Syndrome; Sulfonamides; Treatment Outcome

The treatment of pulmonary hypertension associated with infection by human immunodeficiency virus has not been well defined. Treprostinil is a prostacyclin analogue that has recently been shown to be useful for the treatment of pulmonary hypertension, whether primary, secondary to congenital heart disease, or associated with collagen disease, in a 12-week, double-blind study. We report the results of a one-year follow-up of three patients with pulmonary hypertension associated with human immunodeficiency virus infection who are being treated with treprostinil at our center.. After secondary causes of pulmonary hypertension were excluded by a routine work-up, patients started treatment with subcutaneous prostacyclin (treprostinil) with progressive up-titration of the dose. Functional status and effort capacity were assessed every three months and an echocardiographic study was performed every six months.. All patients showed improvement in clinical status, as shown by the NYHA functional class and the results of the six-minute walking test (increase of at least 75 meters). All the patients remain alive after one year of follow-up. Echocardiographic systolic pulmonary pressure decreased in two patients. No serious adverse events were observed.. Subcutaneous prostacyclin (treprostinil) seems to be an effective and safe therapeutic option for the treatment of pulmonary hypertension associated with human immunodeficiency virus infection.

Topics: Adult; Antihypertensive Agents; Epoprostenol; Female; Hemodynamics; HIV Infections; Humans; Hypertension, Pulmonary; Infusion Pumps; Infusions, Intravenous; Male; Treatment Outcome; Vasodilator Agents

The stability of treprostinil sodium after dilution in three common i.v. infusion vehicles was assessed. The chemical stability of treprostinil sodium was tested over a 48-hour period at 40 degrees C and 75% relative humidity after dilution in each of three diluents: sterile water for injection, 0.9% sodium chloride injection, and 5% dextrose injection, and after passage through an i.v. delivery system. Chemical analysis was conducted by using a validated stability-indicating high-performance liquid chromatographic assay, visually inspecting the solutions, and measuring the pH of each solution. The preservative effectiveness of the solutions was tested by the recovery of inoculations of compendial microorganisms after 48 hours in dilute solutions of treprostinil sodium. All assay results for treprostinil were within 90.0% to 110.0% of the prepared solutions diluted at 0.004 and 0.13 mg/mL treprostinil sodium in sterile water for injection and 0.9% sodium chloride injection. The assay results were the same for dilute treprostinil solutions in 5% dextrose injection at concentrations of 0.02 and 0.13 mg/mL. The pH values for these solutions remained within acceptable values of 6.0 to 7.2 for the stability study. No change in physical appearance or any visible particulate matter was observed. Approximately 70% of metacresol, the preservative, in the dilute treprostinil sodium solutions was removed before reaching the terminal end of the tubing. None of the dilute treprostinil sodium solutions supported microbial growth in the cassette reservoirs for the organisms considered. Treprostinil sodium 0.13 mg/mL solution in sterile water for injection, 0.9% sodium chloride for injection, and 5% dextrose for injection appeared to be stable after storage in controlled ambulatory drug-delivery systems for 48 hours at 40 degrees C and 75% relative humidity. Treprostinil sodium 0.004 mg/mL in sterile water and 0.9% sodium chloride for injection and 0.02 mg/mL in 5% dextrose injection was also stable under the same conditions. None of the solutions showed signs of microbial growth.

Topics: Antihypertensive Agents; Chromatography, High Pressure Liquid; Drug Contamination; Drug Stability; Drug Storage; Epoprostenol; Glucose; Humans; Hydrogen-Ion Concentration; Hypertension, Pulmonary; Infusions, Intravenous; Sodium Chloride; Solutions; Water

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

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

Treatment of arterial pulmonary hypertension with epoprostenol (intravenous prostacyclin) improves survival and quality of life, but the need for an implanted central venous catheter is associated with frequent complications, that often (as in the case of infection or dislodgment) are serious and require catheter replacement. Treprostinil is a prostacyclin analogue suitable for continuous subcutaneous administration. We report the successful transition from intravenous epoprostenol to subcutaneuos treprostinil in four patients with severe pulmonary hypertension who suffered from serious complications associated with the epoprostenol infusion system.

Topics: Adult; Antihypertensive Agents; Bacterial Infections; Catheterization, Central Venous; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Infusions, Intravenous; Injections, Subcutaneous; Middle Aged

Subcutaneous prostacyclin (treprostinil) is an effective short-term treatment for pulmonary hypertension. The most frequently described adverse effect-pain in the area of injection-rarely requires that treatment be withdrawn. Sildenafil is a selective fosfodiesterase-5 inhibitor with pulmonary vasodilating effects. We describe the use of sildenafil as a substitute for treprostinil in a patient with pulmonary hypertension associated with lupus erythematosus. Treatment with treprostinil was discontinued due to uncontrollable abdominal pain.

Topics: Abdominal Pain; Adult; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lupus Erythematosus, Systemic; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Controlled Clinical Trials as Topic; Drug Interactions; Epoprostenol; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Myocardial Contraction; Platelet Aggregation; Vasodilator Agents

Topics: Advertising; Drug Industry; Drug Interactions; Epoprostenol; Herbal Medicine; Humans; Hypertension, Pulmonary; Policy Making; United States; United States Food and Drug Administration; Vasodilator Agents

Topics: Antihypertensive Agents; Bosentan; Contraindications; Drug Approval; Drug Interactions; Drug Monitoring; Endpoint Determination; Epoprostenol; Humans; Hypertension, Pulmonary; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; United States; Vasodilator Agents