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Pulmonary Pharmacology & Therapeutics Dec 2023Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It... (Review)
Review
Tyvaso DPI is a drug-device combination therapy comprised of a small, portable, reusable, breath-powered, dry powder inhaler (DPI) for the delivery of treprostinil. It is approved for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease. Tyvaso DPI utilizes single-use prefilled cartridges to ensure proper dosing. Unlike nebulizer devices, administration of Tyvaso DPI is passive and does not require coordination with the device. The low-flow rate design results in targeted delivery to the peripheral lungs due to minimal drug loss from impaction in the oropharynx. The inert fumaryl diketopiperazine (FDKP) excipient forms microparticles that carry treprostinil into the airways, with a high fraction of the particles in the respirable range. In a clinical study in patients with pulmonary arterial hypertension, Tyvaso DPI had similar exposure and pharmacokinetics, low incidence of adverse events, and high patient satisfaction compared with nebulized treprostinil solution. Tyvaso DPI may be considered as a first prostacyclin agent or for those that do not tolerate other prostacyclin formulations, patients with pulmonary comorbidities, patients with mixed Group 1 and Group 3 pulmonary hypertension, or those that prefer an active lifestyle and need a portable, non-invasive treatment. Tyvaso DPI is a patient-preferred, maintenance-free, safe delivery option that may improve patient compliance and adherence.
Topics: Humans; Dry Powder Inhalers; Hypertension, Pulmonary; Pharmaceutical Preparations; Pulmonary Arterial Hypertension; Epoprostenol; Administration, Inhalation; Familial Primary Pulmonary Hypertension
PubMed: 37967762
DOI: 10.1016/j.pupt.2023.102266 -
Journal of Cardiovascular Pharmacology... Sep 2021Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated... (Review)
Review
Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated pulmonary vascular resistance and ultimately, right ventricular failure. Expanded understanding of PAH pathophysiology as it pertains to the nitric oxide (NO), prostacyclin (prostaglandin I) (PGI) and endothelin-1 pathways has led to recent advancements in targeted drug development and substantial improvements in morbidity and mortality. There are currently several classes of drugs available to target these pathways including phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase (sGC) stimulators, prostacyclin class agents and endothelin receptor antagonists (ERAs). Combination therapy in PAH, either upfront or sequentially, has become a widely adopted treatment strategy, allowing for simultaneous targeting of more than one of these signaling pathways implicated in disease progression. Much of the current treatment landscape has focused on initial combination therapy with ambrisentan and tadalafil, an ERA and PDE5I respectively, following results of the AMBITION study demonstrating combination to be superior to either agent alone as upfront therapy. Consequently, clinicians often consider combination therapy with other drugs and drug classes, as deemed clinically appropriate, for patients with PAH. An alternative regimen that targets the NO and PGI pathways has been adopted by some clinicians as an effective and sometimes preferred therapeutic combination for PAH. Although there is a paucity of prospective data, preclinical data and results from secondary data analysis of clinical studies targeting these pathways may provide novel insights into this alternative combination as a reasonable, and sometimes preferred, alternative approach to combination therapy in PAH. This review of preclinical and clinical data will discuss the current understanding of combination therapy that simultaneously targets the NO and PGI signaling pathways, highlighting the clinical advantages and theoretical biochemical interplay of these agents.
Topics: Antihypertensive Agents; Drug Therapy, Combination; Epoprostenol; Humans; Nitric Oxide; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pyridazines; Tadalafil
PubMed: 33836637
DOI: 10.1177/10742484211006531 -
Mediators of Inflammation 2012Prostacyclin, or PGI(2), is an end product derived from the sequential metabolism of arachidonic acid via cyclooxygenase and PGI synthase (PGIS). The receptor for... (Review)
Review
Prostacyclin, or PGI(2), is an end product derived from the sequential metabolism of arachidonic acid via cyclooxygenase and PGI synthase (PGIS). The receptor for PGI(2), IP, can be found on a variety of cell types and signaling through this receptor exhibits broad physiological effects. Historically, PGI(2) has been understood to play a role in cardiovascular health, specifically having powerful vasodilatory effects via relaxation of smooth muscle and inhibiting of platelet aggregation. For these reasons, PGI(2) has a long history of use for the treatment of pulmonary arterial hypertension (PAH). Only recently, its importance as an immunomodulatory agent has been investigated. PGI(2) regulates both the innate and adaptive immune systems and its effects are, for the most part, thought to be anti-inflammatory or immunosuppressive in nature, which may have implications for its further clinical use.
Topics: Adaptive Immunity; Epoprostenol; Humans; Immunity, Innate; Immunologic Factors; Vasodilation
PubMed: 22851816
DOI: 10.1155/2012/926968 -
Respiratory Care Oct 2020Intravenous formulations of epoprostenol are frequently delivered via nebulizer to treat pulmonary hypertension in acutely ill patients. Although their efficacy as...
BACKGROUND
Intravenous formulations of epoprostenol are frequently delivered via nebulizer to treat pulmonary hypertension in acutely ill patients. Although their efficacy as pulmonary vasodilators has been shown to be comparable to inhaled nitric oxide, the local effects of these formulations within the airways have not been determined. We hypothesized that the alkaline diluents of these compounds would lead to increased airway epithelial cell death and ciliary cessation.
METHODS
Human bronchial epithelial cells were exposed to epoprostenol in glycine and arginine diluents or control fluid. Ciliary beat frequency, lactate dehydrogenase, and total RNA levels were measured before and after exposure. Results were compared between exposure and control groups.
RESULTS
Ciliary beat frequency ceased immediately after exposure to epoprostenol with both diluents. Lactate dehydrogenase levels increased by 200% after exposure to epoprostenol and glycine diluent ( = .002). Total RNA levels were undetectable after exposure to epoprostenol and arginine, indicating complete cell death and lysis ( = .015). Ciliary beat frequency ceased after 30 s of exposure to epoprostenol and glycine ( = .008). There was no difference between cells exposed to epoprostenol and those exposed only to diluent.
CONCLUSIONS
Exposure to intravenous formulations of epoprostenol in glycine and arginine caused increased cell death and ciliary cessation in bronchial epithelial cells. These findings suggest that undesired local effects may occur when these compounds are delivered as inhaled aerosols to patients.
Topics: Administration, Inhalation; Antihypertensive Agents; Epithelium; Epoprostenol; Humans; Hypertension, Pulmonary; Nitric Oxide; Vasodilator Agents
PubMed: 32518088
DOI: 10.4187/respcare.07938 -
Canadian Medical Association Journal Jan 1980Prostaglandin I2 (PGI2), or prostacyclin, is a recently discovered prostaglandin that affects many organ systems. It is both a potent inhibitor of platelet aggregation... (Review)
Review
Prostaglandin I2 (PGI2), or prostacyclin, is a recently discovered prostaglandin that affects many organ systems. It is both a potent inhibitor of platelet aggregation and a powerful vasodilator. The recent demonstration that it is the main prostaglandin synthesized by the blood vessel wall suggests that it may play an important role in limiting platelet-mediated thrombosis. However, despite considerable investigation, the exact physiological role of PGI2 has yet to be elucidated.
Topics: Animals; Arteriosclerosis; Aspirin; Blood Vessels; Cardiovascular Physiological Phenomena; Chemical Phenomena; Chemistry; Depression, Chemical; Epoprostenol; Female; Genitalia, Female; Genitalia, Male; Humans; Hydrocortisone; Kidney; Male; Platelet Aggregation; Prostaglandins; Thrombosis
PubMed: 6988063
DOI: No ID Found -
Medicine Jan 2016Prostacyclin analogs, such as epoprostenol, treprostinil, iloprost, and beraprost, have long been used for pulmonary arterial hypertension (PAH) treatment, yet their... (Comparative Study)
Comparative Study Meta-Analysis Review
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
PubMed: 26825901
DOI: 10.1097/MD.0000000000002575 -
Cleveland Clinic Journal of Medicine Apr 2003The management of pulmonary arterial hypertension (PAH) should aim to provide vasodilation of the pulmonary arteries, treat right ventricular failure, improve functional... (Review)
Review
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
PubMed: 12716139
DOI: 10.3949/ccjm.70.suppl_1.s18 -
Blood Purification 2017Effective delivery of continuous renal replacement therapy (CRRT) depends on the longevity of the filter and circuit used in the CRRT machine. Safe and effective... (Review)
Review
Effective delivery of continuous renal replacement therapy (CRRT) depends on the longevity of the filter and circuit used in the CRRT machine. Safe and effective anticoagulation is crucial for maintaining the patency of these circuits. In children, heparin and citrate are the commonly used anticoagulants but they are limited by serious side effects and thus calls for meticulous monitoring. In conditions where neither of these can be used, prostacyclin can be an effective alternative. Prostacyclin is a platelet inhibitor that can be safely used as an efficient anticoagulant in CRRT. When combined with heparin, it induces a heparin-sparing effect, which can reduce the dosage and side effects of heparin. Furthermore, there is no need for performing time-consuming monitoring tests. Although prostacyclin seems to be an attractive option, there is scanty evidence about its use as an anticoagulant in CRRT in children. We review the evidence and practicalities, and propose a guideline for the use of prostacyclin as an anticoagulant in children requiring CRRT.
Topics: Anticoagulants; Blood Coagulation; Child; Cost-Benefit Analysis; Drug Monitoring; Epoprostenol; Humans; London; Meta-Analysis as Topic; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Renal Replacement Therapy
PubMed: 28118627
DOI: 10.1159/000452754 -
Journal of the American College of... Jun 2004Prostanoids have played a prominent role in the treatment of pulmonary arterial hypertension (PAH). Several compounds and methods of administration have been studied:... (Review)
Review
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
PubMed: 15194179
DOI: 10.1016/j.jacc.2004.02.036 -
Therapeutic Advances in Respiratory... Jun 2011Inhaled 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... (Review)
Review
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
PubMed: 21300738
DOI: 10.1177/1753465810397693