Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous prostacyclin has proven to be effective. However, this treatment requires a permanent central venous catheter with the associated risk of serious complications such as sepsis, thromboembolism, or syncope. Treprostinil, a stable prostacyclin analogue, can be administered by a continuous subcutaneous infusion, avoiding these risks. We conducted a 12-week, double-blind, placebo-controlled multicenter trial in 470 patients with pulmonary arterial hypertension, either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts. Exercise capacity improved with treprostinil and was unchanged with placebo; the between treatment group difference in median six-minute walking distance was 16 m (p = 0.006). Improvement in exercise capacity was greater in the sicker patients and was dose-related, but independent of disease etiology. Concomitantly, treprostinil significantly improved indices of dyspnea, signs and symptoms of pulmonary hypertension, and hemodynamics. The most common side effect attributed to treprostinil was infusion site pain (85%) leading to premature discontinuation from the study in 8% of patients. Three patients in the treprostinil treatment group presented with an episode of gastrointestinal hemorrhage. We conclude that chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with pulmonary arterial hypertension.
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PMID:Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. 1189 47

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 distribution of treprostinil in the UK and Ireland [390157]. In November 2000, Deutsche Banc Alex Brown predicted a sales potential of US $250 million to US $350 million [418736]. In August 2001, Merril Lynch predicted sales of US $10 million to $20 million in 2002 [420652].
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PMID:Treprostinil sodium Pharmacia. 1209 Jul 28

Treprostinil sodium was recently approved in the United States for continuous subcutaneous infusion in the treatment of pulmonary arterial hypertension (PAH). Anticoagulation with warfarin is recommended in PAH therapy. Given the likelihood for treprostinil and warfarin coadministration, a single-blind, controlled, crossover study was conducted to evaluate the effect of treprostinil infusion on the pharmacodynamics and pharmacokinetics of a single dose of warfarin. Area under the effect-time curve (AUEC(0-1)) and maximum effect over the entire sampling phase (E(max)) for warfarin INR were 219.58 and 2.071 with treprostinil and 218.93 and 2.041 with vehicle, respectively. Mean time to attain the peak concentration of R-enantiomer of warfarin (T(max)), half-life, and elimination rate constant (k(el)) were 1.9 hours, 51.688 hours, and 0.0137 per hour, respectively, in the presence of treprostinil and 1.5 hours, 52.579 hours, and 0.0137 per hour, respectively, in the presence of vehicle (control). Results were similar for the S-enantiomer. The 90% confidence intervals for warfarin INR and warfarin R- and S-enantiomer pharmacokinetic parameter (C(max) and AUC( infinity )) ratios were within 0.80-1.25, which was established as the no-effect criterion for treprostinil coadministration. No serious or severe adverse events, anticoagulation-related events, or clinically significant physical or laboratory findings were reported. These findings suggest that a clinically important interaction between treprostinil and warfarin during therapy is unlikely.
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PMID:Effect of continuous subcutaneous treprostinil therapy on the pharmacodynamics and pharmacokinetics of warfarin. 1277 69

In recent years, the better understanding of the pathobiology and pathogenesis of pulmonary arterial hypertension (PAH) has led to the development of new drugs for its treatment. Epoprostenol, which was the first drug approved for PAH, has shown an improvement in the survival at 3 years in patients with primary pulmonary hypertension. Recently, the Food and Drug Administration has approved two new compounds, Bosentan (an oral, non-selective endothelin receptor blocker) and Treprostinil (a subcutaneous prostacyclin analog). At least three multicenter, international studies are currently in progress. These studies include the use of a diet supplement rich in arginine (nitric oxide precursor), the evaluation of an endothelin A-receptor blocker (Sitaxsentan), and the evaluation of Sildenafil (a 5-phosphodiesterase inhibitor). As long as research continues to scrutinize the pathogenesis of this disease, clues to possible new therapies are warranted.
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PMID:[What is new in the treatment of pulmonary artery hypertension?]. 1296 61

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.
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PMID:Treprostinil for pulmonary hypertension. 1515 67

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.
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PMID:Prostanoid therapy for pulmonary arterial hypertension. 1519 79

Treprostinil sodium is a chemically stable analogue of prostacyclin administered as a chronic, continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension (PAH). There has been significant clinical interest in determining the feasibility of delivering treprostinil by intravenous infusion. Therefore, a bioequivalence and comparative pharmacokinetics study of the two routes of administration was conducted in normal volunteers. A randomized, two-period, crossover study design was employed. Each subject was dosed at 10 ng/kg/min for 72 hours by each route, with the infusions separated by a 4-day wash-out period. In the 51 subjects who received at least 24 hours of treprostinil administered subcutaneously and intravenously, the steady-state ratios of the geometric means (i.v./s.c.) and 90% confidence intervals for AUCss and Cmaxss were 92.9% (89.8-96.1%) and 106% (99.4-113%), respectively. Secondary pharmacokinetic assessments confirmed the comparability of the two routes of administration at steady state, and also demonstrated that the elimination half-life of treprostinil was 4.4 and 4.6 hours following intravenous and subcutaneous administration, respectively. Based on these findings it was concluded that intravenously and subcutaneously administered treprostinil are bioequivalent at steady state.
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PMID:Pharmacokinetics and steady-state bioequivalence of treprostinil sodium (Remodulin) administered by the intravenous and subcutaneous route to normal volunteers. 1524 2

(1) Standard treatment for pulmonary artery hypertension usually combines a calcium channel blocker with an anticoagulant, supplemental oxygen, a digitalin and a diuretic, with only limited efficacy. When added to this standard treatment, long-term continuous intravenous epoprostenol (prostacycline) infusion improves survival time and quality of life in patients with severe primary pulmonary artery hypertension, but at a cost of many adverse effects, some of which can be serious. Bosentan, an endothelin receptor antagonist, is an oral alternative. (2) Following the approval of inhaled iloprost, another prostacycline analogue, treprostinil, has been approved for use as a continuous subcutaneous infusion. (3) Its clinical evaluation is based on 2 randomised double-blind placebo-controlled trials with disappointing clinical results: the 6-minute walking distance increased by only 10 meters after 12 weeks of treatment. This modest degree of improvement in an intermediate outcome is unlikely to translate into a tangible improvement in quality of life. (4) The only available comparison with epoprostenol is a clinical pharmacology study in about 20 patients, with no tangible clinical benefit. (5) The adverse effect profile of treprostinil is the same as that of epoprostenol, and is mainly due to its vasodilatory properties (diarrhoea, ankle swelling). In addition, pain and other local reactions are very frequent at the point of infusion. (6) Treprostinil must be administered as a continuous subcutaneous infusion; this is not convenient, but it is easier to set up than central intravenous epoprostenol infusion.
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PMID:Treprostinil: new drug. Pulmonary artery hypertension: just another (disappointing) prostacycline analogue. 1712 24

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.
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PMID:[Update in the diagnosis and therapy for pulmonary arterial hypertension]. 1713 Sep 75

PGI(2) (prostacyclin) is a lipid mediator with vasodilatory and antithrombotic effects used in the treatment of vasoconstrictive/ischemic diseases including pulmonary artery hypertension. However, emerging research supports a role for PGs, including PGI(2), in the regulation of both innate and acquired immunity. As PGI(2) is unstable, we sought to define the effects of various PGI(2) analogs on resident alveolar macrophage (AM) and peritoneal macrophage (PM) innate immune functions. The effects of iloprost, carbaprostacyclin, and treprostinil on the regulation of phagocytosis, bacterial killing, and inflammatory mediator production were determined in both macrophage populations from rats. Iloprost failed to suppress AM functions to the same degree that it did in PMs, a characteristic shared by carbaprostacyclin. This difference reflected greater expression of the G(alphas) protein-coupled I prostanoid receptor and greater cAMP generation in PMs than AMs. Treprostinil inhibited phagocytosis, bacterial killing, and cytokine generation in AMs to a much greater degree than the other PGI(2) analogs and more closely resembled the effects of PGE(2). Studies with the E prostanoid (EP) 2 receptor antagonist AH-6809 and EP2-null macrophages indicated that this was due in part to the previously unknown ability of treprostinil to stimulate the EP2 receptor. The present investigation for the first time identifies differences in immunoregulatory properties of clinically administered PGI(2) analogs. These studies are the first to explore the capacity of PGI(2) to regulate bacterial killing and phagocytosis in macrophages, and our findings may hold important consequences regarding the risk of infection for patients receiving such agents.
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PMID:Synthetic prostacyclin analogs differentially regulate macrophage function via distinct analog-receptor binding specificities. 1723 12


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