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)

We evaluated the role of endothelin-1 (ET-1) and the involvement of nitric oxide in cardiovascular and respiratory dysfunction, during endotoxic shock, in 18 anaesthetised, mechanically ventilated pigs, divided into three groups. Group 1 was i.v. infused with LPS (20 microg/Kg/h for 240 min). Group 2 was pre-treated with bosentan, a dual inhibitor of ET-1 receptors, and at 180 min of endotoxic shock, L-NAME (N(G)-nitro-L-arginine methyl ester, 10 mg/Kg), a non-selective inhibitor of NO synthases, was i.v. administered. Group 3 was infused with LPS and L-NAME was administered similarly to group 2. Results show that LPS caused systemic hypotension, pulmonary biphasic hypertension, decrease in compliance (C(rs)) and increase in resistance (R(max,rs)) of respiratory system. Bosentan completely abolished the pulmonary hypertension and the changes in C(rs)and R(max,rs). L-NAME does not affect the LPS-dependent changes in respiratory mechanics, but it worsens the cardiovascular effects, causing death of pigs. Pre-treatment with bosentan prevents this deleterious effect. Our study demonstrates that the LPS-dependent respiratory effects are mediated by ET-1, which, probably causing pulmonary oedema, is responsible for the decrease in C(rs)and the increase of R(max,rs).
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PMID:Improvement of respiratory function by bosentan during endotoxic shock in the pig. 1154 27

Endothelin receptor antagonists have been proposed for the treatment of a variety of disorders in which the endothelins may act as pathogenic mediators, such as hypertension, congestive heart failure, and cerebral vasospasm. Bosentan is a nonpeptide competitive antagonist, which can be a good tool for studying the endothelin system. It is specific for the endothelin system and blocks the actions of endothelin at both mammalian receptors (A and B). Bosentan has recently moved into Phase III clinical trial. This review will attempt to overview the experimental and clinical effects of bosentan.
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PMID:Endothelin antagonism with bosentan: current status and future perspectives. 1207 May 30

The peptide endothelin plays a significant role in a wide array of pathological conditions, including primary pulmonary hypertension and pulmonary arterial hypertension associated with collagen vascular disease. These are life-threatening conditions that can severely compromise the function of the lungs and heart. Inhibiting the actions of endothelin by blockade of its receptors provides a new and effective approach to therapy for patients with these conditions. Bosentan (Tracleer ) is the first orally-active dual endothelin receptor antagonist and has recently been approved in the US, Canada, Switzerland and the EU for the treatment of pulmonary arterial hypertension. Bosentan significantly improves exercise capacity, symptoms and functional status in patients with this disease and also slows clinical deterioration, which may be indicative of a delay of disease progression. Results from large-scale studies of bosentan in patients with pulmonary arterial hypertension and chronic heart failure have established its long-term safety and tolerability profiles. The introduction of the dual endothelin receptor antagonist bosentan has provided an essential treatment for pulmonary arterial hypertension and ongoing trials are evaluating its potential role in the management of other endothelin-mediated disease states.
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PMID:Bosentan: a dual endothelin receptor antagonist. 1208 9

Bosentan is the first endothelin (ET) receptor antagonist approved by the Food and Drug Administration for the management of pulmonary arterial hypertension (PAH). In patients with World Health Organization Class III and IV PAH, bosentan has demonstrated improvement in dyspnea and exercise tolerance. ET also plays an important role in the pathophysiology of different vascular diseases. Therefore, bosentan also may have the potential to alter the outcome of many other diseases, such as heart failure, hypertension, ischemic heart disease, and renal disease, as well as cerebrovascular disorders. Because of the rarity and the poor prognosis of patients with PAH, as well as the requirement of close monitoring of bosentan (due to its potential of causing liver dysfunction and its teratogenic effects), bosentan is currently available only through a special access program and is distributed by certain selected pharmacies. Patients who are receiving bosentan should be taught to recognize early signs and symptoms of liver dysfunction and possible pregnancy. In addition, bosentan is not only a substrate but also an inducer of CYP3A4 and CYP2C9. Therefore, it is anticipated that numerous drug interactions may occur. Patients should be advised to consult their physicians or pharmacists should they need to consume other prescription or nonprescription medications.
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PMID:Bosentan. 1271 83

Diabetic nephropathy is associated with enhanced renal synthesis of endothelin (ET)-1. The goal of this study was to investigate the effects of dual ET receptor antagonism in the early phase (2 months) and in the late phase (5 months) of diabetic nephropathy in rats, and to compare this approach to angiotensin-converting enzyme inhibition. Four groups of uninephrectomized streptozotocin-induced diabetic rats were assigned to receive orally vehicle, bosentan, enalapril, or their combination. A fifth group consisted of nondiabetic, uninephrectomized rats. At 2 weeks, untreated diabetic rats exhibited increased glomerular filtration rate and renal plasma flow. Bosentan, enalapril, and the combination all prevented hyperfiltration and hyperperfusion. By 5 months, diabetic rats developed marked increases in mean arterial pressure and renal vascular resistance, progressive proteinuria, and renal structural damage with glomerular sclerosis and hypertrophy. Bosentan completely prevented the development of hypertension and renal vasoconstriction, and largely prevented the development of proteinuria and renal structural injury. The renal protective effect of bosentan was comparable to that of enalapril or the combination, although its anti-proteinuric effect was less. Clinical studies are warranted to assess whether ET receptor antagonism can have additive effects on top of ACE inhibition, the current treatment of choice in diabetic nephropathy.
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PMID:Chronic endothelin receptor blockade prevents both early hyperfiltration and late overt diabetic nephropathy in the rat. 1282 26

Blockade of endothelin receptors is a new drug principle for the treatment of pulmonary arterial hypertension. Bosentan is a competitive blocker of endothelin receptors administered by the oral route. In clinical trials it has been shown to increase the functional capacity of patients with pulmonary arterial hypertension. This article describes the background, results of clinical trials, and practical guidelines for the use of bosentan in pulmonary arterial hypertension.
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PMID:[Blockade of endothelin receptor with bosentan--a new principle of treatment in pulmonary arterial hypertension]. 1290 60

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

Pulmonary arterial hypertension is an uncommon but disabling and often fatal condition, in which there is a sustained rise in pulmonary arterial pressure due to progressive obliteration of the pulmonary vascular bed. [symbol: see text] Bosentan (Tracleer-Actelion), which belongs to a new class of drugs called endothelin receptor antagonists, is now available for treating patients with pulmonary arterial hypertension. Here we assess whether bosentan offers worthwhile benefits in the management of patients with this condition.
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PMID:Bosentan for pulmonary arterial hypertension. 1453 Dec 10

Bosentan is a nonpeptide, specific, competitive, dual antagonist at both endothelin receptor subtypes (ET(A) and ET(B)). Orally administered bosentan effectively prevents endothelin 1-induced vasoconstriction in pulmonary vessels in patients with pulmonary arterial hypertension. Improvement in exercise capacity from baseline was significantly greater with bosentan than with placebo in two phase III trials in patients with WHO functional class III or IV pulmonary arterial hypertension (primary or associated with connective tissue disease) despite treatment with vasodilators, diuretics, anticoagulants, cardiac glycosides, or supplemental oxygen. The beneficial effects of bosentan on exercise capacity were maintained for at least 20 weeks. Compared with placebo, bosentan led to a significantly greater improvement from pretreatment values in secondary efficacy endpoints such as the Borg dyspnea index, WHO functional class, and cardiopulmonary hemodynamic parameters (cardiac index, pulmonary vascular resistance, pulmonary artery pressure, pulmonary capillary wedge pressure, mean right atrial pressure). Bosentan significantly reduced the incidence, and delayed the onset, of clinical worsening of pulmonary arterial hypertension compared with placebo. In published clinical trials, adverse events that occurred with similar or greater frequency with bosentan 125 mg twice daily than with placebo included headache, syncope, flushing and abnormal hepatic function. Those that occurred less frequently with bosentan 125 mg twice daily than with placebo included dizziness, worsening of symptoms of pulmonary arterial hypertension, cough and dyspnea.
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PMID:Bosentan. 1472 63

Pulmonary hypertension (PH) is a rare disease with a very poor prognosis. Certain pharmacologic approaches, which reduce pulmonary arterial pressure (PAP) and thereby prevent end-stage cardiopulmonary failure, have been used during recent years. Endothelin-1 has been found to be involved in the pathogenesis of PH. The dual endothelin-receptor antagonist, bosentan, was recently approved for the treatment of pulmonary arterial hypertension. The drug is mainly cleared by hepatic elimination. Severe renal dysfunction does not affect the single-dose pharmacokinetics of bosentan to a clinically relevant extent. Whether renal replacement therapy, however, interferes with the pharmacokinetics of bosentan is unknown. The authors report on the use of bosentan (125 mg twice daily) and its pharmacokinetic monitoring in a 19-year-old woman with PH and end-stage renal disease secondary to scleroderma. Treatment was well tolerated without drug-specific adverse effects. After 12 months of treatment, pulmonary arterial pressure had normalized (48 mm Hg before start of treatment, 27 mm Hg at last follow-up). On the basis of analyzing samples from Genius-hemodialysis by a liquid chromatography assay with tandem mass spectrometry detection, the authors determined the bosentan dialysis clearance to be as low as 3.5 mL/min. Bosentan for the treatment of secondary PH seems to be safe as well as effective in end-stage renal disease patients and no adjustment of the bosentan dosing regimen appears necessary.
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PMID:Treatment of secondary pulmonary hypertension with bosentan and its pharmacokinetic monitoring in ESRD. 1511 84


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