Tezosentan in patients with acuteheart failure and acute coronary syndromes

O’Connor, Christopher M.; Gattis, Wendy A.; Adams, Kirkwood F.; Hasselblad, Vic; Chandler, Bleakley; Frey, Aline; Kobrin, Isaac; Rainisio, Maurizio; Shah, Monica; Teerlink, John R.; Gheorghiade, Mihai

doi:10.1016/s0735-1097(03)00194-3

Cited by 124 publications

(17 citation statements)

References 22 publications

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“…Most impressive data emerged from the intravenous tezosentan [7] studies: resulting in an increase in CI in a range of 24.4–49.9% [8, 9] along with reduced pulmonary and systemic vascular resistance and pressures, in a dose-dependent manner [10]. However these drugs failed to demonstrate any clinical benefit in acute pulmonary edema [11], acute HF exacerbation [12] or chronic HF. Sustained (3 weeks) increase in CI along with reduction in systemic vascular resistance without affecting right-sided pressures or pulmonary resistance was demonstrated with the selective (ET A ) ERA antagonist darusentan [13].…”

Section: Discussionmentioning

confidence: 99%

Clinical and Hemodynamic Effects of Bosentan Dose Optimization in Symptomatic Heart Failure Patients with Severe Systolic Dysfunction, Associated with Secondary Pulmonary Hypertension – A Multi-Center Randomized Study

Kaluski

Cotter²,

Leitman

et al. 2007

Cardiology

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Objective: Toevaluate the effects of bosentan on echo-derived hemodynamic measurements, and clinical variables in symptomatic heart failure (HF) patients. Method: Multi- center, double-blind, randomized (2:1), placebo-controlled study comparing bosentan (8–125 mg b.i.d.) to placebo in patients with New York Heart Association class IIIb–IV HF, left ventricular ejection fraction <35% and systolic pulmonary artery pressure (SPAP) >40 mm Hg. Primary and secondary endpoints were change from baseline to 20 weeks in SPAP and cardiac index, respectively. Safety endpoints were treatment emergent adverse events (AEs), change in body weight, hemoglobin, hematocrit, systolic blood pressure and diuretic use. Results: Ninety-four patients enrolled: 60 to bosentan, 34 to placebo. There was no significant difference between the 2 arms in SPAP change (0.1 ± 11.5 mm Hg , 95% confidence limit (CL) –5.4 to 5.2, p = 0.97), cardiac index shift (0.12 ± 0.45, 95% CL –0.09 to 0.33 , p = 0.24 ) or any of the other 22 echocardigraphic measurements obtained. Therapy-duration was longer in the placebo arm, while more patients in the bosentan arm experienced adverse and serious AEs. Conclusion: In HF patients with left ventricular dysfunction and secondary pulmonary hypertension, bosentan did not provide any measurable hemodynamic benefit, and was associated with more frequent AEs, requiring drug discontinuation.

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Section: Discussionmentioning

confidence: 99%

Clinical and Hemodynamic Effects of Bosentan Dose Optimization in Symptomatic Heart Failure Patients with Severe Systolic Dysfunction, Associated with Secondary Pulmonary Hypertension – A Multi-Center Randomized Study

Kaluski

Cotter²,

Leitman

et al. 2007

Cardiology

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“…The determination of the actual efficacy of the monotherapy with either selective or mixed ET antagonists, or their association with inhibitors of the reninangiotensin system is still to be demonstrated through well controlled clinical trials in the near future. [155][156][157][175][176][177] CHF [56,178] Tezosentan (RO-610612) ETA/ETB Actelion CHF [171,172,179,180] Sitaxsentan (TBC-11251) ETA Texas Biotechnology Corporation AH [147] PAH [159,160] CHF [181] Darusentan …”

Section: Discussionmentioning

confidence: 99%

“…Beneficial effects of tezosentan were observed on the primary end point (improvement of cardiac index at 6 hours), as well as a substantial reduction in pulmonary capillary wedge pressures. In the RITZ-4 trial, the effect of tezosentan in patients with acute decompensated heart failure associated with acute coronary syndromes was evaluated [171]. In this multicenter, randomized, double-blind trial, 193 patients received intravenous tezosentan (25 mg/hour during the first hour and 50 mg/hour up to 48 hours) or placebo.…”

Section: Clinical Studiesmentioning

confidence: 99%

Endothelin Receptor Antagonists: Another Potential Alternative for Cardiovascular Diseases

Tostes

Muscará

2005

CDTCHD

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Endothelin-1 (ET-1), the predominant isoform of the endothelin peptide family, has potent vasoconstrictor, mitogenic, pro-inflammatory and antinatriuretic properties which have been implicated in the pathophysiology of a number of cardiovascular diseases. ET-1 effects are mediated through activation of the G-protein-coupled ETA and ETB receptors, which are found in a variety of cells including endothelial, vascular smooth muscle and mesangial cells. Overexpression of ET-1 has been consistently described in salt-sensitive models of hypertension and in models of renal failure, and has been associated with disease progression. The development of a range of peptidic and nonpeptidic ET-1 receptor antagonists represents an exciting breakthrough in cardiovascular therapeutics. Endothelin antagonists improve endothelium-dependent relaxation and ameliorate vascular and cardiac hypertrophy as well as glomerulosclerosis; interestingly, these beneficial effects seem to occur independently of their capacity to lower blood pressure. The comparison between selective ETA and combined ETA/ETB antagonists in experimental models of cardiovascular diseases reveals no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. In the case of salt-sensitive hypertension, ETA receptor blockade leads to the prevention of vascular hypertrophy and renal function improvement, being likely that these effects are also mediated by ETB receptors based on the fact that the concomitant blockade of ETB receptors prevents the beneficial effects of ETA antagonists. As a whole, the available data indicate that the use of ET-1 receptor antagonists might be of therapeutic interest to prevent hypertension induced end-organ damage; however, the comparative efficacy of selective ETA vs. dual ETA/ETB blockade to prevent target organ injuries in humans still remains to be investigated.

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“…43 In this multicenter, randomized, double-blind trial, 193 patients were randomized to receive intravenous 25 mg tezosentan per hour for the first hour and then 50 mg per hour up to 48 hours or placebo. The primary end point was a composite of death, worsening heart failure, recurrent ischemia, and recurrent or new myocardial infarction within 72 hours.…”

Section: Congestive Heart Failurementioning

confidence: 99%

Endothelin Receptor Blockers in Cardiovascular Disease

Rich¹,

McLaughlin²

2003

Circulation

199

126

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Abstract-The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. Key Words: endothelin Ⅲ heart failure Ⅲ pulmonary heart disease T he endothelin (ET) system, like other vascular regulatory systems, consists of a parent peptide that undergoes enzymatic activation and exerts its biologic effects by modulating specific receptors. Of the 4 active ETs (ET 1 through 4), ET-1 is the predominant isoform in the cardiovascular system, which is generated through the cleavage of prepro ET-1 to big ET-1 and then to ET-1 by the action of ET-converting enzymes. ET-1 is found in endothelial cells and is released toward the vascular smooth muscle consistent with a paracrine role, but it is also produced by smooth muscle cells and cardiomyocytes. 1,2 ET-1 has vasoconstrictive and mitogenic effects, stimulates the production of growth factors such as vascular endothelial growth factor and basic fibroblast growth factor, and potentiates the effects of transforming growth factor-␤ and platelet-derived growth factor. 3-7 Chronic ET-1 stimulation can result in myocardial fibrosis and hypertrophy and vascular fibrosis with extracellular matrix proliferation. 8 In the lung, ET-1 is abundantly expressed in the pulmonary vasculature and appears to play an important role in the regulation of pulmonary vascular tone. 9 ET-1 is also produced in leukocytes where it influences the production of a wide range of cytokines in the inflammatory response. 10 ET is regulated in an autocrine fashion by physiochemical factors such as blood flow, pulsatile stretch, sheer stress, and pH. 11-13 Acute hypoxia leads to selective stimulation of the ET-1 gene and ET synthesis in the pulmonary vasculature. 14 ET-1 biosynthesis is also stimulated by low-density lipoprotein cholesterol and glucose, and thrombin. 15,16 Endogenous inhibitors of ET-1 synthesis include nitric oxide, prostacyclin, atrial natriuretic peptides, and estrogens. [17][18][19][20] ET-1 exerts its major vascular effects through activation of 2 distinct G protein coupled ET A and ET B receptors. ET A receptors are found in the medial smooth muscle layers of the blood vessels, and atrial and ventricular myocardium. 21 When stimulated, the ET A receptors induce vasoconstriction and cellular proliferation by increasing intracellular calcium.ET B receptors are localized on endothelial cells and, to some extent, smooth muscle cells and macrophages. 22 The activation of ET B receptors stimulates the release of nitric oxide and prostacyclin and prevents apoptosis. 23 Normally, t...

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Tezosentan in patients with acuteheart failure and acute coronary syndromes

Cited by 124 publications

References 22 publications

Clinical and Hemodynamic Effects of Bosentan Dose Optimization in Symptomatic Heart Failure Patients with Severe Systolic Dysfunction, Associated with Secondary Pulmonary Hypertension – A Multi-Center Randomized Study

Clinical and Hemodynamic Effects of Bosentan Dose Optimization in Symptomatic Heart Failure Patients with Severe Systolic Dysfunction, Associated with Secondary Pulmonary Hypertension – A Multi-Center Randomized Study

Endothelin Receptor Antagonists: Another Potential Alternative for Cardiovascular Diseases

Endothelin Receptor Blockers in Cardiovascular Disease

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