Disease relevance of Tezosentan

• Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting), were dose-related [1].
• OBJECTIVES: The objective of this study was to evaluate the addition of intravenous (IV) tezosentan to standard therapy for patients with pulmonary edema [2].
• BACKGROUND: Tezosentan is an IV nonselective endothelin (ET)-1 antagonist that yields favorable hemodynamic effects in patients with acute congestive heart failure (CHF) [2].
• A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 h of treatment with each tezosentan dose [1].
• METHODS: Rats with cirrhosis received LPS and then tezosentan or placebo one hour later [3].

High impact information on Tezosentan

• Tezosentan, an endothelin receptor antagonist, limits liver injury in endotoxin challenged cirrhotic rats [3].
• Tezosentan significantly decreased hepatic MPO activity and hepatic neutrophils but had no effect on LPS induced iNOS or COX-2 [3].
• Plasma TNF-alpha levels were significantly lower in rats receiving LPS and tezosentan (182 (38) pg/ml) compared with those receiving LPS alone (821 (212) pg/ml) [3].
• The aim of this study was to investigate the effects of tezosentan, a non-selective ETA and ETB receptor antagonist, in LPS challenged rats with cirrhosis [3].
• OBJECTIVES: We sought to investigate the efficacy and safety of tezosentan, a dual endothelin receptor antagonist, in patients hospitalized for acute heart failure (HF) [1].

Chemical compound and disease context of Tezosentan

• Indomethacin (10 mg/kg), dazoxiben (10 mg/kg), or tezosentan (10-mg/kg bolus plus 10-mg/kg/h infusion) significantly reduced the increase in MPAP and PPG, but had no effect on the systemic hypotension [4].
• OBJECTIVES: Sildenafil, tezosentan, and prostacyclin reduce pulmonary vascular pressures in pulmonary hypertension, but have potential to vasodilate the systemic circulation [5].
• Available data are less compelling, but nonetheless promising, for the use of bosentan in digital ulceration secondary to systemic sclerosis, and tezosentan (another dual receptor blocker) in acute heart failure [6].
• CONCLUSIONS: Tezosentan, a combined endothelin receptor antagonist optimized for parenteral use, induces potent selective pulmonary vasodilation during acute U46619-induced pulmonary hypertension and potent nonselective vasodilation in chronic pulmonary hypertension secondary to increased pulmonary blood flow [7].
• Furthermore, tezosentan significantly attenuated venous hypertension (14 mmHg versus 24 mmHg), as well as lactate (4.0 mmol/l versus 5.6 mmol/l) and haemoglobin (10.2 g/dl versus 11.4 g/dl) concentrations in the venous effluent of the contralateral part of the flap, although microcirculatory blood flow remained virtually unchanged [8].

Biological context of Tezosentan

• All patients received oxygen 8 l/min through a face mask, 3 mg of IV morphine, 80 mg of furosemide, and 1 to 3 mg/h continuous drip isosorbide-dinitrate according to their blood pressure level and were randomized to receive a placebo or tezosentan (50 or 100 mg/h) for up to 24 h [2].
• BACKGROUND: Tezosentan is a dual endothelin receptor antagonist that has been shown to improve cardiac output, decrease pulmonary capillary wedge pressure, and reduce pulmonary and systemic vascular resistance in initial clinical studies in acute decompensated HF [9].
• Human coronary thrombus homogenates exerted vasoconstriction of porcine coronary artery rings that was inhibited by the dual ET receptor blocker tezosentan [10].
• The effect of tezosentan on the systemic vasculature was similar to that of EMD122946, whereas it was smaller in the coronary circulation [11].
• In vivo, treatment of tezosentan before ovulation substantially decreases gonadotropin-induced superovulation [12].

Anatomical context of Tezosentan

• METHODS: Rats were subjected to coronary artery ligation and were treated with either vehicle or tezosentan (10 mg/kg IV bolus) at 1 h and 24 h after MI [13].
• Tezosentan led to a decrease of mean pulmonary artery pressure (PAP) from 33.4 +/- 4.0 mm Hg to 24.7 +/- 2.1 mm Hg and pulmonary vascular resistance (PVR) from 7.8 +/- 1.4 mm Hg.L(-1).min.m2 to 5.2 +/- 0.7 mm Hg.L(-1).min.m2 [14].
• Tezosentan decreased the increments in pulmonary vascular resistance and extravascular lung water index by as much as 60% and 70%, respectively [15].
• Tezosentan decreases pulmonary artery pressure and improves survival rate in an animal model of meconium aspiration [14].
• Tezosentan after 6 hrs of ischemia/reperfusion did not improve the liver microcirculation, whereas the continuous infusion of endothelin-1 after 6 hrs of ischemia/reperfusion further impaired sinusoidal blood flow [16].

Associations of Tezosentan with other chemical compounds

• Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use [17].
• However, in anesthetized dogs, bolus intracoronary injections of the alpha-adrenoceptor agonist phenylephrine produced reductions in coronary blood flow that were partially antagonized by endothelin receptor blockade with tezosentan [18].
• In addition, the post-ischemic activation of NADPH oxidase and XO, and O(2)(-) generation were prevented by IPC, tezosentan, thenoyltrifluoroacetone (mitochondrial complex II inhibitor), and tempol (cell-membrane permeable O(2)(-) scavenger) [19].
• There was no statistically significant difference in the PaO2/FiO2 (partial pressure of O2 in arterial blood/fraction of O2 in the inspired gas) ratio of the tezosentan-treated animals compared with controls; however, lung lymph flow was significantly higher (P<0.05) in the treated animals [20].
• After propranolol, tezosentan resulted in significant decreases (P<0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise [21].

Gene context of Tezosentan

• Tezosentan (10(-4) mol/l) blocked the ET-1-induced response in human and possum GB strips (p<0.001) [22].
• The lower dose of tezosentan also produced a decrease in the endothelin-3-induced gallbladder pressure (P < 0.02) but not in blood pressure, whereas the higher dose reduced the blood pressure with no further reduction in gallbladder pressure (P < 0.05) [23].
• Administration of EDN2 to the ovarian tissue induced rapid contraction, whereas addition of tezosentan, an endothelin receptor antagonist, diminishes the EDN2 effect [12].
• Tezosentan competitively antagonizes the specific binding of (125)I-labeled ET-1 and of the selective ET(B) receptor ligands (125)I-labeled ET-3 and (125)I-labeled sarafotoxin S6c on cells and tissues carrying ET(A) and ET(B) receptors, with inhibitory constants in the nanomolar range, and has high water solubility [17].
• Tezosentan alone did not have any effect on haemodynamics, plasma levels of NO(2)(-)/NO(3)(-) or iNOS activity [24].

Analytical, diagnostic and therapeutic context of Tezosentan

• Three groups were studied: I/R untreated (n=17), I/R pretreated (n=11), and I/R posttreated (n=13) with Tezosentan (15 mg/kg, i.v.). RESULTS: Tezosentan significantly decreased (P<0.05) the rise in Scr from I/R injury (2.0+/-0.4 mg/dl, before and 2.9+/-0.4 mg/dl, after treatment) compared with untreated animals (4.2+/-0.4 mg/dl) [25].
• All animals treated with tezosentan survived, whereas in the control group four out of six animals died [14].
• In addition, four healthy sheep, exposed to an intravenous infusion of endothelin-1 at 20 ng x kg x min, after 1 hr received tezosentan in stepwise increasing doses of 0.5, 1, and 2 mg x kg x hr that were maintained for 1 hr each [15].
• Tezosentan treatment did not produce any alterations in hepatocellular injury or hepatic redox status when compared with the untreated animals receiving 6 hrs of ischemia/reperfusion [16].
• However, the effect was not sustained with higher doses of tezosentan, possibly due to reduced coronary perfusion pressure [26].

References