Selective Endothelin ETA Research Articles

Selective endothelin ETA and dual ETA/ETB receptor blockade improve endothelium-dependent vasodilatation in patients with type 2 diabetes and coronary artery disease

AimsEndothelin-1 contributes to endothelial dysfunction in patients with atherosclerosis and type 2 diabetes. In healthy arteries the ETA receptor mediates the main part of the vasoconstriction induced by endothelin-1 whilst the ETB receptor mediates vasodilatation. The ETB receptor expression is upregulated on vascular smooth muscle cells in atherosclerosis and may contribute to the increased vasoconstrictor tone and endothelial dysfunction observed in this condition. Due to these opposing effects of the ETB receptor it remains unclear whether ETB blockade together with ETA blockade may be detrimental or beneficial. The aim was therefore to compare the effects of selective ETA and dual ETA/ETB blockade on endothelial function in patients with type 2 diabetes and coronary artery disease. Main methodsForearm endothelium-dependent and endothelium-independent vasodilatation was assessed by venous occlusion plethysmography in 12 patients before and after selective ETA or dual ETA/ETB receptor blockade. Key findingsDual ETA/ETB receptor blockade increased baseline forearm blood flow by 30±14% (P<0.01) whereas selective ETA blockade did not (14±8%). Both selective ETA blockade and dual ETA/ETB blockade significantly improved endothelium-dependent vasodilatation. The improvement did not differ between the two treatments. There was also an increase in endothelium-independent vasodilatation with both treatments. Dual ETA/ETB blockade did not significantly increase microvascular flow but improved transcutaneous pO2. SignificanceBoth selective ETA and dual ETA/ETB improve endothelium-dependent vasodilatation in patients with type 2 diabetes and coronary artery disease. ETB blockade increases basal blood flow but does not additionally improve endothelium-dependent vasodilatation.

Selective endothelin ETA and dual ETA/ETB receptor blockade improves endothelial function in patients with type 2 diabetes and coronary artery disease

Selective endothelin ETA and dual ETA/ETB receptor blockade improves endothelial function in patients with type 2 diabetes and coronary artery disease

ATHENA-1: Hemodynamic Improvements Following the Addition of Ambrisentan to Background PDE5i Therapy in Patients With Pulmonary Arterial Hypertension

PURPOSE: Ambrisentan is an ETA-selective endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension (PAH). We examined the changes in several clinical parameters following 24 weeks of ambrisentan given to PAH patients with a suboptimal response to phosphodiesterase-5 inhibitor (PDE5i) therapy.

Potential for Pharmacokinetic Interactions Between Ambrisentan and Cyclosporine

Ambrisentan (ABS), approved for the treatment of pulmonary arterial hypertension and administered as an oral dose once daily, is an ET(A)-selective endothelin receptor antagonist (ERA) and a potential substrate for cytochrome P450 (CYP) 3A4, organic anion-transporting polypeptide (OATP), and P-glycoprotein (P-gp). Cyclosporin A (CsA), an inhibitor of CYP3A4, P-gp, and OATP, may be used concomitantly with ABS. In this open-label, parallel-treatment study, 28 healthy subjects received steady-state ABS (5 mg q.d.) either alone or with steady-state CsA (100-150 mg b.i.d.), and 24 other subjects received steady-state CsA either alone or with steady-state ABS. In the presence of CsA, ABS maximum plasma concentration (C(max)) increased 1.5-fold, and area under the plasma concentration-time curve (AUC)(0-τ) increased twofold. Marginal increases were observed for CsA C(max) (906 vs. 1,014 ng/ml) and AUC(0-τ) (3.05 vs. 3.37 µg·h/ml) in the presence of ABS. Frequent adverse events (AEs) were headache and gastrointestinal disorders. The addition of ABS to steady-state CsA appeared less tolerable as compared with the addition of CsA to steady-state ABS. A maximum ABS dose of 5 mg is recommended if it is coadministered with CsA. No change in CsA dose is recommended if it is coadministered with ABS.

No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers

Ambrisentan is a nonsulfonamide, ETA-selective endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH), and tadalafil is a phosphodiesterase type 5 (PDE-5) inhibitor under investigation for treatment of PAH. Due to the potential combination use, the pharmacokinetic (PK) interactions between these two drugs were assessed in a crossover study in 26 healthy adults. Single-dose PK of ambrisentan (10 mg) and its metabolite, 4-hydroxymethyl ambrisentan, were determined in the absence and presence of multiple doses of tadalafil (40 mg QD). Similarly, single-dose PK of tadalafil (40 mg) were evaluated in the absence and presence of multiple doses of ambrisentan (10 mg QD). In the presence of tadalafil, ambrisentan maximum plasma concentration (Cmax) was similar (105.0% [90% CI: 95.9–115.0%]) and systemic exposure (AUC0–∞) was slightly decreased (87.5% [84.0–91.2%]), compared with ambrisentan alone. Similar changes were observed with 4-hydroxymethyl ambrisentan. Tadalafil Cmax (100.6% [94.4–107.1%]) and AUC0–∞ (100.2% [92.6–108.4%]) showed no difference in the absence and presence of ambrisentan. The safety profile of the drugs combined was similar to that of either drug alone. No dose adjustments should be necessary when these drugs are coadministered. These results are in contrast to previous reports that the sulfonamide-based ERA bosentan can cause marked decreases in the exposure of tadalafil. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4962–4974, 2009

Ambrisentan, an endothelin receptor type A-selective endothelin receptor antagonist, for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular proliferation, which leads to right heart failure and death. Prostacyclin, NO and endothelin are felt to be key mediators in the development of PAH. We present the available published and presented data about ambrisentan, an ETA-selective endothelin receptor antagonist (ERA) and newest ERA agent to be approved by the FDA for the treatment of PAH in patients with WHO functional class II and III symptoms. Randomized, placebo-controlled trials have demonstrated a significant improvement in exercise capacity and decrease in time to clinical worsening, along with evidence to support an improvement in WHO functional class and quality of life for patients receiving ambrisentan. Long-term data have shown a 1-year survival of 95%; of the survivors, 94% remained on ambrisentan monotherapy. Endothelin receptor antagonists as a drug class have previously been associated with peripheral edema, aminotransferases abnormalities and a teratogenic risk to a developing fetus. Peripheral edema was observed in patients receiving ambrisentan; however, a greater percentage was experienced in patients aged > 65 years. In contrast, significant aminotransferase abnormalities were not observed with ambrisentan treatment in the placebo-controlled trials, and in all clinical trials combined the 1-year risk seems to be low (< 3%). Despite these data, the FDA requires monthly liver function tests monitoring. As with other ERAs, monthly pregnancy testing is required in all women of child bearing potential.

685: Ambrisentan Therapy for Idiopathic Pulmonary Arterial Hypertension: 2 Year Follow-Up

Ambrisentan (ABS) is an ETA-selective endothelin receptor antagonist that is approved for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO class II or III symptoms (5 and 10mg once daily). ABS has been shown to improve 6-minute walk distance (6MWD) in two Phase 3, 12-week, placebo-controlled studies (ARIES-1 and ARIES-2). ARIES-E is an ongoing, long-term extension study of ARIES-1 and ARIES-2.

Inhibition of endothelin-1 with darusentan: a novel antihypertensive approach for the treatment of resistant hypertension

Darusentan is an ETA-selective endothelin receptor antagonist that is currently in Phase III clinical development for the treatment of resistant hypertension (RHTN). Current hypertension treatment guidelines describe RHTN as the failure to achieve goal blood pressure despite treatment with full or adequate doses of an appropriate three-drug regimen that includes a diuretic. The exact prevalence of RHTN in the hypertensive community is unknown; however, recent clinical trials suggest that as many as a third of enrolled subjects may demonstrate treatment resistance. While the mechanisms responsible for the development of RHTN are also unknown, one of the few vasoconstrictive signaling pathways that remain unopposed, even in the presence of aggressive treatment with currently available antihypertensive agents, is the endothelin pathway. The efficacy and safety of darusentan, added on to full-dose background therapy including three or more medications, has recently been demonstrated in a randomized, placebo-c...

AMBRISENTAN THERAPY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION: 2-YEAR OUTCOME

PURPOSE: Ambrisentan is an ETA-selective endothelin receptor antagonist (ERA) that is approved for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. Ambrisentan has been shown to improve 6-minute walk distance (6MWD) in two Phase 3, 12-week, placebo-controlled studies (ARIES-1 and ARIES-2). ARIES-E is an ongoing, long term extension study of ARIES-1 and ARIES-2. Two-year, long-term data from the ARIES studies are presented.

Role of angiotensin II, endothelin-1 and L-type calcium channel in the development of glomerular, tubulointerstitial and perivascular fibrosis

Fibrosis is a hallmark of renal damage in several diseases, including arterial hypertension. We, therefore, investigated the role of angiotensin II, endothelin-1 and of L-type calcium channels in the development of the glomerular, vascular, and tubulointerstitial fibrosis in a model of severe angiotensin II-dependent hypertension. Five-week-old Ren-2 transgenic rats (TGRen2) received for 4 weeks a placebo, bosentan (100 mg/kg body weight), irbesartan (50 mg/kg body weight), the ETA-selective endothelin receptor antagonist BMS-182874 (BMS; 52 mg/kg body weight), the combination of irbesartan (50 mg/kg body weight) plus BMS (52 mg/kg body weight), and nifedipine (30 mg/kg body weight). Glomerular volume, tubulointerstitial fibrosis, glomerular, and perivascular fibrosis were accurately quantified by histomorphometry in four-to-six sections per kidney. Glomerular fibrosis was lowered by BMS (P < 0.001), whereas tubulointerstitial fibrosis was blunted by bosentan (P < 0.001) and irbesartan (P < 0.005). Perivascular fibrosis was reduced by nifedipine and BMS. As only irbesartan and irbesartan plus BMS decreased blood pressure (P < 0.001 vs. placebo), these effects on fibrosis were independent of blood pressure. Angiotensin II and L-type calcium channels modulate fibrosis selectively in the tubulointerstitial and in the perivascular compartments, respectively. The prevention of fibrosis with ET-1 receptor antagonism in all three compartments supports a major role of ET-1 in the development of renal fibrosis.

NO CLINICALLY RELEVANT PHARMACOKINETIC INTERACTIONS BETWEEN AMBRISENTAN AND TADALAFIL

PURPOSE: Ambrisentan is an oral, once-daily, ETA-selective endothelin receptor antagonist that is approved for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO class II or III symptoms. Tadalafil is an oral, once-daily, phosphodiesterase type 5 (PDE-5) inhibitor currently under investigation for the treatment of PAH. Concomitant use of these two oral, once-daily therapies for PAH may be likely; therefore, this study was designed to assess the potential for pharmacokinetic (PK) interactions between ambrisentan and tadalafil.

In vitro and in vivo effects of endothelin-1 and YM598, a selective endothelin ETA receptor antagonist, on the lower urinary tract

We investigated the contractile response of the lower urinary tract to endothelin-1 in vitro (rabbits) and in vivo (dogs). We also assessed the effects of a selective endothelin ETA receptor antagonist, (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2, 2′-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), on endothelin-1-induced contractile responses. In the in vitro study, endothelin-1 induced contractile responses in isolated rabbit bladder base, urethra, and prostate tissues. YM598 (10−7–10−5 M) antagonized these endothelin-1-induced contractile responses without affecting the maximal responses. In the in vivo study, endothelin-1 induced the elevation of non-prostatic urethral pressure as well as prostatic urethral pressure even in the presence of tamsulosin (10 μg/kg, i.v.) in anesthetized male dogs. YM598 (0.1–3 mg/kg, i.v.) inhibited these endothelin-1-induced contractile responses in a dose-dependent fashion. These results suggest that endothelin ETA receptors play an important role in the lower urinary tract contraction, and that the selective endothelin ETA receptor antagonist YM598 has ameliorating effects on various urinary dysfunctions, including benign prostatic hyperplasia.

AMBRISENTAN THERAPY FOR PULMONARY ARTERIAL HYPERTENSION: A COMPARISON BY PAH ETIOLOGY

PURPOSE: Ambrisentan is a propanoic acid-class, ETA-selective endothelin receptor antagonist that has been shown to improve efficacy in two Phase 3 placebo-controlled studies (ARIES-1 and ARIES-2) of patients with pulmonary arterial hypertension (PAH). The efficacy and safety of ambrisentan was assessed in these studies for patients with idiopathic PAH (IPAH) or PAH associated with connective tissue diseases (PAH-CTD).

AMBRISENTAN DECREASES BNP IN PATIENTS WITH PAH AND IMPROVEMENTS IN BNP WERE ASSOCIATED WITH IMPROVEMENTS IN 6MWD AND WHO FUNCTIONAL CLASS

PURPOSE: B-type natriuretic peptide (BNP) has been proposed as a prognostic indicator of mortality in patients with pulmonary arterial hypertension (PAH) and reductions in BNP have been shown to parallel improvements in hemodynamics and 6-minute walk distance (6MWD) in patients with PAH. Ambrisentan is an ETA-selective endothelin receptor antagonist that has been shown to improve 6MWD in the two Phase 3 placebo-controlled studies (ARIES-1 and ARIES-2).

The effects of TBC3214, a selective endothelin ETA receptor antagonist, on orthodontic tooth movement in rats

Many chemical messengers are involved in the process of alveolar bone and periodontal ligament remodelling during orthodontic tooth movement. Among them is probably endothelin-1 (ET-1). Its role in this process has been partly explained using tezosentan, which affects endothelin A (ET(A)) and endothelin B (ET(B)) receptors. Tezosentan enhances orthodontic tooth movement. The aim of this study was to determine the possible effects of a highly selective ET(A) antagonist on orthodontic tooth movement in rats. Thirty male Wistar rats, 11-12 weeks of age, divided into three equal groups. In group I, a closed-coil spring was used and they were treated daily with 15 mg/kg body weight of TBC3214, a highly selective ET(A) antagonist. A closed-coil spring was also used in group II and the animals were treated daily with a placebo. Group III were treated daily with a placebo. The coil spring delivered a force of 25 cN and was attached between the upper left first molar and upper left incisor. The distance between the teeth was measured with a digital calliper (accuracy +/- 0.01 mm) on days 0, 7, 14, 21, 24, 32, 37, and 40. The differences in the distance between the teeth were calculated to determine the amount of tooth movement. Statistical analysis was performed using two-way analysis of variance, Bonferroni's correction, and paired t-tests. The distance between the upper left first molar and the upper left incisor decreased in groups I and II. In group I, tooth movement was significantly less on days 32 and 37 (P < 0.01) and on day 40 (P < 0.001) compared with group II. In group III, the distance between the teeth increased during the study (P < 0.001). In animals treated daily with TBC3214, tooth movement was significantly less compared with the animals treated with a placebo. It is concluded that ET-1, which is the predominant form of endothelin isopeptides, is involved in orthodontic tooth movement in rats, probably by enhancing bone resorption via ET(A) receptors.

Sitaxsentan Treatment for Patients With Pulmonary Arterial Hypertension Discontinuing Bosentan

Bosentan, an oral ET(A)/ET(B) receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH). However, some patients discontinue bosentan because of hepatotoxicity or inadequate efficacy. Sitaxsentan, an oral, ET(A)-selective endothelin antagonist currently under investigation, may be an alternative treatment option. In this study we evaluate the safety and efficacy of sitaxsentan in patients discontinuing bosentan. Forty-eight patients with idiopathic PAH or PAH associated with connective-tissue disease or congenital heart disease were randomized (double-blind) to a single daily dose of either 50 mg or 100 mg sitaxsentan. Thirty-five of the 48 patients discontinued bosentan because of inadequate efficacy, as judged by the investigator, and 13 discontinued bosentan for safety concerns. Study end-points included change in 6-minute walk distance (6MWD), change in World Health Organization (WHO) functional class, time to clinical worsening, and change in Borg dyspnea score (Borg) from baseline to Week 12. With 100 mg sitaxsentan, 5 of 15 patients (33%) who discontinued bosentan because inadequate efficacy improved, demonstrating a >15% increase in 6MWD, vs 2 of 20 patients (10%) treated with 50 mg sitaxsentan. Fifteen percent and 20% of these patients had a >15% decrease in 6MWD in the 50- and 100-mg groups, respectively. Similar results were seen for the Borg and WHO functional class. Of the 12 patients discontinuing bosentan because of hepatotoxicity, 1 developed elevated liver enzymes at 13 weeks of sitaxsentan therapy. Overall, sitaxsentan was well tolerated. Sitaxsentan may represent a safe and efficacious alternative endothelin receptor antagonist for patients discontinuing bosentan.

AMBRISENTAN RESCUE THERAPY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION WHO DISCONTINUED BOSENTAN OR SITAXSENTAN DUE TO LIVER FUNCTION ABNORMALITIES

PURPOSE: Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA) with once-daily oral doses that are 10-100 times lower than sulfonamide-class ERAs for pulmonary arterial hypertension (PAH). Ambrisentan doses of 2.5 and 5 mg once-daily have been shown to improve 6-minute walk distance (6MWD) and delay clinical worsening in a placebo-controlled study of patients with PAH (ARIES-2), with no incidence of serum aminotransferases >3xULN (LFT abnormalities). To further evaluate the safety of ambrisentan, an open-label study was conducted of patients who had previously discontinued bosentan, sitaxsentan, or both therapies due to LFT abnormalities.

ARIES-1: A PLACEBO-CONTROLLED, EFFICACY AND SAFETY STUDY OF AMBRISENTAN IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION

PURPOSE: Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA) with once-daily oral doses. Ambrisentan doses of 2.5 and 5 mg once-daily improved 6-minute walk distance (6MWD) and delayed clinical worsening in a placebo-controlled PAH study (ARIES-2), with no incidence of serum aminotransferases >3xULN. ARIES-1 evaluated ambrisentan doses of 5 and 10 mg once-daily, compared to placebo.

NO CLINICALLY RELEVANT PHARMACOKINETIC INTERACTION BETWEEN AMBRISENTAN AND SILDENAFIL

PURPOSE: Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA). Ambrisentan doses of 2.5 and 5 mg once-daily have been shown to improve 6-minute walk distance and delay clinical worsening in a placebo-controlled study (ARIES-2) of patients with pulmonary arterial hypertension (PAH), with no incidence of serum aminotransferases >3xULN. Sildenafil is a phosphodiesterase type 5 inhibitor approved for PAH. Coadministration of sulfonamide-class ERAs have been shown to decrease (bosentan) or increase (sitaxsentan) the systemic exposure (AUC) of sildenafil, while sildenafil has been shown to increase the AUC of bosentan. Therefore, the potential for pharmacokinetic (PK) interactions between ambrisentan and sildenafil were examined.

AMBRISENTAN HAS NO CLINICALLY RELEVANT EFFECT ON THE PHARMACOKINETICS OR PHARMACODYNAMICS OF WARFARIN

PURPOSE: Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA). Ambrisentan doses of 2.5 and 5 mg once-daily have been shown to improve 6-minute walk distance and delay clinical worsening in a placebo-controlled study (ARIES-2) of patients with pulmonary arterial hypertension (PAH), with no incidence of serum aminotransferases >3xULN. Warfarin anticoagulation therapy is common for patients with PAH. When coadministered, sulfonamide-class ERAs have been shown to induce (bosentan) or inhibit (sitaxsentan) the p450-dependent metabolism of warfarin and alter the pharmacokinetic (PK) and pharmacodynamic (PD) effects of warfarin. Therefore, the potential for ambrisentan to affect the PK or PD of warfarin was examined.