Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Vatter, Hartmut; Seifert, Volker

doi:10.1111/j.1527-3466.2006.00063.x

Cited by 61 publications

(32 citation statements)

References 94 publications

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“…Likewise, in a rat model of type 1 diabetes, we observed increased renal inflammation despite animals maintaining normal blood pressure throughout the study . ET A -selective and combined ET A /ET B receptor antagonists have been approved for use in pulmonary hypertension (Rubin et al, 2002;Blalock et al, 2010), but there is a wide variety of cardiovascular-related diseases in which preclinical studies have suggested efficacy (Krum and Liew, 2003;Vatter and Seifert, 2006;Prasad et al, 2009). In recent years, considerable attention has been paid to the possibility of using this class of drugs for the treatment of resistant hypertension and diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Combined Endothelin A Blockade and Chlorthalidone Treatment in a Rat Model of Metabolic Syndrome

Jin

Jeon

Kleven

et al. 2014

J Pharmacol Exp Ther

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Experiments determined whether the combination of endothelin A (ET A ) receptor antagonist [ABT-627, atrasentan; (2R,3R,4S)-4-(1,3-benzodioxol-5-yl)-1-[2-(dibutylamino)-2-oxoethyl]-2-(4-methoxyphenyl)pyrrolidine-3-carboxylic acid] and a thiazide diuretic (chlorthalidone) would be more effective at lowering blood pressure and reducing renal injury in a rodent model of metabolic syndrome compared with either treatment alone. Male Dahl saltsensitive rats were fed a high-fat (36% fat), high-salt (4% NaCl) diet for 4 weeks. Separate groups of rats were then treated with vehicle (control), ABT-627 (ABT; 5 mg/kg per day, in drinking water), chlorthalidone (CLTD; 5 mg/kg per day, in drinking water), or both ABT plus CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 4 weeks, both ABT and CLTD severely attenuated the development of hypertension, whereas the combination further reduced MAP compared with ABT alone.All treatments prevented proteinuria. CLTD and ABT plus CLTD significantly reduced nephrin (a podocyte injury marker) and kidney injury molecule-1 (a tubulointerstitial injury marker) excretion. ABT, with or without CLTD, significantly reduced plasma 8-oxo-29-deoxyguanosine, a measure of DNA oxidation, whereas CLTD alone had no effect. All treatments suppressed the number of ED1 1 cells (macrophages) in the kidney. Plasma tumor necrosis factor receptors 1 and 2 were reduced only in the combined ABT and CLTD group. These results suggest that ABT and CLTD have antihypertensive and renal-protective effects in a model of metabolic syndrome that are maximally effective when both drugs are administered together. The findings support the hypothesis that combined ET A antagonist and diuretic treatment may provide therapeutic benefit for individuals with metabolic syndrome consuming a Western diet.

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Section: Discussionmentioning

confidence: 99%

Combined Endothelin A Blockade and Chlorthalidone Treatment in a Rat Model of Metabolic Syndrome

Jin

Jeon

Kleven

et al. 2014

J Pharmacol Exp Ther

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“…Ambrisentan is an ETA selective antagonist approved in the United States and Europe for the treatment of pulmonary arterial hypertension. 81 Two other candidates for testing would be the ETA and ETB dual antagonists macitentan and bosentan, which are both also approved for the treatment of pulmonary artery hypertension. Macitentan represents an intermediate pharmacological profile between bosentan and ambrisentan, with a 50-fold selectivity for the ETA subtype compared with the ETB subtype.…”

Section: Endothelial and Microcirculatory Dysfunctionmentioning

confidence: 99%

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

Hiatt¹,

Armstrong²,

Larson³

et al. 2015

Circulation Research

133

118

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P eripheral artery disease (PAD) is initiated by atherogenic mechanisms common to all major vascular territories but encompasses several distinctly important clinical sequelae.1 The global burden of PAD is large and rising, with substantial morbidity and mortality found in high-, middle-, and low-income countries. 2 The atherosclerotic occlusive disease underlying PAD is associated with an exercise limitation in the majority of patients, whereas the classic symptoms of intermittent claudication, ischemic rest pain, and ischemic ulceration are less common manifestations. 3 Patients with PAD are also at increased risk of myocardial infarction, ischemic stroke, heart failure, renovascular hypertension, and vascular death reflecting the systemic atherosclerotic burden. [4][5][6] The epidemiology of Peripheral Artery Disease Compendium© 2015 American Heart Association, Inc. The diagnosis of PAD can be ascertained by simple hemodynamic measurements, in particular, the ankle-brachial index (ABI), a test performed by measuring the systolic blood pressure in each arm and the dorsalis pedis and posterior tibial arteries of each ankle. The highest of the dorsalis pedis or posterior tibial artery pressures is the numerator of the ABI specific to each leg, whereas the highest arm pressure on either side is the denominator. A ratio of <0.90 in either leg is considered hemodynamic evidence of PAD. 16 When imaged, PAD can be characterized as one or more arterial stenoses or occlusions involving the distal aorta, iliac, femoral, popliteal, or tibial arteries. 17The underlying mechanisms responsible for the functional limitations in PAD are hemodynamic in origin, which affects the supply of oxygen and substrates to metabolically active tissue: skeletal muscle in the case of intermittent claudication and skin and subcutaneous tissues in the case of critical leg ischemia. However, additional pathophysiologic mechanisms contribute to the limb manifestations, where a reduction in blood flow alone does not fully account for the exercise limitation. Recent research into the pathophysiology of this exercise limitation has identified several important sequelae resultant from the chronic hemodynamic deficit. These changes affecting the vasculature and skeletal muscle distal to the primary hemodynamic lesions likely contribute to the mechanisms of exercise limitation in PAD. These advances are reviewed here with an additional focus on identifying possible future therapeutic strategies. Symptomatic Manifestations and Exercise Limitations in PADIn the coronary circulation, plaque rupture leading to acute ischemic events is a common clinical presentation; in PAD, progressive atherosclerosis leading to chronic stenosis and occlusion, often in series, in the arteries supplying the lower extremities dominates the symptomatic manifestations.6 Limb SymptomsPatients with PAD may present with a range of limb symptoms. Most patients are either asymptomatic or have atypical limb symptoms during exercise, whereas only a third have typical symptoms of c...

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“…10,15,16 The Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial investigated the efficacy and safety of initial combination therapy with oral, once-daily ambrisentan and tadalafil, as compared with monotherapy with either of these agents, in participants with previously untreated pulmonary arterial hypertension. We chose this combination because ambrisentan, 17 a selective endothelin-Areceptor antagonist, and tadalafil, 18 a phosphodiesterase type 5 inhibitor, target different intracellular pathways and do not have pharmacokinetic interactions. 19 …”

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confidence: 99%

Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension

et al. 2015

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BACKGROUNDData on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce. METHODSIn this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentanmonotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response. RESULTSThe primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooledmonotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P<0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONSAmong participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.)

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Ambrisentan, a Non‐peptide Endothelin Receptor Antagonist

Cited by 61 publications

References 94 publications

Combined Endothelin A Blockade and Chlorthalidone Treatment in a Rat Model of Metabolic Syndrome

Combined Endothelin A Blockade and Chlorthalidone Treatment in a Rat Model of Metabolic Syndrome

Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease

Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension

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