Macitentan for the Treatment of Pulmonary Arterial Hypertension

Hong, Irene S.; Coe, Holly V.; Catanzaro, Linda M.

doi:10.1177/1060028013518900

Cited by 16 publications

(8 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Peak concentration is reached in 8 hrs, and the half-life is 16 hrs for the parent compound but 48 hrs for the active metabolite 16. It differs from its dual ERA predecessor, bosentan, by demonstrating prolonged and enhanced attachment to the ET A and ET B receptors, as well as increased penetration into the pulmonary arterial smooth muscle, suggesting the potential for improved clinical efficacy 17,18. Further, the pharmacokinetic profile of macitentan allows for once-daily dosing, as opposed to twice daily for bosentan 19.…”

Section: Mechanismmentioning

confidence: 99%

<p>Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update</p>

Wong¹,

Channick²

2019

DHPS

View full text Add to dashboard Cite

Macitentan is a medication in the endothelin receptor antagonist class, approved for treatment of pulmonary arterial hypertension in 2013 based on the results of the pivotal SERAPHIN Trial (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome). Macitentan was shown in initial trials to reduce the likelihood of a morbidity/mortality event. Real-world use of this medication additionally reveals a reduced risk of hospitalizations related to pulmonary arterial hypertension, improved health-related quality of life scores, potential clinical utility in other conditions (such as chronic thromboembolic pulmonary hypertension and pulmonary hypertension related to congenital heart disease), and has a similar safety profile as demonstrated in initial trials.

show abstract

Section: Mechanismmentioning

confidence: 99%

<p>Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update</p>

Wong¹,

Channick²

2019

DHPS

View full text Add to dashboard Cite

show abstract

“…Macitentan represents an intermediate pharmacological profile between bosentan and ambrisentan, with a 50-fold selectivity for the ETA subtype compared with the ETB subtype. 82,83 Given the high prevalence of diabetes mellitus in patients with PAD, it is interesting to note that studies have also suggested that pioglitazone could improve vascular function. [84][85][86] The relevance of these changes to functional status in patients with PAD remains unknown.…”

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

137

118

View full text Add to dashboard Cite

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...

show abstract

“…e increased ET A receptor level plays an important role in the pathogenesis of multiple cardiovascular diseases, such as hypertension [16,17], pulmonary hypertension [18,19], dilated cardiomyopathy, and microvascular dysfunction [20,21]. ET A receptor knockout can reverse or reduce the aging-induced downregulation of autophagy markers [6].…”

Section: Discussionmentioning

confidence: 99%

The Class III PI3K/Beclin-1 Autophagic Pathway Participates in the mmLDL-Induced Upregulation of ET_A Receptor in Mouse Mesenteric Arteries

Xie

Chen

et al. 2020

Advances in Pharmacological and Pharmaceutical Sciences

View full text Add to dashboard Cite

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular diseases. The current study explored the effect of mmLDL on the endothelin type A (ETA) receptor in mouse mesenteric arteries in vivo, as well as the role of autophagy in this process. mmLDL was injected via the caudal vein, and the Class III PI3K autophagic pathway inhibitor 3-methyladenine (3-MA) was injected intraperitoneally. The animals were divided into physiological saline (NS), mmLDL, and mmLDL + 3-MA groups. The dose-effect curve of endothelin-1- (ET-1-) induced mesenteric artery contraction was measured using myography, while ETA receptor mRNA expression was detected using real-time polymerase chain reactions, and the protein levels of the ETA receptor, class III PI3K, Beclin-1, LC3 II/I, p62, NF-κB, and p-NF-κB were observed using Western blot analysis. mmLDL significantly strengthened ET-1-induced contraction (the Emax value increased from 184.87 ± 7.46% in the NS group to 319.91 ± 20.31% in the mmLDL group (P<0.001), and the pEC50 value increased from 8.05 ± 0.05 to 9.11 ± 0.09 (P<0.01). In addition to upregulating the protein levels of Class III PI3K, Beclin-1, and LC3 II/I and downregulating that of p62, mmLDL significantly increased the mRNA expression and protein level of the ETA receptor and increased the protein level of p-NF-κB. However, these effects were significantly inhibited by 3-MA. mmLDL activates autophagy via the Class III PI3K/Beclin-1 pathway and upregulates the ETA receptor via the downstream NF-κB pathway. Understanding the effect of mmLDL on the ETA receptor and the underlying mechanisms may provide a new idea for the prevention and treatment of cardiovascular diseases.

show abstract

Macitentan for the Treatment of Pulmonary Arterial Hypertension

Cited by 16 publications

References 30 publications

<p>Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update</p>

<p>Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update</p>

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

The Class III PI3K/Beclin-1 Autophagic Pathway Participates in the mmLDL-Induced Upregulation of ET_A Receptor in Mouse Mesenteric Arteries

Contact Info

Product

Resources

About

Macitentan for the Treatment of Pulmonary Arterial Hypertension

Cited by 16 publications

References 30 publications

<p>Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update</p>

<p>Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update</p>

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

The Class III PI3K/Beclin-1 Autophagic Pathway Participates in the mmLDL-Induced Upregulation of ETA Receptor in Mouse Mesenteric Arteries

Contact Info

Product

Resources

About

The Class III PI3K/Beclin-1 Autophagic Pathway Participates in the mmLDL-Induced Upregulation of ET_A Receptor in Mouse Mesenteric Arteries