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Scleroderma
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
The treatment of pulmonary hypertension in systemic sclerosis has had significant advancement in the past ten years. Recent clinical trials of PAH therapy in particular have changed the clinical management of SSc-PAH patients. The AMBITION study (Initial Use of Ambrisentan Plus Tadalafil in Pulmonary Arterial Hypertension) of 500 patients with previously untreated PAH showed a more than 50% reduction in time to clinical worsening in the combination therapy arm compared with either agent alone (54). In a post hoc analysis of 118 patients who had SSc-PAH in the AMBITION trial, initial combination therapy reduced the risk of clinical failure when compared to those who received monotherapy, with a more than 60% reduction in time to clinical worsening in the combination therapy arm (55). The benefit of this combination therapy was further supported in a multicenter observational study of SSc-PAH patients called the Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension in Scleroderma Study (ATPAHSS). This thirty-six-week study of treatment-naive SSc patients with PAH demonstrated that up-front combination therapy significantly improved hemodynamics, RV structure, and function as measured by cardiac magnetic resonance imaging and echocardiography (56). Therefore, based on these seminal studies, in the past five to ten years, initial combination therapy with ambrisentan and tadalafil was used in those with SSc-PAH in the clinical setting.
The Patient with Non-Group 2 Pulmonary Hypertension
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Sophia Anastasia Mouratoglou, George Giannakoulas
Ambrisentan is a selective ETA receptor antagonist administered once daily in a dose of 5 mg or 10 mg. As no significant increase in liver enzymes was observed in clinical trials, no liver function monitoring is deemed necessary. Ambrisentan showed a favorable result in 6-minute walk distance and in WHO functional class and a decrease in B-type natriuretic peptide (BNP) serum levels, as well as a delay in time to clinical worsening compared with placebo in two randomized, controlled clinical trials (ARIES 1 and ARIES 2),49 with a maintained result in functional capacity after two years of drug administration (ARIES E).50
Heart disease
Published in Catherine Nelson-Piercy, Handbook of Obstetric Medicine, 2020
PAH-targeted therapies should be continued in pregnancy. Specific therapies include: – Phosphodiesterase inhibitors (sildenafil, tadalafil). These can be safely continued or instigated in pregnancy.– Endothelin receptor antagonists (bosentan, ambrisentan). These are usually discontinued in pregnancy, as they are teratogenic in rats.– Prostanoid analogues (epoprostenol – intravenous [i.v.], iloprost – nebulized or i.v.) and nitric oxide – inhaled. These can be safely continued or instituted in pregnancy.
Evaluation of herb-drug interaction of ambrisentan with shikonin based on UPLC-MS/MS
Published in Pharmaceutical Biology, 2021
Tian Lan, Ping Fang, Xuemei Ye, Xia Lan, Ren-ai Xu
According to previous reports, ambrisentan had little effect on hepatic CYP450 induction or inhibition. For example, rifampicin, a potent inducer and substrate of CYP3A4, had no clinically effect on pharmacokinetics of ambrisentan (Harrison et al. 2010). And ketoconazole, which is known as a strong inhibitor of CYP3A4, also had no clinically significant effect on the pharmacokinetics of ambrisentan (Richards et al. 2009). Furthermore, it has been reported that the CYP3A4 and OATP1B1 inhibitor clarithromycin increased ambrisentan exposure but clinically likely to be irrelevant (Markert et al. 2013). However, in our study, the increase of ambrisentan exposure in the presence of shikonin indicated that the CYP3A4 inhibition by shikonin could be a potential cause (Tang et al. 2017). Most frequent adverse events of patients receiving ambrisentan were reported peripheral edoema, headache, dizziness and nasal congestion (Elshaboury and Anderson 2013). These side effects were considered mild to moderate in nature. Thus, in the clinic, the combination of ambrisentan and shikonin should be avoided or monitored, because the pharmacokinetics of ambrisentan have been altered significantly. Therefore, exposure to ambrisentan would be significantly increased and its associated side effects would be more serious and frequent. Finally, further studies about the effect of shikonin on ambrisentan metabolism in clinical studies and its inhibitory mechanism should be further investigated.
Effect of ambrisentan on echocardiographic and Doppler measures from patients in China with pulmonary arterial hypertension
Published in Expert Review of Cardiovascular Therapy, 2020
Qin-Hua Zhao, Fu-Hua Peng, Zai-Xin Yu, Gang-Cheng Zhang, Qiu-Shang Ji, Yong Wang, Jin-Ming Liu, Yong Huo, Xiao-Feng Zeng, Jian-Hui Li, Lu Zi, Zhi-Cheng Jing
An open-label, phase IIIb, single-arm, non-interventional study was carried out to determine the effect of ambrisentan on exercise capacity (6-minute walk test) in the Chinese patients with PAH (NCT01808313). The study consisted of a screening period of 4 weeks, a 12-week primary evaluation period and a 12-week dose-adjustment period. Ambrisentan (5 mg) once daily was administered to eligible patients (n = 134) for a 12-week dose adjustment period, during which dose titration to 10 mg was allowed. The total duration of the study was 28 weeks. Details about the average daily dose and exposure have been reported elsewhere [6]. The present study was conducted to retrospectively evaluate the echocardiography data from patients who participated in NCT01808313 conducted from December 2012 to August 2014.
Drugs in phase I and phase II clinical trials for systemic sclerosis
Published in Expert Opinion on Investigational Drugs, 2020
Melody P. Chung, Lorinda Chung
Endothelin receptor blockers in combination with disease-modifying agents with anti-inflammatory properties have been studied as well. It was hypothesized that combination therapy would have additive effects on diminishing fibrosis, inhibiting cellular and humoral hyperactivity, and interfering with smooth muscle proliferation in the vessel wall. The safety and efficacy of ambrisentan in combination with MMF, MTX, or CYC were examined in 15 patients with early dcSSc [89]. Five patients terminated the study early, two because of a serious adverse event that required hospitalization (one with worsening anemia from gastric antral vascular ectasia and the other with anxiety/migraine headache/adynamic ileus) and one patient was lost to follow-up. Ten patients tolerated ambrisentan in combination with an anti-inflammatory agent and showed an overall improvement in their mRSS and their perceived physical health. At 12 months, there was no progression of their disease severity based on the Medsger severity scale. However, given the small sample size and lack of placebo arm, it is difficult to interpret if the improvement in mRSS was due to the natural course of disease, delayed immunomodulatory effects from the antifibrotic agents, or specifically from combination therapy. Further research with a randomized, placebo-controlled, comparative study is needed.