BACKGROUND: Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug-drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH. OBJECTIVE: Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan. METHODS: Healthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0-t), the AUC from zero to infinity (AUC0-∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat's metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout. RESULTS: Ninety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80-1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs. CONCLUSIONS: Macitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects. EudraCT numbers: 2017-003095-31 and 2017-003502-41.

• MeSH
• ABC transportér z rodiny G, člen 2 metabolismus   MeSH
• dospělí MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové proteiny metabolismus   MeSH
• pyrazoly farmakokinetika   MeSH
• pyrimidiny farmakokinetika   farmakologie   MeSH
• rosuvastatin kalcium farmakokinetika   MeSH
• sulfonamidy farmakologie   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• macitentan MeSH Prohlížeč
• nádorové proteiny MeSH
• pyrazoly MeSH
• pyrimidiny MeSH
• riociguat MeSH Prohlížeč
• rosuvastatin kalcium MeSH
• sulfonamidy MeSH

UNLABELLED: SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral endothelin receptor antagonist, in patients with pulmonary arterial hypertension (PAH). The majority of patients were receiving PAH therapy at enrollment, providing the opportunity to evaluate the efficacy and safety of macitentan in combination with other PAH therapies (predominantly phosphodiesterase type 5 inhibitors [PDE-5i]). In patients receiving background therapy, macitentan reduced the risk of morbidity/mortality by 38% compared with placebo (hazard ratio [HR] 0.62; 95% confidence level [CL] 0.43-0.89; p = 0.009). Furthermore, patients receiving macitentan and background therapy had a 37% reduction in the risk of being hospitalized for PAH (HR 0.63; 95% CL 0.41-0.96) compared with patients receiving background therapy only (placebo arm). Macitentan treatment in combination with background therapy was also associated with improvements in exercise capacity, functional class, cardiopulmonary hemodynamics, and health-related quality of life compared with background therapy alone. The safety profile of macitentan as part of a combination therapy regimen was consistent with that of macitentan in the overall SERAPHIN population. The SERAPHIN study has provided evidence that combination therapy with macitentan and a PDE-5i is effective and well tolerated in the management of PAH. Based on these data, and those from subsequent long-term trials, combination therapy is increasingly recognized as an important treatment option for improving long-term outcomes in PAH. CLINICAL TRIAL REGISTRATION NUMBER: NCT00660179.

• MeSH
• antagonisté endotelinového receptoru aplikace a dávkování   MeSH
• dvojitá slepá metoda MeSH
• inhibitory fosfodiesterasy 5 aplikace a dávkování   MeSH
• klinické zkoušky, fáze III jako téma metody   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• plicní hypertenze diagnóza   farmakoterapie   MeSH
• pyrimidiny aplikace a dávkování   MeSH
• sulfonamidy aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• macitentan MeSH Prohlížeč
• pyrimidiny MeSH
• sulfonamidy MeSH

BACKGROUND: Hypoxia effects on pulmonary artery structure and function are key to diseases such as pulmonary hypertension. Recent studies suggest that growth factors called neurotrophins, particularly brain-derived neurotrophic factor (BDNF), can influence lung structure and function, and their role in the pulmonary artery warrants further investigation. In this study, we examined the effect of hypoxia on BDNF in humans, and the influence of hypoxia-enhanced BDNF expression and signaling in human pulmonary artery smooth muscle cells (PASMCs). METHODS AND RESULTS: 48h of 1% hypoxia enhanced BDNF and TrkB expression, as well as release of BDNF. In arteries of patients with pulmonary hypertension, BDNF expression and release was higher at baseline. In isolated PASMCs, hypoxia-induced BDNF increased intracellular Ca2+ responses to serotonin: an effect altered by HIF1α inhibition or by neutralization of extracellular BDNF via chimeric TrkB-Fc. Enhanced BDNF/TrkB signaling increased PASMC survival and proliferation, and decreased apoptosis following hypoxia. CONCLUSIONS: Enhanced expression and signaling of the BDNF-TrkB system in PASMCs is a potential mechanism by which hypoxia can promote changes in pulmonary artery structure and function. Accordingly, the BDNF-TrkB system could be a key player in the pathogenesis of hypoxia-induced pulmonary vascular diseases, and thus a potential target for therapy.

• MeSH
• arteria pulmonalis cytologie   MeSH
• hypoxie buňky účinky léků   MeSH
• lidé MeSH
• membránové glykoproteiny metabolismus   MeSH
• mozkový neurotrofický faktor metabolismus   MeSH
• myocyty hladké svaloviny cytologie   účinky léků   metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• receptor trkB MeSH
• regulace genové exprese účinky léků   MeSH
• tyrosinkinasy metabolismus   MeSH
• vápník metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• BDNF protein, human MeSH Prohlížeč
• membránové glykoproteiny MeSH
• mozkový neurotrofický faktor MeSH
• receptor trkB MeSH
• tropomyosin-related kinase-B, human MeSH Prohlížeč
• tyrosinkinasy MeSH
• vápník MeSH

Within human pulmonary artery, neurotrophin growth factors [NTs; e.g. brain-derived neurotrophic factor (BDNF)] and their high-affinity receptors (tropomyosin-related kinase; Trk) and low-affinity receptors p75 neurotrophin receptor (p75NTR) have been reported, but their functional role is incompletely understood. We tested the hypothesis that BDNF is produced by human pulmonary artery endothelial cells (PAECs). In the context of hypoxia as a risk factor for pulmonary hypertension, we examined the effect of hypoxia on BDNF secretion and consequent autocrine effects on pulmonary endothelium. Initial ELISA analysis of circulating BDNF in 30 healthy human volunteers showed that 72 h exposure to high altitude (~11,000 ft, alveolar PO2 = 100 mmHg) results in higher BDNF compared to samples taken at sea level. Separately, in human PAECs exposed for 24h to normoxia vs. hypoxia (1-3% O2), ELISA of extracellular media showed increased BDNF levels. Furthermore, quantitative PCR of PAECs showed 3-fold enhancement of BDNF gene transcription with hypoxia. In PAECs, BDNF induced NO production (measured using an NO-sensitive fluorescent dye DAF2-DA) that was significantly higher under hypoxic conditions, an effect also noted with the TrkB agonist 7,8-DHF. Importantly, hypoxia-induced NO was blunted by neutralization of secreted BDNF using the chimeric TrkB-Fc. Both hypoxia and BDNF increased iNOS (but not eNOS) mRNA expression. In accordance, BDNF enhancement of NO in hypoxia was not blunted by 50 nM L-NAME (eNOS inhibition) but substantially lower with 100 μM L-NAME (eNOS and iNOS inhibition). Hypoxia and BDNF also induced expression of hypoxia inducible factor 1 alpha (HIF-1α), a subunit of the transcription factor HIF-1, and pharmacological inhibition of HIF-1 diminished hypoxia effects on BDNF expression and secretion, and NO production. These results indicate that human PAECs express and secrete BDNF in response to hypoxia via a HIF-1-regulated pathway.

• Klíčová slova
• Hypoxia inducible factor 1, Neurotrophin, Nitric oxide, Tropomyosin related kinase, eNOS, iNOS,
• MeSH
• arginasa metabolismus   MeSH
• arteria pulmonalis patologie   MeSH
• cévní endotel patologie   MeSH
• endoteliální buňky metabolismus   MeSH
• exprese genu MeSH
• faktor 1 indukovatelný hypoxií metabolismus   MeSH
• hypoxie buňky MeSH
• hypoxie krev   MeSH
• kultivované buňky MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• messenger RNA genetika   metabolismus   MeSH
• mozkový neurotrofický faktor krev   genetika   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• proteinkinasy metabolismus   MeSH
• receptor trkB MeSH
• signální transdukce MeSH
• synthasa oxidu dusnatého, typ II metabolismus   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• tyrosinkinasy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ARG1 protein, human MeSH Prohlížeč
• ARG2 protein, human MeSH Prohlížeč
• arginasa MeSH
• BDNF protein, human MeSH Prohlížeč
• faktor 1 indukovatelný hypoxií MeSH
• membránové glykoproteiny MeSH
• messenger RNA MeSH
• mozkový neurotrofický faktor MeSH
• NOS2 protein, human MeSH Prohlížeč
• NOS3 protein, human MeSH Prohlížeč
• oxid dusnatý MeSH
• proteinkinasy MeSH
• receptor trkB MeSH
• synthasa oxidu dusnatého, typ II MeSH
• synthasa oxidu dusnatého, typ III MeSH
• tropomyosin-related kinase-B, human MeSH Prohlížeč
• tyrosinkinasy MeSH