OBJECTIVES: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). METHODS: Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies. RESULTS: In RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was -0.16 ± 2.86 versus -0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, -0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point. CONCLUSIONS: The primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.

• MeSH
• antagonisté endotelinového receptoru terapeutické užití   škodlivé účinky   MeSH
• časové faktory MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• Fontanova operace * škodlivé účinky   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• paliativní péče MeSH
• prospektivní studie MeSH
• pyrimidiny * terapeutické užití   škodlivé účinky   MeSH
• spotřeba kyslíku účinky léků   MeSH
• sulfonamidy * terapeutické užití   škodlivé účinky   MeSH
• tolerance zátěže účinky léků   MeSH
• vrozené srdeční vady chirurgie   patofyziologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

• MeSH
• antagonisté endotelinového receptoru chemie   farmakologie   terapeutické užití   MeSH
• antihypertenziva chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• pyrimidiny * chemie   farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Plicní arteriální hypertenze vede k hypertrofii, dilataci pravé komory srdeční a terminálně k srdečnímu selhání. Stále jsou nemocní diagnostikováni v pokročilých fázích onemocnění nejčastěji v NYHA klasifikaci III. a IV. stupně. Neléčená plicní arteriální hypertenze má fatální dopad na osud nemocných. Cílem této práce je uvést nově definici, klasifikaci, epidemiologická data a možnosti terapie.

Al-Hiti H. Definition, classification and incidence of pulmonary arterial hypertension Pulmonary arterial hypertension leads to hypertrophy, dilatation of the right ventricle and ultimately to heart failure. Patients are still diagnosed in advanced stages of the disease, most often in NYHA classification III. and IV. stages. Untreated pulmonary arterial hypertension has a fatal impact on the fate of patients. The aim of this work is to introduce a new definition, classification, epidemiological data and treatment options.

• MeSH
• antagonisté endotelinového receptoru farmakologie   terapeutické užití   MeSH
• antikoagulancia farmakologie   terapeutické užití   MeSH
• diagnostické techniky kardiovaskulární MeSH
• diuretika farmakologie   terapeutické užití   MeSH
• inhibitory fosfodiesterasy 5 farmakologie   terapeutické užití   MeSH
• lidé MeSH
• plicní hypertenze * dějiny   epidemiologie   terapie   MeSH
• prostaglandiny farmakologie   terapeutické užití   MeSH
• rizikové faktory MeSH
• srdeční katetrizace metody   MeSH
• srdeční selhání etiologie   MeSH
• transplantace plic MeSH
• Check Tag
• lidé MeSH

BACKGROUND: Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES: The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS: World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS: In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS: Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension [PAH]) [A DUE]; NCT03904693).

• MeSH
• antagonisté endotelinového receptoru MeSH
• inhibitory fosfodiesterasy 5 MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• plicní arteriální hypertenze * MeSH
• pyrimidiny * MeSH
• sulfonamidy * MeSH
• tablety MeSH
• tadalafil MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

BACKGROUND: Association of congestive heart failure (CHF) and chronic kidney disease (CKD) worsens the patient's prognosis and results in poor survival rate. The aim of this study was to examine if addition of endothelin type A (ETA) receptor antagonist to the angiotensin-converting enzyme inhibitor (ACEi) will bring additional beneficial effects in experimental rats. METHODS: CKD was induced by 5/6 renal mass reduction (5/6 NX) and CHF was elicited by volume overload achieved by creation of aorto-caval fistula (ACF). The follow-up was 24 weeks after the first intervention (5/6 NX). The treatment regimens were initiated 6 weeks after 5/6 NX and 2 weeks after ACF creation. RESULTS: The final survival in untreated group was 15%. The treatment with ETA receptor antagonist alone or ACEi alone and the combined treatment improved the survival rate to 64%, 71% and 75%, respectively, however, the difference between the combination and either single treatment regimen was not significant. The combined treatment exerted best renoprotection, causing additional reduction in albuminuria and reducing renal glomerular and tubulointerstitial injury as compared with ACE inhibition alone. CONCLUSIONS: Our results show that treatment with ETA receptor antagonist attenuates the CKD- and CHF-related mortality, and addition of ETA receptor antagonist to the standard blockade of RAS by ACEi exhibits additional renoprotective actions.

• MeSH
• antagonisté endotelinového receptoru A * farmakologie   terapeutické užití   MeSH
• chronická renální insuficience * komplikace   farmakoterapie   metabolismus   MeSH
• endotelin-1 metabolismus   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• krysa rodu rattus MeSH
• ledviny MeSH
• píštěle * metabolismus   MeSH
• potkani transgenní MeSH
• receptor endotelinu A metabolismus   MeSH
• renin-angiotensin systém MeSH
• srdeční selhání * farmakoterapie   etiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Endothelin 1 (ET-1) seems essential in salt-dependent hypertension, and activation of ETA receptors causes renal vasoconstriction. However, the response in the renal medulla and the role of tissue NO availability has never been adequately explored in vivo. We examined effects of ETA and ETB receptor blockade (atrasentan and BQ788) on blood pressure (MAP), medullary blood flow (MBF) and medullary tissue NO. Effects of systemic and intramedullary blocker application were compared in anesthetized normotensive ET-1-pretreated Sprague-Dawley rats (S-D), in salt-dependent hypertension (HS/UNX) and in spontaneously hypertensive rats (SHR). Total renal blood flow (RBF) was measured using a Transonic renal artery probe, MBF as laser-Doppler flux, and tissue NO signal using selective electrodes. In normotensive rats ET-1 significantly increased MAP, decreased RBF (-20%) and renal medullary NO. In HS/UNX rats atrasentan decreased MAP and increased medullary NO, earlier and more profoundly with intravenous infusion. In SHR atrasentan decreased MAP, more effectively with intravenous infusion; the increase in tissue NO (∼10%) was similar with both routes; however, only intramedullary atrasentan increased MBF. No consistent responses to BQ788 were seen. We confirmed dominant role of ETA receptors in regulation of blood pressure and renal hemodynamics in normotensive and hypertensive rats and provided novel evidence for the role of ETA in control of intrarenal NO bioavailability in salt-dependent and spontaneous hypertension. Under conditions of activation of the endothelin system ETB stimulation preserved medullary perfusion.

• MeSH
• antagonisté endotelinového receptoru A farmakologie   terapeutické užití   MeSH
• antagonisté endotelinového receptoru B farmakologie   terapeutické užití   MeSH
• antihypertenziva farmakologie   terapeutické užití   MeSH
• atrasentan farmakologie   terapeutické užití   MeSH
• eliminace ledvinami účinky léků   MeSH
• endotelin-1 farmakologie   terapeutické užití   MeSH
• hemodynamika účinky léků   MeSH
• hypertenze farmakoterapie   metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• ledviny účinky léků   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• oligopeptidy farmakologie   terapeutické užití   MeSH
• oxid dusnatý metabolismus   MeSH
• piperidiny farmakologie   terapeutické užití   MeSH
• potkani inbrední SHR MeSH
• potkani Sprague-Dawley MeSH
• receptor endotelinu A účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Nedávné klinické studie u lidí narazily na omezení blokády renin-angiotensinového systému (RAS) v léčbě a prevenci hypertenzního orgánového poškození. Endotelinové receptory typu A (ETA) a epoxyeikosatrienové kyseliny (EETs) v tomto procesu hrají důležitou roli. Předpokládáme, že kombinovaná blokáda ETA a zvýšená dostupnost EETs, dosažená inhibicí solubilní epoxydové hydrolázy (sEH), sníží krevní tlak a povede k prevenci nebo regresi hypertenzního orgánového poškození. Hypertenzní kmen potkanů TGR (mRen2)27 (TGR) po 5/6 nefrektomii (5/6)NX bude léčen kombinací ETA blokátoru atrasentanu a sEH inhibitoru c-AUCB. Výsledky budou porovnány se strandardní blokádou RAS. Normotenzní HanSD potkani a TGR po zdánlivé nefrektomii budou sloužit jako kontroly. Léčba bude probíhat podle krátkodobých a dlouhodobých protokolů s okamžitou nebo odloženou léčbou. Očekávané výsledky: Kombinovaná blokáda ETA a sEH bude potenciálně efektivním farmakologickým postupem v léčbě hypertenze a/nebo prevence hypertenzního orgánového poškození, případně regrese poškození již vzniklého.; Recent studies in humans have revealed the limits of renin angiotensin system (RAS) blockade in the treatment and prevention of hypertensive organ damage. Endothelin type A (ETA) receptors and epoxyeicosanoid acids (EETs) play an important role in this process. We hypothesize that combined ETA blockade and increased availability of EETs, by soluble epoxyde hydrolase (sEH) inhibition, will decrease blood pressure and lead to prevention or regression of hypertensive organ damage. TGR (mRen2)27 hypertensive rats (TGR) after 5/6 nephrectomy (5/6NX) will be treated with the combination of ETA blocker atrasentan and sEH inhibitor c-AUCB. This will be compared to standard RAS blockade. Normotensive HanSD rats and sham-operated TGR will serve as controls. Short term and long term protocols with immediate or delayed treatment will be used. Expected results: Combined ETA blockade and sEH inhibition will potentially be a new effective pharmacological approach for the treatment of hypertension and/or prevention of the hypertensive organ damage, or regression of a damage already established.

• MeSH
• antagonisté endotelinového receptoru A terapeutické užití   MeSH
• antagonisté receptorů pro angiotenzin terapeutické užití   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze farmakoterapie   komplikace   MeSH
• kombinovaná farmakoterapie metody   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• potkani transgenní MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• farmakoterapie
• angiologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Plicní arteriální hypertenze (PAH) je primární onemocnění plicních arteriol, které je charakterizováno vaskulární proliferací a remodelací. Následně dochází vlivem progredujícího onemocnění ke zvýšení plicní cévní rezistence, selhání pravé komory a v krajním případě úmrtí. I přes konvenční a symptomatickou léčbu PAH se jedná o dosud nevyLéčiteLné onemocnění. Nicméně všechny pokroky dosažené ve farmakologické a nefarmakologické léčbě v posledních dekádách umožňují u nemocných s PAH významné zlepšení kvality života a jeho prodloužení.

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries that is characterized by vascular proliferation and remodeling. It results in a progressive increase in pulmonary vascular resistance and, ultimately, right ventricular failure and death. Despite recent major improvements in symptomatic treatments, no current treatment cures this devastating condition. However, during the past 25 years, treatment options for patients with the disease have evolved to help prolong their survival and improve their quality of life.

• Klíčová slova
• selexipag, ambrisentan, riociguat,
• MeSH
• antagonisté endotelinového receptoru farmakologie   terapeutické užití   MeSH
• blokátory kalciových kanálů terapeutické užití   MeSH
• bosentan terapeutické užití   MeSH
• dyspnoe etiologie   farmakoterapie   komplikace   MeSH
• echokardiografie metody   MeSH
• epoprostenol analogy a deriváty   terapeutické užití   MeSH
• hemodynamika MeSH
• inhibitory fosfodiesterasy 5 farmakologie   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• oxid dusnatý MeSH
• plicní arteriální hypertenze * diagnóza   farmakoterapie   patofyziologie   MeSH
• plicní hypertenze etiologie   farmakoterapie   klasifikace   MeSH
• receptory epoprostenolu agonisté   MeSH
• rozpustná guanylátcyklasa účinky léků   MeSH
• sildenafil citrát aplikace a dávkování   terapeutické užití   MeSH
• směrnice pro lékařskou praxi jako téma MeSH
• Swanova-Ganzova katetrizace metody   MeSH
• systémová sklerodermie komplikace   MeSH
• tadalafil aplikace a dávkování   terapeutické užití   MeSH
• vazodilatancia terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.

• MeSH
• antagonisté endotelinového receptoru škodlivé účinky   terapeutické užití   MeSH
• antihypertenziva škodlivé účinky   terapeutické užití   MeSH
• časové faktory MeSH
• dospělí MeSH
• hodnocení rizik MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• medicína založená na důkazech MeSH
• multicentrické studie jako téma MeSH
• plicní arteriální hypertenze diagnóza   farmakoterapie   mortalita   MeSH
• pozorovací studie jako téma MeSH
• příčina smrti MeSH
• progrese nemoci MeSH
• randomizované kontrolované studie jako téma MeSH
• rizikové faktory MeSH
• senioři MeSH
• výsledek terapie MeSH
• vzácné nemoci diagnóza   farmakoterapie   mortalita   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Previous studies in Ren-2 transgenic hypertensive rats (TGR) after 5/6 renal ablation (5/6 NX) have shown that besides pharmacological blockade of the renin-angiotensin system (RAS) also increasing kidney tissue epoxyeicosatrienoic acids (EET) levels by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for degradation of EETs, and endothelin type A (ETA) receptor blockade retards chronic kidney disease (CKD) progression. This prompted us to evaluate if this progression will be alleviated by the addition of sEH inhibitor and ETA receptor antagonist to the standard complex blockade of RAS (angiotensin-converting enzyme inhibitor plus angiotensin II type 1 receptor blocker) in rats with established CKD. METHODS: The treatment regimens were initiated 6 weeks after 5/6 NX in TGR, and the follow-up period was 60 weeks. RESULTS: The addition of sEH inhibition to RAS blockade improved survival rate, further reduced albuminuria and renal glomerular and kidney tubulointerstitial injury, and attenuated the decline in creatinine clearance - all this as compared with 5/6 NX TGR treated with RAS blockade alone. Addition of ETA receptor antagonist to the combined RAS and sEH blockade not only offered no additional renoprotection but, surprisingly, also abolished the beneficial effects of adding sEH inhibitor to the RAS blockade. CONCLUSION: These data indicate that pharmacological strategies that combine the blockade of RAS and sEH could be a novel tool to combat the progression of CKD. Any attempts to further extend this therapeutic regimen should be made with extreme caution.

• MeSH
• antagonisté endotelinového receptoru A farmakologie   MeSH
• chronická renální insuficience prevence a kontrola   MeSH
• epoxid hydrolasy antagonisté a inhibitory   MeSH
• hypertenze MeSH
• krysa rodu rattus MeSH
• nefrektomie MeSH
• potkani transgenní MeSH
• receptor endotelinu A MeSH
• renin-angiotensin systém účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH