- Klíčová slova
- akutní srdeční selhání,
- MeSH
- diagnostické zobrazování MeSH
- diuretika terapeutické užití MeSH
- dusičnany terapeutické užití MeSH
- kardiogenní šok diagnóza MeSH
- kardiotonika terapeutické užití MeSH
- klinické laboratorní techniky MeSH
- lidé MeSH
- mimotělní membránová oxygenace MeSH
- opioidní analgetika terapeutické užití MeSH
- oxygenoterapie MeSH
- plicní edém etiologie MeSH
- podpůrné srdeční systémy MeSH
- srdeční selhání * diagnóza etiologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).
- MeSH
- kardiotonika škodlivé účinky farmakologie terapeutické užití MeSH
- kardiovaskulární nemoci mortalita MeSH
- kontrakce myokardu účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- močovina škodlivé účinky analogy a deriváty farmakologie terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- srdeční myosiny účinky léků metabolismus MeSH
- systolické srdeční selhání farmakoterapie metabolismus patofyziologie MeSH
- tepový objem MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-β and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.
- MeSH
- antiflogistika farmakologie terapeutické užití MeSH
- antioxidancia terapeutické užití MeSH
- apoptóza * účinky léků MeSH
- hemodynamika účinky léků MeSH
- hypertenze maligní farmakoterapie enzymologie patologie patofyziologie MeSH
- kardiotonika farmakologie terapeutické užití MeSH
- látky reagující s kyselinou thiobarbiturovou metabolismus MeSH
- myokard patologie MeSH
- NG-nitroargininmethylester chemie farmakologie MeSH
- oxidace-redukce MeSH
- potkani inbrední SHR MeSH
- protein X asociovaný s bcl-2 metabolismus MeSH
- resveratrol chemie farmakologie terapeutické užití MeSH
- srdeční komory účinky léků patologie patofyziologie MeSH
- tělesná hmotnost účinky léků MeSH
- velikost orgánu účinky léků MeSH
- zánět komplikace farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cardioprotective activity of dexrazoxane (ICRF-187), the only clinically approved drug against anthracycline-induced cardiotoxicity, has traditionally been attributed to its iron-chelating metabolite. However, recent experimental evidence suggested that the inhibition and/or depletion of topoisomerase IIβ (TOP2B) by dexrazoxane could be cardioprotective. Hence, we evaluated a series of dexrazoxane analogues and found that their cardioprotective activity strongly correlated with their interaction with TOP2B in cardiomyocytes, but was independent of their iron chelation ability. Very tight structure-activity relationships were demonstrated on stereoisomeric forms of 4,4'-(butane-2,3-diyl)bis(piperazine-2,6-dione). In contrast to its rac-form 12, meso-derivative 11 (ICRF-193) showed a favorable binding mode to topoisomerase II in silico, inhibited and depleted TOP2B in cardiomyocytes more efficiently than dexrazoxane, and showed the highest cardioprotective efficiency. Importantly, the observed ICRF-193 cardioprotection did not interfere with the antiproliferative activity of anthracycline. Hence, this study identifies ICRF-193 as the new lead compound in the development of efficient cardioprotective agents.
- MeSH
- daunomycin toxicita MeSH
- DNA-topoisomerasy typu II metabolismus MeSH
- inhibitory topoisomerasy II chemická syntéza metabolismus terapeutické užití MeSH
- kardiomyocyty účinky léků MeSH
- kardiotonika chemická syntéza metabolismus terapeutické užití MeSH
- kardiotoxicita farmakoterapie MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- novorozená zvířata MeSH
- piperaziny chemická syntéza metabolismus terapeutické užití MeSH
- potkani Wistar MeSH
- proliferace buněk účinky léků MeSH
- Saccharomyces cerevisiae - proteiny metabolismus MeSH
- Saccharomyces cerevisiae chemie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVE: To determine whether restricting the use of inotrope after diagnosis of low blood pressure (BP) in the first 72 hours of life affects survival without significant brain injury at 36 weeks of postmenstrual age (PMA) in infants born before 28 weeks of gestation. DESIGN: Double-blind, placebo-controlled randomised trial. Caregivers were masked to group assignment. SETTING: 10 sites across Europe and Canada. PARTICIPANTS: Infants born before 28 weeks of gestation were eligible if they had an invasive mean BP less than their gestational age that persisted for ≥15 min in the first 72 hours of life and a cerebral ultrasound free of significant (≥ grade 3) intraventricular haemorrhage. INTERVENTION: Participants were randomly assigned to saline bolus followed by either a dopamine infusion (standard management) or placebo (5% dextrose) infusion (restrictive management). PRIMARY OUTCOME: Survival to 36 weeks of PMA without severe brain injury. RESULTS: The trial terminated early due to significant enrolment issues (7.7% of planned recruitment). 58 infants were enrolled between February 2015 and September 2017. The two groups were well matched for baseline variables. In the standard group, 18/29 (62%) achieved the primary outcome compared with 20/29 (69%) in the restrictive group (p=0.58). Additional treatments for low BP were used less frequently in the standard arm (11/29 (38%) vs 19/29 (66%), p=0.038). CONCLUSION: Though this study lacked power, we did not detect major differences in clinical outcomes between standard or restrictive approach to treatment. These results will inform future studies in this area. TRIAL REGISTRATION NUMBER: NCT01482559, EudraCT 2010-023988-17.
- MeSH
- dopamin aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- dvojitá slepá metoda MeSH
- gestační stáří MeSH
- hypotenze farmakoterapie mortalita MeSH
- kardiotonika aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- novorozenci extrémně nezralí * MeSH
- novorozenec MeSH
- poranění mozku chemicky indukované MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.g. cyclosporine A, CsA) targeting cyclophilin D (CyPD) which is a key modulator, but not a structural component of the PTP. This limitation might explain controversial findings in clinical studies. Therefore, we investigated the protective effects against I/R injury of small-molecule inhibitors of the PTP (63 and TR002) that do not target CyPD. Both compounds exhibited a dose-dependent inhibition of PTP opening in isolated mitochondria and were more potent than CsA. Notably, PTP inhibition was observed also in mitochondria devoid of CyPD. Compounds 63 and TR002 prevented PTP opening and mitochondrial depolarization induced by Ca2+ overload and by reactive oxygen species in neonatal rat ventricular myocytes (NRVMs). Remarkably, both compounds prevented cell death, contractile dysfunction and sarcomeric derangement induced by anoxia/reoxygenation injury in NRVMs at sub-micromolar concentrations, and were more potent than CsA. Cardioprotection was observed also in adult mouse ventricular myocytes and human iPSc-derived cardiomyocytes, as well as ex vivo in perfused hearts. Thus, this study demonstrates that 63 and TR002 represent novel cardioprotective agents that inhibit PTP opening independent of CyPD targeting.
- MeSH
- buněčné linie MeSH
- kardiomyocyty účinky léků MeSH
- kardiotonika farmakologie terapeutické užití MeSH
- knihovny malých molekul farmakologie terapeutické užití MeSH
- kultivované buňky MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- potkani Sprague-Dawley MeSH
- potkani Wistar MeSH
- přechodový pór mitochondriální permeability antagonisté a inhibitory metabolismus MeSH
- reperfuzní poškození myokardu farmakoterapie metabolismus patologie MeSH
- srdeční mitochondrie účinky léků metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.
- MeSH
- bezpečnost pacientů MeSH
- kardiotonika škodlivé účinky terapeutické užití MeSH
- kontrakce myokardu účinky léků MeSH
- lidé MeSH
- simendan škodlivé účinky terapeutické užití MeSH
- srdeční selhání diagnóza farmakoterapie mortalita patofyziologie MeSH
- vazodilatace účinky léků MeSH
- vazodilatancia škodlivé účinky terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Inotropes aim at increasing cardiac output by enhancing cardiac contractility. They constitute the third pharmacological pillar in the treatment of patients with decompensated heart failure, the other two being diuretics and vasodilators. Three classes of parenterally administered inotropes are currently indicated for decompensated heart failure, (i) the beta adrenergic agonists, including dopamine and dobutamine and also the catecholamines epinephrine and norepinephrine, (ii) the phosphodiesterase III inhibitor milrinone and (iii) the calcium sensitizer levosimendan. These three families of drugs share some pharmacologic traits, but differ profoundly in many of their pleiotropic effects. Identifying the patients in need of inotropic support and selecting the proper inotrope in each case remain challenging. The present consensus, derived by a panel meeting of experts from 21 countries, aims at addressing this very issue in the setting of both acute and advanced heart failure.
Heart is a particularly sensitive organ to iron overload and cardiomyopathy due to the excessive cardiac iron deposition causes most deaths in disorders such as beta-thalassemia major. Free or loosely bound iron ions readily cycle between ferrous and ferric states and catalyze Haber-Weiss reaction that yields highly reactive and toxic hydroxyl radicals. Treatment with iron chelators (desferrioxamine, deferiprone, and deferasirox) substantially improved cardiovascular morbidity and mortality in iron overloaded patients. Furthermore, iron chelators have been studied in various cardiovascular disorders with known or presumed oxidative stress roles (e.g., ischemia/reperfusion injury) also in patients with normal body iron contents. The pharmacodynamic and pharmacokinetic properties of these chelators are critical for effective therapy. For example, the widely clinically used but hydrophilic chelator desferrioxamine suffers from poor plasma membrane permeability, which means that high and clinically unachievable concentrations/doses must be employed to obtain cardioprotection. Therefore, small-molecular and lipophilic chelators with oral availability are more suitable for this purpose, particularly in states without systemic iron overload. Apart from agents that are already used in clinical practice, aroylhydrazone iron chelators, namely salicylaldehyde isonicotinoyl hydrazone (SIH), have provided promising results. However, the use of classical iron-chelating agents is associated with a risk of toxicity due to indiscriminate iron depletion. Recent studies have therefore focused on "masked" prochelators that have little or no affinity for iron until site-specific activation by reactive oxygen species.
- MeSH
- buněčné linie MeSH
- chelátory železa farmakologie terapeutické užití MeSH
- kardiotonika farmakologie terapeutické užití MeSH
- lidé MeSH
- prekurzory léčiv farmakologie terapeutické užití MeSH
- přetížení železem farmakoterapie MeSH
- železo chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.
- MeSH
- jednotky intenzivní péče * MeSH
- kardiogenní šok diagnóza farmakoterapie mortalita patofyziologie MeSH
- kardiorenální syndrom diagnóza farmakoterapie mortalita patofyziologie MeSH
- kardiotonika škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- obnova funkce MeSH
- péče o pacienty v kritickém stavu MeSH
- rizikové faktory MeSH
- septický šok diagnóza farmakoterapie mortalita patofyziologie MeSH
- simendan škodlivé účinky terapeutické užití MeSH
- vazodilatancia škodlivé účinky terapeutické užití MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH