Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Heart Fail ; 21(11): 1426-1433, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31523892

RESUMO

AIMS: Neladenoson bialanate is a partial adenosine A1 receptor agonist with demonstrated beneficial effects on cardiac function in animal models. We aimed to assess the dose-response effect of neladenoson bialanate on cardiac structure and function, clinical outcome, and safety in patients with heart failure (HF) with reduced ejection fraction (HFrEF). METHODS AND RESULTS: PANTHEON was a dose-finding, phase IIb, randomized, double-blind, placebo-controlled trial conducted in 92 centres in 11 countries including 462 patients with chronic HFrEF, randomized to once daily oral dose of neladenoson bialanate (5, 10, 20, 30, and 40 mg) or placebo. The primary endpoints were change from baseline to 20 weeks in left ventricular ejection fraction (LVEF) (echocardiography) and in N-terminal pro-B-type natriuretic peptide (NT-proBNP). Mean age of the patients was 67 years, 17% were female, mean LVEF was 28%, mean NT-proBNP was 2085 ng/L. After 20 weeks of treatment, there was no dose-effect of neladenoson bialanate on changes in NT-proBNP or LVEF (primary endpoints). No effect of neladenoson bialanate was found on left ventricular volumes, high-sensitivity troponin T, or cardiovascular mortality, HF hospitalization, and urgent visits for HF (secondary endpoints). There was a dose-dependent increase in creatinine and cystatin C, and a dose-dependent decrease in estimated glomerular filtration rate and heart rate. CONCLUSIONS: In patients with chronic HFrEF, treatment with neladenoson bialanate was not associated with dose-dependent favourable effects on cardiac structure and function, cardiac risk markers, or clinical outcome but was associated with a dose-dependent decrease in renal function. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02992288.

2.
Eur J Heart Fail ; 20(11): 1601-1610, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30225882

RESUMO

Despite major advances in the treatment of chronic heart failure (HF) with reduced ejection fraction (HFrEF), morbidity and mortality associated with the condition remain high, suggesting the need for additional treatment options, particularly haemodynamically neutral treatments that do not alter blood pressure, heart rate, or renal function. HF with preserved ejection fraction (HFpEF) is also associated with high morbidity and mortality and adequate treatment options are limited; thus there is a critical unmet need for the development of novel therapies for HFpEF. Chronic HFrEF and HFpEF are both systemic disorders that affect not only the heart but several other tissues and organs including skeletal muscle, leading to exercise intolerance and dyspnoea. Partial adenosine A1-receptor agonists represent a novel potential therapy for HF regardless of underlying ejection fraction given their minimal effect on heart rate and blood pressure, and preclinical data demonstrate several possible beneficial mechanisms, including improved mitochondrial function and sarcoplasmic reticulum Ca2+ -ATPase (SERCA2a) activity, enhanced energy substrate utilization, reverse ventricular remodelling, and anti-ischemic, cardioprotective properties. However, data on this class of drugs in humans are scarce, and the optimal dose of the partial adenosine A1 receptor, neladenoson bialanate, has not been defined. Here we describe the design and rationale of two randomized, double-blind, placebo-controlled, parallel-group, dose-finding phase 2b trials, PANTHEON (HFrEF) and PANACHE (HFpEF), that will advance our understanding of the potential benefit and optimal dose of neladenoson bialanate and provide critical information for the planning of future phase 3 trials.


Assuntos
Agonistas do Receptor A1 de Adenosina/administração & dosagem , Dipeptídeos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Piridinas/administração & dosagem , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
3.
Sci Total Environ ; 599-600: 1119-1129, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28511357

RESUMO

Future water scarcities in the face of an increasing population, climate change and the unsustainable use of aquifers will present major challenges to global food production. The ability of water footprints (WFs) to inform water resource management at catchment-scale was investigated on the Steenkoppies Aquifer, South Africa. Yields based on cropping areas were multiplied with season-specific WFs for each crop to determine blue and green water consumption by agriculture. Precipitation and evapotranspiration of natural vegetation and other uses of blue water were included with the agricultural WFs to compare water availability and consumption in a catchment sustainability assessment. This information was used to derive a water balance and develop a catchment WF framework that gave important insights into the hydrology of the aquifer through a simplified method. This method, which requires the monitoring of only a few key variables, including rainfall, agricultural production, WFs of natural vegetation and other blue water flows, can be applied to inform the sustainability of catchment scale water use (as opposed to more complex hydrological studies). Results indicate that current irrigation on the Steenkoppies Aquifer is unsustainable. This is confirmed by declining groundwater levels, and suggests that there should be no further expansion of irrigated agriculture on the Steenkoppies Aquifer. Discrepancies between in- and outflows of water in the catchment indicated that further development of the WF approach is required to improve understanding of the geohydrology of the aquifer and to set and meet sustainability targets for the aquifer. It is envisaged that this 'working' framework can be applied to other water-stressed aquifers around the world.

4.
Circ Heart Fail ; 10(4)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28356300

RESUMO

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Ensaios Clínicos Fase II como Assunto/normas , Insuficiência Cardíaca/tratamento farmacológico , Projetos de Pesquisa/normas , Fármacos Cardiovasculares/efeitos adversos , Ensaios Clínicos Fase II como Assunto/métodos , Consenso , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
5.
Handb Exp Pharmacol ; 243: 177-203, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27770217

RESUMO

Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.


Assuntos
Agonistas do Receptor A1 de Adenosina/uso terapêutico , Agonismo Parcial de Drogas , Insuficiência Cardíaca/tratamento farmacológico , Adenosina/análogos & derivados , Adenosina/farmacologia , Adenosina/uso terapêutico , Agonistas do Receptor A1 de Adenosina/farmacologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Angina Pectoris/tratamento farmacológico , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Doença da Artéria Coronariana , Diabetes Mellitus , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Furanos/farmacologia , Furanos/uso terapêutico , Coração/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Humanos , Resistência à Insulina , Precondicionamento Isquêmico Miocárdico , Lipólise/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/uso terapêutico , Insuficiência Renal , Taquicardia Supraventricular/tratamento farmacológico , Tiazóis/farmacologia , Tiazóis/uso terapêutico
6.
J Chem Ecol ; 35(9): 1137-50, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19795173

RESUMO

The invasive success of Parthenium hysterophorus L. is thought to be partially attributable to allelopathy mediated by the plant metabolite parthenin. To assess the ecological significance of parthenin release from plant material, its persistence and phytotoxicity in soil was studied. Results show parthenin is rapidly degraded with an average DT (50) of 59 h under standard experimental conditions. Degradation was delayed in sterilized soils, at lower soil moisture, and higher parthenin concentrations. Higher temperatures, higher CEC(pot)/clay content of soils, soil preconditioning with parthenin, and P. hysterophorus infestation accelerated degradation. Physico-chemical and biological processes are, therefore, expected to govern the fate of parthenin in soil. Parthenin exhibited low soil phytotoxicity and did not accumulate over time. Along with the indicated reduction in bioavailability and development of hormetic effects, results suggest that for parthenin to have detrimental allelopathic effects, it requires high P. hysterophorus densities that result in high soil levels of parthenin and soil conditions that favor the persistence of parthenin. In light of this, the ecological significance of parthenin is discussed.


Assuntos
Asteraceae/química , Sesquiterpenos/metabolismo , Solo , Biodegradação Ambiental , Fenômenos Biológicos , Sesquiterpenos/química , Sesquiterpenos/toxicidade , Microbiologia do Solo , Temperatura , Fatores de Tempo
7.
Ann Thorac Surg ; 82(2): 486-92, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16863750

RESUMO

BACKGROUND: Morbidity and mortality after coronary artery bypass graft surgery are directly related to specific preoperative risk factors. We assessed the influence of preoperative risk factors on the effect of pexelizumab, a C5 complement inhibitor, to reduce postoperative morbidity and mortality in this post hoc analysis of the Pexelizumab for Reduction in Myocardial Infarction and MOrtality in Coronary Artery Bypass Graft surgery (PRIMO-CABG) trial, a phase III double-blind, placebo-controlled study of 3,099 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. METHODS: The composite endpoint of death or myocardial infarction or both through postoperative day 30 was examined in subpopulations of patients with pre-specified risk factors, which included diabetes mellitus, prior coronary artery bypass graft, urgent intervention, female sex, history of neurologic event, history of congestive heart failure, and two or more previous myocardial infarctions or a recent myocardial infarction. Stratified post hoc analyses were also performed on patients presenting with two or more and three or more of those risk factors. RESULTS: Pexelizumab significantly reduced the incidence of the composite endpoint of death or myocardial infarction through postoperative day 30 by 28% in patients with two or more risk factors (p = 0.004) and 44% in patients with three or more risk factors (p < 0.001). CONCLUSIONS: The C5 complement inhibitor, pexelizumab, reduced morbidity and mortality among high-risk patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Ponte Cardiopulmonar/efeitos adversos , Ponte de Artéria Coronária/efeitos adversos , Infarto do Miocárdio/prevenção & controle , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Ponte de Artéria Coronária/mortalidade , Método Duplo-Cego , Feminino , Humanos , Masculino , Anticorpos de Cadeia Única
8.
Am J Cardiol ; 95(2): 274-6, 2005 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-15642569

RESUMO

This report presents the rationale and study design details of the SHock Inhibition Evaluation with Azimilide study, which is recruiting 624 patients with implantable cardioverter-defibrillators (ICDs) who are at risk for life-threatening ventricular arrhythmia, randomized to azimilide 75 mg, azimilide 125 mg, or placebo and followed for 1 year. The objective of this study is to determine the effect of azimilide versus placebo on the symptomatic ventricular arrhythmia burden using a unique statistical analysis based on the unusual temporal distribution of symptomatic ICD therapies. The primary efficacy end points are time to all-cause shocks and time to all-cause shocks plus symptomatic ventricular arrhythmic events triggering antitachycardia pacing measured from randomization.


Assuntos
Antiarrítmicos/administração & dosagem , Desfibriladores Implantáveis , Imidazolidinas/administração & dosagem , Piperazinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Taquicardia Ventricular/terapia , Método Duplo-Cego , Esquema de Medicação , Humanos , Hidantoínas , Projetos de Pesquisa , Taquicardia Ventricular/tratamento farmacológico , Resultado do Tratamento
9.
Circulation ; 110(24): 3646-54, 2004 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-15533855

RESUMO

BACKGROUND: Although implanted cardioverter defibrillators (ICDs) effectively treat sustained ventricular tachyarrhythmias, up to 50% of ICD recipients eventually require concomitant antiarrhythmic drug therapy to prevent symptomatic arrhythmia recurrences and hence reduce the number of device therapies. METHODS AND RESULTS: A total of 633 ICD recipients were enrolled in a randomized, double-blind, placebo-controlled study to evaluate the effect of daily doses of 75 or 125 mg of azimilide on recurrent symptomatic ventricular tachyarrhythmias and ICD therapies. Total all-cause shocks plus symptomatic ventricular tachycardia (VT) terminated by antitachycardia pacing (ATP) were significantly reduced by azimilide, with relative risk reductions of 57% (hazard ratio [HR]=0.43, 95% CI 0.26 to 0.69, P=0.0006) and 47% (HR=0.53, 95% CI 0.34 to 0.83, P=0.0053) at 75- and 125-mg doses, respectively. The reductions in all-cause shocks with both doses of azimilide did not achieve statistical significance. The incidence of all appropriate ICD therapies (shocks or ATP-terminated VT) was reduced significantly among patients taking 75 mg of azimilide (HR=0.52, 95% CI 0.30 to 0.89, P=0.017) and those taking 125 mg of azimilide (HR=0.38, 95% CI 0.22 to 0.65, P=0.0004). Five patients in the azimilide groups and 1 patient in the placebo group had torsade de pointes; all were successfully treated by the device. One patient taking 75 mg of azimilide had severe but reversible neutropenia. CONCLUSIONS: Azimilide significantly reduced the recurrence of VT or ventricular fibrillation terminated by shocks or ATP in ICD patients, thereby reducing the burden of symptomatic ventricular tachyarrhythmia.


Assuntos
Antiarrítmicos/uso terapêutico , Imidazolidinas/uso terapêutico , Piperazinas/uso terapêutico , Taquicardia Ventricular/prevenção & controle , Antiarrítmicos/efeitos adversos , Desfibriladores Implantáveis , Método Duplo-Cego , Cardioversão Elétrica , Determinação de Ponto Final , Feminino , Humanos , Hidantoínas , Imidazolidinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Prevenção Secundária , Taquicardia Ventricular/terapia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA