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1.
Vasc Health Risk Manag ; 16: 41-51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021227

RESUMO

This review aims to elucidate the optimal dosing of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in the heart failure (HF) treatment paradigm through examination of the trial population characteristics and the mortality benefit observed in the Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF; NCT01035255) trial. Considerations regarding the initiation and titration of sacubitril/valsartan, a first-in-class ARNI, will also be addressed. The approval of sacubitril/valsartan heralded the first novel pharmacological class in over a decade for the treatment of heart failure with reduced ejection fraction (HFrEF). The PARADIGM-HF trial showed that treatment with valsartan/valsartan reduced the risk of first occurrence of either cardiovascular death or HF-related hospitalization (composite primary endpoint) by 20% compared with enalapril in patients with HFrEF. The incremental benefits of treatment with valsartan/valsartan over enalapril demonstrated in the PARADIGM-HF trial led to strong recommendations for its use over ACEIs or angiotensin receptor blockers to further reduce morbidity and mortality in the 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America updates to the guidelines for the management of HF. Although the optimal timing for the initiation of valsartan/valsartan has yet to be determined, its early use is likely to have a positive impact on patient outcomes.


Assuntos
Aminobutiratos/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Tetrazóis/uso terapêutico , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Ensaios Clínicos como Assunto , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/efeitos adversos , Fatores de Risco , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
2.
Int Heart J ; 61(1): 1-6, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31875616

RESUMO

Chronic heart failure (CHF) seriously affects the quality of patients' lives. Sacrubitril/valsartan is a combination angiotensin receptor-neprilysin inhibitor, a new therapeutic drugs to treat CHF.This study aims to observe the impact of sacrubitril/valsartan on clinical treatment and high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-brain natriuretic peptide (NT-ProBNP) serum levels, the improvement of the left atrial diameter (LAD) and left ventricular end diastolic dimension (LVEDD), and the left ventricular ejection fraction (LVEF) in patients with CHF.120 patients were randomly divided into a sacrubitil/valsartan group and a valsantan group, with 60 cases in each. Patients in the sacrubitil/valsartan group were administered sacrubitril/valsartan; while in the valsantan group, they were administered valsartan. The clinical effects, adverse reactions, and rehospitalization were observed eight weeks later, and hs-cTnT and NT-ProBNP serum levels and LAD, LVEDD, and LVEF were assayed.There were 53 cases of positive effect in the sacrubitil/valsartan group and 42 in the valsartan group (P < 0.05). Eight participants demonstrated adverse reactions in the sacrubitil/valsartan group, while 17 in the control group (P < 0.05). Hs-cTnT and NT-ProBNP serum levels, the measurements of LAD, LVEDD, and LVEF in the sacrubitil/valsartan group before the treatments were (24.47 ± 7.54) pg/mL, (10,356.94 ± 5,447.68) pg/mL, (49.41 ± 5.22) mm, (68.06 ± 6.20) mm and (31.12 ±6.65) %; in the valsartan group were (29.752 ± 10.03) pg/mL, (9,518.17 ± 5,905.17) pg/mL, (49.65 ± 4.91) mm, (67.06 ± 3.97) mm, and (30.41 ± 6.11) % (P > 0.05), while in the sacrubitil/valsartan group, the values decreased after the treatments to (17.92 ± 4.74) pg/mL, (3,881.59 ± 2,087.79) pg/mL, (42.18 ± 4.87) mm, (60.35 ± 7.12) mm and (45.35 ± 4.49) %; in the valsartan group to (25.81 ± 7.36) pg/mL, (6,278.35 ± 2,643.11) pg/mL, (46.53 ± 4.80) mm, (64.51 ± 4.34) mm, and (36.47 ± 5.21) % (P < 0.05). There were significant differences within the same group, before and after treatments (P < 0.05).Sacrubitril/valsartan treatment of patients with CHF improves their symptoms and is deserving of clinical application. This is also evident from significantly improved levels of serum hs-cTnT and NT-ProBNP and the left ventricular function.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Troponina T/sangue , Valsartana/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Biomarcadores/sangue , Doença Crônica , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Valsartana/farmacologia
4.
Pharmacol Rev ; 71(4): 539-570, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31537750

RESUMO

Despite the success of renin-angiotensin system (RAS) blockade by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor (AT1R) blockers, current therapies for hypertension and related cardiovascular diseases are still inadequate. Identification of additional components of the RAS and associated vasoactive pathways, as well as new structural and functional insights into established targets, have led to novel therapeutic approaches with the potential to provide improved cardiovascular protection and better blood pressure control and/or reduced adverse side effects. The simultaneous modulation of several neurohumoral mediators in key interconnected blood pressure-regulating pathways has been an attractive approach to improve treatment efficacy, and several novel approaches involve combination therapy or dual-acting agents. In addition, increased understanding of the complexity of the RAS has led to novel approaches aimed at upregulating the ACE2/angiotensin-(1-7)/Mas axis to counter-regulate the harmful effects of the ACE/angiotensin II/angiotensin III/AT1R axis. These advances have opened new avenues for the development of novel drugs targeting the RAS to better treat hypertension and heart failure. Here we focus on new therapies in preclinical and early clinical stages of development, including novel small molecule inhibitors and receptor agonists/antagonists, less conventional strategies such as gene therapy to suppress angiotensinogen at the RNA level, recombinant ACE2 protein, and novel bispecific designer peptides.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Terapia de Alvo Molecular
5.
Anticancer Res ; 39(9): 4597-4602, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519556

RESUMO

Our previous review of the literature assessed the existing knowledge (until 2000) about the possible link between angiotensin-converting enzyme inhibitors (ACEIs) and factors influencing the development of malignancies. We reviewed the literature for reports of statistical associations (or lack thereof) between ACEi treatment and incidence of specific cancers (e.g. breast, gastrointestinal, and skin). We concluded then that results from the epidemiological studies are conflicting, even taking the different methodology and endpoints into consideration, and thus inconclusive. Further investigation is needed beyond the observation period of most of these studies, and additional experimental studies are needed also to study the mechanisms by which agents blocking the renin-angiotensin system may obtain their inhibitory effect on tumor growth and metastasis. The present review elaborates further with more recent evidence from numerous human clinical studies from the past two decades (including large epidemiological studies, and long-term prospective and retrospective studies) on a protective association between ACEi treatment and the prognosis of patients with specific cancer types, malignancy characteristics or stage. Moreover, treatment with ACEI/angiotensin receptor blockers represents an adjuvant therapy with synergistic effects to chemotherapy and may improve patient outcomes (i.e. progression-free survival, and prolonged overall survival) in different types of cancers.


Assuntos
Neoplasias/metabolismo , Neoplasias/mortalidade , Sistema Renina-Angiotensina/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Clínicos como Assunto , Modelos Animais de Doenças , Progressão da Doença , Humanos , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Neoplasias/etiologia , Prognóstico , Resultado do Tratamento
6.
Ther Adv Cardiovasc Dis ; 13: 1753944719868134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31401939

RESUMO

Since the launch of the first orally available angiotensin II (AngII) type 1 receptor (AT1R) blocker (ARB) losartan (Cozaar) in the late 1990s, the class of ARBs (or 'sartans', short for Angiotensin-RecepTor-ANtagonistS) quickly expanded to include candesartan, eprosartan, irbesartan, valsartan, telmisartan, and olmesartan. All ARBs have high affinity for the AT1 receptor, expressed in various tissues, including smooth muscle cells, heart, kidney, and brain. Since activation of AT1R, the target of these drugs, leads, among other effects, to vascular smooth muscle cell growth, proliferation and contraction, activation of fibroblasts, cardiac hypertrophy, aldosterone secretion from the adrenal cortex, thirst-fluid intake (hypervolemia), etc., the ARBs are nowadays one of the most useful cardiovascular drug classes used in clinical practice. However, significant differences in their pharmacological and clinical properties exist that may favor use of particular agents over others within the class, and, in fact, two of these drugs, candesartan and valsartan, continuously appear to distinguish themselves from the rest of the 'pack' in recent clinical trials. The reason(s) for the potential superiority of these two agents within the ARB class are currently unclear but under intense investigation. The present short review gives an overview of the clinical properties of the ARBs currently approved by the United States Food and Drug Administration, with a particular focus on candesartan and valsartan and the areas where these two drugs seem to have a therapeutic edge. In the second part of our review, we outline recent data from our laboratory (mainly) on the molecular effects of the ARB drugs on aldosterone production and on circulating aldosterone levels, which may underlie (at least in part) the apparent clinical superiority of candesartan (and valsartan) over most other ARBs currently in clinical use.


Assuntos
Aldosterona/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Benzimidazóis/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico , Animais , Biomarcadores/sangue , Regulação para Baixo , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Recuperação de Função Fisiológica , Resultado do Tratamento
7.
Life Sci ; 234: 116775, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425697

RESUMO

AIMS: The activation of the angiotensin (Ang) II after acute kidney injury (AKI) triggers oxidative stress and inflammatory cascade which involved not only the kidneys but also the brain. Ang II through the Ang II type 1 receptor (AT1R) may have deleterious effects on hippocampal synaptic transmission and cognitive functions under uremic encephalopathy. The present study was conducted to examine the effects of AT1R antagonist on AKI-induced cognitive and synaptic plasticity impairment. MAIN METHODS: Here, we investigated the effect of AKI and possible pathophysiological roles of AT1R with the selective AT1R antagonist losartan (10 mg/kg/day for consecutive 9 days) on cognitive performance using passive avoidance and Morris water maze tests. In order to understand the synaptic transmission, in vivo short and long-term plasticity were evaluated at the Schaffer collateral-CA1 synapse. Biochemical analysis was also performed to detect possible hippocampal nitric oxide and oxidative stress mechanisms. KEY FINDINGS: Our data provide evidence of hippocampal complication following AKI with increased level of nitrite (P < 0.01 vs. sham) as well as oxidative stress (P < 0.01 vs. sham) that may be responsible for behavioral dysfunction under uremia (spatial memory, P < 0.001; passive avoidance P < 0.01 vs. sham). Losartan treatment effectively protects against cognitive (spatial memory, P < 0.01; passive avoidance P < 0.05 vs. AKI-veh) and synaptic plasticity impairments induced by AKI possibly via modulation of oxidative stress in the hippocampus (P < 0.01 vs. AKI-veh). SIGNIFICANCE: The present study conclusively demonstrated a protective role of AT1R antagonist losartan in hippocampal complication and neurocognitive dysfunction after AKI via modulating oxidative stress.


Assuntos
Lesão Renal Aguda/complicações , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Hipocampo/efeitos dos fármacos , Losartan/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/fisiopatologia , Animais , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo
9.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261874

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the most common primary esophageal malignancy. Telmisartan, an angiotensin II type 1 (AT1) receptor blocker (ARB) and a widely used antihypertensive, has been shown to inhibit proliferation of various cancer types. This study evaluated the effects of telmisartan on human ESCC cell proliferation in vitro and in vivo and sought to identify the microRNAs (miRNAs) involved in these antitumor effects. We examined the effects of telmisartan on three human ESCC cell lines (KYSE150, KYSE180, and KYSE850). Telmisartan inhibited proliferation of these three cell lines by inducing S-phase arrest, which was accompanied by decreased expression of cyclin A2, cyclin-dependent kinase 2, and other cell cycle-related proteins. Additionally, telmisartan reduced levels of phosphorylated ErbB3 and thrombospondin-1 in KYSE180 cells. Furthermore, expression of miRNAs was remarkably altered by telmisartan in vitro. Telmisartan also inhibited tumor growth in vivo in a xenograft mouse model. In conclusion, telmisartan inhibited cell proliferation and tumor growth in ESCC cells by inducing cell-cycle arrest.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Fase S/efeitos dos fármacos , Telmisartan/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Linhagem Celular Tumoral , Ciclina A2/genética , Ciclina A2/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo , Telmisartan/uso terapêutico , Trombospondina 1/genética , Trombospondina 1/metabolismo
10.
Eur J Pharmacol ; 859: 172519, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31271743

RESUMO

Juvenile Paget disease (JPD1), an autosomal-recessive disorder, is characterized by extremely rapid bone turnover due to osteoprotegerin deficiency. Its extra-skeletal manifestations, such as hypertension and heart failure, suggest a pathogenesis with shared skeletal and cardiovascular system components. In spite of this, the effects of anti-hypertensive drugs on bone morphometry remain unknown. We administered an angiotensin II type 1 receptor blocker, olmesartan (5 mg/kg/day) to 8-week-old male mice lacking the osteoprotegerin gene, with and without 1 µg/kg/min of angiotensin II infusion for 14 days. Olmesartan treatment decreased systolic blood pressure, and echocardiography showed increased left ventricular systolic contractility. Three-dimensional micro-computed tomography scans demonstrated that olmesartan treatment increased trabecular bone volume (sham, +176%; angiotensin II infusion, +335%), mineral density (sham, +150%; angiotensin II infusion, +313%), and trabecular number (sham, +407%; angiotensin II infusion, +622%) in the tibia. Olmesartan increased cortical mineral density (sham, +19%; angiotensin II infusion, +24%), decreased the cortical bone section area (sham, -16%; angiotensin II infusion, -18%), decreased thickness (sham, -18%; angiotensin II infusion, -31%), and decreased the lacunar area (sham, -41%; angiotensin II infusion, -27%) in the tibia. Similar trend was observed in the femur. Moreover, olmesartan decreased angiotensin II-induced increases in tartrate-resistant acid phosphatase concentrations in plasma, but it affected neither type I procollagen N-terminal propeptides, nor the receptor activator of nuclear factor kappa-B ligand. Our data suggest that blockade of the angiotensin II type 1 receptor improves bone vulnerability, and helps to maintain the heart's structural integrity in osteoprotegerin-deficient mice.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Densidade Óssea/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Osteíte Deformante/tratamento farmacológico , Osteíte Deformante/fisiopatologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Fêmur/efeitos dos fármacos , Fêmur/patologia , Fêmur/fisiopatologia , Hipertrofia/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Osteíte Deformante/metabolismo , Osteíte Deformante/patologia , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Ligante RANK/sangue , Sístole/efeitos dos fármacos , Sístole/fisiologia , Fosfatase Ácida Resistente a Tartarato/sangue
11.
Trials ; 20(1): 389, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262348

RESUMO

BACKGROUND: Hypertension is an important risk factor for cardiovascular disease, even in the elderly. Fimasartan is a new non-peptide angiotensin II receptor blocker with a selective type I receptor blocking effect. The objective of this study is to confirm the safety and the non-inferiority of the blood pressure-lowering effect of fimasartan compared with those of perindopril, which has been proven safe and effective in elderly patients with hypertension. METHODS: This is a randomized, double-blind, active-controlled, two-parallel group, optional-titration, multicenter, phase 3 study comparing the efficacy and safety of fimasartan and perindopril arginine. The study population consists of individuals 70 years old or older with essential hypertension. The primary outcome will be a change in sitting systolic blood pressure from baseline after the administration of the investigational product for 8 weeks. The secondary outcomes will be a change in sitting diastolic blood pressure from baseline and changes in sitting systolic blood pressure and diastolic blood pressure from baseline after the administration of the investigational product for 4, 16, and 24 weeks. The sample size will be 119 subjects for each group to confer enough power to test for the primary outcome. DISCUSSION: Research to confirm the efficacy and safety of a new medicine compared with those of previously proven anti-hypertensive drugs is beneficial to guide physicians in the selection of therapeutic agents. If it is confirmed that the new drug is not inferior to the existing drug, the drug will be considered as an option in the treatment of hypertension in elderly patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03246555 , registered on July 25, 2017.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/uso terapêutico , Hipertensão Essencial/tratamento farmacológico , Perindopril/uso terapêutico , Pirimidinas/uso terapêutico , Tetrazóis/uso terapêutico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Compostos de Bifenilo/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Diuréticos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Estudos de Equivalência como Asunto , Hipertensão Essencial/diagnóstico , Hipertensão Essencial/fisiopatologia , Feminino , Humanos , Masculino , Estudos Multicêntricos como Assunto , Perindopril/efeitos adversos , Pirimidinas/efeitos adversos , República da Coreia , Tetrazóis/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
13.
J Stroke Cerebrovasc Dis ; 28(8): 2262-2267, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31178359

RESUMO

BACKGROUND AND PURPOSE: Uncertainty persists over the effects of blood pressure-lowering treatment in acute intracerebral hemorrhage (ICH). We assessed the effects of treatment with candesartan in acute ICH and according to different types of hematoma. METHODS: Post-hoc analysis of the Scandinavian Candesartan Acute Stroke Trial, a randomized- and placebo-controlled, double-masked trial of candesartan in patients with any stroke within the acute phase (<30 hours) and high systolic blood pressure (≥140 mm Hg). We collected baseline computed tomography scans of participants with ICH, and characterized hematoma volume (planimetric approach), location (deep versus lobar or infratentorial), hemisphere side, and presence of intraventricular hemorrhage. The trial's 2 coprimary effect variables were the composite endpoint of vascular death, stroke or myocardial infarction, and functional outcome at 6 months according to the modified Rankin scale. We used Cox, ordinal, and binary logistic regression for analysis and adjusted for key, predefined prognostic variables. RESULTS: Of 274 participants with ICH, computed tomography scans were available in 205 patients (74.8%). There were no significant differences between the candesartan and placebo groups with respect to hematoma volume (median 15.6 mL versus 13.5 mL, P = .96), deep location (77% versus 72%, P = .64), right hemisphere (49% versus 51%, P = .46), and presence of intraventricular hemorrhage (18% versus 11%, P = .22). Candesartan was associated with a significant increase in poor functional outcome in patients with deep hematoma (adjusted common odds ratio 2.27, 95% confidence interval 1.23-4.18, P = .009, P for interaction .015), but there was no differential effect on functional outcome or vascular events in any of the other imaging subgroups. CONCLUSIONS: Candesartan was not associated with any beneficial effect when initiated in the acute phase of ICH, a possible adverse effect on functional outcome in patients with deep hematomas cannot be ruled out by this study alone.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Hematoma/tratamento farmacológico , Tetrazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Benzimidazóis/efeitos adversos , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/fisiopatologia , Método Duplo-Cego , Feminino , Hematoma/diagnóstico por imagem , Hematoma/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Países Escandinavos e Nórdicos , Tetrazóis/efeitos adversos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
World J Pediatr Congenit Heart Surg ; 10(3): 292-295, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31084317

RESUMO

BACKGROUND: Heart failure (HF) is the leading cause of hospitalizations and death in patients with adult congenital heart disease (ACHD). Sacubitril/valsartan is a new agent in the treatment of HF, but its effects have not been assessed in ACHD. METHODS: We retrospectively studied all 15 patients with ACHD at our center who were prescribed sacubitril/valsartan between June 2017 and June 2018. We assessed baseline characteristics and clinical and laboratory changes after initiation of sacubitril/valsartan. Adverse events, including renal function, medication intolerance, and worsening HF were documented. RESULTS: The median age was 53.2 (27.6-83.6) years, with a median follow-up duration of 69 (8-419) days. At baseline, all patients had refractory HF despite guideline-directed medical therapy, with ten (67%) patients as New York Heart Association (NYHA) class II, and five (33%) patients NYHA class III. The medication was discontinued in one (7%) patient secondary to worsening kidney function. No patients reported clinical deterioration; four NYHA class III patients with complex CHD, pulmonary hypertension, and cyanosis reported significant improvement to NYHA class II. Baseline creatinine was 1.1 (0.9-1.7) and two weeks after starting sacubitril/valsartan it was 1.3 (0.8-2.5, P = .22). CONCLUSIONS: Sacubitril/valsartan seems to be well tolerated in patients with ACHD who present with refractory HF symptoms. Patients with complex CHD associated with cyanosis and pulmonary hypertension could benefit the most, but larger studies are needed to assess the safety as well as the effectiveness of sacubitril/valsartan in this patient population.


Assuntos
Aminobutiratos/uso terapêutico , Cardiopatias Congênitas/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Volume Sistólico/fisiologia , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Feminino , Seguimentos , Cardiopatias Congênitas/complicações , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
15.
J Renin Angiotensin Aldosterone Syst ; 20(2): 1470320319851310, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31117912

RESUMO

INTRODUCTION: Bone marrow renin-angiotensin system(RAS) modulates acute myeloid leukaemia(AML).The aim of this study is to clarify the relationships between RAS and AML, and to show the effect of losartan and doxorubicin treatment in AML cell lines. METHODS: AML cell lines including CESS, HL-60, MO-1, P31/FUJ, GDM-1 and KASUMI-3 were used as models in this study. RESULTS: After treating the six AML cell lines with a combination of losartan and doxorubicin, they were divided into two groups based on their behaviour: one became more sensitive to drug treatment (Group A) and the other had no change observed in behaviour after drug treatment (Group B). In silico analyses showed that Group A is involved in cellular apoptosis, while Group B is involved in tumour angiogenesis further supporting the in vitro results. CONCLUSION: The combined treatment of the AML cell lines with losartan and doxorubicin resulted in an increase in sensitivity of some of the cell lines. Those leukaemic cells are modulated via the induction of apoptosis, whereas the other cells resistant to the drug treatment are closely related to tumour angiogenesis indicating that RAS-AT1R seems to be differently expressed in different leukaemic blast cells and tumour microenvironments. Pharmaco-biological actions of RAS inhibitors may be different in distinct leukaemic cells based on the pathological behaviour of AML genomic subtypes.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Losartan/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Losartan/farmacologia , Transdução de Sinais/efeitos dos fármacos
16.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945668

RESUMO

The aim of this study was to determine whether the polymorphism of aldosterone synthase (CYP11B2) -344C/T and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) were associated with the response of blood pressure (BP) to telmisartan treatment. After a two-week single-blind placebo run-in period, 148 patients with mild-to-moderate primary hypertension received monotherapy of telmisartan with 80 mg/day and then were followed up for eight weeks. Polymorphisms of CYP11B2 -344C/T and ACE I/D gene were determined through polymerase chain reaction-restriction fragment polymorphism analysis. The relationship between these polymorphisms and changes in BP was monitored and evaluated after eight weeks of treatment. With respect tothe polymorphism of CYP11B2 -344C/T, the reduction in diastolic BP was significantly greater in patients carrying the C allele (CC+CT) compared with those carrying the TT genotype. There was no significant differences between ACE I/D polymorphism and BP reduction after treatment. We concluded that the aldosterone synthase -344C/T polymorphism was related to the antihypertensive treatment with telmisartan in hypertensive patients.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Pressão Sanguínea , Citocromo P-450 CYP11B2/genética , Hipertensão/genética , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único , Telmisartan/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Seguimentos , Genótipo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Método Simples-Cego , Adulto Jovem
17.
J Vet Med Sci ; 81(5): 717-722, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30956271

RESUMO

Maintaining a good ventricular systolic function is important in the long-term therapy of dogs with supraventricular tachyarrhythmia (SVTA). The objective of this study was to evaluate the inhibitory effect of telmisartan on myocardial injury and the resulting ventricular systolic dysfunction in a canine model of SVTA. A total of 14 dogs were randomly assigned to a Telmisartan (oral telmisartan, 1.0 mg/kg daily, n=7) or a Control (no drug administration, n=7) group; the duration of rapid atrial pacing (RAP) was 3 weeks for both groups. The cardiac troponin I (cTnI) concentration in the Control group was significantly increased after 3 weeks compared to that before RAP initiation (baseline), but no significant difference was observed in the Telmisartan group. Moreover, the cTnI concentration at 3 weeks was significantly lower in the Telmisartan group than in the Control group. The left ventricular fractional shortening was significantly decreased at 3 weeks compared to that at baseline in both groups. However, fractional shortening at 3 weeks was significantly higher in the Telmisartan group than in the Control group. The cardiac output values in the Control group were significantly decreased at 3 weeks compared with those at baseline, but no significant difference was observed in the Telmisartan group. This study demonstrates that telmisartan inhibits the reduction in ventricular systolic function and prevents myocardial injury in a canine model of SVTA. Therefore, telmisartan is suggested as a novel treatment for canine SVTA.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Taquicardia Supraventricular/veterinária , Telmisartan/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Animais , Débito Cardíaco/efeitos dos fármacos , Estimulação Cardíaca Artificial/veterinária , Doenças do Cão/tratamento farmacológico , Cães , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Miocárdio/patologia , Taquicardia Supraventricular/tratamento farmacológico , Telmisartan/administração & dosagem , Troponina I/sangue , Troponina I/efeitos dos fármacos , Função Ventricular/efeitos dos fármacos
18.
Hum Immunol ; 80(8): 573-578, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31014826

RESUMO

High levels of angiotensin receptor antibodies (ATRab) are associated with acute cellular and humoral rejection, vascular occlusion, de novo human leucocyte antigen donor specific antibody (HLA DSA) and poor graft survival in kidney transplant recipients (KTR). Since 2015 we proactively managed patients "at risk" (AR) with ATRab >17 U/ml with perioperative plasma exchange (PLEX) and/or angiotensin receptor blockade (ARB). 44 patients were treated with this protocol. 265 KTR with ATRab ≤17 U/ml deemed "low risk" (LR) were transplanted under standard conditions. PLEX and ARB were not associated with increased risk of: delayed graft function requiring haemodialysis (HDx), hyperkalaemia >5.5 mmol/l requiring HDx, and the combined clinical end-point of severe hypotension, blood transfusion and re-operation for bleeding. Rejection rates were similar at 90 days: 8/44 (18%) in the AR group and 36/265 (14%) in the LR group (p = 0.350). Death censored graft survival was the same between the AR and LR groups with a 94% 48-month graft survival - hazard ratio (log-rank) 1.16 [95% CI 0.2-5.8] p = 0.844. Proactive treatment of ATRab >17 U/ml with PLEX and/or ARB is not associated with increased rates of perioperative complications and comparable rates of rejection and death censored graft survival at 4 years compared to KTR <17 U/ml ATRab.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Autoanticorpos/uso terapêutico , Benzimidazóis/uso terapêutico , Rejeição de Enxerto/imunologia , Transplante de Rim , Troca Plasmática/métodos , Receptores de Angiotensina/imunologia , Tetrazóis/uso terapêutico , Adulto , Idoso , Austrália , Autoanticorpos/metabolismo , Feminino , Seguimentos , Rejeição de Enxerto/mortalidade , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
19.
Int J Mol Sci ; 20(8)2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31013989

RESUMO

The incidence of aging-related disorders may be decreased through strategies influencing the expression of longevity genes. Although numerous approaches have been suggested, no effective, safe, and easily applicable approach is yet available. Efficacy of low-dose fluvastatin and valsartan, separately or in combination, on the expression of the longevity genes in middle-aged males, was assessed. Stored blood samples from 130 apparently healthy middle-aged males treated with fluvastatin (10 mg daily), valsartan (20 mg daily), fluvastatin-valsartan combination (10 and 20 mg, respectively), and placebo (control) were analyzed. They were taken before and after 30 days of treatment and, additionally, five months after treatment discontinuation. The expression of the following longevity genes was assessed: SIRT1, PRKAA, KLOTHO, NFE2L2, mTOR, and NF-κB. Treatment with fluvastatin and valsartan in combination significantly increased the expression of SIRT1 (1.8-fold; p < 0.0001), PRKAA (1.5-fold; p = 0.262) and KLOTHO (1.7-fold; p < 0.0001), but not NFE2L2, mTOR and NF-κB. Both fluvastatin and valsartan alone significantly, but to a lesser extent, increased the expression of SIRT1, and did not influence the expression of other genes. Five months after treatment discontinuation, genes expression decreased to the basal levels. In addition, analysis with previously obtained results revealed significant correlation between SIRT1 and both increased telomerase activity and improved arterial wall characteristics. We showed that low-dose fluvastatin and valsartan, separately and in combination, substantially increase expression of SIRT1, PRKAA, and KLOTHO genes, which may be attributed to their so far unreported pleiotropic beneficial effects. This approach could be used for prevention of ageing (and longevity genes)-related disorders.


Assuntos
Fluvastatina/farmacologia , Expressão Gênica/efeitos dos fármacos , Longevidade/genética , Doenças Neurodegenerativas/prevenção & controle , Valsartana/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Adulto , Envelhecimento/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Fluvastatina/uso terapêutico , Glucuronidase/genética , Humanos , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Sirtuína 1/genética , Telomerase/metabolismo , Valsartana/uso terapêutico
20.
Arterioscler Thromb Vasc Biol ; 39(4): 593-602, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30816798

RESUMO

There is a complex interaction between the brain and the cerebral vasculature to meet the metabolic demands of the brain for proper function. Preservation of cerebrovascular function and integrity has a central role in this sophisticated communication within the brain, and any derangements can have deleterious acute and chronic consequences. In almost all forms of cognitive impairment, from mild to Alzheimer disease, there are changes in cerebrovascular function and structure leading to decreased cerebral blood flow, which may initiate or worsen cognitive impairment. In this focused review, we discuss the contribution of 2 major vasoactive pathways to cerebrovascular dysfunction and cognitive impairment in an effort to identify early intervention strategies.


Assuntos
Circulação Cerebrovascular , Transtornos Cognitivos/fisiopatologia , Cognição/fisiologia , Endotelinas/fisiologia , Sistema Renina-Angiotensina/fisiologia , Doença de Alzheimer/fisiopatologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Barreira Hematoencefálica , Encéfalo/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/fisiologia , Previsões , Humanos , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Angiotensina/fisiologia , Receptores de Endotelina/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos
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