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1.
Medicine (Baltimore) ; 98(47): e17978, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764806

RESUMO

RATIONALE: Marfan syndrome is a rare cause of heart failure due to primary or secondary cardiomyopathy. Recently, sacubitril/valsartan-an angiotensin receptor blocker-neprilysin inhibitor-has been added in clinical practice as a standard therapy for heart failure. To our knowledge, there are no data on sacubitril/valsartan's effects on cardiovascular outcomes in patients with Marfan syndrome. PATIENT CONCERNS: A 24-year-old man was admitted to our Internal Medicine Department due to dyspnea, ascites, and leg swelling. Arterial blood gas analysis revealed severe hypoxemia with respiratory and metabolic alkalosis. Hilar congestion was highlighted on chest x-ray. DIAGNOSES: Recurrent acute decompensated heart failure with reduced ejection fraction despite optimal medical therapy in Marfan-related cardiomyopathy. INTERVENTIONS AND OUTCOMES: Sacubitril/valsartan was added to optimal medical therapy after hemodynamic stabilization allowing progressive clinical, laboratoristic, and echocardiographic improvement. Patient maintained a free survival from heart failure and a good quality of life until 9-month follow-up. LESSONS: Sacubitril/valsartan should be effective on pathophysiologic mechanisms and cardiovascular outcomes of Marfan syndrome-related cardiovascular complications.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Síndrome de Marfan/complicações , Tetrazóis/uso terapêutico , Humanos , Masculino , Resultado do Tratamento , Adulto Jovem
2.
Medicine (Baltimore) ; 98(47): e18050, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764831

RESUMO

BACKGROUND: This study aims to systematically explore the efficacy of sacubitril valsartan sodium tablet (SVST) for the treatment of chronic heart failure (CHF). METHODS: Nine electronic databases, including PUBMED, Cochrane Library, EMBASE, PsycINFO, Web of Science, Allied and Complementary Medicine Database, WANGFANG, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure will be searched. Randomized controlled trials on SVST in the treatment of CHF will be collected. The search time limit will be from the establishment of each electronic database until June 1, 2019. Two authors will independently select the literature, carry out the data, and assess the methodological quality. RESULTS: This study will systematically investigate the efficacy and safety of SVST for CHF. The outcomes consist of all-cause mortality, change in body weight, urine output, change in serum sodium; and incidence of any expected and unexpected adverse events. CONCLUSION: The findings of this study will summarize from evidence-based medicine and a scientific basis for the efficacy and safety of SVST in the clinical treatment of CHF. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019138882.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Revisão Sistemática como Assunto , Tetrazóis/uso terapêutico , Doença Crônica , Humanos , Projetos de Pesquisa , Comprimidos , Resultado do Tratamento
3.
Rev Med Suisse ; 15(667): 1882-1886, 2019 Oct 16.
Artigo em Francês | MEDLINE | ID: mdl-31617977

RESUMO

The association of an angiotensin II receptor antagonist and a neprilysin inhibitor (ARNI or Angiotensin Receptor-Neprilysin Inhibitor) is a new actor in the management of heart failure with reduced left ventricular ejection fraction (LVEF). The PARADIGM-HF trial performed in outpatients with a LVEF ≤ 35-40 % demonstrated that sacubitril-valsartan was superior to enalapril in reducing cardiovascular mortality and heart failure hospitalizations. Precautions in the initiation of sacubitril-valsartan, its use as well as its place in the drug management strategy for chronic heart failure are described in the present review. Additional data in patients hospitalized with reduced LVEF, in patients with LVEF > 45 % as well as the effects on blood pressure, renal or cognitive functions are presented.


Assuntos
Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Neprilisina/antagonistas & inibidores , Aminobutiratos/farmacologia , Aminobutiratos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cognição/efeitos dos fármacos , Enalapril/farmacologia , Enalapril/uso terapêutico , Insuficiência Cardíaca/metabolismo , Humanos , Rim/efeitos dos fármacos , Neprilisina/metabolismo , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Resultado do Tratamento
4.
Hypertension ; 74(5): 1075-1083, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31495277

RESUMO

Despite the availability of multiple antihypertensive drugs targeting the different pathways implicated in its pathophysiology, hypertension remains poorly controlled worldwide, and its prevalence is increasing because of the aging of the population and the obesity epidemic. Although nonadherence to treatment contributes to uncontrolled hypertension, it is likely that not all the pathophysiological mechanisms are neutralized by the various classes of antihypertensive treatment currently available, and, the counter-regulatory mechanisms triggered by these treatments may decrease their blood pressure-lowering effect. The development of new antihypertensive drugs acting on new targets, with different modes of action, therefore, remains essential, to improve blood pressure control and reduce the residual burden of cardiovascular risks further. However, the difficulties encountered in the conception, development, costs, and delivery to the market of new classes of antihypertensive agents highlights the hurdles that must be overcome to release and to evaluate their long-term safety and efficacy for hypertension only, especially because of the market pressure of cheap generic drugs. New chemical entities with blood pressure-lowering efficacy are thus being developed more for heart failure or diabetic kidney disease, 2 diseases pathophysiologically associated with hypertension. These include dual angiotensin II receptor-neprilysin inhibitors, soluble guanylate cyclase stimulators, nonsteroidal dihydropyridine-based mineralocorticoid receptor antagonists, as well as sodium-glucose cotransporter 2 inhibitors. However, centrally acting aminopeptidase A inhibitors and endothelin receptor antagonists have a dedicated program of development for hypertension. All these emergent drug classes and their potential use in hypertension are reviewed here.


Assuntos
Anti-Hipertensivos/farmacologia , Drogas em Investigação/química , Drogas em Investigação/classificação , Hipertensão/tratamento farmacológico , Neprilisina/efeitos dos fármacos , Aminobutiratos/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Aprovação de Drogas , Sistemas de Liberação de Medicamentos , Feminino , Previsões , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Masculino , Segurança do Paciente , Tetrazóis/uso terapêutico
5.
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
6.
Medicine (Baltimore) ; 98(28): e16093, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305392

RESUMO

BACKGROUND: LCZ696 has been introduced in patients with hypertension in several trials. Here, we performed a meta-analysis to evaluate the effect and safety of LCZ696 in hypertensive patients. METHODS: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov databases were searched to identify the available randomized controlled trials (RCTs) investigating the effect and safety of LCZ696 in hypertension patients. The last search date was October 31, 2018. RESULTS: Nine RCTs with 6765 subjects were finally included, in which 8 trials compared the effect and safety between LCZ696 and angiotensin receptor antagonists (ARBs). Evidences showed LCZ696, compared with ARBs, achieved a better blood pressure control rate (OR 1.24, 95% CI: 1.14-1.35), specifically, LCZ696 were better at reducing systolic blood pressure [WMD -4.11 mmHg, 95% CI: (-5.13, -3.08) mmHg], diastolic blood pressure [WMD -1.79 mmHg, 95% CI: (-2.22, -1.37) mmHg], mean 24-hour ambulatory systolic blood pressure [WMD -3.24 mmHg, 95% CI: (-4.48, -1.99) mmHg] and mean 24-hour ambulatory diastolic blood pressure [WMD -1.25 mmHg, 95% CI: (-1.81, -0.69) mmHg]. There was no difference in the events of adverse events (risk ratio [RR] 1.01, 95% CI: 0.39-1.09), serious adverse events (RR 0.80, 95% CI: 0.52-1.22) and discontinuation of treatment for any adverse events (RR 0.79, 95% CI: 0.56-1.11) between LCZ696 group and ARB/placebo group, except LCZ696 reduced the rate of headaches (RR 0.69, 95% CI: 0.48-0.99) while increased cough (RR 2.12, 95% CI: 1.11-4.04; P = .02; I = 25%). CONCLUSION: Our finding provides evidence that LCZ 696 was more effective than ARB on blood pressure control and was safe enough in patients with hypertension.


Assuntos
Aminobutiratos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Tetrazóis/uso terapêutico , Aminobutiratos/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tetrazóis/efeitos adversos
7.
Neurology ; 93(6): e559-e567, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31292226

RESUMO

OBJECTIVE: To evaluate the effect of cenobamate in patients with photoparoxysmal-EEG response (PPR) to intermittent photic stimulation (IPS) as proof of principle of efficacy in patients with epilepsy. METHODS: In this multicenter, single-blind study, adults with photosensitive epilepsy, with/without concomitant antiepileptic drug therapy, underwent IPS under 3 eye conditions after a single dose of placebo (day -1, day 2) or cenobamate (day 1; 100, 250, or 400 mg). Complete suppression was a standardized photosensitivity range reduction to 0 over ≥1 time points for all eye conditions. Partial suppression was a ≥3-point reduction over ≥3 testing times vs the same time points on day -1 in ≥1 eye condition. Pharmacokinetics and safety were assessed. RESULTS: Of 6 evaluable patients, 5 reentered to receive higher doses. Cenobamate 100 mg produced partial suppression in 1 of 3 patients; 250 mg produced complete suppression in 1 of 4 and partial suppression in 4 of 4 patients; and 400 mg produced complete suppression in 1 of 4 and partial suppression in 2 of 4 patients. PPR was consistently reduced on days 1 and 2 (>24 hours after cenobamate) vs day -1 (placebo) with the 250- and 400-mg doses. Area under the plasma concentration-time curve (before dose to last measurable concentration) values between 201 and 400 µg/h/mL resulted in partial suppression in 4 of 6 (66%) patients. Most common adverse events were dizziness and somnolence. CONCLUSIONS: This proof-of-principle study demonstrated that cenobamate is a potentially effective product for epilepsy. CLINICALTRIALSGOV IDENTIFIER: NCT00616148. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for patients with photosensitive epilepsy, cenobamate suppresses IPS-induced PPR.


Assuntos
Anticonvulsivantes/uso terapêutico , Carbamatos/uso terapêutico , Clorofenóis/uso terapêutico , Epilepsia Reflexa/tratamento farmacológico , Tetrazóis/uso terapêutico , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Área Sob a Curva , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Clorofenóis/efeitos adversos , Clorofenóis/farmacocinética , Relação Dose-Resposta a Droga , Eletroencefalografia , Feminino , Humanos , Masculino , Estimulação Luminosa , Método Simples-Cego , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Adulto Jovem
8.
J Headache Pain ; 20(1): 84, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340760

RESUMO

OBJECTIVE: To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications. BACKGROUND: While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives. METHODS: SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes. RESULTS: In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications. CONCLUSIONS: Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications. TRIAL REGISTRATION: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.


Assuntos
Benzamidas/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/prevenção & controle , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Adulto , Benzimidazóis/uso terapêutico , Toxinas Botulínicas Tipo A/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tetrazóis/uso terapêutico , Resultado do Tratamento
9.
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
10.
Biomed Pharmacother ; 116: 109040, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170664

RESUMO

Intestinal pathophysiological alterations have recently been revealed to be implicated in the pathogenesis of hypertension, necessitating further investigations to better understand the intestinal effects of anti-hypertensive drugs. The current study thus investigated the pharmacological implications of a commonly used first-line angiotensin II type 1 receptor blocker, candesartan cilexetil, on the intestinal barrier impairment and gut dysbiosis in spontaneously hypertensive rats (SHRs). The results revealed that candesartan treatment protected against ileal and colonic pathologies and increased the intestinal expression of genes encoding tight junction proteins such as cingulin, occludin and tight junction protein 1 in SHRs. Serum level of lipopolysaccharides-binding protein was increased in candesartan-treated SHRs, supporting the notion that candesartan treatment provided protection against hypertension-associated impairment of intestinal barrier. Candesartan treatment also increased the amount of fecal short-chain fatty acids (SCFAs) including acetic acid, propionic acid, and butyric acid in SHRs. Fecal 16S rDNA sequencing further revealed that candesartan treatment normalized hypertension-altered ratio of Firmicutes to Bacteroidetes in SHRs. Most notably, candesartan treatment counteracted hypertension-associated diminishment of lactic acid-producing genus Lactobacillus. Taken together, the current study demonstrates for the first time that candesartan treatment alleviates hypertension-associated pathophysiological alterations in the gut, increases microbial production of SCFAs and preserves gut Lactobacillus under hypertensive conditions, which sheds novel light on the pharmacological implications of candesartan in the treatment of hypertension.


Assuntos
Benzimidazóis/uso terapêutico , Trato Gastrointestinal/fisiopatologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Tetrazóis/uso terapêutico , Animais , Benzimidazóis/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Colo/efeitos dos fármacos , Colo/patologia , Colo/fisiopatologia , Ácidos Graxos/metabolismo , Fezes/química , Fibrose , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Íleo/efeitos dos fármacos , Íleo/patologia , Íleo/fisiopatologia , Lactobacillus/efeitos dos fármacos , Masculino , Permeabilidade , Ratos Endogâmicos SHR , Tetrazóis/farmacologia
12.
World Neurosurg ; 128: e639-e648, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31054336

RESUMO

BACKGROUND: Clazosentan, an endothelin-1 receptor antagonist, has been shown to prevent the development of large vessel angiographic vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). It has been hypothesized that clazosentan can also reverse established angiographic vasospasm. METHODS: The REVERSE (resynchronization reverses remodeling in systolic left ventricular dysfunction) study was a prospective, multicenter, open-label, 2-stage pilot study of adult patients with aSAH who had received intravenous clazosentan (15 mg/hour) after developing moderate-to-severe angiographic vasospasm. The primary efficacy endpoint was the reversal of global cerebral vasospasm in large cerebral artery segments 3 hours after clazosentan initiation. The secondary endpoints included large artery vasospasm reversal at 24 hours and the maximum change in the angiographic cerebral circulation time. The change in vasospasm severity in the proximal and distal segments was investigated in an exploratory analysis. RESULTS: The primary efficacy endpoint was met in 3 of 11 evaluable patients (27.3%; 95% confidence interval, 6.0-61.0). However, recruitment was stopped after stage 1 in accordance with the predefined interim analysis criteria. In the exploratory analysis, 50.0% and 77.8% of the patients showed a significant reversal of vasospasm or improvement to the admission state in ≥2 distal segments at 3 and 24 hours and 28.6% and 77.8% in ≥2 proximal segments, respectively. CONCLUSIONS: Although the main analysis showed a reversal of large vessel vasospasm 3 hours after clazosentan initiation in a few patients, the exploratory analysis indicated a clear pharmacodynamic dilating effect on vasospastic cerebral vessels at 24 hours in most patients, in particular, in the distal arterial beds. This observation supported the inclusion of patients with established vasospasm in the ongoing REACT (prevention and treatment of vasospasm with clazosentan) trial.


Assuntos
Dioxanos/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Hemorragia Subaracnóidea/terapia , Sulfonamidas/uso terapêutico , Tetrazóis/uso terapêutico , Vasoespasmo Intracraniano/tratamento farmacológico , Adulto , Angiografia Digital , Angiografia Cerebral , Embolização Terapêutica , Procedimentos Endovasculares , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Projetos Piloto , Hemorragia Subaracnóidea/complicações , Instrumentos Cirúrgicos , Vasoespasmo Intracraniano/etiologia , Adulto Jovem
13.
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
14.
Biomed Pharmacother ; 116: 108954, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108352

RESUMO

BACKGROUND: This study tested the hypothesis that Entresto could safely and effectively preserve heart and kidney function in rats with cardiorenal syndrome (CRS) induced by 5/6 nephrectomy and intra-peritoneal doxorubicin administration (accumulated dosage up to 7.5 mg/kg) together with daily high-protein-diet (HPD). METHODS AND RESULTS: Adult male Sprague-Dawley rats (n = 24) were equally categorized into Group 1 (sham-operated control + HPD), Group 2 (CRS + HPD) and Group 3 [CRS + HPD + Entresto (100 mg/kg/day orally) since Day 14 after CRS induction] and euthanized by Day 63 after CRS induction. By Day 63, circulatory BUN and creatinine levels and ratios of urine protein to creatinine were significantly higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, whereas left-ventricular ejection fraction and kidney weight showed an opposite pattern among all groups (all p < 0.001). Microscopically, fibrosis area and intensity of oxidative stress (i.e., DCFDA stain) in kidney/heart tissues exhibited a pattern identical to that of creatinine level among all groups (all p < 0.0001). Kidney injury score and protein expressions of autophagy (i.e., beclin-1/Atg-5/protein ratio of LC3-BII/LC3-BI), fibrosis (Smad3/TGF-ß), apoptosis (mitochondrial-Bax/capase2/3/9), oxidative-stress (NOX-4/oxidized protein/xanthine-oxidase/catalase), membranous p47phox phosphorylation and mitochondrial-damage biomarker (cytosolic-cytochrome-C) were higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, while protein expressions of anti-apoptosis (Bcl-2/Bcl-XL) and mitochondrial integrity (mitochondrial-cytochrome-C) markers displayed an opposite pattern among all groups in kidney tissues (all p < 0.0001). CONCLUSION: Oral administration of entresto was safe and could offer protection against CRS-induced heart and kidney damage.


Assuntos
Aminobutiratos/uso terapêutico , Síndrome Cardiorrenal/tratamento farmacológico , Dieta Rica em Proteínas , Rim/patologia , Tetrazóis/uso terapêutico , Aminobutiratos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Nitrogênio da Ureia Sanguínea , Síndrome Cardiorrenal/sangue , Síndrome Cardiorrenal/genética , Síndrome Cardiorrenal/fisiopatologia , Creatinina/sangue , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Miocárdio/patologia , NADPH Oxidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Tetrazóis/farmacologia
15.
Cardiology ; 142(2): 73-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30999300

RESUMO

BACKGROUND: Women are underrepresented in sacubitril/valsartan (SV) clinical trials. The aim of this study was to assess sex-specific differences in efficacy, tolerability, and safety of SV in real-world heart failure with reduced ejection fraction (HFrEF) patients. METHODS: A prospective registry in 10 centers including all patients who started SV during the last 6 months was analyzed in this study. RESULTS: A total of 427 patients were included, 126 (29.5%) were women. There were no substantial differences in HFrEF treatment before SV initiation, although fewer women than men carried an implantable cardioverter defibrillator (57 [45.2%] vs. 173 [58.1%], p = 0.02). SV starting dose was 24/26 mg b.i.d. in 206 patients (48.2%), 49/51 mg b.i.d. in 184 (43.1%), and 97/103 mg b.i.d. in 34 (8.2%), without relevant differences associated to sex. There were no losses during a mean follow-up of 7.0 ± 0.1 months. The proportion of patients who discontinued the drug (16 [12.7%] women vs. 33 [11.0%] men, p = 0.66) or presented SV-related adverse effects (31 [24.6%] women vs. 79 [26.5%] men, p = 0.72) was also similar in both sexes. However, female sex was an independent predictor of functional class improvement in the multivariate analysis (odds ratio 2.33, 95% confidence interval: 1.24-4.38, p = 0.04). CONCLUSIONS: SV in women with HFrEF has a similar tolerability as in men. Females seem to have a more frequent functional class improvement than males.


Assuntos
Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Fatores Sexuais , Volume Sistólico , Tetrazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aminobutiratos/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Espanha , Tetrazóis/farmacologia , Resultado do Tratamento
16.
Dtsch Med Wochenschr ; 144(8): 553-560, 2019 04.
Artigo em Alemão | MEDLINE | ID: mdl-30986864

RESUMO

Enterococci with special resistance patterns (mainly vancomycin-resistant enterococci) play an important role in everyday clinical practice. Rising resistance rates to linezolid, daptomycin or tigecycline are also increasingly reported. Therapeutically, linezolid and daptomycin are the most important substances mainly in infections due to vancomycin-resistant enterococci. Several systematic meta-analyses of bloodstream infections showed discrepant results in the comparison of mortality of linezolid and daptomycin-treated bacteraemias. The containment of enterococci with special resistance patterns is currently receiving great attention. The key hygienic issue in all recommendations for dealing with multidrug-resistant enterococci can be summarized very simply: current scientific evidence is often inconsistent and studies that have clearly tested a single intervention for efficacy are lacking. The present work gives an insight into the current epidemiology and therapeutic strategies. Furthermore, the recently published German KRINKO recommendations are presented.


Assuntos
Antibacterianos/farmacologia , Enterococcus/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/microbiologia , Antibacterianos/uso terapêutico , Daptomicina/farmacologia , Daptomicina/uso terapêutico , Farmacorresistência Bacteriana , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/epidemiologia , Infecções por Bactérias Gram-Positivas/prevenção & controle , Humanos , Linezolida/farmacologia , Linezolida/uso terapêutico , Lipoglicopeptídeos/farmacologia , Lipoglicopeptídeos/uso terapêutico , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Tetrazóis/farmacologia , Tetrazóis/uso terapêutico , Tigeciclina/farmacologia , Tigeciclina/uso terapêutico , Resistência a Vancomicina
17.
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
18.
PLoS One ; 14(4): e0214293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964905

RESUMO

BACKGROUND: Angiotensin II receptor blockers (ARBs) are recommended for treating patients with hypertension. However, comparative safety and efficacy of ARB use in elderly patients have not been well established. This study was designed to determine the efficacy of fimasartan, an ARB, in hypertensive elderly patients by measuring clinic and home blood pressures (BPs) and evaluating safety compared to nonelderly patients. METHOD: In the K-MetS study, a nationwide prospective observational study of hypertensive patients on fimasartan, elderly patients (60 years and older) who were treated for 1 year with fimasartan were recruited. BP was evaluated in clinic and at home. RESULTS: Of the 6 399 enrolled patients, 2 363 were elderly (46.9% males, mean age 67.3 ± 5.7 years). Fimasartan reduced systolic and diastolic BP (SBP and DBP) in clinic from 144.1 ± 17.3 to 127.7 ± 12.9 mmHg and from 85.1 ± 10.4 to 76.8 ± 8.4 mmHg, respectively, (all p<0.0001) in 1 year. Similar results were found in home BPs. These BP changes were consistent with those in nonelderly patients. However, pulse pressure, a better predictor of cardiovascular events in the elderly, decreased more in elderly than in nonelderly patients by -8.2 ± 0.3 in elderly and -7.0 ± 0.2 mmHg (p<0.0001), respectively, after adjustment for confounding factors. Adverse events were reported in 1.6% of elderly hypertensives, independent of dose, which was consistent with results in nonelderly patients. CONCLUSIONS: Fimasartan resulted in better pulse pressure reduction with similar BP reduction efficacy and safety in hypertensive elderly patients compared with nonelderly patients.


Assuntos
Compostos de Bifenilo/uso terapêutico , Pressão Sanguínea , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Pirimidinas/uso terapêutico , Tetrazóis/uso terapêutico , Idoso , Compostos de Bifenilo/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Tetrazóis/efeitos adversos
19.
Neurology ; 92(13): e1435-e1446, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30814321

RESUMO

OBJECTIVE: To assess whether long-term treatment with candesartan/hydrochlorothiazide, rosuvastatin, or their combination can slow cognitive decline in older people at intermediate cardiovascular risk. METHODS: The Heart Outcomes Prevention Evaluation-3 (HOPE-3) study was a double-blind, randomized, placebo-controlled clinical trial using a 2 × 2 factorial design. Participants without known cardiovascular disease or need for treatment were randomized to candesartan (16 mg) plus hydrochlorothiazide (12.5 mg) or placebo and to rosuvastatin (10 mg) or placebo. Participants who were ≥70 years of age completed the Digit Symbol Substitution Test (DSST), the modified Montreal Cognitive Assessment, and the Trail Making Test Part B at baseline and study end. RESULTS: Cognitive assessments were completed by 2,361 participants from 228 centers in 21 countries. Compared with placebo, candesartan/hydrochlorothiazide reduced systolic blood pressure by 6.0 mm Hg, and rosuvastatin reduced low-density lipoprotein cholesterol by 24.8 mg/dL. Participants were followed up for 5.7 years (median), and 1,626 completed both baseline and study-end assessments. Mean participant age was 74 years (SD ±3.5 years); 59% were women; 45% had hypertension; and 24% had ≥12 years of education. The mean difference in change in DSST scores was -0.91 (95% confidence interval [CI] -2.25 to 0.42) for candesartan/hydrochlorothiazide compared with placebo, -0.54 (95% CI -1.88 to 0.80) for rosuvastatin compared with placebo, and -1.43 (95% CI -3.37 to 0.50) for combination therapy vs double placebo. No significant differences were found for other measures. CONCLUSIONS: Long-term blood pressure lowering with candesartan plus hydrochlorothiazide, rosuvastatin, or their combination did not significantly affect cognitive decline in older people. CLINICALTRIALSGOV IDENTIFIER: NCT00468923. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for older people, candesartan plus hydrochlorothiazide, rosuvastatin, or their combination does not significantly affect cognitive decline.


Assuntos
Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Disfunção Cognitiva/epidemiologia , Hidroclorotiazida/uso terapêutico , Hipolipemiantes/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Tetrazóis/uso terapêutico , Idoso , Cognição , Combinação de Medicamentos , Feminino , Humanos , Masculino
20.
Minerva Cardioangiol ; 67(3): 214-222, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30895762

RESUMO

INTRODUCTION: The efficacy and safety of sacubitril/valsartan used as an antihypertensive agent has not yet been completely assessed. Thus, to investigate them in elderly hypertensive patients, a meta-analysis has been performed. EVIDENCE ACQUISITION: The meta-analysis incorporated only randomized controlled trials (RCTs) in which sacubitril/valsartan was compared with a reference drug. The mean reductions in systolic blood pressure (msSBP) and diastolic blood pressure (msDBP) in the sitting position as well as the mean reductions in ambulatory systolic blood pressure (maSBP) and ambulatory diastolic blood pressure (maDBP), were assumed as efficacy endpoints. Adverse events were taken as safety outcomes. EVIDENCE SYNTHESIS: Five RCTs were included for a total of 1513 patients for analysis. In all studies, the comparator drug was an angiotensin receptor blocker (ARB) - valsartan in two cases and olmesartan in the remaining three cases. Compared with ARBs, there was a significant reduction in msSBP (weight mean difference [WMD] -5.41 mmHg, 95% CI: -7.0 to -3.8; P<0.01), msDBP (WMD=-1.22 mmHg, 95% CI: -2.15 to -0.3; P<0.01), maSBP (WMD=-4.58 mmHg, 95% CI: -5.62 to -3.54; P<0.01) and maDBP (WMD=-2.17 mmHg, 95% CI: - 2.78 to -1.56; P<0.01) in elderly hypertensive patients at 12 weeks. CONCLUSIONS: Sacubitril/valsartan may reduce arterial pressure more efficaciously than ARBs in elderly hypertensive patients.


Assuntos
Aminobutiratos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Tetrazóis/uso terapêutico , Valsartana/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Aminobutiratos/efeitos adversos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Anti-Hipertensivos/efeitos adversos , Combinação de Medicamentos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tetrazóis/efeitos adversos , Valsartana/efeitos adversos
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