RESUMO
The chemical structure of piperidine has a unique ability to combine with other molecular fragments. This fact makes it possible to actively use it as an effective basis for the creation of new drug-like substances. Thus, the aim of the current investigation was to study the acute toxicity, local anesthetic potency, and antiarrhythmic activity of the two new synthesized piperidine derivatives under laboratory codes LAS-286 and LAS-294 (local anesthetic substances). The Bulbring & Wajda animal model and method of determining the nociception threshold during electrical stimulation was used to investigate the action of the substance during infiltration anesthesia. An antiarrhythmic activity was observed by the aconitine-induced rat arrhythmia model. Additionally, these compounds were studied in relation to molecular docking to delineate the structure-activity relationships. The tested piperidine derivatives had a low toxicity in the subcutaneous and intravenous administration routes. The experimental results showed a higher prolonged and pronounced local anesthetic activity for LAS-286 at a 0.5% concentration, compared to the reference preparations. The low dosage of 0.1 mg/kg of LAS-294 demonstrated a pronounced preventive antiarrhythmic effect in 90% of cases on the development of mixed arrhythmia, caused by aconitine. The results of molecular docking confirmed a higher binding affinity of the tested piperidines with the Nav1.4 and Nav1.5 macromolecules. The results of the present study are very promising, because these piperidines have shown a high biological activity, which can suggest a potential therapeutic application in the future.
Assuntos
Anestésicos Locais , Antiarrítmicos , Simulação de Acoplamento Molecular , Piperidinas , Animais , Antiarrítmicos/farmacologia , Anestésicos Locais/farmacologia , Piperidinas/farmacologia , Piperidinas/química , Ratos , Masculino , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Relação Estrutura-Atividade , Ratos Wistar , Modelos Animais de DoençasAssuntos
Benzazepinas , Ivabradina , Ivabradina/uso terapêutico , Ivabradina/farmacologia , Humanos , Benzazepinas/uso terapêutico , Benzazepinas/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Antiarrítmicos/uso terapêutico , Antiarrítmicos/farmacologia , Taquicardia Ventricular/tratamento farmacológicoRESUMO
BACKGROUND: Amiodarone (AMIO) is an antiarrhythmic drug with the pKa in the physiological range. Here, we explored how mild extracellular pH (pHe) changes shape the interaction of AMIO with atrial tissue and impact its pharmacological properties in the classical model of sea anemone sodium channel neurotoxin type 2 (ATX) induced late sodium current (INa-Late) and arrhythmias. METHOD: Isolated atrial cardiomyocytes from male Wistar rats and human embryonic kidney cells expressing SCN5A Na+ channels were used for patch-clamp experiments. Isolated right atria (RA) and left atria (LA) tissue were used for bath organ experiments. RESULTS: A more acidophilic pHe caused negative inotropic effects on isolated RA and LA atrial tissue, without modification of the pharmacological properties of AMIO. A pHe of 7.0 changed the sodium current (INa) related components of the action potential (AP), which was enhanced in the presence of AMIO. ATXinduced arrhythmias in isolated RA and LA. Also, ATX prolonged the AP duration and enhanced repolarization dispersion in isolated cardiomyocytes in both pHe 7.4 and pHe 7.0. Pre-incubation of the isolated RA and LA and isolated atrial cardiomyocytes with AMIO prevented arrhythmias induced by ATX only at a pHe of 7.0. Moreover, AMIO was able to block INa-Late induced by ATX only at a pHe of 7.0. CONCLUSION: The pharmacological properties of AMIO concerning healthy rat atrial tissue are not dependent on pHe. However, the prevention of arrhythmias induced by INa-Late is pHe-dependent. The development of drugs analogous to AMIO with charge stabilization may help to create more effective drugs to treat arrhythmias related to the INa-Late.
Assuntos
Potenciais de Ação , Amiodarona , Antiarrítmicos , Arritmias Cardíacas , Átrios do Coração , Miócitos Cardíacos , Ratos Wistar , Animais , Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Masculino , Humanos , Ratos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Potenciais de Ação/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Concentração de Íons de Hidrogênio , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/induzido quimicamente , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Células HEK293 , Sódio/metabolismo , Técnicas de Patch-Clamp , Venenos de Cnidários/farmacologiaAssuntos
Compostos Benzidrílicos , Cardiomiopatias , Cardiomiopatia Chagásica , Glucosídeos , Taquicardia Ventricular , Humanos , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/tratamento farmacológico , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/prevenção & controleRESUMO
BACKGROUND/INTRODUCTION: Heart failure patients with reduced ejection fraction are at high risk for ventricular arrhythmias and sudden cardiac death. Ivabradine, a specific inhibitor of the If current in the sinoatrial node, provides heart rate reduction in sinus rhythm and angina control in chronic coronary syndromes. OBJECTIVE: The effect of ivabradine on ventricular arrhythmias in heart failure patients with reduced ejection fraction patients has not been fully elucidated. The aim of this study was to investigate the effect of ivabradine use on life-threatening arrhythmias and long-term mortality in heart failure patients with reduced ejection fraction patients. METHODS: In this retrospective study, 1,639 patients with heart failure patients with reduced ejection fraction were included. Patients were divided into two groups: ivabradine users and nonusers. Patients presenting with ventricular tachycardia, the presence of ventricular extrasystole, and ventricular tachycardia in 24-h rhythm monitoring, appropriate implantable cardioverter-defibrillator shocks, and long-term mortality outcomes were evaluated according to ivabradine use. RESULTS: After adjustment for all possible variables, admission with ventricular tachycardia was three times higher in ivabradine nonusers (95% confidence interval 1.5-10.2). The presence of premature ventricular contractions and ventricular tachycardias in 24-h rhythm Holter monitoring was notably higher in ivabradine nonusers. According to the adjusted model for all variables, 4.1 times more appropriate implantable cardioverter-defibrillator shocks were observed in the ivabradine nonusers than the users (95%CI 1.8-9.6). Long-term mortality did not differ between these groups after adjustment for all covariates. CONCLUSION: The use of ivabradine reduced the appropriate implantable cardioverter-defibrillator discharge in heart failure patients with reduced ejection fraction patients. Ivabradine has potential in the treatment of ventricular arrhythmias in heart failure patients with reduced ejection fraction patients.
Assuntos
Insuficiência Cardíaca , Taquicardia Ventricular , Disfunção Ventricular Esquerda , Humanos , Ivabradina/uso terapêutico , Ivabradina/farmacologia , Volume Sistólico/fisiologia , Estudos Retrospectivos , Arritmias Cardíacas/tratamento farmacológico , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Taquicardia Ventricular/tratamento farmacológicoRESUMO
BACKGROUND: Despite no evidence showing benefits of hydroxychloroquine and chloroquine with or without azithromycin for COVID-19 treatment, these medications have been largely prescribed in Brazil. OBJECTIVES: To assess outcomes, including in-hospital mortality, electrocardiographic abnormalities, hospital length-of-stay, admission to the intensive care unit, and need for dialysis and mechanical ventilation, in hospitalized COVID-19 patients who received chloroquine or hydroxychloroquine, and to compare outcomes between those patients and their matched controls. METHODS: A retrospective multicenter cohort study that included consecutive laboratory-confirmed COVID-19 patients from 37 Brazilian hospitals from March to September 2020. Propensity score was used to select matching controls by age, sex, cardiovascular comorbidities, and in-hospital use of corticosteroid. A p-value <0.05 was considered statistically significant. RESULTS: From 7,850 COVID-19 patients, 673 (8.6%) received hydroxychloroquine and 67 (0.9%) chloroquine. The median age in the study group was 60 years (46 - 71) and 59.1% were women. During hospitalization, 3.2% of patients presented side effects and 2.2% required therapy discontinuation. Electrocardiographic abnormalities were more prevalent in the chloroquine/hydroxychloroquine group (13.2% vs. 8.2%, p=0.01), and the long corrected QT interval was the main difference (3.6% vs. 0.4%, p<0.001). The median hospital length of stay was longer in the HCQ/CQ + AZT group than in controls (9.0 [5.0, 18.0] vs. 8.0 [4.0, 14.0] days). There was no statistical differences between groups in intensive care unit admission (35.1% vs. 32.0%; p=0.282), invasive mechanical ventilation support (27.0% vs. 22.3%; p=0.074) or mortality (18.9% vs. 18.0%; p=0.682). CONCLUSION: COVID-19 patients treated with chloroquine or hydroxychloroquine had a longer hospital length of stay, when compared to matched controls. Intensive care unit admission, invasive mechanical ventilation, dialysis and in-hospital mortality were similar.
FUNDAMENTO: Apesar da ausência de evidência mostrando benefícios da hidroxicloroquina e da cloroquina combinadas ou não à azitromicina no tratamento da covid-19, esses medicamentos têm sido amplamente prescritos no Brasil. OBJETIVOS: Avaliar desfechos, incluindo moralidade hospitalar, alterações eletrocardiográficas, tempo de internação, admissão na unidade de terapia intensiva, e necessidade de diálise e de ventilação mecânica em pacientes hospitalizados com covid-19 que receberam cloroquina ou hidroxicloroquina, e comparar os desfechos entre aqueles pacientes e seus controles pareados. MÉTODOS: Estudo multicêntrico retrospectivo do tipo coorte que incluiu pacientes com diagnóstico laboratorial de covid-19 de 37 hospitais no Brasil de março a setembro de 2020. Escore de propensão foi usado para selecionar controles pareados quanto a idade, sexo, comorbidades cardiovasculares, e uso de corticosteroides durante a internação. Um valor de p<0,05 foi considerado estatisticamente significativo. RESULTADOS: Dos 7850 pacientes com covid-19, 673 (8,6%) receberam hidroxicloroquina e 67 (0,9%) cloroquina. A idade mediana no grupo de estudo foi 60 (46-71) anos e 59,1% eram mulheres. Durante a internação, 3,2% dos pacientes apresentaram efeitos adversos e 2,2% necessitaram de interromper o tratamento. Alterações eletrocardiográficas foram mais prevalentes no grupo hidroxicloroquina/cloroquina (13,2% vs. 8,2%, p=0,01), e o prolongamento do intervalo QT corrigido foi a principal diferença (3,6% vs. 0,4%, p<0,001). O tempo mediano de internação hospitalar foi maior no grupo usando CQ/HCQ em relação aos controles (9,0 [5,0-18,0] vs. 8,0 [4,0-14,0] dias). Não houve diferenças estatisticamente significativas entre os grupos quanto a admissão na unidade de terapia intensiva (35,1% vs. 32,0%; p=0,282), ventilação mecânica invasiva (27,0% vs. 22,3%; p=0,074) ou mortalidade (18,9% vs. 18,0%; p=0,682). CONCLUSÃO: Pacientes com covid-19 tratados com cloroquina ou hidroxicloroquina apresentaram maior tempo de internação hospitalar, em comparação aos controles. Não houve diferença em relação a admissão em unidade de terapia intensiva, necessidade de ventilação mecânica e mortalidade hospitalar.
Assuntos
Tratamento Farmacológico da COVID-19 , Cloroquina , Hidroxicloroquina , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Arritmias Cardíacas/tratamento farmacológico , Azitromicina/uso terapêutico , Brasil/epidemiologia , Cloroquina/efeitos adversos , Estudos de Coortes , COVID-19 , Hidroxicloroquina/efeitos adversos , Estudos Retrospectivos , SARS-CoV-2RESUMO
BACKGROUND: (-)-Carvone is a monoterpene found in essential oils with antioxidant and anti-inflammatory activity. OBJECTIVE: The aim of this paper was to analyze the antiarrhythmic property of (-)-carvone in the rat heart and its effects on the intracellular Ca2+ signaling. METHODS: The effects of (-)-carvone were evaluated on the ventricular (0.5 mM) and atrial contractility (0.01 - 4 mM) and on electrocardiogram (0.5 mM). Fractional shortening, L-type calcium current (ICa,L) and Ca2+ signaling were measured in the isolated cardiomyocyte (0.5 mM). Antiarrhythmic effect was evaluated in arrhythmia model induced by calcium overload (0.5 mM) (n = 5). P < 0.05 was used as the significance level. RESULTS: In the atrium, (-)-carvone evoked negative inotropism that was concentration-dependent (EC50 0.44 ± 0.11 mM) and decreased the positive inotropism evoked by CaCl2 (0.1 to 8.0 mM) or BAY K8644 (5 to 500 nM), an agonist of L-type Ca2+ channel. In isolated heart, (-)-carvone (0.5 mM) promoted reduction of ventricular contractility (73%) and heart rate (46%), increased PRi (30.7%, time from the onset of the P wave until the R wave) and QTc (9.2%, a measure of the depolarization and repolarization of the ventricles) without changing the QRS complex duration. (-)-Carvone decreased the fractional shortening (61%), ICa,L (79%) and Ca2+ intracellular transient (38%). Furthermore, (-)-carvone showed antiarrhythmic action, verified by decrease of the arrhythmia score (85%) and occurrence of ventricular fibrillation. CONCLUSION: (-)-Carvone decreases Ca2+ entry through L-type Ca2+ channels, reducing the cardiac contractility and intracellular Ca2+, and, therefore, presenting promising antiarrhythmic activity in the rat hearts.
FUNDAMENTO: A (-)-carvona é um monoterpeno encontrado em óleos essenciais com atividade antioxidante e anti-inflamátoria. OBJETIVOS: O objetivo deste estudo foi analisar a propriedade antiarrítmica da (-)-carvona no coração de rato e seus efeitos sobre a sinalização de Ca+2 intracelular. MÉTODOS: Os efeitos da (-)-carvona foram avaliados sobre a contratilidade atrial (0,01 4 mM) e ventricular (0,5 mM), e no eletrocardiograma (0,5mM). A fração de encurtamento, a corrente de cálcio do tipo L (ICa,L) e a sinalização de Ca+2 foram medidas no cardiomiócito isolado (0,5 mM). O efeito antiarrítmico foi avaliado no modelo de arritmia induzida por sobrecarga de cálcio (0,5 mM) (n = 5). Um p < 0,05 foi adotado como nível de significância estatística. RESULTADOS: No átrio, a (-)-carvona causou inotropismo negativo de maneira concentração-dependente (EC50 0,44 ± 0,11 mM) e diminuiu o inotropismo positivo induzido pelo CaCl2 (0,1 8,0 mM) e BAY K8644 (5 - 500 nM), um agonista de canal de cálcio do tipo L. Em coração isolado, a (-)-carvona (0,5mM) reduziu a contratilidade ventricular em 73% e a frequência cardíaca (em 46%), aumentou o Pri (30,7%, tempo desde o início da onda P até a onda R) e o QTc (9,2%, uma medida de despolarização e repolarização dos ventrículos), sem mudar a duração do complexo QRS. A (-)-carvona diminuiu a fração de encurtamento (61%), a (ICa,L) (79%) e o transiente intracelular de Ca+2 (38%). Além disso, a (-)-carvona apresentou ação antiarrítmica, identificada pela redução do escore de arritmia (85%) e ocorrência de fibrilação ventricular. CONCLUSÃO: A (-)-carvona reduz a entrada de Ca+2 através de canais de Ca+2 do tipo L e, assim, diminui a contratilidade cardíaca e o Ca+2 intracelular e apresenta promissora atividade antiarrítmica no coração de ratos.
Assuntos
Sinalização do Cálcio , Cálcio , Potenciais de Ação , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Cálcio/metabolismo , Monoterpenos Cicloexânicos , Contração Miocárdica , Miócitos Cardíacos/fisiologia , RatosRESUMO
AIMS: Eugenol is a natural compound found in the essential oils of many aromatic plants. The compound is used as a local anesthetic because of its inhibitory effect on the voltage-gated Na+ channels (Nav), which are expressed in the nociceptive neurons. Eugenol has shown wide range of activities in the cardiovascular system; most of these activities are attributed to the modulation of voltage-sensitive Ca2+ channels. However, its action on Nav1.5, the main subtype of Nav expressed in the mammalian myocardium, is unknown. The interaction of eugenol with Nav1.5 could also contribute to its antiarrhythmic properties in vitro and ex vivo. We investigated the compound's effect on sodium current (INa) and its possible cardiac antiarrhythmic activity. METHODS: The effect of eugenol on cardiac contractility was investigated using isolated atrium from guinea pig (for isometric force measurements). The compound's effect on INa was evaluated using human embryonic cell transiently expressing human Nav1.5 and patch-clamp technique. KEY FINDINGS: Eugenol caused negative inotropic and chronotropic effects in the atria. In the ex vivo arrhythmia model, eugenol decreased atrial pacing disturbance induced by ouabain. Eugenol reduced the INa in a concentration-dependent manner. Furthermore, the compound left-shifted the stationary inactivation curve, delayed recovery from inactivation of the INa, and preferentially blocked the channel in the inactivated state. Importantly, eugenol was able to attenuate the late sodium current. All these aspects are considered to be antiarrhythmic. SIGNIFICANCE: Overall, our findings demonstrate that eugenol has antiarrhythmic activity due, at least in part, to its interaction with Nav1.5.