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1.
Int Heart J ; 61(2): 338-346, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32173709

RESUMO

Sympathetic nerve activity has arrhythmogenic potential for ventricular arrhythmias associated with structural heart diseases. However, a sufficient amount of beta-blockers occasionally cannot be prescribed in some patients.An experimental study was performed to clarify the therapeutic effects of bepridil, a multiple ionic current inhibitor that does not affect beta-adrenergic receptors, for premature beats occurring during enhanced sympathetic nerve activity. Cardio-sympathetic nerve activity was augmented via stellate-ganglion (SG) stimulation in a canine model (n = 8), and the arrhythmogenic potential and anti-arrhythmic effects of bepridil (2 and 4 mg/kg intravenously) were assessed. For safe use, vagal-stimulation-induced slow HR and programmed electrical stimulation were applied to evaluate possible pro-arrhythmic effects of the drug. Heart rate variability (HRV) indexes were used to estimate cardio-autonomic nerve activity.Either side of the SG-stimulation increased BP and HR. Premature beats were induced in 10/16 SG-stimulations and it was more frequent in left (8/8) rather than right stimulation (2/8). Following 2 mg/kg drug administration, premature beats were still inducible in 8/16 stimulations (7/8 in left and 1/8 in right), but burden of the premature beats decreased from 87.1 ± 46.8 to 62.1 ± 42.6 beats. After 4 mg/kg administration, premature beats were inducible in one SG-stimulation. Proarrhythmic effects were not observed in all experiments. Steady-state HRV indexes and percent increases in SG-stimulation-induced BP-elevation and HR-acceleration were similar among the 3 periods (before, 2 and 4 mg/kg of the drug).Bepridil may be an option for ventricular arrhythmias developed during enhanced cardio-sympathetic nerve activity with minimal effect on autonomic nerve responses.


Assuntos
Antiarrítmicos/uso terapêutico , Bepridil/uso terapêutico , Complexos Ventriculares Prematuros/tratamento farmacológico , Animais , Antiarrítmicos/farmacologia , Bepridil/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cães , Avaliação Pré-Clínica de Medicamentos , Estimulação Elétrica , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Gânglio Estrelado
2.
PLoS Comput Biol ; 16(2): e1007678, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32097431

RESUMO

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that paired-like homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na+ channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency.


Assuntos
Fibrilação Atrial/metabolismo , Simulação por Computador , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/metabolismo , Potenciais de Ação , Animais , Antiarrítmicos/farmacologia , Fibrilação Atrial/genética , Remodelamento Atrial , Cálcio/metabolismo , Eletrofisiologia , Retículo Endoplasmático/metabolismo , Fibrose , Flecainida/farmacologia , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Átrios do Coração/fisiopatologia , Proteínas de Homeodomínio/genética , Humanos , Cinética , Camundongos , Camundongos Knockout , Fenótipo , Canal de Liberação de Cálcio do Receptor de Rianodina/farmacologia , Retículo Sarcoplasmático/metabolismo , Sódio/metabolismo , Fatores de Transcrição/genética
3.
Life Sci ; 244: 117333, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31962132

RESUMO

AIMS: Detect the antiarrhythmic effect of crotonoside (Cro). MAIN METHODS: We used whole-cell patch-clamp techniques to detect the effects of Cro on action potentials (APs) and transmembrane ion currents in isolated rabbit left ventricular myocytes. We also verified the effect of Cro on ventricular arrhythmias caused by aconitine in vivo. KEY FINDINGS: Cro reduced the maximum depolarization velocity (Vmax) of APs and shortened the action potential duration (APD) in a concentration-dependent manner, but it had no significant effect on the resting membrane potential (RMP) or action potential amplitude (APA). It also inhibited the peak sodium current (INa) and L-type calcium current (ICaL) in a concentration-dependent manner with half-maximal inhibitory concentrations (IC50) of 192 µmol/L and 159 µmol/L, respectively. However, Cro had no significant effects on the inward rectifier potassium current (IK1) or rapidly activating delayed rectifier potassium current (IKr). Sea anemone toxin II (ATX II) increased the late sodium current (INaL), but Cro abolished this effect. Moreover, Cro significantly abolished ATX II-induced early afterdepolarizations (EADs) and high extracellular Ca2+ concentration (3.6 mmol/L)-induced delayed afterdepolarizations (DADs). We also verified that Cro effectively delayed the onset time and reduced the incidence of ventricular arrhythmias caused by aconitine in vivo. SIGNIFICANCE: These results revealed that Cro effectively inhibits INa, INaL, and ICaL in ventricular myocytes. Cro has antiarrhythmic potential and thus deserves further study.


Assuntos
Guanina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/metabolismo , Antiarrítmicos/farmacologia , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Canais de Cálcio/efeitos dos fármacos , China , Feminino , Guanina/metabolismo , Ventrículos do Coração/metabolismo , Técnicas de Patch-Clamp/métodos , Coelhos , Sódio/metabolismo , Canais de Sódio/efeitos dos fármacos
4.
Int J Mol Sci ; 20(24)2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31847485

RESUMO

Melatonin is assumed to confer cardioprotective action via antioxidative properties. We evaluated the association between ventricular tachycardia and/or ventricular fibrillation (VT/VF) incidence, oxidative stress, and myocardial electrophysiological parameters in experimental ischemia/reperfusion under melatonin treatment. Melatonin was given to 28 rats (10 mg/kg/day, orally, for 7 days) and 13 animals received placebo. In the anesthetized animals, coronary occlusion was induced for 5 min followed by reperfusion with recording of unipolar electrograms from ventricular epicardium with a 64-lead array. Effects of melatonin on transmembrane potentials were studied in ventricular preparations of 7 rats in normal and "ischemic" conditions. Melatonin treatment was associated with lower VT/VF incidence at reperfusion, shorter baseline activation times (ATs), and activation-repolarization intervals and more complete recovery of repolarization times (RTs) at reperfusion (less baseline-reperfusion difference, ΔRT) (p < 0.05). Superoxide dismutase (SOD) activity was higher in the treated animals and associated with ΔRT (p = 0.001), whereas VT/VF incidence was associated with baseline ATs (p = 0.020). In vitro, melatonin led to a more complete restoration of action potential durations and resting membrane potentials at reoxygenation (p < 0.05). Thus, the antioxidative properties of melatonin were associated with its influence on repolarization duration, whereas the melatonin-related antiarrhythmic effect was associated with its oxidative stress-independent action on ventricular activation.


Assuntos
Antiarrítmicos/farmacologia , Antioxidantes/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Eletrocardiografia/efeitos dos fármacos , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Melatonina/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Eletrofisiologia Cardíaca/métodos , Ventrículos do Coração/efeitos dos fármacos , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ratos , Ratos Wistar , Fibrilação Ventricular/tratamento farmacológico
5.
Yonsei Med J ; 60(12): 1157-1163, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31769246

RESUMO

PURPOSE: Although the economic and mortality burden of atrial fibrillation (AF) is substantial, it remains unclear which treatment strategies for rate and rhythm control are most cost-effective. Consequently, economic factors can play an adjunctive role in guiding treatment selection. MATERIALS AND METHODS: We built a Markov chain Monte Carlo model using the Korean Health Insurance Review & Assessment Service database. Drugs for rate control and rhythm control in AF were analyzed. Cost-effective therapies were selected using a cost-effectiveness ratio, calculated by net cost and quality-adjusted life years (QALY). RESULTS: In the National Health Insurance Service data, 268149 patients with prevalent AF (age ≥18 years) were identified between January 1, 2013 and December 31, 2015. Among them, 212459 and 55690 patients were taking drugs for rate and rhythm control, respectively. Atenolol cost $714/QALY. Among the rate-control medications, the cost of propranolol was lowest at $487/QALY, while that of carvedilol was highest at $1363/QALY. Among the rhythm-control medications, the cost of pilsicainide was lowest at $638/QALY, while that of amiodarone was highest at $986/QALY. Flecainide and propafenone cost $834 and $830/QALY, respectively. The cost-effectiveness threshold of all drugs was lower than $30000/QALY. Compared with atenolol, the rate-control drugs propranolol, betaxolol, bevantolol, bisoprolol, diltiazem, and verapamil, as well as the rhythm-control drugs sotalol, pilsicainide, flecainide, propafenone, and dronedarone, showed better incremental cost-effectiveness ratios. CONCLUSION: Propranolol and pilsicainide appear to be cost-effective in patients with AF in Korea assuming that drug usage or compliance is the same.


Assuntos
Antiarrítmicos/economia , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/economia , Análise Custo-Benefício , Frequência Cardíaca , Antiarrítmicos/farmacologia , Árvores de Decisões , Prescrições de Medicamentos/estatística & dados numéricos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Incidência , Masculino , Qualidade de Vida , República da Coreia
6.
Curr Protein Pept Sci ; 20(10): 996-1003, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389311

RESUMO

Abstract:Throughout the last decade, extensive efforts have been devoted to developing a percutaneous catheter ablation and implantable cardioverter-defibrillator technique for patients suffering from ventricular arrhythmia. Antiarrhythmic drug efficacy for preventing arrhythmias remains disappointing because of adverse cardiovascular effects. Allocryptopine is an isoquinoline alkaloid widely present in medicinal herbs. Studies have indicated that allocryptopine exhibits potential anti-arrhythmic actions in various animal models. The potential therapeutic benefit of allocryptopine in arrhythmia diseases is addressed in this study, focusing on multiple ion channel targets and reduced repolarization dispersion. The limitations of allocryptopine research are clear given a lack of parameters regarding toxicology and pharmacokinetics and clinical efficacy in patients with ventricular arrhythmias. Much remains to be revealed about the properties of allocryptopine.


Assuntos
Antiarrítmicos , Arritmias Cardíacas/tratamento farmacológico , Alcaloides de Berberina , Plantas Medicinais/química , Traqueófitas/química , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Alcaloides de Berberina/química , Alcaloides de Berberina/farmacologia , Alcaloides de Berberina/uso terapêutico , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
7.
Exp Parasitol ; 205: 107747, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442454

RESUMO

Development of new chemotherapeutic agents is an essential issue in the treatment and control of a disease. This study aimed to evaluate the anti-leishmanial activity of amiodarone, an antiarrhythmic class III drug, against Leishmania major, the most prevalent etiological agent of cutaneous leishmaniasis in the old world. The proliferation of promastigotes and intracellular amastigotes in the absence or presence of amiodarone was estimated, in an in vitro study. For in vivo study, five weeks after infection of BALB/c mice with L. major, when the lesions appeared at the injection site, the mice were divided into four groups (n = 6 each); treatment was conducted for 28 consecutive days with vehicle, amiodarone at 40 mg/kg orally and glucantime at 60 mg/kg intraperitoneally. Therapy with amiodarone reduced the size of lesions compared to the untreated group after 12 days. Amiodarone decreased the parasite load and inflammatory responses, particularly the macrophages containing amastigotes, and enhanced granulation tissue formation in the dermis and subcutaneous area. The Tumor necrosis factor-α and Interleukin-6 levels were significantly lower in the cell culture supernatants of the inguinal lymph node in the amiodarone treated group compared to the vehicle and untreated groups. Amiodarone significantly increased the activity of glutathione peroxidase in comparison to the vehicle and untreated groups but did not affect the plasma levels of superoxide dismutase, malondialdehyde, adiponectin, and ferric reducing ability of plasma. Therefore, the anti- L. major activity and immunomodulatory effects of amiodarone reduced the parasitic load and enhanced wound healing in cutaneous leishmaniasis in BALB/c mice. Amiodarone reduced the lesion surface area, but it did not cure it completely.


Assuntos
Amiodarona/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Adiponectina/sangue , Amiodarona/farmacologia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Antiprotozoários/farmacologia , Linhagem Celular , Feminino , Glutationa Peroxidase/metabolismo , Concentração Inibidora 50 , Interleucina-6/análise , Leishmania major/ultraestrutura , Leishmaniose Cutânea/parasitologia , Linfonodos/química , Linfonodos/imunologia , Macrófagos/parasitologia , Malondialdeído/sangue , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Carga Parasitária , Distribuição Aleatória , Pele/parasitologia , Pele/patologia , Pele/ultraestrutura , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/análise
8.
J Vet Cardiol ; 25: 14-24, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31442634

RESUMO

INTRODUCTION: Sotalol is an anti-arrhythmic drug commonly used for the treatment of pathologic tachyarrhythmias in dogs. The ß-adrenergic blockade associated with sotalol administration may result in reduced myocardial contractility, which is clinically relevant for treating dogs with arrhythmias and concurrent myocardial dysfunction. The inotropic properties of sotalol are not well characterized in dogs. ANIMALS, MATERIALS, AND METHODS: Ten healthy, adult, large breed dogs were prospectively enrolled. All dogs underwent physical examination, blood pressure measurement, electrocardiography, 24-h Holter monitoring, and echocardiography including three-dimensional left ventricular volume measurements. Dogs were subsequently administered sotalol (1-2 mg/kg) orally twice daily for 12-16 days, and the same diagnostic tests were performed. Paired statistical analysis was used to compare parameters at baseline and after treatment with sotalol. RESULTS: Standard echocardiographic parameters of systolic function were reduced on sotalol compared to baseline, including ejection fraction via Simpson's method of disks which was 5.8% (95% confidence interval [CI]: 2.77-8.83%, p = 0.002) lower post-treatment. Maximum heart rate on Holter monitor was 17 bpm (95% CI: 9-37 bpm, p = 0.002) lower post-treatment than at baseline. CONCLUSIONS: Sotalol has a mild negative inotropic effect in healthy dogs based on standard echocardiographic measurements. There is also a negative chronotropic effect at higher heart rates based on 24-h Holter monitoring.


Assuntos
Antiarrítmicos/farmacologia , Cardiotônicos/farmacologia , Cães , Sotalol/farmacologia , Animais , Eletrocardiografia Ambulatorial/veterinária , Frequência Cardíaca/efeitos dos fármacos , Estudos Prospectivos
9.
Int J Mol Sci ; 20(13)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262061

RESUMO

Heart failure (HF) frequently coexists with atrial fibrillation (AF) and dysfunction of the sinoatrial node (SAN), the natural pacemaker. HF is associated with chronic adrenergic stimulation, neurohormonal activation, abnormal intracellular calcium handling, elevated cardiac filling pressure and atrial stretch, and fibrosis. Pulmonary veins (PVs), which are the points of onset of ectopic electrical activity, are the most crucial AF triggers. A crosstalk between the SAN and PVs determines PV arrhythmogenesis. HF has different effects on SAN and PV electrophysiological characteristics, which critically modulate the development of AF and sick sinus syndrome. This review provides updates to improve our current understanding of the effects of HF in the electrical activity of the SAN and PVs as well as therapeutic implications for AF.


Assuntos
Fibrilação Atrial/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Veias Pulmonares/fisiopatologia , Nó Sinoatrial/fisiopatologia , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Veias Pulmonares/efeitos dos fármacos , Nó Sinoatrial/efeitos dos fármacos , Nó Sinoatrial/metabolismo
10.
Zhongguo Zhong Yao Za Zhi ; 44(11): 2379-2389, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31359667

RESUMO

To evaluate the efficiency and safety between Wenxin Granule and antiarrhythmic drugs in the treatment of atrial fibrillation(AF). A total of 8 major electronic databases(CNKI, WanFang, VIP, CBM, Cochrane Library, Web of Science, PubMed, EMbase) were retrieved since the establishment of the database to January 10, 2019. Two reviewers extracted data, and assessed the methodological quality of the included studies. The Meta-analysis was made by RevMan 5.3 software. Finally, 42 studies involving 4 657 patients were included. The results of Meta-analysis showed that compared with antiarrhythmic drug, the combined administration with Wenxin Granule and antiarrhythmic drug had a better clinical efficiency(OR=3.37, 95%CI[2.69,4.22],I~2=0%,P<0.000 01)and efficacy on cardioversion(OR=2.32,95%CI[1.67,3.22],I~2=0%,P<0.000 01), with reduction in P_d(MD=-5.48,95%CI [-7.32,-3.64],I~2=0%,P<0.000 01)and P_(max)(MD=-9.91,95%CI[-12.86,-6.95],I~2=0%,P<0.000 01). The comparison between the combined application with Wenxin Granule and the single application of amiodarone showed a clinical efficiency(OR=2.89,95%CI[1.96,4.26],I~2=44%,P<0.000 01),and efficacy on sinus rhythm maintenance(OR=2.58,95%CI[1.82,3.66],I~2=3%,P<0.000 01). The comparison between the combined application with Wenxin Granule and the single application of amiodarone showed a clinical efficiency(OR=0.88,95%CI[0.53,1.46],I~2=0%,P=0.63). The combined treatment with Wenxin Granule has a better clinical efficiency in AF better than amiodarone, with no evidence for more benefits from the single administration with Wenxin Granules.


Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Terapia Combinada , Cardioversão Elétrica , Humanos
11.
Med Sci Monit ; 25: 4856-4868, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31256190

RESUMO

BACKGROUND Results of the landmark Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial comparing rhythm control and rate control strategies has led to dramatic changes in the pharmacological management of non-valvular atrial fibrillation (NVAF) patients. We sought to investigate the effect of antiarrhythmic drugs (AADs) on the clinical outcomes of NVAF patients using "real-world" data from China. MATERIAL AND METHODS We evaluated the association between AAD usage and clinical outcomes using clinical data of 8161 NVAF patients who were AAD-naive before enrollment in the China Atrial Fibrillation Registry, recruited between August 2011 and February 2017. The primary outcome was all-cause mortality. RESULTS Compared with 6167 patients who never used any AADs, 1994 patients in the AAD group had lower incidence (per 100 person-years) of all-cause mortality (1.44 versus 3.91), cardiovascular death (0.45 versus 2.31), ischemic stroke (1.36 versus 2.03), and cardiovascular hospitalization (9.83 versus 10.22) over a mean follow-up duration of 316.7±90.4 days. After adjusting for potential confounders, AAD usage was associated with a lower risk of all-cause mortality [hazard ratio (HR): 0.50, 95% confidence interval (CI): 0.31-0.81] and decreased risk of cardiovascular death (HR: 0.30, 95% CI: 0.13-0.68). Subgroup analysis revealed AAD was associated with higher risk of cardiovascular hospitalization among female patients. CONCLUSIONS AAD usage was associated with lower risk of 1-year all-cause mortality and cardiovascular death in "real-world" patients with NVAF.


Assuntos
Antiarrítmicos/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/mortalidade , Idoso , Antiarrítmicos/farmacologia , China , Feminino , Hospitalização , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Fatores de Risco , Acidente Vascular Cerebral/complicações , Resultado do Tratamento
12.
Prog Biophys Mol Biol ; 144: 128-138, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182191

RESUMO

Cardiac two-pore-domain potassium (K2P) channels have been proposed as novel antiarrhythmic targets. K2P13.1 (THIK-1) channels are expressed in the human heart, and atrial K2P13.1 levels are reduced in patients with atrial fibrillation (AF) or heart failure. The first objective of this study was to investigate acute effects of antiarrhythmic drugs on human K2P13.1 currents. Second, we assessed atrial K2P13.1 remodeling in AF pigs to validate the porcine model for future translational evaluation of K2P13.1-based antiarrhythmic concepts. K2P13.1 protein expression was studied in domestic pigs during AF induced by atrial burst pacing. AF was associated with 66% reduction of K2P13.1 levels in the right atrium at 21-day follow-up. Voltage clamp electrophysiology was employed to elucidate human K2P13.1 channel pharmacology in Xenopus oocytes. Propafenone (-26%; 100 µM), mexiletine (-75%; 1.5 mM), propranolol (-38%; 200 µM), and lidocaine (-59%; 100 µM) significantly inhibited K2P13.1 currents. By contrast, K2P13.1 channels were not markedly affected by quinidine, carvedilol, metoprolol, amiodarone and verapamil. Concentration-dependent K2P13.1 blockade by mexiletine occurred rapidly with membrane depolarization and was frequency-independent. Mexiletine reduced K2P13.1 open rectification properties and shifted current-voltage relationships towards more negative potentials. In conclusion, atrial expression and AF-associated downregulation of K2P13.1 channels in a porcine model resemble human findings and support a general role for K2P13.1 in AF pathophysiology. K2P13.1 current sensitivity to antiarrhythmic drugs provides a starting point for further development of an emerging antiarrhythmic paradigm.


Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/metabolismo , Miocárdio/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Animais , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mexiletina/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/genética , Suínos
13.
J Vet Intern Med ; 33(4): 1585-1592, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31222803

RESUMO

BACKGROUND: Typical atrioventricular accessory pathways (APs) are composed of myocardial cells. They provide electrical connections between atria and ventricles separate from the normal conduction system. Accessory pathways can participate in a macroreentrant circuit resulting in orthodromic atrioventricular reciprocating tachycardia (OAVRT). HYPOTHESIS: Because of ultrastructural similarities of typical AP cells to ventricular myocardial cells, we hypothesized lidocaine would be effective in blocking AP conduction, thus terminating OAVRT. ANIMALS: Thirty-two consecutive client-owned dogs presenting with narrow complex tachyarrhythmias were confirmed to have OAVRT by electrophysiologic study (EPS). METHODS: Prospective, nonrandomized, single-arm study with lidocaine administered IV to dogs during OAVRT in 2 mg/kg boluses to a cumulative dose of 8 mg/kg or development of adverse effects. Electrocardiograms were monitored continuously. Subsequent EPS was performed to confirm OAVRT and the absence of other tachycardia mechanisms. RESULTS: Twenty-seven dogs experienced OAVRT cardioversion with lidocaine, before or at the time of adverse effects. Orthodromic atrioventricular reciprocating tachycardia in 5 dogs did not cardiovert before adverse effects, precluding additional dosing. Median total lidocaine dose for cardioversion was 2 mg/kg (interquartile range, 2-5.5 mg/kg). Dogs with right free wall APs had a significantly higher rate of cardioversion than did dogs with right posteroseptal APs. CONCLUSIONS AND CLINICAL IMPORTANCE: Lidocaine successfully cardioverted OAVRT in 84.4% of dogs in our study before adverse effects precluded additional dosing. In 5 dogs with dose limited by adverse effects, it is unknown whether cardioversion would have occurred at a higher cumulative dose.


Assuntos
Antiarrítmicos/farmacologia , Doenças do Cão/tratamento farmacológico , Lidocaína/farmacologia , Taquicardia Reciprocante/veterinária , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/veterinária , Cães , Feminino , Lidocaína/administração & dosagem , Lidocaína/efeitos adversos , Masculino , Estudos Prospectivos , Taquicardia Reciprocante/tratamento farmacológico
14.
Eur J Pharmacol ; 859: 172488, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31233746

RESUMO

Cardiac arrhythmias are among the most important pathologies that lead to sudden death. The discovery of new therapeutic options against arrhythmias with low adverse effects is of paramount importance. Farnesol is found in essential oils with antioxidant, anti-inflammatory and cardioprotective properties. The aim of this work was to investigate the effects of farnesol on the contractile and electrophysiological properties in rat heart and evaluate its antiarrhythmic action. It was evaluated farnesol effects on the left ventricular developed pressure, ECG, potassium (Ik) and L-type Ca2+ currents (ICa,L), action potential, intracellular Ca2+ transient, Ca2+ sparks and waves and reactive oxygen species production. Antiarrhythmic activity of farnesol was determined in vivo and ex vivo. The results showed that 50 µM farnesol did not alter left ventricular developed pressure, heart rate, ECG parameters and intracellular Ca2+ transient but reduced ICa,L. Farnesol reduced action potential duration at 90% repolarization. Notably, farnesol improved arrhythmia score and the incidence of the most severe arrhythmias. Farnesol attenuated the generation of reactive oxygen species, Ca2+ sparks and waves in isolated cardiomyocytes submitted to Ca2+ overload. In conclusion, farnesol has antiarrhythmic effect mediated by reducing of ICa,L and IK along with a decrease of reactive oxygen species production and normalized Ca2+ sparks and waves.


Assuntos
Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio/metabolismo , Farneseno Álcool/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Eletrocardiografia/efeitos dos fármacos , Farneseno Álcool/uso terapêutico , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Contração Miocárdica/efeitos dos fármacos , Oxigênio/metabolismo , Potássio/metabolismo , Ratos , Ratos Wistar , Disfunção Ventricular Esquerda/tratamento farmacológico
15.
Wiad Lek ; 72(3): 381-383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31050984

RESUMO

OBJECTIVE: Introduction: Cardiac arrhythmia often occurs in the gestational period of pregnant women, contributing to the development of complications of pregnancy, childbirth and perinatal pathology, which requires a more thorough examination of pregnant women and antiarrhythmic treatment, which in turn increases the risk of complications pregnancy and childbirth. Many types of arrhythmias occur in women without structural damage to the cardiovascular system. The aim is to study the occurrence of cardiac rhythm disturbances in healthy pregnant women, depending on the gestational age, the number of previous pregnancies, infectious diseases during pregnancy, and arrhythmia analysis, which required antiarrhythmic treatment. Materials and methods: Retrospectively 60 individual cards of pregnant women were studied. An ECG monitoring was performed to identify the arrhythmia. RESULTS: Results: Among the arrhythmia were: supraventricular and ventricular extrasystoles, unstable paroxysmal tachycardia. All cases of arrhythmia were without lengthening QT interval. Sinus tachycardia was significantly more common in combination with anemia. Heart rhythm disorders are associated with emotional excitement. CONCLUSION: Conclusions: Most violations of the heart rate occurred in the second trimester of pregnancy. With concomitant anemia, sinus tachycardia is significantly more common, and sinus bradycardia is associated with an enlarged uterus in compression of the inferior vena cava. With the increase in the number of pregnancies, the risk of heart rhythm disturbances increases. However, the past infectious diseases of the bronchopulmonary system during pregnancy did not significantly affect the occurrence of rhythm disturbances. The appointment of antiarrhythmic drugs was observed in all pregnant women whose cards were included in the study.


Assuntos
Arritmias Cardíacas , Eletrocardiografia/métodos , Gestantes , Antiarrítmicos/farmacologia , Feminino , Humanos , Gravidez , Estudos Retrospectivos
16.
Biomed Pharmacother ; 115: 108889, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31071512

RESUMO

Amiodarone is a potent antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis. Accumulating evidence has demonstrated that myofibroblast differentiation is related to the pathogenesis of pulmonary fibrosis. In the present study, we treated human embryonic lung fibroblasts (HELFs) with amiodarone, and investigated the relative molecular mechanism of amiodarone-induced pulmonary fibrosis and pathway determinants PD98059 (extracellular signal-regulated kinase (ERK) inhibitor) and SB203580 (p38 mitogen-activated protein kinase (MAPK) inhibitor). Cell proliferation was assessed by Cell Counting Kit-8 (CCK-8). The secretion of collagen Ⅰ was detected by ELISA. The expressions of α-smooth muscle actin (α-SMA), vimentin, phosphorylated ERK1/2 (p-ERK1/2), ERK1/2, phosphorylated p38 MAPK (p-p38), and p38 MAPK were investigated using Western blot analysis. The levels of α-SMA and vimentin were also determined by immunofluorescence and qRT-PCR. We report that amiodarone promoted cell proliferation and collagen Ⅰ secretion, induced α-SMA and vimentin protein and mRNA expression accompanied by increased phosphorylation of ERK1/2 and p38 MAPK, and furthermore, PD98059 and SB203580 remarkably reduced the proliferative response of HELFs compared with amiodarone group and greatly attenuated α-SMA, vimentin and collagen Ⅰ protein production induced by amiodarone. Taken together, our study suggests that amiodarone regulates cell proliferation and myofibroblast differentiation in HELFs through modulating ERK1/2 and p38 MAPK pathways, and these signal pathways may therefore represent an attractive treatment modality in amiodarone-induced pulmonary fibrosis.


Assuntos
Amiodarona/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Miofibroblastos/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Antiarrítmicos/farmacologia , Flavonoides/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Pulmão/citologia , Piridinas/farmacologia
17.
Mater Sci Eng C Mater Biol Appl ; 100: 48-61, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30948084

RESUMO

Dronedarone is a new antiarrhythmic drug for the treatment of atrial fibrillation. This study investigated the complexation of dronedarone hydrochloride with ß­cyclodextrin (ß-CD) and 2­hydroxypropil­ß­CD (HP-ß-CD) using three different techniques. The complexes in the solid state were characterized by DSC, TGA, PXRD, FT-IR, SEM and 1H NMR, demonstrating the formation of the inclusion complexes and exhibiting different properties from the pure drug. Its aqueous solubility increased about 4.0-fold upon complexation with ß-CD and HP-ß-CD. The dissolution rate of the drug was notably improved in all tested physiological pH values from 1.2 to 6.8 in the presence of both cyclodextrins. Furthermore, an in vitro cytotoxic assay revealed that the inclusion complexes could reduce the cytotoxic effects of the drug on 3T3 cells. The overall results suggest that the inclusion complexes with ß-CD and HP-ß-CD may be potentially useful in the preparation of novel pharmaceutical formulations containing dronedarone hydrochloride.


Assuntos
Antiarrítmicos/química , Dronedarona/química , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Células 3T3 , Animais , Antiarrítmicos/síntese química , Antiarrítmicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Dronedarona/síntese química , Dronedarona/farmacologia , Composição de Medicamentos , Liofilização , Camundongos , Microscopia Eletrônica de Varredura , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Termogravimetria , Difração de Raios X
18.
J BUON ; 24(1): 106-115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941958

RESUMO

PURPOSE: Certain anesthetic interventions may influence the postoperative outcome in surgical cancer patients. Our study investigated the antiproliferative effects of propofol and lidocaine in two colon cancer cells lines, fibroblasts and in co-cultures. METHODS: The antiproliferative effects of concentrations of propofol and lidocaine were assessed in HCT-116 and RKO cell lines, in fibroblasts (CCD-18Co) and in co-culture system. RESULTS: Both propofol (2-4 mcg/ml) and lidocaine (2-4 µM) inhibited significantly colon cancer cell proliferation (p<0.05). Caspase-8, heat-shock proteins (HSP-27 and HSP-60), insulin growth factor (IGF)-II, insulin growth factor binding proteins, p53 protein and survivin were significantly differentially expressed in malignant cells and in fibroblasts exposed to lidocaine. CONCLUSION: Lidocaine and propofol selectively inhibited colon cancer cells proliferation. Antiproliferative effects were tumor-, dose- and time-dependent and may be at least partially explained by activation of apoptosis protein pathways. Further studies are necessary to confirm the clinical impact of our data.


Assuntos
Adenocarcinoma/patologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Fibroblastos/patologia , Lidocaína/farmacologia , Propofol/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Adenocarcinoma/tratamento farmacológico , Anestésicos Intravenosos/farmacologia , Antiarrítmicos/farmacologia , Apoptose/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Neoplasias do Colo/tratamento farmacológico , Fibroblastos/efeitos dos fármacos , Humanos , Células Estromais/efeitos dos fármacos , Células Estromais/patologia
19.
Pediatr Cardiol ; 40(5): 925-933, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30929065

RESUMO

OBJECTIVE: To determine the incidence of cardiovascular collapse in children receiving intravenous (IV) amiodarone and to identify the population at risk. DESIGN: A multicenter study of patients ≤ 18 years of age who received intravenous amiodarone between January 2005 and December 2015. A retrospective analysis was performed to identify patients who developed cardiovascular collapse (bradycardia and/or hypotension). RESULTS: Of 456 patients who received amiodarone, cardiovascular collapse occurred in 47 patients (10%). Patient risk factors for collapse in a univariate analysis were as follows: age < 3 months (p = 0.04), depressed cardiac function (p < 0.001), blood pressure below 3rd percentile (p < 0.001), high lactate at baseline (p < 0.001). Administration risk factors included bolus administration (p = 0.04), and bolus administration over ≤ 20 min (p = 0.04). In multivariate analysis, age, baseline blood pressure less than 3rd percentile, and rapid bolus delivery were independent risk factors for cardiovascular collapse in the study group. The mortality rate was significantly higher in the collapse group (28% versus 8%). CONCLUSION: We found an association between IV amiodarone administration and the risk of developing cardiovascular collapse in a significant subset of children. Extreme caution and careful hemodynamic monitoring is recommended when using IV amiodarone in this population, especially in young infants, hemodynamically compromised patients, and in patients receiving rapid amiodarone bolus administration.


Assuntos
Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Bradicardia/induzido quimicamente , Hipotensão/induzido quimicamente , Taquicardia Ectópica de Junção/induzido quimicamente , Taquicardia Ventricular/induzido quimicamente , Administração Intravenosa , Adolescente , Distribuição por Idade , Amiodarona/administração & dosagem , Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Bradicardia/mortalidade , Criança , Pré-Escolar , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipotensão/mortalidade , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Taquicardia Ectópica de Junção/mortalidade , Taquicardia Ventricular/mortalidade
20.
Pharm Biol ; 57(1): 245-249, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30929547

RESUMO

CONTEXT: Allicin is a potential antiarrhythmic agent. The antiarrhythmic properties of allicin rely on its blockade of various cardiac ion channels. The l-type calcium (Cav1.2) channel provides a pivotal substrate for cardiac electrophysiologic activities. The mechanism of allicin on Cav1.2 remains unclear. OBJECTIVE: This study evaluated the potential of allicin on the synthesis and trafficking of Cav1.2 channels. MATERIALS AND METHODS: Primary cardiomyocytes (CMs) from neonatal Sprague-Dawley (SD) rats were exposed to allicin (0, 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 µg/mL) for 24 and 48 h. The CellTiter-Glo assay was performed to measure CM viability. Western blot with grayscale analysis and confocal laser scanning microscopy were used to evaluate the effects of allicin on the synthesis and trafficking of Cav1.2 channel proteins in primary CMs. RESULTS: There was no significant difference in apoptotic toxicity from the actual cell viability (p > 0.05) in any group (0, 0.0001, 0.001, 0.01, 0.1, 1, 10, 100 µg/mL allicin), except that viability in the 0.001 and 0.01 µg/mL groups at 24 h were significantly greater (137.37 and 135.96%) (p < 0.05). Western blot with grayscale analysis revealed no substantial inhibition by allicin of the synthesis of Cav1.2 proteins. Confocal laser scanning microscopy revealed trafficking dysfunction of Cav1.2 channels caused by allicin in primary CMs. CONCLUSION: This study is the first to demonstrate that allicin inhibits cardiac Cav1.2 channels by disrupting trafficking, possibly mediating its antiarrhythmic benefits. Therefore, allicin might serve as a new antiarrhythmic agent in the future.


Assuntos
Antiarrítmicos/farmacologia , Canais de Cálcio Tipo L/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Ácidos Sulfínicos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Masculino , Miócitos Cardíacos/metabolismo , Cultura Primária de Células , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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