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1.
Int J Cardiol ; 354: 22-28, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35278578

RESUMO

AIMS: To evaluate the role of bisoprolol to control symptoms and left ventricular outflow tract obstruction (LVOTO) in a consecutive cohort of adults with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In this retrospective study, patients with HCM with an LVOT gradient ≥50 mmHg after Valsalva manoeuvre and New York Heart Association (NYHA) class II-III symptoms were assigned to receive bisoprolol (starting at 1.25 mg daily). The initial dose was increased every two weeks to achieve the target in LVOT gradient <30 mmHg or the maximum tolerated dose. The primary endpoint was the achievement of a LVOT gradient <30 mmHg and ≥ 1 NYHA class improvement. The secondary endpoints were proportion of patients with LVOT gradient <30 mmHg or < 50 mmHg, proportion of patients with ≥1 NYHA class improvement, and change from baseline in LVOT gradient. Between December 2001 and December 2020, 92 patients were enrolled into the study. Sixteen (17%) patients on bisoprolol met the primary endpoint. Bisoprolol reduced the LVOT gradient to less than 30 mmHg in 33 (36%) patients, to less than 50 mmHg in 57 (62%), and improved NYHA class in 30 (33%). The mean reduction of LVOT gradient on bisoprolol was 28 (±14) mmHg and the percentage reduction was 42 (±21) %. In 35 (38%) patients, bisoprolol did not reduce the gradient to less than 50 mmHg requiring disopyramide and/or myectomy to achieve this goal. CONCLUSION: Treatment with bisoprolol was well-tolerated and effective in relieving obstruction and improving symptoms in a significant proportion of patients with symptomatic obstructive HCM.


Assuntos
Cardiomiopatia Hipertrófica , Obstrução do Fluxo Ventricular Externo , Adulto , Bisoprolol/uso terapêutico , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/tratamento farmacológico , Disopiramida/uso terapêutico , Humanos , Estudos Retrospectivos , Obstrução do Fluxo Ventricular Externo/diagnóstico por imagem , Obstrução do Fluxo Ventricular Externo/tratamento farmacológico
2.
Medicine (Baltimore) ; 100(20): e25959, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34011078

RESUMO

RATIONALE: Syncope often occurs in patients with advanced head and neck cancers due to the stimulation of the autonomic nervous system by the tumor. Here, we describe a case of frequent syncopal episodes after laryngopharyngectomy for hypopharyngeal cancer. As all syncopal episodes were observed during the forenoon, we also evaluated the heart rate variability using ambulatory electrocardiography to determine why the syncopal episodes occurred during a specified period of the day. PATIENT CONCERNS: A 73-year-old Japanese man who underwent laryngopharyngectomy for recurrent hypopharyngeal cancer started experiencing frequent episodes of loss of consciousness that occurred during the same time period (10:00-12:00). He had never experienced syncopal episodes before the operation. From 23 to 41 days postoperatively, he experienced 9 syncopal episodes that occurred regardless of his posture. DIAGNOSES: Pharyngo-esophagoscopy revealed an anastomotic stricture between the free jejunum graft and the upper esophagus. Swallowing videofluoroscopy confirmed the dilatation of the jejunal autograft and a foreign body stuck on the oral side of the anastomosis. Contrast-enhanced computed tomography revealed that the carotid artery was slightly compressed by the edematous free jejunum. The patient was diagnosed with carotid sinus syndrome (CSS) as the free jejunum was dilated when consuming breakfast, which may have caused carotid sinus hypersensitivity and induced a medullary reflex. INTERVENTIONS: Administration of disopyramide was effective in preventing syncope. Heart rate variability analysis using ambulatory electrocardiography showed that parasympathetic dominancy shifted to sympathetic dominancy during 10:00 to 12:00. The significant time regularity of the syncopal episodes may have been affected by modified diurnal variation in autonomic tone activity. OUTCOMES: After the surgical release and re-anastomosis of the pharyngoesophageal stenosis via an open-neck approach, no recurrent episodes of syncope were reported. LESSONS: We reported a case of frequent syncopal episodes limited to the forenoon due to CSS after surgery for hypopharyngeal carcinoma. The patient was treated with anticholinergics followed by the release and re-anastomosis of the pharyngoesophageal stenosis. When syncope occurs after surgery for head and neck lesions, CSS due to postoperative structural changes should be considered as a differential diagnosis of syncope.


Assuntos
Seio Carotídeo/fisiologia , Estenose Esofágica/diagnóstico , Laringectomia/efeitos adversos , Faringectomia/efeitos adversos , Síncope/diagnóstico , Idoso , Anastomose Cirúrgica/efeitos adversos , Desjejum/fisiologia , Deglutição/fisiologia , Disopiramida/administração & dosagem , Eletrocardiografia , Estenose Esofágica/etiologia , Estenose Esofágica/fisiopatologia , Estenose Esofágica/cirurgia , Esôfago/cirurgia , Humanos , Neoplasias Hipofaríngeas/cirurgia , Laringectomia/métodos , Masculino , Faringectomia/métodos , Faringe/cirurgia , Síncope/etiologia , Síncope/fisiopatologia , Síncope/prevenção & controle , Síndrome
3.
S Afr Med J ; 111(3): 208-210, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33944740

RESUMO

Extracorporeal life support is the utilisation of advanced techniques to sustain circulatory and/or ventilatory functions in critically ill patients when standard therapies fail. It is well established in developed countries. There is increasing literature supporting its application in refractory cardiac arrest with a potential reversible cause, a procedure also known as extracorporeal cardiopulmonary resuscitation (eCPR). Two cases where eCPR was successfully utilised in a busy (>30 000 visits per year) private South African emergency department are described here, the first such cases to be reported on the African continent. The first patient had a life-threatening cardiac arrhythmia due to toxin ingestion, and the second a refractory ventricular fibrillation due to acute myocardial infarction. In both these cases the cardiac arrest was witnessed, occurred in the emergency department, and failed to respond to standard advanced resuscitative measures. Both the patients were discharged neurologically intact. Although it is effective, the benefit of this advanced method of resuscitation in a low- to middle-income country is debated.


Assuntos
Infarto do Miocárdio/complicações , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/terapia , Antiarrítmicos/efeitos adversos , Reanimação Cardiopulmonar/métodos , Cardiotoxicidade/etiologia , Cardiotoxicidade/terapia , Disopiramida/efeitos adversos , Oxigenação por Membrana Extracorpórea/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , África do Sul
4.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33514068

RESUMO

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Fibrilação Atrial/tratamento farmacológico , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Animais , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Fibrilação Atrial/genética , Fibrilação Atrial/patologia , Simulação por Computador , Disopiramida/química , Disopiramida/farmacologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/patologia , Humanos , Camundongos , Propafenona/química , Propafenona/uso terapêutico , Quinidina/química , Quinidina/farmacologia
6.
Am J Cardiol ; 128: 75-83, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32650928

RESUMO

Highly reliable identification of adults with hypertrophic cardiomyopathy (HC) at risk for sudden death (SD) has been reported. A significant controversy remains, however, regarding the most reliable risk stratification methodology for children and adolescents with HC. The present study assesses the accuracy of SD prediction and prevention with prophylactic implantable cardioverter-defibrillators (ICDs) in young HC patients. The study group is comprised of 146 HC patients <20 years of age evaluated consecutively over 17 years with prospective risk stratification and ICD decision-making. We relied on ≥1 established individual risk markers considered major within each patient's clinical profile, based on an enhanced American College of Cardiology /American Heart Association (ACC/AHA) guidelines algorithm. Of the 60 largely asymptomatic patients implanted with primary prevention ICDs at age 15 ± 4 years, 9 (15%) experienced device therapy terminating potentially lethal ventricular tachyarrhythmias and restoring sinus rhythm at 19 ± 6 years (range 9 to 29), 5.1 ± 6.0 years after implant; 3 patients had multiple appropriate ICD discharges. The individual risk marker algorithm was associated with 100% sensitivity in predicting SD events (95%CI: 69, 100) and 63% specificity for identifying patients without events (95%CI: 54, 71). Of these patients with device therapy, massive left ventricular hypertrophy (absolute wall thickness ≥30 mm) was the most common predictor, present in 70% of patients either alone or in combination with other risk markers. Each of the 146 study patients have survived to date at 22 ± 5 years, including all 86 without ICD recommendations. In conclusion, an enhanced ACC/AHA risk stratification strategy, based on established individual risk markers, was highly reliable in prospectively predicting SD events in children and adolescents with HC, and preventing arrhythmia-based catastrophes in this susceptible high risk population.


Assuntos
Cardiomiopatia Hipertrófica/terapia , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Adolescente , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Antiarrítmicos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Dispositivos de Terapia de Ressincronização Cardíaca , Cardiomiopatia Hipertrófica/complicações , Criança , Morte Súbita Cardíaca/etiologia , Disopiramida/uso terapêutico , Feminino , Humanos , Masculino , Prevenção Primária , Medição de Risco , Síncope/epidemiologia , Taquicardia Ventricular/epidemiologia , Adulto Jovem
7.
J Vet Cardiol ; 29: 40-46, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32464577

RESUMO

Disopyramide reduces the left ventricular outflow tract (LVOT) pressure gradient and improves symptoms in humans with hypertrophic obstructive cardiomyopathy (HOCM). However, the efficacy of disopyramide in cats has not been reported. We treated a cat with HOCM with carvedilol and disopyramide cotherapy and monitored the changes in LVOT flow velocity and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentration. A 10-month-old neutered male Norwegian Forest cat was referred with a moderate systolic cardiac murmur. Echocardiography revealed thickening of the left ventricular wall, systolic anterior motion of the mitral valve leaflets, and turbulent aortic flow in the LVOT at systole. The LVOT flow velocity was 5.6 m/s. The plasma NT-proBNP concentration exceeded 1,500 pmol/L. The cat was diagnosed with HOCM and the ß-blocker carvedilol was started and gradually increased to 0.30 mg/kg, bid. After 57 days, the LVOT flow velocity (4.8 m/s) and plasma NT-proBNP concentration (870 pmol/L) had decreased but remained elevated. Therefore, disopyramide was added at 5.4 mg/kg po bid and increased to 10.9 mg/kg po bid after 22 days. After 141 days of carvedilol and disopyramide treatment, the systolic anterior motion of the mitral valve leaflets had disappeared and the LVOT flow velocity and plasma NT-proBNP concentration had decreased to 0.7 m/s and 499 pmol/L, respectively. No adverse effect has been observed during the follow-up. Disopyramide might relieve feline LVOT obstruction after only partial response to a beta-blocker. Further large-scale studies are required to investigate the efficacy and safety of disopyramide use in cats with moderate to severe HOCM.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Carvedilol/uso terapêutico , Doenças do Gato/tratamento farmacológico , Disopiramida/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Animais , Cardiomiopatia Hipertrófica/veterinária , Gatos , Ecocardiografia/veterinária , Masculino , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Obstrução do Fluxo Ventricular Externo/tratamento farmacológico , Obstrução do Fluxo Ventricular Externo/veterinária
8.
Bioorg Chem ; 98: 103717, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32171994

RESUMO

A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.


Assuntos
Acetamidas/uso terapêutico , Anticonvulsivantes/uso terapêutico , Disopiramida/uso terapêutico , Convulsões/tratamento farmacológico , Acetamidas/administração & dosagem , Acetamidas/química , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/química , Disopiramida/administração & dosagem , Disopiramida/química , Relação Dose-Resposta a Droga , Eletrochoque , Feminino , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Camundongos , Estrutura Molecular , Pentilenotetrazol/administração & dosagem , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Relação Estrutura-Atividade
9.
Int J Cardiol ; 297: 75-82, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615649

RESUMO

BACKGROUND: Significant left-ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) may result in symptoms and is associated with adverse outcomes. Although disopyramide can reduce resting gradients, nearly 30% of HCM patients do not respond. We sought to study the clinical and echocardiographic variables associated with disopyramide-induced LVOT-gradient reduction. METHODS: Forty-one disopyramide-treated HCM patients (average daily-dose 305 mg) were subdivided into two groups: (1) nineteen responders, with a reduction of LVOT-gradients of at least 30% from baseline, and (2) twenty-two non-responders, in whom LVOT-gradients did not change or increased following treatment. All patients had a thorough clinical and echocardiographic assessment pre- and post-treatment initiation. RESULTS: Patients who responded to disopyramide had better pretreatment left ventricular (LV) systolic function (LV ejection fraction of 67.9 ±â€¯5.6% vs. 59.7 ±â€¯5.8%, p = 0.0001), better LV global longitudinal strain (-17.9 ±â€¯2.3% vs. -16.1 ±â€¯2.5%, p = 0.048), less mitral regurgitation, smaller LV size (indexed LV end-systolic volume of 16.2 ±â€¯5.1 ml/m2 vs. 23.2 ±â€¯6.8 ml/m2, p = 0.001), and lower LV maximal wall thickness (17.2±3 mm vs.19.2 ±â€¯3.4 mm, p = 0.046). Baseline left atrial (LA) volumes were significantly lower in the responders, with higher indices of LA ejection fraction (62 ±â€¯11.2% vs. 50.5 ±â€¯12.2%, p = 0.005), systolic LA strain (34 ±â€¯12.4% vs. 25.8 ±â€¯10.6%, p = 0.04), and LA strain-rate (1.34 ±â€¯0.49%/sec vs. 0.99 ±â€¯0.24%/sec, p = 0.012). In multivariable analysis, the presence of reduced LV systolic function and systolic LA strain-rate remained independently associated with poor response to disopyramide. CONCLUSIONS: Obstructive HCM patients with more severe disease at baseline tend to respond less to disopyramide treatment. In those patients, early referral for alcohol septal ablation or myectomy surgery should be considered.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Disopiramida/uso terapêutico , Obstrução do Fluxo Ventricular Externo/tratamento farmacológico , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Idoso , Função Atrial , Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/fisiopatologia , Estudos de Coortes , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda , Obstrução do Fluxo Ventricular Externo/complicações
10.
Cardiol Clin ; 37(1): 45-54, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30447715

RESUMO

Hypertrophic cardiomyopathy is a heterogenous condition associated with a myriad of symptoms. Just as in other disease states, the aim of medical therapy is the alleviation of suffering, improvement of longevity, and the prevention of complications. This article focuses on the associated comorbidities seen in patients with hypertrophic cardiomyopathy, potential lifestyle interventions, and conventional medical treatments for symptomatic hypertrophic cardiomyopathy.


Assuntos
Cardiomiopatia Hipertrófica/terapia , Estilo de Vida Saudável , Comportamento de Redução do Risco , Antagonistas Adrenérgicos beta/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Cardiotônicos/uso terapêutico , Dieta Saudável , Disopiramida/uso terapêutico , Terapia por Exercício/métodos , Nível de Saúde , Humanos , Obesidade/prevenção & controle , Ranolazina/uso terapêutico , Síndromes da Apneia do Sono/prevenção & controle
11.
Artigo em Inglês | MEDLINE | ID: mdl-30173081

RESUMO

Disopyramide as an antiarrhythmic agent has been used for treating ventricular tachycardia and metabolized into its major metabolite, mono-isopropyl-disopyramide, by CYP3A4. We developed a novel, selective, highly sensitive, accurate, rapid method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of disopyramide and mono-isopropyl-disopyramide in rat plasma. This study is the first report for the assay validation using LC-MS/MS in biological fluids after simple protein-precipitation method. The most sensitive signals by multiple reaction monitoring (MRM) showed at m/z 340.2 → 239.2 and 298.2 → 239.2 with same fragment ion for disopyramide and mono-isopropyl-disopyramide, respectively. The lower limit of quantification (LLOQ) was determined at 2 ng/mL for both analytes and the linear concentration ranges were found to be 2-2000 ng/mL for disopyramide and 2-1000 ng/mL for mono-isopropyl-disopyramide. Finally, this assay was successfully applied to pharmacokinetic analysis of disopyramide and mono-isopropyl-disopyramide after oral and intravenous administration of disopyramide.


Assuntos
Cromatografia Líquida/métodos , Disopiramida/análogos & derivados , Disopiramida/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Disopiramida/química , Disopiramida/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
12.
Artigo em Inglês | MEDLINE | ID: mdl-29940218

RESUMO

INTRODUCTION: Since 2005 the S7B and E14 guidances from ICH and FDA have been in place to assess a potential drug candidate's ability to cause long QT syndrome. To refine these guidelines, the FDA proposed the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, where the assessment of drug effects on cardiac repolarization was one subject of investigation. Within the myocyte validation study, effects of pharmaceutical compounds on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were assessed and this article will focus on the evaluation of the proarrhythmic potential of 23 blinded drugs in four hiPSC-CM cell lines. METHODS: Experiments were performed on the CardioExcyte 96 at different sites. A combined readout of contractility (via impedance) and electrophysiology endpoints (field potentials) was performed. RESULTS: Our data demonstrates that hERG blockers such as dofetilide and further high risk categorized compounds prolong the field potential duration. Arrhythmia were detected in both impedance as well as field potential recordings. Intermediate risk compounds induced arrhythmia in almost all cases at the highest dose. In the case of low risk compounds, either a decrease in FPDmax was observed, or not a significant change from pre-addition control values. DISCUSSION: With exceptions, hiPSC-CMs are sensitive and exhibit at least 10% delayed or shortened repolarization from pre-addition values and arrhythmia after drug application and thus can provide predictive cardiac electrophysiology data. The baseline electrophysiological parameters vary between iPS cells from different sources, therefore positive and negative control recordings are recommended.


Assuntos
Antiarrítmicos/farmacologia , Impedância Elétrica , Acoplamento Excitação-Contração/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Linhagem Celular , Células Cultivadas , Disopiramida/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/normas , Acoplamento Excitação-Contração/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Miócitos Cardíacos/fisiologia , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Sulfonamidas/farmacologia
13.
Cardiol Young ; 28(4): 530-535, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29513203

RESUMO

Hypertrophic cardiomyopathy has a range of clinical severity in children. Treatment options are limited, mainly on account of small patient size. Disopyramide is a sodium channel blocker with negative inotropic properties that effectively reduces left ventricular outflow tract gradients in adults with hypertrophic cardiomyopathy, but its efficacy in children is uncertain. A retrospective chart review of patients ⩽21 years of age with hypertrophic cardiomyopathy at our institution and treated with disopyramide was performed. Left ventricular outflow tract Doppler gradients before and after disopyramide initiation were compared as the primary outcome measure. Nine patients received disopyramide, with a median age of 5.6 years (range 6 days-12.9 years). The median left ventricular outflow tract Doppler gradient before initiation of disopyramide was 81 mmHg (range 30-132 mmHg); eight patients had post-initiation echocardiograms, in which the median lowest recorded Doppler gradient was 43 mmHg (range 15-100 mmHg), for a median % reduction of 58.2% (p=0.002). With median follow-up of 2.5 years, eight of nine patients were still alive, although disopyramide had been discontinued in six of the nine patients. Reasons for discontinuation included septal myomectomy (four patients), heart transplantation (one patient), and side effects (one patient). Disopyramide was effective for the relief of left ventricular outflow tract obstruction in children with hypertrophic cardiomyopathy, although longer-term data suggest that its efficacy is not sustained. In general, it was well tolerated. Further study in larger patient populations is warranted.


Assuntos
Cardiomiopatia Hipertrófica/tratamento farmacológico , Disopiramida/administração & dosagem , Ventrículos do Coração/diagnóstico por imagem , Função Ventricular Esquerda/fisiologia , Adolescente , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Ecocardiografia Doppler , Eletrocardiografia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Adulto Jovem
14.
Pacing Clin Electrophysiol ; 41(5): 444-446, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29148059

RESUMO

Early repolarization (ER) has been associated with an increased risk of sudden cardiac arrest. Interestingly, ventricular arrhythmias seem to be triggered by parasympathetic stimulation. In the present case report, we describe complete control of highly frequent malignant ventricular arrhythmias after adding theophylline to ineffective oral hydroquinidine and high-rate pacing in a patient suffering from malignant ER. We hypothesize that the theophylline-mediated enhanced beta-adrenergic stimulation could reduce the transmural myocardial voltage discrepancy by increasing the inward ICa,L current.


Assuntos
Desfibriladores Implantáveis , Taquicardia Ventricular/tratamento farmacológico , Teofilina/uso terapêutico , Vasodilatadores/uso terapêutico , Antiarrítmicos/uso terapêutico , Criança , Disopiramida/uso terapêutico , Humanos , Masculino , Quinidina/análogos & derivados , Quinidina/uso terapêutico , Recidiva , Taquicardia Ventricular/fisiopatologia
15.
Medicine (Baltimore) ; 96(49): e8755, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29245231

RESUMO

RATIONALE: Cases of severe disopyramide poisoning are rare and few have been reported. We report a case in which activated-charcoal column hemoperfusion was dramatically effective for life-threatening disopyramide poisoning. PATIENT CONCERNS: A teenage girl who had overdosed on disopyramide (total dose, 4950 mg) was brought to our hospital. She was resuscitated from short period cardiopulmonary arrest and subsequently showed severe cardiogenic shock and ventricular arrhythmia. DIAGNOSES: Disopyramide poisoning (self-evident). INTERVENTIONS: As hemodynamics remained unstable after providing percutaneous cardiopulmonary support and intra-aortic balloon pumping, we attempted direct hemoperfusion using a coated activated-charcoal hemoperfusion column. OUTCOMES: Hemodynamics including electrocardiography and serum disopyramide concentration were dramatically improved, and the patient was ambulatory by hospital day 14. LESSONS: Because disopyramide has low molecular weight and a small distribution volume, blood purification is considered to be the most effective therapy. We selected direct hemoperfusion for relatively high protein-binding rate. In fact, clinical status was dramatically improved, and the calculated half-life of the direct hemoperfusion phase was the shortest of all phases. In cases of severe or life-threatening disopyramide poisoning, blood purification therapy including direct hemoperfusion using a coated activated-charcoal column should be performed.


Assuntos
Antiarrítmicos/envenenamento , Disopiramida/envenenamento , Overdose de Drogas/terapia , Hemoperfusão/métodos , Adolescente , Antídotos/uso terapêutico , Carvão Vegetal/uso terapêutico , Feminino , Humanos , Resultado do Tratamento
16.
J Chromatogr A ; 1519: 64-73, 2017 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-28886937

RESUMO

A method that combined on-line immunoextraction with high-performance affinity chromatography was developed to examine the binding of drugs with α1-acid glycoprotein (AGP). Affinity microcolumns containing immobilized polyclonal anti-AGP antibodies were developed that had a capture efficiency of up to 98.4% for AGP and a binding capacity of 0.72nmol AGP when using a 20mm×2.1mm i.d. microcolumn. These microcolumns were employed in various formats to examine the binding of drugs to normal AGP and AGP that had been adsorbed from serum samples for patients with systemic lupus erythematosus (SLE). Drugs that were screened in zonal elution experiments for their overall binding to these types of AGP included chlorpromazine, disopyramide, imipramine, propranolol, and warfarin. Most of these drugs showed an increase in their binding to the AGP from SLE serum when compared to normal AGP (i.e., an increase of 13-76%); however, disopyramide gave a 21-25% decrease in retention when the same AGP samples were compared. Frontal analysis was used to further evaluate the binding of disopyramide and imipramine to these forms of AGP. Both drugs gave a good fit to a model that involved a combination of saturable and non-saturable interactions with AGP. Changes in the non-saturable interactions accounted for most of variations seen in the binding of disopyramide and imipramine with the AGP samples. The methods used in this study could be adapted for use in personalized medicine and the study of other proteins or drugs using aqueous mixtures or clinical samples.


Assuntos
Cromatografia de Afinidade , Interações Medicamentosas , Orosomucoide/metabolismo , Preparações Farmacêuticas/metabolismo , Anticorpos/metabolismo , Clorpromazina/isolamento & purificação , Clorpromazina/metabolismo , Disopiramida/isolamento & purificação , Disopiramida/metabolismo , Humanos , Imipramina/isolamento & purificação , Imipramina/metabolismo , Orosomucoide/química , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/isolamento & purificação , Propranolol/isolamento & purificação , Propranolol/metabolismo , Ligação Proteica , Varfarina/isolamento & purificação , Varfarina/metabolismo
17.
Physiol Meas ; 38(10): 1859-1873, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28812984

RESUMO

OBJECTIVE: Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current I K1) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3. APPROACH: The ten Tusscher et al model of human ventricular myocyte action potential (AP) was modified to recapitulate the changes in I K1 due to heterozygous and homozygous forms of the D172N mutation. Wild-type (WT) and mutant WT-D172N and D172N formulations were incorporated into one-dimensional (1D) and 2D tissue models with transmural heterogeneities. Effects of drugs on channel-blocking activity were modelled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values. Effects of drugs on AP duration (APD), effective refractory period (ERP) and QT interval of pseudo-ECGs were quantified, and both temporal and spatial vulnerability to re-entry was measured. Re-entry was simulated in the 2D ventricular tissue. MAIN RESULTS: At the single cell level, the drugs quinidine, disopyramide, and E-4031 prolonged APD at 90% repolarization (APD90), and decreased maximal transmural voltage heterogeneity (δV); this caused the decreased transmural dispersion of APD90. Quinidine prolonged the QT interval and decreased the T-wave amplitude. Furthermore, quinidine increased ERP and reduced temporal vulnerability and increased spatial vulnerability, resulting in a reduced susceptibility to arrhythmogenesis in SQT3. In the 2D tissue, quinidine was effective in terminating and preventing re-entry associated with the heterozygous D172N condition. Quinidine exhibited significantly better therapeutic effects on SQT3 than disopyramide and E-4031. SIGNIFICANCE: This study substantiates a causal link between quinidine and QT interval prolongation in SQT3 Kir2.1 mutations and highlights possible pharmacological agent quinidine for treating SQT3 patients.


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Disopiramida/farmacologia , Sistema de Condução Cardíaco/anormalidades , Cardiopatias Congênitas/tratamento farmacológico , Ventrículos do Coração/efeitos dos fármacos , Modelos Biológicos , Piperidinas/farmacologia , Piridinas/farmacologia , Quinidina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Disopiramida/uso terapêutico , Sistema de Condução Cardíaco/patologia , Sistema de Condução Cardíaco/fisiopatologia , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Quinidina/uso terapêutico
18.
PLoS One ; 12(6): e0179515, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28632743

RESUMO

AIMS: Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology. METHODS: The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue. RESULTS: At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide. CONCLUSIONS: The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Disopiramida/farmacologia , Piperidinas/farmacologia , Piridinas/farmacologia , Quinidina/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Linhagem Celular , Disopiramida/uso terapêutico , Canal de Potássio ERG1/genética , Eletrocardiografia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Modelos Biológicos , Piperidinas/uso terapêutico , Polimorfismo de Nucleotídeo Único , Piridinas/uso terapêutico , Quinidina/uso terapêutico
19.
Drugs R D ; 17(3): 475-480, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28646384

RESUMO

OBJECTIVE: Human α1-acid glycoprotein has genetic variants, the F1, S, and A variants, which can be separated isoelectrophoretically. These variants show differences in their affinity of binding to several drugs. In this study, we investigated the factors determining drug binding to these α1-acid glycoprotein genetic variants using disopyramide, warfarin, and tamsulosin as marker compounds. METHODS: Binding of the marker drugs to human α1-acid glycoprotein was determined by ultra-filtration in the presence or absence of various other drugs. For screening of the α1-acid glycoprotein variants to which the marker drugs became bound, the effects of various other drugs on their binding were studied. The binding data were analyzed using a competitive inhibition model and the relationship between the estimated dissociation constants and physicochemical properties, such as log P, was also analyzed. RESULTS: The binding of tamsulosin was significantly decreased by aprindine, carvedilol, erythromycin, thioridazine, and warfarin, but not by disopyramide. The dissociation constants of drugs bound to F1/S variants were significantly correlated with their lipophilicity, but those for the A variant were not. CONCLUSIONS: We were able to develop a simple screening method for determining individual α1-acid glycoprotein variants to which drugs would bind. The binding of drugs to F1/S variants may be determined mainly by drug lipophilicity.


Assuntos
Disopiramida/metabolismo , Orosomucoide/metabolismo , Sulfonamidas/metabolismo , Varfarina/metabolismo , Disopiramida/química , Variação Genética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Orosomucoide/genética , Ligação Proteica , Sulfonamidas/química , Tansulosina , Ultrafiltração , Varfarina/química
20.
J Am Heart Assoc ; 6(6)2017 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-28550094

RESUMO

BACKGROUND: Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated. METHODS AND RESULTS: All charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow-up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long-term follow-up (255 patient-years; mean, 447 days; interquartile range, 201-779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty-eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow-up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect. CONCLUSIONS: Initiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT-prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes.


Assuntos
Assistência Ambulatorial , Antiarrítmicos/administração & dosagem , Cardiomiopatia Hipertrófica/tratamento farmacológico , Disopiramida/administração & dosagem , Bloqueadores do Canal de Sódio Disparado por Voltagem/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Idoso , Antiarrítmicos/efeitos adversos , Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/fisiopatologia , Bases de Dados Factuais , Disopiramida/efeitos adversos , Eletrocardiografia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Síncope/induzido quimicamente , Fatores de Tempo , Torsades de Pointes/induzido quimicamente , Resultado do Tratamento , Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos
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