Assuntos
Síndrome de Brugada , Substituição de Medicamentos , Eletrocardiografia , Moricizina/análogos & derivados , Complexos Ventriculares Prematuros/tratamento farmacológico , Administração Oral , Antiarrítmicos/administração & dosagem , Antiarrítmicos/efeitos adversos , Síndrome de Brugada/induzido quimicamente , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/prevenção & controle , Feminino , Humanos , Pessoa de Meia-Idade , Moricizina/administração & dosagem , Moricizina/efeitos adversos , Sotalol/administração & dosagem , Resultado do Tratamento , Complexos Ventriculares Prematuros/diagnóstico , Complexos Ventriculares Prematuros/fisiopatologiaRESUMO
The relative bioavailability of a 200 mg film-coated tablet of [12C]moricizine.HCl in comparison to a 200 mg [13C6]moricizine.HCl oral solution was determined after simultaneous administration to 8 young healthy male subjects. Concentrations of [12C]moricizine.HCl and [13C6]moricizine.HCl were determined by thermospray liquid chromatography-mass spectrometry (LC-MS) using [2H11]moricizine.HCl as the internal standard. The mean absorption and disposition parameters of the tablet versus the solution were the following (%CV): maximum concentration, 0.83 (39%) versus 0.79 (39%) microgram/mL; time of maximum concentration, 0.81 (40%) versus 0.65 (28%) hours; area under the concentration-time curve (AUC), 1.58 (39%) versus 1.49 (37%) micrograms.h/mL; apparent oral clearance, 150.7 (52%) versus 158.1 (50%) L/h; and t1/2, 1.9 (42%) versus 1.9 (42%) hours. The AUC for the tablet averaged 106% of the solution, which likely reflects a greater first-pass effect with the oral solution. Partitioning sources of variation confirmed the low (< 6%) intrasubject coefficient of variation (cv epsilon) afforded via the single-period, dual-isotope design. In contrast, a previous study using the conventional two-period crossover design determined the cv epsilon about moricizine metrics to be in excess of 30%, resulting in classification of this drug as having highly variable absorption. The results of this study further illustrate the benefits of dual, stable isotopes to assess bioavailability and bioequivalence. This paradigm results in a reduction in experimental time and subject inconvenience and lower costs in comparison with the standard crossover study. Perhaps most important is the improved statistical power for the evaluation of bioavailability or bioequivalence in the absence of period and sequence effects that confound the assessment of intrasubject variation in the standard crossover design.
Assuntos
Antiarrítmicos/farmacocinética , Moricizina/farmacocinética , Adulto , Antiarrítmicos/efeitos adversos , Área Sob a Curva , Disponibilidade Biológica , Isótopos de Carbono , Estudos Cross-Over , Fadiga/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Humanos , Hidrogênio , Isótopos , Masculino , Taxa de Depuração Metabólica , Moricizina/efeitos adversos , Moricizina/sangue , Náusea/induzido quimicamente , Soluções Farmacêuticas , Projetos Piloto , Comprimidos com Revestimento Entérico , Equivalência TerapêuticaRESUMO
O diagnóstico correto do tipo de arritmia cardíaca é a primeira etapa na avaliação do paciente. A necessidade da terapêutica antiarrítmica deve ser cuidadosamente avaliada para, em seguida, decidir se a abordagem será farmacológica ou não. A escolha do fármaco antiarrítmico deve ser individualizada, considerando-se a farmacocinética e as interaçöes medicamentosas. A identificação e correção de condiçöes associadas (isquemia miocárdica, disfunção ventricular, distúrbios eletrolíticos) e a avalização periódica da função dos órgãos responsáveis pela metabolização e excreção das drogas são fundamentais para minimizar os efeitos pró-arrítmicos.
Assuntos
Humanos , Antiarrítmicos/classificação , Antiarrítmicos/farmacologia , Disopiramida/sangue , Glicoproteínas/efeitos adversos , Lidocaína/administração & dosagem , Procainamida/administração & dosagem , Quinidina/administração & dosagem , Tosilato de Bretílio/administração & dosagem , Fenitoína/administração & dosagem , Flecainida/administração & dosagem , Mexiletina/efeitos adversos , Moricizina/efeitos adversos , Sotalol/administração & dosagem , TocainideRESUMO
Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.
Assuntos
Antiarrítmicos/farmacologia , Antiarrítmicos/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/farmacocinética , Diltiazem/farmacologia , Diltiazem/farmacocinética , Moricizina/farmacologia , Moricizina/farmacocinética , Adolescente , Adulto , Antiarrítmicos/efeitos adversos , Área Sob a Curva , Biotransformação , Proteínas Sanguíneas/metabolismo , Bloqueadores dos Canais de Cálcio/efeitos adversos , Cromatografia Líquida de Alta Pressão , Diltiazem/efeitos adversos , Interações Medicamentosas , Meia-Vida , Humanos , Masculino , Moricizina/efeitos adversos , Ligação ProteicaRESUMO
A hundred and twenty two patients with premature ventricular contractions and paroxysmal tachycardias were comprehensively studied prior to and following treatment regimen with ethacizin, befol, sodium succinate and their combinations. Besides its significant antiarrhythmic activity, ethacizin displayed a number of adverse cardiac effects, such as excessive negative inotropic and dromotropic ones. Befol and sodium succinate in combination with ethacizin can reduce or even eliminate these side effects in rest and during simulated mental stress and graded exercise. The antiarrhythmic effect of the combined therapy preserved or even became stronger. This therapy may be long performed for arrhythmias even in patients with circulatory insufficiency and cardiac conduction disturbances caused or redoubled by ethacizin.
Assuntos
Antiarrítmicos/efeitos adversos , Antidepressivos/administração & dosagem , Arritmias Cardíacas/tratamento farmacológico , Benzamidas/administração & dosagem , Moricizina/análogos & derivados , Morfolinas/administração & dosagem , Succinatos/administração & dosagem , Antiarrítmicos/administração & dosagem , Arritmias Cardíacas/diagnóstico , Quimioterapia Combinada , Eletrocardiografia , Eletrocardiografia Ambulatorial , Moricizina/administração & dosagem , Moricizina/efeitos adversos , Isquemia Miocárdica/complicações , Isquemia Miocárdica/diagnóstico , Ácido Succínico , Taquicardia Paroxística/diagnóstico , Taquicardia Paroxística/tratamento farmacológico , Complexos Ventriculares Prematuros/diagnóstico , Complexos Ventriculares Prematuros/tratamento farmacológicoRESUMO
In this study we investigated the time to the first arrhythmic, ischemic, or failure event for encainide-flecainide and moricizine versus their respective placebo comparison groups in the Cardiac Arrhythmia Suppression Trial. The purpose was to explore possible mechanisms for the excessive deaths associated with active therapy that have been previously reported. Differences were noted between the active drugs. In particular, encainide-flecainide appeared to convert an ischemic event into death in more cases and more promptly than moricizine. However, the excessive deaths noted on encainide-flecainide were as likely to occur subsequent to a failure event as an ischemic event; for both encainide-flecainide and moricizine, the vast majority of excess deaths appeared to be the result of an increase in arrhythmia events without any protective effect of the drug. We were unable to identify any specific mechanism to explain the adverse effect of encainide and flecainide.
Assuntos
Antiarrítmicos/efeitos adversos , Arritmias Cardíacas/prevenção & controle , Insuficiência Cardíaca/prevenção & controle , Isquemia Miocárdica/prevenção & controle , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/mortalidade , Método Duplo-Cego , Encainida/efeitos adversos , Flecainida/efeitos adversos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Humanos , Moricizina/efeitos adversos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/mortalidade , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/mortalidade , Fatores de Risco , Análise de Sobrevida , Fatores de TempoRESUMO
The Cardiac Arrhythmia Suppression Trial II (CAST II) was a double-masked placebo-controlled randomized trial that compared the survival effects of moricizine to placebo in postmyocardial infarction arrhythmia patients. The quality-of-life outcome measures were designed prospectively for CAST and were previously shown to have high reliability and clinical discriminative validity. The CAST quality-of-life instrument detected significant differences between moricizine and placebo. In particular, moricizine was most strongly associated with inferior social activity and satisfaction scores (p = .014) and lower scores for overall contentment with life (p = .007). Moreover, the quality-of-life measures improved significantly for both the moricizine and placebo treatment groups after entry into the clinical trial. These results indicate that the CAST quality-of-life instrument is sensitive for assessing pharmacological therapies in the treatment of heart disease.
Assuntos
Arritmias Cardíacas/tratamento farmacológico , Moricizina/uso terapêutico , Qualidade de Vida , Idoso , Arritmias Cardíacas/fisiopatologia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Moricizina/efeitos adversos , Efeito Placebo , Placebos , Estudos Prospectivos , Inquéritos e Questionários , Resultado do TratamentoRESUMO
BACKGROUND: The Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular ectopy with antiarrhythmic drugs after a myocardial infarction reduces the incidence of sudden arrhythmic death. Patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The encainide and flecainide arms of the study were discontinued in 1989 (CAST-I) and the moricizine arm in 1991 (CAST-II) because of excess mortality. To explore the mechanisms of these adverse outcomes, we examined the interaction of baseline characteristics with the hazard of therapy with encainide, flecainide, or moricizine compared with their respective placebos. METHODS AND RESULTS: CAST-I comprised 755 patients assigned to flecainide or encainide and 743 patients assigned to placebo, whereas in CAST-II, 502 patients received moricizine and 491 patients received placebo. Clinical and laboratory baseline variables of patients receiving active drug and those receiving placebo were similar. In CAST-I patients, there was a significant interaction of active therapy with both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest for non-Q-wave myocardial infarction (total mortality hazard ratios, 1.8 versus 7.9 for Q-wave versus non-Q-wave infarction, P = .03). Ventricular premature depolarization (VPD) frequency > or = 50/h and heart rate > or = 74 beats per minute each interacted significantly with total mortality/cardiac arrest only. In the sicker CAST-II patients (ejection fraction < or = 40%), only diuretic use at baseline interacted significantly with moricizine use for both all-cause death/cardiac arrest and arrhythmic death/cardiac arrest (total mortality hazard ratios, 1.9 versus 0.7 for diuretic use versus no use, P = .01). CONCLUSIONS: Although active treatment in CAST-I was associated with greater mortality than placebo with respect to almost all baseline variables, the therapeutic hazard was more than expected in patients with non-Q-wave myocardial infarction and (for total mortality) frequent premature VPDs and higher heart rates, suggesting that the adverse effect of encainide or flecainide therapy is greater when ischemic and electrical instability are present. The relative hazard of therapy with moricizine in the sicker CAST-II population was greater in those using diuretics. Thus, although these drugs have the common ability to suppress ventricular ectopy after myocardial infarction, their detrimental effects on survival may be mediated by different mechanisms in different populations, emphasizing the complex, poorly understood hazards associated with antiarrhythmic drug treatment.
Assuntos
Arritmias Cardíacas/prevenção & controle , Encainida/efeitos adversos , Flecainida/efeitos adversos , Moricizina/efeitos adversos , Infarto do Miocárdio/tratamento farmacológico , Encainida/uso terapêutico , Feminino , Flecainida/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Moricizina/uso terapêutico , Infarto do Miocárdio/mortalidade , Estatística como Assunto , Análise de SobrevidaRESUMO
Ethmozin (Moricizine HCl) and ethacizin are two class I antiarrhythmic drugs with different rate constants of interaction with the sodium channel. Computer simulation using the "guarded-receptor" model predicted that the combination of ethacizin and ethmozin should exert a greater decrease in excitability and conduction at short coupling intervals, but little effect at normal heart rates (HR). To test this prediction, we measured intraventricular conduction delay in canine hearts in vivo. In agreement with the model, the combination more potently prolonged the delay only at intervals < 600 ms as compared with ethacizin alone. Combination therapy was tested in 6 patients with idiopathic ventricular ectopic depolarizations (VEDs). Three patients were resistant to either ethmozin or ethacizin monotherapy, and three could not tolerate effective doses because of side effects. Quantitative continuous ECG monitoring showed that total VEDs in the resistant group decreased 0 and 17 +/- 13% for 400 and 800 mg/day ethmozin and 18 +/- 12 and 55 +/- 12% for 100 and 200 mg/day ethacizin, respectively. Combined therapy with ethmozin (400 mg/day) and ethacizin (100 mg/day) reduced the number of VEDs by 78 +/- 2% in these patients without side effects. In the "nonresistant" but intolerant group of patients, use of the combination allowed relief of symptomatic ectopy without side effects. A theoretical model correctly predicted an effective combination of class I antiarrhythmic drugs, one with "fast-off" and one with "slow-off" kinetics, which may provide a general rationale for choosing drug combinations.
Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Moricizina/análogos & derivados , Adulto , Animais , Antiarrítmicos/efeitos adversos , Arritmias Cardíacas/fisiopatologia , Simulação por Computador , Cães , Quimioterapia Combinada , Estimulação Elétrica , Eletrocardiografia , Feminino , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Moricizina/efeitos adversos , Moricizina/uso terapêutico , Receptores de Droga/efeitos dos fármacos , Canais de Sódio/efeitos dos fármacosRESUMO
In patients with history of sustained ventricular tachycarrhythmias, the efficacy and safety of moricizine have not been systematically evaluated by electrophysiological studies. We performed electrophysiological testing in these patients in the drug-free state and then after moricizine loading, and evaluated the safety profile of moricizine during in-hospital loading and follow-up. The study population comprised of 31 patients with clinically sustained ventricular tachyarrhythmia. The underlying heart disease was coronary in 25 patients, cardiomyopathy in 5 patients, and none in 1 patient. The left ventricular (LV) ejection fraction ranged from 15%-69% (mean 39 +/- 15%). During the baseline drug-free electrophysiological testing, sustained ventricular tachycardia was inducible in 27 patients, ventricular fibrillation in 1 patient, and reproducible, nonsustained ventricular tachycardia (15-25 sec) in 3 patients. All 31 patients received moricizine to the maximum tolerated dose (851 +/- 185 mg) over a period of 2-7 days. Six patients developed ventricular proarrhythmia within the first 4 days. Proarrhythmia required multiple cardioversions in three patients, was not associated with QT prolongation, and spontaneously resolved 6-24 hours after withdrawal of moricizine. Of the remaining 25 patients, 24 underwent electrophysiological testing on moricizine and 4 patients (16%) were rendered noninducible. The VT cycle length in the other 20 patients slowed from 243 +/- 30 msec to 299 +/- 60 msec (P < 0.09). Four noninducible patients, two patients with inducible but slowed VT and one patient who had refused further testing were discharged on moricizine.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Arritmias Cardíacas/induzido quimicamente , Moricizina/uso terapêutico , Taquicardia Ventricular/tratamento farmacológico , Estimulação Cardíaca Artificial , Eletrocardiografia/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moricizina/efeitos adversos , Taquicardia Ventricular/fisiopatologiaRESUMO
Moricizine is a Class I antiarrhythmic drug currently approved for the treatment of life-threatening ventricular arrhythmias. The drug has received significant attention because of its role in the Cardiac Arrhythmia Suppression Trial. Previous data suggested that the agent has a relatively low proarrhythmic potential. This may lead clinicians to use the drug empirically for less significant ventricular arrhythmias. We report a case of life-threatening late proarrhythmia caused by moricizine and comment on our experience with this agent. We feel that this drug has significant proarrhythmic potential and should not be used empirically to treat ventricular ectopy especially in patients with underlying structural heart disease.
Assuntos
Antiarrítmicos/efeitos adversos , Arritmia Sinusal/induzido quimicamente , Moricizina/efeitos adversos , Taquicardia Ventricular/tratamento farmacológico , Idoso , Arritmia Sinusal/fisiopatologia , Arritmia Sinusal/terapia , Estimulação Cardíaca Artificial , Eletrocardiografia Ambulatorial , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Taquicardia Ventricular/fisiopatologiaRESUMO
The prevalence of proarrhythmic events during moricizine therapy was studied in 144 patients who were treated for symptomatic ventricular tachycardia or ventricular fibrillation. The overall incidence of proarrhythmia was 15.3%. (Twenty-two patients exhibited 23 events.) Ventricular fibrillation occurred in six patients (which led to three deaths), incessant ventricular tachycardia occurred in seven, and new sustained ventricular tachycardia in four. Patients with proarrhythmia had significantly lower left ventricular ejection fraction (24% vs 39%; p less than 0.0001), higher prevalence of congestive heart failure (68% vs 36%; p less than 0.005), and higher incidence of previous proarrhythmia (45% vs 9%; p less than 0.0001). No significant difference between the two groups was found in respect to age, arrhythmia at presentation, underlying heart disease, moricizine dose, or concomitant drug therapy.
Assuntos
Moricizina/efeitos adversos , Moricizina/uso terapêutico , Taquicardia/induzido quimicamente , Fibrilação Ventricular/induzido quimicamente , Função Ventricular/fisiologia , Avaliação de Medicamentos , Eletrocardiografia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Volume Sistólico/fisiologia , Taquicardia/tratamento farmacológico , Taquicardia/epidemiologia , Fibrilação Ventricular/tratamento farmacológico , Fibrilação Ventricular/epidemiologiaRESUMO
Moricizine has been touted as having a low incidence of proarrhythmic effects. We present a case of proarrhythmia from moricizine, which presented as exercise induced ventricular tachycardia, and review the literature suggesting that this antiarrhythmic drug shares the proarrhythmic profile of other agents with predominant type Ic action. We conclude that moricizine has certain clinical and electrophysiological features that resemble type Ic antiarrhythmic agents. Precautions similar to those used when prescribing other drugs of this type should be followed when prescribing moricizine, including predischarge exercise testing.
Assuntos
Exercício Físico , Moricizina/efeitos adversos , Taquicardia Ventricular/induzido quimicamente , Terapia Combinada , Desfibriladores Implantáveis , Eletrocardiografia , Teste de Esforço , Humanos , Masculino , Pessoa de Meia-Idade , Moricizina/uso terapêutico , Taquicardia Ventricular/terapiaRESUMO
OBJECTIVE: To determine the effect of age on the response to anti-arrhythmic drugs. DESIGN: Randomized controlled trial comparing particular drugs. SETTING: Multi-institutional (The Cardiac Arrhythmia Suppression Trial, CAST). PARTICIPANTS: 2,371 patients, age less than 80, with ventricular arrhythmias after a recent myocardial infarction. Subjects classified by age as less than or equal to 55, 56-65, and 66-79 years. INTERVENTION: Upwardly titrated doses of encainide, flecainide or moricizine. After identification of a tolerated and effective dose of one of the drugs, participants were randomized to that drug and dose versus its placebo for up to 10 months. MAIN OUTCOME MEASURES: Efficacy of drug (suppression of ventricular premature depolarizations and/or non-sustained ventricular tachycardia), side effects and mortality. RESULTS: Older patients had more previous MIs, congestive heart failure (CHF), hypertension, NSVT, repolarization abnormalities, digitalis use, and diuretic use. They had less pathologic Q-waves or electrocardiographic injury pattern, and their left ventricular ejection fraction (LVEF) was lower. First dose VPD suppression with the first drug averaged 53% and is not associated with age (P = 0.29). Adverse events including death are more frequent in older patients taking study drugs (P less than 0.001). This trend is consistent in all three study drugs and at varying LVEFs. History of prior MI, low LVEF, VPD (in log scale), and digitalis therapy also correlates with adverse events (all P less than 0.05). Following adjustment for these factors, older age is an independent predictor of adverse events (relative risk 1.30 per decade of age, P less than 0.001). CONCLUSIONS: Older age increases the susceptibility to adverse cardiac events from a class of relatively toxic antiarrhythmic agents.
Assuntos
Envelhecimento/efeitos dos fármacos , Arritmias Cardíacas/tratamento farmacológico , Encainida/efeitos adversos , Flecainida/efeitos adversos , Moricizina/efeitos adversos , Infarto do Miocárdio/complicações , Adulto , Fatores Etários , Idoso , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiologia , Quimioterapia Combinada , Encainida/administração & dosagem , Encainida/uso terapêutico , Flecainida/administração & dosagem , Flecainida/uso terapêutico , Seguimentos , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Moricizina/administração & dosagem , Moricizina/uso terapêutico , Prognóstico , Volume Sistólico/efeitos dos fármacosRESUMO
The study was undertaken to examine 105 patients with various circulatory diseases complicated by atrial fibrillation. Patients with refractory atrial fibrillation who had taken combined antiarrhythmic therapy were found to be more responsive to the combinations of cordarone + kinilentin (quinidine disulphate) and cordarone + ethacizin. The combinations of cordarone+digoxin and cordarone + finoptin were demonstrated to be less beneficial.
Assuntos
Amiodarona/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Adulto , Idoso , Amiodarona/efeitos adversos , Antiarrítmicos/administração & dosagem , Digoxina/administração & dosagem , Digoxina/efeitos adversos , Quimioterapia Combinada , Humanos , Pessoa de Meia-Idade , Moricizina/administração & dosagem , Moricizina/efeitos adversos , Moricizina/análogos & derivados , Quinidina/administração & dosagem , Quinidina/efeitos adversos , Verapamil/administração & dosagem , Verapamil/efeitos adversosRESUMO
The effects of phenothiazine drugs on the levels of cholesterol in smooth cells of the human aortic intima. Two antiarrhythmics (ethacizin and ethmozine) and two neuroleptics (trifluoperazine and chlorpromazine) were evaluated. The three agents ethacizin, trifluoperazine, and chlorpromazine given in concentrations of 10(-7) to 10(-5) M were ascertained to cause intracellular cholesterol accumulation, whereas ethmozine produced no effects on the intracellular levels of cholesterol. Ethacizin failed to cause cholesterol accumulation when the cells were incubated with ethacizin in the culture medium supplemented with lipid-deficient serum. Ethacizin in a concentration o 10(-5) M was shown to inhibit the synthesis of cholesterol esters and had no action on the intracellular synthesis of steroids.
Assuntos
Aorta/efeitos dos fármacos , Arteriosclerose/induzido quimicamente , Fenotiazinas/efeitos adversos , Antiarrítmicos/efeitos adversos , Aorta/química , Células Cultivadas , Clorpromazina/efeitos adversos , Colesterol/análise , Meios de Cultura , Humanos , Moricizina/efeitos adversos , Moricizina/análogos & derivados , Psicotrópicos/efeitos adversos , Trifluoperazina/efeitos adversosRESUMO
OBJECTIVE: The primary objective of this article is to review the management of ventricular arrythmias in the light of the unfavourable results reported in the Cardiac Arrhythmia Suppression Trial (CAST). STUDY SELECTION, DATA EXTRACTION AND SYNTHESIS: CAST tested the hypothesis that suppression of ventricular arrhythmias recorded on a Holter monitor in patients with myocardial infarction would lead to a decrease in subsequent mortality, presumably by preventing sudden death. In the trial, patients with a myocardial infarction which occurred six days to two years previously and with asymptomatic ventricular premature beats which could be suppressed by one of the antiarrhythmic agents flecainide, encainide or moricizine, were randomised to treatment with one of these agents or placebo. Over a mean follow-up period of 10 months, mortality was significantly higher in those patients receiving flecainide or encainide than in those receiving placebo. On the recommendation of the Data and Safety Monitoring Board the trial in these groups was terminated. More recently CAST II in which moricizine was compared to placebo was also terminated, again because of a higher mortality in the patients receiving active treatment. It is likely that much of the excess mortality can be attributed to proarrhythmic effects of the agents. CONCLUSION: Current management of ventricular arrhythmias are considered in the light of these findings. CAST suggests that specific treatment should be dictated by the presence of associated symptoms and as much by associated structural heart disease as the arrhythmia per se. In particular, specific treatment of ventricular premature beats alone should be avoided. In those with potentially lethal ventricular arrhythmias, referral for appropriate investigation and consideration of non-pharmacological measures is necessary.
Assuntos
Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Antiarrítmicos/efeitos adversos , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/mortalidade , Complexos Cardíacos Prematuros/tratamento farmacológico , Ensaios Clínicos como Assunto , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia Ambulatorial , Encainida/efeitos adversos , Encainida/uso terapêutico , Flecainida/efeitos adversos , Flecainida/uso terapêutico , Ventrículos do Coração , Humanos , Moricizina/efeitos adversos , Moricizina/uso terapêutico , Infarto do Miocárdio/complicações , Função Ventricular Esquerda/fisiologiaRESUMO
OBJECTIVE: To assess the efficacy and toxicity of moricizine in treating patients with serious ventricular arrhythmias and inducible sustained ventricular tachycardia. DESIGN: Uncontrolled clinical trial. SETTING: The intensive care and telemetry units of Northwestern Memorial Hospital, St. Francis Hospital and Medical Center, and Lenox Hill Hospital. PATIENTS: Twenty-six patients with sustained ventricular arrhythmias or hemodynamically significant nonsustained ventricular tachycardia, most of whom failed therapy with at least one class I antiarrhythmic agent. INTERVENTION: Patients were treated with moricizine, 400 to 1000 mg/d. MEASUREMENT: Efficacy was assessed by the results of programmed ventricular stimulation done during moricizine therapy. MAIN RESULTS: Seven of the 26 patients (27%) developed life-threatening ventricular proarrhythmia during moricizine loading. Three patients had incessant sustained ventricular tachycardia, two had incessant nonsustained ventricular tachycardia, one had new sustained ventricular tachycardia, and one had new cardiac arrest. One of these patients died of intractable ventricular fibrillation. No clinical or electrophysiologic variables clearly identified those at risk for proarrhythmia. Only 3 of 26 patients (12%) became noninducible on moricizine. CONCLUSION: Moricizine has a low rate of efficacy and carries a considerable risk for life-threatening proarrhythmia in patients with serious ventricular arrhythmias and inducible ventricular tachycardia who have failed therapy with other class I antiarrhythmic agents.