Antifungal activity of propafenone on Candida spp. strains: interaction with antifungals and possible mechanism of action.

Introduction. The development of new antifungal drugs has become a global priority, given the increasing cases of fungal diseases together with the rising resistance to available antifungal drugs. In this scenario, drug repositioning has emerged as an alternative for such development, with advantages such as reduced research time and costs.Gap statement. Propafenone is an antiarrhythmic drug whose antifungal activity is poorly described, being a good candidate for further study.Aim. This study aims to evaluate propafenone activity against different species of Candida spp. to evaluate its combination with standard antifungals, as well as its possible action mechanism.Methodology. To this end, we carried out tests against strains of Candida albicans, Candida auris, Candida parapsilosis, Candida tropicalis, Candida glabrata and Candida krusei based on the evaluation of the MIC, minimum fungicidal concentration and tolerance level, along with checkerboard and flow cytometry tests with clinical strains and cell structure analysis by scanning electron microscopy (SEM).Results. The results showed that propafenone has a 50% MIC ranging from 32 to 256 µg ml-1, with fungicidal activity and positive interactions with itraconazole in 83.3% of the strains evaluated. The effects of the treatments observed by SEM were extensive damage to the cell structure, while flow cytometry revealed the apoptotic potential of propafenone against Candida spp.Conclusion. Taken together, these results indicate that propafenone has the potential for repositioning as an antifungal drug.

Detoxification effects of long-chain versus a mixture of medium- and long-chain triglyceride-based fat emulsion on propafenone poisoning.

In the present study, we aimed to compare the detoxifying effects of two fat emulsions containing either long-chain triglyceride or a mixture of medium-chain and long-chain triglycerides in the propafenone-poisoned rat model. Rats were randomly divided into 3 groups according to the fat emulsions used: long-chain triglyceride-based fat emulsion (LL) group; medium-chain and long-chain triglyceride-based fat emulsion (ML) group; normal saline (NS) group. Propafenone was continuously pumped (velocity=70 mg/kg per h) until the mean blood pressure dropped to 50% of basal level. Then, LL/ML fat emulsions or NS was intravenously infused instantly with a loading-dose (1.5 mL/kg) and a maintenance dose (0.25 mL/kg per min) for 1 h. Subsequently, the propafenone was added to plasma (3.5 µg/mL) in vitro, mixed with three doses of LL or ML (1, 2, or 4%). Finally, after centrifugation, the concentration of propafenone was measured. Rats treated with LL exhibited accelerated recovery, characterized by higher blood pressure and heart rate. Rats in both the LL and ML groups demonstrated decreased propafenone in plasma (time-points: 15, 25, and 60 min). However, rats that received LL showed lower propafenone in myocardial tissue at the end of detoxification treatment. Rats in the ML group had the lowest value of pH, the minimum content of HCO3-, and the highest production of lactic acid at the end. In the in vitro experiments, propafenone decreased more dramatically in the LL group compared to the ML group. Long-chain triglyceride fat emulsion had a better effect on treating propafenone poisoning in rats.

Detoxification effects of long-chain versus a mixture of medium- and long-chain triglyceride-based fat emulsion on propafenone poisoning

In the present study, we aimed to compare the detoxifying effects of two fat emulsions containing either long-chain triglyceride or a mixture of medium-chain and long-chain triglycerides in the propafenone-poisoned rat model. Rats were randomly divided into 3 groups according to the fat emulsions used: long-chain triglyceride-based fat emulsion (LL) group; medium-chain and long-chain triglyceride-based fat emulsion (ML) group; normal saline (NS) group. Propafenone was continuously pumped (velocity=70 mg/kg per h) until the mean blood pressure dropped to 50% of basal level. Then, LL/ML fat emulsions or NS was intravenously infused instantly with a loading-dose (1.5 mL/kg) and a maintenance dose (0.25 mL/kg per min) for 1 h. Subsequently, the propafenone was added to plasma (3.5 μg/mL) in vitro, mixed with three doses of LL or ML (1, 2, or 4%). Finally, after centrifugation, the concentration of propafenone was measured. Rats treated with LL exhibited accelerated recovery, characterized by higher blood pressure and heart rate. Rats in both the LL and ML groups demonstrated decreased propafenone in plasma (time-points: 15, 25, and 60 min). However, rats that received LL showed lower propafenone in myocardial tissue at the end of detoxification treatment. Rats in the ML group had the lowest value of pH, the minimum content of HCO3-, and the highest production of lactic acid at the end. In the in vitro experiments, propafenone decreased more dramatically in the LL group compared to the ML group. Long-chain triglyceride fat emulsion had a better effect on treating propafenone poisoning in rats.

Arritmias na sala de emergência e UTI. Taquicardias de QRS estreito: fundamentos para a abordagem / Arrythmias in the emergency room and ICU Narrow QRS rachycardias: bases for clinical approach

As taquicardias de QRS estreito apresentam origem supraventricular. O histórico clínico, exame físico e eletrocardiograma na sala de emergência constituem-se nas principais ferramentas para o tratamento do quadro. As taquicardias que apresentam instabilidade hemodinâmica devem ser, imediatamente, revertidas através de cardioversão elétrica sincronizada. Aquelas que se apresentam como estáveis hemodinamicamente podem, se regulares, ser tratadas através de manobras vagais ou através do uso de fármacos endovenosos. Se irregulares, podem caracterizar fibrilação e flutter atrial, sendo, então, avaliados a duração do episódio e o risco de tromboembolismo para determinar não apenas a necessidade de anticoagulação, mas também a estratégia para tratamento do quadro, seja através do controle da frequência cardíaca ou do controle do ritmo, este último podendo ser alcançado através do uso de fármacos (propafenona oral ou amiodarona endovenosa) ou da cardioversão elétrica sincronizada. Dessa forma, o papel do clínico na sala de emergência é fundamental para garantir a condução adequada dos episódios de taquicardia supraventricular, especialmente, na prevenção ou pronta intervenção em caso de deterioração hemodinâmica relacionada ao quadro

Narrow QRS tachycardias are supraventricular in origin. The clinical history, physical exam, and electrocardiogram in the emergency room are the main tools used to manage this condition. Tachycardias that present haemodynamic instability must be promptly reverted through synchronized electrical cardioversion. Those that present haemodynamic stability may be treated with vagal maneuvers or intravenous drugs. If irregular, they may take the form of atrial fibrillation or atrial flutter, and in this case, the duration of the episode and the thromboembolic risk are evaluated to determine not only the need for anticoagulation, but also the treatment strategy, whether through heart rate or rhythm control. The latter may be achieved through the use of drugs (oral propafenone or intravenous amiodarone) or synchronized electrical cardioversion. The role of the clinician in the emergency room is therefore fundamental in ensuring adequate conduct of episodes of supraventricular tachycardia, especially in prevention or prompt intervention in case of haemodynamic deterioration related to the condition

Abordagem das arritmias na Doença de Chagas Crônica / Approach of arrhythmias in chronic Chagas Disease

As arritmias na cardiopatia chagásica (CCH) são responsáveis por incapacitação física e morte em indivíduos adultos em faixa etária precoce e produtiva, decorrendo daí a necessidade de sua abordagem criteriosa e, às vezes, mais agressiva para se obter controle completo. As arritmias cardíacas mais encontradas na CCH são as bradiarritmias e as taquicardias. Entre as bradicardias estão as alterações sinoatriais e os bloqueios atrioventriculares, cujo tratamento padrão é o emprego de implante de marcapasso definitivo. Entre as taquiarritmias, encontram-se as supraventriculares ­ extrassístoles atriais, taquicardia atrial ectópica, "flutter" atrial e fibrilação atrial ­ que provocam morbidades como progressão para disfunção ventricular esquerda e fenômenos tromboembólicos, e as ventriculares, cujo desfecho pode ser a morte súbita instantânea. A abordagem deve ser, inicialmente, por meio de eletrocardiograma de 12 derivações, pela gravação ambulatorial (Holter), ecocardiograma, teste ergométrico, e por fim, o estudo eletrofisiológico e a ressonância nuclear magnética. O tratamento farmacológico pode ser conduzido com o uso dos fármacos existentes em nosso mercado, como amiodarona, propafenona e sotalol. O tratamento invasivo, pode consistir em ablação por cateter, embora com resultados ainda abaixo de índices confortadores, devido à possibilidade de recidivas. O uso de cardiodesfibrilador implantável é a última alternativa, que também tem suas limitações

Arrhythmias in Chagas cardiomyopathy (CCM) are responsible for physical disability and death in adults in early and productive age group, from which arises the need for a judicious and sometimes more aggressive approach to achieve the complete control. The arrhythmias most common in CCM are bradyarrhythmias and tachycardias. Among the bradycardias are the sinoatrial changes and atrioventricular blocks, whose standard treatment is the use of permanent pacemaker implantation. Among tachyarrhythmias are the supraventricular ones - atrial extrasystoles, ectopic atrial tachycardia, atrial flutter and atrial fibrillation - causing morbidity and progression of left ventricular dysfunction and thromboembolic events, and the ventricular ones, whose outcome can be the instantaneous sudden death. The approach should be initially through 12-lead electrocardiogram, by ambulatory ECG recording (Holter), echocardiogram, stress testing, and finally the electrophysiological study and magnetic resonance imaging. Pharmacological treatment can be conducted with the use of marketed drugs such as amiodarone, propafenone and sotalol. The invasive treatment may consist of catheter ablation, although the results are still below comforting rates due to the possibility of recurrence. The use of implantable cardioverter defibrillator is the last alternative, which also has its limitations

Bioequivalência de cloridrato de propafenona 300mg em comprimido revestido em administração pós-prandial em adultos saudáveis / Bioequivalence of propafenone hydrochloride 300mg film coated tablets in healthy adults

OBJETIVO: Avaliar a bioequivalência de duas formulações de cloridrato de propafenona 300mg em comprimido revestido.MÉTODOS: Estudo randomizado, cruzado, aberto, com dois tratamentos, duas sequências e quatro períodos com 60 participantes sadios de ambos os sexos. Os voluntários foram internados em quatro oportunidades durante 24 horas; em cada período, os sujeitos receberam a formulação teste ou a formulação referência, em regime pós-prandial. Foram coletadas 23 amostras de sangue após administração da droga para determinação plasmática da propafenona. Para quantificação da droga, foi utilizada técnica de cromatografia líquida acoplada à espectrometria de massas sequencial. RESULTADOS: As formulações foram consideradas clinicamente bem toleradas. A concentração máxima e a área sob a curva de zero a 36 horas foram comparadas: a média geométrica da razão entre as formulações teste e referência para concentração máxima foi de 110,16%, com intervalo de confiança de 99,44% a 122,04% e coeficiente de variação de 33,95%. A média geométrica da razão entre as formulações teste e referência para a área sob a curva de zero a 36 horas foi de 107,92%, com intervalo de confiança de 99,58% a 116,96% e coeficiente de variação de 26,39%. A média geométrica da razão entre o medicamento teste e referência para área sob a curva de zero ao infinito foi de 107,12%, com intervalo de confiança de de 99,11% a 115,78% e coeficiente de variação de 25,48%. CONCLUSÃO: As formulações teste e referência foram estatisticamente bioequivalentes, de acordo com sua taxa e extensão de absorção.

OBJECTIVE: To evaluate the bioequivalence of two 300mg profanone hydrochloride coated tablets. METHODS: Randomized, cross-over, openstudy, with two treatments, two sequences, and four periods with 60 healthy participants of both genders. The volunteers were admitted in four opportunities over 24 hours; on each period, the subjects received a test formulation, or a reference formulation, in a postprandial administration. Twenty-three samples of blood were collected after oral administration of the drug for determining plasma level of propafenone. Liquid chromatography-mass spectrometry was used for quantifying propafenone. RESULTS: The formulations were considered clinically well tolerated. The maximum concentration and the area under the curve from zero to 36 hours were compared: the geometric mean of the ratio between the test and reference formulations for maximum concentration was 110.16%, with confidence interval of 99.44% - 122.04%), coefficient of variation of 33.95%. The geometric mean of the ratio between the test and reference formulations for the area under the curve of zero to 36 hours was 107.92%, with confidence interval of 99.58% - 116.96%, and coefficient of variation of 26.39%. The geometric mean of the ratio between the formulations for area under the curve of zero to infinitum as 107.12% with confidence interval of 99.11% - 115.78%),and coefficient of variation of 25.48%. CONCLUSION: According to the rate and extension of absorption, the test and reference formulations are statistically bioequivalent.

Falha de estimulação ventricular por variação aguda do limiar de comando induzida pela propafenona em portadora de marcapasso definitivo: relato de caso / Ventricular stimulation failure due to acute propafenone-induced command threshold variation in a patient with permanent pacemaker: case report

Relata-se o caso de uma paciente que, durante troca do gerador do marcapasso definitivo, foi tratada com propafenona após desenvolver fibrilação atrial no período intraoperatório. Os limiares eram moderadamente aumentados no pré-operatório, entretanto, estáveis. Horas após a administração de 600 mg de propafenona, a paciente apresentou síncope justificada pela perda de comando ventricular. A avaliação do dispositivo mostrava perda de captura por aumento do limiar ventricular medido em 5,0V/0,6 ms, corrigida por estimulação com energia máxima de saída do gerador. No dia seguinte, após nova avaliação, o limiar havia retornado ao valor previamente aferido e a energia de saída do gerador diminuiu, mantendo-se estável após seis meses de seguimento...

This is the case report of a patient who was treated with propafenone during the exchange of a permanent pacemaker generator, after the development of atrial fibrillation during the procedure. The thresholds were moderately increased in the preoperative period, however, they were stable. Hours after the administration of 600 mg of propafenone, the patient had a syncope which was explained by the loss of ventricular command. The evaluation of the device showed there was loss of capture due to the ventricular threshold increase, which as measured as 5.0V/0.6 ms and was adjusted by stimulation with maximum outlet energy of the generator. On the following day, after a new assessment, the values had returned to normal, the generator outlet energy decreased, and remained stable after six months of follow-up...

Vernakalant: Perception of state of health in patients with a recent-onset atrial fibrillation.

BACKGROUND: Vernakalant is a new, safe and effective drug used intravenously, which has proved to be more rapid in converting recent onset atrial fibrillation (AF) to sinus rhythm compared to placebo, amiodarone, propafenone, and flecainide in clinical studies. Until now no study has been conducted comparing the perception of state of health in patients who received vernakalant versus propafenone or flecainide for conversion of recent-onset AF. The aim of our study is to compare the change of perception of state of health from screening to hour 2 in patients treated with vernakalant and propafenone or flecainide for conversion of recent-onset AF. METHODS: Eighty hemodynamically stable patients with recent onset AF without structural heart disease were prospectively included. A single oral dose of propafenone 600 mg was administered to 30 patients, 30 patients received intravenous vernakalant and the remaining 20 patients received a single oral dose of flecainide 300 mg. Clinical, laboratory variables and perception of state of health from screening to hour 2 treated with these drugs measured by the EQ-5 D quality-of-life assessments visual analog scale were recorded. RESULTS: Baseline characteristics were similar in the three groups. Treatment with vernakalant resulted in a significantly greater improvement in patient perception of state of health at hour 2 compared with propafenone and flecainide. In the vernakalant group, a mean increase (from baseline) of 12.1 points was seen compared with a mean increase of 5.4 points in the propafenone group or 5.2 points in flecainide group (p < 0.01). CONCLUSIONS: The change of perception of state of health from screening to hour 2 treated with vernakalant had a significantly statistical improvement compared with propafenone or flecainide for conversion recent-onset AF.

Interações medicamentosas em cardiologia: Fármacos antiárritmicos / Drugs interactions in cardiology: Antiarrhythmics drugs

As arritmias cardíacas são geradas por diferentes mecanismoseletrofisiológicos que atuam isoladamente ou interagem entresi para a formação e condução do impulso anormal. Com baseno conhecimento da eletrofisiologia celular e dos mecanismosgeradores de arritmias, diversos fármacos antiarrítmicos foramdesenvolvidos com objetivo de propiciar terapias cada vez maiseficazes e seguras. A necessidade de se agrupar os antiarrítmicos deacordo com seu mecanismo de ação e efeitos no impulsocardíaco, resultou na classificação de Vaughan- Williams que,apesar de amplamente difundida, não contempla algumasmedicações classicamente utilizadas como antiarrítmicos, taiscomo a adenosina e os digitálicos. Os antiarrítmicos são, emgeral, metabolizados pelo fígado por meio dos citocromos.Fármacos que interagem no mesmo sítio de ação em que sãometabolizados podem resultar em potencialização ou inibiçãodos efeitos antiarrítmicos. A redução ou o aumento do nívelsérico do antiarrítmico causado pelo fármaco utilizado concomitantemente,em decorrência da alteração na velocidade demetabolização, da redução na absorção ou somatório de efeitos,pode aumentar o potencial para efeitos colaterais deletérios eefeitos pró-arrítmicos e resultar em efeitos tóxicos potencialmentegraves. O objetivo deste capítulo é revisar os diversosmecanismos de interação medicamentosa que podem ocorrerenvolvendo as classes de antiarrítmicos...

Cardiac arrhythrnias are generated by different electrophysiologicalmechanisms that act alone or interact for the formation andconduction of the abnormal impulse. Based on the knowledge ofcellular electrophysiology and arrhythmia mechanisms, severalantiarrhythrnics were developed in order to provide therapiesincreasingly effective and safe. The need of grouping the antiarrhythmicagents according to their mechanism of action andeffects on cardiac impulse have led to the development of theVaughan- Williams c1assification. Although widespread used,this c1assification does not include some drugs c1assically usedas antiarrhythmics such as adenosine and digitalis.Antiarrhythmic agents are generaUy metabolized by the livervia the cytochrome. Drugs that interact at the same site of actionthat are metabolized may result in potentiation or inhibition ofantiarrhythmic effects. The reduction or increase in serum levelscaused by antiarrhythmic drug used concomitantly, due to thechange in the metabolism, reduction in absorption or summationeffects may increase the potential for deleterious side effects andproarrhythmic effects and result in potentiaUy serious toxic effects.The purpose of this chapter is to review the variousmechanisms of drug interactions that may occur involving theantiarrhythmic drugs...

Propafenone versus vernakalant for conversion of recent-onset atrial fibrillation.

INTRODUCTION: An oral loading dose of propafenone 600 mg is used in our center as in other places around the world for conversion of recent-onset atrial fibrillation (AF) in patients without structural heart disease. Vernakalant is a novel, safe, and effective drug used intravenously and has proved to be more rapid in converting recent-onset AF to sinus rhythm compared with placebo and amiodarone. There is no study that compares vernakalant with propafenone. The aim of our study is to compare the time taken for conversion of recent-onset AF in patients treated with vernakalant and propafenone. METHODS: Thirty-six hemodynamically stable patients with recent-onset AF without structural heart disease were prospectively included. A single oral dose of propafenone 600 mg was administered to 19 patients and 17 received intravenous vernakalant. Clinical and laboratory variables, conversion rate, and time to conversion were recorded. RESULTS: Baseline characteristics were similar in both groups. Time to conversion to sinus rhythm was of 166 min (120-300) in the propafenone group versus 9 min (6-18) in the vernakalant group (P = 0.0001). Conversion rate was of 78% in the propafenone group at 8 h and of 93% in the vernakalant group at 2 h; yet, this difference was not statistically significant (P = 0.4). Time to conversion had a direct impact in hospital stay, which was 43% shorter in the vernakalant group (P = 0.0001). CONCLUSION: Time to conversion of AF to sinus rhythm was significantly shorter in the vernakalant group compared with the propafenone group and was associated with shorter hospital stay.

Preparation and evaluation of unitary doses of propafenone used in children with supraventricular tachycardia: a pilot study.

PURPOSE: The aim was to prepare and evaluate unitary doses of propafenone (UDP) used in children with supraventricular tachycardia. METHODS: UDP were prepared from four brands of tablets at doses of propafenone, 11, 25 and 90 mg, used in the Cardiology Service of this Institute. The stability of doses was determined at 20±5°C and 40°C for up to day 30. Besides, a weight variation test was performed. Plasma levels of propafenone were determined at steady state in 3 children diagnosed with supraventricular tachycardia under treatment with UDP. Concentrations of drug in blood were measured using a high pressure liquid chromatography method, previously validated. RESULTS: The stability of UDP, showed no significant statistical differences (p > 0.05) between doses or brands up to day 30, at both temperatures. The coefficient of variation from the weight variation was less than 6%. The plasma levels of propafenone at steady state were: patient 1, 31.57 ng/ml; patient 2, 226.46 ng/ml; and patient 3, 221.29 ng/ml. CONCLUSIONS: The actual administered dose for the patients could vary up to 6%, and doses prepared from different brands of tablets remain stables for up to day 30 at both temperatures. UDP is a temporal, safe and alternative option when pediatrics formulation of this drug is lacking.

Profuse oral secretions after propafenone administration in neonates.

Propafenone, an antiarrhythmic drug that is effective for treating supraventricular tachycardias, can induce well-known proarrhythmic and systemic adverse effects. We describe a previously unreported adverse effect in 3 newborns: oral propafenone-induced profuse oral secretions and respiratory distress of sufficient severity to necessitate discontinuation of propafenone.