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.

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

Effects of propafenone associated with propofol on myocardial contractility, heart rate, coronary flow, and the incidence of arrhythmia in isolated hearts of rats.

OBJECTIVE: To study the influence of propafenone associated with propofol on myocardial contractility (dP/dt and heart rate), coronary flow, and the incidence of arrhythmia in isolated rat hearts. METHODS: Forty albino rats were anesthetized with sulfuric ether, a modified Langendorff method was performed, and the rats were fed with Krebs-Henseleit (K-H) solution, (95% O2, 5% CO2, pH 7.4+/-0.1, perfusion pressure between 90 and 100cm of water, and temperature 37+/- 0.5 masculine C). Control records were obtained after a stabilization period and rats were distributed into the following 4 groups: I (control), II (100mcg propafenone), III (25mcg propofol), and IV (propafenone-propofol). RESULTS: A decrease (P<0.05) in the heart rate in groups II and IV was observed, with a greater decrease in group II. A decrease was noted in the dP/dt ratio (P< 0.05) in groups II and IV, during all periods. Group III experienced depression from the 1st to the 3rd minute. Coronary flow had a decrease (P<0.05) in all groups, compared with the control group, especially in group IV with a decrease from 14mL/min to 11mL/min. Arrhythmogenic effects of propafenone (pro-arrhythmia) were verified in 50% of group II. In the association with propofol (group IV), no significant difference occurred, and arrhythmias (pro-arrhythmic effect) were observed in 40% of the hearts. CONCLUSION: The association propafenone-propofol was not harmful to the use of propafenone solely, regarding the effects observed in myocardial contractility, coronary flow, and in the incidence of arrhythmias.

Effect of propafenone on the contractile activity of Latissimus dorsi muscle isolated in an organ chamber: experimental study in rats.

OBJECTIVE: To study the effect of propafenone on the contractile function of latissimus dorsi muscle isolated from rats in an organ chamber. METHODS: We studied 20 latissimus dorsi muscles of Wistar rats and divided them into 2 groups: group I (n=10), or control group - we studied the feasibility of muscle contractility; group II (n=10), in which the contralateral muscles were grouped - we analyzed the effect of propafenone on muscle contractility. After building a muscle ring, 8 periods of sequential 2-minute baths were performed, with intervals of preprogrammed electrical stimulation using a pacemaker of 50 stimuli/min. In group II, propafenone, at the concentration of 9.8 microgram/mL, was added to the bath in period 2 and withdrawn in period 4. RESULTS: In group I, no significant depression in muscle contraction occurred up to period 5 (p>0.05). In group II, a significant depression occurred in all periods, except between the last 2 periods (p<0.05). Comparing groups I and II only in period 1, which was a standard period for both groups, we found no significant difference (p>0.05). CONCLUSION: Propafenone had a depressing effect on the contractile function of latissimus dorsi muscle isolated from rats and studied in an organ chamber.

[Use-dependence of propafenone. Clinical demonstration of the hypothesis of modulated receptors]. / Uso-dependencia con propafenona. Demonstración clínica de la hipótesis de los receptores modulados.

UNLABELLED: The aim of this study was to assess use-dependence in patients with ventricular premature contractions (VPC's) treated with propafenone, by means of the increase in heart rate using transesophageal atrial pacing. It was also analyzed whether this phenomenon was related to the antiarrhythmic effect. Fifteen patients with more than 30 symptomatic VPC's/sour were evaluated. Esophageal pacing was performed with cycles of 600 and 400 msec during periods of 1 min and with simultaneous recording of 2 or 3 EKG leads with a paper speed of 100 mm/sec. Holter monitoring (HM) was carried out in all patients. Propafenone was administered in doses of 450 and 900 mg/day, during 5-7 days, at which moment another HM and esophageal stimulation were repeated. The QRS duration (pre-treatment) was 82.6 +/- 13.5 msec (basal) and 82.4 +/- 13 msec during pacing with 600 msec cycle length (p: NS). The QRS duration with P (900 mg/day) was 96.6 +/- 20 msec (basal) (p:NS vs. pre-treatment) but during atrial pacing with 600 msec cycle length it increased to 109.3 +/- 23 msec (p < 0.0004). This use-dependence was also observed with pacing at 600 msec in patients receiving doses of 450 mg/day: 95.3 +/- 13 msec (p < 0.0001 vs. baseline QRS) (Table 1). IN CONCLUSION: 1) there was no significant increase in the QRS duration with P without pacing; 2) propafenone showed use-dependence during atrial stimulation, even with cycle length of 600 msec and with the lower doses.

Uso dependencia con propafenona: demostracion clinica de la hipotesis de los receptores modulados / Use dependence of prepafenone: clinical demonstration of the hypothesis modulated receptors

Mediante sestimulación auricular esofágica se evaluó un aspecto de la hipótesis de los receptores modulados, denominado "uso-dependencia". Esta consiste en el enlentecimiento de la conducción intraventricular, con el aumento de la frecuencia cardíaca en presencia de antiarrítmicos de clase I. Se estudiaron 15 pacientes con > 30 extrasístoles ventriculares sintomáticas/hora tratados con propafenona por vía oral. El marcapaseo auricular mostró incremento en la duración del complejo QRS con ciclos de estimulación de 600 mseg y aun con dosis de 450 mg/día. Se correlacionaron los hallazgos con la variación en la actividad ectópica observada por Holter (AU)

Uso dependencia con propafenona: demostracion clinica de la hipotesis de los receptores modulados / Use dependence of prepafenone: clinical demonstration of the hypothesis modulated receptors

Mediante sestimulación auricular esofágica se evaluó un aspecto de la hipótesis de los receptores modulados, denominado "uso-dependencia". Esta consiste en el enlentecimiento de la conducción intraventricular, con el aumento de la frecuencia cardíaca en presencia de antiarrítmicos de clase I. Se estudiaron 15 pacientes con > 30 extrasístoles ventriculares sintomáticas/hora tratados con propafenona por vía oral. El marcapaseo auricular mostró incremento en la duración del complejo QRS con ciclos de estimulación de 600 mseg y aun con dosis de 450 mg/día. Se correlacionaron los hallazgos con la variación en la actividad ectópica observada por Holter

[Acute effects of propafenone in patients with ventricular pre-excitation]. / Efeitos agudos da propafenona em pacientes com pré-excitação ventricular.

PURPOSE: To evaluate the electrophysiological effects of intravenous propafenone in the anterograde and retrograde effective refractory period of the accessory pathways (AP), in patients with Wolff-Parkinson-White syndrome. METHODS: Forty symptomatic patients were studied. All patients were undergone to electrophysiologic study at baseline and after IV propafenone (2.0mg/kg). Drug effects were analysed according to the basal state of the anterograde and retrograde effective refractory periods of the AP > < 270ms. RESULTS: The mean anterograde and retrograde effective refractory periods of the AP were 275 +/- 76ms and 264 +/- 44ms at the control and 462 +/- 190ms and 438 +/- 184ms after drug respectively (p < 0.01 in both situations). The mean anterograde effective refractory period of the AV node was 236 +/- 40ms (control) and 276 +/- 57ms (post-drug)- p < 0.05. The mean atrial and right ventricular effective refractory period in the control were 210 +/- 23ms and 240 +/- 34ms passing to 215 +/- 24ms and 250 +/- 40 ms after drug respectively (p = ns). After drug, complete anterograde and retrograde block of the AP, occurred in 15 (42%) and 12 (35%) patients respectively. Out of 15 patients with complete anterograde block of the AP, 11 had anterograde effective refractory period of the AP > 270ms and 4, < 270ms (p < 0.02). Out of 12 patients with complete retrograde block of the AP after drug, 4 had retrograde effective refractory period > 270ms and 8, < 270ms (p: ns). CONCLUSION: Propafenone caused significant increase in the anterograde and retrograde effective refractory periods of the AP. There was a tendency of the drug to show better effectiveness in patients with anterograde effective refractory period of the AP > 270ms. This results were not seen in relation to the retrograde effective refractory period of the AP.

Efeitos agudos da propafenona em pacientes com pré-excitaçäo ventricular / Acute Effects of Propafenone in Patients with Ventricular Pré-Excitation

Objetivo - Avaliar os efeitos agudos da propafenona sobre os períodos refratários anterógrado e retrógrado de vias anômalas (VA). Métodos - Foram estudados 40 apcientes sintomáticos. Por técnica de extra-estímulos, determinaram-se os períodos refratários anterógrado e retrógrado das VA em condiçöes de controle e após 2,0mg/Kg de propafenona IV. Os resultados foram analisados em funçäo dos períodos refratários anterógrado e retrógrado das VA><270ms no controle. Resultados - Período refratário anterógrado médio da VA no controle de 275 ñ 76ms e no pós-droga de 462 ñ 190ms (p < 0,01). Período refratário retrógrado médio da VA no controle de 264 ñ 44ms, passando no pós-droga para 438 ñ 184ms (p < 0,01). Período refratário efetivo anterógrado do nódulo AV no controle de 236 ñ 40ms, passando no pós-droga para 276 ñ 47ms (p < 0,05). Período refratário efetivo atrial no controle de 210 ñ 23ms, passando para 215 ñ 24ms (p = ns). Período refratário efetivo ventricular no controle de 240 ñ 34ms, passando no pós-droga para 250 ñ 40ms (p:ns). Notou-se o aparecimento de bloqueio completo anterógrado e retrógrado da VA no pós-droga em, respectivamente, 15 e 12(42//, 35//) pacientes. Dos 15 pacientes com bloqueio anterógrado da VA no pós-droga, 11 apresentavam período refratário anterógrado da VA>270ms (p<0,02). Dos 12 pacientes com bloqueio completo retrógrado da VA no pós-droga, 4 apresentavam período refratário retrógrado da VA > 270ms e 8,<270ms (p=ns). Conclusäo - A propafenona produziu significativo aumento dos períodos refratários efetivos anterógrado e retrógrado das VA. Observou-se tendência a uma maior açäo frente a períodos refratários efetivos anterógrdos das VA>270ms. Este padräo de resposta näo foi observado em relaçäo aos períodos refratários efetivos retrógrdos da VA

Purpose - To evaluate the electrophysialogical effects of intravenous propafenone in the anterograde and retrograde effective refractory period of the accessory pathways (AP), in patients with WolffParkinson-White syndrome. Methods - Forty symptomatic patients were studied.. All patients were undergone to electrophysiologic study at baseline and after IV propafenone (2.0mg/kg). Drug effects were analysed according to the basal state of the anterograde and retrograde effective refractory periods of the AP><270ms. Results - The mean anterograde and retrograde effective refractory periods of the AP were 275±76ms and 264±44ms at the control and 462±190ms and 438±184ms after drug respectively (p<0.01 in both situations). The mean anterograde effective refractory period of the AV node was 236±40ms (control) and 276±57ms (post-drug )- p<0.05. The mean atrial and right ventricular effective refractory period in the control were 210±23ms and 240±34ms passing to 215±24ms and 250±40ms after drug respectively (p=ns). After drug, complete anterograde and retrograde block of the AP, ocurred in 15 (42°/) and 12 (35°/) patients respectively. Out of 15 patients with complete anterograde block of the AP, 11 had anterograde effective refractory period of the AP>270ms and 4,<270ms (p<0.02). Out of 12 patients with complete retrograde block of the AP after drag, 4 had retrograde effective refractory period >270ms and 8, <270ms (p:ns). Conclusion - Propafenone caused signifcant increase in the anterograde and retrograde effective refractory periods of the AP. There was a tendency of the drug to show better effectiveness in patients with anterograde effective refractory period of the AP>270ms. This results were not seen in relation to the retrograde effective refractory peried of the AP

[Electrophysiologic effect of intravenous propafenone in supraventricular tachycardia]. / Efecto electrofisiológico de propafenona endovenosa en las taquicardias supraventriculares.

The electrophysiologic effects of intravenous propafenone were studied in twenty six patients with supraventricular tachycardias. Ten patients (38%) with intranodal reentrance tachycardia common type, and sixteen patients (62%) atrioventricular orthodromic reentrance tachycardia. Propafenone (2 mg/kg intravenously) given over ten minutes period caused termination of the intranodal reentrance tachycardia in 60% of the cases and 50% to the patients with atrioventricular reentrance tachycardia. The antiarrhythmic effects observed are related to the slowing of the conduction velocity and to the prolongation of the refractoriness in the AV node and accessory pathways preventing the reentrance mechanism. The reinduction of the tachycardia was possible in 46% of the patients. This effects was more significative in the group with accessory pathways (50%), and 40% of the patients with intranodal reentrance. The supraventricular tachycardia was inducible by programmed electrical stimulation in 46% of the patients. None of the patients developed side effects to the administration of the propafenone.