Pilsicainide Toxicity-Induced Brugada-Like ST Segment Elevation and Increased Pacing Voltage Threshold.

Pilsicainide is a class Ic antiarrhythmic agent that exhibits fully selective sodium channel blockade. In Japan, it is one of the most prescribed medicines for rhythm control in atrial fibrillation. Pilsicainide is mainly excreted by the kidney. Therefore, the plasma concentration of pilsicainide is likely to be increased in patients with renal insufficiency. In this case report, a 90-year-old woman presented with generalized fatigue and loss of appetite. Her ECG showed marked bradycardia and coved-type ST-segment elevation similar to that of the Brugada type 1 pattern. Owing to dehydration, her renal function indices worsened compared with those measured four months prior. The plasma pilsicainide concentration was elevated to 2.67 µg/mL (therapeutic range: 0.20-0.90 µg/mL), indicating pilsicainide toxicity. A transvenous temporary pacemaker was placed; however, the pacing voltage threshold was increased at several sites within the right ventricle. Pilsicainide administration was immediately discontinued. On day 2 of admission, ventricular backup pacing was no longer required, and there was an improvement in renal function and heart failure symptoms, such as pulmonary edema and cardiomegaly. The ECG changes improved alongside the renal function and as the plasma concentration of pilsicainide decreased. In conclusion, elevated plasma concentrations of pilsicainide can induce life-threatening arrhythmias and pacing failure. Therefore, clinicians should prescribe pilsicainide cautiously, particularly in older patients.

Cardiopulmonary arrest upon admission caused by pilsicainide hydrochloride intoxication: A case report.

A 22-year-old male presented to our hospital after receiving 2450 mg of pilsicainide hydrochloride. Subsequently, he experienced cardiac arrest, and percutaneous cardiopulmonary support was introduced to maintain his circulation. After 3 days of intensive care, he regained consciousness and was transferred to another hospital for treatment related to psychological problems.

Case report: An autopsy case of pilsicainide poisoning.

We present a fatal case of pilsicainide poisoning. Quantitative toxicological analysis revealed that the concentrations of pilsicainide in femoral blood and urine samples were 17.5 µg/mL and 136.9 µg/mL, respectively. No morphological changes due to poisoning were observed. Based on the autopsy findings, results of the toxicological examination, and investigation by the authorities, we concluded that the cause of death was due to pilsicainide poisoning.

Efficacy of a Subcutaneous Implantable Cardioverter Defibrillator in a Child with Early Repolarization Syndrome.

An early repolarization (ER) pattern or J waves are considered to be a benign finding observed in the healthy population, however, it has been pointed out that the ER pattern seen in the inferolateral leads could be an independent risk factor for fatal arrhythmias. We present a pediatric case in which early repolarization syndrome (ERS) was suspected due to the presence of ER or J waves in the inferior leads, which eventually disappeared after the administration of pilsicainide. During the follow-up period, several fatal ventricular arrhythmias were recorded after implantation of a subcutaneous implantable cardiac defibrillator (S-ICD). This report describes the efficacy of S-ICDs in a child with an ER pattern after aborted sudden cardiac death.

Translational Studies on Anti-Atrial Fibrillatory Action of Oseltamivir by its in vivo and in vitro Electropharmacological Analyses.

Oseltamivir has been shown to prolong the atrial conduction time and effective refractory period, and to suppress the onset of burst pacing-induced atrial fibrillation in vitro. To better predict its potential clinical benefit as an anti-atrial fibrillatory drug, we performed translational studies by assessing in vivo anti-atrial fibrillatory effect along with in vivo and in vitro electropharmacological analyses. Oseltamivir in intravenous doses of 3 (n = 6) and 30 mg/kg (n = 7) was administered in conscious state to the persistent atrial fibrillation model dogs to confirm its anti-atrial fibrillatory action. The model was prepared by tachypacing to the atria of chronic atrioventricular block dogs for > 6 weeks. Next, oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously administered to the halothane-anesthetized intact dogs to analyze its in vivo electrophysiological actions (n = 4). Finally, its in vitro effects of 10-1,000 µM on IK,ACh, IKur, IKr, INa and ICaL were analyzed by using cell lines stably expressing Kir3.1/3.4, KV1.5, hERG, NaV1.5 or CaV1.2, respectively (n = 3 for IK,ACh and IKr or n = 6 for IKr, INa and ICaL). Oseltamivir in doses of 3 and 30 mg/kg terminated the atrial fibrillation in 1 out of 6 and in 6 out of 7 atrial fibrillation model dogs, respectively without inducing any lethal ventricular arrhythmia. Its 3 and 30 mg/kg delayed inter-atrial conduction in a frequency-dependent manner, whereas they prolonged atrial effective refractory period in a reverse frequency-dependent manner in the intact dogs. The current assay indicated that IC50 values for IK,ACh and IKr were 160 and 231 µM, respectively, but 1,000 µM inhibited INa, ICaL and IKur by 22, 19 and 13%, respectively. The extent of INa blockade was enhanced at faster beating rate and more depolarized resting membrane potential. Oseltamivir effectively terminated the persistent atrial fibrillation, which may be largely due to the prolongation of the atrial effective refractory period and inter-atrial conduction time induced by IK,ACh and IKr inhibitions along with INa suppression. Thus, oseltamivir can exert a powerful anti-atrial fibrillatory action through its ideal multi-channel blocking property; and oseltamivir would become a promising seed compound for developing efficacious and safe anti-atrial fibrillatory drugs.

Pilsicainide Intoxication with Neuropsychiatric Symptoms Treated with Continuous Hemodiafiltration.

A 72-year-old lady with atrial fibrillation and chronic renal failure was hospitalized due to bradycardic shock with electrocardiographic QRS prolongation. She had experienced limb shaking two days before hospitalization, and additionally developed hallucinations one day before admission. Pilsicainide intoxication was diagnosed from a review of her medications and electrocardiographic findings. Consequently, continuous hemodiafiltration was performed resulting in a resolution of the hallucinations and the QRS prolongation. This is a rare case of psychiatric symptoms caused by pilsicainide intoxication. It is important to know the mode of excretion of a drug and to adjust its dose, so that such drug-related incidents can be avoided.

Paroxysmal atrial fibrillation recurrences and quality of life in symptomatic patients: A crossover study of flecainide and pilsicainide.

BACKGROUND: The therapeutic goals of atrial fibrillation (AF) patients are to reduce symptoms and prevent severe complications associated with AF. This study compared the efficacy of flecainide versus pilsicainide in reducing the frequency of AF and improving quality of life (QOL) in symptomatic paroxysmal AF patients without structural heart disease. METHODS: The Atrial Fibrillation and Quality Of Life (AF-QOL) study was a prospective, multicenter, randomized, open-label crossover study that compared flecainide and pilsicainide as antiarrhythmic drug therapy. Patients were randomized to receive 3 months of treatment with flecainide twice daily or pilsicainide 3 times daily. Each treatment consisted of a dose-finding phase (weeks 1-4) and an efficacy phase (weeks 5-12). Forty-three patients completed the trial. The main outcome was the number of days with documented AF episodes using a patient-operated electrocardiogram. QOL questionnaires (SF-36 and AF-specific QOL scores) were also completed. RESULTS: The median (range) AF frequencies (days/8 weeks) were 2 (0-50) in the flecainide treatment group and 1 (0-54) in the pilsicainide treatment group (no significant between-group difference). No significant difference in the first recurrence of AF during the efficacy phase was noted between flecainide and pilsicainide treatments. The frequency and severity scores of AF-related symptoms improved from baseline to the end of the treatment periods. No significant differences in SF-36 or AF-related QOL scores were noted between the treatment groups. CONCLUSIONS: This study found no difference in AF frequency or QOL between symptomatic paroxysmal AF patients who received flecainide or pilsicainide.

Molecular mechanisms underlying the pilsicainide-induced stabilization of hERG proteins in transfected mammalian cells.

BACKGROUND: Pilsicainide, classified as a relatively selective Na+ channel blocker, also has an inhibitory action on the rapidly-activating delayed-rectifier K+ current (IKr ) through human ether-a-go-go-related gene (hERG) channels. We studied the effects of chronic exposure to pilsicainide on the expression of wild-type (WT) hERG proteins and WT-hERG channel currents, as well as on the expression of mutant hERG proteins, in a heterologous expression system. METHODS: HEK293 cells stably expressing WT or mutant hERG proteins were subjected to Western blotting, immunofluorescence microscopy and patch-clamp experiments. RESULTS: Acute exposure to pilsicainide at 0.03-10 µM influenced neither the expression of WT-hERG proteins nor WT-hERG channel currents. Chronic treatment with 0.03-10 µM pilsicainide for 48 h, however, increased the expression of WT-hERG proteins and channel currents in a concentration-dependent manner. Chronic treatment with 3 µM pilsicainide for 48 h delayed degradation of WT-hERG proteins and increased the channels expressed on the plasma membrane. A cell membrane-impermeant pilsicainide derivative did not influence the expression of WT-hERG, indicating that pilsicainide stabilized the protein inside the cell. Pilsicainide did not influence phosphorylation of Akt (protein kinase B) or expression of heat shock protein families such as HSF-1, hsp70 and hsp90. E4031, a chemical chaperone for hERG, abolished the pilsicainide effect on hERG. Chronic treatment with pilsicainide could also increase the protein expression of trafficking-defective mutant hERG, G601S and R752W. CONCLUSIONS: Pilsicainide penetrates the plasma membrane, stabilizes WT-hERG proteins by acting as a chemical chaperone, and enhances WT-hERG channel currents. This mechanism could also be applicable to modulations of certain mutant-hERG proteins.

Utility of 12-lead and signal-averaged Holter electrocardiograms after pilsicainide provocation for risk stratification in Brugada syndrome.

Non-invasive risk stratification for ventricular fibrillation (VF) in Brugada syndrome (BrS) has not been fully evaluated. The aim of this study was to assess the utility of signal-averaged Holter electrocardiogram (Holter SAECG) and 12-lead Holter electrocardiogram (Holter ECG) after a pilsicainide provocation test for non-invasive risk stratification in BrS. We enrolled 30 consecutive patients with BrS [divided into 2 groups: the VF group, those with a previous history of VF (n = 10); and the non-VF group, those without a history of VF (n = 20)] and 10 control subjects without type 1 ECG. We evaluated late potentials [LP: filtered QRS (f-QRS), RMS40, and LAS40] on the Holter SAECG for 4 h after the pilsicainide provocation and in the same patients on another day without performing the pilsicainide provocation. Furthermore, we measured QRS duration and QTc interval in leads V2 and V5, and J amplitude in lead V2 on the Holter ECG after the pilsicainide provocation. On the Holter SAECG, the f-QRS at 1 h and LAS40 at 3 h after the pilsicainide provocation were significantly larger in the VF group than in the non-VF group (f-QRS at 1 h: 113.9 ± 8.9 vs. 104.9 ± 8 ms; p = 0.01, LAS40 at 3 h: 45.4 ± 5.9 vs. 35.5 ± 7.4 ms; p < 0.001). The receiver-operating characteristic curve analysis for a single parameter of VF occurrence was determined [f-QRS at 1 h: area under the curve (AUC) 0.8, with sensitivity 80% and specificity 80%; and LAS40 at 3 h: AUC 0.87, with sensitivity 90% and specificity 75%]. On the Holter ECG, there were no significant differences in these parameters between the VF and non-VF groups. In conclusion, the LP after the pilsicainide provocation using Holter SAECG may be useful for risk stratification of VF episodes in patients with BrS.

Characterization of microminipigs as an in vivo experimental model for cardiac safety pharmacology.

We pharmacologically characterized microminipigs as an in vivo experimental model by assessing cardiovascular effects of pilsicainide, verapamil and E-4031, which can preferentially inhibit cardiac Na+, Ca2+ and K+ channels, respectively. Intravenous infusion of 1 mg/kg of pilsicainide (n = 4), 0.1 mg/kg of verapamil (n = 4) and 0.01 followed by 0.1 mg/kg of E-4031 (n = 5) over 10 min decreased the heart rate, mean blood pressure and ventricular contractility. Moreover, pilsicainide prolonged the PR interval, QRS width and QTc; verapamil prolonged the PR interval, but shortened the QRS width and QTc; and E-4031 prolonged the QTc, whereas no substantial change was detected in the PR interval or QRS width. Peak plasma concentrations of pilsicainide, verapamil and E-4031 in microminipigs were 1.7-4.8 times higher than those expected in humans and dogs, possibly due to smaller effective volume of drug distribution. The extent of the drug-induced cardiovascular responses was generally greater in microminipigs than in humans and dogs, which could be explained by the following possibilities; namely unique pharmacokinetic profile, less great reflex-mediated increase of sympathetic tone and/or smaller repolarization reserve in microminipigs. These information may make it feasible to apply this new-type animal to a tool for assessing cardiac safety profiles of new chemical entities.

Cardiac conduction defects and Brugada syndrome: A family with overlap syndrome carrying a nonsense SCN5A mutation.

BACKGROUND: Phenotypes often differ even within family members carrying the same SCN5A mutation. We aimed to evaluate the genetic modifiers in a family with Brugada syndrome (BrS) and sick sinus syndrome (SSS) with an SCN5A mutation that causes the truncated alpha-subunit of cardiac Na channel protein. METHODS: To detect the genetic modifiers, we performed targeted panel sequencing of the coding region of 46 genes that are related to primary arrhythmia syndrome, by using a bench-top, next generation sequencer. Phenotype-genotype relationships were evaluated among the family members. RESULTS: Index proband was a 13-year old (yo) boy with cardiac conduction defect as well as BrS. Genetic analysis revealed that he and his three asymptomatic family members carried a novel nonsense mutation: SCN5A-Q779X. Both genotype-positive mother and sister exhibited coved type ST elevation and his sister had SSS, whereas his elder brother exhibited saddleback type ST elevation induced by pilsicainide administration. We detected four non-synonymous variants (DSG2-R773K, SCN1B-L210P, -S248R, and -R250T) in the proband, his mother and his sister, but not in his brother. CONCLUSION: Phenotypic differences between the proband and his brother carrying the same nonsense SCN5A mutation could be explained by modifiers such as SCN1B, and DSG2 gene variants.

Assessment of drug-induced proarrhythmias due to pilsicainide in patients with atrial tachyarrhythmias.

BACKGROUND: Pilsicainide, a pure Na+ channel blocker, is a popular antiarrhythmic drug for the management of atrial tachyarrhythmias (AT), in Japan. However, serious drug-induced proarrhythmias (DIPs) may unexpectedly occur. We assessed the clinical background of AT patients presenting with DIPs caused by pilsicainide. METHODS: This study retrospectively enrolled 874 consecutive patients (543 men, 63.6±15.3 years old, and 57.9±16.5 kg of body weight), who were orally administered pilsicainide for AT management. We evaluated the relationship between DIPs and serum pilsicainide concentration, renal dysfunction (estimate glomerular filtration rate, eGFR), and electrocardiogram (ECG) parameters. RESULTS: Among the patients, 154 (17.6%) had renal dysfunction (eGFR<50 mL/min), including 12 (1.4%) on hemodialysis. DIPs were present in 10 patients (1.1%): all had renal dysfunction, and one was on hemodialysis. The eGFR in DIP patients was significantly lower than that in the non-DIP patients (32.2±15.1 vs. 68.4±22.1 mL/min, p<0.001). Among the clinical factors measured, only renal dysfunction (eGFR<50 mL/min) was significantly associated with DIPs (OR 44.6; 95% CI 5.61-335.0, p<0.001). Interestingly, among the ECG parameters, the corrected QT (QTc) intervals in DIP patients were longer than those in non-DIP patients (555.8±37.6 vs. 430.7±32.6 ms, p<0.001). As pilsicainide concentration increased, both QRS and QTc intervals prolonged. The latter were improved by discontinuing pilsicainide administration, and additional treatments. CONCLUSIONS: DIPs caused by pilsicainide administration were strongly associated with renal dysfunction. Hence, confirmation of renal function would be necessary prior to and/or during the pilsicainide administration.

Quantitation of pilsicainide in microscale samples of human biological fluids using liquid chromatography-tandem mass spectrometry.

This paper describes a sensitive, reliable method to determine pilsicainide (PLC) levels in microscale sample volumes of human biological fluids using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with electrospray ionization (ESI). PLC and quinidine as an internal standard were extracted with diethylether from 0.1mL of alkalinized biological fluids. The extract was injected into an analytical column (l-column 2 ODS, 75mm×2.1mm i.d.). The mobile phase for separation consisted of 5mM ammonium acetate (pH 4.5)/methanol (4:1, v/v) and was delivered at a flow rate of 0.2mL/min. The drift voltage was 100V. The sampling aperture was heated at 120°C and the shield temperature was 260°C. The ion transitions used to monitor analytes were m/z 273→m/z 110 for PLC and m/z 325→m/z 79 for quinidine. The total time for chromatographic separation was less than 8min. The validated concentration ranges of this method for PLC were 5-2000ng/mL in plasma, 5-500ng/mL in ultrafiltered plasma solution, and 25-2000ng/mL in urine. Mean recoveries of PLC in plasma, ultrafiltered plasma solution, and urine were 93.2-99.7%, 91.4-100.6%, and 93.9-104.7%, respectively. Intra- and interday coefficients of variation for PLC were less than 6.0% and 4.3% in plasma, 6.1% and 3.7% in ultrafiltered plasma solution, and 5.4% and 2.5% in urine at the above concentration ranges, respectively. The lower limit of quantification for PLC in plasma, ultrafiltered plasma solution, and urine were 5ng/mL, 5ng/mL, and 25ng/mL, respectively. This method can be applied to pharmacokinetic study and therapeutic drug monitoring in special populations such as neonates, infants, and the elderly by making effective use of residual samples used for general clinical laboratory testing.

Brugada syndrome and idiopathic left ventricular tachycardia unmasked by exercise and a class Ic drug.

The patient was a 33-year-old male. Twenty years ago, he underwent radiofrequency catheter ablation for idiopathic sustained monomorphic ventricular tachycardia (VT) with an RBBB and superior axis pattern. The VT was inducible by programmed stimulation and entrained by rapid pacing. At this presentation, he developed palpitation and VT with the same morphology at the peak exercise on a treadmill with appearance of typical ECG pattern for Brugada syndrome (BrS). Pilsicainide induced the typical ECG pattern and premature ventricular beats (PVBs) of the same morphology as VT. The relationship between BrS and VT of left ventricular origin was discussed.

A Case of Sudden Cardiac Death due to Pilsicainide-Induced Torsades de Pointes.

An 84-year-old male received oral pilsicainide, a pure sodium channel blocker with slow recovery kinetics, to convert his paroxysmal atrial fibrillation to a sinus rhythm; the patient developed sudden cardiac death two days later. The Holter electrocardiogram, which was worn by chance, revealed torsade de pointes with gradually prolonged QT intervals. This drug is rapidly absorbed from the gastrointestinal tract, and most of it is excreted from the kidney. Although the patient's renal function was not highly impaired and the dose of pilsicainide was low, the plasma concentration of pilsicainide may have been high, which can produce torsades de pointes in the octogenarian. Although the oral administration of class IC drugs, including pilsicainide, is effective to terminate atrial fibrillation, careful consideration must be taken before giving these drugs to octogenarians.

Pharmacokinetics of pilsicainide hydrochloride for injection in healthy Chinese volunteers: a randomized, parallel-group, open-label, single-dose study.

BACKGROUND: Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation. OBJECTIVE: The objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride. METHODS: This Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration-time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs. RESULTS: Thirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m(2)) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean Cmax was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) µg/mL, respectively; AUC0-24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h · µg/mL; and AUC0-∞ was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h · µg/mL. The ranges for t½z, CL, and Vz were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC0-24 values in the 0.50-mg/kg dose group (P = 0.044), and Vz showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters. CONCLUSIONS: Pilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC0-24 and AUC0-∞) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC-13003546.

A danger of induction of Brugada syndrome during pill-in-the-pocket therapy for paroxysmal atrial fibrillation.

Rhythm control therapy by sodium channel blockers is widely performed for the treatment of paroxysmal atrial fibrillation. Here, we present a case of acquired Brugada syndrome by pill-in-the-pocket treatment using pilsicainide. It is important that this therapy should be applied only after confirming the drug safety to the patients.