作者: Kurata, Yasutaka ; Notsu, Tomomi ; Fukumura, Kenta ; Tsuneto, Motokazu ; Shirayoshi, Yasuaki ; Li, Peili ; Miake, Junichiro ; Higashi, Yuhei ; Yonemizu, Sayaka ; Ninomiya, Haruaki ; Masuda, Keiichiro ; Hisatome, Ichiro

INTRODUCTIONHuman induced pluripotent stem cells (hiPSCs) harboring cardiac myosin heavy chain 6 promoter can differentiate into functional cardiomyocytes called "iCell cardiomyocytes" under blasticidin treatment condition. While iCell cardiomyocytes are expected to be used for predicting cardiotoxicity of drugs, their responses to antiarrhythmic agents remain to be elucidated. We first examined electrophysiological properties of iCell cardiomyocytes and mRNA levels of ion channels and Ca handling proteins, and then evaluated effects of class I antiarrhythmic agents on their Na⁺ and Ca²⁺ currents.METHODSiCell cardiomyocytes were cultured for 8-14 days (38-44 days after inducing their differentiation), according to the manufacturer's protocol. We determined their action potentials (APs) and sarcolemmal ionic currents using whole-cell patch clamp techniques, and also mRNA levels of ion channels and Ca handling proteins by RT-PCR. Effects of three class I antiarrhythmic agents, pirmenol, pilsicainide and mexiletine, on Na⁺ channel current (I_Na) and L-type Ca²⁺ channel current (I_CaL) were evaluated by the whole-cell patch clamp.RESULTSiCell cardiomyocytes revealed sinoatrial node-type (18%), atrial-type (18%) and ventricular-type (64%) spontaneous APs. The maximum peak amplitudes of I_Na, I_CaL, and rapidly-activating delayed-rectifier K⁺ channel current were -62.7 ± 13.7, -8.1 ± 0.7, and 3.0 ± 1.0 pA/pF, respectively. The hyperpolarization-activated cation channel and inward-rectifier K⁺ channel currents were observed, whereas the T-type Ca²⁺ channel or slowly-activating delayed-rectifier K⁺ channel current was not detectable. mRNAs of Nav1.5, Cav1.2, Kir2.1, HCN4, KvLQT1, hERG and SERCA2 were detected, while that of HCN1, minK or MiRP was not. The class Ia antiarrhythmic agent pirmenol and class Ic agent pilsicainide blocked I_Na in a concentration-dependent manner with IC₅₀ of 0.87 ± 0.37 and 0.88 ± 0.16 μM, respectively; the class Ib agent mexiletine revealed weak I_Na block with a higher IC₅₀ of 30.0 ± 3.0 μM. Pirmenol, pilsicainide and mexiletine blocked I_CaL with IC₅₀ of 2.00 ± 0.39, 7.7 ± 2.5 and 5.0 ± 0.1 μM, respectively.CONCLUSIONSIn iCell cardiomyocytes, I_Na was blocked by the class Ia and Ic antiarrhythmic agents and I_CaL was blocked by all the class I agents within the ranges of clinical concentrations, suggesting their cardiotoxicity.

2005-02-01·Journal of Clinical Pharmacy and Therapeutics4区 · 医学

Appropriate dosing of antiarrhythmic drugs in Japan requires therapeutic drug monitoring*

4区 · 医学

Article

作者: M. Shibakawa ; T. Gunji ; M. Nakai ; M. Takada ; M. Saito ; N. Kawato ; T. Goto ; T. Kotake

OBJECTIVEIn general, drugs are used in accordance with an approved dosage regimen in expectation of an appropriate balance between efficacy and toxicity. However, dose control of drugs with a narrow therapeutic range and marked intersubject variability in pharmacokinetics should be established through individualization of dosing based on therapeutic drug monitoring (TDM). The purpose of this study was to examine differences between the approved dosage regimen and the doses of antiarrhythmic drugs and digoxin used in clinical practice and to examine the influence of TDM on dosing.METHODSPrescription research of antiarrhythmic drugs was performed at five national hospitals in Japan. Prescriptions for antiarrhythmic drugs (cibenzoline, disopyramide, pirmenol, mexiletine, aprindine, flecainide, pilsicainide, amiodarone and digoxin) were counted for the study period. The mean dose and dose distribution of the drugs were determined in each hospital. Comparisons were made of mean dose obtained in the study with the dosage approved by the authority. In addition, the percentage of patients that received TDM was determined.RESULTSA difference was seen between the approved dosage and the actual dose. For all drugs except flecainide, the mean dose was smaller than the approved dosage. For all drugs except digoxin, remarkable variations were seen in the dose distribution among the hospitals. Digoxin showed a similar dose distribution among the five hospitals. Overall, the percentage of patients that received TDM was low except for Hospital A. However, TDM of digoxin was relatively common at four of the hospitals.CONCLUSIONSIt is concluded that, with the exception of digoxin, the appropriate dosing regimen for antiarrhythmic drugs is not yet established. The establishment of appropriate dosing regimens for antiarrhythmic drugs requires the more widespread adoption of TDM.

2005-01-01·Internal Medicine4区 · 医学

Progressive Facilitation of Antegrade Conduction via an Accessory Pathway in a Patient with Wolff-Parkinson-White Syndrome and Permanent Atrial Fibrillation

4区 · 医学

Article

作者: TAKAHASHI, Naohiko ; HARA, Masahide ; NAKAGAWA, Mikiko ; YOSHIMATSU, Hironobu ; SAIKAWA, Tetsunori ; OOIE, Tatsuhiko

The case of a 64-year-old man with Wolff-Parkinson-White syndrome and permanent atrial fibrillation (AF) is reported. The patient was admitted due to electrocardiographic feature of AF with rapid conduction over the left-sided accessory pathway. Administration of pirmenol effectively suppressed the ventricular response via an accessory pathway. A transesophageal echocardiography detected an uncertain thrombus in the left atrial appendage. During the 33-month follow-up period, the ventricular response via an accessory pathway was progressively facilitated. Radiofrequency catheter ablation using a transseptal approach was performed during AF, resulting in complete elimination of the antegrade accessory pathway conduction.

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