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Importance of QT interval determination and renal function assessment during antiarrhythmic drug therapy.

A major concern associated with the use of antiarrhythmic drugs (AAD) is the occurrence of ventricular proarrhythmia, especially torsade de pointes (TdP). The AADs associated with TdP most commonly include quinidine, procainamide, disopyramide, sotalol, and the newer class III agents, such as ibutilide and dofetilide. It is not simply the administration and nature of an AAD but also several additional factors such as heart rate, ventricular hypertrophy, congestive heart failure, gender, age, concomitant drugs, and impaired drug clearance that influence TdP development. Dosing of these agents should be adjusted to take such factors into account to minimize the incidence of proarrhythmia.

Age Factors↗

Restoring Sinus Rhythm in Patients With Atrial Flutter and Fibrillation: Pharmacologic or Electrical Cardioversion?

Atrial fibrillation and atrial flutter, the most frequently encountered tachyarrhythmias requiring treatment, have become a major focus for clinical and basic research in recent years. Restoration and maintenance of sinus rhythmn, having been shown to improve exercise capacity, alleviate symptoms, and reduce the incidence of thromboembolic events, may be the optimal management strategy. Identification of the safest, most efficacious and cost-effective means of restoring sinus rhythm is necessary prior to the institution of optimal antiarrhythmic therapy to maintain sinus rhythm. Potential advantages of pharmacologic compared with electrical cardioversion include lack of need for general anesthesia and likely lower cost. Pharmacologic conversion include lack of need for general anesthesia and likely lower cost. Pharmacologic conversion has been accomplished with drugs that prolong atrial refractorinerss, including class Ia (quinidine, procainamide, disopyramide), class Ic (flecainide, propafenone), and class II (sotalol, amiodarone) compounds. The so-called pure class III agents were created to overcome the blocker side effects of sotalol and the complex pharmacodynamic profile of amiodarone. Two such agents are dofetilide, which selectively blocks the rapid component of the delayed rectifier current (Ikr) and ibutilide, which augments the slow inward sodium current, with a smaller component of action mediated by the block of Ikr. Reported overall conversion rates for recent onset atrial fibrillation and atrial flutter were 31% and 54% for difetilide, respectively, and 29-31% and 38-63%, respectively, for ibutilide. Proarrhythmia, manifested as polymorphic ventricular tachycardia requiring cardioversion, was a significant early side effect of both agents. Data from clinical trtials with these new agents, combined with increasing nowledge of the electrophysiologic substrate for these arrhythmias, has renewed initerest in the development of safer, more efficacious class IIIdrugs for atrial fibrillation and atrial flutter conversion.

Journal Article↗

Involvement of alpha1-acid glycoprotein in inter-individual variation of disposition kinetics of ropivacaine following epidural infusion in off-pump coronary artery bypass grafting.

The influence of drug interaction and protein variants on the binding disposition of ropivacaine to alpha1-acid glycoprotein (AGP) was examined. The subjects were five patients who received epidural infusion of ropivacaine for 24-54 h in off-pump coronary artery bypass grafting followed by drug combination therapy, and 10 healthy volunteers. The post-operation plasma albumin concentration showed little overall change, while the AGP concentration in the five patients decreased for 6 h, then increased gradually to about 3-times the initial value by 54 h. The unbound fraction in plasma (fu) of ropivacaine gradually decreased as the AGP concentration increased, but there was large inter-individual variation among the five patients. In contrast, there was a good correlation between the fu value and AGP concentration when ropivacaine was added to blood samples from the 10 healthy volunteers. Among the volunteers, eight showed F1S variants and two showed F1 variant without S variant of AGP. The fu value of ropivacaine did not differ between these two groups. However, when ropivacaine was added in combination with dipyridamole, the fu values of ropivacaine in blood from volunteers with F1S variants were greater than those in blood from volunteers without S variant. In the case of co-administration of disopyramide or lidocaine, there was no such difference. Among the patients, one showed F1S variants and four showed F1 variant without S variant. The results indicate that variability in the side-effects of therapy with ropivacaine alone is caused by the change of the unbound concentration upon changes in the AGP concentration. However, in combination therapy, it is also important to consider the AGP variant-dependence of the inhibitory effect of concomitantly administered drugs.

Amides↗

Potentially fatal cardiac dysrhythmia and hyperkalemic periodic paralysis.

An 11-year-old boy was evaluated for mild periodic muscular weakness exacerbated on separate occasions by disopyramide phosphate and procainamide. He and his mother both had bidirectional ventricular tachydysrhythmia (BVT), short stature, microcephaly, and clinodactyly. The mother, but not the child, had lingual myotonia. The two antiarrhythmic drugs worsened the muscular weakness without benefiting the cardiac dysrhythmia. Potassium loading produced skeletal muscle weakness and transient conversion of the BVT to normal sinus rhythm. Hypokalemia aggravated the BVT without causing weakness. Acetazolamide had no effect. The patient suffered a nonfatal cardiac arrest after several days of increased carbohydrate intake. Imipramine controlled the dysrhythmia without inducing weakness. Periodic paralysis should be considered as the diagnosis in children with BVT, a potentially fatal condition.

Arrhythmias, Cardiac↗

Possible mechanisms of sudden death and hemoconcentration induced by endothelin-1 and big endothelin-1 in mice.

We investigated the profiles of sudden death and hemoconcentration induced by endothelin-1 (ET-1) and big endothelin-1 (big ET-1) in mice using various compounds as pharmacological tools. In ET-1-induced sudden death (5 nmol/kg, i.v.), pretreatment with the Ca(2+)-channel blockers, diltiazem, nifedipine or verapamil at a dose of 2 mg/kg, i.v. significantly inhibited the mortality and prolonged the latency to death. These Ca(2+)-channel blockers, however, failed to inhibit the rise in hematocrit (Ht), namely hemoconcentration, induced by ET-1 (2.5 nmol/kg). A beta-adrenoceptor agonist, isoproterenol (1 mg/kg) tended to prolong the latency, whereas, a beta-adrenoceptor blocker, propranolol (2 mg/kg), and an alpha- and beta-adrenoceptor blocker, labetalol (5 mg/kg), aggravated the sudden death. Esculetin (10 mg/kg) and fenbufen (10 mg/kg), which are enzyme inhibitors in the arachidonate cascade, prevented only the hemoconcentration. Anti-arrhythmic drugs, lidocaine (1 mg/kg) and disopyramide (20 mg/kg) did not improve any parameters. Big ET-1 also caused sudden death (20 and 25 nmol/kg, i.v.) and hemoconcentration (10 nmol/kg, i.v.). Of several proteinase inhibitors, only a metalloproteinase inhibitor, phosphoramidon (2 mg/kg i.v.), prevented the sudden death and the hemoconcentration induced by big ET-1 but not by ET-1. Ca(2+)-channel blockers exerted their protective effects only when a lower dose of big ET-1 was employed. These results indicate that the sudden death caused by both peptide is mainly due to myocardial ischemia and respiratory disorder, and that hemoconcentration caused by them is due to their vasoconstrictor action but to their effects on the vascular permeability via secondary endogenous factors.

Adrenergic alpha-Antagonists↗

MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs.

The multidrug transporter, MDR1-mediated interaction of digoxin with antiarrhythmic or antianginal drugs was examined in vitro by using the MDR1-overexpressing LLC-GA5-COL150 cells, which were established by transfection with human MDR1 cDNA into porcine kidney epithelial LLC-PK(1) cells. Amiodarone, its active metabolite monodesethyl-amiodarone (DEA), and quinidine markedly inhibited the basal-to-apical transport (renal secretion) of [(3)H]digoxin and increased the apical-to-basal transport (reabsorption), but cibenzoline and lidocaine showed slight inhibition of the transport, and disopyramide and mexiletin had no such effects. The IC(50) values for amiodarone, DEA and quinidine on [(3)H]digoxin transport in LLC-GA5-COL150 cells were 5.48 microM, 1.27 microM and 9.52 microM, respectively. These were comparable to, or only several times the achievable concentration in clinical use, suggesting that MDR1 could be responsible for the drug interaction between digoxin and amiodarone found in clinical reports and that DEA contributes the elevation of digoxin serum concentration. Similarly, dipyridamole altered the transport, but isosorbide showed only slight modification of the transport. The IC(50) value for dipyridamole was 40.0 microM, also only several times the achievable concentration in clinical use, indicating a risk of interaction.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

[Molecular diversity of organic cation transporter (OCT) mediating renal excretion of drugs].

Tubular absorption and urinary secretion are important physiological functions for the maintenance of body fluid homeostasis and detoxification of drugs and xenobiotics. The proximal tubular epithelial cells play a principal role in limiting or preventing the toxicity of administered drugs by actively secreting organic cations from the circulation into the urine. Rat (r) OCT2 was identified as a second member of the organic cation transporter (OCT) family and is predominantly expressed in the kidney. In the reverse-transcriptase-polymerase chain reaction of microdissected nephron segments, rOCT1 mRNA was detected primarily in the superficial and juxtamedullary proximal convoluted tubules, whereas rOCT2 mRNA was detected widely in the superficial and juxtamedullary proximal straight tubules and some other nephron segments. The inhibitory potencies of cationic drugs and endogenous cations on the tetraethylammoniun (TEA) uptake via rOCT1 and rOCT2 indicates that rOCT1 and rOCT2 have similar affinity for many compounds, although there are moderate differences in the affinity for several compounds, such as 1-methyl-4-phenyl-pyridinium, dopamine, disopyramide, and chlorpheniramine. On the other hand, there were gender differences in the expression levels of rOCT2, but not of rOCT1, in rat kidneys; both mRNA and protein levels of rOCT2 in the kidneys were higher in males than females. These results suggest that rOCT1 and rOCT2 play distinct roles in the basolateral membranes of renal tubules mediating tubular secretion of cationic drugs.

Animals↗

[The uptake of nalidixic acid and enoxacin by rat renal cortical slices in rat].

The mechanisms involved in the renal excretion of quinolone and new quinolone antibacterial drugs are still incompletely understood. The purpose of this study was to examine the renal handling of nalidixic acid (NA) and enoxacin (ENX), using the renal cortical slices uptake techniques in rats. It was demonstrated that both NA and ENX were taken against a concentration gradient by a saturable processes resulting from the ratio of slice to medium (ratio of S/M) being dependent on the time and the concentration. It was indicated that the inhibition of uptake by 2,4-dinitrophenol, ouabain and sodium cyanate was shown to be an energy dependence. Probenecid and cimetidine exhibited that they might inhibit NA uptake slightly. ENX uptake was inhibited by probenecid, cimetidine, guanidine and disopyramide, suggesting that ENX might possess an affinity for both anionic and cationic transport mechanisms.

Animals↗

[Consultation and survey for drug interaction in outpatients taking the medicines potentially interact with St. John's Wort].

Ministry Health Welfare of Japan announced the caution for drug interaction of St. John's Wort (SJW), a herbal supplement occasionally used for depression, on May, 2000. Immediately after the announcement, we conducted drug consultation for outpatients prescribed the medicines potentially interacting with SJW. We provided information concerning possible drug interaction with SJW for 741 outpatients (except for pediatrics) during the period of May 22-June 16, 2000. The potential drugs prescribed frequently were warfarin (28.0%), theophylline (19.7%), digitalis (18.4%), carbamazepine (7.2%), disopyramide (6.9%) and cyclosporin (6.3%). Of the patients, 401 subjects were surveyed by collecting the questionnaires to clarify the background of SJW drug interaction. Twenty-two subjects (5.5%) have known commercially available SJW products, 5 subjects (1.2%) have ever taken SJW products before and 2 subjects (0.5%) have taken SJW products concomitant with prescribed medicines. Gender difference was observed in paying attention to SJW products; female subjects (8.6%) tended to have more interest in SJW products than male subjects (2.8%). Two subjects taking SJW have realized for the first time that the supplements they took were SJW products when their package photographs were shown at the consultation. Showing the package photographs might be helpful for making the patients easy to identify the SJW products, because most patients do not pay attention to whether the supplements contain SJW or not. It is recommended that drug consultation should be provided to avoid serious drug interaction with SJW while the outpatients are taking potential medicines prescribed.

Adult↗

Ventricular tachycardia associated with acute myocardial infarction--features, therapeutic effect and prognosis.

This study was performed to delineate the precise features and the treatment of ventricular tachycardia (VT) with acute myocardial infarction (AMI). Results indicate: 1) the incidence of VT in 310 AMI patients was 16.1% (50 patients); 2) the higher incidence of ventricular fibrillation and mortalities were observed in VT group compared with non-VT group; 3) the incidence of VT was higher in inferior infarction group (21.0%) than anterior group (13.1%); 4) more frequent VT were seen in patients with more severe heart failure; 5) two peaks of VT occurrence, on the first day and in the 4th week after the onset of AMI, were recognized especially in anterior infarction group; 6) supraventricular arrhythmias were more frequent than ventricular premature beats during one minute preceding VT; 7) the successful termination of VT was achieved in 63.9% of episodes by thump-version, 61.5% by lidocaine, 66.7% by disopyramide and 100% by mexiletine; 8) prophylactic effect on VT by class Ia antiarrhythmic agents seemed stronger than others; 9) IABP was effective to prevent VT in some cases; 10) poor prognosis was determined by frequent and later onset of VT, and combination of severe heart failure.

Aged↗

Ventricular fibrillation threshold measured by continuous 50 cps stimulation for the evaluation of the antifibrillatory effect of the drugs.

The role of electrophysiologic parameters on the induction of ventricular fibrillation (VF) by continuous 50 cycle per second (cps) electrical stimulation was studied in 21 open chest dogs. The current strength of the 50 cps stimulation required to induce VF when applied to the ventricle for 2 seconds was defined as the ventricular fibrillation threshold (VFT). The intravenous injection of antiarrhythmic drugs raised the VFT in a dose dependent manner. The changes in VFT were associated with a rise in excitation threshold. The slopes of the regression equations relating the excitation threshold to VFT were almost identical, that is, 2.8 with lidocaine, 3.4 with procainamide and 3.2 with disopyramide. Prolongation of refractory period increased the cycle length of ventricular excitations just prior to VF but was not correlated with the changes in VF. Localized myocardial ischemia induced by coronary ligation also resulted in the elevation of VFT. The slope of the regression equation between excitation threshold and VFT was 1.9 which was slightly lower than that observed at the administration of the drugs. The fact that the VFT was mainly attributed to the changes in excitation threshold at the site where the test stimulus was applied would limit the usefulness of the 50 cps continuous stimulation method for the evaluation of vulnerability to VF.

Animals↗

Clinical significance of Vanghan Williams classification for treatment of ventricular tachycardia: study of class IA and IB antiarrhythmic agents.

UNLABELLED: Ninety-eight cases of ventricular tachycardia (VT) were studied using clinical electrophysiological (EP)-pharmacological assessment to compare the efficacy of class IA (disopyramide-DP, procainamide-PA) and class IB (mexiletine-Mex, Lidocaine-Lid, aprindine-AP) agents available in Japan, and to evaluate the clinical significance of class subdivisions for the treatment of VT. In assessing the efficacy of drugs, we evaluated their ability to prevent and terminate induced sustained VT as well as their ability to suppress spontaneous premature ventricular beats (VPB). I. EP properties: DP significantly extended QTc, ERPRV, and the coupling interval by which VT or repetitive ventricular response (RVR) was induced. On the other hand, Mex and AP had no effect. Although no significant extension of QRS width was found, the significant extension of the interval from extrastimulus to the first induced VT or RVR complex by the three drugs indicates that all have suppressive effects on conduction velocity within the reentry circuit. II. CLINICAL SIGNIFICANCE: Correspondence of preventive effects was 67% for DP and PA (class IA), 54% for Mex and Lid (class IB), 55% for DP and Mex, 27% for AP and Mex, and 25% for AP and DP. Correspondence of terminating effect was 85% for DP and PA, 80% for DP and AP, 77% for DP and Mex, 75% for Mex and Lid, and 63% for Mex and AP. For suppression of spontaneous VPB's, correspondence rate was 100% for DP and PA, 39% for DP and Mex, 64% for Mex and Lid, 61% for Mex and AP, and 69% for DP and AP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Clinical and electrocardiographic characteristics of responders and nonresponders to class IA antiarrhythmic drugs.

A retrospective analysis of 44 patients was carried out to evaluate the efficacy of class IA antiarrhythmic drugs (disopyramide and/or procainamide), and of drugs of one or more other classes by means of 24-hour Holter recording. This study included only patients who exhibited 5000 or more ventricular premature complexes (VPCs) during a 24-hour pretrial baseline recording. The drugs that reduced the frequency of VPCs by at least 50% were considered effective. Eighteen patients (41%) responded to class IA drugs (responders) and 26 patients (59%) did not (nonresponders). There was a significant difference between the two groups in relation to the types of disease (p less than 0.01), but no significant difference with regard to other clinical and electrocardiographic characteristics. There was a significant discordance between trials of class IA drugs and class IC drugs (p less than 0.05). The efficacy of class IA drugs is very similar to that of class IB drugs, and only class IC drugs represent the highest efficacy in patients refractory to both class IA and class IB drugs. In conclusion, when ventricular arrhythmias do not respond to class IA or IB drugs, class IC drugs could be chosen as the next regimen.

Adult↗

Long-term prognostic assessment of ventricular tachycardia with respect to sudden death in patients with and without overt heart disease.

The purpose of this study is to investigate the long-term prognosis of ventricular tachycardia (VT) mainly with respect to sudden death (SCD) in patients with ischemic heart disease (IHD), idiopathic cardiomyopathy (ICM), miscellaneous heart disease (MHD) and idiopathic ventricular tachycardia (IVT). The study included 117 patients with VT (80 male, 37 female). The number of patients with IHD, ICM, MHD and IVT were 40, 18, 26 and 33, respectively. Follow-up was conducted by means of a mailed standardized questionnaire. The mean follow-up period was 46.8 +/- 32.0 months (range from 6 to 125 months). In 24 out of the 117 patients the cause of death was SCD, in 9 there was no sudden cardiac death and in 5 no cardiac death. The other 76 were surviving. The number of SCD in IHD, ICM, MHD and IVT was 14/40 (35%), 4/17 (24%), 6/25 (24%) and zero (0%), respectively. The number of having had syncope in IHD, ICM, MHD and IVT was 19/40 (48%), 7/18 (39%), 6/26 (23%) and 6/33 (18%), respectively. Out of the 19 IHD patients with syncope, 15 had had ventricular fibrillation (VF). As for IVT with syncope, only one of the 6 had VF, which was induced by a disopyramide injection. In IVT, the patients with syncope had a significantly higher VT rate than those without syncope (p less than 0.01). There were no significant differences in the electrocardiographical high risk parameters for SCD, the age, follow-up periods, the presence or absence of VF and ejection fraction between the SCD and the surviving groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Electrocardiographic and electrophysiologic studies in patients with torsades de pointe--role of monophasic action potentials.

The study group consisted of 26 patients with a history of documented Torsade de Pointes (TdP) who were divides into 3 groups according to the causes of TdP. Group I consisted of 5 patients with congenital long QT syndrome. Group II consisted of 15 patients with TdP caused by antiarrhythmic drugs. Group III consisted of 6 patients with TdP caused by bradycardia resulting from third degree atrioventricular block. The QT interval was determined from a 12-lead electrocardiogram. Monophasic Action Potential (MAP) was recorded by a 6 F USCI electrode catheter. Isoproterenol infusion resulted in TU abnormality in all patients in Group I and induced a hump at phase 3 slope of MAP in all 3 patients tested. The QT interval change before and after IA administration was significantly larger in Group II patients compared to those without TdP (0.132 +/- 0.062 vs 0.029 +/- 0.31 sec, less than 0.005). Injection of 100 mg. of disopyramide in 2 patients in Group II resulted a hump at phase 3 slope of the MAP in both of them. The QT prolongation associated with decreasing the pacing rate from 70 to 50/min was significantly larger in patients with Group III compared to patients with bradycardia but without TdP (0.02 +/- 0.04 vs 0.07 +/- 0.05 sec, p less than 0.005). The results suggests: 1) different approaches are necessary for evaluation of TU abnormalities in patients with TdP according to the causes of TdP, 2) MAP might be a useful method for evaluating TU abnormality in patients with TdP.

Action Potentials↗

Exercise-induced second-degree atrioventricular block.

In this report we describe 2 patients with exercise-induced, second-degree atrioventricular (AV) block. Case 1 was a 49-year-old man with normal AV conduction at rest but who developed dyspnea on exertion. Treadmill testing showed an exercise-induced 2:1 AV block. Electrophysiologic study (EPS) demonstrated rate-dependent, presumably intrahissian, AV block. Case 2 was a 31-year-old woman with first-degree AV block and complete right bundle branch block with dyspnea on exertion and occasional syncope. She had twice undergone surgical patch closure of an ostium primum atrial septal defect. Exercise testing induced type II second-degree AV block. Atrial pacing during EPS did not disclose rate-dependent type II AV block, but disopyramide induced second-degree AV block.

Adult↗

A case of primary cardiac B cell lymphoma associated with ventricular tachycardia, successfully treated with systemic chemotherapy and radiotherapy: a long-term survival case.

We experienced a long-term survival case of primary cardiac lymphoma (PCL) demonstrating ventricular tachycardia (VT) as an initial sign, which was related to localized myocardial damage by lymphoma cells. A 70-year-old woman with sustained VT was admitted to the Kofu Municipal Hospital. VT ceased with the administration of disopyramide intravenously. The origin of the VT was the free wall of the right ventricular outflow tract (RVOT) as observed by electrocardiography on admission. A solitary mass in the free wall of the RVOT was found by echocardiography, chest computed tomographic scanning and magnetic resonance imaging. There was no evidence of extracardiac involvement. The patient was histologically diagnosed as PCL by endomyocardial biopsy. Chemotherapy started immediately after the diagnosis and the mass showed a marked reduction in size. After 8 cycles of chemotherapy, radiotherapy was performed. Pericardial thickness in the free wall of the RVOT developed without severe side effects. Complete remission has been maintained for 30 months after the initial diagnosis, and no recurrence and arrhythmias have been detected during the follow-up period. It was demonstrated that rapid diagnosis and chemotherapy followed by radiotherapy for PCL achieved better survival.

Aged↗

Successful treatment of malignant neurocardiogenic syncope with repeated tilt training program.

Recent reports have shown that repeated tilt-table testing or tilt training is a very effective therapy for the treatment of neurocardiogenic syncope induced by head-up tilt testing. The present patient experienced repeated syncopal or presyncopal attacks and had shown prolonged asystole on an electrocardiogram during syncope. The presyncope could be reproducibly induced by head-up tilt testing. Oral propranolol and/or disopyramide therapies failed to prevent his symptoms. Tilt training (2 sessions/day) was repeated every day for 4 weeks at home, and then head-up tilt testing was performed again. The syncope or presyncope was not induced by head-up tilt testing. The patient has continued with this training and has had no symptoms during the follow-up period of 1 year.

Electrocardiography↗