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PubMed1996

Negative dromotropic effects of class I antiarrhythmic drugs in anisotropic ventricular muscle.

OBJECTIVE: In a computer simulation study to mimic cardiac action potential, the total open time of the sodium channel at each excitation has been shown by other authors to be longer during propagation parallel (longitudinal, L) to fiber orientation than perpendicular (transverse, T) to that. If this is the case in actual cardiac tissue, the Class I antiarrhythmic drug action on conduction would be affected by their mode of sodium channel block. The present study was designed to test this hypothesis. METHODS: Effects of flecainide (F), quinidine (Q), aprindine (A) and SD3212 (S) on conduction velocity (theta), amplitude of extracellular potentials (phi e), and maximum upstroke velocity (Vmax) of action potentials were examined in isolated rabbit ventricular muscles with microscopic anisotropy. RESULTS: F (0.1-1 microM) or Q (2-10 microM), which blocks the sodium channel mainly during the activated state, caused a concentration- and frequency-dependent decrease in theta and phi e. The reduction was more prominent during L than T propagation, giving rise to a decrease in their anisotropic ratio (theta L/theta T). A (1-5 microM) or S (3-10 microM), which blocks the channel during the inactivated state, also decreased theta and phi e. However, the reduction was similar during L and T propagation, and the anisotropic ratio of theta and phi e remained unaffected. The decrease of maximum upstroke velocity (Vmax) of action potential by F or Q was greater during L than T propagation; VmaxL/VmaxT was decreased significantly. In contrast, the Vmax reduction by A(3 microM) or S (10 microM) was similar during L and T propagation. CONCLUSION: Different state-dependence of sodium channel block may underlie different negative dromotropic effects of Class I drugs in anisotropic cardiac muscle.

Action Potentials↗
PubMed2005

Population-based drug-induced agranulocytosis.

BACKGROUND: Since the publication of a major international case-control study on the risk of agranulocytosis associated with the use of medicines in the 1980s, many new drugs have been introduced in therapeutics. METHODS: Seventeen units of hematology contribute to the case-control surveillance of agranulocytosis and aplastic anemia in Barcelona, Spain. After a follow-up of 78.73 million person-years, 177 community cases of agranulocytosis were compared with 586 sex-, age, and hospital-matched control subjects with regard to previous use of medicines. RESULTS: The annual incidence of community-acquired agranulocytosis was 3.46:1 million, and it increased with age. The fatality rate was 7.0%, and the mortality rate was 0.24:1 million. The drug most strongly associated with a risk of agranulocytosis was ticlopidine hydrochloride with an odds ratio (OR) of 103.23 (95% confidence interval [CI], 12.73-837.44), followed by calcium dobesilate (OR, 77.84 [95% CI, 4.50-1346.20]), antithyroid drugs (OR, 52.75 [95% CI, 5.82-478.03]), dipyrone (metamizole sodium and metamizole magnesium) (OR, 25.76 [95% CI, 8.39-179.12]), and spironolactone (OR, 19.97 [95% CI, 2.27-175.89]). Other drugs associated with a significant risk were pyrithyldione, cinepazide, aprindine hydrochloride, carbamazepine, sulfonamides, phenytoin and phenytoin sodium, beta-lactam antibiotics, erythromycin stearate and erythromycin ethylsuccinate, and diclofenac sodium. Individual attributable incidences for all these drugs, which collectively accounted for 68.6% of cases, were less than 1:1 million per year. CONCLUSIONS: Agranulocytosis is rare but serious. A few drugs account for two thirds of the cases. Our results also provide reassurance regarding the risk associated with a number of newly marketed drugs.

Adolescent↗
PubMed1990

Molecular pharmacological aspects of antiarrhythmic activity, II: Interaction of class I compounds with calmodulin.

We have tested the calmodulin (CaM) inhibitory potency of class I antiarrhythmics in the phosphodiesterase (PDE) assay. The lipophilicity of the test compounds has been quantified by two experimental (log P, RM) and two calculative (sigma f, C log P) procedures. Five antiarrhythmics (asocainol, aprindine, lorcainide, propafenone, and ethmozine) exhibit IC50 values less than 250 microM for the inhibition of the CaM-stimulated PDE activity. Lipophilicity seems to be a prime, but not the sole descriptor of CaM inhibitory potency. The functional means of CaM inhibition by the test compounds for their antiarrhythmic properties remains to be clarified in further investigations.

Anti-Arrhythmia Agents↗
PubMed1986

The contribution of Na channel block to the negative inotropic effect of antiarrhythmic drugs.

The specific Na channel blocker tetrodotoxin (TTX) produces a direct negative inotropic effect on the isolated guinea-pig papillary muscle stimulated at 1 Hz. The toxin is significantly more potent in reducing maximal upstroke velocity of the transmembrane action potential (Vmax, an index of the available Na conductance) than in reducing force of contraction (Fc), the IC50 for Vmax divided by the IC50 for Fc being 0.23 (95% confidence interval, 0.16-0.43). This IC50 ratio defines the negative inotropic influence of Na channel blockade per se, because TTX has no known action other than blocking Na channels. Vmax-reducing to negative inotropic concentration ratios were also obtained for 5 widely used and 2 experimental antiarrhythmic agents belonging to the Na channel-blocking class (class 1). Five of these drugs (aprindine, CCI 22277, disopyramide, mexiletine, and quinidine) differed significantly from TTX in that the Na channel block was associated with a stronger negative inotropic effect. It is concluded that one or more mechanisms in addition to Na channel blockade are involved in the negative inotropic effect of these antiarrhythmic drugs. If the antiarrhythmic activity of class 1 agents depended solely on Na channel block, more selective agents with less negative inotropic action could conceivably be developed.

Animals↗
PubMed1979

Clinical experience of encainide (MJ 9067): a new anti-arrhythmic drug.

Encainide is a new anti-arrhythmic drug, which is highly effective against ventricular extrasystoles, both single and coupled, in the dose range of 80--140 mg i.v. Ventricular extrasystoles were abolished in 31 out of 33 cases treated. The drug is also relatively effective against supraventricular extrasystoles, but has little effect on atrial fibrillation. Both subjects with clinically normal hearts and those with ischaemic heart disease have been successfully treated. The drug prolongs the QRS and QT duration. Its effectiveness appears to be of the same order of magnitude and the range of indications similar to those of aprindine and lorcainide. Further study of the drug seems to be warranted.

Anilides↗
PubMed1979

Intracardiac electrophysiological effects of lorcainide in man.

The electrophysiological effects of lorcainide 1.25 or 2.5 mg/kg given iv over 2 or 4 min, were studied in 21 patients with normal and diseased impulse formation and conduction, by means of intracardiac recording and stimulation. Sinus rate and the effective atrial refractory period rose following both doses of lorcainide. The corrected sinus node recovery time rose only after lorcainide 2.5 mg/kg and then most markedly in patients with sinus node dysfunction. The P-A interval remained unchanged following the drug. The A-H interval during sinus rhythm, and the pooled A-H intervals during atrial pacing, increased slightly, and the functional and effective A-V nodal refactory period changed variably. Wenckebach periods above the bundle of His occurred at lower atrial pacing rates following both doses of lorcainide in 7 patients, at the same atrial pacing rate in 9 and at higher rates in 3. H-V intervals, pooled H-V intervals and QRS-width lengthened in all patients, most markedly in cases with a conduction delay below the His bundle, who had received lorcainide 2.5 mg/kg. Thus, lorcainide shares some electrophysiological properties with procainamide and aprindine. Higher doses should be used with caution in patients with pre-existing conduction delay below the bundle His.

Acetanilides↗
PubMed1990

Identification of antiarrhythmic drugs and their metabolites in urine.

Identification of the antiarrhythmic drugs ajmaline, aprindine, diltiazem, disopyramide, flecainide, gallopamil, lidocaine, lorcainide, mexiletine, phenytoin, prajmaline, propafenone, quinidine, sparteine, tocainide and verapamil and their metabolites in urine is described. After acid hydrolysis of the conjugates, extraction and acetylation, the urine samples were analysed by computerized gas chromatography-mass spectrometry. Using ion chromatography with the selective ions m/z 58, 72, 84, 86, 136, 224, 266, and 426, the possible presence of antiarrhythmic drugs and/or their metabolites was indicated. The identity of positive signals in the reconstructed ion chromatograms was confirmed by a visual or computerized comparison of the stored full mass spectra with the reference spectra. The ion chromatograms, reference mass spectra and gas chromatographic retention indices (OV-101) are documented. The method presented is integrated in a general screening procedure (general unknown analysis) for several groups of drugs.

Acetylation↗
PubMed1980

Hemodynamic effects of newer antiarrhythmic drugs.

The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodyanmic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodyanmic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verampamil are administered either acutely by the intravenous route or chronically by the oral route.

Acebutolol↗
PubMedDate not supplied

Digitalis arrhythmias: role of oscillatory afterpotentials.

Digitalis-induced OAP provide a mechanism of automaticity that may be responsible for many arrhythmias induced by cardiac glycosides. In response to digitalis, OAP occur in tissues of the specialized conducting systems of both ventricles and atria and, under the influence of tension, occasionally in ventricular myocardium. Digitalis, in toxic doses, suppresses "normal" pacemaker activity possibly in part by enhancing overdrive suppression. In contrast to "normal" pacemaker activity, OAP exhibit, both in magnitude and rate of depolarization, postpacing acceleration. This plus the coupled nature of OAP are important characteristics in the generation of complex arrhythmias by OAP. Conduction disturbances may also be related to OAP. At early stages of intoxication OAP may speed conduction of superimposed beats relative to earlier or later beats. More advanced stages of intoxication are associated with conduction block. The occurrence of digitalis-induced OAP is promoted by high concentrations of calcium, low concentrations of potassium, and moderate stretch. OAP can be suppressed by high concentrations of potassium, reduction of extracellular calcium, and exposure to antiarrhythmic agents including diphenylhydantoin, verapamil, and aprindine. The effectiveness of the latter two agents may be related to ability to block transmembrane calcium currents. Digitalis-induced OAP in atrial tissue can be abolished by acetylcholine. A transmembrane current possibly but not necessarily carried by calcium appears to underly the occurrence of OAP. This current demonstrates kinetic properties different from those of the slow inward current associated with the plateau of the cardiac action potential. Calcium is intimately involved in the mechanism causing OAP and may be responsible for aftercontractions observed in conjunction with OAP. Aftercontractions greatly affect contractility and may be responsible at least in part for some of the inotropic actions of digitalis. Thus the occurrence of OAP may be linked to the inotropic actions of digitalis. Digitalis-induced OAP provide a mechanism of automaticity with characteristics paralleling automatic behavior observed in intact animals intoxicated with digitalis. The relative importance of OAP in the genesis of clinically important arrhythmias awaits further investigation.

Action Potentials↗
PubMed1991

High-performance liquid chromatographic method for the determination of nefazodone and its metabolites in human plasma using laboratory robotics.

A quantitative analytical method, using high-performance liquid chromatography and ultraviolet detection, has been established for the determination of nefazodone (NEF) and its metabolites, m-chlorophenylpiperazine (mCPP),p-hydroxynefazodone (PHN), and hydroxynefazodone (HO-NEF), in human plasma. The fully automated, robotic procedure consisted of addition of internal standard (aprindine), extraction with butyl chloride, followed by phase separation, organic phase evaporation, reconstitution of the residue, and injection onto the chromatographic system. The limits of detection for NEF, mCPP, PHN, and HO-NEF were 5, 1, 10, and 5 ng/ml, respectively, at a signal-to-noise ratio of 4. The method had a linear range of 10-1000 ng/ml for NEF and HO-NEF, 20-2000 ng/ml for PHN, and 2.5-250 ng/ml for mCPP. Correlation coefficients of 0.996 or greater were obtained during validation and study sample analysis.

Adolescent↗
PubMed1999

Enhancing effects of salicylate on tonic and phasic block of Na+ channels by class 1 antiarrhythmic agents in the ventricular myocytes and the guinea pig papillary muscle.

OBJECTIVE: To study the interaction between salicylate and class 1 antiarrhythmic agents. METHODS: The effects of salicylate on class 1 antiarrhythmic agent-induced tonic and phasic block of the Na+ current (INa) of ventricular myocytes and the upstroke velocity of the action potential (Vmax) of papillary muscles were examined by both the patch clamp technique and conventional microelectrode techniques. RESULTS: Salicylate enhanced quinidine-induced tonic and phasic block of INa at a holding potential of -100 mV but not at a holding potential of -140 mV; this enhancement was accompanied by a shift of the hinfinity curve in the presence of quinidine in a further hyperpolarized direction, although salicylate alone did not affect INa. Salicylate enhanced the tonic and phasic block of Vmax induced by quinidine, aprindine and disopyramide but had little effect on that induced by procainamide or mexiletine; the enhancing effects were related to the liposolubility of the drugs. CONCLUSIONS: Salicylate enhanced tonic and phasic block of Na+ channels induced by class 1 highly liposoluble antiarrhythmic agents. Based on the modulated receptor hypothesis, it is probable that this enhancement was mediated by an increase in the affinity of Na+ channel blockers with high lipid solubility to the inactivated state channels.

Action Potentials↗
PubMed2000

Propiverine-induced Parkinsonism: a case report and a pharmacokinetic/pharmacodynamic study in mice.

PURPOSE: We present a case report of propiverine-induced Parkinsonism. We previously reported the induction of catalepsy by amiodarone, aprindine and procaine, which possess a diethylaminomethyl moiety and demonstrated selective blockade of dopamine D2 receptors by these drugs in mice. We hypothesized that drugs possessing a diethylaminomethyl structure may generally induce Parkinsonism and/or catalepsy. METHODS: Thus, we performed a study to examine whether oxybutynin, pentoxyverine and etafenone, as well as propiverine, induce catalepsy in mice. RESULTS: The intensity of drug-induced catalepsy was in the order: haloperidol > etafenone > pentoxyverine > propiverine > oxybutynin. In vivo occupancy of dopamine D1, D2 and mACh receptors in the striatum was also examined. The in vitro binding affinities to the D1, D2 and mACh receptors in the striatum synaptic membrane were within the ranges of 2.4-140 microM, 380-4,200 nM, and 1.2-2,800 nM, respectively. CONCLUSIONS: These results support the idea that any drug possessing a diethylaminomethyl moiety may contribute to the induction of catalepsy, possibly by occupying dopamine receptors.

Animals↗
PubMed1991

Risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs: The International Agranulocytosis and Aplastic Anemia Study.

The risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs were estimated in a population-based case-control study conducted in Israel and Europe (total population, 23 million). Cardiovascular drug use in the week before onset of illness was compared between 270 patients hospitalized with agranulocytosis and 1870 hospitalized control subjects. Propranolol (relative risk, 2.5), dipyridamole (3.8), digoxin (2.5), and acetyldigoxin (9.9) were significantly associated with agranulocytosis. The excess risks attributable to these drugs ranged from one to three cases per 10 million persons exposed for up to 1 week. Increased risks were also observed for cinepazide (used by six cases and no control subjects), procainamide (7, 1), and aprindine (5, 1); based on crude relative risk estimates, the excess risks for the latter two drugs were approximately three per million persons exposed for up to 1 week. The use of cardiovascular drugs in a 5-month period ending 1 month before hospital admission was compared between 152 patients with aplastic anemia and 2180 control subjects. Furosemide was the only significantly associated drug (relative risk, 3.1); the excess risk attributable to any exposure in a 5-month interval was 1.7 per million.

Adrenergic beta-Antagonists↗
PubMed1998

Inhibitory effects of antiarrhythmic drugs on phenacetin O-deethylation catalysed by human CYP1A2.

AIMS: The aim of the study was to clarify whether the pharmacokinetic interaction between theophylline and mexiletine is mediated by inhibition of CYP1A2 and to assess the possible interaction potential of other antiarrhythmic drugs with drugs metabolized by CYP1A2. METHODS: The inhibitory effects of mexiletine and 10 antiarrhythmic drugs on phenacetin O-deethylation, a marker reaction of CYP1A2, were studied using human liver microsomes and cDNA-expressed CYP1A2. RESULTS: Propafenone and mexiletine inhibited phenacetin O-deethylation with IC50 values of 29 and 37 microM, respectively. Disopyramide, procainamide and pilsicainide produced negligible inhibition of phenacetin O-deethylation (IC50 >1 mM). Amiodarone, bepridil, aprindine, lignocaine, flecainide and quinidine inhibited phenacetin O-deethylation in a concentration-dependent manner, although the inhibitory effects were relatively weak with IC50 values ranging from 86 to 704 microM. Propafenone and mexiletine selectively abolished the high-affinity component of phenacetin O-deethylation in human liver microsomes. In addition, propafenone and mexiletine inhibited phenacetin O-deethylation catalysed by cDNA-expressed CYP1A2. CONCLUSIONS: These data suggest that, among the antiarrhythmic drugs studied, propafenone and mexiletine are relatively potent inhibitors of CYP1A2, which may cause a drug-drug interaction with drugs metabolized by CYP1A2.

Anti-Arrhythmia Agents↗
PubMed2004

Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome.

INTRODUCTION: Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy. METHODS AND RESULTS: Eighteen symptomatic LQTS patients (12 families) were genetically diagnosed as having heterozygous KCNQ1 variants and received beta-blocker therapy. Cardiac events recurred in 4 members (3 families) despite continued therapy during mean follow-up of 70 months. Three of these patients (2 families) had the same mutation [A341V (KCNQ1)]; and the other had R243H (KCNQ1). The latter patient took aprindine, which seemed to be responsible for the event. By functional assay using a heterologous mammalian expression system, we found that A341V (KCNQ1) is a loss-of-function type mutation (not dominant negative). Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2). Functional assay of the S706C (KCNH2) mutation was found to reduce the current density of expressed heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation curve. Action potential simulation study was conducted based on the KYOTO model to estimate the influence of additional gene modifiers. In both models mimicking LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was increased compared with the LQT1 model under the setting of beta-adrenergic stimulation. CONCLUSION: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.

Action Potentials↗
PubMed1991

Effects of a new antiarrhythmic drug TYB-3823 on canine ventricular arrhythmia models.

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, TYB-3823 [1-(2,6-dimethylphenyl)-4,4-dimethyl-aminoguanidine hydrochloride], were investigated. To determine the antiarrhythmic effects, spontaneously occurring adrenaline-, digitalis-, and two-stage coronary ligation-induced arrhythmias were used. TYB-3823 suppressed these three arrhythmia models. The antiarrhythmic plasma concentrations, IC50, of TYB-3823 for digitalis-, coronary ligation-, and adrenaline-induced arrhythmias were 7.8, 16.8, and 5.0 micrograms/ml, respectively. In the blood perfused sinoatrial (SA) node and papillary muscle (PM) preparations, TYB-3823 decreased the sinoatrial rate (SAR) and contractile force following an initial small positive inotropic effect and increased the intraventricular conduction time and coronary blood flow. These results indicate that TYB-3823 is similar to other class I antiarrhythmic agents, such as aprindine and nicainoprol, in the antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.

Animals↗
PubMed2005

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

OBJECTIVE: In 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. METHODS: Prescription 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. RESULTS: A 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. CONCLUSIONS: It 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.

Anti-Arrhythmia Agents↗
PubMed1980

Evaluation of antagonism of aconitine-induced dysrhythmias in mice as a method of detecting and assessing antidysrhythmic activity.

1 Antagonism of aconitine-induced dysrhythmias in mice as a method of detecting and assessing antidysrhythmia activity was evaluated. 2 Aconitine-induced dysrhythmias in mice appear to be selectively sensitive to antidysrhythmia agents (administered intraperitoneally) which reduce the inward sodium current in cardiac cells. 3 Antidysrhythmic agents whose mechanism of action is thought to depend on beta-adrenoceptor blockade, prolongation of cardiac monophasic action potentials or calcium antagonism are ineffective in delaying the onset of aconitine-induced dysrhythmias in mice. The inactive drugs were practolol, sotalol, bretylium, amiodarone and verapamil. 4 Comparisons of anti-dysrhythmic activities of test drugs should be based on more than one ED value and should take account of efficacy as well as potency. 5 The mouse aconitine test is a useful and rapid method of evaluating oral antidysrhythmic activity in terms of potency, efficacy and duration of action. 6 With respect to potency, efficacy, oral activity, duration of action and safety, 3 alpha-amino-5 alpha-androstan-2 beta-ol-17-one hydrochloride (Org 6001) offered the most satisfactory overall profile of the active drugs tested (Org 6001, aprindine, quinidine, disopyramide, lignocaine, mexiletine, procainamide and propranolol).

Aconitine↗