Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Procainamide”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,081 records · Page 60Linked to original sources
PubMed1998

Postrepolarization refractoriness versus conduction slowing caused by class I antiarrhythmic drugs: antiarrhythmic and proarrhythmic effects.

BACKGROUND: Conduction block may be both antiarrhythmic and proarrhythmic. Drug-induced postrepolarization refractoriness (PRR) may prevent premature excitation and tachyarrhythmia induction. The effects of propafenone and procainamide on these parameters, and their antiarrhythmic or proarrhythmic consequences, were investigated. METHODS AND RESULTS: In 11 isolated Langendorff-perfused rabbit hearts, monophasic action potentials (MAPs) were recorded simultaneously from six to seven different right and left ventricular sites, along with a volume-conducted ECG. All recordings were used to discern ventricular tachycardia (VT) or ventricular fibrillation (VF) induced by repetitive extrastimulation (S2-S5) or 10-second burst stimulation at 25 to 200 Hz at baseline and after addition of procainamide (20 micromol/L) or propafenone (1 micromol/L) to the perfusate. MAPs were analyzed for action potential duration at 90% repolarization (APD90), conduction times (CT) between the pacing site and the other MAPs, and PRR (effective refractory period-APD90=PRR) and related to the induction of VT or VF. During steady-state pacing, procainamide and propafenone prolonged APD90 by 12% and 14%, respectively. Procainamide slowed mean CT by 40% during S2-S5 pacing, whereas propafenone slowed mean CT by up to 400% (P<0.001 versus baseline and procainamide). Wavelength was not changed significantly by procainamide but was shortened fourfold by propafenone at S5. Both drugs produced PRR, which was associated with a 70% decrease in VF inducibility with procainamide and elimination of VF with propafenone. Despite this protection from VF, monomorphic VT was induced with propafenone in 57% of burst stimulations. CONCLUSIONS: Drug-induced PRR protects against VF induction. Propafenone promotes slow monomorphic VT, probably by use-dependent conduction slowing and wavelength shortening.

Action Potentials↗
PubMed1987

Chronic flecainide therapy selected by electrophysiology testing of intravenous flecainide.

The utility of flecainide acetate was evaluated in 93 patients by means of electrophysiologic studies before and after intravenous flecainide administration to determine long-term efficacy. Twenty patients had a prior history of at least one cardiac arrest and 73 patients had sustained ventricular tachycardia (VT). The mean radionuclear ejection fraction was 32 +/- 5%. Flecainide was evaluated in 93 patients, with 44 patients no longer having VT following flecainide (47% efficacy). Procainamide was evaluated in 69 patients; 24 patients had an adverse reaction to reaction to procainamide and 28 of the 69 patients were protected on procainamide (40% efficacy). The mean serum concentration of flecainide achieved in the protected group was 298 +/- 36 ng/ml and 4.3 micrograms/ml for procainamide. Both flecainide and procainamide significantly prolonged refractoriness, lengthened QRS duration, while only procainamide increased the QT interval. All 93 patients were discharged on antiarrhythmic therapy, 42 on flecainide, 27 on other antiarrhythmic therapy guided by electrophysiologic testing, and 24 on amiodarone (when all other agents failed). Six of the 42 patients on flecainide complained of adverse side effects, but none were severe enough to warrant stopping therapy. Of the 42 patients on flecainide, four (9%) died suddenly over 18 +/- 4 months. Twenty-seven patients were on other therapy; eight of these have died, three suddenly (11%), four with myocardial infarctions, and one due to congestive heart failure. Twenty-four patients started amiodarone; 11 have died, five (21%) suddenly, four of congestive heart failure, one of pulmonary fibrosis, and one with myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed2005

Intrapericardial drug delivery: pharmacologic properties and long-term safety in swine.

BACKGROUND: Intrapericardial drug delivery is a promising new technique, but the pharmacologic properties of various agents delivered via this route are not known. Furthermore, the long-term safety of intrapericardial catheters has not been previously examined. METHODS: Using a pericardial access device, a catheter connected to a drug-delivery system was implanted in five pigs. Plasma levels and electrocardiographic measurements were obtained after intravenous and intrapericardial administration of digoxin and procainamide. Histological examination was performed after the device had been implanted for a total of 6 months. RESULTS: The QTc interval did not change significantly after digoxin or procainamide intravenous administration. QTc decreased by 47+/-23 ms (p=0.046) 8 h after digoxin intrapericardial administration and increased by 128+/-60 ms (p=0.002) 1 h after procainamide intrapericardial administration. The QRS duration did not change significantly after intravenous administration of either agent, but it increased by 17+/-9 ms (p=0.004) 1 h and by 15+/-4 ms (p=0.01) 8 h after procainamide intrapericardial administration. After intravenous procainamide the RR interval decreased, but it did not change significantly after intrapericardial administration of either agent. Histology showed moderate inflammatory infiltration and fibrosis adjacent to the catheter. CONCLUSIONS: Intrapericardial delivery of digitalis and procainamide produces unique electrophysiological properties. In contrast to satisfactory success of the implantation technique, long-term dwell of the catheter in the pericardium induces moderate, albeit probably clinically significant, fibrosis.

Animals↗
PubMedDate not supplied

Clinical pharmacokinetics of N-acetylprocainamide.

Since N-acetylprocainamide was identified in the urine of patients receiving procainamide, this compound has been studied both as a metabolite of procainamide and as a separate antiarrhythmic agent. N-acetylprocainamide absorption following oral administration is more than 8-% complete. 59 to 89% of N-acetylprocainamide is excreted unchanged in the urine in subjects with normal renal function. Deacetylation of N-acetylprocainamide to procainamide is a minor route of N-acetylprocainamide elimination. The half-life of N-acetylprocainamide in patients with normal renal function has been reported to vary between 4.3 and 15.1 hours. Total body clearance (mean +/- SD) of N-acetylprocainamide in patients with normal renal function has been reported to range from 2.08 +/- 0.36 ml/min/kg to 3.28 +/- 0.52 ml/min/kg. There is a linear relationship between N-acetylprocainamide clearance and creatinine clearance. The half-life of N-acetylprocainamide in functionally anephric patients may be as long as 42 hours; however, it can be effectively cleared from plasma by haemodialysis. N-acetylprocainamide is 10% protein-bound. There is an age-related decline in N-acetylprocainamide clearance, mostly due to the decrease in creatinine clearance that occurs with ageing. In the neonate, the half-life of acetylprocainamide is prolonged. Several therapeutic trials carried out to assess the effectiveness of N-acetylprocainamide in suppressing chronic ventricular premature beats have now been reported. If there is a therapeutic response to N-acetylprocainamide it will probably occur at a plasma concentration between 15 and 25 micrograms/ml. A high degree of overlap has been reported between the concentration range associated with arrhythmic suppression and the range of concentrations where intolerable side effects begin to occur. No severe cardiac toxicity has been reported with oral therapy despite plasma concentrations as high as 40 micrograms/ml. However, hypotension has been reported in association with a rapid intravenous bolus of N-acetylprocainamide. A maximum intravenous infusion rate of 50 mg/min has been recommended. N-acetylprocainamide in patients receiving procainamide; however, N-acetylprocainamide concentrations remain below the therapeutic range in patients with normal renal function. In patients with renal failure receiving procainamide, N-acetylprocainamide concentrations rise dramatically. The dose of N-acetylprocainamide must be adjusted in patients with renal insufficiency, and it should be used more cautiously in the very old and very young. N-acetylprocainamide plasma concentration monitoring would be valuable clinically in patients with renal insufficiency receiving either N-acetylprocainamide or procainamide, and in the very young and the aged.

Acecainide↗
PubMed2005

Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs.

Exposing genetically predisposed individuals to certain environmental agents is believed to cause human lupus. How environmental agents interact with the host to cause lupus is poorly understood. Procainamide and hydralazine are drugs that cause lupus in genetically predisposed individuals. Understanding how these environmental agents cause lupus may indicate mechanisms relevant to the idiopathic disease. Abnormal T cell DNA methylation, a repressive epigenetic DNA modification, is implicated in procainamide and hydralazine induced lupus, as well as idiopathic lupus. Procainamide is a competitive DNA methyltransferase (Dnmt) inhibitor, hydralazine inhibits ERK pathway signaling thereby decreasing Dnmt expression, and in lupus T cells decreased ERK pathway signaling causing a similar Dnmt decrease. T cells treated with procainamide, hydralazine, and other Dnmt and ERK pathway inhibitors cause lupus in mice. Whether the same genetic regulatory elements demethylate in T cells treated with Dnmt inhibitors, ERK pathway inhibitors, and in human lupus is unknown. CD70 (TNFSF7) is a B cell costimulatory molecule overexpressed on CD4(+) lupus T cells as well as procainamide and hydralazine treated T cells, and contributes to excessive B cell stimulation in vitro and in lupus. In this report we identify a genetic element that suppresses CD70 expression when methylated, and which demethylates in lupus and in T cells treated with Dnmt and ERK pathway inhibitors including procainamide and hydralazine. The results support a model in which demethylation of specific genetic elements in T cells, caused by decreasing Dnmt expression or inhibiting its function, contributes to drug-induced and idiopathic lupus through altered gene expression.

5' Flanking Region↗
PubMed1984

Effects of 4 antiarrhythmic drugs on sinoatrial conduction time in isolated and blood-perfused dog atria.

We examined the effects of four antiarrhythmic drugs (quinidine, disopyramide, procainamide and propranolol) on sinus cycle length (SCL), sinoatrial conduction time (SACT) measured by a constant atrial pacing technique, and atrial developed tension (DT), using isolated blood-perfused dog atrial preparations. When an infusion rate of 10-40 micrograms/min of quinidine, disopyramide or procainamide was continuously given into the sinus node artery and propranolol at a rate of 1-4 micrograms/min, all the agents prolonged SCL and SACT, and reduced DT dose-dependently, but not in the same fashion. Propranolol caused almost a parallel action in prolongation of SCL and SACT, and reduction of DT in increasing doses. Quinidine, disopyramide and procainamide caused negative inotropic and chronotropic effects with only a small prolongation of SACT in a relatively small dose. At larger doses, quinidine and disopyramide produced a relatively more marked prolongation of SACT than procainamide. In the doses used, quinidine, disopyramide and procainamide caused relatively small depression of DT in contrast to propranolol. The order of potencies for inducing a prolongation of SACT was propranolol greater than quinidine = disopyramide greater than procainamide.

Animals↗
PubMed1998

Effects of class I and III antiarrhythmic drugs on ventricular tachycardia-interrupting critical paced cycle length with rapid pacing.

The most common mechanism of sustained ventricular tachycardia (VT) is re-entry with an excitable gap, but the electrophysiologic properties and response to antiarrhythmic drugs in the area of slow conduction are not yet fully known. The purpose of this study was to assess the effects of a class I antiarrhythmic drug (procainamide) and class III agents (amiodarone, E-4031, and MS-551) on re-entrant VT using the width of the zone of entrainment. The cycle length (CL) of VT (VTCL), the block CL that was the longest paced CL that interrupted the VT, and the width of the zone of entrainment, defined as the difference between VTCL and block CL, were compared before and after treatment with antiarrhythmic drugs. The VTCL was prolonged significantly from 308+/-63 to 410+/-77 msec after procainamide (p<0.005) but was not changed after the administration of the class III agents: from 294+/-50 to 292+/-13 msec after amiodarone, and from 305+/-47 to 313+/-31 msec after E-4031 or MS-551 (p=NS). The block CL was prolonged from 255+/-61 to 331+/-70 msec after procainamide (p <0.01), from 256+/-20 to 260+/-25 msec after amiodarone, and unchanged after E-4031 or MS-551 (253+/-31 msec before and 270+/-43 msec after) (p=NS). The width of the zone of entrainment as a representative of the width of the excitable gap was changed from 52+/-26 to 79+/-35 msec (p<0.05) after procainamide, whereas it was unchanged after amiodarone (48+/-7 msec before and 43+/-7 msec after) and after E-4031 or MS-551 (50+/-10 msec before and 40+/-9 msec after). Therefore, amiodarone, E-4031, and MS-551 did not affect VTCL and block CL whereas procainamide increased these parameters. The excitable gap substituting as the zone of entrainment was increased by procainamide but slightly reduced by amiodarone, E-4031, and MS-551. The effects of these antiarrhythmic drugs on the excitable gap of re-entrant VT were variable and should be examined further.

Adolescent↗
PubMed1986

Effects of lupus-inducing drugs on the B to Z transition of synthetic DNA.

Five drugs associated with systemic lupus erythematosus were studied for their effect on the salt-induced right-handed (B) to left-handed (Z) transition of poly(dG-me5dC) X poly(dG-me5dC). Using circular dichroism spectroscopy, procainamide and hydralazine were found to reduce the midpoint of B to Z transition from 0.8M NaCl to 0.5M NaCl and to increase the rate of this transition at 1M NaCl. Isoniazid and D-penicillamine had less effect on the midpoint of transition and practically no effect on the kinetics. N-acetyl procainamide (a structurally related control for procainamide) and L-canavanine had no effect. Procainamide caused slight reduction in the helix-coil transition (melting) temperature of calf thymus DNA. At a concentration of 1:1 (DNA phosphate:drug ratio), procainamide and hydralazine also caused the aggregation of calf thymus DNA. Since altered DNA conformations, such as Z-DNA, are more immunogenic, these results suggest that the induction or stabilization of Z-DNA by these drugs might be important in the pathogenesis of at least some cases of systemic lupus erythematosus.

Canavanine↗
PubMedDate not supplied

Effective use of magnesium for acquired torsade de pointes in a 4-month-old infant.

We report a 4-month-old infant with torsade de pointes secondary to procainamide treatment. The infant presented with atrial flutter and converted to normal sinus rhythm with intravenous procainamide. Oral procainamide therapy was initiated as the infusion was tapered, and the patient subsequently developed incessant torsade de pointes. Once the proarrhythmia was recognized, procainamide was withheld, and intravenous magnesium was administered. The torsade de pointes resolved after one bolus of magnesium sulfate. An infusion regimen of magnesium was given until the procainamide and N-acetylprocainamide concentrations became undetectable. Intravenous magnesium should be administered to newborns with acquired torsade de pointes; dosing guidelines for its use are suggested.

Amiodarone↗
PubMed1982

Termination of ventricular tachycardia: role of tachycardia cycle length.

The mode of termination of ventricular tachycardia (VT) and its relation to tachycardia cycle length was evaluated in 139 patients. Tachycardia was terminated by programmed stimulation in 110 patients (79%) and cardioversion was required in 29 patients (21%). Single, double, and triple ventricular extrastimuli terminated the tachycardia in 23 of 85 (27%), 39 of 62 (63%), and 7 of 16 patients (44%), respectively. In all patients requiring 1 extrastimulus, in 35 patients (90%) requiring 2 extrastimuli, and in 6 patients (86%) requiring 3 extrastimuli, the tachycardia cycle length exceeded 300 ms. Rapid ventricular pacing terminated tachycardia in 41 of 54 patients (76%). In 21 (51%) of these patients the tachycardia cycle length exceeded 300 ms. However, rapid ventricular pacing caused acceleration of the arrhythmia in 19 patients (35%). The ability of procainamide to modify the termination of VT was studied in 23 patients. In 7 of these patients (30%) procainamide increased the tachycardia cycle length by 49 +/- 42 ms (p less than 0.01) and did not modify the mode of termination. In 6 patients (26%) procainamide increased cycle length by 142 +/- 108 ms (p less than 0.01), but termination was more difficult. In 10 patients (44%) procainamide increased the cycle length by 138 +/- 110 ms (p less than 0.001) and termination was easier. We conclude that termination of VT by timed extrastimuli requires a tachycardia cycle length longer than 300 ms. Rapid pacing or cardioversion is usually required when the cycle length is less than 300 ms. Although procainamide slows tachycardia, it can unpredictably make termination more difficult in 1 of 4 patients.

Adolescent↗
PubMed1977

Antiarrhythmic and electrophysiological effects of CH-200.

A new antiarrhythmic drug CH-200, 5-phenacyl-thieno[3,2-c]yridinium, was compared with procainamide and lidocaine in a two-stage coronary ligation arrhythmia model for its efficacy and electrophysiological properties. CH-200 suppressed arrhythmia in beagle dogs more effectively than did procainamide and lidocaine. The antiarrhythmic effects of CH-200 and procainamide developed slowly and lasted longer than those of lidocaine. Electrophysiological studies with CH-200 showed that it decreased max dV/dt of the action potential. This effect was dependent on the heart rate: the higher the rate, the stronger the effect. CH-200, procainamide and lidocaine prolonged the effective refractory period and this effect seemed to be responsible for suppressing the arrhythmia after coronary ligation. CH-200 and procainamide increased the frequency of ventricular pacemaker activity, while lidocaine decreased it. These effects appear to be unimportant for the antiarrhythmic effects.

Acetophenones↗
PubMed1999

Modified polypeptides containing gamma-benzyl glutamic acid as drug delivery platforms.

We previously reported the development of diffusion-controlled biodegradable polypeptides for drug delivery purposes. In this paper, we describe the synthesis of three modified polypeptides that contain gamma-benzyl glutamic acid as the common structural backbone. The properties of these polymers were characterized with regard to their potential application as drug delivery platforms. Procainamide hydrochloride, a hydrophilic drug, and protamine sulfate, a low molecular weight protein, were used as model drugs for examining release rate profiles from these polymers. The homopolymer of poly(gamma-benzyl-L-glutamic acid), PBLG, showed a highly helical configuration and a moderate release rate of procainamide. Modification of structural attributes by random copolymerization of the D- and L- isomers of gamma-benzyl glutamic acid produced poly(gamma-benzyl-D,L-glutamic acid), PBDLG, which displayed a significantly slower release of procainamide when compared to PBLG. The modification of polymer bulk hydrophobicity by copolymerization of PBLG (A) with poly(ethylene glycol) (B) yielded an ABA triblock copolymer exhibiting much faster release rates for both procainamide and protamine than those demonstrated by the other two polymers. Using this triblock copolymer, protamine release rates ranging from 2 weeks to approximately 2 months were obtained by simply varying the polymer processing conditions and protein particle size. A nearly complete release of protein was obtained from the triblock copolymer blends and this occurred without reliance upon degradation of the polymer backbone. Fickian diffusion-controlled release mechanisms were implied for release of procainamide and protamine from these polypeptide formulations based on the linear relationship displayed between cumulative drug release and the square root of time.

Chemistry, Pharmaceutical↗
PubMed1992

Prediction of antiarrhythmic efficacy of class I and III agents in patients with ventricular tachycardia by signal-averaged ECG analysis.

The effects of procainamide and dofetilide (pure Class III antiarrhythmic agent) on the signal-averaged ECG (SAECG) were examined in relation to the results of programmed ventricular stimulation studies in 25 patients with inducible sustained monomorphic ventricular tachycardia. Procainamide prolonged significantly the total QRS and low amplitude signal durations (140 +/- 31 msec vs 166 +/- 48 msec, P < 0.0001; 50 +/- 25 msec vs 65 +/- 38 msec, P < 0.002, respectively) whereas the root mean square voltage of the last 40 msec of the QRS complex was significantly reduced (22 +/- 21 microV vs 13 +/- 12 microV, P < 0.006). Procainamide was effective (prevention of the inducibility of sustained ventricular tachycardia or prolongation of the cycle length of ventricular tachycardia by > 100 msec) in 15 of 27 drug trials. Of the procainamide induced SAECG changes, the fractional prolongation of the total QRS duration was the best parameter that identified effectively treated patients (24% +/- 16% in responders vs 10% +/- 11% in nonresponders, P < 0.014). A fractional prolongation of the total QRS duration by > 15% identified effectively treated patients with a sensitivity of 87%, specificity of 81%, and an overall predictive accuracy of 84%. Dofetilide did not change the SAECG, and no SAECG parameter predicted the results of programmed ventricular stimulation. The effects of both drugs on the spectral analysis (area ratios) and on the spectral temporal mapping (the values of normality factor) of the SAECG were not consistent. In conclusion, antiarrhythmic efficacy of procainamide can be predicted by the degree of drug induced prolongation of the signal-averaged QRS complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1982

Interaction between drug acetylation and ethanol, acetate, pyruvate, citrate, and L(-) carnitine in isolated rat liver parenchymal cells.

The acetylation of sulfanilamide and procainamide in suspensions of isolated rat parenchymal cells was studied in absence and presence of ethanol (33mM), citrate (4 mM), pyruvate (4 mM), and L(-)carnitine (2 mM). Ethanol treatment enhanced the sulfanilamide acetylation whereas the acetylation of procainamide was considered to be unchanged. Acetate (1-5 mM), citrate, and pyruvate treatment enhanced the acetylation of both sulfanilamide and procainamide. Acetate (4 mM) increased both Km and Vmax of both sulfanilamide and procainamide acetylation. Combined treatment with L(-)carnitine and either acetate, pyruvate, or citrate enhanced the acetylation rate of sulfanilamide more than acetate, pyruvate, or citrate, respectively alone. In cell suspensions treated with L(-) carnitine and acetate or pyruvate, the acetylation kinetics of sulfanilamide changed from zero-to apparent first-order. With procainamide as test drug, a further increase of the acetylation rate was found when L(-) carnitine was added to citrate pyruvate. Acetyl-CoA increased the rate of sulfanilamide acetylation in rat liver homogenates in a dose dependent manner.

Acetates↗
PubMed1970

Direct current shock and antidysrhythmic drugs.

A review is given of 457 episodes of atrial fibrillation that occurred in 318 patients and were treated by DC shock. Antidysrhythmic drugs, such as quinidine, procainamide, and propranolol, given singly or in combination, were used concomitantly in 389 instances, and DC shock alone was given in 68 instances. The combined effects of quinidine and DC shock, and of procainamide and DC shock were studied in the experimental animal.Combined DC shock and drug therapy gave a higher conversion rate than DC shock alone, and a statistically significant difference was found in respect of the group of patients receiving procainamide and propranolol together (p<0.01). Antidysrhythmic drugs failed on the whole to reduce the incidence of DC shock-induced dysrhythmias. However, the incidence of certain digitalis and DC shock-induced dysrhythmias was significantly less when propranolol and procainamide were given as pretreatment than when procainamide or quinidine was given alone (p<0.01). In animal experiments, quinidine had no protective action against digitalis and DC shock-induced ectopic tachycardias. Clinical and experimental observations suggest that the cardiotoxicity of these drugs may be enhanced by DC shock. Immediate or delayed post-shock rhythm disorders can be drug related and, therefore, great caution should be exercised in the use of antidysrhythmic drugs in conjunction with DC shock therapy.

Animals↗
PubMed1989

Drug-induced immune-complex disease.

A range of drugs including hydralazine, isoniazid, procainamide and penicillamine cause toxic side effects which resemble systemic lupus erythematosus (SLE). Deficiencies of C1, C4 and C2 are associated with idiopathic SLE, and these defects may compromise the ability of the patient to deal with immune complexes. Immune complexes with protein as antigen, such as has been reported to be diagnostic of procainamide-induced SLE, interact more with the C4A isotype of C4 than the C4B isotype. It is shown that hydralazine, isoniazid and penicillamine inhibit the covalent binding of C4 to a complement-activating surface and that the drugs themselves become covalently bound to C4. For each of these drugs, C4A is inhibited more than C4B, and it is suggested that this is an important contributory factor in the development of the toxic side effects to these drugs involving immune-complex deposition. For procainamide, it is shown that the hydroxylamine metabolite rather than the drug itself inhibits the covalent binding reaction of C4. Hydralazine, isoniazid and procainamide are metabolised by the polymorphic N-acetyltransferase, and slow acetylators are at increased risk of drug-induced lupus. For procainamide, oxidation to the hydroxylamine form is an alternative metabolic route of increased importance in slow acetylators, and it is suggested that investigation of C4 type in susceptible patients could provide a means of identifying those at greatest risk of immunotoxicity.

Humans↗
PubMed1993

Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness.

BACKGROUND: Antiarrhythmic drugs are considered to terminate atrial fibrillation by prolonging refractoriness, but direct experimental evaluation of this concept has been limited. The atria are activated rapidly during atrial fibrillation, and antiarrhythmic drugs are known to have important rate-dependent actions. The potential role of such properties in determining drug effects during atrial fibrillation has not been evaluated. METHODS AND RESULTS: We evaluated the effects of representative class Ia (procainamide), Ic (propafenone), and III (sotalol) antiarrhythmic drugs on sustained cholinergic atrial fibrillation and atrial electrophysiological properties in anesthetized, open-chest dogs. Loading and maintenance doses were used to produce stable plasma concentrations, and computer-based 112-electrode epicardial mapping was used to study atrial conduction and activation during atrial fibrillation. Clinically used doses of procainamide and propafenone terminated atrial fibrillation in 13 of 13 (100%) and 7 of 10 (70%) dogs, respectively, but a dose of sotalol (2 mg/kg IV) in the clinical range terminated atrial fibrillation in only 2 of 8 (25%) dogs (P = .0005 vs procainamide, P = .08 vs propafenone). Procainamide and propafenone prevented atrial fibrillation induction in 13 of 13 (100%) and 7 of 10 (70%) dogs, respectively, compared with none of 8 dogs for 2 mg/kg sotalol (P < .0001 vs procainamide, P = .004 vs propafenone). A larger dose of sotalol (cumulative dose, 8 mg/kg) was uniformly effective in terminating atrial fibrillation and preventing its induction. All drugs significantly increased atrial refractory period, with effects that were use dependent for propafenone but reverse use dependent for sotalol. Effective doses of all drugs significantly increased the wavelength for reentry at rapid atrial rates in the presence of vagal stimulation into the range observed under drug-free conditions in the absence of vagal input. The inefficacy of clinical doses of sotalol was explained by the reverse use dependence of its effects on refractoriness, which resulted in reduced effects on wavelength at rapid rates. The effects of propafenone on refractoriness were significantly increased at rapid rates, contributing to its ability to increase wavelength and terminate atrial fibrillation. Activation mapping showed that drugs terminated atrial fibrillation by reducing the number and increasing the size of reentry circuits, leading to termination by mechanisms related to block in the remaining circuit(s). CONCLUSIONS: We conclude that antiarrhythmic drugs terminate experimental atrial fibrillation by increasing the wavelength for reentry at rapid rates, leading to a reduction in the number of functional reentry circuits and, eventually, failure of reentrant excitation. Use-dependent effects on refractoriness can limit (in the case of the reverse use dependence of sotalol) or contribute (in the case of propafenone) to antiarrhythmic drug efficacy against atrial fibrillation by determining drug-induced changes in wavelength at rapid atrial rates.

Animals↗
PubMed1998

[Study on the combined therapy of DNA-methyltransferase inhibitor and interferon-alpha/beta for mouse spontaneously arose renal cell carcinoma, and immunological mechanism induced by the therapy].

BACKGROUND: In order to change the immunological environment of T-helper2 (Th2) predominance, namely humoural immunity, in renal cell carcinoma, we tried to examine the efficacy of combined treatment with DNA-methyltransferase inhibitor (Procainamide) and interferon (IFN)-alpha/beta in basic experiments, and also examined the immunological mechanism induced by this treatment modality. MATERIALS AND METHODS: The monotherapy of Procainamide (10 mg/kg, 20 mg/kg, 30 mg/kg, everyday for 3 weeks, i.p.) and of natural murine IFN-alpha/beta (1 x 10(4) I.U./mouse, 3 times for a week, total 9 times, s.c.), and combined treatment with these 2 drugs for mouse spontaneously arose renal cell carcinoma (RC-2) were undertaken. Furthermore, we examined the expression of cytokine mRNA related to the Th-subset in murine spleen under the tumour burden by the RT-PCR methods. RESULTS: 1) Regarding the anti-tumour efficacy of two kinds of monotherapy (Procainamide and IFN-alpha/beta), no effective result was obtained. On the other hand, the combined treatment with these two drugs induced effective anti-tumour efficacy in the relative mean tumour weight ratio (TRW/CRW), mean tumour weight and the survival rate compared with the control and each monotherapy, especially in the administration of Procainamide dosed at 30 mg/kg. As to the histological degeneration induced by the combined therapy, there still remained the viable tumour cells (grade IIb). 2) In an effort to analyse the immunological changes induced by the administration of Procainamide, there observed the expression of Th1-derived cytokines mRNA such as IFN-gamma, IL-2 and tumour necrosis factor-beta, and except for interleukin (IL)-10, there also observed the disappearance of Th2-derived cytokines mRNA such as IL-4, IL-5 and IL-6 in the murine spleen. CONCLUSION: We draw the conclusion that the treatment with DNA-methyltransferase inhibitor may change the humoural immunological environment into the cellular immunological environment enabling the effective anti-tumour efficacy combined with IFN-alpha/beta in renal cell carcinoma.

Animals↗