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In conclusion, it was the differential responses of slow and rapid acetylators to procainamide therapy that gave the initial clues that acetylprocainamide might be a safer drug than procainamide. So far, the experience with acetylprocainamide has been encouraging.
BACKGROUND: A delay in the recovery of effective mechanical atrial function after cardioversion for atrial fibrillation can predispose to thromboembolism. The aim of the present study was to assess the influence of clinical and echocardiographic parameters on the recovery of left atrial contraction after cardioversion of atrial fibrillation. METHODS: One hundred and 36 consecutive patients were evaluated and 80 were randomly cardioverted using either DC shock or i.v. procainamide. Patients who recovered sinus rhythm (26 patients treated with procainamide and 39 patients cardioverted with DC shock) underwent a complete Doppler echocardiographic examination 1 hour after the restoration of sinus rhythm and after 1 and 7 days and 1, 3, and 6 months. The following parameters were evaluated: age, underlying cardiac disease, duration and etiology of atrial fibrillation, mode of cardioversion, left ventricular diameters and function, left atrial diameters and function, assessed as atrial ejection force. The relation between these variables and atrial ejection force was tested. RESULTS: Atrial ejection force was greater immediately and at 24 hours after cardioversion in patients who underwent pharmacological therapy compared to patients treated with DC shock. In all groups atrial ejection force increased over time. The mode of cardioversion was significantly associated with the recovery of left atrial mechanical function by day 1 in univariate and multivariate analyses (odds ratio 0.14, 95% confidence interval 0.03-1.6). The other variable associated with atrial ejection force was left atrial size (odds ratio 0.15, 95% confidence interval 0.17-1.9). CONCLUSIONS: Atrial ejection force can be easily measured after cardioversion to obtain accurate information about the recovery of left atrial mechanical function. In the present study the recovery of left atrial function was influenced by the mode of cardioversion and left atrial size.
The management of arrhythmias during pregnancy is, in principle, similar to that in nonpregnant patients, however, special consideration must be given, to avoid adverse fetal effects. In pregnant women without organic heart disease, no drug therapy is usually needed for the management of supraventricular or ventricular premature beats, but potential stimulants, such as smoking, caffeine, and alcohol should be eliminated. In patients with mitral valve prolapse beta blocker may be preferred drug. In pregnant patients with organic heart disease, paroxysmal atrial or ventricular tachycardia may induce hemodynamic changes with consequences to the fetus. In paroxysmal atrial tachycardia vagal stimulation maneuvers should tried and, if this is not effective, adenosine or beta-adrenergic blocking agents should be used. Alternatively, verapamil may be given. In pregnant with atrial fibrillation, the goal of treatment is conversion to sinus rhythm or control of the ventricular rate by digoxin. Synchronized electrical cardioversion may become necessary when signs of cardiac decompensation or hypotension were developed. Ventricular arrhythmias may occur in the pregnant women with cardiomyopathy, valvular heart disease, mitral valve prolapse and congenital Q-T prolongation. Termination of ventricular arrhythmias can usually be achieved by intravenous lignocaine or procainamide or by electrical cardioversion. To prevent recurrences, quinidine can be used if the arrhythmia was not induced by QT prolongation or procainamide.
To be positively selected, immature thymocytes must receive signaling through their T-cell receptor (TCR), and engagement of relatively low-affinity self-peptides permits further T-cell maturation. However, mature T cells no longer overtly respond to such low-affinity antigens, indicating that T cells acquire a higher threshold for activation during thymopoiesis. We wondered whether partial interference in positive selection could produce T cells that respond to the selecting self-peptide. This possibility was tested by injecting procainamide-hydroxylamine (PAHA), a lupus-inducing drug, into the thymus of adult normal mice. Three weeks after the second injection, IgG antichromatin antibodies appeared in the circulation and remained for several months. The murine antichromatin antibodies reacted with the (H2A-H2B)-DNA subnucleosome complex, the predominant specificity in patients with procainamide-induced lupus. In thymus organ and reaggregate cultures, PAHA had no effect on negative selection of T cells with high affinity for a co-present antigen, but acted on CD4+ CD8+ immature T cells as they underwent positive selection. TCR transgenic T cells specific to cytochrome c peptide 88-104 acquired the capacity to respond to the low-affinity analogue at position 99 (lys-->ala) if PAHA was present during their development. PAHA also blocked the capacity of a T-cell line to become anergic after anti-CD3 treatment, suggesting that PAHA prevents the production of negative regulators that accumulate in response to partial signaling through the TCR. These results are consistent with the view that T cells acquire self-tolerance during positive selection, and disruption of this process can result in autoreactive T cells and systemic autoimmunity.
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease affecting a variety of tissues and organs. The diagnosis of SLE can be made only after several related illnesses are considered and ruled out. The etiology of SLE is unclear, but hormonal factors, environmental toxins, infectious viruses, genetic predisposition, and certain medications have all been considered risk factors. Idiopathic SLE is seen predominantly in young women, with a female:male ratio of approximately 10:1. Each patient is unique and may suffer from a variety of signs and symptoms. The disease is highly unpredictable, and most patients experience flare-ups or fluctuations. The epidemiologic characteristics of medication-induced SLE (MI-SLE) are different from those of idiopathic SLE. Musculoskeletal symptoms predominate the clinical presentation of MI-SLE, while renal and central nervous system involvement is rare or absent. Moreover, a greater percentage of caucasian patients with no female predominance is evidenced in MI-SLE. Several medications can produce positive results on an antinuclear antibody test with or without evidence of clinical lupus. Hydralazine and procainamide are the most commonly recognized medications for inducing SLE. The onset of procainamide- and hydralazine-induced SLE occurs after 50 years of age, which is directly related to the age of the population using these medications. Estrogen-containing oral contraceptives and ibuprofen can exacerbate the symptoms of idiopathic SLE. Clinical judgment dictates the importance of careful patient monitoring and selection of therapy.
In experimental work, three groups of 10 dogs each were subjected to ligation of the circumflex coronary artery. One group was given prophylactic medication with procainamide and another group was allowed a 2 hour interval between thoracotomy and ligation. The effects of these measures on the incidence of ventricular arrhythmias during the 30 minutes immediately after coronary artery occlusion were then compared. The two groups of animals on which these preventive measures were tested both showed a significant reduction in incidence of arrhythmias as compared to the control group. The therapeutic use of procainamide was also assessed by administering the drug intravenously to all animals developing postligation arrhythmias in the two groups which were not prophylactically medicated. In 46 per cent of these cases, the arrhythmias were suppressed and threatened ventricular fibrillation was obviated.
The antinociceptive effect of subcortically administered nicotine was investigated in the rat using the hot-plate and tail-flick tests. Adult male Sprague-Dawley rats were implanted with guide cannulas aimed at 185 sites in the forebrain, midbrain and hindbrain. After 1 week, nicotine was injected in 0.5 microliter of 50 mM phosphate buffer, pH 7.4. The pedunculopontine tegmental nucleus (PPTg) of the mesopontine tegmentum and the nucleus raphe magnus (NRM) of the ventral medulla were the most sensitive sites of nicotine-induced antinociception. The median effective doses of nicotine to inhibit hot-plate or tail-flick nociception after PPTg or NRM administration ranged between 1.4 and 3 nmol. The lack of effect of s.c. injections of naloxone on the antinociception induced by nicotine in the PPTg or NRM ruled out endogenous opioid mechanisms. Coadministration of mecamylamine or pirenzepine with nicotine into the NRM competitively antagonized nicotine-induced antinociception. The administration of the muscurinic cholinergic type 2 receptor antagonist methoctramine into the NRM produced a strong antinociceptive response which was blocked by prior treatment of the NRM with hemicholinium-3. Hemicholinium-3 pretreatment of either the PPTg or the NRM antagonized the antinociception induced by nicotine at these sites. Hemicholinium-3 pretreatment of the NRM also antagonized the antinociception produced by s.c. administered nicotine. The antinociceptive effects of nicotine injected in the PPTg were blocked by procainamide injections in the NRM; however, the antinociceptive effects of nicotine injected in the NRM were not blocked by bilateral injections of procainamide in the PPTg. Both lesioning the PPTg with ibotenic acid and pretreating the NRM with hemicholinium-3 abolished completely the antinociception induced by nicotine or (+)-cis-dioxolane microinjections into the PPTg. However, neither ibotenic acid-induced nor electrolytic lesions of the PPTg alone altered CRL. The data support the existence of a tonically active cholinergic pathway which is under autoinhibitory control that originates in the PPTg, terminates in the NRM and modulates nociception by activating descending pain inhibitory systems relaying within the NRM.
The effects of berbamine (Ber, 10 mg.kg-1 iv) on ischemic ventricular tachyarrhythmia and electrophysiologic consequences in both normal and ischemic myocardia were studied in the open-chest dogs subjected to programmed electrical stimulation (PES) on 5-8 d after acute myocardial infarction. Its effects were compared with procainamide's (PA). Both drugs distinctly lengthened the QTc interval and the effective refractory period (ERP) of normal and infarct ventricular myocardium, decreased the dispersion of ERP in infarct myocardium (IDR) and the dispersion of ERP in left ventricle (VDR), and increased the diastolic excitability threshold (DET) of normal and infarct ventricular myocardium remarkably. The PES-induced ventricular tachycardia (VT) or ventricular fibrillation (VF) was prevented in 5 out of 6 dogs treated with berbamine and procainamide respectively. (Normal saline did not prevent PES-induced VT or VF). The results suggest that berbamine may be effective in preventing the onset of reentrant ventricular tachyarrhythmia after myocardial ischemic damage.
Atrial flutter (AF) is a potentially dangerous arrhythmia in children, which is difficult to be converted into sinus rhythm by drug therapy alone. In four young patients (3 had history of cardiac surgery, 1 had Ebstein's anomaly), the AF which had failed to medical therapy was converted into sinus rhythm by an intracardiac atrial pacing: In two patients the AF was terminated by atrial pacing alone, and in the other two the AF was converted into sinus rhythm by atrial pacing after procainamide infusion. In all patients an entrainment of AF was observed during the atrial pacing, which favored a reentrant mechanism for the AF in these patients. Evidences of sinus node dysfunction were observed in all three postoperative patients. We conclude that atrial pacing with or without procainamide infusion is an effective method for the conversion of atrial flutter. In addition, for patients with AF and concomitant sinus node dysfunction, this method can ensure the patients' safetiness.
Three patients who developed torsade de pointes associated with antiarrhythmic or psychotropic drugs are described, and the electrocardiographic characteristics, clinical presentation, predisposing factors, and management of this form of ventricular tachycardia are reviewed. The first patient was a 56-year-old schizophrenic man receiving thioridazine hydrochloride, trifluoperazine hydrochloride, and benztropine mesylate who was admitted to a hospital after a syncopal episode. Subsequently, the patient experienced several episodes of ventricular tachycardia combined with multifocal premature ventricular contractions (PVCs) and torsade de pointes; the arrhythmias were attributed to antipsychotic therapy. The second patient was a 69-year-old man who experienced ventricular tachycardia that progressed to ventricular fibrillation 41 days after surgery. Quinidine sulfate probably induced the ventricular tachycardia, which was identified as torsade de pointes. The third patient was a 71-year-old man admitted to the hospital for treatment of refractory ventricular arrhythmias. Previous drug therapy with quinidine sulfate and procainamide hydrochloride had been associated with torsade de pointes. Despite unsuccessful treatment of ventricular ectopy, the patient was discharged on maintenance therapy with pindolol, topical nitrates, and phenytoin. No additional episodes of torsade de pointes have been observed. Torsade de pointes is characterized by polymorphous electrocardiographic appearance and delayed repolarization (prolonged QT interval). It may occur in association with a number of disease states and also as a complication of treatment with therapeutic doses of drugs that affect repolarization (quinidine, disopyramide, procainamide, and phenothiazines). Clinical outcomes range from asymptomatic, self-terminating arrhythmias to ventricular fibrillation resulting in cardiac arrest. The definitive emergency therapy for torsade de pointes is overdrive pacing; cautious isoproterenol administration can also be used. Lidocaine and bretylium are often ineffective in treating this form of ventricular tachycardia. Potassium and magnesium repletion appear to be essential in abolishing drug-induced torsade de pointes. Drug-induced torsade de pointes is best prevented by avoiding agents known to induce arrhythmias in patients with a pre-existing prolonged QT interval. Periodic serum electrolyte assessment is warranted, and new drugs that prolong the QT interval should be considered potential causative agents of torsade de pointes.
Antiarrhythmic properties of N-acetylprocainamide, an active metabolite of procainamide, were studied in 15 patients who presented with a cardiac arrest or documented sustained ventricular tachycardia. Programmed electrical stimulation studies were performed. All patients tested had inducible ventricular tachycardia by programmed electrical stimulation techniques while off all antiarrhythmic therapy. Patients were then tested on procainamide 1000 mg administered intravenously, and ventricular tachycardia could be provoked in 8 of 10 patients. Twenty-four to 36 hours later, N-acetylprocainamide was administered, intravenously, and programmed stimulation was performed after 20 minutes. N-acetylprocainamide did not significantly change heart rate, mean arterial blood pressure, electrocardiographic intervals, A-H or H-V conduction times. N-acetylprocainamide prevented ventricular tachycardia induction in 6 of 15 patients. The mean serum N-acetylprocainamide levels in the group protected was 15.7 +/- 4 micrograms/ml and 16.2 +/- 4 micrograms/ml in the group not protected. These 6 patients were discharged on N-acetylprocainamide 1.5 grams orally every 8 hours. Three patients have been maintained on chronic N-acetylprocainamide every 8 hours. Three patients have been maintained on chronic N-acetylprocainamide therapy (6 +/- 2 months), two patients had breakthrough ventricular tachycardia on follow-up Holter monitoring and alternative therapy was given. N-acetylprocainamide has antiarrhythmic efficacy in preventing induction of ventricular tachycardia by programmed electrical stimulation in a high risk group of patients. On chronic oral therapy, N-acetylprocainamide appears to be well tolerated with antiarrhythmic efficacy that may be enhanced with further upward dose titration.
Michaelis-Menten constants for two in vivo monomorphically N-acetylated substrates, p-aminobenzoic acid and p-aminosalicylic acid, and two in vivo polymorphically N-acetylated substrates, sulfamethazine and procainamide, were determined with an improved assay procedure using liver N-acetyltransferase from rapid and slow acetylator rabbit. The slow rabbit liver isozyme proves to be a Vmax and a Km variant for p-aminobenzoic acid and p-aminosalicylic acid. Mean differences in the apparent Vmax for rapid acetylators were 39-fold greater for p-aminobenzoic acid and 16-fold greater for p-aminosalicylic acid. The apparent Km values for the slow acetylator enzyme were lower than 5 microM, whereas the apparent Km values for the rapid acetylator phenotype were at least 15 times higher, with a value of 105 +/- 21 microM for p-aminobenzoic acid and 74 +/- 16 microM for p-aminosalicylic acid. In contrast, for the polymorphic substrates, sulfamethazine and procainamide, rapid rabbit liver N-acetyltransferase was only a Vmax variant with a mean specific activity that was 13-fold higher than that for slow acetylator.
Administration of triiodothyroacetic acid (triac) to pregnant rats produces cardiac hypertrophy and myofibrillar disarray in the hearts of the newborn offspring. Previous experiments have shown that concurrent administration of dl exprenolol or dl or d propranolol prevent the disarray but not the hypertrophy, suggesting that membrane stabilization and not beta-adrenergic blockade may be responsible for modifying the actions of triac. In order to clarify this, further experiments have been carried out whereby timolol, a beta-blocking agent with minimal or no membrane stabilizing activity, and procainamide, a pure membrane stabilizing compound, have been administered with triac. Timolol had no effect, but procainamide reduced the level of disarray and the hypertrophy to a minor degree. The results have thus confirmed the proposal that membrane stabilization is of major importance in modifying the actions of triac.
Derivation of standard curves for the EMIT therapeutic drug monitoring system involves several mathematical algorithms, all of which can be rewritten in the form of a linear equation y = mx + b. We examined the stability of the standard curve in terms of slope and y-intercept for three drug assays (procainamide, gentamicin, and carbamazepine) by generating calibration curves intermittently for periods as long as 90 days. Controls at three concentrations were assayed after each calibration to validate the standard curves. On the basis of 98% confidence intervals, the slopes of standard curves for procainamide, gentamicin, and carbamazepine were stable for 89, 80, and 57 days, respectively. Control values generated from standard-curve manipulations (adjustments to the y-intercept) indicated consistent accuracy and precision throughout the entire study, as compared with control values determined after each calibration. The increased utility of the standard curve and reagents suggests that full recalibration on a regular basis is not always necessary.
Heavy male Sprague-Dawley rats die of ventricular fibrillation within 2 to 3 h after isoproterenol administration. Thus, the isoproteronol-treated heavy rat would be a useful model for screening drugs that may prevent sudden cardiac death. Isoproterenol (1 mg/kg s.c.) caused ventricular fibrillation in 79% of 121 vehicle-pretreated heavy rats (greater than 500 g); 82% of the fibrillating rats died, but the remaining 18% spontaneously reverted and survived. A protecting agent should increase the number of survivors by reducing the incidence of ventricular fibrillation and/or by increasing the incidence of spontaneous reversions. Pretreatment (i.p.) with quinidine (40 mg/kg), procainamide (40 mg/kg), phenytoin (40 mg/kg), clofilium (5 mg/kg), verapamil (10 mg/kg), or propranolol (10 mg/kg) reduced the incidence of isoproterenol-induced ventricular fibrillation and death; bretylium (10 mg/kg) and nicotinic acid (100 mg/kg) had no effect. A lower dose of propranolol (2.5 mg/kg) or clofilium (1.5 mg/kg) but not quinidine (10 mg/kg), procainamide (10 mg/kg), or phenytoin (10 mg/kg) also reduced the incidence of ventricular fibrillation. Only clofilium tended to increase the incidence of spontaneous reversions.
Cytosolic acetyl coenzyme A-dependent N-acetyltransferase enzyme (E.C. 2.3.1.5) from inbred hamsters of each acetylator genotype was partially purified by ion-exchange chromatography. Two distinct N-acetyltransferase enzymes were identified; the first one exhibited a polymorphic expression across acetylator genotypes whereas the second exhibited a monomorphic expression. The monomorphic enzyme had consistently high isoniazid and procainamide N-acetyltransferase activity in homozygous rapid acetylator (Bio. 87.20), homozygous slow acetylator (Bio. 82.73/H), obligate heterozygous rapid acetylator F1 progeny and in each of the three acetylator genotypes of F2 progeny. In contrast, the polymorphic enzyme exhibited marked acetylator genotype-dependent N-acetyltransferase activity. High p-aminobenzoic acid N-acetyltransferase activity was exhibited in the homozygous rapid acetylator parental and F2 generation progeny, intermediate activity was exhibited in the heterozygous rapid acetylator F1 and F2 generation progeny and very low or nondetectable activity was exhibited in homozygous slow acetylator parental and F2 generation progeny. A similar gene dose-response relationship was exhibited by the polymorphic N-acetyltransferase enzyme toward isoniazid and procainamide. These results provide new insight into the biochemical basis for the substrate-dependent polymorphic and monomorphic expression of N-acetylation capacity in the inbred hamster.
The present study examined the effect of two drugs, which contain either an aromatic amine or hydrazine moiety and are known to induce lupus like syndromes in man (procainamide and hydralazine) and an aliphatic amine (dansylcadaverine), on pokeweed mitogen (PWM)-induced B cell production of immunoglobulin G (IgG). These compounds all inhibited IgG production and generation of IgG plaque forming cells, whereas derivatives of them, without free amine groups, had little or no effect. The compounds inhibited differentiation of B cells to plasma cells, rather than production and secretion of IgG. Mitogen free culture supernatants of peripheral blood mononuclear cells (PBM) activated by the oxidizing mitogen, neuraminidase and galactose oxidase (NAGO), prevented the inhibition of B cell maturation. Moreover, incubation of NAGO treated PBM with hydralazine prevented the production of soluble factors capable of promoting B cell maturation in the presence of hydralazine. We conclude from these studies that procainamide, hydralazine and dansylcadaverine inhibit PWM-induced B cell maturation to plasma cells by an indirect mechanism, via inhibition of production of lymphokines by helper cells. The primary amine or hydrazine group appears to be required for the inhibitory effect, since analogues of the inhibitory compounds, without primary amine groups, are non-inhibitory.
Congenital myotonia was diagnosed in an inbred Chow Chow pup with severe muscle stiffness that regressed with exercise. Voluntary movement, percussion, or needle insertion caused sustained contraction of the muscles involved. Electromyographic recordings from several muscles contained myotonic discharges. Creatine kinase activity was mildly increased. Slight myofiber hypertrophy and a few atrophic fibers were seen in muscle biopsy specimens. Treatment of the pup with procainamide caused a marked decrease in clinical signs. Myotonia congenita in the Chow Chow appears to be inherited as an autosomal recessive trait. This condition can be diagnosed on the basis of clinical signs. Satisfactory clinical management of myotonia congenita can be achieved with procainamide.