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PubMed2005

N-substituted 4-aminobenzamides (procainamide analogs): an assessment of multiple cellular effects concerning ion trapping.

Procainamide and related triethylamine-substituted 4-aminobenzamides, such as metoclopramide and declopramide, exert cellular effects potentially exploitable in oncology at millimolar concentrations (DNA demethylation, nuclear factor-kappaB inhibition, apoptosis) and display anti-inflammatory properties. However, these drugs induce massive cell vacuolization at similar concentrations, a response initiated by vacuolar (V-) ATPase-dependent ion trapping into and osmotic swelling of acidic organelles. We have examined whether this overlooked response might be related to the effects on cell proliferation and viability using cultured vascular smooth muscle cells and tumor-derived cell lines (Morris 7777 hepatoma, HT-1080 fibrosarcoma). Giant vacuole formation, of confirmed trans-Golgi origin (labeled with C5-ceramide, p230, golgin-97), is a cellular response to all tested amines in the series (> or = 2.5 mM), including triethylamine. These drugs and the V-ATPase inhibitor bafilomycin A1 inhibited smooth muscle cell proliferation, suggesting that acidification of a cellular compartment is essential to cell division. The cytotoxicity was maximal with metoclopramide, and this effect was minimally influenced by bafilomycin A1; furthermore, metoclopramide (2.5 mM) induced apoptosis in tumor cells as judged by poly(ADP-ribose)polymerase (PARP) cleavage. Triethylamine and procainamide exhibit a low level of cytotoxicity variably reduced by bafilomycin co-treatment. In Morris cells, the secretion of alpha-fetoprotein is inhibited by amines, consistent with the impairment of the secretory pathway. The most highly substituted 4-aminobenzamides are significant NF-kappaB inhibitors in smooth muscle cells. Although some effects of 4-aminobenzamides are independent of V-ATPase-driven ion trapping (inhibition of NF-kappaB nuclear translocation, agent-specific cytotoxicity, PARP cleavage), other effects are dependent on this phenomenon (vacuolization, a component of the cytotoxicity, inhibition of secretion).

Amines↗
PubMed1976

Clinicopathological study of a patient with procainamide-induced systemic lupus erythematosus.

A patient who developed a multisystem involvement of systemic lupus erythematosus (SLE) after 9 years of procainamide therapy, during which time he ingested enormous amounts of the drug, is described. The patient first suffered from recurrent episodes of pleuritis and arthritis, after which he developed a characteristic SLE nephritis associated with a high level of antinative DNA antibodies and a low level of complement. He finally died from a complication of a nonbacterial endocarditis. Autopsy showed polyserositis and typical deposits of electron-dense material on the glomerular basement membrane, and confirmed the clinical diagnosis of Libman-Sacks endocarditis. The possibility that procainamide-induced SLE might have all the clinical, immunological, and pathological features of spontaneous SLE, especially in patients exposed to large doses of the drug for many years, is discussed.

Humans↗
PubMed1989

Pulmonary thromboembolism associated with procainamide induced lupus syndrome and anticardiolipin antibodies.

Procainamide is the commonest cause of a drug induced lupus syndrome. Long term administration of this compound may induce a variety of immunological abnormalities, including antinuclear antibodies. Uncommonly, 'lupus anticoagulants' have been demonstrated in the absence of other evidence of drug induced lupus. Details of a 67 year old man who developed not only drug induced lupus but also antiphospholipid antibodies which were associated with multiple pulmonary thromboemboli after the administration of procainamide are recorded.

Aged↗
PubMed1999

Mechanism of procainamide-induced prevention of spontaneous wave break during ventricular fibrillation. Insight into the maintenance of fibrillation wave fronts.

BACKGROUND: Ventricular fibrillation (VF) is maintained by 2 mechanisms: first by reentry formation and second by spontaneous wave break or wave splitting. We hypothesized that spontaneous wave break results from a critical shortening of the action potential duration (APD) during VF and that its prevention by procainamide eliminates spontaneous wave break. METHODS AND RESULTS: The endocardial surfaces of 7 isolated, perfused swine right ventricles were mapped with a 3.2x3.8 cm plaque with 477 bipolar electrodes. Activation pattern during VF was visualized dynamically while simultaneously recording epicardial action potentials with a glass microelectrode. APD restitution curves were constructed during VF (dynamic) and during S(1)S(2) protocols. At baseline, VF was maintained by 5.3+/-1 wavelets. Procainamide (PA) at 10 microgram/mL decreased the number of wavelets to 3.5+/-1 (P<0.05). At baseline VF was maintained by spontaneous wave break and by new reentrant wave front formation. PA eliminated spontaneous wave break during VF while having no effect on reentry formation. PA increased the cycle length of the VF (148.5+/-41.2 ms vs 81+/-10 ms, P<0.01) and the core area of the reentry from 5.8 to 14.5 mm(2) (P<0.05). Dynamic APD restitution curve during VF showed that PA eliminated the initiation of activation with APDs shorter than 30 ms. The effects of PA on cellular properties and wave front dynamics were reversed during 60 minutes of drug-free perfusion. CONCLUSIONS: Critically short APDs during VF promote spontaneous wave break. Their elimination with PA, however, maintains VF by generating new reentrant wave front.

Action Potentials↗
PubMed1978

Abolition and modification of reentry within the His-Purkinje system by procainamide in man.

The effects of intravenous procainamide infusion of 10--14 mg/kg body weight (i.e., 750 mg) of procainamide (PA) on reentry within the His-Purkinje system (HPS) were studied in 13 patients using His bundle electrograms and ventricular extrastimulus method. PA abolished reentry in eight patients (group 1) and decreased the width of reentry zone in the remaining five (group 2). At comparable S1S2 intervals, the S2H2 intervals after PA were longer than control in all patients. In group 1 patients, after PA, reentry did not occur even at S2H2 intervals that were significantly longer than control critical S2H2 intervals. In two of eight patients in group 1, PA abolished reentry by converting unidirectional block into bidirectional block in the antegrade limb (right bundle) of the reentry circuit. In the remaining six patients reentry was abolished because of consistent retrograde block of S2 impulse at some point between the site of stimulation and the His bundle recording site. In group 2, reentry was initiated after PA at approximately the same S1S2 intervals as in control, but required significantly longer S2H2 intervals; in these patients the zone of reentry was shortened due to increase in effective refractory period of the ventricular muscle. PA significantly increased the functional refractory period of HPS and the effective refractory period of ventricular muscle. The results of this study differ from the previously reported effects of lower concentrations of PA which facilitated reentry within the same circuit. We conclude that the effects of PA on reentry are dose-related and can both facilitate and suppress reentry, depending on critical changes in conduction and refractoriness of the HPS.

Adult↗
PubMed2005

Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.

BACKGROUND: Cardiac arrest with preserved left ventricular function may be caused by uncommon genetic conditions. Although these may be evident on the ECG, long-term monitoring or provocative testing is often necessary to unmask latent primary electrical disease. METHODS AND RESULTS: Patients with unexplained cardiac arrest and no evident cardiac disease (normal left ventricular function, coronary arteries, and resting corrected QT) underwent pharmacological challenge with adrenaline and procainamide infusions to unmask subclinical primary electrical disease. Family members underwent noninvasive screening and directed provocative testing on the basis of findings in the proband. Eighteen patients (mean+/-SD age, 41+/-17 years; 11 female) with unexplained cardiac arrest were assessed. The final diagnosis was catecholaminergic ventricular tachycardia (CPVT) in 10 patients (56%), Brugada syndrome in 2 patients (11%), and unexplained (idiopathic ventricular fibrillation) in 6 patients (33%). Of 55 family members (mean+/-SD age, 27+/-17 years; 33 female), 9 additional affected family members were detected from 2 families, with a single Brugada syndrome patient and 8 CPVT patients. CONCLUSIONS: Provocative testing with adrenaline and procainamide infusions is useful in unmasking the etiology of apparent unexplained cardiac arrest. This approach helps to diagnose primary electrical disease, such as CPVT and Brugada syndrome, and provides the opportunity for therapeutic intervention in identified, asymptomatic family members who harbor the same disease.

Anti-Arrhythmia Agents↗
PubMed1989

Procainamide for dyspnea in myotonic dystrophy.

We report the case of a patient with myotonic dystrophy who developed tachypnea and severe dyspnea without respiratory failure. Myotonia of inspiratory muscles was diagnosed on the grounds of marked prolongation of transdiaphragmatic pressure (Pdi) decay during sniffs. In view of the recognized sensory role of inspiratory muscles in dyspnea, it was hypothesized that antimyotonic therapy might relieve dyspnea in this patient. Procainamide therapy induced a decrease in half relaxation time of Pdi during sniffs and yielded a striking clinical improvement with cessation of tachypnea and dyspnea. Later, this beneficial effect was maintained by tocainide after procainamide was stopped because of a lupus syndrome. We conclude that myotonia of respiratory muscles can cause severe dyspnea that can be improved by antimyotonic therapy.

Diaphragm↗
PubMed1983

Immunomodulatory effect of procainamide in man. Inhibition of human suppressor T-cell activity in vitro.

Procainamide (PA) induces the production of a number of autoantibodies in a high proportion of treated individuals and in some a syndrome closely resembling systemic lupus erythematosus. The mechanism underlying this action of PA is unclear. To examine the possibility that PA might induce autoantibody formation by altering normal immunoregulatory mechanisms, the action of this drug on an in vitro model of antibody formation in man was examined. PA was found to augment the generation of immunoglobulin-secreting cells (ISC) from human peripheral blood mononuclear cells (PBM) in response to pokeweed mitogen but had no effect on pokeweed mitogen-induced tritiated thymidine incorporation. When purified populations of B and T cells were used, PA enhanced the generation of ISC in B-cell cultures supported by untreated T cells but not by T cells treated with mitomycin C. These results indicate that PA augmented B-cell responses by inhibiting suppressor T-cell activity and not by augmenting helper T-cell or B-cell function. N-Acetyl-procainamide had no effect on the generation of ISC in this system. The effect of PA on concanavalin A (Con A)-induced suppressor cell activity was also examined to determine whether PA altered the generation or expression of suppressor T-cell function. PBM were cultured with 30 microgram/ml of Con A for 48 h to generate suppressor cells. When these were co-cultured with fresh PBM, the number of ISC generated was decreased by 58.1 +/- 3.4% (mean +/- SEM, n = 6). Cells that had been similarly incubated without Con A were not inhibitory. The addition of PA to the Con A-stimulated cultures inhibited the generation of suppressor cells as indicated by the fact that the response of fresh cells co-cultured with the Con A-stimulated cells was diminished by only 27.2 +/- 4.3%. In this system too, N-acetyl-procaimamide had no effect. By contrast, adding PA only to the co-culture of Con A-stimulated cells with fresh PBM had a less marked effect on suppressor cell function. These results indicate that the major action of PA is to inhibit the generation of suppressor T-cell activity. Such an effect may explain the capacity of this agent to induce autoantibody formation in treated individuals.

Antibody Formation↗
PubMed1991

The in vitro uptake and metabolism of lignocaine, procainamide and pethidine by tissues of the hindquarters of sheep.

1. In vitro studies using tissue slices or tissue homogenates of liver, skeletal muscle, fat skin and blood were conducted to determine whether the uptake of procainamide, lignocaine and pethidine into the hindquarters of sheep was due to distribution or metabolism. Both homogenates and slice preparations of liver showed significant metabolism or uptake, confirming the viability of the preparations. 2. None of the drugs was metabolized in blood and there was minimal uptake of the drugs into the skin. 3. There was metabolism of pethidine in skeletal muscle and substantial uptake of pethidine into fat, indicating that the rapid rate of uptake and prolonged elution of pethidine in the hindquarters was due to both distribution and metabolism. 4. No metabolism of lignocaine in muscle was found, but there was substantial uptake into fat, indicating that the rapid rate of uptake and prolonged elution of lignocaine in the hindquarters was due to its distribution into fat. 5. There was negligible uptake of procainamide into either muscle or fat, presumably due to its relatively low lipophilicity.

Adipose Tissue↗
PubMed1988

Procainamide induces a transitory impairment of B cell mitogenesis in beagle dogs.

Beagle dogs (3 to 6 years old) were treated with 100-150 mg procainamide HC1/kg/day. After 2, 5, and 9 months of treatment, peripheral blood lymphocytes were isolated and stimulated with pokeweed mitogen. The data demonstrated a suppression of mitogenesis only at 2 and 5 months after procainamide treatment. The lymphocytes from dogs treated for 9 months had a normal response to pokeweed mitogen. At no time during this experiment were any significant levels of serum antinuclear antibodies detected nor was any change in the number of cycling lymphocytes apparent in the experimental versus control groups. The resting membrane potential of both control and experimental groups was similar and pokeweed mitogen depolarized the cells from both groups.

Animals↗
PubMed1990

Interaction of bisoprolol and procainamide in human cardiac impulse generation and conduction.

Combined treatment of beta-adrenoceptor-blocking agents and class I antiarrhythmic drugs can potentially have profound and deleterious effects on cardiac impulse formation and conduction. We studied the effect of 5 mg of oral bisoprolol daily and 10 mg/kg of procainamide intravenously with programmed electrical stimulation of the heart in 10 patients with postinfarction ventricular tachyarrhythmias. Oral bisoprolol slowed sinus rhythm and atrioventricular nodal conduction; ventricular effective refractory periods were increased significantly after several days of oral bisoprolol treatment. Combined treatment of oral bisoprolol and intravenous procainamide did not produce clinically relevant changes in parameters of cardiac impulse formation and conduction. This study shows that combined use of bisoprolol and a class I antiarrhythmic drug appears to be safe in patients with ventricular tachyarrhythrhythmias late after myocardial infarction.

Administration, Oral↗
PubMedDate not supplied

[Pharmacokinetics of procainamide and its metabolite depending on acetylator phenotype].

Procainamide (Pa) and its active metabolite--N-acetylprocainamide (NAPA)--pharmacokinetics was studied in 12 healthy volunteers in relation to acetylation phenotype. Acetylation phenotype was determined with sulphadimidine test. Blood serum levels of PA and NAPA were determined 0.5; 1.0; 1.5; 2.0; 3.0; 4.0; 8.0; and 12 hours following a single oral dose of 500 mg. Blood levels of both PA and NAPA were assayed with immunofluorescence polarization technique (FPIA), using TDx apparatus manufactured by Abbott. Pharmacokinetic parameters were calculated with the aid of pharmacokinetics independent of the model principles. All results were analysed statistically (AWOA). It was found that PA and NAPA pharmacokinetics depends on acetylation phenotype. Blood serum PA levels were higher in slow acetylators during the whole follow-up whereas NAPA levels were lower. Blood serum PA levels in rapid acetylators were decreased while NAPA levels were increased. Acetylation phenotype determined in sulphadimidine test confirmed bimodal procainamide acetylation.

Acecainide↗
PubMedDate not supplied

Interaction between potassium concentration and inhibition of myocardial Na(+)-K(+)-ATPase by two class 1A antiarrhythmic drugs: quinidine and procainamide.

The inhibitory actions of quinidine and procainamide on the Mg(2+)-dependent ATP hydrolytic action of myocardial Na(+)-K(+)-ATPase (EC 3.6.1.3) were studied in guinea-pig heart preparations incubated in media containing 2.5, 5 and 10 mM of K+. The IC50 values for quinidine were 0.23 +/- 0.02 mM at 2.5 mM K+, 0.56 +/- 0.18 mM at 5 mM K+ and 0.82 +/- 0.05 mM at 10 mM K+, and those of procainamide were 7.2 +/- 1.8 mM at 2.5 mM K+, 13.7 +/- 2.3 mM at 5 mM K+ and 35.5 +/- 3.3 mM at 10 mM K+. Thus, reducing the K+ concentration from the "standard" 5 mM to 2.5 mM showed a significant right-to-left shift in the inhibitory potencies of the drugs, while increasing it to 10 mM resulted in opposite effects. The results show that the inhibitory actions of both drugs on the ATP-hydrolytic action of myocardial Na(+)-K(+)-ATPase depend on the K+ concentration of the incubation medium. These effects seem to be related to the mode by which antiarrhythmic drugs may induce or aggravate cardiac arrhythmias. In addition, the present results suggest that hypokalemia may exacerbate arrhythmias during treatment with these drugs.

Animals↗
PubMed1991

Insight into interstitial drug disposition: lymph concentrations of lidocaine, procainamide and meperidine in the hindquarters of unanesthetized and anesthetized sheep.

Drug concentrations in the lymph of the hindquarters of sheep were used to gain insight into drug disposition within the interstitial space. Lidocaine, procainamide and meperidine were each infused into the right atrium of adult merino ewes for 220 min. The time courses of drug concentrations in arterial and inferior vena caval (IVC, draining the hindquarters) blood and hindquarter lymph were determined. It was found that in unanesthetized sheep the mean (+/- S.D., n = 3) lidocaine, procainamide and meperidine concentrations in the hindquarter lymph, were 74 +/- 11, 107 +/- 25 and 94 +/- 17%, respectively, of the arterial and 92 +/- 15, 113 +/- 27 and 134 +/- 28%, respectively, of the IVC blood drug concentrations. Drug binding in lymph, determined by equilibrium dialysis, was not significantly higher than that in blood, except for lidocaine at an initial buffer concentration of 5 micrograms/ml. When the studies were repeated with different animals under halothane anesthesia, the lymph/arterial and lymph/IVC blood drug concentration ratios of the three drugs decreased to 66 +/- 9, 73 +/- 13 and 71 +/- 13% and 77 +/- 8, 88 +/- 19 and 85 +/- 10%, respectively. These values were all significantly lower than those in unanesthetized animals. The results suggest that drug protein binding in interstitial fluid and the status of the microcirculation are important determinants of drug distribution in the interstitial and intracellular spaces. The data also confirm the assumption made in pharmacokinetic studies based upon mass balance principles that the rate of drug removal from organs by lymph is negligible.

Anesthesia↗
PubMed1990

A new series of antiarrhythmic procainamide derivatives: toxicity and activity-simulated passive absorption relation.

Several compounds derived from benzamidines and nicotinic pyridinic amidines with a structure similar to that of procainamide, exhibit notable antiarrhythmic properties after injection into animals. The diffusion rate of these different compounds through a solid lipidic artificial membrane was studied with Dibbern's apparatus. A statistical relation was established between the diffusion rate and the principal pharmacological parameters obtained after intraperitoneal injection (toxicity and anthiarrhythmic activity). Essential structural elements seem to determine a better bioavailability than procainamide: character of the substitution (in para) of the benzenic cycle; length of the lateral chain.

Absorption↗
PubMed1986

Procainamide, N-acetylprocainamide, antinuclear antibody and systemic lupus erythematosus.

Long-term therapy with procainamide (PA) leads to the systemic lupus erythematosus syndrome (SLE) in about 30% of patients and 80% develop antinuclear antibodies. Acetylation of procainamide results in the formation of N-acetylprocainamide (NAPA) the propensity of which to induce SLE and to increase antinuclear antibodies is negligible while its antiarrhythmic properties remain. Slow acetylators of PA have a greater tendency to induce SLE consistent with the observation that it is the level of PA that is responsible for the observed immunologically-mediated side effects of the compound. This is also suggested by the remission of PA-induced SLE when PA is replaced with NAPA for the control of cardiac arrhythmias. Thus, NAPA, compared to the parent compound, has little tendency to induce SLE.

Acecainide↗
PubMed1988

Longer plasma half-life for procainamide utilizing a very sensitive high performance liquid chromatography assay.

The reported biological half-life of the antiarrhythmic drug procainamide (PA) is between 2 and 4 h. To reassess this, the disposition kinetics of the drug and its pharmacologically active metabolite, N-acetyl procainamide (NAPA), were determined using a newly developed high performance liquid chromatography (HPLC) method. The assay involved extraction from plasma of PA and NAPA with methylene chloride, followed by a brief washing of the extract with water, separation and evaporation of the organic layer, reconstitution in the mobile phase [water/methanol/acetic acid/triethylamine (74:25:1:0.03)], and injection into the HPLC system. At an ultraviolet light detection wavelength of 280 nm, the samples were chromatographed on a reverse-phase column. The minimum quantifiable concentration was 0.005 microgram/ml for both the drug and its metabolite. With this sensitivity it was possible to measure PA and NAPA plasma concentrations in samples taken as late as 24 h after single 375-mg oral doses of PA HCl to 13 healthy volunteers. When only the data points up to 12 h were included in the calculation, the drug t1/2 was 3.50 +/- 0.82 h (mean +/- SD) and in agreement with those reported previously. However, the t1/2 became significantly longer (8.52 +/- 3.58 h) when the 16- and 24-h data points were also included. The t1/2 of NAPA was 8.06 +/- 1.33 h and close to the reported values.

Acecainide↗