Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specific factors predisposing to thrombosis in patients with LAs have not been resolved. With extensive cross-reactivity, and several proposed sites of action, LAs and their effects may be heterogeneous. While the risk of thrombosis with phenothiazine-induced LAs is probably low, the incidence of thrombosis in association with procainamide-induced LAs is uncertain. Procainamide is a commonly used antiarrhythmic drug associated with the induction of autoantibodies, and occasionally with a lupus-like syndrome. Serologic and coagulation profile monitoring may be required to detect patients in whom LAs develop since these individuals may be at increased risk for thrombosis. Monitoring may be especially important in patients who are receiving procainamide and who have atherosclerosis and cardiac disease, since they may be at increased risk for thrombosis of coronary and other arteries. Future prospective studies are needed to investigate whether the development of lupus anticoagulants during procainamide therapy increases the risk of thrombosis.
 ...
PMID:Procainamide-induced lupus anticoagulants and thrombosis. 312 75

Procainamide is a widely used antiarrhythmic that is fraught with therapeutic limitations such as a short half-life, production of autoimmune antibodies and a lupus-like syndrome, and complex pharmacokinetics. We synthesized the congeners of procainamide possessing one or two methyl substituents ortho to the 4-amino moiety (compounds 4 and 5, respectively), in order to sterically encumber the 4-amino substituent and prevent or diminish the rate of metabolic N-acetylation. Moreover, we anticipated that this structural alteration might eliminate the autoimmune toxicities associated with procainamide. Like procainamide, the two methylated analogues significantly reduced the rate of rise and amplitude of the action potential when studied in isolated canine Purkinje fibers. Whereas procainamide caused no significant change in action potential duration (APD), both methylated congeners significantly reduced APD at 70% and 95% repolarization. Moreover, the dimethylated congener was significantly more efficacious than procainamide in reducing ERP (effective refractory period) and increasing the ERP/APD70. The ability of these compounds to block ouabain-induced arrhythmias was studied in anesthetized dogs. Addition of two methyl groups ortho to the amine produced an increase in potency: The conversion doses for procainamide and the monomethyl and dimethyl congeners were 19.0, 18.3, and 14.3 mg/kg, respectively, following iv administration. After iv administration to rats, procainamide was extensively metabolized to N-acetylprocainamide and displayed a half-life of 0.4 h. In contrast, dimethylprocainamide was not metabolized by N-acetylation, had a half-life of 1.4 h, and provided greater peak plasma concentrations. Thus, addition of methyl substituents ortho to the 4-amino group of procainamide alters the electrophysiological characteristics of the compound, increases its potency against ouabain-induced arrhythmias in vivo, increases its plasma half-life, and prevents N-acetylation.
 ...
PMID:Electrophysiologic and antiarrhythmic activities of 4-amino-N-[2-(diethylamino)ethyl]-3,5-dimethylbenzamide, a sterically hindered procainamide analogue. 338 24

Procainamide-induced lupus is a well-recognized syndrome, but the events leading up to clinical symptoms are obscure. In the present study, serologic changes in a 69-year-old man were monitored during his treatment with procainamide and after discontinuation of procainamide because of symptoms of drug-induced lupus. Antihistone antibodies of unique specificity and in vivo complement activation were detected after one year of procainamide therapy during a period prior to development of significant clinical symptoms. Antihistone antibodies and complement activation substantially increased during a full-blown episode of lupus-like symptoms. Progressive return to normal laboratory findings occurred after procainamide was discontinued. The antihistone/complement profile may be useful in the diagnosis of drug-induced lupus and warn of impending clinical deterioration in patients with minimal symptoms.
 ...
PMID:Serologic changes during induction of lupus-like disease by procainamide. 370 85

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.
 ...
PMID:Effects of lupus-inducing drugs on the B to Z transition of synthetic DNA. 371 55

Patients treated with procainamide and other drugs commonly develop antinuclear antibodies and occasionally symptoms of lupus erythematosus. However, the pathological events which lead to clinical symptoms in some patients but only abnormal serology in others have not been established. The present study examines the incidence, amount, immunoglobulin class, and antigen-binding specificity of anti-histone and anti-denatured DNA (anti-dDNA) antibodies in three groups of patients. These comprised a prospective study of patients treated with procainamide, patients with clinical drug-induced lupus symptoms, and a group undergoing therapy for many years without any symptoms. Procainamide elicited IgG and IgM anti-dDNA antibodies concordantly. Anti-histone IgM antibodies also appeared de novo during this period but IgG anti-histone antibodies were detected less frequently. Asymptomatic patients tended to have an antibody profile consisting of highly elevated anti-dDNA, IgM antibodies reactive with all histones and IgG antibodies specific for only one or two histone classes. In contrast symptomatic patients usually had little anti-dDNA or antibodies to individual histones but had pronounced IgG antibodies to the histone complex H2A-H2B. This unique antibody was characteristics of procainamide-induced lupus and was not detected in patients whose disease was induced by hydralazine. Anti-(H2A-H2B) decreased after procainamide was discontinued, concomitant with subsidence of symptoms. The finding that autoantibodies elicited by procainamide in patients with lupus symptoms have a characteristic immunoglobulin class and specificity may be of pathogenic significance and suggests that patients susceptible to procainamide-induced lupus have a unique immune response. In addition, this information could be of diagnostic value in predicting which procainamide-treated patients will develop overt symptoms of lupus.
 ...
PMID:IgG antibodies to the histone complex H2A-H2B characterize procainamide-induced lupus. 387 29

Procainamide (PA) has been a mainstay of treatment against acute and chronic supraventricular and ventricular arrhythmias for more than 30 years. PA's clinical pharmacology has been studied extensively and its bioavailability (75-95%); volume of distribution (1.5-2.5 liters per kg), plasma protein-binding (15-25%), half-time for elimination (3-7 hours), and metabolism are known. PA's efficacy against acute ventricular arrhythmias and chronic stable VPDs is associated with plasma drug concentrations of 4 to 10 micrograms per ml; but much higher plasma concentrations may be required against sustained ventricular arrhythmias. From 30 to 60% of a PA dose is excreted as the metabolite, N-acetylprocainamide (NAPA), and PA's metabolism is determined genetically (fast or slow acetylation phenotype). Studies in patients with VPDs indicate that NAPA is also antiarrhythmic, although the contribution of NAPA to the antiarrhythmic effect after PA is not known. Studies in patients with the systemic lupus-like syndrome from PA show that NAPA is not associated with this. Investigations comparing efficacy and adverse effects of PA with those of new antiarrhythmic agents available for clinical trials are indicated in the future.
 ...
PMID:Procainamide: clinical pharmacology and efficacy against ventricular arrhythmias. 608 35

Procainamide is probably the most common offending drug responsible for the drug-induced lupus erythematosus syndrome today. Pericarditis has been reported to occur in from 14 to 18 per cent of the cases of procainamide-induced lupus erythematosus, and occasional reports of massive pericardial effusion, pericardial tamponade and constrictive pericarditis have appeared in the literature. We describe a patient who presented with features of procainamide-induced lupus erythematosus without any clinical evidence of pericarditis. He underwent coronary bypass surgery 12 days after administration of the drug was stopped and was found to have a significant pericardial effusion at the time of surgery; histologic examination of pericardial tissue and pericardial fluid confirmed that the pericardial effusion was related to the procainamide-induced lupus syndrome. The incidence of pericarditis in procainamide-induced lupus erythematosus may be higher than presently accepted figures would indicate. Symptoms and signs related to procainamide-induced lupus pericarditis may cause diagnostic confusion with common postoperative bypass complications; the full implications of this disease entity to the patient undergoing coronary bypass are unknown.
 ...
PMID:Procainamide-induced lupus erythematosus pericarditis encountered during coronary bypass sugery. 615 82

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.
 ...
PMID:Immunomodulatory effect of procainamide in man. Inhibition of human suppressor T-cell activity in vitro. 621 16

Procainamide has a high propensity for the induction of an autoimmune response. The immune response is highly selective and the autoantibodies so induced are directed against nuclear histones. Acetylator phenotypes play an important role in the immune response, with slow acetylators developing antihistone antibodies much sooner than fast acetylators. In the early detection of drug-induced lupus syndromes, the finding of antihistone antibodies in the absence of other types of antinuclear antibodies greatly aids in establishing the diagnosis.
 ...
PMID:Autoallergic reactions induced by procainamide. 638 37

Procainamide has become the most frequent cause of the drug-induced lupus syndrome. Like other drugs that produce this syndrome, procainamide induces disease that closely resembles idiopathic SLE but differs from it in race and sex distribution, in rare involvement of the kidneys and central nervous system, and in the absence of antibody to native DNA. Although complete remission of the signs and symptoms of the disease occurs in most patients following discontinuation of the drug, some patients continue to be symptomatic and require treatment with corticosteroids. With prolonged procainamide therapy, antinuclear antibody develops in at least 50% of patients, and the lupus syndrome develops in approximately 20%. At present, it does not appear that a cumulative or daily dose of procainamide can be exclusively implicated in the appearance of antinuclear antibody or symptoms. Acetylation status may be one of the determining factors in the development of the SLE syndrome.
 ...
PMID:SLE: idiopathic or drug-induced? 696 85


<< Previous 1 2 3 Next >>