Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: Comparison with procainamide

Roden, Dan M.; Reele, Stots B.; Higgins, Stanley B.; Wilkinson, Grant R.; Smith, Raymond A.; Oates, John A.; Woosley, Raymond L.

doi:10.1016/0002-9149(80)90016-8

Cited by 153 publications

(30 citation statements)

References 11 publications

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“…These effects occurred at concentrations that are achieved in vivo by Pca and Hyd. Therapeutic levels of hydralazine are 0.5-5.0 p M (15), and Pca levels achieved in vivo are in excess of 10 p M (6,16). These results suggest that the lupus caused by Pca and Hyd may result, in part, from induction of autoreactive T cells in vivo.…”

Section: Discussionmentioning

confidence: 86%

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N‐acetylprocainamide is a less potent inducer of t cell autoreactivity than procainamide

Richardson

Cornacchia

Golbus

et al. 1988

Arthritis & Rheumatism

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We have reported that an inhibitor of DNA methylation, 5-azacytidine, makes cloned, antigenspecific CD4+ T cells autoreactive, and that procainamide and hydralazine mimic this effect. Those results suggested that procainamide and hydralazine may induce autoimmunity by inhibiting DNA methylation and causing T cell autoreactivity. We report now that Nacetylprocainamide, a procainamide derivative that does not induce lupus, is also a DNA methylation inhibitor, but it is 100 times less potent than procainamide in inducing T cell autoreactivity.DNA methylation inhibitors induce expression of genes normally suppressed by mechanisms associated with cytosine methylation (1) and, in certain systems, can change cellular phenotype and alter differentiation (2,3). We have previously reported that 5-azacytidine (5-azaC), a DNA methylation inhibitor, made 4 cloned antigen-reactive T cells respond to autologous class I1 major histocompatibility complex (MHC) determinants without specific antigen, presumably by inducing expression of suppressed genes (4). This response was termed autoreactivity.In those studies, we demonstrated that the 5- azaC-treated T cells responded to autologous but not allogeneic macrophages, and that monoclonal antibodies to class I1 but not class I MHC determinants would inhibit activation (4). Those results suggested the possibility that similar inhibition of T cell DNA methylation in vivo could lead to an autoimmune disease.To determine if inhibitors of DNA methylation could produce an autoimmune disease, we tested whether 2 drugs known to induce a lupus-like syndrome inhibit DNA methylation and induce T cell autoreactivity. We found that hydralazine (Hyd) and procainamide (Pca) mimicked the effects of 5-azaC on T cells by inducing T cell autoreactivity in these cloned lines and decreasing deoxymethylcytidine (d"C) content in T cell DNA, thus supporting the hypothesis that DNA methylation inhibitors may induce autoimmune disease (5).To further test this hypothesis, we compared Pca and Hyd with structural analogs, using the assays previously developed. N-acetylprocainamide (Napa) is a procainamide derivative that rarely induces lupus ( 6 4 , and hydralazine is a phthalazine (Phth) derivative containing a hydrazine side chain (l-hydrazinophthalazine) (9,lO). Previously, investigators speculated that the hydrazine side chain of hydralazine may be responsible for the lupus-like syndrome (9); therefore, we compared Pca with Napa and Hyd with Phth, for the ability to induce T cell autoreactivity and inhibit DNA methylation. MATERIALS AND METHODST cell cultures. CD4 + , cloned, tetanus toxoid (TTh reactive, interleukin-2 (IL-2tdependent T cell lines were generated and maintained as previously described (4,ll).

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Section: Discussionmentioning

confidence: 86%

“…Napa is a Pca derivative that is an effective antiarrhythmic agent like Pca, but it rarely induces the lupus-like syndrome (6)(7)(8). Hyd is a Phth derivative containing a hydrazine side chain (9,lO).…”

Section: Discussionmentioning

confidence: 99%

N‐acetylprocainamide is a less potent inducer of t cell autoreactivity than procainamide

Richardson

Cornacchia

Golbus

et al. 1988

Arthritis & Rheumatism

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“…Using an arbitrary 0-4+ scale to quantitate the degree of histologic change in the kidneys, livers, and lungs, and combining the scores of all 3 organs for each mouse, mice receiving Pca-treated cells developed significantly more total tissue damage than did mice receiving Napatreated cells (mean f SEM 2.1 f 0.2 versus 0.5 2 0.2; P < 0.001 by Student's t-test), and mice receiving Hyd-treated cells developed greater tissue damage than did mice receiving Phth-treated cells (1.8 5 0.3 versus the proposed relationship between T cell LFA-1 overexpression, autoreactivity, and autoimmunity, using 2 drugs known to cause drug-induced lupus and analogs known or proposed to be less potent. The effects of Pca were compared with Napa, which is known to be less potent in causing lupus (8,9), and those of Hyd were compared with Phth to test the proposed role of the hydrazine side chain in inducing autoimmunity. HU was included to control for possible effects due to DNA synthesis inhibition, and to evaluate the effect of a drug that increases DNA methylation (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…We also compared cells treated with these drugs for their ability to induce autoimmunity in vivo. The effects of Pca were compared with those of N-acetylprocainamide (Napa), a metabolite which does not induce lupus (8,9). The effects of Hyd were compared with those of phthalazine (Phth), the parent molecule of Hyd, but lacking the hydrazine side chain.…”

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confidence: 99%

Mechanisms of drug‐induced lupus. IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo

Yung

Chang

Hemati

et al. 1997

Arthritis & Rheumatism

108

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Objective. T cells treated with DNA methylation inhibitors overexpress lymphocyte function-associated antigen 1 (LFA-l), which results in autoreactivity, and the autoreactive cells cause a lupus-like disease in vivo, suggesting a mechanism by which some agents may cause drug-induced lupus. This study compared the effects of procainamide (Pca) and hydralazine (Hyd) with those of structural analogs, to determine if the degree of LFA-1 overexpression and T cell autoreactivity correlated with the ability of the agents to induce autoimmunity.Methods. Cloned murine T helper 2 cells were treated with Pca, N-acetylprocainamide, Hyd, Phthalazine, or hydroxyurea (HU). The treated cells were then compared for LFA-1 overexpression, autoreactivity, and the ability to induce autoimmunity in vivo.Results. Pca and Hyd were more potent than their analogs or HU in all 3 assays.Conclusion. The results support a relationship between LFA-1 overexpression, T cell autoreactivity, and autoimmunity, and suggest a mechanism by which Pca and Hyd, but not the analogs, may cause druginduced lupus.Procainamide (Pca) and hydralazine (Hyd) cause a lupus-like disease in some individuals, but the mechanism by which these drugs induce autoimmunity is uncertain. Understanding the mechanism is important, because similar mechanisms could contribute to the

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“…Other antiarrhythmic agents have been shown to have actions mediated by active metabolites, including lidocaine (26), procainamide (27), and quinidine (22). In the case of encainide, this was a possibility first suspected in early studies based on a disparity between the pharmacokinetic characteristics of the parent drug and the pharmacodynamic responses observed in the study group of patients (1).…”

Section: Discussionmentioning

confidence: 99%

Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.

Carey¹,

Duff²,

Roden³

et al. 1984

J. Clin. Invest.

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As bstract. To assess the relative contributions of encainide and its putatively active metabolites, O-demethyl encainide (ODE) and 3 methoxy-O-demethyl encainide (3MODE), to the drug's pharmacologic effects, we compared intravenous infusions and sustained oral therapy in two phenotypically distinct groups of patients, extensive and poor metabolizers ofencainide. Unlike poor metabolizers, extensive metabolizers had appreciable quantities of both metabolites detectable in plasma and had fourfold shorter elimination half-lives for encainide. By quantitating electrocardiogram intervals, arrhythmia frequency, and plasma concentrations, we found that, in poor metabolizers, arrhythmia suppression and ventricular complex (QRS) prolongation were correlated positively with encainide concentrations (r . 0.570, P < 0.014). In these two subjects, antiarrhythmic concentrations of encainide (>265 ng/ml) were at least fivefold higher than those sustained in the six extensive metabolizers during steady state oral therapy. In extensive metabolizers, encainide concentrations were uncorrelated with effects. Arrhythmia suppression and QRS prolongation in extensive metabolizers correlated best with ODE (r . 0.816, P < 0.001); QTc change correlated positively

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Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: Comparison with procainamide

Cited by 153 publications

References 11 publications

N‐acetylprocainamide is a less potent inducer of t cell autoreactivity than procainamide

N‐acetylprocainamide is a less potent inducer of t cell autoreactivity than procainamide

Mechanisms of drug‐induced lupus. IV. Comparison of procainamide and hydralazine with analogs in vitro and in vivo

Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.

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