Plasma Concentration and Urinary Excretion Kinetics of Acetyl Strophanthidin

Selden, Richard F.; Klein, Michael D.; Smith, Thomas W.

doi:10.1161/01.cir.47.4.744

Cited by 27 publications

(5 citation statements)

References 28 publications

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“…The effects of this synthetic cardiac glycoside are additive to those of digoxin at myocardial receptors, so that the quantity which must be infused before ECG signs of cardiotoxicity occur may be used as an index of the tendency to digoxin toxicity. The value of acetylstrophanthidin is that its additive cardiac effects are rapid in onset and highly transient, its plasma elimination half-life being 1.2 h in dogs and 2.3 h in man (Selden, Klein & Smith, 1973). This is much shorter than that of any other digitalis analogue and the decay of its pharmacological effect is even more rapid (Klein, Nejad, Lown, Hagemeijer & Barr, 1971).…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Cardiotoxicity and Plasma Digoxin Concentration in Conscious Dogs

Chapple

Hughes

Johnson

1976

British J Pharmacology

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I The tendency of a given oral dose of digoxin to induce cardiac dysrhythmia was determined indirectly at various times after its administration to eight conscious dogs by measurement of the intravenous dose of acetylstrophanthidin necessary to induce toxic changes in the ECG. Acetylstrophanthidin was used because its rapid elimination from the body permitted estimates to be made 45, 180 and 360 min after digoxin administration. 2 Each dog underwent four studies in which doses of 0.05, 0.1, 0.2 and 0.4 mg/kg digoxin were used in a randomized sequence allowing at least ten days between each dose. 3 Digoxin reduced the amount of acetylstrophanthidin required to cause toxic changes in the ECG; this increase in cardiac sensitivity was dose-dependent. 4 There was no correlation between plasma levels of digoxin and the tendency to dysrhythmia, since peak plasma concentrations of digoxin were reached at about 60 min after dosing whereas maximal sensitivity to acetylstrophanthidin was found 3 to 6 h after administration of digoxin. 5These results suggest that there is little or no increased risk of cardiotoxicity during periods of transient increase in plasma levels ofdigoxin.

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Section: Discussionmentioning

confidence: 99%

The Relationship Between Cardiotoxicity and Plasma Digoxin Concentration in Conscious Dogs

Chapple

Hughes

Johnson

1976

British J Pharmacology

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“…In both dogs and normal human subjects, AS appears to be eliminated through hepatic and gastrointestinal rather than renal routes. 50 The degree of plasma protein binding of AS, its distribution space, and the effects of congestive heart failure and liver dysfunction upon AS catabolism remain unknown. Many examples of discordant results between SDL and AS titration testing, however, could not be wholly accounted for by deranged liver function or a shrunken skeletal muscle mass, diverting larger amounts of AS to the heart and thereby reducing myocardial tolerance.…”

Section: {--T 1------t+---ii;;:----mentioning

confidence: 99%

Comparison of Serum Digoxin Level Measurement with Acetyl Strophanthidin Tolerance Testing

et al. 1974

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SUMMARYSerum digoxin levels (SDL) were compared with tolerance for the rapidly acting cardiac aglycone, acetyl strophanthidin (AS). AS titration tests were performed on 133 patients with diverse cardiac disorders. All were receiving maintenance digoxin. Both exquisite AS sensitivity and tolerance for a 1.0 mg AS were associated with a wide range of SDL values. Concordance and discordance between the two methods in assessing degree of digitalization were evaluated by considering SDL of 1.4 ng/ml to be the mean value for patients without glycoside-induced cardiac arrhythmia. An SDL of <1.5 ng/ml with tolerance for 1.0 mg AS and an SDL of >1.4 ng/ml with sensitivity to 1.0 mg AS or less constituted concordant responses. An SDL of <1.5 ng/ml with intolerance for 1.0 mg or less AS and an SDL of >1.4 ng/ml with tolerance for 1.0 mg AS comprised discordant responses. In 60 of 144 (42%) AS titrations discordant results were observed. Severe pulmonic, coronary, and aortic valvular heart disease, as well as old age, contributed to unusual AS sensitivitv. Titration with AS clarified pharmacologic quantification of SDL by providing insight into optimum therapeutic glycoside dose. Development of a radioimmunoassay for digoxin promised to resolve questions concerning appropriate dosage of this commonly employed digitalis glycoside. Several studies indicated that the quantity of drug present in the serum could be determined with precision. 9 Serum digoxin concentration measurements delineated a therapeutic range of values and provided a convenient marker for differentiating toxic from nontoxic patients with cardiac arrhythmias.20' 21 Eighty-five percent of patients with manifestations suggesting digitalis intoxication showed blood levels above 2.0 ng/ml; while a similar percentage of those without evidence of overdosage had concentrations below this value.22 However, the range of overlap between toxic and nontoxic groups was wide, from 1.6-3.0 ng/ml.22 More recent reports indicate an even wider range of overlap, extending through virtually the entire serum digoxin concentration span encountered clinically.23Implicit in the clinical use of serum digoxin levels for assessing the state of digitalization are two assumptions: first, that blood levels reflect faithfully myocardial drug concentrations, and second, that a given concentration is associated with specific effect.

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“…Antibodies of high affinity for ouabain and acetyl strophanthidin were raised in rabbits by repeated injection of a conjugate of ouabain covalently linked to a poly D,L-alanyl derivative of human serum albumin, as previously described (6). The average intrinsic affinity constant for ouabain of the antibody population used in the present studies, as determined by equilibrium dialysis, was 1.6 X 10' M-1 (6), and cross-reactivity experiments with acetyl strophanthidin demonstrated an affinity of the same order of magnitude (6,7). Gamma globulin fractions were prepared by ammonium sulfate fractionation (8) Responses of 12 normal and 7 failure muscles to 4 X 107 M acetyl strophanthidin are summarized in Fig.…”

Section: Methodsmentioning

confidence: 82%

Reversal of Ouabain and Acetyl Strophanthidin Effects in Normal and Failing Cardiac Muscle by Specific Antibody

Gold¹,

Smith²

1974

J. Clin. Invest.

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A B S T R A C T Isolated cat right ventricular papillary muscles were used to study the effects of antibodies with high affinity for ouabain and acetyl strophanthidin on myocardium exposed to these cardioactive steroids. strophanthidin-antibody complex did not alter the myocardial contractile response to subsequently added cardioactive steroids.Spontaneous automaticity occurring as a toxic response to ouabain or acetyl strophanthidin in eight muscles was rapidly reversed by specific antibody at a time when positive inotropic effects were still fully manifest. Early contracture was also reversed by specific antibody. These studies provide further support for the concept that cardiac glycoside-specific antibodies are capable of reversing established cellular effects of cardioactive steroids. INTRODUCTIONSeveral recent studies have shown that cardiac glycosidespecific antibodies can reverse established effects of digitalis glycosides in biological systems (1-3). In addition to reversal of cardiac glycoside-induced effects on in vitro systems, it has been demonstrated that advanced cardiac digoxin toxicity in the intact dog can be reversed by digoxin-specific antibody (4, 5).To assess the effect of cardiac glycoside-specilic antibody on digitalis-treated myocardium, we have studied the effects of ouabain-specific antibody on isolated cat right ventricular papillary muscles exposed to ouabain and acetyl strophanthidin. In the experiments to be described, special attention has been directed to (a) the time-course of reversal of digitalis-induced inotropy by antibody and its relation to reversal of inotropy by washout alone; (b) the effect of congestive heart failure, induced by chronic pulmonary artery constriction, on papillary muscle responses to digitalis and specific antibody; (c) the relation of cardioactive steroid concentration to specific antibody concentration required to reverse established effects; (d) the question of whether

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Plasma Concentration and Urinary Excretion Kinetics of Acetyl Strophanthidin

Cited by 27 publications

References 28 publications

The Relationship Between Cardiotoxicity and Plasma Digoxin Concentration in Conscious Dogs

The Relationship Between Cardiotoxicity and Plasma Digoxin Concentration in Conscious Dogs

Comparison of Serum Digoxin Level Measurement with Acetyl Strophanthidin Tolerance Testing

Reversal of Ouabain and Acetyl Strophanthidin Effects in Normal and Failing Cardiac Muscle by Specific Antibody

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