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

Abstract

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

Effects of sheep digoxin-specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs.

“…Dr Received for publication 10 February 1976 and in revised form 21 October 1976. ficity for the unconjugated digitalis glycoside, digoxin (2). In vitro, antibodies to digoxin or to other cardiac glycosides are capable of removing these glycosides from mammalian cells (3,4) and of preventing or of reversing many of the pharmacologic and toxic effects of the glycosides on such cells (3)(4)(5)(6)(7)(8)(9)(10). In vivo, antidigoxin antibodies are capable of preventing or of reversing lethal digoxin intoxication in experimental animals (11)(12)(13).…”

Reversal of Advanced Digitoxin Toxicity and Modification of Pharmacokinetics by Specific Antibodies and Fab Fragments

“…The feasibility of this approach was suggested by earlier studies using digitalis-specific antibodies or their Fab fragments for reversal of glyco- side-induced effects in vitro (4)(5)(6)(7)(42)(43)(44) and toxic arrhythmias in vivo (3)(4)(5)45 With regard to potential therapeutic use, the first requisite of an antibody population or the Fab fragments derived therefrom is high affinity and specificity for the drug molecule which is to be counteracted. In the case of cardiac glycosides such as digitoxin and digoxin, toxic effects may be manifest at free plasma concentrations of 10 nM or less (30,48).…”

“…Substantial experimental literature now exists demonstrating reversal of established effects of digoxin (3)(4)(5) as well as ouabain (6,7) by specific antibodies or their Fab fragments, and Fab fragments of digoxin-specific antibodies have recently been used clinically to reverse toxicity after suicidal digoxin ingestion with high-grade atrioventricular block and intractable hyperkalemia (8).…”

Extracellular versus intracellular digoxin action on bovine myocardium, using a digoxin antibody and intracellular glycoside application.

“…DISCUSSION Butler & Chen (1967) showed that specific high-affinity antibodies for the cardiac glycoside digoxin can neutralize the effects of this drug. Since then the immunological reversal ofpharmacologically inotropic and toxic arrhythmogenic digitalis effects has been demonstrated in a number of in vitro and in vivo studies Schmidt & Butler, 1971;Mandel, Bigger & Butler, 1972;Gold & Smith, 1974;Butler, Smith, Schmidt & Haber, 1977).…”

“…The time courses of digoxin removal by simple washout and by antibody application were of the same order of magnitude (half-time -70 min). Gold & Smith (1974) using ouabain on cat papillary muscle reported a mean half-time of 181 + 24 min (S.E. of mean) for inotropy reversal in drug-free media and a shortening of mean t4 to 124 + 24 min (s.E.…”