ACCUMULATION AND RELEASE OF <sup>3</sup>H‐DIGOXIN BY GUINEA‐PIG HEART MUSCLE

Kuschinsky, K.; Lahrtz, Hg.; Lüllmann, Heinz; Zwieten, P. A. van

doi:10.1111/j.1476-5381.1967.tb02138.x

Cited by 56 publications

(21 citation statements)

References 13 publications

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“…Uptake of cardiac glycosides at 370 C Previous studies (Godfraind &Lesne, 1967 andKuschinsky et al, 1967;Kuschinsky, LAullmann & van Zwieten, 1968) have shown that equilibrium uptake of cardiac glycosides requires at least three hours to be achieved. The uptake of 3H-digitoxin, 3H-ouabain and 3H-dihydro-ouabain after 4 h incubation was investigated at different drug concentrations (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…One of the most intriguing questions is the role of the inhibition of the sodium pump in the inotropic action of cardiac glycosides. Since it was shown that cardiac glycosides were taken up from the perfusion medium by isolated heart muscle (Godfraind & Lesne, 1967; Kuschinsky, Lahrtz, Lullmann & van Zwieten, 1967), several workers have analysed the factors controlling this process, as well as studying the subcellular localization of 3H-glycoside (Dutta, Goswami, Datta, Lindower & Marks, 1968;Dutta, Goswami, Lindower & Marks, 1968).…”

Section: Introductionmentioning

confidence: 99%

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The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle

Godfraind

Lesne

1972

British J Pharmacology

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Summary1. The uptake of 3H-digitoxin, 3H-ouabain and 3H-dihydro-ouabain by isolated guinea-pig atria has been studied and compared with the inhibition of the sodium pump and with the inotropic effect.2. Analysis of the curve relating the uptake of digitoxin and ouabain at equilibrium to the bath concentration enabled a non-saturable and a saturable binding site to be distinguished. 3. The uptake of inactive doses of dihydro-ouabain was only by a nonsaturable mechanism. 4. The uptake of labelled digitoxin and ouabain was reduced in the presence of another glycoside. The amount of bound glycoside was nearly equivalent to the estimated non-saturable uptake. 5. The uptake was reduced at 40 C to the clearance of the non-saturable site. 6. ED50 of digitoxin and of ouabain for inhibition of the sodium pump were measured and compared to the ED50 for inotropic effect and to the concentrations producing a half-saturation of the saturable binding site. 7. It is concluded that binding to the saturable site may be responsible for the cardiac actions of the glycosides.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle

Godfraind

Lesne

1972

British J Pharmacology

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“…Since canine tissues were not analyzed in the current study, the extravascular sources of digoxin cannot be identified. It is of interest, however, that tissue digoxin appears to consist of intracellular and cell membranebound components (4,40) and that antidigoxin antibodies remove intracellular glycoside from human erythrocytes more rapidly than they remove the glycoside from cell membrane-binding sites (4). In this connection, it is possible that the prolonged phase of removal of digoxin from an extravascular compartment during hours 6-24 in the antibody-treated dogs is contributed to by slow dissociation of digoxin from specific binding sites on cell membranes, analogous to the slow dissociation of digoxin from such sites on human erythrocyte membranes with consequent slow sequestration by antidigoxin antibodies (4).…”

Section: Discussionmentioning

confidence: 99%

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

Butler¹,

Schmidt²,

Smith³

et al. 1977

J. Clin. Invest.

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A B S T R A C T Intact sheep antidigoxin antibodies and their Fab fragments have both been found to exert profound effects on digoxin pharmacokinetics in [3H]digoxin-treated dogs. Both classes of molecule remove digoxin from the extravascular space and sequester it in the circulation in protein-bound form, a form in which the digoxin is presumably inactive. These two classes of molecule differ, however, in that the intact antibody molecules interfere with digoxin excretion, thereby promoting the retention of the glycoside; this retained digoxin is eventually released in free, active form when the administered antibody is metabolically degraded. In contrast, urinary excretion of digoxin continues in Fab-treated dogs, with significant quantities of digoxin being excreted promptly in the urine in complex with Fab fragments. These differences in urinary excretion, together with the probable decreased immunogenicity of sheep antidigoxin Fab fragments, suggest that such fragments possess potential advantages over intact antibody molecules for use in the therapy of life-threatening digoxin intoxication in man.

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“…Substantial differences exist in plasma protein binding and pharmacokinetics of digitoxin compared with shorter-acting glycosides (13,14). The apolar nature of the digitoxin molecule results in a high degree of binding to serum albumin and presumably accounts as well for substantially higher myocardial tissue to medium glycoside concentration ratios compared with digoxin or ouabain in in vitro studies (15,16). Qualitative as well as quantitative differences in myocardial binding ofdigitoxin compared with more polar glycosides have been documented by Dutta et al (17).…”

Section: Introductionmentioning

confidence: 91%

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

Ochs¹,

Smith²

1977

J. Clin. Invest.

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A B S T R A C T The effects of Fab fragments of highaffinity specific antibodies have been studied in a canine experimental model of lethal digitoxin toxicity. Selected antiserum from sheep immunized and boosted with a digoxin-serum albumin conjugate contained antibodies that cross-reacted with digitoxin with an average intrinsic association constant of 1.4 x 10"0 M-1 as determined by equilibrium dialysis.Rapid second-order association kinetics (kf = 3.7x 106 M-1 per s) and slow dissociation kinetics (kr = 1.9 X 10-4 per s) were documented for the antibody-digitoxin complex. Eight dogs given 0.5 mg/ kg digitoxin intravenously developed ventricular tachycardia after 23±4 (SEM) min. Control nonspecific Fab fragments were then given. All animals died an average of 101+36 min after digitoxin administration. Another eight dogs given the same digitoxin dose similarly developed ventricular tachycardia after 28+3 min. This group then received a molar equivalent dose of specific Fab fragments intravenously over 3 min, followed by a 30-min infusion of one-third of the initial dose. All dogs survived. Conducted sinus beats reappeared 18+4 min after initial Fab infusion, and stable normal sinus rhythm was present at 54 ± 16 min. Plasma total digitoxin concentrations increased threefold during the hour after initial Fab infusion, while plasma free digitoxin concentration decreased to less than 0.1 ng/ml. Effects on digitoxin pharmacokinetics of these Fab fragments and the antibody population from which they were derived were further investigated in a primate species. Unlike common laboratory animals previously studied, the rhesus monkey was found to have a prolonged elimination half-life, estimated at 135Dr. Ochs was a Fellow of Deutsche Forschungsgemeinschaft.Received for publication 20 January 1977 and in revised form 5 July 1977. and 118 h by radioimmunoassay and [3H]digitoxin measurements, respectively, similar to man and thus providing a clinically relevant experimental model. Intravenous administration of 2 mol of specific Fab fragments per mole of digitoxin 6 h after 0.2 mg of digitoxin produced a rapid 4.3-fold increase in plasma total digitoxin concentration followed by a rapid fall (t1 4 h) accompanied by a 14-fold enhancement of urinary digitoxin excretion over control values during the 6-h period after Fab was given. Analytical studies were consistent with increased excretion of native digitoxin rather than metabolites, and the glycoside was found in equilibrium dialysis studies to be excreted in the urine in Fab-bound form. Administration of 2 mol of specific antibody binding sites per mole of digitoxin as intact IgG caused a greater and more prolonged increase in plasma total digitoxin concentration, peaking 13-fold above control levels. In contrast to the effects of Fab, however, specific IgG reduced the rate of urinary digitoxin excretion substantially below control values. We conclude that Fab fragments of antibodies with high affinity for digitoxin are capable of rapid reversal of advanced, otherwise let...

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ACCUMULATION AND RELEASE OF ³H‐DIGOXIN BY GUINEA‐PIG HEART MUSCLE

Cited by 56 publications

References 13 publications

The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle

The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle

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

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

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ACCUMULATION AND RELEASE OF 3H‐DIGOXIN BY GUINEA‐PIG HEART MUSCLE

Cited by 56 publications

References 13 publications

The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle

The uptake of cardiac glycosides in relation to their actions in isolated cardiac muscle

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

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

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ACCUMULATION AND RELEASE OF ³H‐DIGOXIN BY GUINEA‐PIG HEART MUSCLE