Digitoxin Studies

Gjerdrum, Kjell

doi:10.1111/j.1365-2796.1972.tb00007.x

Journal of Internal Medicine

1972

DOI: 10.1111/j.1365-2796.1972.tb00007.x

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Digitoxin Studies

Kjell Gjerdrum

Abstract: Serum digitoxin has been determined in 144 patients by a modified Rb‐ATPase method. Mean digitoxin concentration during maintenance therapy increased with the daily dose: 0.036 mg/day – 10.8 ng/ml, 0.05 mg/day – 11.2 ng/ml, 0.071 mg/day – 16.1 ng/ml, 0.1 mg/day – 18.1 ng/ml. The increase in serum after different loading doses is presented. After withdrawal of maintenance therapy in patients the mean serum half life was 6.9 days (S.D. = 2.7 days). The correlation serum half life—serum creatinine was significant… Show more

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1981

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Cited by 4 publications

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Interindividual differences in the pharmacokinetics of digitoxin and digoxin during long-term treatment

Haustein

1981

Eur J Clin Pharmacol

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Patients suffering from congestive heart failure received maintenance doses of digitoxin (N = 10) or digoxin (N = 8). The plasma glycoside concentration was determined, and after a single dose of 3H-digitoxin or 3H-digoxin, the decline and excretion of radioactivity were measured over a period of 7 (digitoxin) and 3 days (digoxin). Plasma radioactivity declined with a T1/2 beta between 77 and 234 h (mean 138 h) in the case of digitoxin and with a T1/2 beta between 9.2 and 38.6 h (mean 23.5 h) for digoxin. A close correlation between T1/2 beta and excreted radioactivity and T1/2 beta and total plasma level was found for digitoxin. In 4 patients TLC of urine showed that interindividual variations in digitoxin elimination could possibly be attributed to variation in metabolism, resulting in the production of different metabolites. Predicted digitoxin plasma levels agreed well with measured values. The maintenance dose could be calculated from the total body clearance (VCl) and a presumed plasma glycoside level. The recommended technique facilitates dosage calculations in patients treated with digitoxin.

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Interindividual differences in the pharmacokinetics of digitoxin and digoxin during long-term treatment

Haustein

1981

Eur J Clin Pharmacol

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A standard approach to compiling clinical pharmacokinetic data

Sheiner

Benet

Pagliaro

1981

Journal of Pharmacokinetics and Biopharmaceutics

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A standard format for a Clinical Pharmacokinetic Summary is proposed. It consists of a heading, tables, notes, and references for each drug reviewed. The table presents a unified and logical set of clinically useful population pharmacokinetic parameters. They concern four major areas: absorption, distribution, elimination, and the relationship of concentration to effect. Within each major group, parameters dealing with extents and rates of processes are given. Each such parameter is really two: a population mea value (for example, average volume of distribution) and the standard deviation of individual values about this mean. The first value allows individual predictions of dosage or drug level to be made; the second allows computation of the likely proximity of subsequently observed quantities to those predictions. The table presents single consensus values for each population parameter, rather than a list of values. A procedure for computing these consensus values, and for revising them in the light of new data, or reinterpreted old data, is given. Examples of Summaries are given. The method appears applicable to a variety of drugs. We suggest our approach as a standard one for preparing Clinical Pharmacokinetic Summaries, and urge our colleagues to consider it for that purpose.

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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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Digitoxin Studies

Cited by 4 publications

References 15 publications

Interindividual differences in the pharmacokinetics of digitoxin and digoxin during long-term treatment

Interindividual differences in the pharmacokinetics of digitoxin and digoxin during long-term treatment

A standard approach to compiling clinical pharmacokinetic data

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

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