Vincent P. Butler

Determination of Therapeutic and Toxic Serum Digoxin Concentrations by Radioimmunoassay

Abstract A sensitive (0.2 ng per milliliter), precise (standard deviation 3 to 4 per cent), and specific radioimmunoassay for serum digoxin concentration has been developed. Levels are determined by measurement of the extent to which digoxin in the patients serum competes with tritium-labeled digoxin, added in vitro, for digoxin-specific antibody binding sites. Mean values in nontoxic patients with normal renal function receiving 0.25 or 0.50 mg per day were 1.1 and 1.4 ng per milliliter respectively; the ranges fell within relatively narrow limits. Patients with cardiac arrhythmias attributed to digoxin toxicity had a mean level of 3.3 ng per milliliter, and little overlap with the nontoxic group (p less than 0.001). A determination can be completed in one hour, and may provide useful information to the clinician faced with the difficult problem of evaluating his patients state of digitalization.

Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies.

Purified Fab fragments of ovine digoxin-specific antibodies reversed severe digoxin intoxication in a patient who had taken 22.5 mg of the drug with suicidal intent. Atrioventricular block with extreme bradycardia was temporarily managed by pacing, but progressive, intractable hyperkalemia (serum potassium of 8.7 meq per liter) with increasing pacing threshold and progressive intraventricular conduction delay was controlled only after infusion of 1100 mg of Fab. Sinus rhythm returned 10 minutes after completion of Fab infusion. Within five hours, the serum potassium concentration fell to 4.0 meq per liter. Free digoxin concentrations in serum fell sharply to undetectable levels, whereas total serum digoxin concentration concomitantly increased 12-fold. Renal excretion of digoxin bound to Fab was documented. Reversal of toxicity was not accompanied by hemodynamic instability, and antibodies to sheep Fab fragments were not detected in the patients serum after treatment. Thus, purified digoxin-specific Fab fragments are capable of rapid reversal of advanced digoxin toxicity.

Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases

Purified Fab fragments of digoxin-specific antibodies obtained from sheep were used to treat 26 patients with advanced, life-threatening digoxin (23 cases) or digitoxin (3 cases) toxicity. These patients had advanced cardiac arrhythmias, and in some cases hyperkalemia, which were resistant to conventional treatment. All patients had an initial favorable response to doses of Fab fragments calculated (in most cases) to be equivalent, on a molar basis, to the amount of cardiac glycoside in the patients body. In four patients treated after prolonged hypotension and low cardiac output, death ensued from cerebral or myocardial hypoperfusion. In one case the available Fab fragment supply was inadequate to reverse a massive suicidal ingestion of digoxin, and the patient died after recurrent ventricular arrhythmias. In the remaining 21 patients, cardiac rhythm disturbances and hyperkalemia were rapidly reversed, and full recovery ensued. There were no adverse reactions to the treatment. We conclude that the use of purified digoxin-specific Fab fragments is a safe and effective means to reverse advanced, life-threatening digitalis intoxication.

Variation in Biologic Availability of Digoxin from Four Preparations

Abstract The unexplained association of unusually large maintenance doses of digoxin and low serum digoxin concentrations in several patients prompted a study of the biologic availability of various digoxin products recently available for use on the wards of a New York City municipal hospital. In crossover studies in which 0.5 mg of digoxin was administered orally to normal volunteers, marked differences in serum digoxin levels achieved over a five-hour period were demonstrated. With one product peak serum levels were seven times those obtained with another. Significant variation between different lots prepared by a single manufacturer was also observed. Evidence of biologic as well as chemical equivalency of digoxin products for use in man should be required.

Urinary excretion of reduced metabolites of digoxin.

The urinary excretion of the relatively cardioinactive reduced metabolites of digoxin, dihydrodigoxin and related compounds was measured by radioimmunoassay in 131 normal subjects during studies of the bioavailability of digoxin preparations. Digoxin reduction products (DRP) constitute more than 5 percent of the excretion of digoxin and its metabolites in one-third of the volunteers after the administration of single or multiple doses of digoxin. There was little or no output of DRP during the first 8 hours after a single dose, with maximal excretion usually occurring on the second day. Most subjects who excreted more than 5 percent DRP on one occasion did so with each subsequent exposure to digoxin. Six volunteers, however, in whom substantial amounts of DRP had previously been found, failed to excrete detectable quantities after subsequent doses. In two, this change occurred shortly after they took erythromycin. Urinary DRP were less after the intravenous administration compared to the oral administration of digoxin. After oral doses, DRP excretion tended to vary inversely with the bioavailability of the preparation. The findings are consistent with the hypothesis that DRP are formed as the result of the activity of a variable component of the intestinal flora. Prospective studies will be necessary to prove this hypothesis.

Inhibition of Digoxin Absorption by Neomycin

The effect of the administration of the antibiotic neomycin sulfate on the absorption of digoxin was assessed in crossover studies in normal human volunteers. Doses of neomycin (1 and 3 g) markedly depressed serum digoxin concentrations, the areas under the serum concentration-time curves, and cumulative 6-day urinary digoxin excretion after the oral ingestion of 0.5 mg of the cardiac glycoside in tablet form. Neomycin also prolonged the mean time at which peak serum digoxin levels were attained by 1.7 to 3 hr. The inhibition of digoxin absorption was also seen: (1) when the antibiotic was given 3 or 6 hr before the cardiac glycoside, (2) with digoxin tablets of varying dissolution rate, (3) when digoxin or neomycin solutions were used instead of tablets, and (4) in a patient who had had a total gastrectomy. When neomycin was administered with maintenance doses of digoxin, steady state serum digoxin concentrations were significantly reduced. When neomycin was given after a 9-day period of digitalization, the terminal serum digoxin half-life was not significantly shortened. Single doses of neomycin did not interfere with the extent of absorption of d-xylose. In vitro, neomycin did not affect the movement of digoxin across dialysis membranes, nor did it precipitate digoxin out of human bile or intestinal fluid. Neomycin thus clearly depresses the rate and extent of digoxin absorption in man. The mechanism of this effect remains to be established.

Current Status of the Rheumatoid Factor

Excerpt This review of the rheumatoid factor will present certain established facts about the physicochemical and immunochemical nature of the rheumatoid factor, certain clinical observations that ...

Serum digitalis measurements in the assessment of digitalis resistance and sensitivity

Antibodies to digitalis glycosides have been elicited in experimental animals and have been utilized in the development of rapid, sensitive, specific and convenient radioimmunoassay methods for the clinical measurement of digoxin and other cardiac glycosides in man. The use of these assay methods has supplemented earlier studies with radiolabeled digitalis preparations and has made it possible to obtain much new information concerning factors which may contribute to the well known patient to patient variability in digitalis dosage requirements and in sensitivity to the toxic effects of cardiac glycosides. In some patients with a poor clinical response to digitalis, the finding of a serum concentration which is relatively low for the dose prescribed may suggest that true digitalis resistance is not present and may raise questions of poor patient compliance, tablet inadequacies, intestinal malabsorption, increased metabolic degradation or hyperthyroidism; if the cause of the low serum level cannot be identified or corrected, serial serum measurements should enable safe and rational upward adjustment of dosage. In some patients with digitalis toxicity, the finding of a serum level which is relativity high for the dose prescribed may suggest that the patient is not sensitive to digitalis but rather is excreting it slowly; in such instances in elderly patients (with decreased glomerular filtration rates) and in patients with renal disease, serial digitalis measurements are useful adjuncts to clinical observation in determining optimal digitalis dosage schedules. A knowledge of serum digitalis concentrations should enable us to develop sound principles for a more rational approach to the clinical administration of cardiac glycosides, especially in patients with unusually high dosage requirements or with unusual sensitivity to relatively small doses of digitalis.

Digoxin Tablet Bioavailability: Single-Dose and Steady-State Assessment

Abstract Variation in the biological availability of digoxin tablets is a significant problem, and the relative accuracy and reliability of various methods of assessing absorption of the glycoside ...

PRODUCTION AND PROPERTIES OF DIGOXIN-SPECIFIC ANTIBODIES*

Much has been learned in the past two decades concerning the interaction of digitalis glycosides with Na+, K+-ATPase,1-8 but it has not been definitively established that the therapeutic and toxic effects of these cardioactive glycosides on mammalian cells are mediated through the interaction with, and inhibition of, Na+, K+-ATPase by drugs of this class.9 Furthermore, despite the major advances in our knowledge concerning the interaction of digitalis with Na+, K+-ATPase, no specific inactivator or antagonist of this interaction has been described, although such an inactivator might yield useful information concerning the cellular mechanism of digitalis action; in addition, such an inactivator, if not toxic itself, might provide a useful adjunct in the clinical recognition and treatment of digitalis intoxication. It occurred t o us that, if antibodies t o digitalis could be elicited in experimental animals, such antibodies, by virtue of their capacity t o bind digitalis specifically, might be useful as specific antagonists or inactivators of digitalis glycosides. We therefore set out to elicit digitalisspecific antibodies, not only for the purpose of digitalis measurement, but also because we felt that such antibodies would be useful in the study of the mechanism of action of digitalis and in the clinical therapy of severe digitalis intoxication in man. We chose t o elicit antibodies specific for the digitalis glycoside digoxin.I0-l2