Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning.

OBJECTIVE: Despite administration of Fab fragments in digitalis poisoning, high mortality rates are consistently reported. A previous study suggested that Fab fragments prescribed as first-line therapy might improve mortality rate. Our objective was to evaluate this approach. DESIGN: Retrospective chart review (January 1990 to January 2004). SETTING: University hospital intensive care unit. PATIENTS: Consecutive patients admitted for cardiac glycoside poisoning. INTERVENTION: First-line therapy with Fab fragments (with or without atropine) in either curative or prophylactic doses. MEASUREMENTS AND MAIN RESULTS: A total of 141 patients were admitted for digitalis poisoning of whom 66 received first-line Fab fragment therapy. Their median age was 74 years (25th to 75th percentiles: 51-83); 76% were women. Half were intoxicated by digitoxin and half by digoxin. Median serum concentration was 168 (108-205) ng/mL for digitoxin and 6.2 (4.3-13.5) ng/mL for digoxin. Conduction disturbances were reported in 45 cases (68%) and ventricular arrhythmia in six cases (9%). Fab fragments were administered as curative treatment in 21 patients (32%) and prophylactically in 45 patients (68%). The median cumulative dose was 4 (4-6) vials. No adverse effects were reported. Five patients (7.6%) died. CONCLUSIONS: First-line therapy with Fab fragments in patients with digitalis poisoning was associated with a low mortality rate.

Antibodies and digitalis: the modern revolution in the use of an ancient drug.

Although digitalis glycosides have been widely used in clinical medicine since the classic description by William Withering in 1785, it was not until the advent of a specific immunoassay that their clinical pharmacology could be examined intensively under a wide variety of circumstances. The insights gained into the relations among dosage, plasma concentration, bioavailability, distribution, metabolism, excretion and interactions with other drugs and the manifestations of toxicity certainly have reduced the frequency of adverse reactions to this highly toxic but useful group of drugs. More recently, antibodies have also been utilized as specific antidotes for digitalis toxicity, with dramatic life-saving effect.

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.

Recognition and management of digitalis toxicity.

The most important step in the management of toxicity due to any of the cardiac glycosides is its recognition. Despite the development of an accurate clinical assay for serum levels of digoxin greater than 20 years ago, digitalis toxicity remains common and difficult to confirm, even if suspected, due primarily to 2 factors. First, the signs and symptoms of digitalis toxicity, most commonly an abnormal electrocardiogram showing ventricular or atrial arrhythmias, with or without some degree of concurrent atrioventricular block, often also occur in patients with congestive heart failure (CHF) and underlying coronary atherosclerosis who are not receiving a cardiac glycoside. Second, due to digoxin's narrow therapeutic ratio, the marked degree of variability in the sensitivity of individual patients to its toxic effects, and the common problem of obtaining blood samples inappropriately during the early distribution phase following dosing, a serum digoxin concentration often does not serve as a reliable indicator of toxicity. Despite these difficulties in diagnosis, the management of digoxin toxicity has been made much more effective with the widespread availability of F(ab) fragments of anti-digoxin antibodies. This drug provides the clinician with a rapidly acting, safe antidote for all commonly used digitalis preparations. Conventional therapy for digoxin toxicity remains the maintenance of serum potassium levels greater than or equal to 4 mEq/liter, reversal of decompensated CHF or overt myocardial ischemia, attention to serum magnesium levels and the patient's acid-base status, appropriate antiarrhythmics in the event of ventricular arrhythmias, and a temporary pacemaker for high-grade atrioventricular block. Nevertheless, the high specificity and documented safety of the antibody preparation provides a needed safety net for the continuing use of cardiac glycosides as first-line inotropic agents in the modern therapy of chronic CHF.

Hypothalamic digitalis-like substance is released with sodium-loading in rats.

Role of the hypothalamic digitalis-like substance (EDLS) on the hypertension associated with an excess intake of sodium and the releasing mechanism were investigated. The blood pressure in rats fed with a sodium diet increased significantly after 4 weeks of the treatment compared to the control rats fed with a regular diet, which was accompanied by increased urinary output of the EDLS. Electrical lesions of the AV3V area in the hypothalamus significantly decreased both the urinary EDLS level and the blood pressure elevated by the sodium-loading. With the immunohistochemistry using digoxin antibody, the immunoreactives were localized in the neurons of paraventricular and supraoptic nuclei and some other hypothalamic areas, and were also seen in the nerve fibers distributed in the basal hypothalamus, infundibulum, and pituitary posterior lobe. Assuming that the CSF sodium is responsible for the release of EDLS, hypertonic NaCl (2.5 M) was infused into the lateral ventricle for 30 minutes. Blood pressure increased gradually, attaining peak rises about 30 minutes later. The plasma content of the EDLS was significantly greater in the hypertonic NaCl group than the control group treated with either the artificial CSF or 2.5 M of urea solution. On the other hand, the hypothalamic content decreased with the infusion of the hypertonic saline. Furthermore, the continuous intracerebroventricular infusions of the hypertonic NaCl with osmotic minipumps in conscious rats significantly increased the arterial pressure after 6 days. Thereby, the plasma level of the EDLS was significantly greater than the control rats that received only the artificial CSF.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous inotropic substance from heart tissue has digitalis-like properties.

In the past few years, we developed an extraction procedure which we successfully used to isolate a crude fraction containing digitalis-like substance (DLS) from porcine left ventricular tissue. In this study, the crude fraction was found to cross-react with digoxin antibodies and showed immunoreactivity of 4.25 +/- 0.6 ng digoxin equivalent/ml. On further purification of the crude fraction using silica gel G column chromatography, a fraction C was obtained, which was highly positive inotropic on canine trabeculae and it dose-dependently inhibited ouabain sensitive 86Rb+ uptake in rat heart slices. A 50% inhibition of uptake was obtained by 25 microliters of fraction C. Fraction C also inhibited canine kidney Na+, K(+)-ATPase (Sigma, U.S.A.) dose-dependently and a 50% inhibition of this enzyme required 17 microliters of fraction C. Ashing of the fraction C at 500 degrees C resulted in loss of inotropic and enzyme inhibitory activities, indicating an organic nature of the unknown digitalis-like substance.

[The treatment of digitalis poisoning with antibiotics (author's transl)]. / Zur Antikörpertherapie der Digitalisintoxikation.

Digitalis intoxication occurs frequently and proves fatal in 5-10% of all cases. Treatment is limited to symptomatic measures. Glycoside-specific antibodies offer a new way of treatment of digitalis intoxication. In our experiments with cats, they were found to be highly effective in reversing digoxin-induced arrhythmias. Specific antibodies have previously been employed in a patient with suicidal digoxin intoxication. We report a case of nonsuicidal Lanatosid-C intoxication treated with F(ab')2-fragments of digoxin-specific antibodies from the sheep. The treatment was successful and without side-effects. Serum concentration of free digoxin and total digoxin measured during and after treatment showed a decrease of free and a sharp raise in total digoxin. For clinical use, antibody fragments are superior to intact antibodies. Problems and possible indications concerning the treatment of digitalis intoxication with antibodies are briefly discussed.

Preparation and experimentation of an antidigitalin monoclonal antibody: interest in human treatment.

A monoclonal antidigitalin antibody was obtained following the immunization of BALB/mice with digitalin coupled to BSA, and the fusion of lymphocytes from these mice with murin myeloma 8653. The supernatants were screened by a radioimmunoassay in which the supernatant was incubated with digitalin coupled to I125. This monoclonal antibody "Dig 278" has an antigen binding ratio of 95%; is an IgGl; has a titre of 1/1000 and its affinity constant, as determined by a Scatchard plot, was 1,20(9) L/M. By experimenting with the monoclonal antibodies on 15 rabbits, we have obtained the reversal of heart rhythm disorders and the survival of animals injected with a lethal dose of digitalin. All the controls died. This antibody could prove useful in treating advanced cases of digitalin intoxication and for which no satisfactory treatment is available at present.

Cross reactivity of digitoxin and spironolactone in two radioimmunoassays for serum digoxin.

We measured the cross reactivity of two medications--digitoxin and spironolactone--in two digoxin radioimmunoassay (liquid and solid-phase) kit procedures. Both tests showed similar average percentages of cross reactivity with digitoxin (7.2 and 8.9% for intravenous, and 11.9 and 10.9% for oral administration), but no cross reactivity with spironolactone or its metabolites after equal intravenous or oral doses.

[Production of an anti-digitalin monoclonal antibody (author's transl)]. / Production d'un anticorps monoclonal anti-digitaline.

Anti-digitalin monoclonal antibodies were obtained by hybridization of lymphoid cells from mice immunized with the drug and the 8653 myeloma cells from BALB/c Mice. Two of these antibodies were submitted to immunochemical analysis which revealed that they belonged to IgM and IgGl classes, and the high affinity of one of them (1,2 x 10(9) M(-1)). The availability os such antibodies opens new perspectives for the treatment of digitalin intoxication and the possibility of establishing a standardized radioimmunoassay.

The effect of digitalis glycosides-specific antisera on the binding of the glycosides to (Na+ + K+)-ATPase.

The capability of digitalis glycoside-specific antisera to reverse the glycoside-induced inhibition of (Na+ + K+)-ATPase activity was examined. The antisera-induced reversal of the ATPase inhibition caused by digoxin was considerably slower (k-1 = 0.1177 . 10-3 .S-1) than the reversal caused by dihydrodigoxin and dihydrodigitoxin (k-1 = 4.462 . 10-3 . S-1 and K-1 = 3.609 .10-3 . S-1, respectively). In addition, the dissociation rate constants of the ouabain-induced dissociation of the various glycosides from the glycoside-ATPase complex were determined: The dissociation rate constants of the antisera-induced restoration of enzyme activity and that of the ouabain-induced dissociation of glycosides from the glycoside-enzyme complex were not significantly different.