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PubMed1992

[The monitoring of plasma digoxin levels during acute digitalis poisoning treated with Fab anti-digoxin fragments].

Life-threatening digitalis intoxication is treated using digoxin specific antibody fragments (Fab) that bind and inactivate the drug. The free digoxin serum concentration could be useful in the management of Fab-treated patients, but the standard methods of measurement can be clinically misleading because Fab anti-digoxin interferes with digitalis immunoassay measurements. A case involving Fab therapy of a digoxin overdosed patient, in which two laboratory methods gave very different results, is reported. The radioimmunologic assay (RIA), widely used in laboratories, yielded high values without relation to true serum free digoxin concentration. On the contrary, the recently introduced fluoroenzymatic sequential immunoassay (FEIA), which accurately measures free glycoside concentration, was a valuable aid in monitoring Fab treatment. Therefore, cardiologists' knowledge of a possible interference of specific anti-digoxin fragment treatment with many immunoassays may greatly enhance the rational management of these patients.

Acute Disease↗
PubMed1985

Endogenous digoxin-like immunoreactive factors: impact on digoxin measurements and potential physiological implications.

Various laboratories have reported endogenous digoxin-like immunoreactive factor(s) (DLIF) in blood from patients in renal failure or liver failure, from newborn infants, and from third-trimester pregnant women. Similar immunoreactivity has been detected in amniotic fluid, in cord blood, and in urine and serum from normal subjects. The factor(s) giving rise to this immunoreactivity cross react with antibodies used in many currently available immunoassays for digoxin, sometimes causing apparent digoxin concentrations exceeding the therapeutic range obtained for exogenous digoxin, with consequent errors in measurement and in subsequent clinical interpretation of digoxin results. Here, I summarize findings in our laboratory and those of others. DLIF evidently exist in three states in serum: tightly protein-bound, weakly protein-bound, and unbound (free). In normal subjects, greater than 90% of the total DLIF in serum is tightly but reversibly bound to serum proteins and is not readily detectable by direct measurement of digoxin in serum with conventional immunoassays. However, there seems to be a redistribution of the more weakly bound and unbound components in patients with renal failure, pregnant women, and newborns. The increased values detected in these groups are ascribable to increased amounts of weakly bound and unbound DLIF rather than to increased total DLIF. Carrier proteins may play a prominent role in the transport of these factors in blood. I discuss the potential physiological and pharmacological implications of detecting endogenous immunoreactive factors that cross react with antibodies to drugs.

Adult↗
PubMed1979

Value of serum digoxin concentration measurement in the control of digoxin therapy in atrial fibrillation.

The association between steady-state serum digoxin concentrations and control of ventricular response rate (VRR) was studied in 53 consecutive patients with atrial fibrillation. Decreases in VRR were significantly correlated with serum digoxin (rs = -0.22, P less than 0.05). Clinical responses were appropriate to serum digoxin concentrations in 37 patients (69.8%) and were inappropriate in 16 (30.2%) (P less than 0.05). Complicating clinical factors were present in all eight patients with inappropriate responses to therapeutic serum digoxin (0.5 to 2.0 ng/ml) (P = 0.046), but were also found in many patients with appropriate responses and thus could not serve to differentiate between the two categories. Digitalis intoxication occurred in one of the three patients with a concentration of serum digoxin greater than 2 ng/ml (P = 0.056). In 30% of our patients with atrial fibrillation, monitoring of serum digoxin was of value in identifying inappropriate therapeutic responses indistinguishable by clinical means and in defining the subgroup of refractory cases, which allows the prevention of digitalis intoxication.

Atrial Fibrillation↗
PubMed1978

Human myocardium and plasma digoxin concentration in patients on long-term digoxin therapy.

Digoxin concentration of 14 left ventricular papillary muscles and 36 right atrial appendages of 45 patients undergoing cardiac surgery were determined by the NEN 125J-radioimmunoassay. Blood specimens for digoxin assay were withdrawn immediately before operation, 12 to 16 hr after the last digitalis dose. Mean papillary muscle digoxin concentration was 76.1 ng/g +/- 25.5; mean ratio to plasma digoxin level, 36.8:1. The mean concentration of right atrial appendages was 41.8 ng/g; mean ratio, 29.9:1. Most of the tissue specimens were examined histologically using Hematoxylin-Eosin and van Gieson stains. No clear relation between tissue digoxin concentration and hisological alteration, i.e., the degree of fibrosis or lipomatosis, could be found, although most severe alterations were found in right atrial appendages corresponding to a higher variation in tissue concentrations and a poorer correlation to plasma digoxin (r = 0.47, respectively for papillary muscle r = 0.73).

Adult↗
PubMed1982

Effect of quinidine on the renal clearance of digoxin in the presence of low and high serum digoxin concentrations.

The effect of an infusion of quinidine, 180 micrograms/kg/Min (base) on the fractional clearance of digoxin (CDIG/Cin) was studied in saline volume-expanded dogs given a constant infusion of digoxin of either 0.0067 micrograms/kg/min (low dose) or 0.120 micrograms/kg/min (high dose). CDIG/CIN decreased 28% from 1.42 +/- 0.36 during control periods to 1.01 +/- 0.03 (P less than .05) with quinidine in dogs given the low dose. In dogs given the high dose of digoxin, CDIG/CIN decreased 22% from 0.76 +/- 0.17 to 0.59 +/- 0.05 (p less than .05) with quinidine. It is concluded that quinidine reduces CDIG/CIN. High doses of digoxin also reduce CDIG/CIN. Inasmuch as quinidine reduces CDIG/CIN to the same extent in the presence of low or high dose digoxin, the effect of quinidine would appear to be mediated through a mechanism different from that of digoxin.

Animals↗
PubMed1994

Digoxin immunoassay with cross-reactivity of digoxin metabolites proportional to their biological activity.

Our objective was to identify commercially available digoxin immunoassays whose cross-reactivity with digoxin metabolites paralleled the pharmacological activity of the metabolites. We measured the immunoreactivity of digoxigenin bis- and monodigitoxosides, digoxigenin, and dihydrodigoxin in four immunoassays and compared the immunoactivities with pharmacological activities from studies involving whole-animal and receptor (Na,K-ATPase)-based assays. Correlation coefficients for comparisons of immunoassay reactivity and human heart receptor reactivities were: ACS, 0.96; TDx, 0.60; Stratus, 0.57; and Magic, 0.42. Comparison with other biological assays showed a similar trend. The major difference in metabolite cross-reactivities among the immunoassays was that of digoxigenin (ACS, 0.7%; TDx, 103%; Stratus, 108%; Magic, 153%), which has approximately 10% bioactivity relative to digoxin. Measured recovery of mixtures of digoxin and metabolites confirmed these findings. We conclude that the monoclonal antibody in the ACS digoxin assay closely mimics Na,K-ATPase in detecting digoxin and its metabolites. This finding provides a basis for developing therapeutic drug monitoring immunoassays capable of approximating the true pharmacological activity of a mixture of drug metabolites.

Animals↗
PubMed1987

The influence of digoxin-specific antibody fragments on digoxin disposition in the rat.

Pentobarbitone-anaesthetized bile duct-cannulated female rats were injected intravenously with an equimolar dose of digoxin-specific sheep antibody fragments (DS-Fab) at 2 or 60 min after a dose of [3H]digoxin. The plasma drug levels were promptly elevated by 7-fold or 12-30-fold when the DS-Fab were given at 2 or 60 min respectively. When tissue drug concentrations were measured 2 min after a dose of DS-Fab (given 60 min after digoxin) which caused a 30-fold increase in plasma concentration, reductions could be detected if corrections were made for the presence in the tissues of high plasma concentrations of DS-Fab-bound drug. For instance, reductions in the heart, liver and small intestine were 63, 58 and 48% respectively. However, by 120 min after digoxin injection the only detectable effects on tissue drug concentration were in the kidney, where concentrations had increased 14-fold or 7-fold when the DS-Fab were given at 2 or 60 min respectively. Over the 120 min period the urinary excretion of digoxin-derived radioactivity was enhanced, and in the case where DS-Fab were given at 2 min, a 3-fold increase in urinary excretion was seen, which resulted in a net increase in the overall drug elimination. This greater urinary elimination was accompanied by a marked increase in the amount of bound drug in the urine (control and experimental values were 4 and 36% respectively). The cumulative biliary excretion of radioactivity seemed to be slightly reduced by DS-Fab administration at 2 or 60 min, although this was not statistically significant. A lack of significant drug-specific binding in the bile suggested that the liver is not involved in the elimination of hapten-DS-Fab complexes. There was little effect on the intestinal secretion of the drug.

Animals↗
PubMed1980

Digoxin "receptors" in neonates: an explanation of less sensitivity to digoxin than in adults.

To investigate the possibility of altered digoxin receptor binding properties in neonates, we compared digoxin binding with erythrocytes from neonates and adults. Neonatal erythrocytes had two and a half times as many digoxin binding sites as adult erythrocytes. The neonatal "receptors" also had dissociation constants for digoxin that were twice the adult value. These findings suggest that differences in binding properties may explain the clinical observation of decreased sensitivity to digoxin in neonates and infants.

Adult↗
PubMed2000

Analysis of the use of digoxin immune fab for the treatment of non-life-threatening digoxin toxicity.

BACKGROUND: Studies indicate that digoxin toxicity often results in lengthy hospitalizations and considerable costs, both of which may be decreased through the routine use of digoxin immune Fab (FAB). METHODS: A computer-based decision analysis model was developed to compare the treatment of non-life-threatening digoxin toxicity with either FAB or standard therapy from the hospital perspective. A cost-minimization analysis was then performed to compare overall total costs (primary endpoint) for each treatment branch. A secondary endpoint of length of hospital stay (LOS) was also compared between the 2 groups. Clinical variables (serum digoxin concentration [SDC], creatinine clearance [Clcr], and body weight), event probabilities, and other model-specific variables were varied in univariate and multivariate sensitivity analyses. RESULTS: FAB was associated with an incremental cost of $54 compared with standard therapy ($2,784 vs. $2,730, respectively) but reduced LOS by 1.5 days (1.5 days vs. 3.0 days, respectively). Sensitivity analyses show that FAB is less costly at SDC > 3.5 ng/mL and Clcr < 22 mL/min. FAB reduced LOS at SDC > 2.3 ng/mL. Monte Carlo simulation revealed that FAB was less costly in 37% of the cases and reduced LOS 72% of the time compared with standard therapy. CONCLUSIONS: The abbreviated LOS associated with the use of FAB in patients with non-life-threatening digoxin toxicity may translate into lower treatment costs in many clinical scenarios, making it a cost-saving alternative to standard therapy in patients with high SDC and renal dysfunction.

Cardiotonic Agents↗
PubMed1979

The characteristics of the binding of 12-alpha-[3H]-digoxin to the membranes of intact human erythrocytes: relevance to digoxin therapy.

1 The characteristics of the binding of 12-alpha-[3H]-digoxin to the membranes of intact human erythrocytes are described. 2 Only one class of binding site can be demonstrated. Binding is time- and temperature-dependent, saturable and slowly reversible; it is inhibited by other cardiac glycosides and by potassium. 3 Pre-incubation with unlabelled digoxin reduces the subsequent binding of 12-alpha-[3H]-digoxin in stoichiometric fashion. 4 The possible application of the measurement of the binding of 12-alpha-[3H]-digoxin to the study of biochemical pharmacological events occurring during digoxin therapy is discussed.

Cardiac Glycosides↗
PubMed1991

Monitoring serum digoxin concentrations during digoxin immune Fab therapy.

Measurement of serum digoxin concentrations (SDCs) is used routinely in the diagnosis of digoxin toxicity. Following administration of the antidote, digoxin immune antigen binding fragments (Fab), SDC monitoring is hampered by assay-related problems because of the presence of Fab in the serum. Recent evidence has suggested several available methods to monitor free SDC during Fab therapy. This report describes the utility of monitoring free SDC following Fab administration. Free SDCs were obtained using an ultrafiltration and fluorescence polarization immunoassay system in three patients over periods of up to 204 hours after Fab administration. In each case, the decline in free SDC was temporally related to the resolution of digoxin toxicity; in one case, digoxin intoxication recurred and was associated with a rebound increase in free SDC. In addition to the therapeutic benefits, prospective monitoring of free SDC in two of the patients also may have resulted in cost savings secondary to reduced hospital stay or less use of Fab.

Adult↗
PubMed2000

Preparation of specific antisera to digoxin by using digoxin C-3' and C-3" hemisuccinate-bovine serum albumin conjugates.

The preparation and antigenic properties of digoxin C-3' and C-3" hemisuccinate-bovine serum albumin (BSA) conjugates are described. The antisera were prepared by immunizing rabbits with each of the digoxin-BSA conjugates, and properties of the antisera were characterized by RIA with 3H-labeled digoxin. The antidigoxin antiserum from immunization with digoxin 3'-hemisuccinate-BSA conjugate possessed high specificity for digoxin, exhibiting fairly low cross-reactions with dihydrodigoxin (2.1%), digoxigenin monodigitoxoside (0.9%), digoxigenin bisdigitoxoside (0.6%), and digoxigenin (0.1%).

Cross Reactions↗
PubMed1975

Improved computer-assisted digoxin therapy. A method using feedback of measured serum digoxin concentrations.

Automated feedback control methods were applied to a medical problem, in a computer program that used measured serum digoxin concentrations (as feedback) to predict future concentrations and to achieve desired concentrations. The system was validated by comparing its ability with the corresponding ability of physicians to regulate digoxin dosage. The prospective, randomized study included 51 patients. In the presence of varying amounts of feedback (serum digoxin concentration) information, the computer always predicted future digoxin concentrations as accurately as did physicians. For both computer and physician, the decrease in the prediction errors when two concentrations were known against that when no concentrations were known was significant: mean absolute error decreased from 0.40 to 0.25 ng/ml for the physicians and from 0.45 to 0.27 ng/ml for the computer. Thus the computer system is capable of simulating and reproducing a sophisticated aspect of physician behavior: "learning" about individual patient responses. The computer achieved desired concentrations more accurately than did physicians, especially when two or more previous digoxin concentrations were abailable (mean absolute achievement error for computer, 0.28 ng/ml; for physicians, 0.50 ng/ml).

Achievement↗
PubMedDate not supplied

Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. The Captopril-Digoxin Multicenter Research Group.

This multicenter, double-blind, placebo-controlled study compares the effects of captopril treatment with those of digoxin treatment during maintenance diuretic therapy in patients with mild to moderate heart failure. Compared with placebo, captopril therapy resulted in significantly improved exercise time (mean increase, 82 s vs 35 s) and improved New York Heart Association class (41% vs 22%), but digoxin therapy did not. Digoxin treatment increased ejection fraction (4.4% increase) compared with captopril therapy (1.8% increase) and placebo (0.9% increase). The number of ventricular premature beats decreased 45% in the captopril group and increased 4% in the digoxin group in patients with more than ten ventricular premature beats per hour. Treatment failures, increased requirements for diuretic therapy, and hospitalizations were significantly more frequent in patients receiving placebo compared with those receiving either active drug. Transitory hypotension occurred more frequently with administration of captopril. Captopril treatment is significantly more effective than placebo and is an alternative to digoxin therapy in patients with mild to moderate heart failure who are receiving diuretic maintenance therapy.

Captopril↗
PubMed1989

Immunofluorescence detection of digoxin with monoclonal digoxin specific antibody.

The present study primarily focuses on the analysis of digoxin binding of the heart muscle cells. The primary aim of the investigation was to demonstrate the cardiac glycoside morphologically. The direct immunofluorescence staining technique with digoxin specific monoclonal antibody or Fab fragments and FITC or Texas-Red conjugated antisera are useful for morphological demonstration of digoxin binding and localization in cardiac cells. With the immunofluorescence method, linkage can be observed on the sarcolemma membrane and on the wall of capillaries and arterioles in myocardial cells treated by cardiac glycoside. The specificity of reaction is provided by the negative reaction of cells, not treated by digoxin. Intensity of reaction depends on concentration. The photometric measuring of fluorescence enables the quantitative analysis of cardiac glycoside. It shows the sensitivity of the method in that cardiac glycoside linked to the cell membrane can be detected in the upper sphere of a therapeutic dose. Application of the immunofluorescence method is manifold and relatively simple, and this quick method can be used in diagnoses and in the study of cardiac glycoside receptors of cell membrane. On the basis of our own experiments it is possible to study the kinetics of digoxin linkage. The use of this method is demonstrated for investigation of single cell suspension and cryostat sections.

Animals↗
PubMed1988

False-positive serum digoxin concentrations determined by three digoxin assays in patients with liver disease.

The incidence and magnitude of false-positive serum digoxin concentrations (SDCs) determined by three digoxin assays in patients with liver disease were studied. Patients with biochemical evidence of liver disease were enrolled in the study if they had never received a cardiac glycoside, were not pregnant, were not receiving spironolactone, did not have moderate to severe renal impairment, and did not have transient elevations in liver function test results. Blood specimens from each patient were assayed for apparent SDCs in triplicate using a fluorescence polarization immunoassay (FPIA, TDx Digoxin II, Abbott) and a digoxin radioimmunoassay (RIA, GammaCoat I125, Clinical Assays) and in duplicate using a fluorometric enzyme immunoassay (Dade Stratus, American Dade). Forty-two patients met the study criteria. The percentage of patients exhibiting detectable apparent SDCs (greater than or equal to 0.2 ng/mL) was 57% with RIA, 55% with FPIA, and 28% with the fluorometric enzyme immunoassay. Apparent SDCs ranged from 0.2 to 0.6 ng/mL (RIA), 0.2 to 1.56 ng/mL (FPIA), and 0.2 to 0.38 ng/mL (fluorometric enzyme immunoassay). Values obtained using the fluorometric enzyme immunoassay were significantly different from the apparent SDCs determined using RIA and FPIA; however, no significant difference was found between the values obtained using RIA and FPIA. Significant correlations were found between the apparent SDCs determined using RIA and serum bilirubin values and between the apparent SDCs determined using the fluorometric enzyme immunoassay and alkaline phosphatase values. Of the three assay methods tested, the fluorometric enzyme immunoassay showed the least cross-sensitivity to digoxin-like immunoreactive substance (DLIS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1979

An improvement in digoxin bioavailability. Studies with soft gelatin capsules containing a solution of digoxin.

A study of relative bioavailability of two digoxin formulations was carried out on 28 healthy volunteer human subjects of both sexes. A commercial digoxin in tablet form was compared with a new commercial formulation which contains a solution of digoxin in soft gelatin capsules. The parameters investigated were: plasma levels, area under the plasma level-time curve, daily urinary excretion of digoxin and a series of polycardiographic measurements, all the parameters being evaluated in a steady-state condition (14 days of treatment). All the parameters investigated demonstrated better bioavailability in the capsules than in the tablets, the average improvement being 26.1%. The better bioavailability of digoxin capsules also resulted in more rapid and wider variations in the polycardiographic parameters.

Adult↗
PubMed1982

Fab fragments of digoxin-specific antibodies used to reverse ventricular fibrillation induced by digoxin ingestion in a child.

Digitalis poisoning is a rare problem in children, but it may be life threatening. A case of massive overdose of digoxin in a 2 1/2-year-old boy that produced prolonged ventricular fibrillation refractory to conventional therapy is reported. After two hours the boy was given digoxin-specific Fab fragments of antibody in sufficient quantity to bind his estimated dose of 10 mg. By completion of the treatment minutes later, normal rhythm and circulation were restored. The serum free digoxin level before antibody administration was greater than 100 ng/ml, and it rapidly fell to undetectable levels after antibody was given. Digoxin bound to the antibody had a clearance half-life of approximately 48 hours. The child had no apparent neurologic damage and his intellectual function was normal on discharge. He had a transient hematuria and a residual incomplete right bundle branch block. Administration of purified Fab fragments of digoxin-specific antibodies can be life saving in children with digitalis poisoning, and prolonged cardiopulmonary resuscitation in children is justified when the cause of cardiac arrest is potentially reversible.

Animals↗