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PubMed1989

Digoxin elimination in a functionally anephric patient after digoxin-specific Fab fragment therapy.

The elimination of total digoxin after digoxin-specific Fab fragment therapy in a patient in end-stage renal disease is described. Two-component, nonlinear exponential regression of the patient's total digoxin concentration data revealed biphasic elimination: a fast phase with a half-life of 43 h and a slow phase with a half-life of 330 h. Serum total digoxin concentration decreased 20% 12 h after the initiation of Fab fragment therapy. The mean serum concentrations of total digoxin and apparent total digoxin as measured by fluorescence polarization immunoassay during a 520-h period after the initiation of therapy were 18.42 and 14.77 ng/ml, respectively (n = 15). The correlation between the two measurements was good (r = 0.987). The time course of free digoxin concentration obtained after ultrafiltration at 2, 20, or 37 degrees C is also described. The free digoxin concentrations (n = 10) at these temperatures averaged over a 282-h period were 0.35, 0.53, and 0.82 ng/ml, respectively (p less than 0.001, 2 degrees C vs. 37 degrees C).

Aged↗

PubMed1991

Highly specific radioimmunoassay for digoxin using a monoclonal antibody selected for lack of interference by digoxin-like immunoreactive substances in cord blood sera.

Four digoxin radioimmunoassays (RIA) were evaluated using four antidigoxin monoclonal antibodies (MAb) with different binding specificities for digoxin metabolites and other glycosides. These RIA have been used to measure the apparent digoxin concentrations in the sera of patients treated with digoxin, in cord blood sera and in rat intestine aqueous extracts. Two MAb strongly recognized digoxin-like immunoreactive substances (DLIS) in cord blood sera and in rat intestine aqueous extract. In contrast, one MAb (2C2), which recognizes active digoxin metabolites and does not cross-react with inactive metabolites nor with digotoxin, showed no reactivity with DLIS in the cord blood sera tested. This MAb was used in a new digoxin RIA that was rapid, sensitive, reproducible, and specific for digoxin and its active metabolites.

Antibodies, Monoclonal↗

PubMed1996

Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein.

1. We have used mice with a disrupted mdr 1a P-glycoprotein gene (mdr 1a (-/-) mice) to study the role of P-glycoprotein in the pharmacokinetics of digoxin, a model P-glycoprotein substrate. 2. [3H]-digoxin at a dose of 0.2 mg kg-1 was administered as a single i.v. or oral bolus injection. We focussed on intestinal mucosa and brain endothelial cells, two major pharmacological barriers, as the mdr 1a P-glycoprotein is the only P-glycoprotein normally present in these tissues. 3. Predominant faecal excretion of [3H]-digoxin in wild-type mice shifted towards predominantly urinary excretion in mdr 1a (-/-) mice. 4. After interruption of the biliary excretion into the intestine, we found a substantial excretion of [3H]-digoxin via the gut mucosa in wild-type mice (16% of administered dose over 90 min). This was only 2% in mdr 1a (-/-) mice. Biliary excretion of [3H]-digoxin was not dramatically decreased (24% in wild-type mice versus 16% in mdr 1a (-/-) mice). 5. After a single bolus injection, brain levels of [3H]-digoxin in wild-type mice remained very low, whereas in mdr 1a (-/-) mice these levels continuously increased over a period of 3 days, resulting in a approximately 200 fold higher concentration than in wild-type mice. 6. These data demonstrate the in vivo contribution of intestinal P-glycoprotein to direct elimination of [3H]-digoxin from the systemic circulation and to the pattern of [3H]-digoxin disposition, and they underline the importance of P-glycoprotein for the blood-brain barrier.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

The plasma disposition and renal elimination of digoxin-specific Fab fragments and digoxin in the rabbit.

Administering digoxin-specific antibody fragments (DSFab, 1.9 mg kg-1, i.v.) to rabbits 1 h after digoxin (15 micrograms kg-1 or 12.5 microCi kg-1, i.v.) produced a redistribution of digoxin associated with a 5-fold elevation in total plasma concentration and 36-86% reductions in elimination half-life, apparent volume of distribution at steady-state and total body clearance (CLT). Renal clearance (CLR) was also reduced (54%), but urinary digoxin excretion was increased by one-third (35% vs 25%). This apparent anomaly is due to the large rise in total plasma digoxin concentration with a consequent increase in the area under the plasma concentration curve (AUC). The AUC, which is the denominator term in calculating CLR (and CLT), was increased to a greater extent than urinary digoxin excretion (numerator term in calculating CLR) so that an overall reduction in CLR occurred. The initial presence of digoxin appeared to alter the distribution of DSFab, since their plasma concentrations were markedly higher when the antibody was given after the hapten. The digoxin also reduced (from 3 to 1%) the amount of detectable DSFab in the urine.

Animals↗

PubMed1969

Everest MS: Measurement of digoxin in plasma and its use in diagnosis of digoxin intoxication.

A method for measuring the plasma-digoxin concentration uses the measurement of its inhibitory effect on (86)Rb uptake by human red cells in vitro. Patients receiving digoxin in whom there was no clinical evidence of digoxin intoxication had plasma digoxin concentrations ranging from 0.8 to 4.5 mmug./ml. Patients presenting with convincing clinical evidence of digoxin intoxication had plasma digoxin concentrations ranging from 4 to greater than 8 mmug./ml. It is suggested that the plasma digoxin concentration may be used as an aid in the diagnosis of digoxin intoxication.

Aged↗

PubMed1980

Age-related differences in tolerance to digoxin. Lower digoxin concentration in myocardial microsomal fraction in infant rats.

To clarify the mechanism responsible for age-related differences in tolerance to digitalis, we studied the potassium contents of serum and myocardium and the digoxin concentrations of serum, myocardium, and myocardial microsomal fraction in infant and adult rats. While serum potassium concentration was the same in both infant and adult rats, the potassium content of myocardium found in the infant rats was significantly higher than that in the adult ones. Digoxin concentration of serum in infant rats was lower than that in the adult ones after a bolus injection of the same dose of digoxin per kilogram of body weight was given. Digoxin concentration of microsomal fraction, obtained 1 hour after the administration of 0.2 mg/Kg of digoxin in infant rats, was lower than that obtained 1 hour after the administration of 0.1 mg/Kg of digoxin in adult ones even though the digoxin concentrations of serum and myocardium in infant rats were significantly higher than those obtained in adult ones. Thus, less sensitivity to digitalis found in infant rats may be attributable to the higher potassium content of myocardium and the lower digoxin concentration of microsomal fraction.

Aging↗

PubMed1980

[Evaluation of stat assay of serum digoxin concentration by radioimmunoassay and its application for digoxin regimen based in pharmacokinetics (author's transl)].

Serum digoxin concentration measured by stat RIA (phadebas digoxin RIA kit) correlated well with results obtained by complete assays. The results of stat assay can be reported within 1 hour, measuring one or more samples together with 2 standard samples in duplicates. Precise measurement can be expected with serum digoxin concentration over 0.5 ng/ml. The stat assay allows to apply the theory of pharmacokinetics for the estimation of digoxin concentration at steady states measuring minimum digoxin concentration (Cn(min)) on the 3rd to 6th day after the start of digoxin therapy. The estimated serum digoxin levels were well agreed with measured values with the difference ranging from 1.6 to 8.6% in CV. The method is useful for the planning and assessment of appropriate digoxin regimen.

Aged↗

PubMed1975

A two compartment open model for digoxin pharmacokinetics in patients receiving a wide range of digoxin doses.

The pharmacokinetic parameters for a two compartment open model were defined for six patients receiving a wide range of Digoxin doses. It was demonstrated that the two compartment model is a valid one to use for Digoxin pharmacokinetics. This model is an useful concept because it can explain the necessity to vary Digoxin dosage in patients with different body weights, the time course of the effect of Digoxin and certain causes of increased tolerance to Digoxin. There were no alterations in the parameters of this model or of the percent of an injected Digoxin dose excreted in the urine and stool in our patients in atrial fibrillation who appeared to require larger doses to control their ventricular rates. This also suggests that the kinetics of excretion of Digoxin are not influenced by altering the Digoxin dose.

Atrial Fibrillation↗

PubMed1986

[Diltiazem and digoxin interaction. Development of digoxin plasma levels and electrocardiographic parameters in healthy subjects].

In order to determine the interaction between diltiazem and digoxin, plasma digoxin concentrations and the principal ECG parameters (24 hour Holter monitoring) were measured in 10 healthy volunteers under basal conditions (P0), with 0.375 mg/day of digoxin (P1 = 17 days), during association with 240 mg/day of diltiazem (P2 = 17 days) and then again on digoxin alone (P3 = 10 days). The addition of diltiazem was associated with a 20.4% rise in plasma digoxin concentrations (0.59 ng/ml vs 0.49 ng.ml). There was no significant variation of plasma digoxin after withdrawal of diltiazem; in some cases it remained unchanged, in others it fell or continued to rise. During the administration of digoxin and diltiazem, the mean RR period and the duration of the maximal pauses increased (p less than 0.05); the RR interval also increased (p less than 0.01) but the mean QRS duration and the QTc interval did not change significantly with respect to their values on digoxin alone. After withdrawal of diltiazem, the PR interval was the only parameter to decrease significantly (p less than 0.05). These results suggest that patients receiving this drug association should be followed up carefully.

Adult↗

PubMed1987

Minimizing analytical interferences from digoxin-like immunoreactive substances (DLIS) in cases of digoxin toxicity.

Recently, the value of therapeutic drug monitoring for digoxin has been called into question by the finding of endogenous digoxin-like immunoreactive substances (DLIS) in the serum of individuals, especially premature and full-term neonates, not being treated with digoxin. In some cases, values have been as high as 10 micrograms/L. Levels as high as 20 micrograms/L and 80 micrograms/g can be found in bile and meconium. Because of the magnitude of this interference, it is essential that methods be developed for measuring digoxin in the presence of DLIS. This is particularly important when such analyses are required in forensic science cases of suspected digoxin toxicity. This report outlines the high performance liquid chromatographic (HPLC) and radioimmunoassay (RIA) methods that we used in assessing the relative contribution made by digoxin, its metabolites, and DLIS to serum and tissue digoxin concentrations obtained by RIA in a forensic pediatric case of suspected digoxin toxicity.

Blood Proteins↗

PubMed1986

Methods for eliminating interferences in digoxin immunoassays caused by digoxin-like factors.

Endogenous, circulating digoxin-like immunoreactive factors (DLIF) are known to cross react with many antisera used in digoxin assays, complicating the quantification of serum digoxin. We have explored ways to decrease or remove the interference from DLIF in such assays. Prolonging the assay incubation from 30 to 60 min decreased apparent digoxin concentrations (attributable to DLIF) by an average of 68% in the digoxin radioimmunoassays studied. The serum protein-binding of DLIF was also exploited to remove them from serum. Ultrafiltration, performed as part of a simple centrifugation step, removed approximately 90% of the DLIF. Analytical-recovery studies with true digoxin also demonstrated ultrafiltration to be an adequate method (greater than 95% of digoxin was recovered) for routine clinical use. Heat- or acid-precipitation of protein removed DLIF less effectively. Appropriate incubation times and ultrafiltration can dramatically minimize or eliminate DLIF interference in digoxin immunoassays.

Blood Proteins↗

PubMed1982

[Bioavailability of digoxin and beta-methyl-digoxin in patients with liver and gastro-intestinal diseases ].

The bioavailability of digoxin and beta-methyl-digoxin (BMD) was tested with a single dose on the grounds of peak serum concentration, tmax, area under the serum concentration-time curve and the cumulative 24 hour urinary excretion on one group of patients with liver disease (n = 20) and one with gastrointestinal disease (n = 10). Despite the smaller dose (0.5 mg BMD against 0.75 mg digoxin), peak serum concentration was significantly higher with BMD in both groups and was also reached earlier than with digoxin. The extent of absorption was also higher in both groups with BMD than with digoxin. A comparison of the results on hand with the results obtained in corresponding tests on healthy persons showed no significant differences with BMD. The excellent bioavailability of BMD was therefore also proved on patients with gastrointestinal diseases, whereas with digoxin the absorption in these patients was retarded, compared with healthy persons, but the extent of absorption was not reduced either. In gastrointestinal diseases with unknown conditions of absorption, the better bioavailability of BMD is probably of advantage, when compared with digoxin. According to medical literature, t/2 of BMD may be prolonged in liver diseases, so that in such cases the dose of BMD has to be adjusted or the use of digoxin is recommended.

Adult↗

PubMed1995

Digoxin-induced delayed afterdepolarizations: biphasic effects of digoxin on action potential duration and the Q-T interval in cardiac Purkinje fibers.

Few reports exist of digoxin-induced delayed afterdepolarizations (DADs) and triggered activity recorded in cardiac fibers, and the electrophysiological characteristics of digoxin-induced DADs and triggered activity have not been reported in detail. We studied the electrophysiological properties of digoxin-induced DADs and triggered activity is sheep cardiac Purkinje fibers. Transmembrane voltage was recorded using conventional microelectrodes and extracellular electrograms were recorded using a high-gain, signal averaging method. DADs were induced by digoxin (1.25 microM, n = 9 fibers). After exposure to the drug for 20.8 +/- 2.0 min at the pacing cycle lengths of 990, 690, and 490 msec, the DAD amplitudes were 3.7 +/- 0.3, 5.7 +/- 0.6, 6.4 +/- 0.8 mV, respectively. The coupling intervals of DADs to the previous action potential at the same cycle lengths were 845.8 +/- 37.6, 581.3 +/- 23.1, 434.6 +/- 7.0 msec, respectively. Thus, digoxin-induced DADs show typical frequency dependence. Digoxin-induced DADs also occasionally caused triggered action potentials. DADs also were recorded simultaneously using an extracellular signal averaging technique. DADs were easily detected an most of the DAD characteristics measured intracellular could be confirmed in the extracellular electrograms. Digoxin induced a biphasic effect on the action potential duration (measured at 50% of repolarization (APD50) and on the Q-T interval measured from the extracellular electrograms, and in an additional group of fibers (n = 5) this was studied in detail. Digoxin initially lengthened the APD50 and the Q-T interval within the first 10 min of drug exposure, at a time when DADs had not yet developed.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗

PubMed1996

[Interference of digoxin like immunoreactive substances with four recent reagents for digoxin determination].

The sensitivity of four new digoxin assay methods (on mini-Vidas bioMérieux, with Cedia reagent on Hitachi 911, with Syva Emit 2000 third generation reagent on Cobas-Mira and with Roche digoxin Online reagent on Cobas-Mira) to interference by digoxin like immunoreactive substances (DLIS) was studied in sera from 21 healthy controls, 18 pregnant women (9th month of pregnancy), 26 newborn infants and 42 patients with chronic renal failure undergoing hemodialysis. None of these individuals had been treated with digoxin or others cardiotonic drugs. For each method, results are different according to the population being studied, suggesting that the nature of DLIS is not the same. On the whole, interferences with DLIS seem to be more important in samples from newborn infants (for three methods out of four, the mean concentration of digoxin is significantly different from those observed in control samples). Digoxin assay on mini-Vidas and with Cedia reagent seems to be more sensitive to interference by DLIS, especially in samples from newborn infants and less in samples from pregnant women and patients with chronic renal failure. Online and Emit 2000 reagents seem to be poorly sensitive to interference by DLIS. However, for Emit 2000, the mean concentration of digoxin in samples from newborn infants is significantly different from the one observed in control samples. These results show that testing the sensitivity of new digoxine assay methods to interference by DLIS is very important because it can be a limitation to the use of a reagent independently of its analytical qualities.

Cardenolides↗

PubMed1986

The effects of captopril on serum digoxin and urinary urea and digoxin clearances in patients with congestive heart failure.

The effect of captopril as long-term treatment in 20 patients with congestive heart failure has been studied in a double-blind trial. Captopril caused a significant increase in serum digoxin levels. No patients developed evidence of digoxin toxicity. Serum and total body potassium rose and the frequency of ventricular arrhythmias showed a modest decline. Creatinine clearance and radioisotopically measured glomerular filtration rate fell, but there was a poor relationship between these and the increase in serum digoxin. In a further open study on 12 patients, creatinine, urea, and digoxin clearance were significantly reduced by captopril. However, digoxin clearance declined more than creatinine clearance (89 +/- 25 mumol/L to 69 +/- 22 mumol/L and 81 +/- 14 mumol/L to 72 +/- 19 mumol/L, respectively, p less than 0.05 for the difference). Fractional excretion of urea and digoxin filtered at the glomerulus declined, indicating greater tubular reabsorption or reduced tubular secretion of these compounds. Captopril causes an increase in serum digoxin by reducing renal clearance of the drug.

Captopril↗

PubMed1992

Comparison of lisinopril versus digoxin for congestive heart failure during maintenance diuretic therapy. The Lisinopril-Digoxin Study Group.

Lisinopril 5-20 mg once daily was compared with digoxin 0.125-0.375 mg once daily in a double-blind, randomized, parallel-group study involving 217 patients with mild-to-moderate heart failure (New York Heart Association [NYHA] grades II-III) who were maintained on optimized diuretic therapy. After 6 weeks of treatment, digoxin and lisinopril had increased exercise duration by 18 seconds (p = 0.015) and 32 seconds (p = 0.0007), respectively, versus the baseline run-in period. The difference between treatments was not statistically significant (p = 0.1343). After 12 weeks, digoxin and lisinopril had increased exercise duration by 29 seconds and 51 seconds, respectively. The effect of digoxin compared with the baseline value was not significant but that for lisinopril was (p = 0.0027). The difference between treatments approached statistical significance (p = 0.0813). There was no difference between lisinopril and digoxin with regard to their effects on the frequency of ventricular ectopic counts, couplets, or nonsustained ventricular tachycardia. Blood pressures were not significantly different between treatments, although both systolic and diastolic blood pressure were consistently lower in the lisinopril group throughout randomized treatment. The proportions of patients demonstrating an improvement in NYHA grading were similar for both lisinopril and digoxin. Both treatments had similar effects on the symptoms of heart failure. Both drugs appeared to be equally well tolerated with a similar frequency of adverse events reported for both drugs (30% for lisinopril vs 29% for digoxin). Withdrawals from treatment were of a similar frequency for both treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1984

The effect of immunization with digoxin-specific antibodies on digoxin disposition in the mouse.

After intravenous dosing, digoxin was rapidly distributed to tissues, with a distribution half-life of 3.0 min. The highest digoxin concentrations at 1 hr post dosing were found in lymph nodes, adrenals, gallbladder (including contents), liver and kidney respectively. Digoxin concentrations in the heart, spleen, brain, lung, skeletal muscle and fat were similar to, or lower than, those in the plasma. The apparent volume of distribution (AVd) was 1 l/kg, and the plasma elimination half-life and clearance (Cl) 2.8 hr and 0.25 l/kg per hr respectively. When digoxin was given one day after passive immunization with digoxin-specific immunoglobulin G (IgG) or Fab fragments the respective plasma digoxin concentrations were elevated some 26- and 5-fold respectively compared with control values. Consequently there were reductions in AVd (93 and 32%) and Cl (94 and 50%). The effect of IgG treatment on clearance was still apparent when the hapten was given up to 14 days after immunization, while the weaker effect of Fab-treatment was less persistent. Although tissue digoxin concentrations were slightly lower in the immunised mice, it was only in the lymph nodes at 10 and 14 days after IgG treatment that the reduction in hapten concentration was statistically significant.

Animals↗

PubMed1998

Digoxin visual toxicity with therapeutic blood levels of digoxin.

PURPOSE: To report two cases of digoxin-related visual disturbances associated with therapeutic blood levels of digoxin. METHODS: Case reports. One patient reported shimmering lights in the field of vision of both eyes; the second patient had a corrected visual acuity of BE, 20/40 and generalized visual field depression in both eyes. Both patients experienced these symptoms while receiving digoxin. RESULTS: Both patients had digoxin blood levels in the therapeutic range (1.7 and 1.0 ng/ml, respectively). Therapeutic levels are 0.5 to 2.0 ng/ml. After discontinuing digoxin, the first patient noted that the shimmering light symptoms resolved, and the second patient had improved visual acuity and visual fields. CONCLUSIONS: Digoxin-related visual toxicity may be associated with therapeutic blood levels of digoxin. Recognition of this entity may avoid unnecessary testing and frustration.

Aged↗