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PubMed1983

An electrophysiologic study of the digoxin--quinidine interaction.

To study the electrophysiologic mechanisms responsible for the digitalis-quinidine interaction, 27 mongrel dogs were given either quinidine alone, digoxin alone, or digoxin followed by the digoxin-quinidine combination, via the oral route for sufficient time to permit accumulation of steady-state plasma levels. As anticipated, digoxin levels increased significantly in the presence of quinidine (P less than 0.05). Whereas digoxin alone had no significant effect on the ECG, quinidine alone prolonged the Q-T interval (P less than 0.05), and the combination prolonged both the QRS complex and the Q-T interval (P less than 0.05). Digoxin alone had no significant effect on the Purkinje fiber transmembrane potential, whereas quinidine reduced action potential (AP) amplitude and maximum upstroke velocity (Vmax) significantly. The combination significantly reduced AP amplitude Vmax, and maximum diastolic potential and prolonged AP reduced AP amplitude, Vmax, and maximum diastolic potential and prolonged AP duration. The changes induced by the drug combination appeared to be the sum of changes induced by each drug alone.

Animals↗
PubMedDate not supplied

Antiarrhythmic effect of lorcainide in patients taking digoxin.

To assess the antiarrhythmic effect of lorcainide and determine whether there is a pharmacokinetic interaction between lorcainide and digoxin, 12 patients with frequent premature ventricular depolarizations (PVDs) who were taking digoxin were treated with lorcainide. During a placebo period, serum digoxin concentration was measured for three days; plasma lorcainide concentration, a 12-lead electrocardiogram (ECG), and a 24-hour continuous ECG were measured on the day before the patients began lorcainide and repeated on days 3, 7, and 14 of treatment. Lorcainide was given 100 mg bid or 100 mg tid. Lorcainide did not suppress group mean PVDs per hour, pairs, or ventricular tachycardia. Only four patients (33%) responded with greater than or equal to 80% suppression of PVDs. Mean ejection fraction for responders was 46 +/- 6%, and for nonresponders it was 28 +/- 9% (P less than .01). There was no significant pharmacokinetic interaction between lorcainide and digoxin. Mean digoxin concentration did not change after lorcainide administration; two patients had greater than or equal to 50% increase in serum digoxin concentration. Patients with heart failure or reduced ejection fraction define a subset who have unpredictable effects from lorcainide, including a reduced antiarrhythmic effect.

Adult↗
PubMed1989

Chronic treatment with fluvoxamine, clovoxamine, and placebo: interaction with digoxin and effects on sleep and alertness.

The influence of 17 days of administration of fluvoxamine or clovoxamine, two new antidepressant agents, on the kinetics of a single intravenous dose of digoxin, and on self-rated parameters of sedation, mood, and sleep, was evaluated in a series of healthy volunteers. In the fluvoxamine study, subjects received fluvoxamine, 100 mg daily, or matching placebo for 17 consecutive days in a crossover design. For the clovoxamine study, subjects received clovoxamine, 150 mg daily, or placebo for 17 days. All treatments were double blind. At the end of each treatment, digoxin kinetics were evaluated following a single 1.25 mg intravenous dose. Compared to the placebo condition, fluvoxamine had no significant influence on digoxin elimination half-life (57 vs 47 hours), volume of distribution (10.5 vs 10.3 liters/kg), total clearance (2.4 vs 3.0 ml/min/kg), or 72 hour urinary excretion (33 vs 37 percent of the dose). Likewise clovoxamine did not alter digoxin elimination half-life (39 vs 40 hours), volume of distribution (10.7 vs 10.2 liters/kg), or total clearance 3.4 vs 3.4 ml/min/kg). 72 hour urinary excretion of digoxin was slightly increased by clovoxamine (41 vs 50 percent of the dose, P less than .05). Self-ratings indicated a sedating effect of fluvoxamine, with reports of difficulty attaining morning alertness. These effects were not reported with clovoxamine. Thus clovoxamine and fluvoxamine appear to have differential effects on sleep and alertness in healthy volunteers. However, neither have an important influence on the kinetics of digoxin.

Adult↗
PubMed1989

Extension of the serum digoxin concentration--response relationship to patient management.

The purposes of this investigation were to demonstrate how computer simulations may be employed to extrapolate data obtained from a single intravenous digoxin dose to multiple oral dosing patterns and how these simulations may apply to clinical situations. The intravenous data were obtained from a previous study of the pharmacokinetics of serum digoxin and its inotropic response (derived from systolic intervals) in 12 normal male volunteers. The simulations were applied to various clinical situations including variations in oral dosing, alternate loading doses, no loading versus loading dose, and intravenous versus oral dosing. A nonlinear relationship was found between response and the post-distribution serum digoxin concentration in the therapeutic range. Thus, the increase in inotropic response is less than proportional to the increase in digoxin concentration in serum. This nonlinear relationship has several important clinical implications for loading and maintenance dosing protocols. Such concepts may be important relative to more rational clinical use of digoxin and to decreasing digoxin toxicity.

Computer Simulation↗
PubMed1991

Digoxin-like immunoreactive substance in renal transplant patients.

Digoxin-like immunoreactive substance (DLIS) has been detected in several patient populations that were not receiving digoxin, including those patients with end-stage renal disease. The structure and physiologic significance of this compound are unknown, and the fate of DLIS after renal transplantation has not been studied. The authors prospectively evaluated 163 patients (not receiving digoxin) before and after transplantation for the presence of DLIS. Three different assays were used: radioimmunoassay (RIA), affinity mediated immunoassay (ACA), and fluorescence polarization immunoassay (TDX I). Depending on the assay method used, 11% (RIA), 6% (ACA), and 9% (TDX) of patients had detectable DLIS pretransplant. Using all 3 assays, a total of 34 patients (21%) were found to have DLIS. The mean serum digoxin concentration was 0.41 +/- 0.13 ng/mL (range: 0.2-1.2 ng/mL) and DLIS was detectable by greater than 1 assay method in seven patients. DLIS persisted longer in patients who had delayed allograft function (13.7 +/- 7 days) than in those who did not (3 +/- 1.9 days), P less than .05. In summary, detection of DLIS in renal transplant recipients appears to be an infrequent occurrence when using a single digoxin assay method. When detected, the concentration of DLIS is often below the usual therapeutic range for digoxin and disappears once allograft function is established. The authors conclude that the presence of DLIS is unlikely to be clinically significant in the renal transplant population.

Adult↗
PubMed1995

The influence of reduced dietary fat absorption induced by orlistat on the pharmacokinetics of digoxin in healthy volunteers.

To assess the influence of an orlistat-induced reduction in dietary fat absorption on the pharmacokinetics of digoxin, an open-label, placebo-controlled, randomized, two-way crossover study was performed in 12 healthy volunteers. Each subject received single 0.4-mg doses of digoxin (soft gelatin capsules) administered orally on the fourth day of orlistat (120 mg three times daily for 6 days) and placebo (three times daily for 6 days) treatment, separated by at least an 11-day washout period. Serial blood samples were collected before and at appropriate intervals after each digoxin dose to determine plasma concentrations of unchanged digoxin. The 90% confidence intervals for the ratio of geometric least-squares means (for Cmax, AUC0-48, AUC0-t, and AUC) and for the difference of arithmetic least-squares means (for tmax and lambda z) indicate that the pharmacokinetics of digoxin was not altered by treatment with orlistat. This results suggests that a approximately 30% reduction in dietary fat absorption will not change the efficacy of digoxin in cardiac patients.

Adolescent↗
PubMed1989

Removal of digoxin from the circulation using immobilized monoclonal antibodies.

High-affinity (Ka = 3.0 X 10(8) M-1) monoclonal antidigoxin antibodies were covalently coupled to Sepharose CL-6B, Bio Gel A5m, Affi-gel 15, and agarose:polyacrolein microsphere (APAM) beads. Antibody immobilized to these supports was characterized in its ability to remove digoxin in vitro from biological fluids. Equilibrium binding studies of digoxin in plasma revealed that antibody coupled to Sepharose, Bio Gel, and Affi-gel 15 retained 38-42% of theoretical binding capacity, whereas antibody coupled to APAM beads retained only 13%. Increasing flow rates from 0.5 to 5.0 mL/min across antibody immobilized to APAM beads decreased the removal of digoxin from plasma from 90 to 55%. In comparison, no decreases were observed in the amount of digoxin removed from plasma as the flow rates were increased across antibody immobilized to the other agarose supports. Antibody coupled to Affi-gel 15 was used for in vivo extracorporeal hemoperfusion studies. These studies indicated that although 5-20% of the total dose was removed from three guinea pigs, plasma digoxin levels were not lowered when compared with preperfusion concentrations. In addition, antibody columns which were reused following regeneration with glycine:HCl, pH 2.5 revealed that 80% of the original antibody activity was lost after two hemoperfusions. Hematological parameters were unchanged with the exception that platelets were significantly decreased following the 3-h perfusion study. These data indicate that immobilized antidigoxin antibodies were able to remove digoxin from the circulation, and immunoaffinity hemoperfusion may be a viable means of removing substances from blood.

Animals↗
PubMed1989

Digoxin immunoassay with monoclonal and polyclonal antibodies using time-resolved fluorometry.

We describe a nonisotopic heterogeneous competitive immunoassay of digoxin in serum using either Fab fragments of a polyclonal antibody or a high-affinity monoclonal antibody. In the assay, digoxin competes with immobilized digoxin (digoxin:thyroglobulin conjugate) for binding to a biotinylated immunoreactant (Fab or monoclonal). The amount of biotinylated moiety bound to the solid phase (white polystyrene microtiter wells), which is inversely related to the amount of digoxin in the sample, is then quantified by adding streptavidin labeled with the europium chelator 4,7-bis(chlorosulfophenyl)-1,10- phenanthroline-2,9-dicarboxylic acid (BCPDA) in the presence of excess Eu3+. The fluorescent immunocomplex formed is measured directly on the dry solid phase by time-resolved fluorometry. The assay is simple to perform and its characteristics are similar to those of other currently used immunoassay techniques. The Fab fragments and the monoclonal antibody procedure performed equally well on the system. Our results suggest that monoclonal antibodies with high affinity for digoxin can be used for the routine determination of the drug in serum.

Antibodies, Monoclonal↗
PubMed1989

Digoxin--a redundant drug in congestive cardiac failure.

Controversy continues concerning the use of digoxin as a positive inotropic agent in the treatment of heart failure in patients in sinus rhythm. Digoxin is properly used to control the heart rate in patients in atrial fibrillation. The findings from 14 uncontrolled and 6 controlled clinical trials have been examined. Digoxin does exert a small chronic positive inotropic effect. Although some individual patients, particularly those with fluid overload, appear to benefit from digoxin, controlled clinical trials in patients, most of whom have been treated with diuretics, have failed to demonstrate an increase of exercise capacity. No mortality trial has been attempted. Digoxin has the potential to be harmful in patients with ischemic heart disease. Alternative and safer therapies have been shown to be equal or superior to digoxin.

Digoxin↗
PubMed1990

Digoxin infusion versus bolus injection in rapid atrial fibrillation: relation between serum level and response.

Using available data on time-concentration and time-effect relationships in normal persons the results of infusion of digoxin in various time periods were simulated and compared with administration of digoxin by bolus injections, using a three-compartment pharmacokinetic model to which a separate small side-effect compartment was subsequently added. The validity of the simulations was tested in 11 patients with rapid atrial fibrillation. Serum digoxin concentrations, ventricular rate and side effects were monitored in a double-blind study comparing an infusion of 1.5 mg digoxin over 6 h with administration of three bolus injections of 0.5 mg digoxin 8 h apart. In agreement with the predictions of the model, the maximal fall in ventricular rate was reached after 8-9 h in the infusion group and after 19-20 h in the bolus injection group, without any detectable difference in side effects. There were certain discrepancies between the results of the clinical study and the predictions of the model, e.g. in serum digoxin concentrations, perhaps due to impaired clearance in the patients. However, it is concluded that the tested model is valid in elderly patients with rapid atrial fibrillation.

Adult↗
PubMed1975

A solid phase radioimmunoassay for digoxin and its acylated derivatives.

A solid phase radioimmunoassay (RIA) is presented for the determination of digoxin and its acylated derivatives. In the procedure the antiserum is covalently bound to bromacetylcellulose. Therefore the free and the immunologically bound digoxin fractions can easily be separated by centrifuging. The radioactivity in the supernatant representing the unbound digoxin is proportional to the digoxin concentration in the sample. This modification of the RIA for digoxin is far more time saving than the separation procedure using dextran-coated charcoal as an absorbent; nevertheless both methods are equally sensitive, specific and reliable. The use of the solid phase assay is demonstrated comparing the bioavailability of various digoxin derivatives.

Acylation↗
PubMed1985

Decreased renal clearance of digoxin in chronic congestive heart failure.

Renal digoxin clearance was compared in patients suffering from atrial fibrillation with well preserved cardiac function (n = 9; salt intake +/- 170 mmol daily) and patients with chronic congestive heart failure (n = 10; salt intake 50 mmol daily and maintenance treatment with diuretics). There was no difference between the groups concerning digoxin dosage, creatinine clearance, diuresis or sodium excretion in the urine. Digoxin clearance in chronic heart failure proved to be significantly lower than in atrial fibrillation (48 +/- 21 vs 71 +/- 36 ml X min-1, p less than 0.05), and Cdig/Ccreat was similarly reduced at 0.73 +/- 0.15 compared to 1.09 +/- 0.27 (p less than 0.005). Steady state serum digoxin concentration was significantly higher in patients with congestive heart failure (1.44 +/- 0.47 vs 0.87 +/- 0.33 micrograms X 1(-1), p less than 0.01). Chronic congestive heart failure is a state with reduced digoxin clearance by the kidney, which could lead to digoxin intoxication not explicable by overdose, reduced renal function or the effect of interacting drugs.

Aged↗
PubMed1984

Increased metabolism to dihydrodigoxin after intake of a microencapsulated formulation of digoxin.

A capsule preparation containing small, enteric-coated granules of digoxin was developed to prevent acid hydrolysis of the drug in the stomach and to diminish the variation in plasma glycoside concentration during the intervals between doses. The absorption and metabolism of tritiated digoxin after a single oral loading dose of this formulation (Formulation C) were compared to those after ingestion of a digoxin solution (Formulation S) by 8 healthy men. Drug concentrations were measured by radioimmunoassay (RIA) and liquid chromatography (LC). The percentage of the digoxin dose excreted in the urine during 72 h, as measured by RIA, was significantly lower after the capsule (20.5 +/- 2.0% vs 36.2 +/- 3.0% after S, mean +/- SEM) but total urinary radioactivity after the two treatments was similar (C 35.3 +/- 5.2 and S 41.2 +/- 2.6%; p greater than 0.05). The discrepancy was mainly due to significantly greater excretion of dihydrodigoxin after the capsule (m 12.8%, range 0-28.6% of the dose) than after the digoxin solution (m 5.4%, range 0-14.5%). Dihydrodigoxin was not measured by the RIA. The recovery of hydrolysis metabolites (LC) was greater during the first 24 h after S (2.3 +/- 0.6% vs 0.9 +/- 0.3% after C; p less than 0.05). The peak plasma concentration of digoxin (RIA) was significantly reduced and delayed after intake of C (2.5 +/- 0.4 nmol/l at 3.8 +/- 0.3 h vs. 8.3 +/- 0.8 nmol/l at 0.9 +/- 0.1 h after S), and so was the shortening of electromechanical systole at 1.5 h, 2.5 h, and 3 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Digoxin-felodipine interaction in patients with congestive heart failure.

A possible interaction between felodipine and digoxin was studied in 23 patients with congestive heart failure before and after 8 weeks treatment with both drugs. A modest, non-significant increase in serum digoxin level 2 h postdose (+15%) was found in the felodipine group (n = 11) compared to placebo (n = 12), with no change in the trough and 6 h postdose levels. There was a bimodal distribution of the observed changes in serum digoxin level 2 h postdose: a significant increase (p less than 0.001) was observed only in patients with a high plasma felodipine level, which may have been caused by changes in the absorption rate in those patients. Changes in the elimination of digoxin after felodipine therapy appeared unlikely, since the trough and 6 h post-dose levels were unchanged. Analysis of the clinical characteristics, haemodynamics and laboratory values revealed no significant differences between the subgroups. The observed increase in serum digoxin warrants monitoring the trough and peak levels digoxin in patients with congestive heart failure who are also being treated with felodipine.

Aged↗
PubMed1975

Bioavailability studies with Digoxin-Sandoz and Lanoxin.

Various brands of digoxin tablets, and even different batches of one brand, may differ greatly in bioavailability. Digoxin-Sandoz tablets have been compared with Lanoxin manufactured between 1969 and 1972 and after May 1972. Comparisons were also made between and within batches of Digoxin-Sandoz tablets. Three separate cross-over studies were conducted involving a total of 20 volunteers. Digoxin-Sandoz tablets were shown to have a constant bioavailability and to produce plasma concentrations very similar to ""new'' Lanoxin. Storage for 2 years of one batch of Digoxin-Sandoz did not alter the bioavailability. Particle size was shown to influence bioavailability. Care should be exercised when plasma data alone are interpreted as an index of bioavailability. Measures of bioavailability based on plasma data obtained up to 6 h after administration differed from those based on cumulative urinary excretion data (in this study by a factor of about 2), which can lead to the belief that a difference in bioavailability is much greater than is actually the case. Data from cumulative urinary excretion, collected over a sufficiently long period of time, are likely to be the most reliable method for determining the bioavailability of a substance such as digoxin.

Adult↗
PubMed1977

Distribution and elimination of digoxin in infants.

The distribution and elimination of intravenous digoxin were investigated in seven neonates and infants with heart failure. Serum digoxin concentrations during a 24 h period were determined by radioimmunoassay, using 125I as tracer. The serum values declined biexponentially after the injection and could be fitted to a two-compartment open model by non-linear least-squares regression. The calculated mean half-lives of the distribution (alpha) phase in neonates and infants were 37 and 28 min, respectively. The mean half-life of the elimination (beta) phase in neonates was 44 h, as compared to 19 h in infants. The mean volume of the central compartment and the mean volume of distribution at steady-state were calculated to be 1.3 and 9.91/kg, respectively; no significant differences between neonates and infants were found. The relation between these volumes indicates that digoxin is extensively distributed in tissues. The steady-state distribution volumes of digoxin in neonates and infants exceed those reported in adults. The larger volume of distribution might explain in part why infants with cardiac insufficiency require larger doses of digoxin than adults (on a mg/kg body weight basis) to obtain the same serum concentrations. Elimination of digoxin from the body was slower in neonates than in infants.

Digoxin↗
PubMed1981

Quinidine-digoxin interaction: effect of quinidine on 86Rb-uptake of human erythrocytes.

Co-administration of quinidine results in a marked increase in serum digoxin concentration (SDC). The implication of this increase in SDC in regard to an increased digoxin effect on the heart is controversial. The 86Rb-erythrocyte-assay represents a perfect model to study whether quinidine interferes with digoxin at the Na-K-ATPase (the so called glycoside receptor) and thus presumably with the inotropic effect of the glycoside. The inhibitory effect of digoxin (0-150 ng/ml) on the 86Rb-uptake was measured in the absence and presence of quinidine in therapeutic or higher concentrations (0-60 microgram/ml). Addition of quinidine produced no effect on digoxin-induced inhibition of Na-K-ATPase activity. Together with our clinical observations these results strongly suggest that the increased SDC during concomitant quinidine therapy actually reflects an increased digoxin effect on the heart.

Digoxin↗
PubMed1978

[A simplified radioimmunoassay for digoxin determination using a 125-j-labelled, solid-phase kit (author's transl)].

Our experience with a commercially available kit (Radioimmunoassay DIGOXIN, Boehringer, Mannheim) using (125J)-labelled digoxin and antibody-coated tubes is reported. This simplified method requires only two pepetting steps per sample and results can be obtained in 70 min. The intra- and interassay coefficient of variation ranged between 7% and 8%. The specific digoxin antibody gave no clinical relevant cross-reactions with spironolactone or prednisone (less than 0.0007%). Of the digoxin metabolites the aglucone digoxigenin showed 31% cross-reaction while the more important cardioactive metabolites digoxigenin-bis- and mono-digitoxide had the same binding affinity to the antibody as digoxin, beta-methyldigoxin and beta-acetyldigoxin. Cross-reaction with digitoxin was 6.8%. More than double-fold dilution of serum protein concentration showed little influence on the digoxin values measured. The results obtained by this new kit compare closely with those obtained by our tritium-labelled kit (r = 0.94, p less than 0.001). Therefore, the upper therapeutic limit of 1.9 ng/ml can be adopted for this method.

Antibodies↗