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Digoxin-induced cardiac toxicity in the anaesthetized guinea-pigs and effect of heparin infusion.

We have examined the effects of heparin infusion on the arrhythmias induced by digoxin. Digoxin treatment consisted of 0.6 mg kg-1 given i.v. 15 min after the beginning of heparin infusion. Heparin infusions (1.7 IU, 3.4 IU and 6.8 IU kg-1 min-1) were begun 15 min before digoxin injection and continued for another 30 min. ECG, blood pressure, heart rate and arrhythmias were recorded starting 15 min before and continuing for 60 min after the digoxin injection. Heparin at the infusion rates of 3.4 IU and 6.8 IU kg-1.min-1 reduced significantly the arrhythmia scores. On the other hand, heparin did not significantly alter the arterial blood pressure and heart rate values affected by digoxin.

Animals↗

Competitive solid-phase enzyme immunoassay for measuring digoxin in serum.

In this clinically useful enzyme immunoassay of digoxin in serum, we mix sample, beta-galactosidase-labeled digoxin, and anti-digoxin Fab fragments for 30 min at room temperature, then use Sepharose-bound second antibody for phase separation, and measure the unbound enzyme activity directly in the supernate of the equilibrium reaction mixture. The immunoassay buffer--phosphate-buffered isotonic saline with added rabbit globulin (4 g/L), hydrolyzed gelatin (2 g/L), Brij 96 detergent (5 g/L), glycerol (0.25 mol/L), and N-acetyl-8-anilinonaphthalene-1-sulfonic acid (2 mmol/L)--minimizes serum matrix effects for convenient measuring of unbound enzyme--digoxin conjugate. The immunoassay developed with Fab fragments has better displacement characteristics than that with intact antibody. Performance of the assay compares favorably with that of other manual digoxin immunoassays; in comparison studies with EMIT involving 110 clinical specimens, the coefficient of correlation was 0.97.

Antibody Formation↗

Digoxin--issues and controversies.

This review deals briefly with the clinical pharmacology of digoxin and reviews in some depth the problems inherent in methods of digoxin measurement. Digoxin-like factors (materials that cross react in digoxin immunoassays) are discussed, and some current evidence suggesting the existence of a new hormone, endoxin (endogenous digoxin), is summarized.

Administration, Oral↗

Single dose bioavailability of two different digoxin tablets.

In a single dose bioequivalence study in 10 healthy young adults the absorption profiles and bioavailability of two digoxin containing tablets (A = digoxin-Pharbita 0.25 mg and reference drug B) were compared and related to the in vitro dissolution rate of both tablets. Two tablets of each product (= 0.50 mg of digoxin) were taken at random on an empty stomach; two weeks elapsed between the two treatments. Frequent blood sampling was performed up to 24 h after intake of the dose. Digoxin plasma concentrations were measured by means of radioimmunoassay. No significant differences (p greater than 0.05) were found in the mean values of the peak plasma concentration (cmax), time to peak (tmax) and area under the plasma concentration versus time curve for the period of 0-10 h after drug intake (AUC0-10), although in most subjects the absorption process after intake of product A was slightly faster, with slightly higher peak. This might be related to a slightly faster release of digoxin from the product A dosage form, as was seen from the dissolution test data. The relative bioavailability of product A as compared to product B, accounted for 97.7 +/- 28.7% (mean +/- S.D.). These results indicate, that both products can be considered as being bioequivalent.

Adult↗

Effects of digoxin, placebo and ibopamine on exercise tolerance and cardiac rhythm of patients with chronic post-infarct left ventricular failure.

This study compares the effects of digoxin, placebo and ibopamine (SB-7505), the orally active 3,4-diisobutyryl ester of N-methyl-dopamine, on exercise tolerance and cardiac rhythm of 14 patients whose left ventricular heart failure (end-diastolic pressure, 26.3 +/- 5.9 mmHg; ejection fraction, 0.42 +/- 0.10%) depended on a previous myocardial infarction. Patients were admitted to the study while on chronic oral digoxin treatment (serum levels between 1.1 and 1.9 ng/ml). Placebo instead of digoxin was given for the following month. Thereafter ibopamine 50 mg t.i.d. for one month was given. A sequence of one-month treatments with digoxin, placebo and ibopamine was repeated, then ibopamine was administered continuously for the next two months. The concurrent treatment (diuretics in all patients, nitroderivates in twelve, calcium antagonists in two) remained unchanged during the observation period. Symptoms-limited exercise tests and 24-h Holter recordings were obtained at admission, at the end of each one-month treatment and at the end of the observation period. Two patients developed unstable angina without increase of serum creatine phosphokinase while on ibopamine and were withdrawn. Out of the 12 patients that concluded the trial, one required supplementary doses of diuretic at the end of the second period on placebo. The results obtained during the trial suggest that: a) therapeutic plasma levels of digoxin have no deleterious effect on cardiac rhythm nor significantly increase exercise tolerance as compared with placebo; b) diuretics and nitrates appear to sustain the clinical stability of these patients as a group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

[Pharmacodynamic and pharmacokinetic approaches to optimization of the use of digoxin in the subacute period of myocardial infarction in late middle-age and elderly patients].

The efficiency of digoxin in elderly and old patients with subacute myocardial infarction is dependent on the original disorders of left-ventricular systolic phase structure. Changes in systolic phase structural parameters in the presence of supporting digoxin therapy show correspondence to changes of these parameters in response to a single digoxin dose. Digoxin's positive inotropic effect was similar in patients with the sinus rhythm and those with atrial fibrillation. The positive inotropic action of digoxin is not associated with a negative chronotropic effect in patients with sinus rhythm and normal heart rate.

Aged↗

Imprinting, digoxin uptake and storage in Tetrahymena.

Tetrahymenas after a single exposure to high concentration of digoxin, release glycoside into the culture medium even three days after removal of the drug. After nine or fifteen days, however, this effect subsides. Re-administration of digoxin causes the digoxin consumption (storage) of Tetrahymenas to increase. This observation indicates that the digoxin imprinting previously demonstrated in mammals occurs also in Tetrahymena. The experiments raise the possibility that also Tetrahymenas are capable of producing a digoxin-like substance detectable by radioimmunoassay.

Animals↗

Digoxin-like immunoreactive substance in postmortem blood of infants and children.

A digoxin-like immunoreactive substance (DLIS) has been reported in the serum of infants not receiving digoxin. This study was undertaken to determine if DLIS is present in the postmortem blood and tissues of infants or children and whether the endogenous substance could interfere with forensic toxicological analysis in suspected overdose. Ninety blood specimens taken from the heart at autopsy of children or infants were screened for DLIS using commercial radioimmunoassay kits. The average age at death in these cases was 8.6 months, the median age was 2 months. DLIS equivalent to 0.25 to 2.0 ng/mL digoxin was found in one third of the cases. The incidence of positive findings was 5/6 stillborns, 10/45 Sudden Infant Death Syndrome (SIDS), 10/15 deaths as a result of infection, 4/7 homicides, 1/8 deaths caused by congenital defects, and 0/9 accidental deaths. The body distribution of DLIS was investigated and highest levels were found in the liver. Findings of DLIS in blood were correlated with renal failure, (elevated vitreous urea nitrogen), electrolyte imbalance, and liver trauma. Apparent concentrations were in the equivalent therapeutic range of digoxin and would not be confused with accidental or intentional overdose with digoxin.

Autopsy↗

Effect of long-term administration of digoxin on exercise performance in chronic airflow obstruction.

We have studied the effect of long-term digoxin on exercise performance in 15 patients with pulmonary heart disease due to severe chronic airflow obstruction (FEV1/VC ratio 29 +/- 6%: mean +/- SD). Digoxin (0.25 mg/day) was given for 8 weeks in a randomized, double-blind crossover, placebo-controlled trial. All patients were ambulatory and had clinical features of right ventricular dysfunction but no clinical evidence of left ventricular dysfunction. Assessments included progressive and steady-state exercise, pulmonary function studies and evaluation of right and left ventricular function. In all patients the right ventricular ejection fraction was reduced; in 4 patients the left ventricular ejection fraction was also reduced. In patients whose left ventricular ejection fraction was initially abnormal, 8 weeks of digoxin increased left ventricular ejection fraction to normal. In spite of the improvement in resting ventricular function, exercise performance, the cardiopulmonary response to exercise, pulmonary function and general health status did not improve. We conclude that in patients with pulmonary heart disease: 1) digoxin improves ventricular function only if left ventricular function is reduced, and 2) despite the improvement in ventricular function digoxin does not improve pulmonary function, cardiopulmonary response to exercise or general feeling of well being.

Aged↗

[Kinetics of beta-methyl-digoxin in different degrees of renal function (author's transl)].

Creatinine clearance was evaluated in individuals with varying degrees of renal function following the administration of beta-methyl-digoxin. From the results of the experiment it can be deduced that significantly increased hematic values and renal clearance values definitely lower than normal appear only in patients of a creatinine clearance of less than 50 ml/min. Furthermore, a positive correlation between creatinine clearance values and beta-methyl-digoxin levels was noticed. This correlation was in proportion to the amount of serum albumin. The degree of distribution of free digitalis and digitalis bound to proteins within the vascular system played an important role in the complex kinetics of digoxin. This relationship is suggested as an indirect index of the proportions of free beta-methyl-digoxin and of beta-methyl-digoxin bound to plasma proteins.

Creatinine↗

Absorption of orally administered digoxin after massive resection of the small bowel.

Digoxin absorption was studied in a patient after massive small bowel resection (with only 15 cm. of jejunum left) after mesenteric thrombosis. Oral administration of 0.25 mg. digoxin tablets resulted in therapeutic blood levels between 0.7 and 2.2 ng./ml. Measurement of the urinary excretion of the drug in steady state revealed more than 80% of the maintenance dose. Renal digoxin clearance was 125 ml./min. This resulted in slowing of the heart rate from 120 to 80/min. with no side-effects. It is thus concluded that total absorption of digoxin might be normal in a patient with only 15 cm. of jejunum and that usual dogs of digoxin were sufficient for a therapeutic effect and "therapeutic" blood levels

Aged↗

Serum digoxin by radioimmunoassay.

Using the radioimmunoassay technique for measuring serum digoxin, it was found that patients who were given 0.25 mg. digoxin orally per day had a mean serum level of 0.83 +/- 0.06 ng. per ml. In patients given 0.5 mg. daily the mean level was 1.30 +/- 0.14 ng. A higher 24-hour urinary excretion of digoxin was associated with the higher serum levels in the latter group. Individuals who exhibited electrocardiographic evidence of digoxin toxicity had a mean serum level of 2.81 +/- 0.21 ng. The majority of patients with high serum levels had evidence of impaired renal function, and it is in this clinical situation that knowledge of serum digoxin levels is likely to be most helpful in determining dose schedules.The method is specific, sensitive and reproducible. Repeated measurements on the same patient on maintenance therapy showed little variation. To obtain dependable serum levels blood should be drawn at least five hours after oral, and three hours after intravenous administration.

Administration, Oral↗

[Serum glycoside concentration and digoxin intoxication].

Serum digoxin levels, estimated by radioimmuno assay, technique, and the pattern of cardiac arrhythmias due to digoxin intoxication seem to be correlated in cases with high serum digoxin levels. The prognostic value of those correlations is demonstrated and discussed. Serial observations of the course of cardiac arrhythmias under the suspicion of digoxin intoxication together with blood level measurements allow to introduce more objective criteria in clinical management of poor risk patients receiving digoxin.

Arrhythmias, Cardiac↗

[Significance of serum digoxin concentration and its influencing factors].

In recent years it has become possible by means of a radioimmunoassay to measure Digoxin concentration in the serum of digitalized patients. With this method it could be shown that the resorption of Digoxin is decreased by partial resection of the samll intestines, by malabsorption syndromes, after ingestion of Neomycin, Colestyramine and antacids. In renal insufficiency, however, the elimination half-life period of Digoxin is increased conspiciously (from about 35 hours up to about 120 hours). This results in a raised serum concentration of cardiac glycosides unless the dosage is decreased considerably. The incidence of Digitalis intoxication in Digitalis treated patients has been reported to rank as high as 20%. There is, however, no strict correlation between the serum glycoside level and the clinical symptoms, because the glykoside concentration in the serum does not represent the pharmacologically active concentration at the receptor. Experimental investigations of cardiac glycoside binding to the receptor for cardiac glycosides in human heart cell membranes revealed, that receptor bound Digoxin for instance is diminished in serious renal insufficiency and it depends on the serum concentration of potassium, calcium and magnesium. In hypoxia, after myocardial infarction and in myxedema the sensitivity for cardiac glycosides is increased. The opposite is true in hyperthyreoidism, fever and in children. All of these factors have to be kept in mind and paid attention to in the clinical evaluation of the measured Digoxin concentration in the serum.

Cardiac Complexes, Premature↗

[Pharmacokinetics of digoxin and methyldigoxin in patients with acute hepatitis (author's transl)].

After i.v. application of 3h-digoxin or 3H-methyldigoxin to 5 healthy volunteers and 5 patients with acute hepatitis, respectively (0.75 mg daily for 3 days and 0.375 for the following 2 days) total radioactivity in urine and plasma were determined. Chloroform-soluble and -insoluble glycosides were separated and the chloroform-soluble fraction was determined by TLC. 3 days after methyldigoxin application plasma levels reached toxic values in the patient group (2.73 +/- 0.48 ng/ml), whereas in patients receiving digoxin a mean plasma level of 0.91 +/- 0.21 ng/ml was obtained. During the first 24 hours following administration of digoxin 44 +/- 12% of the dose were recovered in urine of control subjects and 48 +/- 13% in patients with acute hepatitis, after methyldigoxin 34 +/- 5% and 34 +/- 8%, respectively. Metabolism of digoxin in patients with acute hepatitis was unaltered, whereas a diminished demethylation rate of methyldigoxin could be observed. 16 patients with acute hepatitis and 7 healthy volunteers received unlabelled digoxin p.o. as maintenance dose. Plasma glycoside concentrations were studied by radioimmunoassay. The average glycoside plasma concentrations were 0.59 +/- 0.21 ng/ml and 0.63 +/- 0.24 ng/ml, respectively.

Animals↗

[Relation between serum levels and inotropic effect of digoxin in advanced cardiac failure during long-term treatment].

The aim of this study was to determine the relationship of digoxin serum levels to their inotropic effects in advanced cardiac failure during long-term therapy with different dosages. The study was based on the analysis of left ventricular systolic time intervals (STI) measured at 97 follow-up appointments of 20 patients in advanced, stable cardiac failure over an average period of 37 days. The dosage of digoxin was varied at successive consultations so that the serum digoxin levels reached 0.50 ng/ml on at least one occasion. The serum digoxin levels (SD) varied between 0 and 4 ng/ml. Four levels of SD were individualised: A) "control" SD less than 0.25 ng/ml (22 consultations); B) SD: 0.25 to 1 ng/ml (n = 25); C) SD: 1.0 to 2.0 ng/ml (n = 29); D) SD greater than 2 ng/ml (n = 21) including 6 cases with clinical and/or ECG signs of digoxin toxicity. A progressive significant shortening of the electromechanical systolic index (Q-S2 I) was observed up to levels of 2 ng/ml (B and C, -18 ms and -28 ms respectively). The same phenomenon was observed with the ejection time index (ETi) and pre-ejection time index (PETi) (-7 ms and -14 ms; -11 ms and -15 ms respectively) compared to the basal values. At SD greater than 2 ng/ml the reduction remained stable and then started to decrease (positive difference between C and D). These changes were observed in the absence of significant variations of the heart rate. There was a significant linear relationship between the variations of the STI and SD in 15 out of 18 patients (in whom the regression could be calculated, these patients having attended at least 3 appointments). These linear relationships were observed for the Q-S2 i (11-18), the ETi (9-18) and/or PETi (10-18). An unexpected increase in the pre-ejection period was observed in 2 patients. In conclusion, a linear relationship has been shown between SD and inotropic effect which is particularly noticeable at SD levels less than 2 ng/ml. When SD is greater than 2 ng/ml, further increases in SD are associated with smaller variations of the STI. On the other hand, a significant inotropic effect is observed with small doses and SD levels less than 1 ng/ml. This inotropic effect persists unchanged at long-term.

Aged↗

Digoxin metabolism in patients.

In 100 patients receiving digoxin to control heart disease, metabolic reduction of the lactone ring of digoxin was investigated. An average of 12.4% +/- 11% (range 2.2% to 52%) of the lipid-extractable cardenolides in a 24-hour urine sample contained the reduced lactone ring. Fifty-three excreted more than 10% while seven excreted more than 35% of these metabolic products. Reduction was not influenced by age, sex, dose, or blood level of digoxin. One patient who excreted 52% reduced products in the urine had 40% reduced digoxin-metabolites in the blood; the main metabolite was dihydrodigoxin. We found no influence of other drug therapy or concurrent disease on reduction of digoxin in this group.

Adolescent↗

Electrocardiogram and high plasma digoxin concentration.

In 48 patients a significantly elevated plasma digoxin concentration (2.5 micrograms/l or more) correlated with the clinical symptoms and the electrocardiogram. The rhythm and conduction disturbances as well as the corrected Q-T interval and the P-T-Q index in the electrocardiogram were analyzed. In 23 patients rhythm and conduction disturbances were found. The clinical symptoms of digoxin overdose were found in 23 patients. There was no significant relationship between the corrected Q-T interval in the electrocardiogram and digoxin concentrations (r = 0.19); P-T-Q index and plasma digoxin concentrations were found to have similar values (r = 0.27), as did prolonged P-Q interval and plasma digoxin concentrations (r = 0.32). A total of 17 of 48 patients had had chronic renal failure. An S-T segment depression mostly of decreasing type was found in the whole group, suggesting that this sign was more reliable as an indicator of digitalis effect than corrected Q-T interval, P-T-Q index, or prolonged P-R interval.

Adult↗