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PubMed1980

Alteration of digoxin toxicity by 6-hydroxydopamine and soironolactone.

The possibility that the Na+-K+ ATPase of cardiac adrenergic neurons is the toxic receptor site of cardiac glycosides was investigated by performing a chemical sympathectomy in dogs using 6-hydroxydopamine to destroy the adrenergic neurons. No alteration was seen in the therapeutic, toxic, or lethal dose of digoxin after the administration of 6-hydroxydopamine, indicating that the toxic receptor of digoxin is not located on the adrenergic nerve endings. Pretreatment of control dogs with spironolactone increased the toxic and lethal dose of digoxin without changing the therapeutic dose of digoxin. However, spironolactone pretreatment of chemically sympathectomized dogs produced an increase pretreatment of chemically sympathectomized dogs produced an increase in the therapeutic, toxic, and lethal doses of digoxin. Therefore, the destruction of this neuronal tissue decreases the therapeutic effectiveness of digoxin in the presence of spironolactone, and abolishes the ability of spironolactone to alter the therapeutic ratio of digoxin.

Animals↗
PubMed1979

Spironolactone-associated digoxin radioimmunoassay interference.

Apparent digoxin was measured in the serum of 21 patients receiving spironolactone and in 21 controls, by use of a sequential-saturation 3H-radioimmunoassay (RIA) and an equilibrium 125I-RIA. No patient had been given digoxin for at least four weeks. "Digoxin" values in the former group were significantly (p less than 0.05) higher than in the control group, and often were in or near the "therapeutic" range by the equilibrium 125I-RIA, but not by the sequential-saturation 3H-RIA. Canrenone (a major active metabolite of spironolactone) in the serum of the former group was measured by a newly developed liquid-chromatographic technique and correlated (r = 0.73) with "digoxin" concentrations by the 125I-RIA. However, external addition of canrenone to control serum in comparable concentrations did not cause appreciable "digoxin" values by the 125I-RIA. These findings suggest that other metabolites of spironolactone are responsible for the assay interference, the degree of which appears to depend on antibody specificity. Therefore, assay specificity should be established in clinical laboratories by using digoxin-free serum from patients ingesting spironolactone, and not by using spironolactone- or canrenone-fortified digoxin-free serum.

Digoxin↗
PubMed1995

Digoxin affects potassium homeostasis during exercise in patients with heart failure.

OBJECTIVE: The aim was to evaluate whether digitalisation of heart failure patients affects extrarenal potassium handling during and following exercise, and to assess digoxin receptor occupancy in human skeletal muscle in vivo. METHODS: In a paired study of before versus after digitalisation, 10 patients with congestive heart failure underwent identical exercise sessions consisting of three bouts of increasing work rates, 41-93 W, on a cycle ergometer. The final bouts were followed by exercise to exhaustion. The femoral vessels and brachial artery were catheterised. Arterial blood pressure, heart rate, leg blood flow, cardiac output, plasma potassium, haemoglobin, pH, and skeletal muscle receptor occupancy with digoxin in biopsies were determined. RESULTS: Occupancy of skeletal muscle Na/K-ATPase with digoxin was 9% (P < 0.05). Following digitalisation femoral venous plasma potassium increased by 0.2-0.3 mmol.litre-1 (P < 0.05) at work rates of 69 W, 93 W, and at exhaustion, as well as during the first 3 min of recovery. Following digitalisation the femoral venoarterial difference in plasma potassium increased by 50-100% (P < 0.05) during exercise, and decreased by 66-75% (P < 0.05) during early recovery. Total loss of potassium from the leg increased by 138%. The effects of digitalisation on plasma potassium were not the outcome of changes in haemodynamics, because cardiac output and leg blood flow increased by up to 13% and 19% (P < 0.05), nor was it the outcome of changes in haemoconcentration or pH. CONCLUSIONS: Extrarenal potassium handling is altered as a result of digoxin treatment. This is likely to reflect a reduced capacity of skeletal muscle Na/K-ATPase for active potassium uptake because of inhibition by digoxin, adding to the reduction of skeletal muscle Na/K-ATPase concentration induced by heart failure per se. In heart failure patients, improved haemodynamics induced by digoxin may, however, increase the capacity for physical conditioning. Thus the impairment of extrarenal potassium homeostasis by heart failure and digoxin treatment may be counterbalanced by training.

Cardiac Output↗
PubMed1994

Utilization of antidrug antibody fragments for the optimization of intraperitoneal drug therapy: studies using digoxin as a model drug.

The direct administration of chemotherapeutic agents into the peritoneal cavity has been investigated as a method to treat cancers residing within the peritoneum. The benefits of i.p. drug administration are limited, however, by the systemic toxicity of antineoplastic drugs which diffuse out of the peritoneum and into the general circulation. We propose that antidrug antibody fragments may be useful in binding chemotherapeutics in the general circulation, thereby reducing the systemic tissue exposure and toxicity resulting from such i.p. therapy. Inasmuch as antibody fragments directed against antineoplastic agents are not available, we tested our hypothesis by using i.v. administered ovine antidigoxin Fab fragments and determined their ability to limit digoxin tissue exposure and toxicity in mice after an i.p. digoxin injection. The rate of digoxin disappearance from the peritoneal cavity and the fraction of digoxin unbound in the peritoneal cavity were also assessed to determine the effect of the antibody fragments on peritoneal exposure. Our results showed that the antidigoxin antibody fragments can greatly decrease digoxin tissue exposure and toxicity without affecting peritoneal exposure, unbound fraction of digoxin in the peritoneum or peritoneal digoxin disappearance rate. Although the utility of drug-binding antibodies and antibody fragments for the treatment of drug intoxication is well known, these results demonstrated the potential ability of antidrug antibody fragments to improve the site-specificity of drug therapy.

Animals↗
PubMed1977

Enhancement of phrenic nerve activity by digoxin: an effect dependent upon intact ninth and tenth cranial nerves.

Digitalis increases phrenic nerve activity and causes hyperventilation. To determine whether this effect on respiration is caused by central drug actions on brainstem respiratory neurons or by peripheral drug actions which increase excitatory afferent drive to central respiratory neurons, digoxin was administered intravenously to cats with or without intact IXth and Xth cranial nerves. Digoxin caused marked increases in phrenic nerve activity in cats with intact afferent cranial nerves, but it had no effect in cats with severed afferent nerves. This suggested that effects of digoxin on respiration depend upon afferent input to respiratory neurons. However, digoxin may have had subliminal effects on central neurons which increased phrenic activity only in the presence of excitatory input. To test this possibility, effects of intravenously administered digoxin were observed on centrally evoked submaximal responses in the phrenic nerve. Subarrhythmic, arrhythmic or lethal doses of digoxin had no effect on excitatory phrenic responses evoked from the pons. Thus, effects of digoxin on phrenic nerve activity appeared to be due primarily to drug actions on peripheral neural sites which had excitatory influences on respiration.

Animals↗
PubMedDate not supplied

Does any correlation exist between a high plasma digoxin concentration and an electrocardiogram in younger and older patients.

In a group of 152 elderly patients (age range between 65 to 92 years) and 54 patients (aged 35 to 64 years) plasma digoxin level measuring 2.5-6.2 nmol/1 were correlated with the clinical symptoms and the electrocardiogram. The conduction disturbances and arrhythmias as well as the P-R interval, P-T-Q index and corrected Q-T interval in the ECG were analyzed. The clinical symptoms of hypersaturation with digitalis were present in 54.6% of the elderly and 35.2% of the younger patients. Conduction disturbances were found in 42% of the elderly and 22.2% of the younger patients, while arrhythmias appeared in 40.1% of the elderly and 31.5% of the younger ones. 17.8% of the elderly and 46.3% of the younger patients were without these changes. The correlation between P-R interval and high plasma digoxin level in the elderly (p < 0.01) and younger patients (p < 0.05), as well as between the P-T-Q index and high plasma digoxin level in the elderly (p < 0.01) was found. There was no correlation between the corrected Q-T interval and high plasma digoxin level in both groups. No correlation was found between a high plasma digoxin level and serum creatinine level in both groups, neither between a high plasma digoxin level and serum potassium level in both groups. The effect of digitalis has not been shown to be a cause of specific changes in an electrocardiogram neither in the elderly nor in younger patients. However, the association between prolonged P-R interval as well as changes in the P-T-Q index and high plasma digoxin level has been found more often in the elderly than in the younger patients.

Adult↗
PubMed1996

Evaluation of five immunoassays for the determination of digoxin in serum.

Five immunoassays for the determination of digoxin have been evaluated (Digoxin II, Abbott; Cedia Digoxin XL, Microgenics; Coat-a-Count Digoxin, Diagnostic Procedure Corporation, DPC; "On-line" Digoxin, Roche Diagnostic Systems; EMIT 2000 Digoxin, Syva). Four of them required no sample pre-treatment. The methods included a radioimmunoassay, fluoroimmunoassay, two enzyme-immunoassays and a turbidimetric immunoassay: the last three mentioned were adapted to the Cobas Mira Plus. The intra- and inter-assay precision was lower than 9%, except for Microgenics. The calibration stability fluctuated from 120 days for Abbott to 27 days for the Roche test, 7 days for the Syva assay and 2 days for Microgenics. The DPC test was not assayed for calibration stability. The interference from "digoxin-like immunoreactive factor(s)" differed according to the assay. The highest interference was seen with Abbott and Microgenics, and the lowest with the DPC test. The comparison among all the methods offered values of "r" higher than 0.95 except Microgenics and Syva assays where "r" was 0.896. The results obtained with Roche and Microgenics were higher than 12% of the remaining assays.

Digoxin↗
PubMed1977

Comparison of the cardiac effects of ASI-222 HCl, an aminosugar cardiac glycoside, and digoxin.

The effects of ASI-222 HCl and digoxin on cardiac contractile force, dP/dt, heart rate and mean blood pressure in the dog were evaluated following i.v. administration. Additional studies were performed on isolated, electrically driven rabbit atria with both ASI-222 and digoxin. Our data show that ASI-222 (40 microgram/kg) in non-vagotomized dogs produced a two-fold greater increase in cardiac contractile force and dP/dt than did an equimolar dose of digoxin. ASI-222 caused a peak increase in contractile force and dP/dt 10 min after administration, whereas the peak to digoxin occurred at 30 min. ASI-222 was more effective in non-vagotomized dogs in increasing contractile force and dP/dt than in vagatonized dogs. The inotropic responses to digoxin were not reduced by vagotomy. Studies on isolated electrically driven rabbit atria indicate ASI-222 to be 7-8 times more potent than digoxin in increasing contractile force. These data demonstrate that ASI-222 produces an earlier and greater increase in contractile force and dP/dt than digoxin in equimolar doses.

Aminoglycosides↗
PubMed1990

Urinary excretion of digoxin-like factor (DLF) and ADH during DOCA-salt and Goldblatt 2 kidney-1 clip hypertension development.

Urinary digoxin-like factor, ADH, sodium and potassium excretion and urine osmolality were studied during the development of two pathogenically different models of hypertension, DOCA-salt (low-renin) and Gold-blatt 2 kidney-1 clip (renin-dependent). Urinary digoxin-like factor was increased in rats that were given saline (NaCl 1%) to drink, uninephrectomized-salt and DOCA-salt rats, with no significant differences between the two groups urinary ADH was elevated in DOCA-salt rats during the study, compared with uninephrectomized-salt rats. Urinary digoxin-like factor and urinary ADH were not significantly modified in Goldblatt 2 kidney-1 clip and sham-operated rats. In addition, positive correlations between digoxin-like factor urinary excretion and urinary ADH and also with sodium urinary excretion were found. These data suggest that: a) digoxin-like factor and ADH could play a role in the pathogenesis of DOCA-salt but not in Goldblatt 2 kidney-1 clip hypertension. b) A common mechanism may stimulate ADH and digoxin-like factor simultaneously. c) Digoxin-like factor plays a role in the control of urinary sodium excretion.

Animals↗
PubMed1994

Augmented Digoxin Concentrations with Carvedilol Dosing in Mild-Moderate Heart Failure.

Carvedilol is a partially selective beta-adrenergic blocking agent. Recent clinical studies have suggested that carvedilol may improve left ventricular function and symptoms in patients with heart failure. The effects of carvedilol on serum digoxin levels in subjects with heart failure is unknown. Therefore, 22 New York Heart Association functional class II--III patients with idiopathic dilated cardiomyopathy were studied in a prospective, double-blind, placebo-controlled trial. The patients were selected from a clinical trial evaluating the efficacy and hemodynamic effects of chronic carvedilol treatment in heart failure. Carvedilol administration was associated with a 26% increase in steady-state serum digoxin concentrations versus placebo (p = NS). No patients required digoxin dosage adjustments and there were no clinically significant adverse events directly attributable to an increase of serum digoxin concentration. Thus, clinical significant changes in serum digoxin concentrations are not observed in most patients who receive carvedilol. However, the small increase in serum digoxin concentrations warrants caution be exercised in patients with elevated digoxin concentrations during coadministration of carvedilol.

Journal Article↗
PubMed1971

Reversal of digoxin toxicity with specific antibodies.

To determine whether digoxin-specific antibodies can reverse established digoxin toxicity in the dog, digoxin intoxication was produced by the intramuscular administration of digoxin, 0.09 mg/kg, on each of 3 consecutive days. All animals developed toxic arrhythmias (atrioventricular block, ventricular premature contractions and/or ventricular tachycardia). In control animals not receiving antidigoxin antibodies, the arrhythmias persisted throughout a 6 hr study period. Seven of the nine control dogs were dead within 24 hr and one moribund animal was sacrificed at that time; the last animal died within 48 hr.In contrast, in six of eight dogs given digoxin-specific antibodies in canine plasma and/or rabbit serum, the arrhythmias reverted to a sinus mechanism within 30-90 min after the start of the infusion. At the end of a 6 hr period of study, these six dogs were in normal sinus rhythm and all eight were alive and in normal sinus rhythm at the end of 72 hr. This study provides evidence that digoxin-specific antibodies can reverse severe established digoxin toxicity in the dog.

Animals↗
PubMed1997

Digoxin's Minimal Inotropic Effect Is Not Limited by Sodium-Calcium Exchange in the Intact Immature Rabbit Heart.

BACKGROUND: In the intact immature heart, how much digoxin can drive sodium-calcium exchange has not been studied in the context of sodium-calcium exchanger abundance. METHODS AND RESULTS: The effects of digoxin and low potassium on contractility in the intact, paced and isovolumically contracting immature rabbit heart were studied in both the absence and presence of L-type calcium channel blockade. Without calcium channel blockade, digoxin increased contractility minimally and only at 10(_6) M/L. In contrast, low potassium (2.2 mM/L) substantially increased contractility in all experiments, a result indicating abundant sodium-calcium exchanger activity. During nifedipine-induced calcium channel blockade, digoxin (10(_6) M/L) allowed modest recovery of contractility, whereas digoxin and low potassium together allowed complete recovery as assessed by dP/dt(max); however, all hearts so perfused subsequently developed ventricular fibrillation, presumably because of calcium overload. CONCLUSIONS: In intact immature rabbit heart, digoxin can drive sodium-calcium exchange and thus increase contractility to only a minimal extent. This effect does not appear to be limited by intrinsic exchanger activity, which appears abundant in this preparation. Rather, digoxin's inability to drive the sodium-calcium exchanger may be due to developmental differences in binding to the sodium pump. The sodium-calcium exchanger itself seems capable not only of providing enough intracellular calcium for normal contraction, but also of overloading the myocardium with calcium, despite L-type calcium channel blockade.

Journal Article↗
PubMed1976

Pharmacological experiments as a basis for the administration of digoxin in the horse.

It is shown that the concentration of ouabain necessary for 50 per cent inhibition of the Na+K activated membrane ATPase of red cells is similar in man and horse. This is taken to indicate that the two species have similar sensitivity towards cardiac glycosides in general. In five adult healthy horses plasma digoxin concentration was measured with a radioimmunoassay technique after a single intravenous injection of 1 mg/100 kg body weight digoxin. The half time of elimination was 23 h and the apparent volume of distribution 7.3 litres/kg. An approximate estimate of plasma protein binding of digoxin was obtained by measuring digoxin with a fluorimetric assay in the ultrafiltrate from horse plasma containing 2-20 mug/ml. At concentrations below 10(-5)(g/ml 20 to 40 per cent of digoxin present in horse plasma is bound to protein. With this information and by using effective digoxin concentration measured in humans an average daily maintenance dose of 0-5-0-75 mg/100 kg body weight was calculated which may serve as a guideline in the treatment of congestive heart failure with digoxin in the horse.

Adenosine Triphosphatases↗
PubMed2003

Association of serum digoxin concentration and outcomes in patients with heart failure.

CONTEXT: The Digitalis Investigation Group (DIG) trial reported that digoxin provided no overall mortality benefit and only a modest reduction in hospitalizations among patients with heart failure and depressed left ventricular systolic function. The clinical outcomes associated with digoxin therapy at different serum concentrations in the DIG trial have not been assessed. OBJECTIVE: To assess variations in serum digoxin concentration (SDC) and their association with mortality and hospitalization in patients with heart failure. DESIGN, SETTING, AND PATIENTS: Post hoc analysis of the randomized, double-blinded, placebo-controlled DIG trial, conducted from August 1991 to December 1995, with the main analysis restricted to men with a left ventricular ejection fraction of 45% or less (n = 3782). Patients randomly assigned to receive digoxin were divided into 3 groups based on SDC at 1 month (0.5-0.8 ng/mL, n = 572; 0.9-1.1 ng/mL, n = 322; and > or =1.2 ng/mL, n = 277) and compared with patients randomly assigned to receive placebo (n = 2611). MAIN OUTCOME MEASURE: All-cause mortality at a mean follow-up of 37 months. RESULTS: Higher SDCs were associated with increased crude all-cause mortality rates (0.5-0.8 ng/mL, 29.9%; 0.9-1.1 ng/mL, 38.8%; and > or =1.2 ng/mL, 48.0%; P =.006 for trend). Patients with SDCs of 0.5 to 0.8 ng/mL had a 6.3% (95% confidence interval [CI], 2.1%-10.5%) lower mortality rate compared with patients receiving placebo. Digoxin was not associated with a reduction in mortality among patients with SDCs of 0.9 to 1.1 ng/mL (2.6% increase; 95% CI, - 3.0% to 8.3%), whereas patients with SDCs of 1.2 ng/mL and higher had an 11.8% (95% CI, 5.7%-18.0%) higher absolute mortality rate than patients receiving placebo. The association between SDC and mortality persisted after multivariable adjustment (SDC 0.5-0.8 ng/mL hazard ratio [HR] 0.80, 95% CI, 0.68-0.94; SDC 0.9-1.1 ng/mL HR 0.89, 95% CI, 0.74-1.08; SDC > or =1.2 ng/mL HR 1.16, 95% CI, 0.96-1.39; and HR of 1.00 [referent] for placebo). CONCLUSIONS: Our findings demonstrate that higher SDCs were associated with increased mortality and suggest that the effectiveness of digoxin therapy in men with heart failure and a left ventricular ejection fraction of 45% or less may be optimized in the SDC range of 0.5 to 0.8 ng/mL.

Cardiotonic Agents↗
PubMed1975

Determinants of the renal clearance of digoxin.

The renal clearances of digoxin, creatinine, and urea nitrogen were determined simultaneously in each of 41 patients receiving digoxin, in most of whom there was prerenal azotemia. Mean plus or minus SD values were: blood urea nitrogen (BUN), 26.1 plus or minus 12.8 mg per 100 ml; creatine, 1.1 + 0.41 mg per 100 ml; creatinine clearance, 78 plus or minus 42 ml/min/1.73 m2; digoxin clearance, 66.6 plus or minus 42.1 ml/min/1.73 m2; urea nitrogen clearance, 27.8 plus or minus 19.2 ml/min/1.73 m2. Correlation analysis revealed that urea clearance is superior to creatinine clearance, and BUN is superior to serum creatinine concentration in the degree of relationship to renal digoxin clearance. Moreover, using partial correlation techniques, it is apparent that in these patinets digoxin clearance was significantly related to urine flow rate. These findings are compatible with the hypothesis that digoxin undergoes some degree of tubular reabsorption as well as filtration and secretion.

Adult↗
PubMedDate not supplied

Calculation of serum digoxin levels in patients with normal and impaired renal function.

Serum digoxin levels were examined in 55 patients with varying degrees of renal function impairment who were receiving chronic oral digoxin therapy. Three methods of predicting digoxin serum levels were investigated. Each method may be applied using serum creatinine values and does not require urinary data. Correlations between calculated and actual digoxin levels in combined male and female patients were improved when changes in digoxin distribution volumes in renal impairment were considered. Correlations between calculated and actual digoxin levels were poor in male patients but were again improved by incorporating changes in drug distribution volume. Correlations obtained in female patients were superior to those obtained in male patients and appeared to be independent of the method of calculation employed.

Adult↗
PubMed1981

Effect of magnesium--aluminum hydroxide and kaolin--pectin on absorption of digoxin from tablets and capsules.

Twelve healthy fasting volunteers received two 0.2-mg digoxin capsules or tablets with 60 ml water, 60 ml Maalox, or 60 ml Kaopectate in a randomized, single-dose, six-way crossover study. Concentrations of digoxin in multiple plasma samples and in all urine collected during the 24 hours after each dose were determined by radioimmunoassay. Compared to the water treatment, administration of both tablets and capsules with Maalox or Kaopectate reduced the peak digoxin plasma concentrations but did not significantly influence the time of peak concentration. Neither Maalox nor Kaopectate influenced the area under the 24-hour plasma concentration--time curve for either tablets or capsules. However, 24-hour urinary recovery of digoxin from tablets tended to be reduced by Maalox and Kaopectate; this was not the case with capsules. Digoxin capsules may have an advantage over currently available tablets in clinical situations requiring digoxin coadministration with nonabsorbable gastrointestinal preparations.

Adult↗
PubMedDate not supplied

Digoxin pharmacokinetics in congestive heart failure.

The steady-state pharmacokinetics of oral digoxin in eight hospitalized patients was compared upon their admission with marked right-sided congestive heart failure and later when they were compensated. Large intersubject variations in the serum digoxin concentration profiles were observed. However, over a 24-hour dosing interval, digoxin concentrations in each patient studied during heart failure were either similar or higher than those observed when the patient became compensated. There were no significant differences in digoxin half-life of elimination between the two states. In contrast, the mean ratio of the fraction of digoxin dose absorbed to its apparent volume of distribution was increased by 37 per cent (P less than 0.05) in heart failure. Contrary to the prevailing notion, we found that the oral administration of supplemental doses of digoxin only on the basis of its reduced serum concentration in patients with congestive heart failure is unwarranted.

Adult↗