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PubMed1984

Quinidine-induced changes in serum and skeletal muscle digoxin concentration; evidence of saturable binding of digoxin to skeletal muscle.

Eleven patients with atrial fibrillation on maintenance digoxin therapy were investigated by analysis of serum (SDC) and skeletal muscle (SMDC) digoxin concentrations before and 24 h and 2 weeks after starting quinidine treatment. After cardioversion the maintenance dose of digoxin was reduced in order to obtain the same steady-state SDC after 2 weeks, as before quinidine. SDC was increased by quinidine therapy from 1.56 to 2.40 nmol/l after 24 h. With the reduced digoxin dose SDC was 1.68 nmol/l after 2 weeks. The ratio SMDC/SDC decreased after 24 h of quinidine treatment from 35.4 to 29.0 (p less than 0.01). After 2 weeks of quinidine treatment with the reduced digoxin dose, the ratio had risen to 38.1, which did not differ significantly from the initial ratio. The present data suggest that the reduced skeletal muscle binding of digoxin during quinidine therapy is due to saturation of digoxin binding sites secondary to the increase in the total body load of digoxin at steady-state, and not to direct interference by quinidine with digoxin binding sites.

Aged↗
PubMed1987

Comparative effects of nadolol-digoxin combination therapy and digoxin monotherapy for chronic atrial fibrillation.

In some patients with chronic atrial fibrillation, treatment with digitalis alone may fail to produce a satisfactory decrease in heart rate at rest or during exercise or emotional stress. Findings of a few clinical studies suggest that beta blockade in combination with digitalis therapy may be of benefit in these patients. In a randomized, double-blind, placebo-controlled, parallel-group, 8-week study of 32 patients with chronic atrial fibrillation, the effects of digoxin therapy alone were compared with a combination of digoxin and nadolol. Criteria for entry into the study included ventricular rate at rest greater than or equal to 80/min or greater than or equal to 120/min with exercise, and serum digoxin levels within the therapeutic range. After digoxin dose titration to produce therapeutic levels, digoxin dosage remained constant throughout the balance of the study. After a 2-week, single-blind placebo lead-in period, patients were randomized to receive either digoxin plus placebo or a combination of digoxin and nadolol. The dose of nadolol/placebo was titrated from 20 to 120 mg daily as tolerated. Twenty-four hour ambulatory electrocardiographic (Holter) recordings, symptom-limited exercise treadmill tests and serum digoxin and nadolol levels were obtained at the end of the single and double-blind treatment periods. Comparing endpoint with baseline, results from Holter recordings showed that patients treated with a combination of digoxin and nadolol had significant (p less than 0.001) decreases in 24 hour average (78 +/- 4 to 63 +/- 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Dose-dependent reversal of digoxin-inhibited activity of an in vitro Na+K+ATPase model by digoxin-specific antibody.

We investigated the potency of digoxin-specific Fab fragments to reverse digoxin-induced Na+K+ATPase inhibition in rat brain microsomes according to (a) the extent of initial inhibition of Na+K+ATPase and (b) the neutralizing dose of antibody. Mathematical analysis of the digoxin concentration-Na+K+ATPase inhibition curve supports the existence of 2 digoxin sensitive Na+K+ATPase isoforms. The IC50 was 1.3 x 10(-4) M and 2.5 x 10(-8) M for the low (alpha 1) and high (alpha 2) digoxin affinity isoenzyme, respectively. The reversal of digoxin-induced Na+K+ATPase inhibition was dependent on the digoxin-specific Fab concentration. The maximal effect was observed when the Fab:digoxin ratio was stoichiometrical and addition of an excess of antibodies did not result in a complete reversal of inhibition at the 4 digoxin concentrations studied. This simple and rapid in vitro model will be a useful tool to predict the efficacy of a new generation of antibodies.

Animals↗
PubMed2006

Digoxin use and digoxin toxicity in the post-DIG trial era.

BACKGROUND: The advent of medical therapies for congestive heart failure that have proven survival benefits, specifically angiotensin-converting enzyme (ACE) inhibitors, beta-adrenergic antagonists, and the aldosterone antagonists, have called into question the use of digoxin for patients with normal sinus rhythm, left ventricular dysfunction, and symptomatic heart failure. This issue appears to have been heightened after the publication of the results of the Digitalis Investigation Group (DIG) Trial in 1997 that did not demonstrate a statistically significant impact of digoxin on mortality. METHODS AND RESULTS: We used data from a large heart failure registry to examine digoxin use at the time of hospital admission for heart failure, a surveillance system for recording toxic drug exposures to describe patterns in digoxin toxicity and industry estimates for the use of digoxin antibody. Digoxin use has decreased significantly from 31.4% in late 2001 to 23.5% in late 2004 (P < .00001) independent of patient age, gender, or baseline creatinine. Conversely, the number of toxic or potentially toxic exposures to digoxin requiring hospitalization has not decreased. CONCLUSION: Digoxin use is decreasing but there has not been a similar decline in cases of toxicity. Further analyses are required to delineate the reasons underlying these trends and the appropriateness of prescribing practices for both digoxin and its antidote.

Aged↗
PubMed1996

Comparison of four digoxin immunoassays with respect to interference from digoxin-like immunoreactive factors.

OBJECTIVES: Comparison of a new monoclonal digoxin assay with three polyclonal digoxin assays for their cross-reactivity to digoxin-like immunoreactive factors (DLIF) and digoxin metabolites. DESIGN AND METHODS: Sixty-six nondigitalized patient samples from 5 different groups: neonates, women in 3rd trimester pregnancy, and patients with liver or renal diseases, or undergoing organ transplants, and 139 samples from digoxin-treated patients of 4 categories (hospital sick, liver, renal, and outpatients) were compared in 4 different digoxin assays: (a) ACS Digoxin (ACS) developed for the automated chemiluminescent Ciba Corning ACS 180 system, (b) Baxter Stratus (Stratus, a fluoroimmunoassay), (c) Ciba-Corning Magic (Magic, a radioimmunoassay), and (d) an in-house radioimmunoassay (RIA). The ACS and RIA were also compared for their cross-reactivity to four principal digoxin metabolites. RESULTS AND CONCLUSION: Among the nondigitalized specimens, no significant DLIF interference was found for all 4 assays among the pregnant women or liver and transplant patients. However, the neonates registered high DLIF interference with Magic and RIA, but none for ACS or Stratus. DLIF interference in renal samples was highest in the Magic assay and lowest in RIA. Among the specimens with digoxin, a higher number of discrepant samples were found from the sick patients than from outpatients. In 75% of such discrepant samples, the ACS result was less than other assay results, suggesting DLIF as the probable cause. The two assays differed most in their cross-reactivity to the deglycated metabolites, digoxigenin and its mono-digitoxoside.

Adult↗
PubMed1998

Superiority of "triple" drug therapy in heart failure: insights from the PROVED and RADIANCE trials. Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin. Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme.

OBJECTIVES: We sought to study the efficacy of "triple" therapy with digoxin, diuretic and angiotensin-converting enzyme inhibitor (ACEI) compared to other combinations of these drugs in patients with symptomatic left ventricular systolic dysfunction. BACKGROUND: Controversy continues concerning the role of combining digoxin with diuretic and ACEI in the initial management of patients with heart failure. METHODS: The study utilized data from two studies of digoxin efficacy: Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED) and Randomized Assessment of Digoxin and Inhibitors of Angiotensin-Converting Enzyme (RADIANCE). Worsening heart failure defined as augmentation of heart failure therapy or an emergency room visit or hospitalization for increased heart failure was the main outcome measure. RESULTS: A total of 266 patients comprising the four treatment groups of the combined PROVED (diuretic alone or digoxin and diuretic) and RADIANCE (ACEI and diuretic, or digoxin, diuretic and ACEI) trials were analyzed. Worsening heart failure occurred in only 4 of the 85 patients who continued digoxin, diuretic and ACEI therapy (4.7%) compared to 18 of the 42 patients (19%) on digoxin and diuretic therapy (p=0.009), to 23 of the 93 patients (25%) on ACEI and diuretic therapy (p=0.001) and to 18 of the 46 patients (39%) on diuretic alone (p < 0.001). Life table and multivariate analysis also demonstrated that worsening heart failure was least likely in patients treated with triple therapy (p < 0.01 vs. all other groups). CONCLUSION: Pending definitive, prospective clinical trials, our results argue for triple therapy as the initial management of patients with symptomatic heart failure due to systolic dysfunction.

Adult↗
PubMed1983

Effects of physical activity and immobilization on plasma digoxin concentration and renal digoxin clearance.

Plasma digoxin concentration and renal digoxin clearance were determined during 2 hr of normal physical activity and during 2 hr of complete immobilization in eight healthy subjects on steady-state digoxin dosing. Mean plasma digoxin concentration rose from 0.64 +/- 0.13 ng/ml during physical activity to 1.04 +/- 0.19 ng/ml (63%) after 2 hr of rest. Resumption of physical activity resulted in gradual decline of plasma digoxin, and subsequent strenuous exercise reduced the value to preimmobilization level. Mean renal digoxin clearance was reduced from 168.4 +/- 18.7 ml/min during physical activity to 137.2 +/- 32.7 ml/min during rest whereas creatinine clearance was unchanged. The rise in plasma digoxin during rest is presumed to be due to changes in the binding of the drug to tissues such as skeletal muscles. Our findings indicate that attention should be given to the state of physical activity when kinetic studies are performed or when digoxin therapy is monitored by means of plasma digoxin analysis.

Adult↗
PubMed1984

Effect of nifedipine on serum digoxin concentration and renal digoxin clearance.

Nifedipine has been reported either to decrease or not to affect digoxin elimination. We studied the effect of oral nifedipine on steady-state digoxin concentrations and renal clearance in 20 healthy male subjects. After 2 wk of digitalization, all received digoxin, 0.375 mg a day, with placebo for 2 wk, then digoxin and nifedipine, 18.5 +/- 4 mg every 8 hr, for 2 wk, and then digoxin with placebo for 2 wk. Mean (+/- SD) digoxin concentrations of 0.74 +/- 0.20 and 0.75 +/- 0.25 ng/ml on placebo were not altered by nifedipine (0.77 +/- 0.23 ng/ml). Digoxin clearance was 2.2 +/- 0.6 and 2.7 +/- 0.8 ml/kg/min on placebo and 2.5 +/- 0.6 ml/kg/min on nifedipine. No change in pharmacologic effect of digoxin by nifedipine was observed, but mean blood pressure was lower and heart rates were accelerated. These data indicate that oral nifedipine does not alter digoxin concentrations or decrease renal clearance in healthy subjects.

Adult↗
PubMed1984

Variable cross-reactivity of digoxin metabolites in digoxin immunoassays.

The authors investigated the cross-reactivity of the major known digoxin metabolites--digoxigenin, digoxigenin monodigitoxoside, digoxigenin bisdigitoxoside, and dihydrodigoxin--and of digitoxin in three 125I-radioimmunoassays and one enzyme immunoassay for digoxin. Digitoxin and dihydrodigoxin exhibit low cross-reactivity and nonparallel dilution responses for these assays. The cross-reactivities of the other three substances are significant for all assays studied with digoxigenin and monodigitoxoside having nonparallel and enhanced tracer displacement compared with digoxin itself. The authors demonstrate that because of nonparallel tracer displacement estimates of cross-reactivity calculated by the 50% displacement method fail to adequately predict the error induced in digoxin assays by digitoxin. They conclude that digoxin metabolites in serum are measured to various extents as the parent digoxin compound by all of the immunoassays they studied. In view of the varying biologic activity of digoxin metabolites and the large patient to patient variations in digoxin metabolism, the cross-reactivities the authors observe may help to explain the discrepancies in correlation of clinical response to measured serum digoxin values reported in other studies.

Cross Reactions↗
PubMed1989

Effects of digoxin immune Fab (ovine) on digoxin immunoassays.

Digoxin immune Fab (ovine) (Digibind) is a preparation of Fab fragments of antidigoxin antibodies that is used as an antidote for severe digitalis toxicity. To assess the effects of its presence on digoxin immunoassays, specimens were prepared that simulated typical samples from treated patients and were distributed to a number of laboratories for analysis as unknowns. The antidote interfered to a varying extent with all assays reported. The results suggest that most competitive immunoassays will yield results that bear little relation to concentrations of total digoxin or free digoxin (i.e., digoxin not bound to the antidote). The aca, Dimension, and CEDIA sequential immunoassays moderately overestimated the free digoxin concentration. Free digoxin levels appeared to be only slightly overestimated by the Aria, Stratus, and Syva assays. The TDx Digoxin II assay yielded slight to moderate underestimates of the total digoxin concentration.

Antidotes↗
PubMed1987

Digoxin toxicity in patients with high serum digoxin concentrations.

A retrospective study of the clinical course and outcome of patients with serum digoxin concentrations (SDCs) greater than 3 ng/mL was conducted to determine the probability of a patient without initial signs or symptoms of digoxin toxicity subsequently developing signs or symptoms. Of 123 patients with SDCs greater than 3 ng/mL, 54 had no apparent signs or symptoms of toxicity at the time the index SDC was determined (group 1). Of these 54, two patients developed definite digoxin toxicity, although neither suffered significant morbidity. Digoxin administration was reduced or discontinued in all patients but one in group 1. There were no significant differences between the patients who had no signs or symptoms of digoxin toxicity (group 1) and those who did have signs or symptoms (group 2) in the mean SDC (3.9 +/- 0.1 vs 4.2 +/- 0.2 ng/mL, respectively), the serum creatinine (2.9 +/- 0.2 vs 3.4 +/- 0.4 mg/dL), or the incidence of atrial fibrillation (29/54 vs. 35/69) and coronary artery disease (21/54 vs. 18/69). The authors conclude that clinically stable patients receiving digoxin who have elevated SDCs but are without signs or symptoms of digoxin toxicity are at low risk of developing serious digoxin toxicity and do not generally require treatment beyond the discontinuation of digoxin therapy.

Aged↗
PubMed1975

Cardiac arrhythmias, electrolytes, and digoxin concentration in plasma and urine in patients treated with digoxin.

Cardiac arrhythmias, digoxin concentration in plasma and urine, digoxin and creatine clearances, electrolytes in plasma and in erythrocytes, and subjective symptoms have been carefully studied for 5 consecutive days in 19 patients with definite or suspected digitalis intoxication. The digoxin treatment was discontinued during the observation period. Eleven controls without any signs of toxicity were similarly followed on unchanged maintenance dosage. All patients were independently classified as toxic or non-toxic from the follow-up of extended ECG recordings and subjective symptoms. In 9 definitely toxic patients a plasma digoxin concentration 3.1 plus or minus 0.7 ng/ml was found, as compared to 1.4 plus or minus 0.5 ng/ml for the 11 controls. In the suspect toxic group 1.5-3.9 ng/ml was found. The high digoxin level in the toxic group corresponds to a low digoxin clearance. In the toxic patients cardiac arrhythmias were related in most cases to a plasma digoxin level above 2.5 ng/ml and usually disappeared when the concentration had decreased below this. Suspect toxic patients, classified as probably non-toxic, and controls had with two exceptions plasma digoxin levels below 2 ng/ml. It is suggested that digitalis toxicity should be considered at a plasma digoxin concentration above 2 ng/ml. It must be stressed that this limit is not absolute and is affected by, among other things, a disturbance of intra- and extracellular electrolytes.

Arrhythmias, Cardiac↗
PubMed1985

Effect of quinine on plasma digoxin concentration and renal digoxin clearance.

In order to explore the digoxin-quinine interaction, digoxin steady state pharmacokinetics was studied before and during quinine coadministration in seven healthy subjects. Quinine (250 mg/day) increased mean plasma digoxin concentration from 0.64 +/- 0.12 to 0.80 +/- 0.18 ng/ml (p less than 0.05) within one week. Urinary digoxin recovery rose from 154.0 +/- 18.8 to 181.5 +/- 22.6 micrograms/24 h (p less than 0.01), whereas renal digoxin clearance was unaltered in the presence of quinine (181.5 +/- 24.2 vs. 174.1 +/- 26.5 ml/min). An increase in quinine dose (to 750 mg/day) caused further increments in plasma digoxin levels, whereas renal digoxin clearance remained unchanged. Quinine elevates plasma digoxin concentrations in a stepwise fashion probably due to an impairment of extrarenal digoxin clearance.

Adult↗
PubMed1977

Effects of sheep digoxin-specific antibodies and their Fab fragments on digoxin pharmacokinetics in dogs.

Intact sheep antidigoxin antibodies and their Fab fragments have both been found to exert profound effects on digoxin pharmacokinetics in [3H] digoxin-treated dogs. Both classes of molecule remove digoxin from the extravascular space and sequester it in the circulation in protein-bound form, a form in which the digoxin is presumably inactive. These two classes of molecule differ, however, in that the intact antibody molecules interfere with digoxin excretion, thereby promoting the retention of the glycoside; this retained digoxin is eventually released in free, active form when the administered antibody is metabolically degraded. In contrast, urinary excretion of digoxin continues in Fab-treated dogs, with significant quantities of digoxin being excreted promptly in the urine in complex with Fab fragments. These differences in urinary excretion, together with the probable decreased immunogenicity of sheep antidigoxin Fab fragments, suggest that such fragments possess potential advantages over intact antibody molecules for use in the therapy of life-threatening digoxin intoxication in man.

Animals↗
PubMed2002

Digoxin poisoning and anuric acute renal failure: efficiency of the treatment associating digoxin-specific antibodies (Fab) and plasma exchanges.

Digoxin-specific antibodies (Fab) are currently the treatment of choice for digoxin intoxication. These fragments bind to digoxin, leading to Fab-digoxin complexes, and promote the release of receptor-bound digoxin. These complexes are renally excreted. In the case of anuria, they could be dissociated and lead to renewed intoxication. In this case plasma exchanges are proposed. We report the case of an anuric patient with digoxin intoxication, treated with a Fab injection, followed by a plasma exchange 16 hours later, a second Fab injection was given followed by two plasma exchanges, 38 and 86 hours later. The disappearance of cardiac abnormalities showed the efficiency of the Fab, the drop in serum digoxin concentration and the high digoxin concentration in the exchanged plasma indicate effective elimination. The association of Fab and plasma exchanges could be proposed in the case of digoxin intoxication in the anuric patient.

Acute Kidney Injury↗
PubMed2002

Development of radioimmunoassay for measurement of serum digoxin in digitalized patients using novel anti-digoxin antiserum.

There is an antiserum elicited by digoxin 3'-hemisuccinate-bovine serum albumin (BSA) conjugate possessing high specificity for digoxin. Our study focused on development of RIA using this novel antiserum for measurement of digoxin in serum from digitalized patients. The property of the new antiserum was investigated by RIA with digoxin 3'-hemisuccinyl-[3H]leucine. The separation of bound and free fractions was performed using a dextran-coated charcoal suspension. The new antiserum bound approximately 50% of digoxin 3'-hemisuccinyl-[3H]leucine with a final dilution of 1:30000. The intra- and inter-assay coefficients of variation were <9% in the range of 0.52-4.17 ng/ml. The mean digoxin concentration in serum samples (n=35) from digitalized patients was estimated to be 0.68 ng/ml, which was lower than its measurement of digoxin with the commercial antidigoxin BSA serum and monoclonal anti-digoxin. It is apparent that the RIA described here has sufficient precision. The RIA system was available for the measurement of digoxin in serum from digitalized patients.

Animals↗
PubMed2002

Endogenous and exogenous digoxin-like immunoreactive substances: impact on therapeutic drug monitoring of digoxin.

Endogenous digoxin-like immunoreactive substance (DLIS) was first reported in volume-expanded dogs. Its presence has been confirmed in blood, urine, and other body fluids. Elevated DLIS concentrations are encountered in patients with volume-expanded conditions such as uremia, essential hypertension, liver disease, and preeclampsia. DLISs cross-react with antidigoxin antibodies and falsely elevate serum digoxin concentrations, interfering in interpretation of results for therapeutic digoxin monitoring. Falsely lower digoxin values due to the presence of DLISs have been reported. The association of DLISs with volume expansion led to speculation that they could be natriuretic hormones. Several structures have been proposed for DLISs, including nonesterified fatty acid, phospholipid, lysophospholipid, bile acid, bile salt, and steroid. Exogenous DLISs can be found in serum after ingestion of various Chinese medicines and therapy with spironolactone, canrenone, or potassium canrenoate. Like endogenous DLISs, exogenous DLISs interfere with serum digoxin assays, complicating therapeutic digoxin monitoring. However, most reported endogenous and exogenous DLISs are strongly protein-bound while digoxin is weakly protein-bound. Therefore, interference of both endogenous and exogenous DLISs in serum digoxin measurement can be eliminated by monitoring digoxin concentrations in the protein-free ultrafiltrates.

Cardenolides↗
PubMed1981

Effect of phenobarbital on serum digoxin concentration during administration of liposome-entrapped digoxin: an examination of possible drug interactions.

The effect of concomitant administration in normal dogs of phenobarbital with either oral free digoxin, oral liposome-entrapped digoxin were examined. Phenobarbital induced a transient rise in serum digoxin concentrations during concomitant administration of oral free digoxin. Phenobarbital did not affect serum concentrations of either oral or intravenous liposome-entrapped digoxin. The results suggest that liposome-entrapped digoxin may be protected against transient fluctuations in serum concentrations during concomitant administration of phenobarbital. The protective liposome encapsulation of digoxin may prevent digoxin toxicosis in dogs induced by elevations in serum digoxin concentrations during concomitant administration of phenobarbital.

Animals↗