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At least 19 recordsLinked to original sources

PubMed1992

Digoxin and digoxin derivative induced arrhythmias: in vitro binding and in vivo abolition of arrhythmias by digoxin immune Fab (DIGIBAND).

OBJECTIVE: The aim was to compare the binding characteristics of a highly purified digoxin specific antigen binding fragment (digoxin immune Fab: DIGIBIND) with digoxin and with two commonly used derivatives of digoxin, beta methyl digoxin and beta acetyl digoxin, and to assess its ability to abolish the arrhythmogenic effects of these digitalis glycosides. METHODS: The binding characteristics of DIGIBIND with digoxin, beta methyl digoxin, and beta acetyl digoxin were assessed in vitro by measuring their ability to inhibit the binding of DIGIBIND to 3H-digoxin. From these studies the affinities of the interactions between DIGIBIND and these glycosides, and the binding capacity of DIGIBIND for each of these glycosides, could be measured. The ability of DIGIBIND to abolish the arrhythmogenic effects of digoxin, beta methyl digoxin, and beta acetyl digoxin was assessed using an in vivo anaesthetised guinea pig model (n = 36, weight 300-400 g), in which these glycosides were infused intravenously (50 micrograms.kg-1 x min-1) until the onset of ventricular arrhythmias, at which point the total amount of glycoside given was calculated. A single bolus dose of either vehicle or DIGIBIND was then given intravenously, and the time to restoration of normal cardiac rhythm noted. After the administration of DIGIBIND, a second infusion of the same glycoside was given to reinitiate the ventricular arrhythmias. The time to onset of the arrhythmias was noted, and the additional amount of glycoside given calculated. RESULTS: In vitro studies showed the binding of DIGIBIND to 3H-digoxin to be inhibited by digoxin and by the two derivatives. The affinities of these interactions with DIGIBIND were significantly different, that for digoxin being some twofold greater than that for beta methyl digoxin and beta acetyl digoxin. The ED50 concentrations were 14.1 (95% CI 12.2, 15.2), 29.2(26.1, 32.7), and 36.2(33.0, 39.8) nM, respectively. However, there were no significant differences between these glycosides in their binding capacities. The in vivo studies showed that intravenous infusion of digoxin, beta methyl digoxin, or beta acetyl digoxin induced similar ventricular arrhythmias. The onset of the arrhythmias was clearly discernible, and required a significantly lower dose of digoxin compared with that of beta methyl digoxin and beta acetyl digoxin. These doses were 667(SEM 55), 868(33), and 854(40) nmol.kg-1, respectively. Termination of the infusion had no effect on the arrhythmias, and in those animals which received a bolus intravenous injection of saline there was no return to normal cardiac rhythm. By contrast, in animals which received a bolus intravenous injection of DIGIBIND, there was complete abolition of the arrhythmias within 4-6 min. Although the dose of DIGIBIND given to abolish digoxin induced arrhythmias was approximately 25% less than that given to abolish beta methyl digoxin and beta acetyl digoxin induced arrhythmias (p < 0.05), the time to restoration of normal cardiac rhythm after DIGIBIND was not significantly different for digoxin compared with beta methyl digoxin and beta acetyl digoxin, at 4.6(0.9), 4.9(0.8), and 5.7(0.8) min, respectively. To reinitiate the arrhythmias in those animals which had received DIGIBIND, a dose of glycoside was required which was not significantly different from that given prior to the DIGIBIND. This observation therefore confirmed the stoichiometric relationship between DIGIBIND and each of the glycosides in respect of the neutralising action of DIGIBIND in abolishing the arrhythmogenic effects of these agents. CONCLUSIONS: Although there is some small difference in the affinities of the binding interactions, there is no difference in the binding capacities of DIGIBIND for digoxin, beta methyl digoxin, or beta acetyl digoxin in vitro. These binding interactions are manifest as the ability of DIGIBIND to abolish the arrhythmogenic effects of digoxin and the two derivatives in vivo.

Acetyldigoxins↗

PubMed1992

Determination of free serum digoxin concentrations in digoxin toxic patients after administration of digoxin fab antibodies.

Digoxin fab antibody therapy is known to interfere with digoxin immunoassays causing spurious serum digoxin concentrations. The reliability and precision of three digoxin immunoassays--Baxter Dade Stratus (BDS), Syva affinity column enzyme-mediated immunoassay (EMIT), and the reference assay Abbott TDx fluorescence polarization immunoassay following ultrafiltration (FPIA-UF)--were compared in eight digoxin toxic patients treated with digoxin fab antibodies. Five to eight blood samples were drawn serially up to 204 h post digoxin fab therapy. The serum digoxin concentration in each sample was determined by each of the three assays. The mean (+/- SD) area under the serum digoxin concentration-time curve was significantly lower for FPIA-UF than for BDS or EMIT (86.1 +/- 58.2 vs 158.1 +/- 88.6 and 176.3 +/- 115.3 h.ng/ml p less than 0.01, respectively). BDS correlated better with FPIA-UF (r2 = 0.71) than did EMIT (r2 = 0.45). Predictive performance of the BDS and EMIT assays demonstrated that the mean prediction error (bias) (0.62 vs 0.78 ng/ml) and the mean squared prediction error (precision) (0.48 vs 0.76) differed significantly from zero (p less than 0.05). However, BDS had significantly less bias and greater precision than did EMIT (p less than 0.05). In the presence of digoxin fab antibodies, BDS is a better predictor of free serum digoxin concentration than is EMIT, but both have considerable bias. Based on these results, FPIA-UF should be the assay of choice for determining free serum digoxin concentrations during fab therapy.

Adult↗

PubMed1990

Monitoring free digoxin instead of total digoxin in patients with congestive heart failure and high concentrations of digoxin-like immunoreactive substances.

Digoxin-like immunoreactive substances (DLIS) are present in patients with conditions associated with volume expansion (including hypervolemic hypertension, renal failure, and liver failure) and in pre-eclampsia and premature birth. These strongly-protein-bound substances cross-react with anti-digoxin antibodies and cause falsely increased measured concentrations of digoxin in serum. Patients with congestive heart failure (CHF) often have volume expansion and are receiving digoxin therapy. They are also very sensitive to digoxin toxicity and have a very narrow therapeutic range (1.0-1.9 nmol/L). We found monitoring the concentrations of free digoxin (in protein-free ultrafiltrates) helpful in eliminating the interferences of DLIS in CHF patients. DLIS concentrations were measured by fluorescence polarization assay. Concentrations of DLIS were detectable in significantly more (58.3%) of the 12 CHF patients (group A) who were not receiving digoxin than in the 22 normal volunteers tested (13.6%) (P less than 0.05 by both chi-square and Fisher's exact test). Protein-free filtrates from patients or normal volunteers did not show any measurable DLIS activities. We also determined the concentrations of total and free digoxin in 12 patients with CHF who were receiving digoxin (group B) and compared the results with those for 22 patients receiving digoxin without the diagnosis of CHF or any known pathological conditions that could increase DLIS concentrations. The ratio of free to total digoxin in patients in group B was significantly lower (mean = 52.8%, SD 10.2%) than in those receiving digoxin (mean = 72.7%, SD 6.5%) for other reasons (independent two-tailed t-test, P less than 0.05).

Digoxin↗

PubMed1989

Kinetics of digoxin and anti-digoxin antibody fragments during treatment of digoxin toxicity.

Anti-digoxin antibody fragments (ADAF, 80 mg) were infused intravenously to successfully treat severe digoxin toxicity in an 82 year old woman. During treatment, total and free digoxin were determined using an Abbot TDX analyser and an ultrafiltration technique. ADAF were measured by an enzyme-linked immunosorbent assay. By 1 h after ADAF, total serum digoxin concentrations had risen 12-fold from a pretreatment level of 15.4 nmol l-1 but free digoxin fell from 10 to 0.1 nmol l-1, indicating greater than 99.9% digoxin binding to ADAF. However, the low free levels had rebounded to 7.7 nmol l-1 by 12 h, but despite this rise the patient's condition had improved. A serum ADAF/digoxin molar ratio of around five was associated with the low concentration of free digoxin at 1 h, while at later times with ratios roughly between 3 and 4, the free digoxin concentrations ranged between 2.0 and 7.7 nmol l-1. ADAF were mainly confined to the plasma during the first hour, but subsequently distributed into an apparent volume of 193 ml kg-1. The elimination half-lives of ADAF and total digoxin were 96 and 55 h, respectively. More than 50% of the estimated digoxin load had been excreted in the urine by 5 days; for ADAF the equivalent figure was only about 3%. Renal and/or bacterial degradation may have contributed to the low detection of urinary ADAF.

Aged↗

PubMed1978

Monitoring digoxin therapy. The use of plasma digoxin concentration measurements in the diagnosis of digoxin toxicity.

The usefulness of measuring plasma digoxin concentrations in the diagnosis of digoxin toxicity has been assessed in 83 in-patients. The mean plasma digoxin concentration in clinically toxic patients was significantly higher than the mean concentration in non-toxic patients. The overlap between the groups, however, was extensive and could partly be accounted for by hypokalaemia in those toxic patients whose plasma digoxin concentration was less than 3 ng/ml. There was, in addition, a higher incidence of hyperkalaemia, without obvious cause, in toxic patients than in non-toxic patients. Consideration of the incidence of various non-cardiac factors, specifically plasma potassium concentration greater than 5.0 mmol/l, plasma creatinine concentration greater than 150 mumol/l, daily maintenance dose greater than 6 microgram/kg, and age greater than 60 years, led to the development of guidelines to aid in the diagnosis of digoxin toxicity. Patients with plasma digoxin concentration greater than 3 ng/ml or with hypokalaemia should be considered probably toxic and those with plasma digoxin concentration greater than or equal to 3 ng/ml in the absence of hypokalaemia should only be considered toxic if they have at least two of the non-cardiac factors outlined above. Plasma digoxin concentrations could not be predicted with more than 31 per cent certainty by considering the magnitude of those non-cardiac factors.

Aged↗

PubMed1986

Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication.

17 patients with severe digoxin intoxication were successfully treated with 320 to 480 mg Fab fragments of digoxin-specific IgG from sheep. The infusion period ranged between 0.5 and 7 h. Serum and urine concentrations of digoxin bound to Fab fragments, and in 11 cases unbound Fab fragments in serum, were determined during and after the infusion. The renal clearance of bound digoxin and therefore of the antibody was 13.6 ml/min. The median extrarenal clearance of the Fab fragments was 10.9 ml/min. The half-life of the serum concentrations starting at 12 h was 14.3 h, and the value was increased to 25.4 h when regression began at 24 h; the corresponding apparent distribution volumes were 25.9 and 541. These figures exceed the volume of the extracellular space and suggest intracellular penetration of the Fab fragments. The dosage of the antibody should be sufficiently high to bind digoxin in the most severe cases of poisoning. The maximum serum concentrations of bound antibody were 30 mg/l after 3 h and 20 mg/l after 5 h. A loading dose of 160 mg followed by an infusion of 0.5 mg/min was sufficient to absorb digoxin re-diffusing into the serum during the first 8 h. In some cases free digoxin reappeared in the serum 8-12 h after beginning the treatment. This might be prevented by infusing a further ampoule at a rate of 0.1 mg/min or less.

Adolescent↗

PubMed1977

Serum glycoside concentrations after single or repeated intravenous doses of beta-methyl-digoxin and digoxin.

The aim of the present investigation was to estimate the ratio of the intravenous doses of beta-methyl-digoxin and digoxin required to produce identical serum glycoside concentrations in man. 20 patients on intravenous maintenance therapy were changed from beta-methyl-digoxin to the identical dose of digoxin or vice versa. Each drug was given for 7 days. Serum concentrations 13% higher were found during administraton of beta-methyl-digoxin. Assuming a half life of 60 h after withdrawal, the dose of digoxin producing the same minimum serum concentration was estimated to be 1.16 times higher than that of beta-methyl-digoxin. 18 healthy volunteers received 0.4 mg beta-methyl- digoxin, and 23 the same dose of digoxin, as an intravenous infusion over 2 h. The serum concentrations and urinary glycoside excretion were measured over a period of 32 hrs. During the first hour after the infusion the serum concentration of digoxin declined more rapidly than that of beeta-methyl-digoxin. Thereafter, the ratio of the serum concentrtions did not change appreciably up to the end of the investigation. The area under the serum concentration/time curve was about 13% greater for beta-methyl-digoxin than for digoxin; this difference was not significant. The average renal clearance was 96 +- 9 ml for beta-methyl-digoxin, 151 +- 13 ml for digoxin. Since the total body clearance of digoxin is only about 1.16 times higher than that of beta-methyl-digoxin, the lower renal clearance of beta-methyl-digoxin must partly be compensated by higher extrarenal clearance. From the ratios of the areas under the serum concentration/time curves after single doses of beta-methyl-digoxin and digoxin, and the minimum serum concentrations during maintenance therapy, it was concluded that the dose of digoxin to produce the same average serum concentrations would be about 1.15 times higher than that of beta-methyl-dogoxin. In comparison wtih the large variations in individual dosage of digoxin and beta-methyl-digoxin, this difference is too small to be of practical importance.

Aged↗

PubMed1987

Increase in serum digoxin concentration produced by quinidine does not increase the potential for digoxin-induced ventricular arrhythmias in dogs.

Chronic treatment of dogs with digoxin alone, quinidine alone and digoxin in combination with quinidine was initiated in dogs to assess changes in arrhythmogenic potential associated with the quinidine-induced increase in serum digoxin concentration observed during combined digoxin and quinidine treatment. The arrhythmogenic potential of digoxin was evaluated through the use of the acetylstrophanthidin (AcS) tolerance test. AcS was infused at a rate of 5 micrograms/kg/min until ventricular arrhythmias occurred during a drug-free period and during chronic treatment with digoxin, quinidine and digoxin plus quinidine. The dose of AcS required to initiate ventricular arrhythmias is inversely related to the arrhythmogenic potential of digoxin present at the time of AcS infusion. Administration of quinidine alone in two different dosage regimens produced serum quinidine concentrations of 5.99 +/- 1.18 and 2.99 +/- 0.43 micrograms/ml and significantly increased AcS tolerance, whereas digoxin alone, over a wide range of serum digoxin concentrations, significantly decreased AcS tolerance. This decrease in AcS tolerance was linearly related to the serum digoxin concentration. The addition of quinidine treatment to animals receiving digoxin resulted in a significant elevation in the steady-state serum digoxin concentration. However, the AcS tolerance determined during the elevated serum digoxin concentration induced by quinidine was greater than that determined during treatment with the same dose of digoxin alone. Thus, quinidine administration to animals receiving digoxin resulted in a significant increase in the steady-state serum digoxin concentration but did not increase the arrhythmogenic potential of digoxin over that observed during treatment with the same dose of digoxin alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1976

Tissue digoxin concentrations at digoxin intoxication in normal, acutely hypokalemic, and acutely hyperglycemic dogs.

Thirty intact dogs were studied to determine digoxin concentration in various tissues after ventricular tachycardia had been induced by digoxin infusion. A control group was infused solely with digoxin. A second group was made acutely hypokalemic by glucose-insulin infusion before the digoxin infusion. A third group was infused with glucose and digoxin to determine the effect of increased blood glucose levels and osmalarity on the induction of ventricular tachycardia. Results were: (1) The amount of digoxin infused to produce ventricular tachycardia did not differ getween the normal and hypokalemic groups. (2) The concentration of digoxin in various parts of the heart, other muscle tissue, renal cortex, and liver did not differ between the normal and acutely hypokalemic dogs although the amount excreted in bile and urine was reduced in hypokalemia. (3) Acute hypokalemia did not sensitize the myocardium to the arrhythmogenic effects of digoxin. (4) Ventricular tachcardia occurred at a similar plasma digoxin level in normal and acutely hypokalemic dogs. (5) In dogs with a lowered plasma potassium level, junctional tachycardia occurred whereas it did not occur in normal dogs or those with only a high blood glucose level. (6) Ventricular tachycardia occurred in the hyperglycemic dogs at a plasma digoxin level of 170 ng/ml, which was significantly greater than in the other experiments (7) Acute hyperglycemia reduced the mean rate of myocaridal uptake of digoxin into atria and right and left ventricular tissue; and the concentration of digoxin in atria, left ventricle, and interventricular septum was lower at the time of ventricular tachycardia than occurred in normal dogs. (8) Lowering the plasma potassium level in the presence of acute hyperglycemia, which occurred with the glucose-insulin infusion, did increase the myocardial uptake of digoxin. Similar effects of hyperglycemia were noted on mean hepatic uptake and excretion of digoxin and also the renal uptake of the glycoside.

Animals↗

PubMed1976

A comparison of the bioavailability of digoxin in capsule, tablet, and solution taken orally with intravenous digoxin.

Six healthy volunteers were given five single-dose treatments of 0.40 mg digoxin either intravenously, in liquid form, in conventional tablet form (dissolution rate 76 per cent in 1-hour), or in new capsule preparations containing 0.05, 0.10, or 0.20 mg digoxin per capsule. Serum levels, area under the concentration-time curve, and daily urinary digoxin excretion were measured for six days. Higher serum digoxin levels were seen after ingestion of the capsules than after the tablets, with peak levels for the former being 2.2-2.8 times higher than after tablet digoxin. Bioavailability was assessed further by comparing the area under a six-hour concentration-time curve, and again the capsules gave a consistently higher value than the tablets. In addition, the absorption of 0.40 mg digoxin from any of the capsule preparations was much greater than 0.50 mg digoxin in commercially available tablets. The six-day cumulative urinary digoxin excretion was also greater for the capsules than for the 0.20-mg tablets. In comparison with intravenous digoxin, tablets provide 75 per cent maximum bioavailability, whereas the capsule preparations of digoxin improve the bioavailability of digoxin and the 0.20-mg digoxin capsule is absorbed better than 0.25-mg digoxin tablet.

Adult↗

PubMed1989

Beta-methyl digoxin: a better absorbable digoxin.

Since Megges and Repke [1961] showed that acetylation of the hydroxyl groups in the aglycone or the sugar side chain of the digitalis molecule results in a derivative with enhanced and more complete absorption from the gastrointestinal tract, several new compounds resulting from acetylation or methylation of digoxin molecule have been developed. Beta-methyl digoxin (beta-methyl digoxin) is a methyl derivative (methyl group in position 4 of the digitoxose residue) of digoxin. Enhanced and more complete gastrointestinal absorption of tritium labeled beta-methyl digoxin [Rennekamp et al. 1972] has been confirmed. Weiss et al. [1975], based on the serum levels following oral administration, calculated that to achieve comparable levels, digoxin dose would have to be increased by 1.55 times compared to that of beta-methyl digoxin. These and other studies supported an earlier notion that beta-methyl digoxin was a better and desirable cardiotropic agent than the digoxin. Comparison of cardiac effects using equivalent doses of the two compounds however, showed no difference [Das et al. 1977]. Following oral administration, the serum glycoside levels to beta-methyl digoxin indeed were significantly greater than those with digoxin. However, these differences in serum levels were not of sufficient magnitude to influence detectable cardiac inotropic effects, hence, the search for a better digoxin should continue.

Digoxin↗

PubMed1987

Determination of free digoxin concentrations in serum for monitoring Fab treatment of digoxin overdose.

A rapid method for assessing the free digoxin concentration in the serum of digoxin-overdosed patients receiving treatment with digoxin-specific Fab fragments has been developed. For this method, a protein-free ultrafiltrate is prepared from the patient's serum, and the digoxin in the ultrafiltrate (free digoxin) is measured by fluorescence polarization immunoassay. Both the inaccuracies associated with measurements of total digoxin by immunoassay in the presence of Fab and the long turnaround time associated with measurements of free digoxin by equilibrium dialysis were avoided. Good correlation was observed between measurements of free digoxin by this ultrafiltration technique and by equilibrium dialysis. The ultrafiltration method was used to evaluate the concentrations of free digoxin in a digoxin-overdosed patient treated with Fab at our hospital. In retrospect, the results suggest that her hospital stay could have been shortened by a timely appreciation of her increased concentration of free digoxin. Using the ultrafiltration method, one can determine free digoxin concentrations quickly, conveniently, and accurately in the clinical laboratory. This procedure therefore should be a valuable aid in monitoring the efficacy and adequacy of Fab treatment.

Adolescent↗

PubMed1989

Pharmacokinetics and efficacy of digoxin specific Fab fragments in a child following massive digoxin overdose.

The use of digoxin-specific Fab fragments (d-Fab) to treat life-threatening digitalis intoxication has been widely substantiated in adults. This reports a case of a 2-year-old girl who ingested 90-92, 0.25 mg tablets of digoxin and within four hours, developed vomiting, lethargy, tachycardia and AV block (Mobitz type I and II). These symptoms were associated with total and free serum digoxin concentrations of 17.1 and 12.4 ng/ml, respectively. Following GI decontamination, a total dFab dose of 1280 mg (32 vials) was given with resolution of electrocardiographic abnormalities within 40 minutes and a concomitant reduction in the free serum digoxin concentration to 0.11 ng/ml. Repeated blood sampling over 19 days revealed an apparent elimination half-life (t1/2) of 134.9 and 129.9 hr for total and free digoxin, respectively. The long t1/2 for digoxin corresponded to a low apparent renal clearance of total digoxin which ranged from 0.56 to 0.82 ml/minute over four separate collection intervals. The free serum digoxin concentration never exceeded 3% of the total concentration and the patient did not develop a recurrence of toxic symptoms or any adverse effects (e.g. fever) attributable to dFab. Administration of an equimolar dFab dose to children following acute, massive digoxin intoxication represents safe, effective treatment which produces a prompt, sustained reversal of toxic effects. Digoxin specific Fab fragments should be promptly administered to any infant or child with significant, life-threatening symptoms following acute digoxin intoxication.

Child, Preschool↗

PubMed1978

The influence of digoxin particle size on absorption of digoxin and the effect of propantheline and metoclopramide.

1 The influence of particle size on absorption of digoxin was studied in ten healthy volunteers who received 0.5 mg digoxin as two standard Lanoxin tablets, or tablets containing micronized digoxin or large particle size digoxin. Tablets were given 30 min after 15 mg propantheline, 10 mg metoclopramine or a placebo tablet, and following an overnight fast. 2 The overall mean cumulative 4 day urinary excretion of digoxin was significantly lower (P less than 0.01) after large particle size digoxin than after standard or micronized digoxin. Mean cumulative urinary excretion following large particle size digoxin was reduced when administered after metoclopramide and increased after propantheline, the difference between these two treatments being significant (P less than 0.05). There was a significantly lower (P less than 0.05) overall mean cumulative excretion following standard by comparison with micronized digoxin. However, by comparison with placebo, neither metoclopramide nor propantheline significantly altered mean cumulative excretion after standard or micronized digoxin. Propantheline and metoclopramide affect absorption of digoxin from formulations of large particle size and slow dissolution rate only.

Adult↗

PubMed1978

Digoxin toxicity compared with myocardial digoxin and potassium concentration.

1 Twenty-nine dogs were given digoxin (0.25 mg) by mouth twice daily for eight days. Some of them (group 1) also received diuretics and others (group 2) a mineralocorticoid. The dogs were then given an intravenous bolus injection of digoxin and plasma and cardiac muscle were analysed for digoxin and potassium. 2 In the digitalized dogs, myocardial potassium concentration decreased following the intravenous injection of either 0.05 or 0.15 mg/kg digoxin; in contrast, in those dogs given diuretics or mineralocorticoid the potassium concentration increased. 3 Ventricular arrhythmias occurred after digoxin injection (0.05 mg/kg) in the hypokalemic dogs, in those given a mineralocortocoid and in those dogs which received a toxic digoxin dose (0.15 mg/kg). No arrhythmias where seen in the control (digitalized) group. 4 Myocardial digoxin concentrations were similar in the control digitalized group and in the mineralocorticoid-treated dogs after the intravenous administration of the lower digoxin dose (0.05 mg/kg). The myocardial digoxin concentration was significantly higher in the hypokalemic group and in the group receiving the higher digoxin dose (0.15 mg/kg). 5 There was no obvious relationship between the occurrence of arrhythmias and the myocardial concentration of digoxin or potassium.

Animals↗

PubMed1987

The effect of digoxin dosage on the digoxin-quinidine interaction in the bile duct-cannulated rat.

Pretreating anaesthetized bile duct-cannulated rats with 9 mg kg-1 quinidine significantly decreased the cumulative biliary excretion of digoxin and its metabolites after 10 or 100 micrograms kg-1 [3H]digoxin, although the effect was more marked in animals receiving the high dose of digoxin. In contrast, however, although quinidine pretreatment raised plasma radioactivity levels by 50-80% in animals given the higher dose of digoxin, no significant effect on circulating plasma levels was observed in rats receiving 10 micrograms kg-1 digoxin. Generally, quinidine had no statistically significant effect on other aspects of digoxin disposition, although with both digoxin doses there were trends towards a reduction in the direct intestinal secretion and urinary excretion of digoxin-derived radioactivity with an increase in tissue levels of radioactivity (apart from the small intestine wall where concentrations were reduced). The radioactivity in the bile after 100 or 10 micrograms kg-1 digoxin comprised about 25 and 33% of digoxin and digoxigenin bis-digitoxoside, respectively, as well as appreciable amounts of the monodigitoxoside and a highly polar component. This metabolite profile was unaffected by quinidine. The influence of cardiac glycoside dosage shown by the present work indicates that the digoxin-quinidine interaction and possibly analogous interactions involving other cardiac glycosides, may not always be readily detectable from plasma concentration data.

Animals↗

PubMed1991

The plasma kinetics of digoxin-specific Fab fragments and digoxin in the rabbit.

The plasma kinetics of total and free digoxin, and digoxin-specific antibody fragments (DSFab) in rabbits which had been given [3H]digoxin one hour before DSFab has been studied over a 5 day period. Injection of DSFab caused a 4- to 5-fold rise in total digoxin and reduced elimination half-life (t1/2 beta), apparent volume of distribution at steady-state (Vdss) and systemic clearance (CL) by 40, 90 and 75% respectively. Early in the experimental period, DSFab reduced free digoxin concentration (measured by ultrafiltration) from 4.1 ng mL-1 to a minimum of 1.3 ng mL-1 at 15 min. However, the concentration had rebound to 2.5 ng mL-1 by 60 min. Subsequently, free digoxin fell to 0.63 ng mL-1 and remained relatively constant over a 7 to 90 h period. The distribution half-life, t1/2 beta, Vdss and CL for DSFab (concentrations measured by enzyme-linked immunosorbent assay) were 0.3 h, 3.2 h, 185 mL kg-1 and 57 mL kg-1 h-1, respectively. A considerable molar excess (about 5) of DSFab in the plasma was necessary to maintain minimum free digoxin concentrations. When the DSFab:digoxin molar ratio was less than 4 during the initial treatment period, free (toxicologically active) concentrations increased. With the elevation in total digoxin, however, an opposite situation appeared to apply. By 24 h the relatively short DSFab t1/2 beta meant that the plasma DSFab concentration was less than 0.05 micrograms mL-1 giving a DSFab:digoxin molar ratio of below 0.06, yet the antibody-induced rise in total digoxin concentration was still detectable at 100 h.

Animals↗

PubMed1987

Digoxin-like immunoreactivity eliminated from serum by centrifugal ultrafiltration before fluorescence polarization immunoassay of digoxin.

Digoxin determined in the Abbott "TDx" by fluorescence polarization immunoassay by the manufacturer's recommended method involving precipitation of protein with 5-sulfosalicylic acid (SSA) is subject to interference from endogenous compounds having digoxin-like immunoreactivity. Guided by the work of Graves et al. (Clin Chem 1986;32:1506-9), we eliminated interference caused by digoxin-like immunoreactivity by substituting ultrafiltration for precipitation with SSA to remove protein. Using the manufacturer's method, we quantified digoxin in serum from 53 patients in three clinically defined groups who were receiving no digoxin, finding apparent digoxin in excess of the 200 ng/L detection limit in 24% of the 17 pregnant women, 59% of the 17 renal-dialysis patients, and all of 19 neonatal cord-blood samples examined. No measurable digoxin immunoreactivity was observed by fluorescence polarization immunoassay for any of the 53 clinically defined patients after removal of protein by ultrafiltration. For 22 men for whom digoxin was prescribed, digoxin measurement after protein removal by SSA and by ultrafiltration correlated well (r = 0.98), with good proportionality (slope = 1.04). Analytical recovery of added digoxin from adulterated serum was 115% after SSA, but 100% after ultrafiltration. Thus, before this assay procedure, we recommend ultrafiltration, to remove digoxin-like interference.

Digoxin↗