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PubMed1975

Effect of particle size on the bioavailability of digoxin.

The bioavailability of digoxin in three tablets prepared from materials with different particle sizes was measured in healthy volunteers in a cross-over study using an alcoholic solution of digoxin as a reference standard. Its bioavailability in tablets with particle sizes of 7 mu or 13 mu was 78-97% of that of digoxin in solution. The tablet with largest particle size (102 mu) showed markedly lower bioavailability than the reference solution, namely 39%. It is obvious that particle size is an important determinant of the dissolution rate and bioavailability of digoxin.

Administration, Oral↗

PubMed1986

Effect of cimetidine on digoxin disposition in peptic ulcer patients.

Cimetidine inhibits the renal tubular secretion of creatinine and digoxin is partly excreted by the same pathway. In order to investigate a possible interaction between the two drugs, a randomized cross-over acute study has been conducted. Six patients with duodenal ulcers were given a single dose of digoxin (Dig) 0.75 mg i.v. with and without oral cimetidine 1200 mg/day. Cimetidine significantly reduced creatinine clearance from 157 to 132 ml/min. There was no significant difference in inulin clearance, 99.2 vs 97.5 ml/min, Dig elimination half life 53.9 vs 56.9 h, apparent volume of distribution 11.3 vs 11.6 l/kg, systemic clearance 2.42 vs 2.35 ml/min/kg, renal clearance 1.48 vs 1.62 ml/min/kg or urinary excretion of digoxin 49.5 vs 51.6% of dose without or with cimetidine. These results suggest that cimetidine does not influence the disposition of digoxin.

Adult↗

PubMed1982

Quinidine-digoxin interaction: evidence for involvement of an extrarenal mechanism.

The influence of quinidine 750mg per day for one week on serum digoxin concentration (SDC) was evaluated in digitalized anuric patients on chronic haemodialysis. During quinidine administration the SDC increased markedly, from 0.84 +/- 0.37 to 1.58 +/- 0.72 ng/ml (p less than 0.01), a comparable effect ot that reported previously in patients with normal renal function. Neither in vitro nor in vivo did quinidine alter the serum protein binding of digoxin. The increase in SDC in anuric patients indicates a decrease in the extrarenal clearance of digoxin, which means that mechanisms other than of renal origin are also involved in the interaction of quinidine and digoxin. There was great interindividual variability in the extent of the quinidine-induced rise in SDC. Regardless of the state of renal function, careful monitoring of digitalized patients seems mandatory once quinidine treatment is initiated.

Anuria↗

PubMedDate not supplied

Single daily dose of digoxin for maintenance therapy of infants and children with cardiac disease: is it reliable?

Between July 1990 and September 1991, 30 infants and children, most of whom had a congenital heart defect and who had been treated at least during the previous 20 days by two daily doses of digoxin and were in a stable clinical condition, were selected at random. A maintenance dose of digoxin was administered at 24-h intervals for 7 days in the study group (n = 15); no change was made in the 12-h dosage interval in the control group (n = 15). When the serum digoxin concentrations were compared, no significant difference was found between pre- and poststudy values in the study group (1.0 +/- 0.6 and 0.8 +/- 0.3 ng/ml, respectively) or between the control and study groups (0.9 +/- 0.6 and 0.8 +/- 0.3 ng/ml, respectively) in terms of trough serum digoxin concentrations. Although the peak serum concentrations in the study group were increased significantly (2.3 +/- 0.8 ng/ml) compared with prestudy peak levels (1.6 +/- 0.7 ng/ml, p < 0.05) and with the level in the control group (1.5 +/- 0.8 ng/ml, p < 0.05), a toxic concentration was not reached, and toxicity symptoms were not observed clinically. Blood pressure, heart rate, and liver size did not change significantly in any patient during the study.

Child, Preschool↗

PubMed1986

Digoxin-diltiazem interaction: a pharmacokinetic evaluation.

The pharmacokinetics of digoxin were studied before and after a 2 week course of diltiazem, 30 mg four times daily, in 7 healthy volunteers. Each subject received an IV dose of digoxin before starting diltiazem and again on day 15 of the study. Diltiazem was continued until all sera and urine were collected. During the control and diltiazem phases, respectively, the terminal elimination rate constants were 0.0231 +/- 0.007 h-1 and 0.0254 +/- 0.007 h-1, the volumes of distribution were 10.5 +/- 3.95 l/kg and 10.2 +/- 3.26 l/kg, and the total body clearances were 3.72 +/- 0.78 ml X min-1 X kg-1 and 4.09 +/- 0.94 ml X min-1 X kg-1. None of these pharmacokinetic parameters of digoxin were significantly different before or during diltiazem administration. Overall, there does not appear to be an interaction between digoxin and diltiazem.

Adult↗

PubMed1983

Renal clearance of digoxin in man after sodium loading or furosemide treatment.

To evaluate the influence of different types of natriuresis on the renal clearance of digoxin (Cldig) and the Cldig/Clcr ratio, studies were performed in which sodium-depleted patients were placed on a moderately high sodium diet for 6 days. In another group natriuresis was evoked by furosemide. In the first study, in 10 patients, there was a 10-fold increase in Na excretion and a small rise in diuresis (V) and Clcr, which was accompanied by an increase in Cldig from 57.5 +/- 32, and 60.7 +/- 27.3 (duplicate measurements) to 103.9 +/- 55.4 (p less than 0.01) and 103.8 +/- 46.5 ml min-1 (p less than 0.01). Cldig/Clcr rose from 0.60 +/- 0.24 and 0.61 +/- 0.16 to 0.91 +/- 0.31 and 0.91 +/- 0.21, respectively (both p less than 0.005). Serum digoxin concentration declined from 1.24 +/- 0.35 and 1.19 +/- 0.40 to 1.02 +/- 0.35 and 0.97 +/- 0.32 micrograms/l (both p less than 0.01) during the high sodium diet. In the furosemide-induced natriuresis (6 patients), changes in Na excretion and V were a multiple of those caused by Na loading, but the Cldig/Clcr ratio was not increased. The results are in accordance with the concept of digoxin backdiffusion in the proximal tubules, which is dependent on proximal Na reabsorption. In the more distal segments of the nephron, where the action of furosemide occurs, there does not appear to be any transtubular movement of digoxin.

Creatinine↗

PubMed1989

Pharmacodynamic modeling of digoxin-induced bradycardia.

Digoxin-induced bradycardia in dogs was used to evaluate several pharmacodynamic models. Digoxin plasma concentrations and response were monitored in beagle dogs administered either 0.05 or 0.025 mg/kg of digoxin iv as an infusion over 5 min. The models investigated were the linking model, the linear model, the effect compartment model, and the inhibitory model. Regression procedures for investigating the effect compartment model were conducted with Emax (the maximal response, where response was the percentage decrease in heart rate) as a variable with an upper bound of 100%, with a constant value of 100%, or alternately with a constant value equal to the maximal observed response. Based on statistical criteria the effect model using Emax as a variable was found to be the best model for describing digoxin-induced bradycardia. For the effect compartment model, CPss(50) (concentration at steady state that will produce 50% of the maximal response) ranged from 3.8-9.8 ng/ml; delta (exponent describing the steepness of the concentration-response relationship) ranged from 0.6-7.1. The implication of these models in understanding concentration-effect relationships are discussed.

Animals↗

PubMed1981

Pharmacokinetics of digoxin in the turkey and comparison with other species.

Digoxin was administered by bolus intravenous injection to seven broad-breasted white turkey poults at doses of 0.1, 0.15, or 0.2 mg/kg. Plasma digoxin concentrations were measured by a 125I radioimmunoassay at selected times over the subsequent 24 hr. The data were fitted to a two compartment open pharmacokinetic model. Overall mean values for kinetic variables were: distribution halflife, 38.96 min; elimination halflife, 11.03 hr; volume of distribution in the central compartment, 1.54 liters/kg; total body clearance, 5.81 ml/min/kg. Different doses did not appear to have a significant effect on the identifiable pharmacokinetic variables, suggesting that digoxin disposition is dose independent in the turkey. The results obtained in turkeys were compared with data reported for rats, cats, dogs, and humans. The value for total body clearance of digoxin in the turkey was similar to values found in man, dogs, and cats but considerably less than values reported for rats. The value for elimination halflife in turkeys was somewhat less than values reported for infants and dogs; however, it was considerably different than values reported for rats and cats.

Adult↗

PubMed1975

[Bioavailability of beta-acetyldigoxin and digoxin (author's transl)].

Five beta-acetyldigoxin and two digoxin preparations were given orally to eleven healthy volunteers. In a single dose crossover study bioavailability of the oral preparations was compared to an intravenous injection of digoxin as a standard for complete bioavailability. A mean bioavailability of 82% (sx = 1.8) was found for beta-acetyldigoxin tablets (Novodigal¿), PETN/beta-acetyldigoxin tablets (Nitro-Novodigal¿), oxyfedrin/beta-acetyldigoxin tablets (ildamen¿-Novodigal¿) and beta-acetyldigoxin liquid. Analysis of variance shows no differences in absorption for the five tested beta-acetyldigoxin preparations. Beta-Acetyldigoxin administered orally in an alcoholic solution is nearly completely absorbed (94%) whereas a corresponding digoxin solution is available to a significantly lesser content (79.2%). Comparable differences in absorption were found for beta-acetyldigoxin tablets (81%) and digoxin tablets (Digacin¿) (63.5%).

Administration, Oral↗

PubMed1977

[Radioimmunological estimation of digoxin in urine (author's transl)].

When separating free and antibody bound digoxin, dextrancoated charcoal suspensions in protein-free urine dilutions develop an improve sieve effect which improves with aging of the suspensions. On addition of albumin to the dilution medium (buffer), the adsorptive capacities become stabilized. In urine dilutions less than of 1:50, false positive digoxin concentrations were measured. Determinations of 0-5 ng digoxin/ml in the diluted urine (1:100) and in the buffer solution show identical results. The recovery of added digoxin (1 ng and 2 ng/ml) is 100%; the lower detection limit is 3.6 mug/l urine. Between-assay variation for means of duplicates shows in the main measuring range (1.5-2.8 ng digoxin/ml) a variation coefficient less than of 4.5%; for a commercial test this value is distinctly higher. Dihydrodigoxin is measured at 3% only. Application of this method for measuring cumulative glycoside elimination of 5 healthy persons (0.5 mg digoxin daily intravenously during 2 weeks) results in a minimal interindividual variation of 5.1%. In a test preparation with a bioavailability of 94.6% the variation is 5.2%.

Biological Availability↗

PubMed1982

Digoxin-like natriuretic activity in the urine of salt loaded healthy subjects.

In previous studies we have demonstrated a natriuretic factor of small molecular weight (less than 1,000 Daltons) in the serum and urine of salt loaded subjects. This factor isolated from salt loaded animals inhibits the Na-K-ATPase enzyme system. In addition, the natriuretic material isolated from plasma of salt-loaded dogs was shown to bind to specific digoxin antibodies. It was therefore suggested that a digitalis-like endogenous natriuretic factor (endoxin) is released in response to saline loading. In the present study we therefore investigated the presence of such an endogenous natriuretic digitalis-like activity in the urine of healthy volunteers during high salt intake. Using Sephadex G-25 for chromatographic separation of urine a material elutes as a single peak in the natriuretic post-salt fraction IV which is specifically bound to digoxin antiserum complex. Mean peak activity amounted to 1.55 +/- 0.48 ng/ml digoxin equivalents. We further purified the natriuretic material by immunoprecipitation with the digoxin antiserum complex. This purification procedure resulted in a more than 10-fold increase in specific natriuretic activity from 2.7 +/- 0.4 to 30.4 +/- 5.8 muEq Na+ x min-1 x mg-1. Thus the digitalis-like natriuretic activity previously observed in the plasma of saline loaded dogs is also present in the urine of healthy subjects during high dietary salt intake. Immunoprecipitation may offer a meaningful tool for further isolation and identification of the natriuretic hormone(s).

Adult↗

PubMed1989

Oral N-acetylprocainamide compared to quinidine plus digoxin in the chronic suppression of atrial flutter in humans.

Antiarrhythmic therapy for the suppression of atrial flutter has conventionally entailed the use of a class Ia agent such as quinidine or procainamide. However, atrial flutter often recurs despite the use of these conventional antiarrhythmic regimens. Experimental and clinical evidence suggests that the pharmacologic suppression of atrial flutter may depend on the prolongation of the atrial action potential duration and consequently the voltage-dependent refractoriness. Therefore, the efficacy and tolerance of the class III antiarrhythmic agent N-acetylprocainamide was compared to that of the conventional regimen of the class Ia agent quinidine combined with digoxin (to control ventricular response) in patients with a history of symptomatic sustained atrial flutter. The study was randomized but nonblinded, with a crossover to the alternate regimen if the first failed. Eighteen patients entered the study and were followed for up to 18 months. Of the 12 receiving N-acetylprocainamide (eight randomized and four crossovers), one (8%) failed therapy due to side effects, but none had atrial flutter. Of the 11 receiving quinidine and digoxin (10 randomized and one crossover), three (28%) had a recurrence of atrial flutter, two of whom also had intolerable side effects, and two more (18%) had side effects alone requiring withdrawal of therapy (total 46% failed). The probability of therapeutic success over time was greater (p less than 0.04) for N-acetylprocainamide than for quinidine and digoxin. The data suggest that N-acetylprocainamide may be more effective and better tolerated than the conventional regimen of quinidine plus digoxin. Therefore, large-scale blinded studies of the efficacy of N-acetylprocainamide in the suppression of atrial flutter may be warranted.

Acecainide↗

PubMed1990

Further evidence for the dissociation of digoxin-like immunoreactivity from Na+,K(+)-ATPase inhibitory activity.

The effects of adrenalectomy or nephrectomy, carried out one hour previously, on the levels of endogenous digitalis-like factors were determined in rat plasma. Factors were assayed by digoxin-like immunoreactivity and direct Na+,K(+)-ATPase inhibitory activity. Digoxin-like immunoreactivity significantly decreased one hour after bilateral ablation of adrenals, while Na+,K(+)-ATPase inhibitory activity remained unaltered. There were no changes in either activity one hour after bilateral nephrectomy. These results suggest that digoxin-like immunoreactivity may be derived from the adrenal gland or under adrenal control and the major substances detected by digoxin-like immunoreactivity and direct Na+,K(+)-ATPase inhibitory activity may be different.

Adrenal Glands↗

PubMed1987

Prescribing digoxin in geriatric units: the unexplained variability in dosage requirements.

Some physicians regard patients of Geriatric Units as a homogeneous population with respect to digoxin dosage requirements. Others advocate the use of pharmacokinetic models in prescribing digoxin for the elderly. Sixty in-patients of Geriatric Units were studied and the results compared with those previously obtained from 129 patients of other adult Units; all were receiving maintenance digoxin. For each patient the dose required to achieve a mean steady-state serum digoxin concentration of 1.6 nmol X l-1, the standardized dose, was calculated, assuming proportionality between the dose given and the concentration achieved. A mean of four estimates of standardized dose for each individual was used in the analysis. Threefold ranges of standardized dose covered the requirements of approximately 85% of patients both of Geriatric Units (62.5 to 187.5 micrograms per day) and of other adult Units (125 to 375 micrograms per day). The variables, serum creatinine concentration, sex, age, and body weight were of relatively little value in predicting the standardized dose for the patients in Geriatric Units. There was a sub-group of these in-patients for whom the standardized dose was extremely large.

Adult↗

PubMed1994

Bioavailability of digoxin tablets in healthy volunteers.

The bioavailability of digoxin generic tablets manufactured in Korea (formulations A & B) were compared to a standard (formulation C; Lanoxin brand digoxin, Burroughs Wellcome, USA) in 12 healthy Korean male volunteers (mean age 31.4 years) in a single dose, randomized, complete block crossover study. Using a Latin square design, each of the subjects was randomized to the order number and allocated to each of the three treatments of 0.5 mg oral digoxin. Digoxin concentrations in serum and urine samples collected for 48 hours after dosing were measured by fluorescence polarization immunoassay and radioimmunoassay, respectively. Treatments were compared by using nonlinear least squares regression analysis to evaluate the following pharmacokinetic parameters: maximum serum concentration (Cmax); time of maximum serum concentration (Tmax); area under the serum concentration-time curve for 0-12 hours (AUC0-12); and cummulative urinary excretion for 0-48 hours (CUE0-48). Mean AUC0-12, Cmax, and CUE0-48 values for formulations B and C were significantly different from formulation A (p < 0.001), but not significantly different from each other. Based on AUC0-12 and CUE0-48, respectively, the relative availability of formulation B was 87.5% and 89.6% and the relative availability of formulation A was 43% and 35% when compared to formulation C (the standard).

Adult↗

PubMed2003

Permanently oriented antibody immobilization for digoxin determination with a flow-through fluoroimmunosensor.

This paper reports a new flow-through fluoroimmunosensor, the function of which is based on antibodies immobilized on an inmunoreactor of controlled-pore glass (CPG), for determination of digoxin, used in the treatment of congestive heart failure and artery disease. The immunosensor has a detection limit of 1.20 microg L(-1) and provides high reproducibility (RSD=4.5% for a concentration of 0.0025 mg L(-1), and RSD=6.7% for 0.01 mg L(-1)). The optimum working concentration range was found to be 1.2 x 10(-3)-4.0 x 10(-2) mg L(-1). The lifetime of the immunosensor was about 50 immunoassays; if stored unused its lifetime can be extended to three months. A sample speed of about 10-12 samples per hour can be attained. Possible interference from substances with structures similar to digoxin (morphine, heroin, tebaine, codeine, pentazocine and narcotine) was investigated. No cross-reactivity was seen at the highest digoxin: interferent ratio studied (1:100). The proposed fluoroimmunosensor was successfully used to determine digoxin concentrations in human serum samples.

Antibodies↗

PubMed1996

Effect of physical activity on serum concentrations of digoxin and digitoxin.

OBJECTIVE: To study the influence of moderate physical activity on serum concentrations of digoxin, digitoxin and albumin. METHODS: Blood samples were drawn from 10 consecutive mobile patients on digoxin and 12 patients on digitoxin therapy before and following a 10-min walking period. Digitalis serum concentrations were determined by radioimmunoassay, and albumin serum concentrations by laser nephelometry. RESULTS: Following physical activity, digoxin serum concentrations dropped immediately to 79% of baseline values and remained significantly decreased for 20 min. Digitoxin concentrations did not change significantly. CONCLUSION: In contrast to digoxin, the effect of physical activity the serum concentration of digitoxin can be disregarded.

Adult↗

PubMed1999

Plasma and cerebrospinal fluid endogenous digoxin-like immunoreactivity in patients with aneurysmal subarachnoid haemorrhage.

Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals, collectively known as either digitalis-like (DLF) or ouabain-like (OLF) factors, presumed to be endogenous hormones regulating the biological activity of the NA+/ K(+)-ATPase and its isoforms. This substance has been postulated to enhance renal tubular sodium excretion and to increase peripheral vascular resistance. Digoxin-like immunoreactive substance (DLIS) was observed in plasma of some patients with spontaneous subarachnoid haemorrhage (SSAH). Accumulating evidence suggests the central nervous system as a site of synthesis, but also as a site of hypertensinogenic action of endogenous cardioglycosides. The present study intends to establish the ratio of the DLIS in plasma to that in cerebrospinal fluid (CSF) in patients with SSAH and to investigate possible connection of this substance with development of arterial vasospasm. A prospective analysis of DLIS levels was performed on plasma and CSF samples obtained in 40 patients who had suffered a recent SSAH. DLIS levels were determined by the fluorescence polarisation immuno-assay method immediately after the admission to the Ward, and again seven days later. The comparison of CSF and plasma DLIS levels did not show statistically significant differences between the results--neither for the first (Z = 0.530; P = 0.591) nor for the seventh day after the disease onset (Z = 0.448; P = 0.654). Three possible hypothetical explanations of these results are offered: a) substance determined by digoxin immuno-assay has no essential likeness to digoxin; b) loss of the haemato-encephalic barrier integrity enabling free substance exchange between plasma and central nervous system; c) digoxin-like substance production within the central nervous system. Further, comparison of DLIS plasma levels (7th day from onset of SSAH) with angiography results showed that patients with multiple vasospasm had essentially higher plasma DLIS levels compared to patients with no vasospasms (Z = 2.59; P = 0.0097). The amount of extravasated blood, assessed on the basis of cranial CT scanning, was also connected with higher plasma DLIS levels (X2 = 3.29; P = 0.0305). The enhanced arterial narrowing which occurs in SSAH may be in part mediated by increased digitalis-like factor activity.

Adult↗