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PubMed1997

Comparability of a new turbidimetric digoxin test with other immunochemical tests and with HPLC--a multicenter evaluation.

A new turbidimetric inhibition immunoassay for digoxin (Tina-quant [a] Digoxin, Boehringer Mannheim) was evaluated in seven laboratories. It can be performed without sample pretreatment with ready-to-use reagents on nondedicated analyzers in combination with routine clinical chemistry. The studies revealed a good analytical performance: lower limit of detection 0.12 microg/L (3 SD from mean of blank); linearity up to 7.5 microg/L; median between-run CVs 8.1% (0.6 microg/L), 2.8% (1.5 microg/L), 1.9% (3 microg/L); mean analytical recovery in control sera 98-102%; slopes from 0.97 to 1.09 and intercepts from -0.28 to 0.10 microg/L in comparison with four immunoassays; and a high resistance to common interferents. The test was more resistant to digoxin-like immunoreactive factor (DLIF) interference than other methods, showing cross-reactivity only in some intensive care patient samples. Among 192 patients in whom DLIF is expected (e.g., pregnant women, patients with renal failure, newborns), 90% of results were < or =0.26 microg/L digoxin. Cortisol showed no cross-reactivity and digoxigenin had a low reactivity. An interlaboratory survey revealed a good comparability of the Tina-quant [a] test with the median of all methods (slope 0.99, intercept -0.06 microg/L). An HPLC method for digoxin based on isocratic separation of samples on an RP-18 column followed by detection by an immunoassay yielded a reasonable comparability with the immunochemical tests with noncritical samples. Divergent results of immunoassays caused by DLIFs or different cross-reactivities with digoxin metabolites or derivatives can be explained by the use of this HPLC method.

Anticoagulants↗
PubMed1977

[Clinical value of determination of digoxin concentration in blood during treatment of cardiac insufficiency].

The concentration of digoxin in blood was determined by the radio-immunologic method in 41 patients with circulatory insufficiency and permanent form of auricular fibrillation who were treated with the drug. In 85.5% of cases the therapeutic digoxin concentrations did not exceed 2 ng/ml. The therapeutic concentrations ranged from 0.3 to 3.6 ng/ml, the toxic from 0.9 to 6 ng/ml. A relationship was established between the dose of digoxin and its concentration in the blood of patients with normal renal filtration. It is concluded that the blood digoxin concentrations alone, without the clinical data being taken into account, cannot be a reliable criterion in assessment of the level of saturation with cardiac glycosides. Study of the dynamics of blood digoxin concentration in each patient allows its determination to be used to assess the tolerance to the drug, choose the adequate maintenance dose and the time for its correction, and to confirm the clinical signs of digitalis intoxication if the concentration of digoxin is above 2.5 ng/ml.

Administration, Oral↗
PubMedDate not supplied

Two cases of clarithromycin-induced digoxin toxicity.

Two patients experienced clarithromycin-induced digoxin toxicity. Both had stable renal function within normal limits and had been maintained on a consistent dosage of digoxin. No changes in drug therapy had been made except for the addition of clarithromycin. Administration of clarithromycin to patients receiving long-term digoxin therapy may induce digoxin toxicity. When concomitant therapy is employed, patients should be closely monitored for clinical signs and symptoms of digoxin toxicity, and digoxin concentrations should be measured to avoid it.

Aged↗
PubMedDate not supplied

Thapsigargin attenuates the potentiation of positive inotropic effect of digoxin induced by pretreatment with rimalkalim in the guinea pig heart.

The influence of thapsigargin, a selective inhibitor of sarcoplasmic reticulum (SR) Ca2+ ATPase, on the positive inotropic effects of digoxin before and after pretreatment with rimalkalim [(3S,4R)-3-hydroxy-2,2-dimethyl-4-(oxopyrrolidinyl)-6-phenyl-su lfonylchroman hemihydrate (formerly HOE 234)], a known activator of ATP-sensitive K+ channels, was studied in the guinea pig heart. The isolated papillary muscles from the guinea pig heart were used to study these effects. The following parameters were measured: force of contraction (Fc), rate of rise (+dF/dt) and rate of fall (-dF/dt) of Fc, time to peak contraction (ttp) and time to 10% of the total amplitude of force (tt10). After pretreatment with rimalkalim (1 microM), digoxin caused a significant increase in the amplitude of Fc and significant shortening of ttp and tt10 (p < 0.05 compared with the values obtained with digoxin alone). Thapsigargin (1 microM), a selective inhibitor of sarcoplasmic reticulum Ca2+ ATPase, added to rimalkalim, prevented the enhancement of the amplitude of Fc induced by digoxin after pretreatment with rimalkalim but had no significant influence on the effects of digoxin itself. The results demonstrate significant influence of activation of KATP channels on digoxin-induced positive inotropic effects in the guinea pig heart. Attenuation of this effects of rimalkalim by addition of thapsigargin suggests that activation of SR Ca2+ ATPase can be included in this interaction.

Animals↗
PubMed1998

[Digoxin: continuous or discontinuous treatment?].

In our country, patients with congestive heart failure who are treated chronically with digoxin are usually advised by their physicians to stop taking the medication two days a week. This is probably aimed at decreasing digitalis toxicity. Based on digoxin pharmacokinetics we assumed that the drug plasmatic level should diminish by 40 to 50%, below the therapeutic concentration of 0.8 to 2 milligrams, after two days of suspension. The objectives of this study were: a) to analyze the reduction of the plasmatic concentration of digoxin after a two day interruption of treatment, b) to compare the plasmatic levels of the drug between patients who received continuous and discontinuous treatment. A prospective, randomized and simple blind trial was designed. A total of 36 patients with congestive heart failure and systolic dysfunction with atrial fibrillation or sinus rythm were included. Group 1 (19 patients) received continuous treatment and Group 2 (17 patients) took the drug from Monday to Friday. In the continuous treatment group there was no significant difference between the Monday (1.06 +/- 0.55 milligrams) and the Friday (1.1 +/- 0.57 milligrams) digoxin concentrations. In the discontinuous treatment group the Monday digoxin concentration (0.611 +/- 0.396 milligrams) was lower than the Friday one (1.04 +/- 0.58 milligrams). The difference was statistically significant with a p = 0.000002. In conclusion, the two days a week suspension schedule reduces the plasmatic concentration of digoxin to subtherapeutic levels while the continuous regime maintains stable concentrations within the therapeutic range. Adjusting the dose to the creatinine clearance, average concentrations of 1 milligram are obtained. These results suggest that digitalis intoxication could be prevented by adjusting the dose according to renal function rather than interrupting the treatment as it is usually done in our country.

Adolescent↗
PubMed2000

Effects of angiotensin-converting enzyme inhibitors and digoxin on health outcomes of very old patients with heart failure. SAGE Study Group. Systematic Assessment of Geriatric drug use via Epidemiology.

BACKGROUND: Randomized trials have shown that angiotensin-converting enzyme (ACE) inhibitors reduce mortality and morbidity, and improve symptoms and exercise tolerance in selected patients with congestive heart failure (CHF). There is, however, no evidence on the effectiveness of ACE inhibitors in the typical, very old and frail patients with CHF. OBJECTIVE: To compare the effects of ACE inhibitors and digoxin on 1-year mortality, morbidity, and physical function among patients aged 85 years. METHODS: We conducted a retrospective cohort study using the SAGE database, a long-term care database linking patient information with drug utilization data. Among 64637 patients with CHF admitted to all nursing homes in 5 states between 1992 and 1995, we identified 19492 patients taking either an ACE inhibitor (n = 4911) or digoxin (n = 14890). Record of date of death was derived from Medicare enrollment files, and we used the part A Medicare files to identify hospital admissions and discharge diagnoses. As a measure of physical function, we used a scale for activities of daily living performance. The effect of ACE inhibitors was estimated using Cox proportional hazards models with digoxin users as the reference group. RESULTS: The overall mortality rate among ACE inhibitor recipients was more than 10% less than that of digoxin users (relative rate, 0.89; 95% confidence interval, 0.83-0.95). Mortality was equally reduced regardless of concomitant cardiovascular conditions and baseline physical function. Treatment with ACE inhibitors was associated with a tendency toward reduced hospital admissions that was more evident among patients with greater functional impairment. The adjusted relative rate for hospitalization for any reason was 0.96 (95% confidence interval, 0.91-1.01). The rate of functional decline was greatly reduced among ACE inhibitor recipients (relative rate, 0.74; 95% confidence interval, 0.69-0.80), and this effect was consistent and independent of background comorbidity and baseline physical function. CONCLUSIONS: These data suggest that survival and functional benefits of ACE inhibitor therapy extend to patients with CHF 85 years and older, and mostly women, both systematically underrepresented in randomized trials. Alternatively, digoxin has a detrimental effect in this population.

Activities of Daily Living↗
PubMedDate not supplied

Excretion of digoxin and its metabolites in urine after a single oral dose in healthy subjects.

The 3-day urinary excretion of digoxin, its conjugated and unconjugated hydrolytic metabolites and dihydrodigoxin, was studied in 8 healthy men after oral administration of tritiated digoxin. Analysis was performed by high pressure liquid chromatography (HPLC). The total radioactivity corresponded to 45.4 +/- 2.0 per cent (mean +/- S.E.M.) of the dose. By HPLC 42.4 +/- 2.7 per cent was recovered before and 44.0 +/- 2.7 per cent after deconjugation of the samples. Digoxin and dihydrodigoxin constituted 40.3 +/- 2.9 per cent; of this 0.7 +/- 0.4 per cent was dihydrodigoxin. The sum of the hydrolytic metabolites was 2.1 +/- 0.3 per cent before and 3.4 +/- 0.5 per cent after deconjugation. No correlation was found between gastric pH and the production of hydrolytic metabolites. The relative amount of these metabolites was maximal (mean 13.4 per cent of the excretion) in the 4-8 h sampling period. During the first 8 h an average of 8.6 per cent of the radioactivity was not recovered by HPLC. The metabolism of digoxin as judged by urinary excretion was limited and showed great variation during the early hours after treatment. The excretion of unchanged digoxin in some individuals constituted as little as 60 per cent over the first 12 h after dosing.

Adult↗
PubMedDate not supplied

Effect of quinidine on the intestinal secretion of digoxin in guinea pigs.

Following i.v. injection of digoxin (10 micrograms kg-1) the ratio between digoxin concentrations in the lumen of jejunal loops perfused in situ and in plasma (L/P) of guinea pigs increased linearly with time. After 3 h, L/P was 8.7, indicating net secretion of digoxin against a concentration gradient. In quinidine treated animals (100 mg kg-1 p.o., 2 h before experiment) both the L/P ratio (5.7; p less than 0.01) and the digoxin content of jejunal tissue (-32 per cent; p less than 0.01) were markedly reduced. It is suggested that quinidine reduces the extrarenal clearance of digoxin at least in part by inhibiting the intestinal secretion of this glycoside.

Animals↗
PubMed2002

Pharmacoepidemiologic detection of calcium channel blocker-induced change on digoxin clearance using multiple trough screen analysis.

Nonlinear mixed effects modeling was used to estimate the effects of digoxin-calcium channel blockers (verapamil, diltiazem, nifedipine) in 336 serum levels gathered from 172 patients (104 male and 68 female) receiving oral digoxin as hospital in-patients. The final model describing digoxin clearance (CL) was CL (l/day)=(87.9+2.71C(cr))0.872(CCB)0.880(CHF)0.937(SPI)0.854(DFAC), where C(cr) is the estimated creatinine clearance (ml/min); CCB=1 for concomitant administration of calcium channel blockers and CCB=zero otherwise; CHF=1 for the patients with congestive heart failure and CHF=zero otherwise; SPI=1 for concomitant administration of spironolactone and SPI=zero otherwise; DFAC=1 for administration of a half-tablet of digoxin and DFAC=zero otherwise. Concomitant administration of calcium channel blockers resulted in a 13% decrease in digoxin relative clearance.

Adolescent↗
PubMed2001

Digoxin withdrawal in patients with dilated cardiomyopathy following normalization of ejection fraction with beta blockers.

BACKGROUND: The effect of withdrawal of digoxin on left ventricular function in patients with a history of idiopathic dilated cardiomyopathy (IDCM) following normalization of left ventricular ejection fraction (LVEF) with beta blockers remains unknown. HYPOTHESIS: This study was undertaken to determine the effect of digoxin withdrawal on left ventricular function in patients with IDCM. METHODS: In 8 consecutive patients with IDCM (5 men, 3 women) who had normalization of LVEF following beta-blocker treatment, digoxin was withdrawn as part of an office protocol. and LVEF was followed. Baseline EF prior to beta blocker initiation (carvedilol = 6, atenolol = 1, metoprolol 1) was measured with isotope ventriculography (IVG), echocardiography, or left ventriculography. Post beta blocker ejection fraction (post BB EF) was measured in all patients with IVG at a mean of 17.25 +/- 5.38 months. Follow-up EF was measured using IVG after digoxin withdrawal at a mean of 6.99 +/- 4.34 months. RESULTS: An experienced blinded reader interpreted the IVG scans. Baseline EF was 28.5 +/- 8.26; post BB EF and follow-up EF were 56.1 +/- 4.65 and 51.0 +/- 7.35, respectively (p = 0.05). CONCLUSION: These data provide potential evidence that digoxin withdrawal can result in a small but significant reduction in LVEF in patients with IDCM who had normalization of LVEF after treatment with beta blockers. Mean LVEF, however, remained within normal (> 50%) on beta-blocker therapy and without digitalis. Large, randomized controlled trials are needed to confirm these findings.

Adrenergic beta-Antagonists↗
PubMed1975

Superior bioavailability of digoxin solution in capsules.

The bioavailability of various formulations of digoxin was assessed after single and multiple doses in a series of crossover studies in human volunteers. Digoxin tablets that were 97% dissolved in 1 hr in vitro were not significantly better absorbed than tablets with a dissolution rate of 78%. A solution given in capsule form had greater bioavailability than tablets of 97% dissolution rate; serum and urinary glycoside levels after 0.4 mg doses of the encapsulated solution were similar to those attained after 0.5 mg doses of tablets with dissolution rates of 78% and 97%. The bioavailability of the solution in capsule form exceeded that of equal doses of the same solution given as a liquid or that of a standard elixir. No increase in gastrointestinal or cardiac toxicity was detected. Inter- and intrasubject variation in bioavailability was not decreased. Above a certain level, dissolution rate is no longer the limiting factor in digoxin absorption. The mechanism of the enhanced bioavailability of concentrated liquid digoxin in capsule form remains to be determined. Such a preparation deserves further consideration as a possible replacement for digoxin tablets.

Adult↗
PubMed1976

Tissue and erythrocyte distribution of digoxin in infants.

The distribution of digoxin in the myocardium, skeletal muscle, erythrocytes, and plasma (or serum) was studied in 19 infants. There was a linear relationship between myocardium and serum concentrations and no saturation was observed over the serum concentration range of 0.5-8.6 ng/ml. Myocardium uptake of digoxin was nearly twice as great in infants as in adults at any given serum concentration. Erythrocyte: plasma concentration ratios of digoxin were one-third smaller during digitalization than during maintenance digoxin therapy. The latter ratios were also three times greater in infants than found previously in adults. Their findings are consistent with a greater apparent volume of distribution of digoxin in infants and may partly explain the unusually large therapeutic doses needed in infants.

Digoxin↗
PubMed1976

Studies on digitalis. VI. The effect of heparin on serum protein binding of digitoxin and digoxin.

The aim of the present study was to investigate the nature of the previously reported changes in the serum protein binding of digitoxin and digoxin in uremic patients under treatment with hemodialysis. Kinetic studies on protein binding during hemodialysis showed that the free fraction of digitoxin rose from 2.6% to 6.9% after 5 min of hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from hemodialysis and remained elevated during the dialyzing period. Free digoxin rose from 78.3% to 87.1% during the same period. In vitro hemodialysis experiments showed that such changes occurred only in vivo. Injection of heparin (5,000 IU) to control subjects produced similar kinetic changes in the protein binding of digitoxin and digoxin. Free fatty acids changed in the same way. These results indicate that the heparin-induced release of free fatty acids causes displacement of digitoxin and digoxin from their albumin-binding sites. Patients on hemodialysis have lower serum levels of digitoxin and cardioactive metabolites (mean, 8.9 ng/ml) than control patients (mean, 16.7 ng/ml) (p less than 0.005) on similar doses (mean, 0.085 mg/day). They should be maintained on the same digotoxin doses as uremic and control patients, but serum digitoxin levels should be adjusted to 10 to 15 ng/ml in hemodialysis patients compared to 15 to 25 ng/ml in uremic patients and in patients with normal renal function.

Blood Proteins↗
PubMed1978

Serum digoxin and empiric methods in identification of digitoxicity.

A prospective study of consecutive patients admitted to a medical service was undertaken to evaluate the prevalence of cardiac digitalis toxicity and the relative diagnostic values of serum digoxin versus an empiric method, based on calculations of digoxin dose in relation to kidney function and body weight. Of 711 patients admitted, 109 were treated with digitalis on admission. Sixteen of the patients developed cardiac arrhythmias consistent with digitalis intoxication. Five of these, none with serum digoxin above 1.6 ng/ml, were not toxic. The remaining eleven patients, all with serum digoxin levels above 1.6 ng/ml, were either definitely or possibly toxic. A similar borderline between intoxicated and nonintoxicated patients could not be established on the basis of calculations based on body weight and renal function. In all cases in which suspicion of digitalis intoxication was raised, serum digoxin measurements could discriminate between the toxic and the nontoxic patients.

Aged↗
PubMed1978

Effect of a standard breakfast on digoxin absorption in normal subjects.

The influence of food on absorption of digoxin was studied in 6 healthy volunteers who received 1.0 mg digoxin as 4 tablets of Lanoxin either after an overnight fast, immediately after a standard breakfast, or 90 min after a standard breakfast. There was no significant difference between the three regimens in terms of area under the plasma concentration-time curve for 79 hr or in the 10-day cumulative urinary excretion. The mean peak plasma concentration was higher (p less than 0.05) when digoxin was given fasting (4.2 +/- 0.46 ng/ml) than immediately after food (2.8 +/- 0.24 ng/ml). The mean peak plasma concentration when digoxin was administered 90 min after food (3.3 +/- 0.30 ng/ml) was intermediate but not significantly different from either of the other mean peak concentrations. The results demonstrate that ingestion of food decreases rate but not extent of absorption of concurrently administered digoxin.

Adult↗
PubMed1978

Suppression of renal excretion of digoxin in hypokalemic patients.

Inulin and digoxin clearances were simultaneously measured in 19 normokalemic and 4 hypokalemic patients. In normokalemia the renal digoxin clearance exceeded the inulin clearance, indicating both glomerular filtration and active tubular secretion of digoxin. The tubular secretion increased with increasing plasma digoxin concentration. In hypokalemia, however, the tubular secretion of digoxin was significantly reduced but increased after the plasma potassium level was raised to normal.

Adult↗
PubMed1979

Biotransformation and elimination of digoxin with normal and minimal renal function.

Six subjects with normal renal function (NRF) and 6 patients with minimal renal function (MRF) on 3 times weekly hemodialysis received 150 muCi3H-digoxin-12 alpha orally. Serial urine collections were made for five days or more. Digoxin and metabolites were separated using diethylaminoethyl Sephadex LH-20 column chromatography. Mean cumulative percentages of the ingested radioactivity excreted over five days in NRF and MRF groups were: digoin, 54.5% and 14.7%; bis-digitoxoside of digoxigenin, 2.0% and 0.59%; mono-digitoxoside, 0.8% and 0.19%; digoxigenin, 0.25% and 0.03%; and dihydrodigoxin, 0.3% and 0.03%. Half-lives based on the mean rates of disappearance from urine comparing NRF and MRF groups were: for digoxin 40 hr and 120 hr; for bis-digitoxoside, 11.5 hr and 46 hr; for mono-digitoxoside, 8.5 hr and 12 hr; for digoxigenin, 2 hr and 7.5 hr; and for dihydrodigoxin, 1.2 hr and 7.0 hr. Considering the relationships of the five-day cumulative excretion and half-lives of digoxin and metabolites in the NRF and MRF groups, it appears unlikely that there is a major alteration in the biotransformation of digoxin in advanced renal failure when there appears to be a shift from renal to slower biliary excretion.

Adult↗
PubMed1979

Lack of effect of bran on digoxin absorption.

The effect of dietary fiber on digoxin absorption was investigated in 12 patients taking digoxin. Steady-state serum digoxin concentrations were determined while subjects were on a regular diet and while they were on a diet supplemented with 22 gm bran daily. During the period of bran supplementation, the serum digoxin concentration did not change (average change, +0.5%; 90% confidence interval, -12% to +14%). Bran does not cause a clinically significant reduction in digoxin absorption.

Aged↗