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PubMed1986

Detection of digoxin, digitoxin, their cardioactive metabolites and derivatives by high-performance liquid chromatography and high-performance liquid chromatography-radioimmunoassay.

High-performance liquid chromatographic (HPLC) systems are described for the separation of the cardioactive metabolites of the digoxin and digitoxin series that are formed by the splitting of digitoxose sugar residues from the aglycone steroid: isocratic separation of digoxin and its cardioactive metabolites; isocratic separation of digitoxin and its cardioactive metabolites; and gradient elution separation of the digoxin and digitoxin series including beta-acetyl- and beta-methyldigoxin. Separations were performed on a 10-microns bonded octadecyl phase column using various mixtures of acetonitrile--water and acetonitrile--methanol--water as the mobile phase. These methods provide high peak resolution and are well suited for collecting elution fractions, e.g. to link up with sensitive immunological measurements. An HPLC-radioimmunoassay method is described for the quantitation of digoxin, digitoxin and their metabolites in human tissues.

Chromatography, High Pressure Liquid↗
PubMed2005

Digitoxin inhibits the growth of cancer cell lines at concentrations commonly found in cardiac patients.

The cardiac glycosides digitoxin (1) and digoxin (3) have been used in cardiac diseases for many years. During this time several reports have suggested the possible use of digitalis in medical oncology. Several analogues of digitoxin (1) were evaluated for growth inhibition activity in three human cancer cell lines; this study showed that digitoxin (1) was the most active compound and revealed some structural features that may play a role in the growth inhibition activity of these drugs. The IC50 values for 1 (3-33 nM) were within or below the concentration range seen in the plasma of patients with cardiac disease receiving this glycoside (20-33 nM). A renal adenocarcinoma cancer cell line (TK-10) was hypersensitive to this drug, and digitoxin toxicity on these cells was mediated by apoptosis. In vitro experiments showed that 1 at 30 nM induced levels of DNA-topoisomerase II cleavable complexes similar to etoposide, a topoisomerase II poison widely used in cancer chemotherapy. Using the individual cell assay TARDIS, cells exposed to 1 for 30 min showed low but statistically significant levels of DNA-topoisomerase II cleavable complexes; however these complexes disappeared after 24 h exposure.

Antineoplastic Agents↗
PubMed1983

Digitoxin kinetics and renal excretion in children.

Digitoxin kinetics were investigated in 11 children, three girls and eight boys, with a mean age of 7.1 yr (5.9 to 9.2). Five children received digitoxin, 17.5 to 20 micrograms/kg IV, and six other children received 20 micrograms/kg as an oral solution. Digitoxin was given as a single dose 24 to 48 hr after cardiac surgery, and patients were monitored in an intensive care unit for 24 hr. Serum and urine digitoxin concentrations were determined by radioimmunoassay. Children had larger apparent volumes of distribution (1 l/kg) than adults (0.57 l/kg). Mean serum elimination t 1/2 was 6.4 days in children (3 to 11.2) and 8.2 days in adults (5.9 to 11.3). Total body clearance was much greater in children (0.085 ml X min-1 X kg-1) than in adults (0.036 ml X min-1 X kg-1). This was because of an increase in metabolic clearance, although there was no difference in renal clearance in children and adults. Absolute oral bioavailability, measured by comparing serum AUCs after intravenous and oral doses, was complete. Peak serum concentrations of 23 to 50 ng/ml developed 90 to 120 min after the oral dose. A single digitalization dose of 20 micrograms/kg was well tolerated and did not induce arrhythmias.

Administration, Oral↗
PubMed1988

[Digitalis therapy in chronic heart failure. Digitoxin in patients in sinus rhythm pretreated with diuretics].

Eight patients in sinus rhythm with chronic heart failure were studied. After individually adjusted six-week treatment with diuretics (hydrochlorothiazide-triamtere and/or frusemide) all patients were clearly improved symptomatically. Subsequently they additionally received digitoxin for six weeks, 0.07-0.1 mg daily. Before and at the end of the digitoxin period cardiac volume was determined radiologically, echocardiography was performed and haemodynamic parameters determined at rest and on exercise via indwelling catheters. During digitoxin administration there was a slight increase in cardiac output from 4.63 +/- 0.82 to 5.05 +/- 0.98 l/min (P less than 0.1) at rest and from 7.22 +/- 1.94 to 7.79 +/- 2.59 l/min at rest. The mean values of all other haemodynamic parameters remained unchanged. These results suggest that in patients with chronic heart failure and sinus rhythm any clinical or haemodynamic improvement achieved will not be significantly bettered by digitoxin.

Adult↗
PubMed1980

Digoxin- and digitoxin-induced changes in monophasic action potential of the right ventricle of the dog heart.

The effects of digitoxin and digoxin on right ventricular monophasic action potentials were studied in intact dogs during an 8 hour observation period. Pentobarbital anaesthesia was used, and monophasic action potential recordings were obtained with the suction electrode technique. Intravenous injection of 2.0 mg digitoxin to six dogs, 2.0 mg digoxin to two dogs and 1.0 mg digoxin to five dogs caused a rapid increase in the time taken for 90% repolarisation with return to control values after 20 to 30 min. A late increase in 50 and 90% repolarisation times was observed 2 to 4 h after digitoxin, while digoxin had no such effect. The late action potential prolonging effect was inversely correlated to serum concentrations in the early elimination phase (2 to 8 h after the injection) since it reached a maximum towards the end of the observation period. Digitoxin and digoxin thus differed in their late effects on ventricular monophasic action potentials in intact dogs and may possess different antiarrhythmic activity.

Action Potentials↗
PubMed1989

Digitoxin in patients with hepatorenal insufficiency after repeated oral administration.

Following chronic oral administration of digitoxin 0.1 mg day-1 the pharmacokinetics of this glycoside were studied in seven patients with hepatorenal insufficiency and were compared with those of seven healthy volunteers. Liver cirrhosis of the patients was confirmed by liver biopsy. Mean creatinine clearance of the healthy subjects was 129.7 +/- 3.3 ml min-1 (mean +/- SEM), that of the patients was 25.6 +/- 20.4 ml min-1. Mean antipyrine clearance (parameter of oxidative liver function) was 49.7 +/- 6.0 ml min-1 in the volunteers and 22.0 +/- 2.9 ml min-1 in the patients. Plasma protein binding of digitoxin (PPB) was 95.0 +/- 1.1% in the patients and 96.7 +/- 0.6% in the healthy subjects (n.s.). Total body clearance of digitoxin (Cltot) was 0.0728 +/- 0.0120 ml min-1 kg-1 in the patients and 0.0615 +/- 0.0027 ml min-1 kg-1 in normals (n.s.]. Mean steady state plasma levels (Css) of the patients were 18.3 +/- 4.7 ng ml-1 and 15.8 +/- 1.3 ng ml-1 in the normals (n.s.). Our data obtained from chronic oral administration do not indicate a reduced total body clearance of digitoxin in patients with hepatorenal insufficiency.

Administration, Oral↗
PubMedDate not supplied

Differences in color vision impairment caused by digoxin, digitoxin, or pengitoxin.

Color discrimination ability of 53 patients with congestive heart failure and 32 healthy volunteers treated with digoxin, digitoxin, or pengitoxin was determined with the Farnworth's Munsell 100 hue test. The patients had been treated with digitalis glycosides for several months prior to color vision testing. The volunteers received glycosides until a steady-state plasma concentration was reached. Glycoside plasma levels were measured by radioimmunoassay on the 3 days prior to color vision testing. The total error scores, indices of color discrimination, increased with the glycoside plasma levels. Subjects treated with digitoxin or pengitoxin exhibited no marked elevation in total error score at therapeutic concentrations, whereas 17 of 28 subjects with therapeutic digoxin plasma concentrations (less than 2.0 ng/ml) showed disturbed color discrimination. At toxic plasma levels all 5 digoxin-treated subjects, 7 of 13 digitoxin-treated subjects, and 3 of 8 pengitoxin-treated subjects showed impairment of color discrimination. The greater tendency of digoxin to impair color vision in comparison with digitoxin and pengitoxin may be related to a higher uptake or different distribution in the retina.

Acetyldigoxins↗
PubMedDate not supplied

Effect of ketanserin on the kinetics of digoxin and digitoxin.

The influence of the serotonin antagonist ketanserin on the kinetics of digoxin and digitoxin were evaluated in healthy volunteers. Subjects received a single intravenous dose of digoxin (1.25 mg) or of digitoxin (1.0 mg) on two occasions: once in the control state, and again during treatment with ketanserin, 40 mg twice daily. Ketanserin caused a prolongation of digoxin elimination half-life (50 versus 40 h) and reduction in clearance (2.4 versus 3.7 ml/min/kg), but differences were not significant. For digitoxin, ketanserin caused a small but significant (p less than 0.005) increase in volume of distribution (0.89 versus 0.78 L/kg), but no significant effect on half-life (7.0 versus 6.8 days), or clearance (0.063 versus 0.059 ml/min/kg). Thus, ketanserin coadministration is not likely to alter steady-state concentrations of digoxin or digitoxin during clinical use of these two digitalis glycosides.

Adult↗
PubMed1980

The effectiveness of digoxin-specific F(ab')2-antibody fragments in the treatment of digitoxin poisoning: experimental investigations in the cat.

In animal experiments heterologous digoxin-specific F(ab')2 antibody fragments have been found to be effective for the treatment of arrhythmias induced by toxic doses of digoxin. So far they have been successfully employed in three patients suffering from digoxin poisoning. The present study was undertaken to test whether these antibodies are also effective in the treatment of digitoxin poisoning. Ventricular tachycardia, induced in digitalized cats by intravenous injections of digitoxin, was fatal in four out of five controls. However, sinus rhythm was reinstated in all the animals treated with digoxin-specific F(ab')2 after onset of the arrhythmia. Cross-reactivity between the antibodies used and digitoxin, while slight in vitro, is, nevertheless, sufficient to justify their clinical use in cases of digitoxin poisoning.

Animals↗
PubMedDate not supplied

Pharmacokinetics of tritiated ouabain, digoxin and digitoxin in guinea-pigs.

1. Elimination rates of tritiated ouabain, digoxin and digitoxin after single intravenous administrations were investigated in guinea-pigs, the total radioactivity in whole blood being traced for a period of up to 2 weeks. 2. In the initial rapid phase of elimination between 2 and 30 min following intravenous glycoside administration, the concentration decline of radioactivity in the blood was found to be identical for the three glycosides investigated, this part of the elimination curve displaying a hyperbolic shape. 3. During this early elimination phase, rapid metabolic degradation and excretion of digoxin had already taken place. The maximum concentration of radioactivity in the bile was reached 4 min following intravenous administration of 3H-digoxin. The positive inotropic response occurred in the cat heart-lung preparation 1.5 min after intravenous injection of a therapeutic dose of digoxin, indicating a quick occupation of binding sites in the tissues. 4. The biological half-lives of tritiated ouabain, digoxin and digitoxin averaged 11 h, 2.5 days and 4.1 days, respectively, as determined by the terminal exponential elimination phase, in guinea-pigs. This terminal phase was attained 6-12, 7-24, and 24-48 h after administration of ouabain, digoxin and digitoxin, respectively. 5. The findings reveal that in guinea-pig, as has been demonstrated in man, the elimination rates of the three glycosides increase according to their hydrophobic properties. 6. The biological half-lives of tritiated ouabain, digoxin and digitoxin obtained in the guinea-pig closely resemble those found in healthy man.

Animals↗
PubMed1991

Relationship between red blood cell potassium and plasma digitoxin concentrations in intoxicated patients.

After severe acute self-poisoning by cardiac glycosides, significant and persistent depletion of red blood cell K+ due to inhibition of Na+K+ ATPase is seen. Because of a delay between the time course of plasma digitalis concentrations and that of red blood cell K+ depletion, no direct relation exists between the two, and RBC K+ has hitherto not been considered useful as prognostic indicators of clinical outcome. In an effort to solve this problem, red blood cell K+ was measured by atomic absorption spectrophotometry and plasma digitoxin concentration assayed in six patients admitted to an intensive care unit after digitoxin self-poisoning. Using the effect compartment model of Sheiner, a relationship based on a sigmoid Emax model was able to relate the digitoxin concentration at the action site to red blood cell K+ depletion. Thus the duration of red blood cell K+ depletion could be predicted from two relative simple in vitro assays. Since RBC K+ is a marker of the inhibition of Na+K+ ATPase by digitoxin, this method could be of use for the management of patients self-poisoned with digitalis.

Adult↗
PubMed1985

Effects of digitoxin and hypokalaemia on pancreatic NaHCO3 secretion and pancreatic Na,K-ATPase activity.

To study the role played by Na,K-ATPase in the pancreatic secretion of NaHCO3, experiments were performed in 20 anaesthetized, secretin-infused pigs (3.0 clinical units X kg b. wt. X h-I). The relationship between pancreatic NaHCO3 secretion and arterial pH was obtained before and during Na,K-ATPase inhibition by digitoxin and hypokalaemia. Na,K-ATPase activity in pancreatic tissue homogenate averaged 5.45 (5.02-6.68) mumol Pi X mg X protein X h-I. Retrograde injection of 0.5 ml 1.4 X 10(-4) mol X l-I digitoxin into pancreatic ducts reduced pancreatic Na,K-ATPase activity by 3I(I8-47)%, while intra-arterial injection of 0.2 mg X kg b. wt-I digitoxin reduced pancreatic Na,K-ATPase activity by 50(45-56)%. Digitoxin and hypokalaemia reduced the rate of pancreatic NaHCO3 and shifted the normal, proportional relationship between NaHCO3 secretion and arterial pH towards higher pH. Hypokalaemia reduced Na,K-ATPase activity and NaHCO3 secretion in proportion. These effects indicate that Na,K-ATPase helps to sustain the requisite electrochemical potential gradients for driving H+ ions, and hence HCO-3 ions, out of secretory cells.

Animals↗
PubMed1978

The metabolism of digitoxin in hepatic cirrhosis of human subjects.

Digitoxin, 1 mg, was orally administered to 12 cirrhotic patients (the 6 in a clinically compensated and the 6 in a decompensated state) and their serum concentrations were measured at 6 hours and everyday through 7 days by radioimmunoassay. The serum half-life of digitoxin in these groups and normal subjects, determined from the serum concentrations, was as follows: 4.7 +/- 0.55 days for controls, 4.9 +/- 0.45 days for the compensated group and 5.3 +/- 0.35 days for the decompensated group. No statistically significant difference could be found in half-life among these groups. (P less than 0.2). The same dose of digitoxin was orally administered to 6 cirrhotic patients and 6 control subjects and their left ventricular systolic time intervals, LVET and QS2, were determined at 6 hours and every morning for 7 days. Cardiac responses, exhibited by decrease in the systolic time intervals, in both control subjects and cirrhotic patients dissipated in fair parallel during the ensuing 4 days and returned to base line level by 5 days. From these both biological half-life and physiological effect, it may be concluded that overall metabolism of digitoxin in cirrhotic patients is not disturbed.

Administration, Oral↗
PubMedDate not supplied

Effect of plasma exchange on the steady-state kinetics of digoxin and digitoxin.

The pharmacokinetic effect of extracorporeal elimination can be evaluated from the extracorporeal elimination rate constant, from the amount of drug removed, and from extracorporeal clearance. To compare the validity of these approaches in clinical practice, the effect of multiple plasma exchanges on the steady-state kinetics of digoxin (5 patients) and digitoxin (9) was investigated. For digoxin, an unchanged elimination half-life (28 hours) and only slight increase in the total body clearance was found (from 203 to 204 ml/min). There was a more pronounced effect on the kinetics of digitoxin, where the elimination half-life decreased from 4.3 to 3.6 days, and the total body clearance increased from 4.4 to 4.7 ml/min. For digoxin there was no statistically significant difference between observed and predicted steady-state trough plasma concentrations. For digitoxin, the observed trough plasma concentrations at steady-state correlated well (p less than 0.05) with the predicted concentrations calculated from the amount removed or from extracorporeal clearance. The magnitude of the kinetic effect of plasma exchange is overestimated using the extracorporeal elimination rate constant; but the effect of extracorporeal elimination can be adequately evaluated from the amount of drug removed and from extracorporeal clearance. These later approaches can be considered model-independent. Thus, the influence of multiple plasma exchanges on the steady-state kinetics of digoxin and digitoxin will be limited and dosage adjustment is not required, if these drugs are given after - not before - the procedure and hypoalbuminaemia is corrected.

Adult↗
PubMed1982

Massive digitoxin intoxication. Treatment of Amberlite XAD 4 resin hemoperfusion.

Amberlite XAD 4 resin hemoperfusion was studied in the treatment of massive digitoxin overdosage. In vitro experiments using 4 hour resin hemoperfusion showed that digitoxin is removed 100 percent from an isotonic saline reservoir, 83 +/- 14 percent from plasma, and 42 +/- 7 percent from whole blood. In dogs, serum level reduction is fast: 50 +/- 12 percent in 15 minutes, 71 +/- 6 percent in 180 minutes; mean plasma clearance is 24 +/- 6.5 ml/min for a 150 ml/min plasma flow rate. Eleven patients with massive digitoxin overdosage recovered with resin hemoperfusion. Serum level reduction was 32 +/- 14 percent with a 325 g resin column, 59 +/- 6 percent with two 325 g resin columns in series as compared with a 4.5 +/- 1.7 percent reduction without perfusion. Hemoperfusion increased the rate of spontaneous removal of digitoxin 8.6 +/- 3.3 times with a 325 g resin column, and 14 +/- 7.4 times with two 325 g resin columns.

Adult↗
PubMed2000

Comparing the toxicity of digoxin and digitoxin in a geriatric population: should an old drug be rediscovered?

BACKGROUND: Little information is available regarding toxicity rates of the two available forms of cardiac glycosides (digoxin, digitoxin) when used in elderly patients. METHODS: We retrospectively analyzed the charts of all patients more than 60 years of age who were chronically managed with a cardiac glycoside and were hospitalized during the period January 1995 through January 1998. Toxicity was defined as any clinical event that required either a reduction in dose of the drug or its discontinuance. RESULTS: Toxicity occurred among 7.6% of hospitalizations in which digitoxin was used, compared with 18.3% of hospitalizations in which digoxin was used. In multivariate analysis, the odds of toxicity adjusted for other clinical characteristics were three times greater for patients taking digoxin than for patients taking digitoxin. CONCLUSION: Hospitalized elderly patients taking digitoxin had a lower rate of toxicity than those taking digoxin.

Aged↗
PubMed2003

Determination of the cardiac glycosides digoxin and digitoxin by liquid chromatography combined with isotope-dilution mass spectrometry (LC-IDMS)--a candidate reference measurement procedure.

This article describes a method of high analytical sensitivity, reproducibility and trueness for the determination of digoxin and digitoxin in serum or plasma at therapeutic levels using a combination of high-pressure liquid chromatography (HPLC), isotope-dilution mass spectrometry (IDMS) and caesium-adduct formation. A method for threefold deuterium substitution in the glycosides was developed, which could be performed within 24 hours without distillation giving yields > 98% of the theoretical value. Extraction from a serum or plasma matrix was performed using a liquid-phase extraction with ammonium acetate buffer/tertiary butylmethyl ether/ethyl acetate at pH 9.5. The HPLC-separation used a 10 x 2 mm LiChrospher RP-18 5 microm guard column in combination with a 125 x 2 mm main column of the same material and a gradient containing methanol, caesium ions and formic acid. Quantification of digoxin and digitoxin was made with IDMS using deuterated internal standards and the system run in single ion monitoring (SIM) mode. The methods had a lower limit of determination of 0.25 microg/l for digoxin and digitoxin, a trueness between 97.5 and 104% for digoxin and between 98 and 101% for digitoxin, respectively and had a coefficient of variation of less than 3% in the therapeutic range for both glycosides. Maximally 1 ml serum or plasma was needed for the procedure. The method is used to set target values for materials used in external quality assessment surveys (EQAS) run by INSTAND as part of a national EQAS-programme.)

Calibration↗
PubMed1992

Results of the multicenter evaluation of a homogeneous immunoassay for digitoxin based on the cloned enzyme donor immunoassay technology.

We evaluated a CEDIA assay for the determination of digitoxin in serum on random access analyzers. The multicenter evaluation included studies on the analytical range, calibration stability and reproducibility of the new assay. Moreover, recovery in controls, transferability of results obtained in different laboratories, comparability with routine methods, and the effect of various interfering factors have been analyzed. Summarized the analytical performance was comparable to that of routine methods. The CEDIA Digitoxin assay represents an attractive alternative to established digitoxin immunoassays because it can be performed on random access analyzers, thus permitting the simultaneous determination of digitoxin and other serum analytes without sample splitting.

Digitoxin↗