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PubMed1993

Effect of fat substitutes, sucrose polyester and tricarballylate triester, on digitoxin absorption in the rat.

The effect of non-absorbable fat substitutes (sucrose polyester (SPE) and tricarballylate triester (TCTE)) on [3H]digitoxin intestinal absorption was studied in the rat using a small intestine in-situ perfusion technique. The effect of SPE and TCTE was compared with that of sunflower oil, oleic acid, and saline. After 120 min perfusion, 5% SPE emulsion significantly reduced (P < 0.001) digitoxin absorption compared with all other treated groups. Five per cent TCTE emulsion had a less marked effect than SPE (P = 0.0002) and did not differ from sunflower oil. No difference was found between saline and 5% oleate emulsion, which did not reduce digitoxin absorption compared with other treated groups (P < 0.02). When taurocholic acid and lipase were added, results for the saline-, TCTE-, and SPE-treated groups were similar to those above, but the sunflower oil-treated group showed significantly enhanced (P < 0.01) digitoxin absorption. Thin-layer chromatography of the lipid phases showed hydrolysis of sunflower oil in the presence of taurocholic acid and lipase, but not of TCTE or SPE. The inhibitory effect of the non-absorbable fat substitutes on digitoxin absorption could be related to drug sequestration by the persistent oil phase constituted by the undigested and then unabsorbed fat substitutes. That part of digitoxin dissolved in the undigested oil phase is consequently unavailable for intestinal absorption.

Animals↗
PubMed1987

Digoxin-like immunoreactive substance in chronic hemodialysis patients: effect on digitoxin radioimmunoassay.

Digoxin-like immunoreactive substance(s) (DLIS) in the sera of patients with renal insufficiency may confound attempts to monitor serum digoxin levels. We investigated whether DLIS would affect the radioimmunoassay (RIA) for digitoxin. DLIS was detected by RIA in 9 of 38 chronic hemodialysis patients and in none of 25 healthy controls. Digitoxin levels were not elevated in either the control or dialysis group, and false-positive results for digitoxin by RIA were not obtained in any patient with DLIS. It is concluded that DLIS does not interfere with the digitoxin RIA, nor are digitoxin levels spuriously elevated in chronic hemodialysis patients. Digitoxin may be a preferable preparation for digitalis-dependent dialysis patients with DLIS.

Digitoxin↗
PubMed1975

Serum digitoxin concentrations in infants and children.

Serum digitoxin levels were measured in 18 infants (under two years) and in 23 children (aged 2-13 years) receiving maintenance therapy. Digitalization was carried out because of heart failure in 17 infants and 13 children and for control of dysrhythmia in one infant and 10 children. Mean maintenance dosage for infants was 0.0042 plus or minus 0.0008 (sd) mg/kg/day and for children was 0.0031 plus or minus 0.0012 mg/kg/day. The mean serum digitoxin level was not significantly different in infants (30 plus or minus 10 ng/ml, range 14-58) from that found for children (34 plus or minus 11 ng/ml, range 19-61). Both values were significantly different (P smaller than 0.001) from those determined in this laboratory for adults (mean 24 plus or minus 7 ng/ml, range 5-39). In four infants with electrocardiographic or other evidence of toxicity, the mean serum level was 71 plus or minus 2 ng/ml (range 68-72), and in four children with electrocardiographic or other evidence of toxicity, the mean serum level for digitoxin was 72 plus or minus 14 ng/ml (range 53-84). The data suggest that infants and children tolerate a higher serum digitoxin concentration without any evidence of toxicity and may require more digitoxin (mg/kg) for therapeutic effect than do adults. Serum digitoxin levels may serve as an important guide in determining the adequacy of digitalization and in the recognition and management of digitalis toxicity.

Adolescent↗
PubMed1994

Preparation and antigenic properties of digitoxin-bovine serum albumin conjugates linked at the digitoxose C-3' and C-3" positions.

In order to obtain specific antisera to digitoxin, four new types of hapten-bovine serum albumin (BSA) conjugates were synthesized from digitoxin. The haptens were linked to the carrier protein through hemisuccinate and hemisuccinylglycine bridges at the C-3' and C-3" positions in the digitoxose chain. The antisera were prepared by immunizing rabbits with each digitoxin-BSA conjugate and the properties of the antisera were investigated by RIA with 3H-labeled digitoxin. Among these antisera, the antiserum raised against digitoxin 3'-hemisuccinate-BSA conjugate possessed high specificity for digitoxin, exhibiting only minor cross-reactions with digitoxigenin bisdigitoxoside (4.0%), dihydrodigitoxin (2.8%), digoxin (2.4%), digitoxigenin monodigitoxoside (0.23%) and digitoxigenin (< 0.05%).

Animals↗
PubMed1986

Clinical evaluation of a new digitoxin enzyme-immunoassay.

A solid-phase enzyme-immunoassay for the determination of the digitoxin concentration in human serum (Enzymun-Test Digitoxin) was developed, and subsequently evaluated in seven laboratories. The test is based on the competition principle. Polystyrene tubes coated with anti-digitoxin antibodies (from sheep) were used as the solid phase. In the concentration range 10-40 micrograms/l, the coefficient of variation for the majority of laboratories was between 2 and 7%. The day-to-day precision only slightly differed from the within-run precision. The measuring range was between 4 and 60 micrograms/l. Enzymun-Test Digitoxin showed good agreement with three known methods for digitoxin determination. No influence on the values was observed in lipaemic, uraemic and icteric samples, dysproteinaemia sera and in the presence of various digoxin derivatives. The new enzyme-immunoassay permits the practical and reliable determination of serum digitoxin and is suited for use in routine analysis.

Cross Reactions↗
PubMed1980

Digitoxin-quinidine interaction: pharmacokinetic evaluation.

The effect of quinidine on digitoxin single-dose pharmacokinetics was evaluated in five healthy adults. Blood was collected for 3 weeks, and a complete urine collection was obtained for 4 days, after a single intravenous dose of digitoxin. The protocol was conducted once while each subject was taking oral quinidine, for 3 weeks, and then repeated 10 days after discontinuing quinidine treatment. Quinidine induced the following changes in digitoxin pharmacokinetics: Elimination half-life was prolonged from 174 +/- 25 to 261 +/- 58 hours (p less than 0.02); total body clearance decreased from 1.54 +/- 0.40 to 1.09 +/- 0.31 mL/h . kg (p less than 0.05); renal clearance decreased from 0.65 +/- 0.07 to 0.46 +/- 0.17 mL/h . kg (p less than 0.05). Digitoxin volume of distribution and protein binding were unaltered by quinidine. Quinidine caused a rise in serum digitoxin levels. Digitoxin total body clearance was decreased by quinidine to an extent comparable to that reported for digoxin; however, the mechanism of the interaction with the two digitalis glycosides may, in part, be different.

Adult↗
PubMed1976

The effect of colestipol on digitoxin plasma levels.

The effect of colestipol (colestipol hydrochloride; U-26 597 A), a copolymer of tetraethylenepentamine and epichlorhydrine, on plasma digitoxin levels has been investigated. Recently, it has been stated that colestipol decreases the enterohepatic circulation and the plasma half-life of digitoxin. Colestipol was administered to 11 patients having a digitoxin plasma level which is generally accepted to be above the therapeutic range (greater than 40 ng/ml). The elimination rate of digitoxin measured by serial radioimmunoassay in these colestipol treated patients was compared with the elimination rate of digitoxin in 11 patients not treated with colestipol. The results of this study did not demonstrate a significant difference in the mean (+/- S.D.) digitoxin plasma half-life between the colestipol treated (6.3 +/- 1.3 days) and the non-colestipol treated patients (6.8 +/- 1.0 days).

Antidotes↗
PubMed1987

Digitoxin elimination in healthy subjects taking ampicillin.

The present study was carried out to evaluate the changes in digitoxin kinetics during ampicillin administration. Subjects were informed of the nature of the study and the treatment was applied to those who gave their written consent. Six healthy volunteers received a single oral dose of 1.0 mg of digitoxin. Three days later, they were given orally ampicillin trihydrate, 500 mg four times daily, for five consecutive days. Blood samples were taken at 24, 36, 48, 60, 72, 96, 120, 144, 168 and 192 hours after digitoxin. Compliance with ampicillin regimen was verified by fluorimetric measurement of serum ampicillin. Concentrations of serum digitoxin were determined by radioimmunoassay. The mean digitoxin elimination half-life changed from 162.8 +/- 12.9 h before to 181.3 +/- 10.1 h (mean +/- s.e. mean) after ampicillin. These differences were not significant. No consistent evidence of a kinetic interaction between digitoxin and the broad-spectrum antibiotic ampicillin was found.

Adult↗
PubMed1984

Pharmacokinetics and bioavailability of digitoxin by a specific assay.

The pharmacokinetics and bioavailability of digitoxin were examined in six normal human subjects using an assay that separates digitoxin from its metabolites. After intravenous administration, the mean systemic clearance was 2.44 ml/min; the volume of distribution was 0.47 l/kg; and the elimination half-life was 6.5 days. After oral administration, the elimination half-life was 5.8 days. The bioavailability was 81.5% using the specific assay. Using a non-specific, direct serum digitoxin radioimmunoassay the bioavailability was 98.0%. Assay of aqueous fractions from extracted serum samples indicated higher levels of water-soluble metabolites following oral compared to intravenous digitoxin administration. These findings suggest that previously reported values for digitoxin bioavailability using non-specific methods may be falsely elevated due to the presence of digitoxin metabolites in serum.

Adult↗
PubMed1981

Digitalis therapy in renal failure with special regard to digitoxin.

When prescribing cardiac glycosides for patients with renal failure, one should consider the different pharmacokinetics of the two most important glycosides, digoxin and digitoxin. Whereas steady state plasma concentrations of digoxin are altered proportionally to renal clearance of creatinine, those of digitoxin remain the same throughout a wide range of renal impairment. The steady state level of both glycosides is partly determined by several clinical factors such as dose, body weight, height, age and serum potassium. However, it is thought that bioavailability, volume of distribution, biotransformation, and total body clearance have the greatest importance for the variability of the plasma glycoside concentrations in patients with normal and with impaired renal function. The bioavailability and biotransformation of digoxin do not vary between healthy subjects and patients with renal insufficiency. As the volume of distribution is smaller in patients with severe renal failure that in normal subjects, the loading dose has to be altered. With decreasing creatinine clearance the total body clearance as well as the renal clearance of digoxin is reduced. On the basis of this assumption maintenance dosage regiments must be adjusted. For digitoxin, the four above-mentioned pharmacokinetic parameters are not altered in patients with renal failure compared to healthy subjects. Moreover, investigations dealing with this problem have suggested an altered protein binding of digitoxin and its metabolites as a possible factor in avoiding accumulation of the drug. However, it is one of the aims of this article to show that a decreased urinary excretion of digitoxin and metabolites is compensated by an increased excretion via the feces. Loading dose and maintenance dose of digitoxin do not have to be adjusted in patients with renal failure.

Biological Availability↗
PubMed1982

Studies on the Production of Digitalis Cardenolides by Plant Tissue Culture: II. EFFECT OF LIGHT AND PLANT GROWTH SUBSTANCES ON DIGITOXIN FORMATION BY UNDIFFERENTIATED CELLS AND SHOOT-FORMING CULTURES OF DIGITALIS PURPUREA L. GROWN IN LIQUID MEDIA.

Undifferentiated, highly chlorophyllous cell cultures; undifferentiated white cell cultures; green, shoot-forming cultures; and white, shoot-forming cultures of Digitalis purpurea L. were established and subcultured every 3 weeks in liquid media in the light or in the dark. The digitoxin content, the chlorophyll content, and the ribulose bisphosphate carboxylase activity of these cultures were assayed. The light-grown, green, shoot-forming cultures accumulated considerable amounts of digitoxin (about 20 to 40 micrograms per gram dry weight), and the white, shoot-forming cultures without chloroplasts accumulated about one-third that amount of digitoxin. The chlorophyll content and the ribulose bisphosphate carboxylase activity of the undifferentiated green cells were about the same as they were in the green, shoot-forming cultures, but the digitoxin content of the former was extremely low (about 0.05 to 0.2 microgram per gram dry weight), which is about the same as that in undifferentiated white cells without chloroplasts. Thus, it was concluded that the chloroplasts are not essential for the synthesis of digitoxin in Digitalis cells. The optimum concentrations of the tested compounds for accumulation of digitoxin were: benzyladenine, 0.01 to 1 milligram per liter; indoleacetic acid, 0.1 to 1 milligram per liter; alpha-naphthaleneacetic acid; 0.1 milligram per liter; and 2,4-dichlorophenoxyacetic acid, 0.01 milligram per liter.

Journal Article↗
PubMed1976

Accidental digitoxin poisoning.

A healthy 141/2-month-old child ingested 1.5 mg of digitoxin by accident. Digitoxin was wrongly identified as digoxin, the initial electrocardiogram was misinterpreted, and the vomiting was underestimated as an important symptom of toxicity. Symptoms persisted and the patient was hospitalized. Serial digitoxin levels were obtained and correlated with ECG and clinical course. It appears that serial digitoxin levels can be a useful adjunct in diagnosis, assessment of severity, and indication of recovery from digitoxin poisoning. In each patient, it is imperative that ECG, pharmacologic, and clinical indicators of digitalis toxicity be accurately identified for proper assessment of severity and appropriate management.

Absorption↗
PubMed1975

Studies on digitalis. III. Biliary excretion and enterohepatic circulation of digitoxin and its cardioactive metabolites.

Simultaneous serum, urine, and bile measurements of digitoxin and its cardioactive metabolites were preformed in 5 cholecystectomized patients with T tube drainage. A 86Rb method was used for serum and urine analysis. The recovery of digitoxin and cardioactive metabolites in two extractions with dichloromethane was 93%; 7% was left in bile. Peak bile concentrations had a mean value of 41.6 ng/ml and were seen after 15 to 60 min. Bile concentration was higher than serum and urine concentration after 24 hr. Mean T/2 of serum elimination was 4.3 days and 8.1 days in 5 control subjects (p less than 0.01). Mean urine concentration T/2 was 10.4 days and 7.2 days in the control subjects (not significant). Mean bile concentration T/2 was 3.5 days. Urinary excretion of digitoxin and cardioactive metabolites was the same in the two groups. The biliary fistula group excreted 22.5% in urine and bile of a dose after 8 days, whereas it was 15.8% in the control subjects. The ratio between the cumulative excretion in urine and bile varied between 1.6 and 2.2. These findings demonstrate that direct interruption of the enterohepatic circulation leads to a marked reduction in serum half-time of digitoxin and cardioactive metabolites, but T/2 is still longer than for other glycosides, indicating that factors other than the enterohepatic circulation are of importance in the slow elimination of digitoxin.

Adult↗
PubMed1979

Enhanced transformation of digitoxin to dihydrodigitoxin in humans with renal failure.

A gas-chromatographic mass-spectroscopic technique was used to identify dihydrodigitoxin, a metabolite of digitoxin, in the plasma of healthy volunteers and patients with renal failure. Digitoxin and dihydrodigitoxin were extracted from plasma and derivatized with heptafluorbutyric anhydride. In normal subjects, only minimal concentrations of dihydrodigitoxin in plasma could be determined (1 ng/ml) after an intravenous bolus injection of digitoxin. Under a chronic treatment with a daily dose of 0.1 mg digitoxin in three out of seven individuals, detectable dihydrodigitoxin plasma levels were observed (0.7, 1.5, and 1.7 ng/ml) (Table I). On the other hand, in seven patients with renal failure, high dihydrodigitoxin plasma concentrations (8.9 +/- 0.9 ng/ml) were shown which were in a similar range as those of the parent compound (8.7 +/- 2.2 ng/ml) under a maintenance treatment with digitoxin.

Adult↗
PubMed1998

Induction of digoxin-like material production, and the digoxin binding in the unicellular organism Tetrahymena by digitoxin.

Thin layer chromatographic, and laser-confocal microscopic analyses with a monoclonal antibody to digoxin also displaying high affinity to digoxigenin, were used to determine the presence and localization of cardioactive glycosides. Tetrahymena pyriformis was found to possess digitoxigenin-like material, but digoxin, digitoxin, digoxigenin, gitoxin and lanatoside C were not detected. Digitoxin treatment elicited the appearance of a digoxin-like material in the progeny generations. Digoxin was taken up by untreated Tetrahymena, especially strongly 24 h after digitoxin treatment. While the cardenolide was localized in vesicles of the cell body in untreated Tetrahymena, the engulfed digoxin appeared in the epiplasmic layer and also in the cilia after digitoxin pretreatment. Digoxin pretreatment did not increase digoxin uptake. These data indicate that Tetrahymena has: (1) the capacity to discriminate between closely related molecules; (2) the ability to induce digoxin-like material production; and/or (3) enzymes that can effect a digitoxin-digoxin transformation.

Animals↗
PubMedDate not supplied

Massive digitoxin intoxication treated with digoxin-specific antibodies in a child.

A 20-month-old girl with massive digitoxin intoxication (initial digitoxin serum level: 629 ng/ml) was successfully treated with digoxin-specific antibody fragments (Fab). She presented with moderate signs of digitalis toxicity (somnolence, bradycardia, first-degree AV block) and improved rapidly during fractional Fab administration. Free serum-digitoxin disappeared after 6 vials of Fab (480 mg), but was measurable again on days 6 and 7. This case demonstrated that digoxin-specific antibodies, despite a 30-100 times lesser affinity for digitoxin, are effective in massive digitoxin intoxications. A rebound phenomenon may occur several days later and should be taken into consideration.

Digitoxin↗
PubMed1977

Plasma digoxin levels in anuric patients and normal subjects taking digitoxin.

Plasma digoxin suspected to be elevated in anuric patients taking digitoxin was determined by radioimmunoassay in 15 anuric patients and 15 normal persons subjected to 0.1 mg digitoxin therapy per day. All plasma digoxin values from the anuric patients and the normal subjects were far below the lower limit of the therapeutic range of plasma digoxin. There existed no difference between the digoxin values determined in anuric patients and subjects with normal renal function; in both groups there was a scatter of digoxin values about the cross reaction line between digitoxin and digoxin antibody. It is concluded from the results that digoxin retention in anuric patients taking digitoxin plays an insignificant role; thus, the pharmacological effect is mediated by digitoxin itself.

Anuria↗
PubMedDate not supplied

Digitoxin and its metabolites in patients with liver cirrhosis.

Pharmacokinetic profile and urinary excretion of digitoxin and 4 metabolites were investigated in 9 patients with biopsy confirmed liver cirrhosis (median antipyrine clearance 20.0 +/- 5.4 ml/min; X +/- SEM) and were compared with that of 8 healthy volunteers (antipyrine clearance 36.9 +/- 4.9 ml/min) following intravenous and p.o. administration of 1 mg digitoxin. The kinetic parameters derived from the digotoxin plasma concentration time curve and from urinary recovery including total clearance of unchanged digitoxin did not differ significantly between both groups investigated. Renal clearance of digitoxin was 0.017 +/- 0.005 ml/min/kg in the patient group and 0.011 +/- 0.002 ml/min/kg in the volunteers (NS); it was 0.00340 +/- 0.00047 ml/min/kg and 0.00223 +/- 0.00039 ml/min/kg, respectively for digitoxigenin-bis-digitoxoside (NS), 0.00006 +/- 0.00001 ml/min/kg and 0.00016 +/- 0.00005 ml/min/kg for digitoxigenin-mono-digitoxoside (P < 0.05), 0.00041 +/- 0.00013 ml/min/kg and 0.00088 +/- 0.00032 ml/min/kg for digitoxigenin (P < 0.05), 0.00135 +/- 0.00049 ml/min/kg and 0.00113 +/- 0.00042 ml/min/kg for digoxin (NS). In conclusion, hydrolysis of digitoxin is altered in liver cirrhosis, whereby a significant reduction in the renal clearance and urinary recovery of digitoxigenin-mono-digitoxoside and digitoxigenin was seen in the present study.

Adult↗