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PubMed1981

Inotropic effects of digitoxin in isolated guinea-pig heart under conditions which alter contraction.

In order to examine which calcium pool(s) might contribute to the therapeutic action of digitalis, the positive inotropic effect of digitoxin was quantified under conditions in which different calcium pools were either predominant or suppressed. Isolated left atrial muscle of guinea-pig heart was stimulated at 0.5 Hz at 30 degrees C. After a brief rest period, the first contraction (post-rest contraction) observed when electrical stimulation was resumed was markedly greater than the contraction observed under 0.5 Hz stimulation. Post-rest contraction was apparently dependent on the rest period and related to a ryanodine-sensitive, verapamil-insensitive calcium pool. Post-rest contraction was moderately enhanced by 0.2 microM digitoxin, either in the absence or presence of verapamil. A step-wise increase in the frequency of stimulation following the rest period caused a typical staircase phenomenon, which was markedly suppressed by verapamil but not by ryanodine. Digitoxin markedly augmented the staircase in the absence or presence of ryanodine. Paired-pulse stimulation markedly increased the developed tension, which was slightly reduced by verapamil but not by ryanodine. Digitoxin substantially increased the developed tension evoked by paired-pulse stimulation. In left atrial preparations of rat heart, an increase in stimulation frequency decreased the force of contraction; however, paired-pulse stimulation increased the force, indicating that the enhancement of developed tension by an increase in stimulation frequency and that by paired-pulse stimulation have different mechanisms. Thus, the positive inotropic action of digitoxin does not appear to be restricted to a specific calcium pool; however, the inotropic effect was greater under the conditions in which superficial calcium pool plays a predominant role.

Animals↗
PubMed1982

Effect of age, clonidine or propranolol on behavioral toxicity induced with digitoxin in mice.

In three experiments, behavioral toxicity induced by 5 different dose levels of digitoxin was investigated in mice that were treated with either clonidine or propranolol or were either young (70-140 days), middle aged (240-260) or old (450-600). Observed on four drug-induced behavior categories, it was found that both clonidine and propranolol attenuated the toxic effects of relatively low dose levels of digitoxin, while at higher digitoxin dose levels only propranolol was able to reduce significantly the ED50 and the LD50. The results were discussed in terms of adrenergic mechanisms mediating digitoxin toxicity. Aged mice were found to be the least and middle aged the most resistant to the toxic effects of digitoxin.

Aging↗
PubMed1999

Characterisation of the binding of digitoxin and acetyldigitoxin to human serum albumin by high-performance affinity chromatography.

Zonal elution and high-performance affinity chromatography were used to examine interactions of the drugs digitoxin and acetyldigitoxin with the protein human serum albumin (HSA). This was done by injecting small amounts of digitoxin and acetyldigitoxin onto an immobilized HSA column in the presence of mobile phases that contained various concentrations of digitoxin, acetyldigitoxin or other solutes as competing agents. A fixed concentration of beta-cyclodextrin was also present in the mobile phase as a solubilising agent. It was found that digitoxin and acetyldigitoxin each had strong interactions at a single common binding site on HSA, but with slightly different equilibrium constants for this region. Neither compound showed any competition with warfarin or L-tryptophan, which were used as probes for binding at the warfarin-azapropazone and indole-benzodiazepine sites of HSA. These results confirmed the presence of a separate binding region on HSA for digitoxin-related compounds.

Acetyldigitoxins↗
PubMed1999

Effectiveness of digitoxin versus trichlormethiazide/amiloride in congestive heart failure NYHA class II/III and sinus rhythm.

The effects of digitoxin and/or diuretic agents were investigated in patients with congestive heart failure (CHF) in sinus rhythm with respect to changes in hemodynamic parameters, cardiac dimensions, and bicycle ergometric exercise capacity. In a randomized, double-blind study 16 male patients with CHF NYHA class II and III received a placebo for 1 week (baseline) and then were randomly allocated, double blind, to take either digitoxin (digitalis group, DI: N = 8) or trichlormethiazide/amiloride (diuretic group, DG: N = 8) for 3 weeks (VP I). The patients who were first treated with digitoxin received the diuretic agent for a further 3 weeks and vice versa (VP II). At baseline and after VP I and II, a physical examination, two-dimensional echocardiography, and bicycle ergometry were performed. Heart rate (HR), systolic (BPs), and diastolic (BPd) blood pressure at rest, and BPs and 50 watts, were not significantly changed during the observation period. HR at 50 watts was decreased in DI (11.5 +/- 10.1 beats/min.) after VP I and II, but not in DG. BPd was significantly reduced after VP II in DI (8.2 +/- 4.6 mmHg) and in DG (9.3 +/- 8.9 mmHg). DI presents at baseline significantly higher end-diastolic (LVEDV) and end-systolic (LVESV) left ventricular dimensions, whereas left atrial diameter (LA) and stroke volume (SV) and ejection fraction (LVEF) were not significantly different. After VP I, a significantly decreased LA was found in DI, but not in DG. After VP II, all cardiac dimensions were significantly reduced compared with the baseline in DI, whereas in DG only a decrease in LVESV was found. SV was significantly increased in DI, but not in DG after VP I, SV and LVEF were significantly improved in DI and in DG after VP II. Exercise capacity did not change significantly in DI and DG. Digitoxin in combination with trichlormethiazide/amiloride is effective in reducing primarily enlarged left atrial and left ventricular dimensions, and is sufficient to improve the impaired systolic left ventricular function in CHF of NYHA class II and III in sinus rhythm. However, a significant increase in exercise capacity was not found. Treatment with digitoxin seems to be more relevant as a monotherapy with trichlormethiazide/amiloride.

Aged↗
PubMed1983

Influence of serum proteins on erythrocyte uptake of digoxin and digitoxin.

My purpose was to find out whether changes in serum protein content (albumin and gamma globulin) influenced erythrocyte uptake of glycosides and the capacity of erythrocytes to equilibrate glycoside levels when there are changes in protein binding. Heparinized human blood was incubated with 3H-digoxin, 6 ng/ml, and 3H-digitoxin, 44 ng/ml for 15 min. After centrifugation, distribution between plasma and erythrocytes was determined by liquid scintillation. Ratios between erythrocyte and plasma concentrations were 0.84 and 0.11 for digoxin and digitoxin. Replacing plasma by a protein-free isotonic solution led to increased erythrocyte uptake by 15% and 540% for digoxin and digitoxin. Erythrocyte uptake for both drugs was also determined in varying amounts of albumin (0 to 120 gm/l) and gamma globulin (0 to 25 gm/l). Only albumin influenced the erythrocyte uptake of these drugs. Calculations of free and bound plasma levels for both drugs showed that free digitoxin increased when albumin concentrations were equal to or less than 10 gm/l and remained constant (3%) for albumin concentrations between 15 and 120 gm/l. Free digoxin plasma levels rise when the albumin concentration is equal to or less than 15 gm/l and do not change at albumin levels between 30 and 120 gm/l. These data indicate that blood components play an important role in equilibrating changes in free digoxin and digitoxin levels.

Adult↗
PubMed1998

Effects of digoxin and digitoxin on circadian blood pressure profile in healthy volunteers.

BACKGROUND: The aim of the study was to investigate the potential effects of chronic digoxin or digitoxin treatment or circadian blood pressure profile in normotensive subjects. METHODS: In two randomized double-blind, placebo-controlled cross-over protocols, 22 healthy normotensive subjects were enrolled, 12 subjects in either study. After adequate loading doses, digoxin 0.25 mg twice daily or digitoxin 0.1 mg daily was given for a total of 10 days. Automatic 24-h ambulatory blood pressure measurements were carried out at days 4 and 10 of either glycoside or placebo. RESULTS: Digoxin treatment significantly decreased heart rate (HR) and diastolic blood pressure (DBP) during the overnight sleeping phase of day 10 compared with placebo (HR, 4 beats min-1; DBP, 8 mmHg; P < 0.05). Digitoxin treatment significantly decreased heart rate and diastolic blood pressure during the overnight sleeping phase of day 4 (HR, 8 beats min-1; DBP, 7 mmHg) and day 10 (HR, 7 beats min-1; DBP, 5 mmHg) compared with placebo (P < 0.05). Neither digoxin nor digitoxin significantly affected systolic blood pressure. CONCLUSIONS: Both digoxin and digitoxin, within therapeutic steady-state plasma concentrations, reduced diastolic blood pressure and heart rate during overnight sleep, presumably because of increased parasympathetic activity or decreased sympathetic activity.

Adult↗
PubMed1977

[Pharmacokinetics of digitoxin in chronic renal failure (author's transl)].

Digitoxin concentration, measured by radio-immunoassay, was significantly lower in 51 patients in chronic renal failure (23.2 +/- 7.8 mug/l) than in 29 patients in heart failure (26.5 +/- 7.3 mug/l), although both groups were on the same maintenance dose of 0.1 mg daily. Despite a normal serum albumin concentration, digitoxin protein binding was less in uraemic patients than in those with normal renal function. Renal failure did not affect intestinal digitoxin absorption. In patients in chronic renal failure elimination half-time was significantly shorter (5.7 +/- 0.9 days) than in healthy controls (7.6 +/- 1.6 days). There was no significant difference in the excretion of water-soluble ("cardioinactive") digitoxin metabolites in urine between patients in chronic renal and those in heart failure. In patients with normal renal function, of dichloromethane-soluble (cardioactive) metabolites only digitoxin could be demonstrated by thin-layer chromatography. The results indicate that patients in chronic renal failure can safely be given the same dose as those with normal renal function, without danger of over- or underdosage.

Adult↗
PubMed1994

[Reversible thrombocytopenia due to digitoxin overdose].

A 65-year-old woman, known to have peptic ulcers, developed nausea and retching. Clinical examination demonstrated pain on pressure in the epigastrium with otherwise normative findings for age. Two gastric ulcers and gastritis with erosions were seen at endoscopy. The patient, who was being treated with digitoxin for heart failure, reported having taken up to four digitoxin tablets (0.07 mg each) daily because she had insomnia. The plasma digitoxin level was between 150 and 160 nmol/l (therapeutic range 17-33 nmol/l), while the ECG showed no signs of digitalis intoxication. Initially the platelet count was 40,000/microliter: there had been no history of thrombocytopenia or symptoms of abnormal haemostasis. Other laboratory tests were within normal limits. After digitoxin had been discontinued, the platelet count rose without further treatment to 373,000/microliter 3 weeks after hospital admission by which time the digitoxin level had fallen to 48.9 nmol/l. The gastrointestinal symptoms regressed completely on treatment with omeprazole (40 mg three times daily for 8 days) and ranitidine (150 mg twice daily).

Aged↗
PubMed1998

Prolonged digitoxin half-life in very elderly patients.

The digitoxin half-life in elderly patients in the eight and ninth decade was more prolonged (mean +/- SD: 25 +/- 9 days) than in younger people (6.7 +/- 1.7). These elderly patients accumulated digitoxin even on a dose of 0.05 mg/ day. The symptoms of digitoxin intoxication disappeared on discontinuation of medication. When digitoxin is used in the treatment for heart failure in the very elderly patients, one should be aware of the possibility of digitoxin intoxication, even on a low dose.

Aged, 80 and over↗
PubMedDate not supplied

The affinity of human serum albumin for [3H]-digitoxin is dependent on albumin concentration.

Binding of [3H]-digitoxin to human serum albumin and human serum was investigated in order to characterize the relationship between binding and albumin concentration. Binding was determined by equilibrium dialysis at 37 degrees, 24 hr was required to reach equilibrium. Volume shift and protein dilution were avoided by adding dextran 70 to the buffer compartment. [3H]-Digitoxin binding both to purified albumin and to normal serum was markedly pH-dependent, the bound/unbound ratio being highly significantly (P < 0.001) inversely correlated to pH in the range 6-8.5. When albumin concentration was increased within the physiological range, the ratio bound/unbound [3H]-digitoxin increased much less than expected from predictions using the law of mass action. Binding saturation experiments revealed that the equilibrium dissociation constant for [3H]-digitoxin was increased at higher albumin concentrations without any decrease in the number of binding sites per albumin molecule. In conclusion, the results strongly indicate that binding estimates in therapeutic monitoring of digitoxin in patients with elevated or reduced albumin concentration should not be based on the law of mass action but on empiric relationships between albumin concentration and binding.

Adult↗
PubMed1991

Binding of diazepam, salicylic acid and digitoxin to albumin isolated from fetal and adult serum.

Albumin was isolated from pooled fetal serum obtained at normal delivery at term and from pooled adult plasma. Albumin isolation was carried out by means of PEG precipitation followed by ion exchange chromatography on DEAE-Sephadex A 50 and then on SP-Sephadex C 50. The binding of diazepam (1 microM), salicylic acid (2 mM) and digitoxin (6 nM) to albumin (40 g/l) was measured by equilibrium dialysis at 37 degrees C. The unbound fraction (mean +/- SD) for fetal and adult albumin of diazepam was 1.86 +/- 0.24 and 1.82 +/- 0.15% (NS), that of digitoxin was 3.18 +/- 0.27 and 3.36 +/- 0.04% (NS) and that of salicylic acid was 11.65 +/- 0.99 and 9.47 +/- 0.75% (p less than 0.05), respectively. With both fetal and adult albumin, a single class of binding sites was observed for diazepam and digitoxin, whereas two classes of binding sites were observed for salicylic acid. The number of binding sites (n, moles of drug per mole of albumin) for fetal and adult albumin was 0.83 and 1.02 for diazepam and 0.014 and 0.018 for digitoxin, respectively. For salicylic acid, n was 1.45 (fetal albumin) and 1.55 (adult albumin) for the higher affinity site, and 3.06 (fetal albumin) and 3.27 (adult albumin) for the lower affinity site. The association constant (Ka, M-1) for diazepam was 1.36 x 10(5) (fetal albumin) and 1.00 x 10(5) (adult albumin) and that for digitoxin was 4.12 x 10(6) (fetal albumin) and 2.7 x 10(6) (adult albumin). For salicylic acid, Ka was 38.4 x 10(3) (fetal albumin) and 35.8 x 10(3) (adult albumin) for the higher affinity site, and 2.7 x 10(3) (fetal albumin) and 4.3 x 10(3) (adult albumin) for the lower affinity site. This work shows that fetal and adult albumin have similar binding properties and corroborates our previous findings with furosemide.

Adult↗
PubMed1975

The effect of chronic digitoxin administration on the contractile state of normal and nonfailing hypertrophied myocardium.

To determine the effect of prolonged digitoxin administration on contractile function of nonfailing myocardium, right ventricular papillary muscle mechanics were examined after 6 or 24 wk of glycoside administration to control and pulmonary artery banded cats. Resting length-tension relations were not affected by digitoxin; however, isometrically developed force and the maximal rate of force development at the peak of the length-tension curve were increased in all treated groups. In untreated animals, banding resulted in a 28% incidence of deaths from heart failure. 6 wk after constriction, contractile function was depressed whereas normal function was observed 24 wk after banding. Digitoxin significantly reduced mortality from heart failure and enhanced the recovery of contractile function; contractile function in the 6 wk banded treated group approached that of untreated control and 24-wk banded groups. The long-term effects of digitoxin on contractile function were not importantly related to the temporal association between banding and institution of glycoside administration. Development of myocardial hypertrophy was comparable in treated and untreated banded groups.These results demonstrate that a significant positive inotropic effect persists in both normal and nonfailing hypertrophied myocardium during chronic digitoxin administration.

Animals↗
PubMed1983

Subcellular distribution of 3H-digitoxin and its metabolites in the hearts of the cats with a hypersensitivity to the drug.

To clarify the cause of hypersensitivity to digitoxin, an experiment was carried out with cats. The most potent hypersensitivity to digitoxin has been observed 48 hr after the injection of a loading dose. However, 1 hr after this injection, the cats failed to show the hypersensitivity. One, 24 and 48 hr after the injection of 3H-digitoxin, the contents of digitoxin and its metabolites in subcellular fractions of hearts were measured. Digitoxin contents in microsomal fractions 48 hr after the injection only slightly decreased. while those in mitochondrial and nuclear fractions markedly decreased as compared with the check at 1 hr. An increase of sodium ions and a decrease of potassium ions in the hearts were seen 48 hr after the injection. These facts may be related to the cause of hypersensitivity.

Animals↗
PubMed1981

Acute, massive poisoning with digitoxin: report of seven cases and discussion of treatment.

Severe digitoxin poisoning in seven patients is reported. Doses taken varied from 2 to 20 mg, and maximal plasma concentrations of digitoxin from 50 to 237 nmol/L. One patient died from ventricular fibrillation, and the course in another was considerably protracted due to severe complications. The course in all patients was more dependent on underlying heart disease than on the plasma digitoxin concentration. Based on our own experiences and survey of the literature the following treatment is proposed: Gastric aspiration and lavage followed by instillation of activated charcoal should even be performed many hours after drug intake. In order to interrupt the enterohepatic circulation of digitoxin, repeated doses of charcoal should be given. Charcoal is preferable to cholestyramine because of its better tolerability. Ventricular arrhythmias should not be treated unless they are serious, because most antiarrhythmic drugs may further impede the AV-conduction. Phenytoin is the drug of choice, because the AV-conduction is less affected or even improved, and because the metabolism of digitoxin is accelerated. Conduction disturbances with bradycardia are frequently seen and may occur suddenly. Prophylactic introduction of a transvenous pacing catheter is therefore recommended as a routine procedure.

Adolescent↗
PubMed1981

Digitoxin elimination reduced during quinidine therapy.

Elevated serum digoxin concentrations and clinical toxicity have been reported in patients receiving quinidine. The present study was undertaken to ascertain whether a similar interaction occurs between quinidine and another cardiac glycoside, digitoxin, and if so to evaluate the pharmacokinetic basis in five healthy volunteers. In the presence of quinidine the serum digitoxin concentration was elevated, the mean digitoxin elimination half-life was increased from 87.8 +/- 11.6 to 218.3 +/- 20.6 h (mean +/- SEM) (p < 0.01), and mean total body clearance was reduced from 5.01 +/- 1.18 to 1.87 +/- 0.20 mL/h x kg (p < 0.052). No change was observed in the apparent volume of distribution or in the volume of the central compartment for digitoxin. The data suggest that the mechanism for this interaction is a reduction in elimination and not displacement of digitoxin from tissue binding sites.

Adult↗
PubMed1976

Neurotoxicity of digitoxin in adult and newborn rats: drug distribution.

Electrocardiographic monitoring of adult and 1 week old (newborn) rats during severe acute digitoxin toxicity demonstrated a lack of acrdiotoxicity despite marked neurotoxicity in both age groups. To examine the possibility that drug disposition is a factor in the unusual digitoxin sensitivity of newborn rats, 3H-digitoxin distribution in liver, heart, brain, kidney, adrenal, blood and fat was compared in 1 and 3 week old (weanling) rats at 2, 12 and 24 hr. H3-label was rapidly sequestered by the liver in weanlings but not in newborn rats. Newborns had significantly higher concentrations of 3H-substance in all other organs, particularly in brain (greater than 25% of the administered dose at 24 hr), indicating a cerebrotoxic basis for the newborn's sensitivity to digitoxin. Only trace amounts of 3H-substance were recovered from adult rat brain during severe neurotoxicity (72 hr) suggesting that digitoxin metabolites may be potent cerebrotoxins. Extremely high adrenal concentrations were noted in all animals.

Aging↗
PubMed1976

The effects of digitoxin and its metabolites on the transmembrane potential and contractile characteristics of guinea-pig ventricle strips.

The effects of 10(-7) and 10(-6) M digitoxin, and some of its metabolites, digitoxigenin-bis-digitoxoside, digitoxigenin-mono-digitoxoside and digitoxigenin on the transmembrane potential and contractile characteristics of guinea-pig right ventricle strips were studied to define the role of the sugar side-chain in these cleavage products of digitoxin. Digitoxin and digitoxigenin produced their maximum inotropic responses, without induction of arrhythmias, at about 30 min. However, the bis and mono compounds produced arrhythmias within 12 min, so the inotropy recorded may not be the maximum response. Digitoxin with 3 sugar residues and the bis compound with 2 sugar residues produced a prolongation in the action potenital duration. In contrast, the mono compound with one sugar residue and the digitoxigenin with no sugar residue produced a shortening of the action potential duration. There may be a relationship between the number of sugar moieties and the action potential duration; digitoxin and its bis derivative increased the action potential duration and mono- and digitoxigenin decreased the action potential duration. There also appeared to be an unusual relationship between the number of sugar moieties and induction of arrhythmias; arrhythmogenicity occurred at the doses employed with only the bis- and mono-digitoxoside. Finally, there appeared to be no simple relationship between chemical structure and inotropic potency.

Action Potentials↗
PubMed1975

Studies on biliary excreted metabolites of [G-3H]digitoxin in rats.

Metabolites of [G-3H]digitoxin in the rat bile have been studied by combining column chromatography on Sephadex LH 20 and TLC on silica gel. Bile was collected during 6 hrs, after i.p. injection of 800 mug/kg of [G-3H]digitoxin. The following digitoxigenin containing compounds were separated: -mono-digitoxoside (43%, mostly conjugated), -bis-digitoxoside and digitoxin (12% and 2% resp., mainly non-conjugated). C-12beta-hydroxylated metabolites related to digoxigenin were identified as -bis-digitoxoside (18%), digoxin (4%) and -mono-digitoxoside (traces only). The results indicate that even with regard to the C12-hydroxylation the main metabolic pathway of digitoxin proved to be the cleavage of the third and second digitoxose and the conjugation of digitoxigenin -mono-digitoxoside. However the cleavage of the genin linked digitoxose as well as the epimerisation of the genin do not play a role in the detoxication of digitoxin in vivo. Besides these findings three groups of yet unknown metabolites amounting up to 10% of the excreted radioactivity were separated from the identified metabolites. Acid hydrolysis of these compounds yielded digitoxigenin or digoxigenin. Therefore it may be concluded that metabolic changes in the sugar moiety are their common characteristics.

Animals↗