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PubMed1992

Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies.

A massive digitoxin (DGTX) intoxication in a 36-year-old man (35 mg DGTX) was treated by prolonged and repeated i.v.-infusions of Fab fragments of anti-digitalis antibodies (FAB). Blood and urine samples were collected over a 98 h period for monitoring the efficacy and adequacy of FAB treatment. DGTX concentrations were determined after protein precipitation (release of FAB-bound and protein-bound DGTX) in unprocessed serum and urine samples, and after aliquots of these samples had been dialysed in vitro against DGTX-free buffer (elimination of DGTX not bound to FAB). The difference in DGTX concentration between the unprocessed and dialysed samples was the amount of DGTX bound to plasma proteins and the small fraction of unbound DGTX being relevant for the therapeutic and toxic effects of the drug. Before FAB therapy was started, the total serum DGTX concentration was 535 nmol/l. The first FAB infusion (320 mg) was started 11 h after drug ingestion. Since this amount of FAB was insufficient to bind all DGTX present in the serum, cardiac DGTX toxicity (total AV-block) persisted. During a second FAB infusion (400 mg) the patient reverted to regular AV-conduction. At this time most of the DGTX in serum was FAB-bound. Toxic symptoms (sinus arrest) reappeared twice and were accompanied by increasing amounts of non-antibody-bound DGTX in the serum. Additional application of FAB (2 x 80 mg) resulted in the immediate disappearance of arrhythmia. During FAB-treatment total DGTX serum concentrations and renal DGTX clearance rose, indicating redistribution of drug from tissue to serum and urinary elimination of FAB-bound DGTX, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

[Pharmacokinetics and cardiac effect of beta-acetyldigoxin and digitoxin in combination therapy with nifedipine].

The effect of nifedipine (N) on the pharmacokinetics and pharmacodynamics of beta-acetyldigoxin (AD; n = 11) and digitoxin (DGT; n = 10) was studied in 21 patients with cardiac insufficiency stage II-III NYHA. Glycoside plasma concentration and renal excretion as well as electrocardiogram heart rate, atrioventricular transconduction time (PQ), duration of electrical systole corrected for heart rate (QTc), mean amplitude of T waves in leads V2 to V6 (TV2-6) and systolic time intervals total electromechanical systole index (QS21), left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), PEP/LVET-ratio were recorded repeatedly before and during co-administrations of 40-60 mg/day N. Plasma AD concentrations were 0.64 +/- 0.22 ng/ml (mean +/- SD) before and 0.61 +/- 0.21 ng/ml during co-administration of N over 10-14 days, plasma DGT concentrations 13.9 +/- 4.1 ng/ml before and 13.7 +/- 4.5 ng/ml during co-administration of N over 4-6 weeks. Daily glycoside excretion was not affected by treatment with N. Heart rate and PQ-interval were not significantly changed during co-administration of N whereas T-wave flattening was intensified and QT-duration was lengthened. Concomitant treatment of AD and N led to an increase of PEPI and PEP/LVET compared to AD alone in ten patients whereas the systolic time intervals after concomitant treatment of DGT and N in most patients did not differ from those after DGT alone. From our findings we conclude that N had no clinically significant effect on pharmacokinetics and pharmacodynamics of AD or DGT.

Acetyldigitoxins↗
PubMed1985

[Pharmacokinetic and cardiac efficacy of beta-acetyldigoxin and digitoxin in combination therapy with diltiazem].

The effect of diltiazem (D) on the pharmacokinetics and pharmacodynamics of beta-acetyldigoxin (AD; n = 12) and digitoxin (DGT; n = 10) was studied in 22 patients with cardiac insufficiency stages II-III by the New York Heart Association. Glycoside plasma concentration and renal excretion as well as electrocardiogram [heart rate, atrioventricular transconduction time (PQ), duration of electrical systole corrected for heart rate (QTc), mean amplitude of T-waves in leads V2 to V6 (TV2-6)] and systole time intervals [total electromechanical systole index (QS21), left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), PEP/LVET ratio] were recorded repeatedly before and during co-administration of 180 mg/day D. In eight patients digoxin plasma levels increased continuously during additional D administration. After reaching a new steady state at 0.93 +/- 0.35 ng/ml digoxin concentrations were at an average 43% higher than before D administration (0.65 +/- 0.27 ng/ml) with a simultaneous increase in renal glycoside excretion. The other four patients showed neither changes in digoxin concentrations in plasma nor in renal glycoside excretion. Only half the patients treated with DGT and D revealed an increase in DGT plasma levels of 21.4%. Daily renal glycoside excretion was not altered by D administration. In accordance to the increasing AD plasma concentration, PQ-interval was prolonged and T-wave flattening was intensified, whereas the systolic time intervals after concomitant treatment of AD and D did not differ from those after AD alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyldigoxins↗
PubMed1984

A new approach of ordered mixing applied to digitoxin tablets.

In ordered mixing it is assumed that mixing very different amounts of two materials is improved by adsorption of small particles onto large carrier particles. This hypothesis could be confirmed with tablets of 120 mg containing 0.1 mg digitoxin, prepared by dry coating of particles.

Adsorption↗
PubMed1980

Binding of digitoxin, digoxin and gitoxin to human serum albumin.

The binding of three digitalis glycosides, digitoxin, digoxin and gitoxin, to human serum albumin was studied in vitro by equilibrium dialysis. The results obtained showed that binding is a non saturable process and that probably the same binding mechanism is involved for each of the three drugs. Their binding sites seem to be different from of those of acidic and basic drugs. However, the three drugs were found to be partially displaced by large amounts of fatty acids.

Digitalis Glycosides↗
PubMed1979

Direct photoaffinity labeling of the primary region of the ouabain binding site of (Na+ + K+)-ATPase with [3H]ouabain, [3H]digitoxin and [3H]digitoxigenin.

The tritiated cardiotonic steroids, ouabain, digitoxin, and digitoxigenin are shown to photolabel the large polypeptide but not the glycoprotein or proteolipid component of the (Na+ + K+)-ATPase when they are bound to the inhibitory site and exposed to light of 220 or 254 nm. The extent of photolabeling is low, less than 1%, and is limited by photocross-linking of the enzyme. The mechanism of photoincorporation does not appear to be either photolysis of the lactone ring in ouabain or photolysis of tryptophan or tyrosine residues in the polypeptide.

Affinity Labels↗
PubMed1982

The effect of age on the biliary excretion of digitoxin and its metabolites in female BN/Bi rats.

The biliary excretion of digitoxin (Dt3) and its metabolites was studied in female BN/Bi rats of different ages ranging from 3 to 30 mth. The disappearance of radioactivity from plasma after an i.v. injection of [3H]Dt3 (0.01 mg/100 g body weight) gradually slowed as rat age advanced. The 2-h biliary recovery of radioactivity (percent of the dose) also showed an age-dependent decrease resulting in a 43% decrease at 30 mth compared to the 3-mth-old value. The amount of unchanged Dt3 in the bile, which was about 20% of the total activity in the bile of 3-mth-old rats, did not decrease with age, while the excretion of various Dt3 metabolites all decreased with age. It is suggested that the capacity of the liver to metabolize Dt3 is decreased with age in female BN/Bi rats, which may cause an alteration in the Dt3 pharmacokinetics with age.

Aging↗
PubMed1984

The digitoxin metabolism in isolated hepatocytes from young and old male Wistar rats.

The metabolism of digitoxin (Dt3) in isolated hepatocyte preparations was studied in young (3-mth-old) male and female rats, young castrated (3-mth-old) male rats and old (22- to 28-mth-old) male rats. When hepatocytes were incubated with [3H]Dt3, the predominant metabolite of Dt3 was digitoxigenin-bis-digitoxoside (Dt2) which was 70-90% of the total metabolites in the three male rat groups. Only in the young female rat group was the proportion of Dt2 (40%) slightly exceeded by that of digoxigenin-bis-digitoxoside (Dg2) (50%). A kinetic analysis for Dt3 degradation velocity obtained from studies using different Dt3 concentrations in old male rats yielded a Vmax of only 21% of the young value. In young castrated males, the Vmax also decreased to 13% of the young non-castrated males, which is approaching the young female value. The changes were primarily due to the decline of Dt2 formation velocity in these groups. Apparent Km values also decreased with both castration and aging. The plasma testosterone levels which were much higher in young male rats than in female rats became significantly lower in young castrated rats as well as in old male rats. The results suggest that apparent decreases in Vmax and Km values observed in old male rats for Dt3 metabolic degradation may be at least partly through the steroidal hormone control, presumably, the decline of androgenic induction during aging.

Aging↗
PubMed1982

Biliary excretion of digitoxin and its metabolites in young and old male Wistar rats.

The biliary excretion of digitoxin (Dt3) and its metabolites were compared between young (3-month-old) and old (25-month-old) male Wistar rats after an iv injection of [3H]Dt3 (0.03 mg/100g body weight) for 2 hrs. The 2-hr. total biliary recovery of iv injected radioactivity (percent of the dose) was two times lower in old rats (7.40 +/- 1.36% mean +/- SD) compared with young rats (14.74 +/- 4.10%). This difference was primarily due to the decrease in the excretion of Dt3 metabolites in the bile, while the excretion of the parent drug, Dt3 was 1.3 times higher in old rats. Among various Dt3 metabolites in the bile, digitoxigenin bis-digitoxoside (Dt2), digoxigen bis-digitoxoside (Dg2), and polar (conjugated) metabolites were major components, which all decreased with age. In accord with the decreased excretion of the radioactivity in the bile of old rats, the plasma disappearance of radioactivity was generally slower in old animals compared with young ones, yielding significantly higher plasma levels at different times of observation. Despite the increase in plasma radioactivity, the radioactivity concentration in the liver 2 hrs. after the injection was almost equal between the two age groups. It is suggested that at least in this rat strain and sex the biliary excretion of Dt3 metabolites was markedly age-dependent, presumably due to the decreased capacity of the liver to biotransform Dt3 with age. Furthermore, the lower liver plasma radioactivity ratio in old animals suggested the possibility that the distribution of Dt3 in the liver may also decrease with age.

Aging↗
PubMed1991

Pregnanes that bind to the digitalis receptor: synthesis of 14-hydroxy-5 beta,14 beta-pregnane glycosides from digitoxin and digitoxigenin.

The preparation of the mono-, bis-, and trisdigitoxosides of 14-hydroxy-5 beta,14 beta-pregnan-20-one and 14,20 beta-dihydroxy-5 beta,14 beta-pregnane by two routes, based on the conversion of the alpha,beta-unsaturated gamma-lactone in digitoxin to the 20-ketone and 20 beta-alcohol by ozonolysis and zinc-acetic acid treatment followed by lithium tri-tert-butoxyaluminum hydride reduction, are described. Synthesis of the alpha-L-rhamnoside derivatives is described also. Structures were confirmed by 1H and 13C NMR spectra. These derivatives show strong interaction with the cardiac glycoside receptor of heart muscle in an [3H]ouabain radioligand binding assay. Structure-activity relationships which are reported for glycosides and genins show that the alpha-L-rhamnoside derivatives are more potent than the beta-D-digitoxoside or the beta-D-glucoside and that the beta-D-glucosides are more potent than the mono-, bis-, and trisdigitoxosides. Potency is not increased by the addition of the second and third digitoxose units.

Digitalis↗
PubMed1976

Delayed onset and reduced severity of adrenal-compression hypertension in rats treated with digitoxin.

1. Bilateral compression of adrenal glands combined with unilateral nephrectomy and followed by imposition of a high sodium chloride intake caused severe hypertension in all rats, accompanied by enlargement of the heart, kidneys and adrenal glands, atrophy of the thymus and severe nephrosclerosis. 2. Digitoxin treatment delayed the onset, reduced the incidence and ameliorated the magnitude of the hypertensive response in such rats; it also reduced the degree of cardiac hypertrophy, the severity of nephrosclerosis and completely prevented enlargement of the adrenals and kidneys or atrophy of the thymus.

Adrenal Glands↗
PubMed1999

Digitoxin is a potential anticancer agent for several types of cancer.

The ability of digitalis to block cell proliferation has been well established for some time. Recently, digitalis in non-toxic concentrations has been showed to induce apoptosis in different malignant cell lines. In light of the pivotal role of apoptosis in cancer development and progression and this new experimental finding concerning digitalis, it seems probable that the apoptosis-inducing capability is explained by mechanisms other than just Na+/K+ ATPase inhibition. In this article, features of the cardiac glycosides which make them interesting to evaluate further as potential anticancer drugs are discussed. Some new data concerning inhibition and apoptosis in three human glioblastoma cell lines by digitoxin are also presented.

Antineoplastic Agents↗
PubMedDate not supplied

Effect of nanoparticles on digitoxin uptake and pharmacologic activity in rat glomerular mesangial cell cultures.

Our experiments analyzed the uptake of free and nanoparticles (NP)-associated digitoxin (DGT) by rat glomerular mesangial cells. NP were prepared by the nanoprecipitation method using the biodegradable polyester, polycaprolactone (PCL). Prior to in vitro experiments, the systems were characterized by means of spectrofluorimetry, dynamic light scattering, and size exclusion chromatography (SEC). The loading efficiency was 80.30 +/- 1.03% of the initial DGT amount in the preparation, and the average particle size was 176 +/- 8 and 161 +/- 6 nm for DGT-NP and "empty" NP, respectively. SEC studies revealed noncovalent interactions among the different chemical compounds in the formulation. In vitro experiments were conducted at 37 degrees C and pH 7.5 by incubating "empty" NP, free DGT or DGT-NP (10 microg PCL/mL; 100 ng DGT/mL) with glomerular mesangial cells for 30 and 60 min. Uptake of DGT by the cells was favored by its incorporation into PCL-NP and showed time dependency. After 30 min of incubation, no significant differences of drug uptake were seen between free DGT (13.1 +/- 2.8%) or DGT-NP (17.4 +/- 4.9%); however, the uptake of DGT, when it was associated to the polymeric carrier, increased by approximately 2-fold (37.8 +/- 5.7%) at 60 min, whereas no significant changes were observed for free drug (20.0 +/- 6.8%). The pharmacologic activity of the drug was evaluated by measuring the planar cell surface area (PCSA). "Empty" NP, free drug, or DGT-NP did not produce significant variations on the PCSA as compared with control cells after a 30-min incubation. Nonetheless, DGT-NP reduced the PCSA to 82.51 +/- 8.42% of control values when the incubation lasted 60 min. The ability of cells to exclude the trypan blue dye and the leakage of lactate dehydrogenase into the medium revealed no signs of increased toxicity from incorporation of DGT into PCL-NP. Therefore, PCL-NP improved drug uptake by the cells without altering the pharmacologic activity and toxicity of the drug. Thus, they can be a useful approach to target drugs to the kidneys or the heart.

Animals↗
PubMed1976

Effect of digitoxin on cardiac hypertrophy induced by pericardiectomy and exercise.

Removal of the pericardium in combination with a mild exercise programme of swimming resulted in a significant increase in heart weight and heart weight/body weight ratio of young rats. Heart weight/body weight ratios were 3.46+/-0.25 in the sedentary control animals, 4.16+/-0.26 in pericardiectomized animals swimming 2 h each day, and 4.60+/-0.22 in pericardiectomized animals swimming 6h/d. The effect of pericardiectomy on the development of cardiac hypertrophy is additive to that of mild exercise (2h/d) but not to prolonged exercise (6h/d). The administration of digitoxin significantly decreased the development of cardiac hypertrophy in pericardiectomized animals that were exercised for 2 h/d but not those exercised for 6 h/d. These findings further substantiate the physiological effect on the heart of the pericardium. The effects of pericardiectomy should be considered in experimental studies of cardiac hypertrophy and in clinical studies involving cardiac surgery.

Animals↗
PubMed1971

Cat assay for the emetic action of digitalis and related glycosides (digitoxin, digoxin, lanatoside C, ouabain and calactin).

1. A titration assay with two end points is described for comparison of the emetic and lethal potencies of digitalis-like drugs.2. A drug was infused at constant rate to a conscious, unrestrained cat, through an indwelling venous cannula. At the moment of vomiting the cat was rapidly anaesthetized and infusion continued at the same rate until the moment of cardiac arrest.3. With very slow and very fast infusions, the emetic and lethal doses tended to rise. In the range between these extremes (which varied from drug to drug) they were independent of time.4. The observations could be accounted for by analogue computation, assuming that the drugs entered an initial pool and were distributed at finite rates to receptors in the CNS (vomiting centre) and heart.5. Half times of metabolic loss derived from this computation for digitoxin, digoxin and ouabain (17, 9.9 and 1.8 h, respectively) were in the same ratio as the threefold longer half times reported for these drugs in man.6. When measured with infusion rates in the time independent range, the ratio of lethal to emetic doses did not vary between the drugs studied. All caused vomiting at 40% of the lethal dose.7. From a review of the literature, the emetic and cardiotoxic actions of digitalis-like drugs appear inseparable and probably share a common biochemical mechanism.8. It is concluded that foreseeable improvements in digitalis-like drugs are small and would depend on the elimination of any local emetic effect on gut receptors which they may have.

Animals↗
PubMed1977

Experimental cardiac hypertrophy and the synthesis of poly (A) containing RNA and of myocardial proteins in the rat: the effect of digitoxin treatment.

The synthesis of poly(A) containing RNA was increased in heart of non-digitalized and digitalized rats after aortic constriction, the increase being of the same degree as that of the RNA lacking this sequence. No differences were found, either in the absence or presence of polyuridylic acid, in the incorporation of radioactivity into protein by cardiac ribosomes isolated from animals treated differently. It may be concluded, that after the constriction of the aorta the synthesis of mRNA proceeds at a similar rate as that of the bulk RNA, and that the treatment of the animals with digitoxin does not abolish the stimulus for hypertrophy.

Animals↗
PubMed1989

Effects of digitoxin and lithium, used as a marker of passive Na transport, on secretin-dependent bile flow in the pig.

The present study was performed in anaesthetized pigs, and the first aim was to assess the role of Na,K-ATPase in secretin-dependent biliary HCO3 secretion (JbHCO3). Intra-arterial administration of the cardiac glycoside digitoxin (0.2 mg/kg-1) reduced hepatic Na K-ATPase activity, JbHCO3 and secretin-dependent bile flow by 24, 55 and 34% respectively. In the second part of this study lithium (Li) was used as a marker of passive Na transport to assess the electrochemical gradient for Na flux into bile duct lumen during secretin-stimulated bile flow and impeded biliary osmotic water flow by i.v. infusion of glucose. At plasma glucose 85 (73-96) mmol l-1, bile [Na] and [Li] exceeded their concentrations in plasma by 57 and 47% respectively. By using the Nernst equation, transepithelial potential difference (PD) during hyperglycaemia was estimated to be -6.2 (0 to -10.8) mV (ductal lumen negative), which corresponds to a [Li]bile/[Li]plasma ratio of 1.3 (1.0-1.5). The ratio was not significantly different from the observed [Li]bile/[Li]plasma ratio of 1.4 (1.3-1.5). It is concluded (1) that Na, K-ATPase is necessary for JbHCO3, probably by sustaining the cell membrane PD (cell interior negative) which is a driving force for apical electrogenic HCO3 secretion, and (2) transepithelial Li (and hence Na) flux is driven solely by the negative transcellular PD during secretin-stimulated bile flow in the pig.

Animals↗