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PubMed2004

The dynamics of cell proliferation.

The article provides a mathematical description based on the theory of differential equations, for the proliferation of malignant cells (cancer). A model is developed which enables us to describe and predict the dynamics of cell proliferation much better than by using ordinary curve fitting procedures. By using differential equations the ability to foresee the dynamics of cell proliferation is in general much better than by using polynomial extrapolations. Complex time relations can be revealed. The mass of each living cell and the number of living cells are described as functions of time, accounting for each living cell's age since cell-birth. The linkage between micro-dynamics and the population dynamics is furnished by coupling the mass increase of each living cell up against the mitosis rate. A comparison is made by in vitro experiments with cancer cells exposed to digitoxin, a new promising anti-cancer drug. Theoretical results for the total number of cells (living or dead) is found to be in good agreement with experiments for the cell line considered, assuming different concentrations of digitoxin. It is shown that for the chosen cell line, the proliferation is halted by an increased time from birth to mitosis of the cells. The delay is probably connected with changes in the Ca concentration inside the cell. The enhanced time between the birth and mitosis of a cell leads effectively to smaller mitosis rates and thereby smaller proliferation rates. This mechanism is different from the earlier results on digitoxin for different cell lines where an increased rate of apoptosis was reported. But we find it reasonable that cell lines can react differently to digitoxin. A development from enhanced time between birth and mitosis to apoptosis can be furnished, dependent of the sensitivity of the cell lines. This mechanism is in general very different from the mechanism appealed to by standard chemotherapy and radiotherapy where the death ratios of the cells are mainly affected. Thus the analysis supports the view that a quite different mechanism is invoked when using digitoxin. This is important, since by appealing to different types of mechanism in parallel during cancer treatment, more selectivity in the targeting of benign versus malignant cells can be invoked. This increases the probability of successful treatment. The critical digitoxin level concentration, i.e. the concentration level where the number of living cells is not increasing, is approximately 50 ng/ml for the cell line we investigated in this article. Therapeutic plasma concentration of digitoxin when treating cardiac congestion is about 15-33 ng/ml, but individual tolerances are large. The effect of digitoxin during cancer treatment is therefore very promising. The dynamic model constitutes a new powerful tool, supported by empirics, describing the mechanism or process by which the number of malignant cells during anti-cancer treatment can be studied and reduced.

Animals↗
PubMed1990

Immunopharmacological activity of monoclonal antidigitoxin.

A monoclonal antibody specific to digitoxin was developed and Fab fragments were prepared using the conventional papain method. The affinity constant was determined as 10(9)M-1 and the cross reactivity with digoxin was 2%. The Fab fragments were used for the reversal of acute digitoxin poisoning in rabbits (100% mortality). Fab fragments were administered over a 40 or 80 minute period just after digitoxin infusion. Rabbits treated with specific Fab fragments were protected by a bistoichiometrical dose. Evaluation of plasma digitoxin confirmed that the specific Fab fragments were able to extract and sequestrate digitoxin. The digitoxin-Fab fragment complexes were removed by renal excretion. Our data provide evidence of the benefit of monoclonal Fab fragments specific for digitoxin for the reversal of acute digitoxin poisoning.

Animals↗
PubMed1975

[Gycoside serum concentrations under maintenance therapy with Lanicor, Card-Lamuran, MF708d, and Lanitop (author's transl)].

The biological availability of digitoxin from Lanicor was compared with that from two different galenical preparations of Card-Lamuran (Card-Lamuran and MF708d both containing equal amounts of active ingredients: 0,125 mg digitoxin and 10 mg raubasine). The patients who were kept on their individually adjusted oral digitoxin maintenance dosage received the three preparations in a randomised order. Additionally, the equivalent dosages of Lanicor and Lanitop were determined from the data on their biological availability. In 24 patients with heart failure (mean age 70.5 years), radioimmunoassay of the glycoside concentration in the serum was performed. The patients were cardially well compensated with Lanicor and it could be assumed that there would be no change in the daily maintenance dosage for the entire period of the study (42 days). Our results show that digitoxin had the same bio-availability from Lanicor and the two different galenical preparations of Card-Lamuran and MF708d. Patients can therefore safely be switched from one of these preparations to the other. On average, doses of Lanicor 1.55 times higher than those of Lanitop must be given to obtain the same serum glycoside concentrations. The variation of this factor was no greater than the variation in serum concentrations of digitoxin during continued maintenance therapy with Lanicor. The mean serum concentrations of digitoxin under maintenance therapy in our geriatric patients (mean value 2.1 mg/ml) were higher than the digitoxin concentrations published in the literature for younger patients (average 1.4 ng/ml). The calculated daily maintenance doses providing a digitoxin concentration of 1.4 mg/ml were ca. 0.3 mg Lanicor and ca. 0.2 mg Lanitop. This is somewhat less than generally assumed. This agrees with the clinical experience that the glycoside maintenance dosage in elderly patients is generally less than in middle-aged patients.

Age Factors↗
PubMed2002

Progesterone attenuates the inhibitory effects of cardiotonic digitalis on pregnenolone production in rat luteal cells.

Previous studies have shown that digoxin decreases testosterone secretion in testicular interstitial cells. However, the effect of digoxin on progesterone secretion in luteal cells is unclear. Progesterone is known as an endogenous digoxin-like hormone (EDLH). This study investigates how digitalis affected progesterone production and whether progesterone antagonized the effects of digitalis. Digoxin or digitoxin, but not ouabain, decreased the basal and human chorionic gonadotropin (hCG)-stimulated progesterone secretion as well as the activity of cytochrome P450 side chain cleavage enzyme (P450scc) in luteal cells. 8-Br-cAMP and forskolin did not affect the reduction. Neither the amount of P450scc, the amount of steroidogenic acute regulatory (StAR) protein, nor the activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) was affected by digoxin or digitoxin. Moreover, in testicular interstitial and luteal cells, progesterone partially attenuated the reduction of pregnenolone by digoxin or digitoxin and the progesterone antagonist, RU486, blocked this attenuation. These new findings indicated that (1) digoxin or digitoxin inhibited pregnenolone production by decreasing the activity of P450scc enzyme, but not Na(+)-K(+)-ATPase, resulting in a decrease on progesterone secretion in rat luteal cells, and (2) the inhibitory effect on pregnenolone production by digoxin or digitoxin was reversed partially by progesterone. In conclusion, digoxin or digitoxin decreased progesterone production via the inhibition of pregnenolone by decreasing P450scc activity. Progesterone, an EDLH, could antagonize the effects of digoxin or digitoxin in luteal cells.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Evidence for an intracellular site of action in the heart for two hydrophobic cardiac steroids.

Although cardiac steroids (CS) have long been used to treat cardiac insufficiency, the mechanism(s) of action of these agents remain open to question. While many results indicate that inhibition of Na+,K+-ATPase underlies both the therapeutic and toxic actions of CS, other studies suggest that actions on the SR membrane system may be important. We used two experimental approaches and measurements of left ventricular diastolic pressure (LVDP) in isolated guinea pig hearts to test whether CS had an intracellular site of action. In the first approach, we compared the inotropic effects of a hydrophilic CS, ouabain, and a hydrophobic CS, digitoxin, after the activity of the Na+ pump was reduced by perfusing hearts with solutions maintained at 5 degrees C. Under these conditions, exposure of hearts to 1 microM ouabain for 60 min did not increase LVDP above control levels. In contrast, an equi-effective concentration of digitoxin (0.3 microM) increased LVDP by 40 +/- 8.5% (p < 0.01) over pre-drug control levels. In the second experimental approach, we compared the inotropic effects of ouabain and digitoxin in the presence of rapid-cooling contractures (RCC), which result in the release of SR Ca2+. Hearts were perfused with Tyrode solution or Tyrode solution containing either digitoxin (0.3 microM) or ouabain (1 microM) for 180 sec, rapidly cooled and the RCC responses were analyzed. Compared to RCC elicited in Tyrode solution alone, or in Tyrode solution containing ouabain, RCC in the presence of digitoxin reached peak amplitudes more rapidly, but elicited reduced peak amplitude values. Based on these findings, we suggest that: 1) the ability of the hydrophobic CS, digitoxin, but not the hydrophilic CS, ouabain, to produce a positive inotropic effect at 5 degrees C, when the activity of the Na+ pump is markedly reduced, is consistent with a mechanism other than Na+ pump inhibition and involves an intracellular location; and 2) the diminished RCC observed in the presence of the hydrophobic CS, digitoxin, indicate that this alternative mechanism may involve effects on the SR Ca2+ release channel.

Animals↗
PubMed1976

Mechanism of interaction of digitalis with estradiol binding sites in rat uteri.

Digitalis preparations have a weak estrogenic effect in man. The data in animals are equivocal. We have studied.the biologic effect of both digitoxin and digoxin on the rat uterus in vivo and the interaction of these drugs with the rat uterus estrogen receptor in vitro. Digitoxin and estradiol significantly increased the uterine weight of immature rats, while digoxin did not. The interaction of digitoxin and digoxin with the rat uterus estrogen cytosol receptor was studied using protamine sulfate precipitation and dextran-coated charcoal (DCC) assays. Both methods gave a Kd for the estradiol-receptor interaction between 0.8-3.1 X 10(-9) M (n = 20). Digitoxin at concentrations of 0.5-2.0 X 10(-6) M significantly inhibited the binding of estradiol to the specific or saturable binding sites with minimal inhibition of hormonal binding to nonspecific sites. The binding was competitive with a calculated Ki for digitoxin of 5.2-7.8 X 10(-7) M (n = 18). Digoxin failed to inhibit estradiol binding to the receptor protein in vitro. We conclude that digitoxin probably acts directly as a weak estrogen and that this effect probably explains the estrogen-like side effects seen with digitoxin therapy in man.

Animals↗
PubMedDate not supplied

Protein binding of cardiac glycosides in disease states.

Digitoxin in 97% bound to serum albumin and digoxin only to the extent of 24%. Hypoalbuminaemia significantly changes the protein binding of digoxin in Kwashorkor serum and the binding of digitoxin in patients with chronic active hepatitis and the nephrotic syndrome. Sprue patiens with normal albumin values have normal binding of digitoxin. Preliminary data in patients with thyrotoxicosis and myxoedema show digitoxin binding within the normal range. The effect of uraemia per se on digitoxin binding is controversial as both normal and slightly decreased values have been reported. In uraemic patients on treatment with haemodialysis, heparin administration has been shown to be a powerful serum binding displacing agent for both digitoxin and digoxin, the mechanism probably being a heparin-induced release of free fatty acids. Patients with a significant decrease in serum protein binding of digitoxin or digoxin should be maintained on a total serum concentration lower than usually considered within the therapeutic range.

Blood Proteins↗
PubMed1985

Relations between high-affinity binding sites of markers for binding regions on human serum albumin.

Binding of warfarin, digitoxin, diazepam, salicylate and Phenol Red, individually or in different pair combinations, to defatted human serum albumin at ligand/protein molar ratios less than 1:1 was studied at pH 7.0. The binding was determined by ultrafiltration. Some of the experiments were repeated with the use of equilibrium dialysis in order to strengthen the results. Irrespective of the method used, all ligands bind to one high-affinity binding site with an association constant in the range 10(4)-10(6) M-1. High-affinity binding of the following pair of ligands took place independently: warfarin-Phenol Red, warfarin-diazepam, warfarin-digitoxin and digitoxin-diazepam. Simultaneous binding of warfarin and salicylate led to a mutual decrease in binding of one another, as did simultaneous binding of digitoxin and Phenol Red. Both effects could be accounted for by a coupling constant. The coupling constant is the factor by which the primary association constants are affected; in these examples of anti-co-operativity the factor has a value between 0 and 1. In the first example it was calculated to be 0.8 and in the latter 0.5. Finally, digitoxin and salicylate were found to compete for a common high-affinity binding site. The present findings support the proposal of four separate primary binding sites for warfarin, digitoxin (and salicylate), diazepam and Phenol Red. An attempt to correlate this partial binding model for serum albumin with other models in the literature is made.

Binding Sites↗
PubMed1998

Bidirectional (positive/negative) interference in a digoxin immunoassay: importance of antibody specificity.

The importance of high specificity in immunoassays used in therapeutic monitoring is highlighted by a case study in which therapeutic-to-toxic borderline digoxin levels were measured by a digoxin immunoassay in the serum sample from a patient administered digitoxin rather than digoxin. The sample, mistakenly sent to the laboratory for digoxin analysis, gave discordant results in three digoxin immunoassays: 1.99 and 0.79 ng/ml in assays using polyclonal antibodies (fluorescence-polarization immunoassay and microparticle enzyme immunoassay, respectively), and <0.1 ng/ml in a chemiluminescent immunoassay using more specific monoclonal antibody. The presence of digitoxin (approximately 40 ng/ml) in the sample was confirmed by three different digitoxin immunoassays. Based on these results, the interference of different levels of digitoxin was studied in the presence of 0, 0.85, 1.9, and 4.7 ng/ml digoxin in all three digoxin assays. The chemiluminescent assay showed no significant interference. The fluorescence-polarization immunoassay showed positive interference in all cases; however, the microparticle enzyme immunoassay showed a bidirectional interference: a positive interference observed at digoxin level <1.8 ng/ml, changing to a negative interference at higher digoxin concentrations. The authors conclude that in countries such as Germany, where both digoxin and digitoxin may be prescribed, caution should be used to interpret digoxin immunoassay results. Digoxin assays, with cross-reactivity to digitoxin <0.1% should be used.

Antibody Specificity↗
PubMed2005

Inhibiting biosynthesis and/or metabolism of progestins in the ventral tegmental area attenuates lordosis of rats in behavioural oestrus.

In the ventral tegmental area (VTA), lordosis of rats is facilitated by 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). Central 3alpha,5alpha-THP results from metabolism of peripheral progesterone, from the ovaries and/or adrenals, by sequential enzymatic activity of 5alpha-reductase and 3alpha-hydroxysteroid oxidoreductase (3alpha-HSOR). In addition, in glial cells, cholesterol is converted into pregnenolone by the P450 side-chain cleavage enzyme (P450scc), which is then metabolized to progesterone by 3beta-hydroxysteroid dehydrogenase, and subsequently reduced to 3alpha,5alpha-THP. We hypothesize that, in the VTA, formation of 3alpha,5alpha-THP by both metabolism and biosynthesis is necessary for facilitation of lordosis of female rats. In Experiment 1, naturally-receptive rats received bilateral VTA infusions of a P450scc inhibitor, digitoxin (1 microg/side); a 5alpha-reductase inhibitor, finasteride (10 microg/side); digitoxin (1 microg/side)+finasteride (10 microg/side); or vehicle and were tested 3 h later for lordosis. In Experiment 2, the effects of VTA infusions of digitoxin, finasteride, digitoxin+finasteride, or vehicle on lordosis and midbrain and plasma 3alpha,5alpha-THP levels were examined. In Experiment 3, we investigated whether infusions of 3alpha,5alpha-THP to the VTA reinstated lordosis and midbrain 3alpha,5alpha-THP levels following administration of inhibitors. VTA infusions of digitoxin, finasteride, or digitoxin+finasteride, significantly and similarly reduced lordosis and midbrain, but not plasma 3alpha,5alpha-THP levels, compared to vehicle. Following receipt of inhibitor infusions, 3alpha,5alpha-THP to the VTA restored lordosis and midbrain 3alpha,5alpha-THP levels. These data suggest that, in the VTA, both central biosynthesis of progesterone and metabolism of progesterone (from central and/or peripheral sources) to 3alpha,5alpha-THP are important for mediating lordosis of rats.

Animals↗
PubMed1971

Metabolism of cardiac glycosides studied in the isolated perfused guinea-pig liver.

1. Metabolic degradation of tritiated ouabain, digoxin, and digitoxin has been investigated quantitatively using the isolated perfused guinea-pig liver. The cardiac glycosides and their metabolites have been extracted from the plasma, liver, and bile by different solvents and identified as far as possible by radio-chromatographic analysis.2. The total metabolic activity in the experimental system was localized in the liver.3. The hydrophilic glycoside ouabain could not penetrate into the metabolically active compartment of the liver and was, therefore, not degraded. The more lipophilic compound digitoxin, however, was completely degraded due to its high affinity for the metabolically active sites. The unchanged digitoxin cannot enter the aqueous bile fluid in contrast to its more hydrophilic metabolites.4. The only detectable metabolic degradation of digoxin was a conjugation with glucuronic and/or sulphuric acid, but a cleavage of sugar molecules seemed not to occur.5. In the case of digitoxin the metabolic processes are more complicated: sugar cleavage, conjugation, and C-12 hydroxylation take place simultaneously. An immediate hydroxylation of digitoxin leading to digoxin was not observed. After administration of digitoxin conjugation products as well as digoxigenin-bis-and digoxigenin-mono-digitoxosides were present in each of the compartments investigated, but the digitoxosides of digitoxigenin were intermediates in concentrations too low to be determined indicating a very high rate of conjugation and/or C-12 hydroxylation as compared with the cleavage of the digitoxoses.6. A scheme for the metabolic pathways of the cardiac glycosides based on experimental results is presented. The metabolic behaviour of each of the three compounds involved is closely related to their physicochemical properties, especially the lipid solubility.

Animals↗
PubMed1978

Interaction of digitalis and spironolactone with human sex steroid receptors.

Spironolactone and digitoxin have previously been shown to interact with cytosol androgen and estrogen receptors, respectively, in the rat. The interaction of digitoxin with human uterine cytosol estrogen binding protein and spironolactone with human prostate and newborn prepuce cytosol dihydrotestosterone (DHT) binding protein has been analyzed in this study. Specific estradiol binding was found only in premenopausal uteri. The dissociation constant for estradiol binding was 0.6--2.3 X 10(-9) M (n - 12). Digitoxin in concentrations varying between 0.5--2.0 X 10(-6) M inhibited specific estradiol binding with a Ki of 2.0--7.3 X 10(-7) M (n = 9). The dissociation constants for DHT and the human androgen cytosol binding protein in prostate and newborn prepuce were 0.27--3.0 X 10(-8) M (n = 12) and 0.6--2.0 X 10(-8) M (n = 5), respectively. Spironolactone at concentrations of 0.3--2.0 X 10(-6) M competitively inhibited this binding with an affinity about one order of magnitude less than that of DHT. Digitoxin and spironolactone did not displace estradiol and DHT, respectively, from testosterone-estrogen binding globulin in male or female plasma. The interaction of digitoxin with the human uterus estrogen binding protein and spironolactone with the human prostate and prepuce androgen binding protein is similar to our previous observations in the rat, and may explain the weak estrogenic effects of digitoxin and spironolactone in man.

Binding, Competitive↗
PubMed1990

Ocular digitalis effects in normal subjects.

Several visual functions were examined before and during self-application of therapeutic doses of digitoxin. The ERG recordings showed a reduction of the critical flicker fusion frequency from 70 Hz to 35-40 Hz. Recovery of color vision after macular photostress was examined with Nagel's anomaloscope and Jaeger's tritanomaloscope. After digitoxin intake the matching range at the tritanomaloscope was enlarged. Following macular photostress the recovery time of both the Rayleigh and the Trendelenburg matches was significantly prolonged. The mesoptometer readings did not show any changes during the application of digitalis. This demonstrates that the process of neural adaptation is intact during digitoxin therapy. The error score in the Lanthony desaturated 15 panel test was slightly increased after digitalis application. The Farnsworth-Munsell 100-hue test showed a marked increase in the total error score. There were no changes in the standard panel D-15. The Ishihara pseudoisochromatic plates were read without mistakes after digitalis medication. The chromatic visual acuity for red-green and blue was examined by recording the maximum reading distance for the Velhagen pseudoisochromatic plates "65" (Jaeger's test) and "49". For both plates the reading distance was reduced by 50% during digitoxin therapy. Computerized perimetry by colored stimuli (Tübingen Automatic Perimeter by Aulhorn and Durst) did not reveal any definitive changes in sensitivity thresholds with therapeutic serum levels of digitalis. Spectral increment sensitivity for the isolated blue cone system (Wald-Marré approach) was not influenced by therapeutic doses of digitoxin. Topical digitoxin application (0.02 mg/10 ml) did not interfere with the pupillary light reflex (infrared pupillography) or with the accommodative amplitude or intraocular pressure. It did, however, result in toxic keratopathy with swelling of endothelial cells and edema of the corneal stroma and epithelium. All changes disappeared after withdrawal of digitalis.

Accommodation, Ocular↗
PubMed2002

Modifying specificity of antidigoxin antibodies using insertional mutagenesis.

Certain antibodies (Abs) elicited using the cardiac glycoside digoxin (digoxigenin tridigitoxoside) bind preferentially to analogs that differ from digoxin by substitutions on the cardenolide rings, the lactone, or by the presence or absence of attached sugars. Antibody 26-10 binds equally well to digoxin and digitoxin, which differ only by the presence in the former and the absence in the latter of an hydroxyl group at C12. Other antidigoxin Abs, however, can distinguish between these ligands by three orders of magnitude in binding. Inspection of the structure of Fab 26-10 complexed with digoxin shows a gap in complementarity in the region between the digoxin O12 and LCDR3. We proposed that insertions in LCDR3 might result in Abs that bind digitoxin preferentially. We produced libraries of mutants displayed on bacteriophage which were randomized at LCDR3 and contained LCDR3 insertions. Mutants were selected by panning against digoxin and analogs. The mutants bound digitoxin preferentially up to 47-fold greater than digoxin. The mutants that bound well to digitoxin demonstrated a consensus sequence including the substitution of Trp at position L:94. Using site-directed mutagenesis, the binding to digitoxin was shown to be maximized by the combination of an insertion and L:Trp94 mutation, moving the L 94 side chain closer to digoxin. We also selected mutants that bound preferentially to gitoxin, which, like digitoxin, lacks the 12-hydroxyl, increasing relative binding to gitoxin up to 600-fold compared to the unmutated Ab 26-10.

Amino Acid Sequence↗
PubMed1986

[The mode of cardiac action of cardiotonic steroids isolated from Toad Cake in perfused working guinea-pig heart and effect of cinobufagin on experimental heart failure].

The effects of bufadienolides (bufalin, bufotalin, cinobufagin, cinobufotalin, gamabufotalin and resibufogenin) isolated from Toad Cake was compared to that of cardenolides (digitoxin and ouabain) on cardiac function in a guinea-pig working heart preparation. All the steroids showed the cardiotonic effect in a concentration-dependent manner, and the minimum threshold concentration was 10(-8) M for bufalin, cinobufagin, gamabufotalin and digitoxin and 10(-7) M for bufotalin, cinobufotalin and ouabain. In addition, the order of maximum efficacy of cardiotonic action was as follows: cinobufagin (3 X 10(-7) M) = ouabain (3 X 10(-7) M) greater than digitoxin (1 X 10(-7) M) = gamabufotalin (3 X 10(-7) M) greater than cinobufotalin (3 X 10(-7) M) greater than bufotalin (1 X 10(-7) M). The effect of cinobufagin was examined on experimentally induced heart failure caused by acute local ischemia through ligation of the left anterior descending coronary artery in perfused guinea-pig heart. Cinobufagin (3 X 10(-7) M) and digitoxin (1 X 10(-7) M) reestablished the coronary flow of perfused guinea-pig heart to 90% and 98% of the level prior to the coronary artery ligation. The cardiac output and left ventricular pressure of perfused heart were increased to the level prior to the acute local ischemia, and the left ventricular work was increased by cinobufagin (3 X 10(-7) M) and digitoxin (1 X 10(-7) M) to 108% and 106%, respectively, of the pre-ligation level. These results indicate that cinobufagin possesses strong cardiotonic action, similar, to digitoxin, in experimentally induced heart failure due to acute local ischemia.

Animals↗
PubMed1980

Digitalis glycosides in serum, urine, and cerebrospinal fluid, determined with a commercial radioimmunoassay.

We evaluated a commercial (Clinical Assays, Inc.) 125I radioimmunoassay for digitoxin for use in measuring cardiac glycosides in serum, buffer, urine, and cerebrospinal-fluid samples. We also assessed interference of seven cardioactive metabolites of digitoxin, including digoxin, with the assay. The precision of the assay was adequate for all matrixes studied for glycoside concentrations less than 5 microgram/L. Reactivity in the assay was dependent on the nature of the matrix: buffer and serum samples containing digitoxin showed a stronger reactivity than did samples of urine and cerebrospinal fluid. Patients' samples must therefore be analyzed with a standard curve prepared by use of the same matrix. The digitoxosides of digitoxin showed a slightly higher reactivity in the assay than did digitoxin itself, but digitoxigenin showed a 50% lesser reactivity. Digoxin, its digitoxosides, and digoxigenin hardly react at all in the assay and so do not interfere with digitoxin determinations.

Animals↗
PubMed2002

Do cardiac glycosides affect platelet function? A flow cytometric study in healthy volunteers.

OBJECTIVE: Cardiac glycosides exert their inotropic effect by increasing intracellular calcium. Increased intracellular calcium is a key event in platelet aggregation. In aggregometer studies, digitalis has been found to augment platelet agonist responses. A prothrombotic effect of digitalis might be concealed since heart failure and atrial fibrillation per se predispose to thromboembolism. The present study investigates the effects of digitoxin on platelet function in healthy volunteers. METHODS: Twenty healthy, non-smoking volunteers were randomised to receive digitoxin ( n = 10, 0.6 mg day 1, 0.4 mg day 2, then 0.1 mg daily) or placebo ( n = 10) for 10 days. Platelet function was then analysed ex vivo using three-colour whole-blood-flow cytometry, both in non-stimulated mode and after agonist stimulation with 0.1 micromol/l adenosine diphosphate (ADP), 10 micromol/l ADP and 5.0 micromol/l epinephrine (final concentrations). Expression of activated fibrinogen receptor, von Willebrand's factor receptor and P-selectin, formation of platelet-platelet and platelet-leukocyte aggregates and particle size were examined. RESULTS: No significant difference between the placebo and the digitoxin group (digitoxin levels 17-42 nmol/l) was found, neither on a global level nor for any isolated parameter. CONCLUSIONS: Theory and in vitro data suggest that digitoxin treatment could activate platelets. No evidence for this was found in healthy volunteers. This observation is strengthened by the unequivocal results for all parameters measured. However, thrombosis-prone patients with heart failure and/or atrial fibrillation may respond differently to digitalis therapy.

Adult↗
PubMed1983

Binding of dihydrodigitoxin to beef and human cardiac (Na+ + K+)-ATPase: evidence for two binding sites in cell membranes.

The specific binding of three cardiac glycosides, 3H-ouabain, 3H-digitoxin and 3H-dihydrodigitoxin, to beef cardiac (Na+ + K+)-ATPase was compared. Non-specific binding was defined as that in the presence of 0.1 mM unlabelled compound, or in the absence of ligands. The dissociation constants (KD-values) calculated from the inhibition of 3H-ouabain binding were: ouabain, 2.9 X 10(-9)M; digitoxin, 1.1 X 10(-9)M; and dihydrodigitoxin 2.7 X 10(-8)M. The concentrations which inhibited beef cardiac (Na+ + K+)-ATPase by 50% were: ouabain, 5.9 X 10(-9)M; digitoxin, 1.6 X 10(-9)M; and dihydrodigitoxin, 2.5 X 10(-8)M. Ouabain and digitoxin showed straight Scatchard plots for one site of high affinity (ouabain, KD = 2.6 X 10(-9)M; digitoxin, KD = 1.7 X 10(-9)M). However, dihydrodigitoxin gave a curved Scatchard plot. Analysis of this binding by the methods of M. J. Weidemann, H. Erdelt and M. Klingenberger (Eur. J. Biochem. 16, 313 (1970) for two binding sites gave the following results: for Mg2+,Pi-supported binding, the KD of the high affinity site was 1.6 X 10(-8)M with a capacity similar to that for ouabain of about 30 pmole/mg protein. For binding supported by Na+,ATP,Mg2+, the KD-value of the high affinity site was 5.3 X 10(-8)M of similar capacity. The low affinity binding site (KD = 4.0 X 10(-6)M for Mg2+,Pi; KD = 5.5 X 10(-6)M for Na+,ATP,Mg2+) bound about 350 pmole/mg protein. The low affinity site but not the high affinity site was also present in heat-denatured enzyme. Binding supported by Mg2+,Pi showed one low affinity site only for ouabain and dihydrodigitoxin in the presence of 200 mM Na+. The high affinity sites for these three cardiac glycosides were further characterized by measurement of the association and dissociation rate constants. The specific binding of 3H-ouabain and 3H-dihydrodigitoxin to human cardiac (Na+ + K+)-ATPase was measured. 3H-Ouabain showed a straight Scatchard plot for one high affinity site only (KD = 4.5 X 10(-9) M, capacity about 15 pmole/mg protein). 3H-Dihydrodigitoxin gave two binding sites: a high affinity site (KD = 1.8 X 10(-8) M) of similar capacity to ouabain, and a low affinity site (KD = 2.0 X 10(-6) M) of about 10-fold greater capacity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗