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PubMed1996

Gitaloxin poisoning in a child.

Gitaloxin is a digitalis glycoside used for the same indications as digoxin and digitoxin. The successful outcome for a 2 1/2-year-old boy who accidentally ingested 3 mg of gitaloxin (100 times the normal therapeutic dose) is reported. At admission the child presented with irregular heart rhythm. He subsequently started vomiting, even after continuous gastric feeding. Only 48 h after ingestion of gitaloxin he became somnolent and developed bradyarrhythmia. The symptoms disappeared 96 h later; the bradyarrhythmia, however, (second-degree atrioventricular block) decreased progressively only after 120 h. The initial clinical presentation of gitaloxin poisoning may be misleading and careful observation in a pediatric intensive care unit is mandatory. A cross-reaction between the fluorescence polarization immunoassay for digitoxin and the radioimmunoassay for gitaloxin was found and was used as a helpful, but rough, estimate of the severity of gitaloxin poisoning, in the absence of a specific measurement of gitaloxin.

Bradycardia↗

PubMed1990

Changes in histamine secretion from mast cells caused by digitalis glycosides.

Cardiotonic glycosides modify histamine secretion from rat mast cells in the following way. (1) Preincubation (30 min) of mast cells with liposoluble glycosides (10(-4) mol/l) increases the spontaneous histamine secretion by about 5%. (2) Preincubation of mast cells with 10(-4) mol/l liposoluble glycosides (digitoxin, digoxin, digitoxigenine) decreases histamine release induced by compound 48/80 in the presence of calcium, whereas the water soluble glycoside, strophanthin G, has no effect on the secretion. (3) Preincubation of mast cells in a calcium-free medium with the glycosides (10(-4) mol/l) has a dual-effect on histamine secretion induced by compound 48/80: water soluble glycosides (strophanthin G and K) potentiate histamine release, whereas the liposoluble glycosides (digitoxin, digitoxigenine) decrease the secretory response. The difference in the activity of different glycosides could be explained by their dual effects, namely an inhibition of Na+K(+)-ATPase which leads to an increase in histamine release, and intracellular action(s) of liposoluble glycosides leading to a decrease of histamine secretion.

Animals↗

PubMed1985

Transport functions of the liver. Lack of correlation between hepatocellular ouabain uptake and binding to (Na+ + K+)-ATPase.

Ouabain uptake was studied on isolated rat hepatocytes. Hepatocellular uptake of the glycoside is saturable (Km = 348 mumol/l, Vmax = 1.4 nmol/mg cell protein per min), energy dependent and accumulative. Concentrative ouabain uptake is not present on permeable hepatocytes, Ehrlich ascites tumor cells and AS-30D ascites hepatoma cells. There is no correlation between ouabain binding to rat liver (Na+ + K+)ATPase and ouabain uptake into isolated rat hepatocytes. While ouabain uptake is competitively inhibited by cevadine, binding to (Na+ + K+)-ATPase is not affected by the alkaloid. Although the affinities of digitoxin and ouabain to (Na+ + K+)-ATPase are similar, digitoxin is 10000-times more potent in inhibiting [3H]ouabain uptake as compared to ouabain. That binding to (Na+ + K+)-ATPase appears to be no precondition for ouabain uptake was also found in experiments with plasmamembranes derived from Ehrlich ascites tumor cells and AS-30D hepatoma cells. While tumor cell (Na+ + K+)-ATPase is ouabain sensitive, the intact cells are transport deficient. Hepatic ouabain uptake might be related to bile acid transport. Several inhibitors of the bile acid uptake system also inhibit ouabain uptake.

Animals↗

PubMed1987

Studies on the pregnenolone-16 alpha-carbonitrile-inducible form of rat liver microsomal cytochrome P-450 and UDP-glucuronosyltransferase.

Treatment of rats with pregnenolone-16 alpha-carbonitrile (PCN) markedly induces rat liver microsomal cytochrome P-450p and UDP-GT-dt1, a glucuronosyltransferase active towards the digitoxin metabolite, digitoxigenin monodigitoxoside. The present study characterizes the regulation of these two enzymes in rats treated with different xenobiotics. Like PCN, treatment of rats with dexamethasone, spironolactone, troleandomycin or erythromycin estolate markedly induced both UDP-GT-dt1 and cytochrome P-450p (measured as erythromycin demethylase and testosterone 2 beta-, 6 beta-, 15 beta-, and 18-hydroxylase activities). However, compared to PCN and dexamethasone, both troleandomycin and erythromycin estolate preferentially induced cytochrome P-450p, whereas spironolactone preferentially induced UDP-GT-dt1. Treatment of rats with the polychlorinated biphenyl mixture, Aroclor 1254, increased both cytochrome P-450p and UDP-GT-dt1 activity to about 40% of that in liver microsomes from rats induced with PCN or dexamethasone. Treatment of rats with phenobarbital or chlordane caused a relatively small increase in cytochrome P-450p and UDP-GT-dt1 activity. Neither enzyme was induced by treatment of rats with 3-methylcholanthrene, rifampin or digitoxin. The induction of cytochrome P-450p and UDP-GT-dt1 by PCN followed similar dose-response curves. Although cytochrome P-450p and UDP-GT-dt1 are differentially affected by the age and the sex of rats, the enzymes responded similarly, but not identically, to xenobiotic treatment. This suggests that cytochrome P-450p and UDP-GT-dt1 are co-inducible but not coordinately regulated.

Animals↗

PubMed1991

Digitalis: is there a future for this classical ethnopharmacological remedy?

Withering's (1741-1799) greatest merit is not so much that of having discovered the therapeutic value of foxglove in hydropsy, since this indication (among others) was already part of traditional medicine, but actually during a decade of carefully recording clinical observations, he authoritatively settled definite guidelines for its use. In spite of its further utilization in many additional illnesses such as madness, foxglove, and later its main heteroside digitoxine, progressively reached their eventual place in the treatment of supraventricular arrhythmias and in congestive heart failure. In the latter indication, however, its value is now being questioned; it is being accused of augmenting myocardial work due to its vasoconstrictor properties, of favoring dysrhythmic events in a disease already burdened with a 50% arrhythmia mortality, and actually of having a low therapeutic index. Even though being discarded by a number of cardiologists, digitoxine still remains in the appraisal of others as an indispensable medicine.

Digitalis↗

PubMed1989

Evidence for the existence of the same endogenous digitalis-like factor in several mammalian species.

1. Endogenous digitalis-like activity was studied comparatively in four mammalian species: guinea pig, dog, cow and rat. 2. Water extracts were prepared from guinea pig, dog, cow and rat hearts and assayed by ouabain radioreceptorassay, digoxin radioimmunoassay and digitoxin radioimmunoassay. Extracts were further analysed by fractionation by gel permeation chromatography with Sephadex G-25. 3. A similar behaviour was observed with the four species in the three assays. Extracts displaced tritiated ouabain binding to its receptor and labeled digoxin analogue binding to antidigoxin antibodies in a competitive manner. Displacement of labeled digitoxin analogue to antidigitoxin antibodies did not follow Michaelis-Menten kinetics. IC50 ratios between assays were similar for the four species studied. 4. Extracts from the four species exhibited a similar pattern when fractionated with Sephadex G-25. Endogenous digoxin-like immunoreactivity eluted after the salts, suggesting that the active material is of a molecular weight of less than 1000. 5. Results suggest that a similar endogenous factor endowed with digitalis-like characteristics is present in all mammalian species.

Animals↗

PubMed1992

Characterization of ouabain high-affinity binding to rat cerebral cortex. Modulation by melatonin.

High-affinity [3H]ouabain binding to membrane preparations of rat cerebral cortex was examined using a rapid filtration procedure. At 37 degrees C, binding reached equilibrium in about 60 min. Scatchard analyses of the data at equilibrium revealed a single population of binding sites with a dissociation constant of KD = 3.1 +/- 0.36 nM and a binding site concentration of Bmax = 246.4 +/- 18.4 fmol/mg protein. Kinetic analyses of the association and dissociation curves indicated a kinetic KD = 4.6 nM, which is in good agreement with the value obtained at equilibrium. When various digitalis compounds were tested for their ability to inhibit [3H]ouabain binding, the following Ki values (nM) were obtained: ouabain (3.9); digoxin (18); acetyl-digitoxin (66); k-strophanthin (95); digitoxin (236). When melatonin was added to the incubation medium, the ability of ouabain to inhibit [3H]ouabain binding increased in a dose-related manner to yield the following Ki values (nM): melatonin 10 nM (2); melatonin 20 nM (1.2); melatonin 40 nM (0.8). These data suggest the existence in the rat cerebral cortex of high-affinity ouabain binding sites which may be a locus for the molecular action of melatonin.

Animals↗

PubMed2004

Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography.

High-performance affinity chromatography was used to study the binding of phenytoin to an immobilized human serum albumin (HSA) column. This was accomplished through frontal analysis and competitive binding zonal elution experiments, the latter of which used four probe compounds for the major and minor binding sites of HSA injected into the presence of mobile phases containing known concentrations of phenytoin. It was found that phenytoin can interact with HSA at the warfarin-azapropazone, indole-benzodiazepine, tamoxifen, and digitoxin sites of this protein. The association constants for phenytoin at the indole-benzodiazepine and digitoxin sites were determined to be 1.04 (+/-0.05) x 10(4)M(-1) and 6.5 (+/-0.6) x 10(3)M(-1), respectively, at pH 7.4 and 37 degrees C. Both allosteric interactions and direct binding for phenytoin appear to take place at the warfarin-azapropazone and tamoxifen sites. This rather complex binding system indicates the importance of identifying the binding regions on HSA for specific drugs as a means for understanding the transport of such substances in blood and in characterizing their potential for drug-drug interactions.

Anticonvulsants↗

PubMed2004

Generalization of a habituated feeding deterrent response to unrelated antifeedants following prolonged exposure in a generalist herbivore, Trichoplusia ni.

The possibility of generalization of habituated response to unrelated feeding deterrents following prolonged exposure was examined in third instar Trichoplusia ni (Lepidoptera: Noctuidae) larvae by rearing them on antifeedants and then testing with other unrelated antifeedants. We introduced neonate larvae (< 24-hr old) onto cabbage leaves treated with crude seed extracts of Melia volkensii (Meliaceae) or oil of Origanum vulgare ("oregano") (Lamiaceae) and allowed them to feed until early in the third instar. Naive larvae were reared on cabbage leaves treated with carrier solvent alone. Both experienced and naïve larvae were tested for feeding deterrent response with the same and the different extracts in a leaf disc choice bioassay. Habituation was generalized to both M. volkensii and oregano following prolonged exposure to either plant extract and also to a pure allelochemical, thymol, following prolonged exposure to either digitoxin or xanthotoxin. However, there was no generalization of the habituated response to oregano following prolonged exposure to digitoxin or thymol, or to thymol or xanthotoxin following prolonged exposure to oregano or M. volkensii. Our results demonstrate that habituated response to feeding deterrents in a polyphagous insect herbivore can be generalized among and between plant extracts and pure allelochemicals, but not in all situations. The implications of such behavioral plasticity in herbivorous insects for the use of antifeedants as crop protectants or for host plant shifts is discussed.

Animals↗

PubMed2001

Pressor and vascular effects of cardiac glycosides.

BACKGROUND: For the past two decades, it has generally been accepted ('Blaustein hypothesis') that cardiac glycosides such as ouabain and digoxin increase the sodium and calcium content of smooth muscle cells, so inducing arterial vasoconstriction and a rise in blood pressure. Recent data from an experimental study we carried out led us to question this assumption. DESIGN: A retrospective literature survey covering 20 years and including animal and human studies was performed. Representative results are presented. RESULTS: Contradictory effects of cardiac glycosides on blood pressure and vasculature have been described. Increased, decreased or unaltered blood-pressure values have been observed following administration of the glycosides ouabain, digoxin and digitoxin. Moreover, vasoconstricting as well as vasodilating effects of cardiac glycosides have been demonstrated. Several recent studies show that cardiac glycosides such as digoxin and digitoxin can lead to a reduction of at least diastolic blood pressure. CONCLUSION: A slight vasodilation of resistance vessels followed by a fall in diastolic blood pressure could be a contributing factor for the beneficial effects of cardiac glycosides in patients with congestive heart failure. This vasodilation may be caused by central (neurohumoral) effects of digitalis glycosides.

Animals↗

PubMed1990

Batch Cultures of Somatic Embryos of Digitalis lanata in Gaslift Fermenters. Development and Cardenolide Accumulation.

Somatic embryos of DIGITALIS LANATA STRAIN VII were successfully grown as batch cultures in gaslift fermenters. Embryo development and formation of cardenolides in the embryos resembled those of cultures grown in shake flasks. Both processes depended on the developmental stage of the embryos at the time point of inoculation, the homogeneity of the embryo structures, the density of the inoculum, the composition of the nutrient medium, the intensity of irradiation, and the composition of the gas mixtures used for agitation of the embryo suspension. The cultures contained 0.7&-1.0 (micro,mol digitoxin equivalents g (-1) dry wt. (2.6-6.5 micromol digitoxin equivalents l (-1)) after a cultivation period of 28 d.

Journal Article↗

PubMed1990

Cardenolides in Digitalis lanata Cells Transformed with Ti-Plasmids.

Crown galls were induced by transformation of leaves, leaf discs, and shoots of the plant DIGITALIS LANATA with the AGROBACTERIUM TUMEFACIENS strains C58 pTi C58, B6S3 pTi B6S3, and A136 pTi A6NCtmr-338::Tn5. Integration of plasmid DNA in the genome of D. LANATA was demonstrated by hybridization experiments. The transformed cells synthesized opines and showed hormone-autotrophic growth. The crown galls formed on leaves of D. LANATA plants contained digitoxigenin derivatives (up to 0.8 muimol digitoxin equivalents g (-1) dry weight). Transformed cell lines derived from the crown galls built cardenolides IN VITRO (ca. 0.03 mumol digitoxin equivalents g (-1) dry weight). The rate of cardenolide biosynthesis IN VITRO did not decrease during a cultivation period of 12 months.

Journal Article↗

PubMed1992

[The coincidence of rapidly progressing dilated cardiomyopathy and primary hyperparathyroidism. The course before and after the removal of a parathyroid adenoma].

Severe cardiac arrhythmias (Lown class IVa), rapid loss of physical capacity and dyspnoea on the slightest exertion occurred in a 55-year-old man with idiopathic dilated cardiomyopathy. In the preceding year he had recurrent diarrhoea and lost 23 kg in weight. He was found to have hypercalcaemia (3-3.2 mmol/l). The heart failure significantly improved under treatment with twice daily 12.5 mg captopril, 100 mg spironolactone daily, furosemide 40 mg twice daily, and digitoxin 0.07 mg daily. The arrhythmia responded to verapamil 80 mg and quinidine 160 mg, both drugs three times daily. Primary hyperparathyroidism was found to be the cause of the hypercalcaemia (parathormone 84 pmol/l). After the parathyroid adenoma had been removed the patient's condition again improved markedly. There were only rare monotopic extrasystoles, cardiac size regressed, and diuretics were no longer necessary. His medication at present is verapamil (80 mg three times daily), captopril (12.5 mg three times daily) and digitoxin (0.07 mg daily). It is concluded that the hypercalcaemia influenced the severity of the cardiomyopathy. It would seem that both intra- and extracellular calcium homoeostasis is of great importance in dilated cardiomyopathy.

Adenoma↗

PubMed2003

Cardioactive steroid poisoning from an herbal cleansing preparation.

We describe a case of unintentional poisoning from a cardioactive steroid and the subsequent analytic investigation. A 36-year-old woman with no past medical history and taking no conventional medications ingested an herbal preparation marketed for "internal cleansing." Its ingredients were neither known to the patient nor listed on the accompanying literature. The next morning, nausea, vomiting, and weakness developed. In the emergency department, her blood pressure was 110/60 mm Hg, and her pulse rate was 30 beats/min. Her ECG revealed a junctional rhythm at a rate of 30 beats/min and a digitalis effect on the ST segments. After empiric therapy with 10 vials of digoxin-specific Fab (Digibind), her symptoms resolved, and she reverted to a sinus rhythm at a rate of 68 beats/min. Her serum digoxin concentration measured by means of the fluorescence polarization immunoassay (Abbott TDx) was 1.7 ng/mL. Further serum analysis with the Tina Quant digoxin assay, a more digoxin-specific immunoassay, found a concentration of 0.34 ng/mL, and an enzyme immunoassay for digitoxin revealed a concentration of 20 ng/mL (therapeutic range 10 to 30 ng/mL). Serum analysis by means of high-performance liquid chromatography revealed the presence of active digitoxin metabolites; the parent compound was not present. When the diagnosis of cardioactive steroid poisoning is suspected clinically, laboratory analysis can confirm the presence of cardioactive steroids by using immunoassays of varying specificity. An empiric dose of 10 vials of digoxin-specific Fab might be beneficial in patients poisoned with an unknown cardioactive steroid.

Adult↗

PubMed1988

Variable region framework differences result in decreased or increased affinity of variant anti-digoxin antibodies.

Rare spontaneous variants of the anti-digoxin antibody-producing hybridoma 40-150 (Ko = 5.4 x 10(9) M-1) were selected for altered antigen binding by two-color fluorescence-activated cell sorting. The parent antibody binds digoxin 890-fold greater than digitoxin. The variant 40-150 A2.4 has reduced affinity for digoxin (Ko = 9.2 x 10(6) M-1) and binds digoxin 33-fold greater than digitoxin. A second-order variant, derived from 40-150 A2.4 (designated 40-150 A2.4 P.10), demonstrated partial regain of digoxin binding (Ko = 4.4 x 10(8) M-1). The altered binding of the variant 40-150 A2.4 was accounted for by a point mutation resulting in substitution of arginine for serine at position 94 in the heavy chain variable region. Antibody 40-150 A2.4 P.10 also contains this arginine but owes its enhanced antigen binding to deletion of two amino acids from the heavy chain amino terminus. This unusual sequence alteration in an immunoglobulin framework region confers increased affinity for antigen.

Amino Acid Sequence↗

PubMed2003

Endogenous glycosides in critically ill patients.

OBJECTIVE: To determine the incidence of critically ill patients displaying endogenous digitalis-like-immunoreactive substances (DLIS) and to examine the relationship of these hormones to routine laboratory variables, the underlying disease, myocardial function, hemodynamic status, severity of illness, systemic inflammation, and mortality rate. DESIGN: Sera of 401 consecutive critically ill patients, not treated with cardiac glycosides, were analyzed for DLIS (digitoxin and digoxin, TDx; Abbott Diagnostics, North Chicago, IL) and endogenous ouabain. Normal values of endogenous ouabain were determined in 62 healthy volunteers. We measured pro- and anti-inflammatory mediators (L-selectin, tumor necrosis factor-alpha, interleukin-1beta, interleukin-2, interleukin-6, interleukin-10), C-reactive protein, and serum amyloid A protein as well as patients' Acute Physiology and Chronic Health Evaluation II and Goris scores. In a subgroup of patients with a pulmonary artery catheter (n = 95), we determined cardiac output, pulmonary artery occlusion pressure, systemic and pulmonary vascular resistance, left ventricular stroke volume, and right and left stroke work. SETTING: Two surgical intensive care units of an university hospital. SUBJECTS: Sera of 401 consecutive critically ill patients. INTERVENTIONS: Blood sampling. MEASUREMENTS AND MAIN RESULTS: Of the 401 patients tested, 343 had nonmeasurable DLIS concentrations (DLIS-negative), and 58 (14.5%) had positive digoxin (n = 18) or digitoxin (n = 34) concentrations (DLIS-positive) or were positive in both tests (n = 6). Mean endogenous ouabain concentrations were nine-fold increased in DLIS-positive (3.59 +/- 1.43 nmol/L) and three-fold increased in DLIS-negative (1.34 +/-.81 nmol/L) patients compared with controls (0.38 +/- 0.31 nmol/L). DLIS and ouabain concentrations closely correlated with the Acute Physiology and Chronic Health Evaluation II and Goris score and were associated with increased concentrations of transaminases, bilirubin, aldosterone, cortisol, serum creatinine, fractional sodium excretion, proinflammatory mediators, C-reactive protein, and serum amyloid A (p <or=.009). The hospital mortality rates of DLIS-positive and DLIS-negative patients were 12% and 3.2%, respectively, and for patients with ouabain concentrations above and below 2 nmol/L 38.6% and 0.6%, respectively. In DLIS-positive patients with pulmonary artery catheter (n = 23), cardiac output, stroke volume, and left ventricular stroke work were decreased, and pulmonary artery occlusion pressure and central venous pressure were increased (p <or=.009). CONCLUSIONS: Different types of endogenous glycosides including endogenous ouabain are elevated in a significant proportion of critically ill patients. The occurrence of these substances is associated with increased morbidity and hospital mortality rates, possibly due to systemic inflammatory processes. DLIS but not endogenous ouabain concentrations were found to be related to left ventricular function.

APACHE↗

PubMed1991

Pluripotent mouse embryonic stem cells are able to differentiate into cardiomyocytes expressing chronotropic responses to adrenergic and cholinergic agents and Ca2+ channel blockers.

A defined cultivation system was developed for the differentiation of pluripotent embryonic stem cells of the mouse into spontaneously beating cardiomyocytes, allowing investigations of chronotropic responses, as well as electrophysiological studies of different cardioactive drugs in vitro. The beta-adrenoceptor agonists (-)isoprenaline and clenbuterol, the mediators of cAMP metabolism, forskolin and isobutylmethylxanthine (IBMX), the alpha 1-adrenoceptor agonist (-)phenylephrine, and the heart glycoside digitoxin induced a positive, the muscarinic cholinoceptor agonist carbachol and L-type Ca2+ channel blockers nisoldipine, gallopamil and diltiazem induced a negative chronotropic response. In early differentiated cardiomyocytes beta 1-, alpha 1-, but not beta 2-adrenoceptors, cholinoceptors, as well as L-type Ca2+ channels participated in the chronotropic response. In terminally differentiated cardiomyocytes beta 2-adrenoceptors and digitoxin responses were also functionally expressed. The contractions of spontaneously beating cardiomyocytes were concomitant with rhythmic action potentials very similar to those described for embryonic cardiomyocytes and sinus-node cells. We conclude that cardiomyocytes differentiating from pluripotent embryonic stem cells are able to develop adrenoceptors and cholinoceptors and signal transduction pathways as well as L-type Ca2+ channels as a consequence of cell-cell interactions during embryoid body formation in vitro, independent of the development in living organisms. The cellular system described may be useful as in vitro assay for toxicological investigations of chronotropic drugs and a model system for studying commitment and cellular differentiation in vitro.

1-Methyl-3-isobutylxanthine↗

PubMed1987

How fast do cardioactive steroids act independently of diffusion in guinea-pig myocardium?

1 The rate of onset of the inotropic effect of different cardioactive steroids (in order of increasing potency: dihydroouabain, digoxigenin, digoxin, ouabain, digitoxin) was studied in guinea-pig papillary muscles stimulated at 0.5 Hz. For an estimate of diffusion rate the time to defined levels of effect was evaluated in relation to the diameter of cylindrical muscles. 2 The dependence of onset rates on muscle diameter was more pronounced with a highly potent steroid, e.g., digitoxin, than with a less potent compound, e.g., dihydroouabain; that is, the apparent rate of diffusion was inversely correlated with the inotropic potency. Reduction of the ratio of receptor to steroid concentration with increase of ouabain or K+ concentration enhanced the apparent rate of diffusion. 3 Extrapolation to negligibly short diffusion distance indicated that the effects of the various steroids develop faster in the absence of diffusion. The effect of 50 mumol l-1 of dihydroouabain appeared more quickly than with ouabain in the perfused heart. The time courses of the inotropic effect in perfused hearts and in papillary muscles of diameters less than 0.75 mm were superimposable, indicating that the onset of the dihydroouabain effect was not controlled by diffusion. 4 After the interference of diffusion had been excluded, the rates of onset of action correlated inversely with the inotropic potencies of the steroids. The dissociation rate of the drug-receptor complex appeared to be related to the different receptor affinities.

Animals↗