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PubMed1977

[Pharmacokinetics of cardiac glycosides and clinical consequences].

The purpose of pharmacokinetics of cardiac glycosides is to study the time courses of glycosides in biological fluids, tissues and excreta. The extent of accumulation of a given dose at uniform time intervals depends only from the overall elimination rate constant. By knowing the elimination rate constant the extent to which a cardiac glycoside would accumulate in the body following a fixed dosing regimen can be calculated. The higher accumulation in the central nervous system requires a much longer time. Therefore it may be assumed that the brain is a deep compartment for cardiac glycosides and this compartment cannot be detected by analysis of plasma glycoside concentrations. Central side effects of cardiac glycosides may occur at therapeutic plasma levels. In renal disease a lower maintenance dose of digoxin and methyldigoxin should be administered or the same dose less frequently. Digitoxin does not accumulate in patients with renal failure or in anuria since the extrarenal elimination of digitoxin is much higher compared to digoxin and methyldigoxin.

Biological Availability↗

PubMed1979

Cardenolide analogues: 10--characterization of cardiac glycosides by chemical ionization mass spectrometry.

The potential of chemical ionization mass spectrometry for the characterization of naturally occurring and semi-synthetic cardiac glycosides has been investigated. Methane, isobutane and ammonia were used as reactant gases. With the exception of ouabain, the ammonia chemical ionization mass spectra of the cardiac glycosides examined in this work contained abundant [M + NH4]+ions and abundant fragment ions formed by cleavage of glycoside bonds. Ammonia chemical ionization mass spectrometry was found to provide a rapid and sensitive method for the characterization of the products of glycosidation reactions. In contrast, the methane and isobutane chemical ionization mass spectra of the cardiac glycosides, with the exception of ouabain, did not contain protonated molecular ions and did not contain abundant fragment ions above m/z 400.

Ammonia↗

PubMed1977

Some pharmacological studies on the cardiotonic effects of furanosteroidal glycosides.

Cardiotonic effects and cardiotoxicities of three furanosteroidal glycosides were compared with those of standard cardiac glycosides (digitoxin, gitoxin, etc.). Furanosteroidal glycosides showed positive inotropic effects in both isolated guinea-pig atria and rabbit hearts. The positive inotropic effect of 17beta-(3-furyl)-5beta,14beta-androstane-3beta,14,16beta-triol-3-bisdigitoxoside(FGBD) corresponded to that of digitoxin in isolated guinea-pig atria and frog hearts. Intravenous and oral administration of FGBD and 17beta-(3-furyl)-5beta,14beta-androstane-3beta,14,16beta-triol-3-tridigitoxoside(FGTD) in higher doses induced cardiac arrest after vomiting, bradycardia, ventricular rhythm, and ventricular fibrillation in pigeons and cats. Comparison of lethal doses between intravenous and oral administration of cardiac glycosides in pigeons and cats suggested that gastrointestinal absorption of FGBD and FGTD is inferior to that of digitoxin but superior to that of gitoxigenin bisdigitoxoside and gitoxin. Cardiotonic effects of furanosteroidal glycosides were confirmed in isolated guinea-pig, rabbit and frog hearts.

Androstanes↗

PubMed1979

Investigation of cardiac glycoside levels in human post mortem blood and tissues determined by a special radioimmunoassay procedure.

Even after the introduction of radioimmunological methods the question of a cardiac glycoside causing or contributing to the death of a patient can not be answered satisfactorily. By means of a special radioimmunoassay procedure for digoxin as well as for the structurally related methyl- and acetylderivatives we measured the concentrations in human blood and post mortem tissues. We investigated the glycoside contents in the blood of intravenously digitalised (Novodigal) al) patients before and after death. At autopsy blood specimens were taken from the heart and the femoral vein. We found an increase of the glycoside level up to a highly toxic range (7--15 ng/ml) especially in the heart blood. Thus post mortem blood levels of digoxin and its derivatives are not suitable for a final decision in alleged cases of fatal poisonings. Measuring various concentrations in tussues and body fluids of the above cardiac glycosides mentioned revealed the kidney concentration to be of high value in confirming a digitalis poisoning. This organ and the heart show the highest tissue concentrations. Interpretations of fatal digitalis poisonings should be based on the additional knowlege of these concentrations. Individual cardiac glycosides may be analyzed by a combination of thin layer chromatography and radioimmunoassay.

Cardiac Glycosides↗

PubMedDate not supplied

Studies on a plasma cardiac glycoside assay based upon displacement of 3-H-ouabain from Na+-K+-ATPase.

We tested an assay system introduced for plasma glycoside measurements, basing on the displacement of 3-H-ouabain from Na+-K+-ATPase by unlabeled glycoside. ATPase preparations from hog, cat and guinea pig were used. Displacements were performed using 20 cardiac glycosides, genins and derivatives with different cardiac activity. Most of the glycosides and derivatives do not induce a continuous 3-H-ouabain displacement from the ATPase, but a very steep increase of unbound 3-H-ouabain between 10-minus 7 and 2 times 10-minus 7 M. Therefore this assay system shows a satisfactory discrimination only in a short concentration range. This behavior and a relatively low sensitivity make the ATPase displacement assay problematic for clinical and pharmacokinetical plasma glycoside measurements.

Adenosine Triphosphatases↗

PubMed1977

Studies on the production of daunomycinone-derived glycosides and related metabolites in Streptomyces coeruleorubidus and Streptomyces peucetius.

Strains of Streptomyces coeruleorubidus ISP 5145, JA 10092 and 39-146, differing mutually in antibiotic activity, were found to produce identical spectrum of metabolites (at least nine antibiotically active glycosides, 13-dihydrodaunomycinone, epsilon-rhodomycinone and a larger number of unidentified compounds); only trace quantities of daunomycin and daunomycinone could be detected. A fraction of glycosides with a higher RF (0.4-0.7), isolated from strain 39-146, could be transformed to daunomycin by mild hydrolysis and to daunomycinone by total hydrolysis. Streptomyces peucetius IMI 101 335 differed from Streptomyces coeruleorubidus in an increased production of epsilon-rhodomycinone and a lower content of glycosides; the zone of daunomycin was most pronounced among the glycoside spots. Streptomyces coeruleorubidus 39-146 exhibited the highest activity in a medium containing 3.5% soluble starch, 3.0% soybean meal, 0.3% NaCl and 0.3% CaCo3; glucose was a more useful carbon source for the remaining strains. The activity of Streptomyces coeruleoribidus was inhibited by 1-propanol, Na-propionate, 5,5-diethylbarbiturate and bacitracin. Ferrous sulphate stimulated the production of glycosides only in strain JA 10092, decreasing simultaneously the production of aglycones.

Chromatography, Thin Layer↗

PubMed1979

[Effect of triterpene glycosides on plasma membrane permeability for UV-absorbing substances in Saccharomyces carlsbergensis yeast cells].

The effect of triterpene glycosides of cauloside C from Caulophyllum robustum M, stichoposide A from Stichopus japonicus S. and theasaponine from Thea sinensis Z. on permeability of plasmic membranes of Saccharomyces carlsbergensis for UV-absorbing substances was studied. It was found that incorporation of 14C-uridine from the endocellular pool into the yeast acid-insoluble fraction decreased under the effect of the triterpene glycosides as a result of the precursor leakage from the cell into the medium. It was found that the triterpene glycosides stimulated the leakage of the UV-absorbing substances with an absorption maximum at 260 nm from the cells. The maximum membranotropic effect was observed at 30--40 degrees C and in the presence of monovalent potassium, sodium, ammonium and lithium ions in the medium. Cauloside C and theasaponine, pentacyclic glycosides had the highest effect on the permeability at pH 4.8--5.6, while stichoposide A, a tetracyclic glycoside, had the highest effect at pH 7.0.

Cell Membrane Permeability↗

PubMed1976

[Concentration of cardiac glycosides in the heart and brain (author's transl)].

In cats the concentration of cardio-active glycosides in the heart and brain were investigated with trititum-labelled substances. Steady-state conditions were achieved by repeated i.v. injections of ouabain, digoxin, beta-methyldigoxin, digitoxin, and oleandrin over 5 days. 5 h after the last application glycoside concentrations were measured in plasma, urine, heart, cerebrum and cerebellum. Furthermore the metabolic pattern in these compartments was determined. 1. The glycoside concentration in the heart per g wet weight ranges only from 0.93 (oleandrin) to 1.88% (ouabain) of the daily administered dose per kg. 2. The concentrations in the brain show much higher differences between the diverse glycosides: ouabain with a concentration of 0.02%/g wet weight in the cerebrum shows the lowest and oleandrin with 1.60% the highest value. 3. By calculating the mean relative weights for the hearts (3.9 g/kg) and the brains (11.1 g/kg) 3.7% of the daily administered ouabain activity were found in the whole heart and only 0.18% in the whole brain. In contrast to these data the content of heart and brain after giving the more lipophilic oleandrin was 3.6% and 17.7% (!), respectively. 4. Under steady-state conditions the glycosides ouabain, digoxin, beta-methyldigoxin and digitoxin in heart and brain are mainly unchanged whereas oleandrin is transformed at a higher rate to polar metabolites.

Animals↗

PubMed1977

[Determination of glycoside concentrations in human tissue by means of radioimmunoassay (author's transl)].

After extraction of myocardial and skeletal muscle biopsy and autopsy specimens tissue glycoside concentrations can be determined by radioimmunoassay. Total tissue extraction of digoxin and beta-methyl-digoxin varies between 87 and 95%, the variation coefficient for repeated determinations is 10.2%. Glycoside concentrations of left ventricular papillary muscle obtained after mitral valve replacement were 69.0 +/- 25.05 ng/g with a tissue to serum relation of 46.6 +/- 8.96:1 and a correlation coefficient of r = 0.8442. In autopsy left ventricular papillary muscle glycoside concentrations were 105.2 +/- 27.35 ng/g with an almost identical tissue to serum relation of 46.2 +/- 9.57:1 and a corresponding serum concentration of 2.3 +/- 0.63 ng/ml. In adults glycoside concentrations of autopsy specimens of the right ventricle were significantly lower by 28 to 30% than those of the left ventricle. Glycoside concentrations of skeletal muscle specimens (m. pectorialis major) were 14.7 +/- 10.35 ng/g with a tissue to serum relation of 9.7 +/- 3.00:1 (r = 0.8377), which corresponds to approximately 1/5 to 1/4 of the concentrations of the left ventricular myocardium.

Aged↗

PubMed1979

Species restriction of the mitogenicity induced by lanatoside C. Lymphocyte activation by digitalis glycosides is confined to cells from digitalis resistant species.

Activation of Na+, K+-ATPase has previously been suggested to be the triggering signal in mitogen-induced cell activation. Using a digitalis glycoside known to be a potent polyclonal B-cell activator, this hypothesis could be tested since digitalis activates ATPase at different concentrations in various species, depending on the degree of sensitivity to the toxic effects of glycosides. Lanatoside C was found to stimulate lymphocytes from glycoside resistant species such as rat, mouse and hamster. The possible involvement of Na+, K+-ATPase was made less likely by the similarity in dose--response profile in these cells although they have been reported to display varying degrees of glycoside resistance. Furthermore, using lymphocytes from digitalis-sensitive species such as man, guinea-pig or rabbit, no mitogenicity could be recorded, strongly suggesting a lack of correlation between glycoside-induced effects on Na+, K+-ATPase and cell activation.

Adenosine Triphosphatases↗

PubMed1977

Influence of canrenoate-K and cardiac glycosides on their tissue distribution and elimination.

The combination of cardiac glycosides and canrenoate-potassium (CR-K) produces synergistic effects on hemodynamics. On the other hand, CR-K antagonizes digitalis-induced cardiac arrhythmias. Therefore, it was the purpose of this study to determine interactions between these substances, particularly of their myocardial uptake. The additional administration of CR-K leads to significantly higher concentrations of digoxin and ouabain in heart, liver, adrenal gland and spleen. Contrary to this, additional digoxin reduces the concentration of CR-K in the tissue. Particularly obvious is the reduced concentration in the kidney, adrenal gland, pancreas, brain and spleen. The renal excretion of digoxin and ouabain is reduced by the additional administration of CR-K, while digoxin accelerates the CR-K excretion within the first 60 min after application. Metabolic interference was not detected in the combination of cardiac glycosides and CR-K. The mechanisms for the interactions between cardiac glycosides and CR-K during the distribution phase are discussed. The inhomogenous interference of their myocardial uptake makes a common cardiac receptor for the synergistic effect of cardiac glycosides and CR-K rather unlikely. CR-K does not have a suppressant effect on digitalis-induced arrhythmias due to any diminution of the glycoside uptake by myocardial tissue.

Animals↗

PubMedDate not supplied

Cell membrane receptors for cardiac glycosides in the heart.

Cell membranes contain special binding proteins for hormones and drugs. These binding sites ("receptors") located on the outside surface are linked to or are part of an enzyme facing the inner side of the membrane and are transducing and probably amplifying the information carried by the pharmacological agent to the cell. As the first step of their action cardiac glycosides reversibly bind with high affinity to specific receptors in cardiac cells and by this inhibit the (Na+ + K+)-ATPase, which is the enzyme system responsible for the active transmembraneous transport of sodium and potassium. It is thought that the inhibition of this active cation transport precedes the positive inotropic effect. Cardio-inactive glycosides have but low affinity to this receptor and thus do inhibit the (Na+ + K+)-activated ATPase only at very high concentrations. The characterization of the cardiac glycoside-receptor interaction in the heart reveals several factors that influence the affinity of the binding sites for the glycosides and thereby determine the sensitivity to this widely used group of potent drugs.

Adenosine Triphosphatases↗

PubMed1976

Rapid and sensitive high-resolution procedure for digitalis glycoside analysis by derivatization liquid chromatography.

The separation and quantitative determination of digitalis glycosides by high performance liquid chromatography following derivatization with 4-nitrobenzoylchloride (4-NBC1) is described. The compounds of primary interest were the digitalis glycosides and aglycones of the pharmaceutically important A, B and C series, The derivatization step results in higher extinction values at a more favourable wavelength (260 nm), which permits the use of low-cost ultraviolet detectors. Detection limits are below 20 ng/ml for all of the glycosides tested. The chromatographic properties are also improved by reducing the polarity without a decrease in selectivity. The use of low-polarity and low-viscosity solvent systems on silica gel adsorbents permits rapid isocratic separations of complex mixtures as they usually occur in pharmaceutical products and extracts. The quantitative potential of this method was demonstrated by analyzing ampoule solutions containing desacetyl lanatoside C as the active compound. The active substance, by-products and degradation products were determined down to 0.1% of the total glycoside concentration in one ampoule.

Chromatography, High Pressure Liquid↗

PubMed1977

Synthesis of episilon-rhodomycinone glycosides.

Twenty-six episilon-rhodomycinone glycosides have been synthesized. These include the episilon-rhodomycinone glycosides of 2-deoxy-L-fucose, 2-deoxy-L-rhamnose, and 2-deoxy-D-ribose as well as their 2-hydroxyl derivatives. NMR spectroscopy showed that all the glycosides prepared had the saccharide residues linked to position 10 of episilon-rhodomycinone and helped establish the anomeric purity and configuration of several glycosides. Preliminary screening results show that 2-deoxy-di-O-acetyl-D-ribopyranosyl-episilon-rhodomycinone has an activity T/C of 125 on P388 tumors.

Animals↗

PubMed1976

Kinetics of active sodium transport in rat proximal tubules and its variation by cardiac glycosides at zero net volume and ion fluxes. Evidence for a multisite sodium transport system.

1. Transepithelial Na concentration difference, deltaCNa, across proximal tubules of rat kidney was measured at varying intraluminal Na concentrations (CNainfinity) under conditions of zero net volume and Na flux. Simultaneous stopped-flow intratubular and artificial peritubular capillary perfusion techniques were used together with intratubular raffinose to achieve zero net fluxes. Under these conditions in rat proximal tubules, deltaCNa represents active transport, JactNa, factored by permeability, PNa, plus an electrical factor depending on transepithelial potential difference. 2. The relationship between CNainfinity and deltaCNa appeared sigmoidal with saturation being reached when intratubular Na was above 80 m-mole/kg. In the presence of ouabain (10(-2)M) and scilliroside (10(-3)M) the relationship remained the same. The maximum deltaCNa was reduced by approximately 50% by cardiac glycoside inhibition whereas the half-saturation constant was essentially unchanged. These changes from the control represent simple non-competitive inhibition by the cardiac glycosides. 3. Absence of potential difference (p.d.) measurements precludes exact description of the relation between true active transport and substrate concentration but much evidence indicates that the apparently sigmoid relation in the presence and absence of cardiac glycoside inhibition, would be retained if correction of deltaCNa values were possible. Such results could then be explained if there are at least three or more sites for Na on the pump system, of which at least two are not cardiac glycoside sensitive. They would also unequivocally exclude the presence of a single-site single-pump system or the simple algebraic addition of two such units since the kinetic curves for both would be hyperbolic rather than sigmoidal.

Animals↗

PubMed1977

Ionic currents in cardiac muscle: a framework for glycoside action.

This paper briefly reviews the current state of understanding of cardiac excitation--contraction coupling and its relation to glycoside action. Evidence that inotropic action of glycosides might result from increased influx of Ca2+ during action potential is reviewed. Recent voltage clamp studies that show little if any direct effect on Ca2+ influx during the action potential are cited. It is suggested that the primary inotropic effects derive from altered ionic exchange mechanisms secondary to inhibition of Na+,K+-ATPase. The role of ionic currents in glycoside toxicity is considered, with discussion of a dynamic, depolarizing current that appears shortly after action potential. This current is apparently an inward movement of positive ions that is strongly mediated by extracellular Ca2+ levels. It is noted that such spontaneous depolarizations of the membrane have been observed in several other circumstances where strong positive inotropism has been induced. The conclusion is reached that membrane ionic currents probably play only a secondary role in glycoside inotropism and in many of the toxic effects.

Action Potentials↗

PubMed1977

Recent advances in cardiac glycoside-Na+,K+-ATPase interaction.

Na+,K+-ATPase has been purified from lamb kidney and consists of two polypeptide peaks on polyacrylamide gel electrophoresis with an enzyme activity of 1,000 mumole Pi/mg pro per hr. A scheme depicting the interaction of cardiac glycoside with the enzyme and ligand effects on binding has been constructed. Under all ligand conditions, ouabain binding tends to reach the same maximum if sufficient ouabain is present. Initial rates vary with ligand conditions. Using a chase method, the rate of dissociation of the glycoside from the enzyme is not influenced by the ligands present, although with separation of the enzyme-glycoside complex from the binding medium, differences are noted. The effect of ouabain on Na binding demonstrated two classes of sites, KD = 0.2 mM and KD = 18 mM. Denaturation decreased the high affinity sites. There was also a good correlation between ouabain binding and inhibition of Na binding. Clearly, ligands are critical in regulating cardiac glycoside interaction with the enzyme.

Adenosine Triphosphatases↗

PubMed1977

Contribution to the biochemical characterization of cardiac glycosides concerning their influence on ATP-ases.

1. A comparison of the complex binding constants of different glycosides show no significant differences between these different glycosides at least not in the model containing ATP. 2. There are greater differences regarding the ATP-ase activity of the different glycoside complexes measured by means of the Rb-transport method. 3. The absorption of different proscillaridin and methylproscillaridin preparations was investigated with this method. 4. Using the rat as experimental animal the effect of different glycosides on the Na-K and Ca ATP-ase of the heart muscle was demonstrated showing a remarkable activation of the Ca-activated ATP-ase caused by proscillaridin. In order to find an explanation for the therapeutic and toxic effects these investigations have to be repeated in the pig, which shows more similarities in the ATP-ase distribution to man than the rat.

Adenosine Triphosphatases↗