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PubMed1983

Improvement of the oral bioavailability of digitalis glycosides by cyclodextrin complexation.

Inclusion complexes of the digitalis glycosides digitoxin, digoxin, and methyl digoxin with three cyclodextrins (alpha-, beta-, gamma-homologues) in water and in the solid state were studied by a solubility method, IR and 1H-NMR spectroscopy, and X-ray diffractometry. Solid complexes (in a molar ratio of 1:4) of the digitalis glycosides with gamma-cyclodextrin were prepared and their in vivo absorption examined. The rapidly dissolving form of the gamma-cyclodextrin complex significantly increased plasma levels of digoxin (approximately 5.4-fold) after oral administration to dogs.

Animals↗
PubMed1977

[Use and mechanism of action of digitalis glycosides as anti-arrhythmic drugs].

Digitalis glycosides are used in the supraventricular arrhythmias either to slow the ventricular response or to restore or maintain sinus rhythm. The direct cellular effects of digitalis are probably not involved in its antiarrhythmic action. The indirect effects of digitalis through parasympathetic stimulation and adrenergic inhibition explain the results obtained when treating arrhythmias. At toxic doses, adrenergic stimulation may contribute to the arrhythmias of digitalis toxicity.

Anti-Arrhythmia Agents↗
PubMed1993

Human skeletal muscle digitalis glycoside receptors (Na,K-ATPase)--importance during digitalization.

The aims of the present study were to evaluate in humans the putative importance of skeletal muscle digitalis glycoside receptors (Na,K-ATPase) in the volume of distribution of digoxin and to assess whether therapeutic digoxin exposure might cause digitalis receptor upregulation in skeletal muscle. Samples of the vastus lateralis were obtained postmortem from 11 long-term (9 months to 9 years) digitalized (125-187.5 micrograms daily) and eight undigitalized subjects. In intact samples from digitalized patients, vanadate-facilitated 3H-ouabain binding increased 15% (p < 0.02) from 150 +/- 18 to 173 +/- 13 pmol/g wet wt. (mean +/- SEM) after clearing receptors of bound digoxin by washing samples in excess specific digoxin antibody fragments. 3H-ouabain binding in the untreated group was 257 +/- 28 and 274 +/- 26 pmol/g wet wt. (7%, p > 0.30) before and after washing in specific digoxin antibody fragments, respectively. Thus, the present study indicates a approximately 13% occupancy of skeletal muscle digitalis glycoside receptors with digoxin during digitalization. In light of the large skeletal muscle contribution to body mass, this indicates that the skeletal muscle Na,K-ATPase pool constitutes a major volume of distribution for digoxin during digitalization. The results gave no indication of skeletal muscle digitalis glycoside receptor upregulation in response to digoxin treatment. On the contrary, there was evidence of significantly lower (37%, p < 0.005) digitalis glycoside receptor concentration in the vastus lateralis of the digitalized patients, which may be of importance for skeletal muscle incapacity in heart failure.

Aged↗
PubMed1976

Clinical use of digitalis glycosides.

The pharmacology of digitalis compounds is reviewed, and the clinical use of the cardiac glycosides is discussed with particular attention to the selection of patients for digitalis therapy and to a study of the usefulness of various methods to monitor digitalis therapy. The discussion includes pharmacokinetics, clinical considerations, and digitalis toxicity and its treatment. It is concluded that the digitalis glycosides remain the most useful and reliable drugs for producing a long-term increase in myocardial contractility. However, in view of the high frequency of toxicity, it is important to consider the possibility that these drugs may have been overused.

Digitalis Glycosides↗
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↗
PubMed1972

Species and ionic influences on the accumulation of digitalis glycosides by isolated perfused hearts.

1. The ability of isolated perfused guinea-pig (digitalis-sensitive species) and rat (digitalis-resistant species) hearts to accumulate radio-labelled digitalis glycosides was studied in relation to the ionic composition of the perfusion medium.2. It was observed that in both species much less digoxin was accumulated than was digitoxin or proscillaridin.3. The accumulation of digoxin was markedly inhibited in a low sodium or in high potassium medium. These effects were similar, but relatively less marked, with digitoxin and proscillaridin. Calcium and magnesium removal had relatively smaller effects on the accumulation of both polar and non-polar glycosides.4. The low accumulation of all digitaloids by the rat heart in comparison to the guinea-pig heart may be due to the formation of unstable complexes between the cellular membranes in the rat heart and the various digitaloids used in this study. Although digitaloids have a reduced affinity for rat hearts and rat heart membranes in comparison to guinea-pigs, the order of the accumulation of different glycosides in both species is the same, i.e. much less with polar glycosides than with non-polar glycosides.5. It was concluded that non-polar glycosides such as digitoxin and proscillaridin demonstrate the same ion-dependent accumulation mechanism as do the more polar glycosides such as digoxin and ouabain. In addition, the non-polar glycosides possess high capacity for ion-independent binding presumably due to lipophilic interactions with membranes.

Animals↗
PubMed1989

Sympathoinhibitory responses to digitalis glycosides in heart failure patients. Direct evidence from sympathetic neural recordings.

Digitalis glycosides exert both excitatory and inhibitory autonomic actions in animals and produce vasoconstriction in normal humans but produce vasodilation in heart failure patients. To determine whether or not these contrasting vascular responses are due to differing autonomic actions of the drug, we compared the responses to intravenous administration of Cedilanid-D (0.02 mg/kg) in eight normal subjects (mean age, 23 +/- 1 years) and eight patients with moderate-to-severe heart failure (mean age, 52 +/- 5 years, NYHA Class III-IV). Hemodynamics and efferent sympathetic nerve activity to muscle (MSNA) were measured during 5-minute periods before (control) and 20 minutes after drug administration. In the heart failure patients, Cedilanid-D significantly increased systolic and pulse pressures, whereas mean arterial pressure was unchanged. There was a decrease in right atrial pressure and a tendency for a decrease in pulmonary artery diastolic pressure with a slowing of heart rate. Cardiac index increased by 24 +/- 7%. Short-term administration of digitalis in these heart failure patients produced a fall in forearm vascular resistance (from 37.6 +/- 8.2 to 31.8 +/- 8.1 units, p less than 0.05) and an early, profound, and sustained decrease in MSNA (from 831.0 +/- 118.4 to 474.4 +/- 103.6 units/100 heart beats, p less than 0.01). Digitalis glycosides produced different vascular and MSNA responses in the normal subjects. In the normal volunteers, the drug significantly increased systolic, mean, and pulse pressures and decreased central venous pressure and heart rate. Despite the significant increase in arterial pressure, there was no change in forearm vascular resistance (from 11.7 +/- 1.0 to 12.7 +/- 1.0 units, p = NS) or MSNA (from 494.8 +/- 88.5 to 369.1 +/- 60.5 units/100 heart beats, p = NS), suggesting a sympathoexcitatory response in normal subjects. To determine whether or not the digitalis-induced sympathoinhibition in the heart failure patients was simply due to an inotropic effect (stimulation of inhibitory cardiac mechanoreceptors), we studied the responses of seven additional patients with heart failure before and during administration of dobutamine (3.4 +/- 0.4 micrograms/kg/min). Dobutamine produced a 34 +/- 3% increase in cardiac index, no significant change in systemic arterial pressures, a decrease in pulmonary artery diastolic and right atrial pressures, and no change in heart rate or forearm vascular resistance (from 30.2 +/- 4.3 to 26.5 +/- 4.7 units, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMedDate not supplied

Digitalis glycosides: a discussion of the similarities and differences in actions and existing controversies.

The writing of this review was initiated to answer the question of whether differences in the actions of the various digitalis glycosides exist and to discuss current controversies in the research area of the digitalis glycosides. Data obtained in our laboratory indicated that the effect of digoxin on postganglionic cardiac sympathetic neural discharge in the minute prior to the occurrence of arrhythmia differed from that of ouabain. This raised the question of whether data published in other laboratories would support the contention that differences in glycosides do exist. To answer this question, a review of the literature was begun. Our survey of these studies are cited in the tables of this review. These tables summarize the actions of glycosides in vivo and in vitro in different animal models. The reader should bear in mind that the data included within the tables do not represent an inclusive summary of all studies in the literature. For detailed review articles, the reader is referred to the following references: Gillis et al; Gillis and Quest; Roberts et al; Lathers and Roberts; Farah and Alousi; Benthe; Levitt et al; Smith and Haber; Somberg; Lee and Klaus; Mason; Schwartz. Furthermore the summary of the results for each particular study cited in the table may not, in all cases, include each finding of the published data. Nevertheless, the tables do provide a summary of data obtained in various species with different glycosides in several different areas of research, and as such, represent an abridged compendium for the research working in the field of digitalis glycosides. This review has been organized firstly to consider glycoside-induced alterations in the autonomic nervous system and, secondly, to examine their direct actions on the heart.

Animals↗
PubMed1999

Monoclonal antibodies that distinguish between two related digitalis glycosides, ouabain and digoxin.

The exogenous digitalis glycosides, ouabain and digoxin, have been widely used in humans to treat congestive heart failure and cardiac arrhythmias. Several reports have also pointed to the existence of endogenous ouabain- and digoxin-like compounds, but their precise roles in mammalian physiology and various disorders of the circulation are not clear. In an attempt to produce specific Abs for the purification and identification of endogenous ouabain-like compounds, somatic cell fusion was used to produce mAbs specific for ouabain. Our attempts to produce ouabain-specific mAbs were unsuccessful when ouabain was coupled to exogenous proteins such as bovine gamma-globulins, BSA, and human serum albumin. However, when ouabain was coupled to an Ab of A/J mice origin and the same strain of mouse was used for immunization with ouabain-Ab conjugate, three Abs (1-10, 5A12, and 7-1) specific for ouabain were obtained. In assays of fluorescence quenching and saturation equilibrium with tritiated ouabain, Ab 1-10 exhibited 200 nM affinity for ouabain. These three mAbs are distinguished from existing Abs to ouabain and digoxin by their specificity for ouabain and lack of cross-reactivity with digoxin. Specificity studies showed that the loss of cross-reactivity was correlated with the presence of a hydroxyl group at either position 12beta (digoxin) or 16beta (gitoxin) of the steroid ring. These Abs can be used to develop assays for detection and characterization of ouabain-like molecules in vivo.

Animals↗