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PubMed2004

Interference of Uzara glycosides in assays of digitalis glycosides.

OBJECTIVE: Presentation of a case report and pharmacokinetic investigation in healthy volunteers on the potential interference between cardiac glycosides and glycosides of Uzara, a herbal antidiarrheal preparation. METHODS: Pharmacokinetic pilot investigation of apparent digitoxin and digoxin serum concentrations in 4 healthy volunteers after single-dose administration of 30 drops Uzara (approximately 1.5 ml approximately = 22 mg glycosides). RESULTS: Maximal apparent serum concentrations of digitoxin between 198.0 microg/l and 919.8 microg/l (therapeutic range: 10-25 microg/l) occurred at 4-8 hours after administration. The terminal half-life of the glycosides was 8.87 +/- 2.20 hours. For digoxin, maximal apparent serum concentrations ranged between 1.4 microg/l and 6.34 microg/l (therapeutic range: 0.9-2.0 microg/l) at 6 hours post dosing. CONCLUSIONS: Administration of a single dose of an Uzara preparation, an over-the-counter product, results in false high serum concentrations of digitoxin and digoxin. As described in the manufacturers Summary of Product Characteristics, this preparation should not be given to patients with cardiac failure or arrhythmia who require treatment with cardiac glycosides because of the demonstrated pharmacological actions of uzara glycosides.

Adult↗
PubMed1991

[The past and the present of cardiac glycosides. III. Pharmacokinetics].

The molecular structure is one of the keypoints that govern both the extent of extracardiac action of cardiac glycosides and their different kinetics. The apolar, fat soluble digitoxin is very well absorbed from the intestine, its onset of action is slow, binds to a high degree to albumin and undergoes enterohepatic recirculation which accounts for a long elimination half time and stability of plasmatic levels. Digitoxin is largely excreted via gastrointestinal tract. The absorption of digoxin is less reliable, onset of action occurs earlier and the binding to albumin is considerably less than that of digitoxin. The drawback, however small, of digoxin lies in a lower stability of plasma levels and prevailing renal excretion. The molecule of strophatin is highly polar, its absorption from the intestine negligible and can be administered only intravenously. The onset of action is prompt, elimination half time short and about half the injected amount is excreted extrarenally.

Cardiac Glycosides↗
PubMed1988

Evaluation of cross-reactivity of urinary digoxin-like substance in different radioimmunoassays.

For the accuracy of routine monitoring of digoxin and digitoxin it seems important to get information on the cross-reactivity of endogenous digitalis-like substances (EDLS). To obtain EDLS, urine was passed on Sep-Pak columns and eluted in fractions by increasing concentrations of acetonitrile. Dilution series of two fractions were subjected to radioimmunoassay (RIA) with respect to digoxin- and digitoxin-like activity, using commercial kits from New England Nuclear, Farmos Diagnostica, and Diagnostic Products Corporation. Cross-reactivity and the degree of parallelism between dilution curves and standard curves varied markedly between the procedures. Recovery studies showed that the presence of EDLS, even at concentrations below the limit of determination of the respective assay, can influence the recovery of digoxin and digitoxin. When higher concentrations of EDLS were present, the combined effects of EDLS and drugs were not always additive. This again stresses the need for any RIA to be carefully characterized to minimize important sources of errors. Required prerequisites are detailed and highly specific information on specificity and the influence of endogenous interfering substances is given. To warrant reliable measurements of digoxin, it is important to identify the cross-reactive material known as EDLS.

Adult↗
PubMed1979

A specific cardiac glycoside for cardiac failure and another for atrial fibrillation?

Ouabain produces a greater degree of prolongation of the P-R interval than digitoxin in rats when dosages which produce similar inotropic responses are used. When digitoxin is administered after pretreatment with propranolol, it produces prolongation of the P-R interval comparable to that produced by ouabain. Indications in the literature that these findings may apply to human beings suggest that in some situations atrial fibrillation may be better controlled with a hydrophilic digitalis preparation (e.g. ouabain), whereas cardiac failure with a tendency to atrioventricular block may be better controlled with a lipophilic preparation (e.g. digitoxin).

Animals↗
PubMed1983

Binding of selected drugs to a "treated" inline filter.

The binding of several drugs to an inline i.v. filter that had been treated to inhibit drug-binding was studied. Solutions of mithramycin, vincristine sulfate, digitoxin, insulin, dactinomycin, and nitroglycerin in both 5% dextrose injection and 0.9% sodium chloride injection were allowed to flow through an i.v. administration set containing a 0.22-micron cellulose ester filter that had been treated with a proprietary agent. Actual administration conditions were simulated by using drug concentrations and flow rates commonly employed in clinical practice. The amount of each drug retained by the filter was determined by assaying aliquots of the solutions sampled before and after the solution passed through the filter membrane. In a second experiment, drug binding to the filter membrane was measured by incubating small pieces of the treated membrane in drug solutions and determining concentrations periodically until equilibrium was reached. Untreated filter membrane pieces were used as a control. In the experiment simulating actual i.v. administration, cumulative binding of mithramycin, vincristine sulfate, dactinomycin, and nitroglycerin to the treated filter was less than 6% of the initial dose infused; approximately 8-12% of the initial amounts of digitoxin and insulin were bound to the filter. In the equilibrium binding studies, the untreated filters bound twice as much digitoxin, 5-7 times as much mithramycin, vincristine sulfate, and dactinomycin, and 20 times as much insulin as the treated filters. The amount of nitroglycerin bound to the treated and untreated filters was not substantially different. Insulin had a greater binding tendency in 5% dextrose injection than in 0.9% sodium chloride injection in both experiments regardless of the filter treatment. Treatment of a cellulose ester i.v. filter with the proprietary agent used in this study facilitates drug delivery through this filter.

Adsorption↗
PubMed1976

[Effects of pentaformylgitoxin (gitoformate) on the cardiovascular system of anesthetized cats].

In small and medium doses 3 beta, 14 beta-dihydroxy-16 beta-formyloxy-5 beta-card-20-[22]-enolide-3-tetraformyltridigitoxoside (pentaformylgitoxin; gitoformate) shows a greater positive inotropic and blood pressure increasing potency than do digitoxin and beta-acetyldigoxin. In high doses this influence on contractility is exceeded by digitoxin, that on blood pressure is equalled. None of the substances tested changes heart rate. Arrhythmias with gitoformate are only seen in lethal doses, with digitoxin and beta-acetyldigoxin two dose levels earlier.

Animals↗
PubMed1999

Characterization of minor site probes for human serum albumin by high-performance affinity chromatography.

This study used high-performance affinity chromatography (HPAC) and immobilized human serum albumin (HSA) columns to examine the specificity and cross-reactivity of various compounds that have been proposed as markers for the minor binding sites of HSA. These agents included acetyldigitoxin and digitoxin as probes for the digitoxin site, phenol red as a probe for the bilirubin site, and cisor trans-clomiphene as markers for the tamoxifen site. None of these probes showed any significant binding at HSA's indole-benzodiazepine site. However, phenol red did bind at the warfarin-azapropazone site of HSA, and cis/trans-clomiphene gave positive allosteric effects caused by the binding of warfarin to HSA. Digitoxin and acetyldigitoxin were found to bind to a common, unique region on HSA; cis- and trans-clomiphene also appeared to interact at a unique site, although trans-clomiphene displayed additional direct competition with phenol red. From these results it was possible to develop a model that described the general relationship between these binding regions on HSA. This information should be useful in future studies that employ HPAC for characterizing the binding of HSA to other drugs or clinical agents.

Binding Sites↗
PubMed1988

[Disorders of color perception in subtoxic and toxic digoxin and serum digoxin concentrations].

Using the Farnsworth-Munsell 100-hue test, investigations were carried out in 14 patients with subtoxic to toxic serum concentrations of digoxin (greater than 2.0 ng/ml) and 13 patients with subtoxic to toxic serum concentrations of digitoxin (greater than 30 ng/ml), in order to detect color vision deficiencies related to serum levels of digitalis. As compared to the control group (n = 24) the total error scores were significantly increased for both glycosides and all serum level ranges. No evidence was found indicating that digoxin and digitoxin influence color vision differently. The FM 100-hue test indicated definite improvements in the digoxin group within one day of discontinuing the glycosides, while the digitoxin group only started to normalize a week later. The results are discussed, taking the different pharmacokinetics of the two digitalis glycosides into account.

Aged↗
PubMed1999

Interaction of cyclomaltononaose (delta-CD) with several drugs.

The effects of delta-cyclodextrin (delta-CD; cyclomaltononaose) on solubility of 14 drugs that are slightly soluble or insoluble in water were studied and compared with those of conventional cyclodextrins (CDs) such as alpha-cyclodextrin (alpha-CD), beta-cyclodextrin (beta-CD), and gamma-cyclodextrin (gamma-CD). In general, delta-CD had a weak complex-forming ability with the drugs examined in comparison with beta-CD and gamma-CD. However, in the case of digitoxin, delta-CD enhanced solubility of the guest molecules. To determine the mechanism of inclusion complex formation of delta-CD with digitoxin, the interaction of both drugs was investigated by the solubility method and spectroscopic methods such as ultraviolet (UV) and 1H-NMR (nuclear magnetic resonance). The changes in chemical shift (1H) and hypsochromic shift of UV suggested that digitoxin was partially included in the cavity of delta-CD.

Chemistry, Pharmaceutical↗
PubMed1991

Lidocaine and ATPase inhibitor interaction with the chloroplast envelope.

Photosynthetic capacity of isolated intact chloroplasts is known to be sensitive to K(+) fluxes across the chloroplast envelope. However, little is known about the system of chloroplast envelope proteins that regulate this K(+) movement. The research described in this report focused on characterizing some of the components of this transport system by examining inhibitor effects on chloroplast metabolism. Digitoxin, an inhibitor of membrane-bound Na(+)/K(+) ATPases, was found to reduce stromal K(+) at a range of external K(+) and inhibit photosynthesis. Scatchard plot analysis revealed a specific protein receptor site with a K(m) for digitoxin binding of 13 nanomolar. Studies suggested that the receptor site was on the interior of the envelope. The effect of a class of amine anesthetics that are known to be K(+) channel blockers on chloroplast metabolism was also studied. Under conditions that facilitate low stromal pH and concomitant photosynthetic inhibition, the anesthetic, lidocaine, was found to stimulate photosynthesis. This stimulation was associated with the maintenance of higher stromal K(+). Comparison of the effects on photosynthesis of lidocaine analogs which varied in lipophilicity suggested a lipophilic pathway for anesthetic action. The results of experiments with lidocaine and digitoxin were consistent with the hypothesis that a K(+) channel and a K(+)-pumping envelope ATPase contribute to overall K(+) flux across the chloroplast envelope. Under appropriate assay conditions, photosynthetic capacity of isolated chloroplasts was shown to be much affected by the activity of these putative envelope proteins.

Journal Article↗
PubMed1983

Drug binding in sera deficient in lipoproteins, albumin or orosomucoid.

The relative role of lipoproteins, albumin and orosomucoid in the serum binding variation of various drugs was examined by separate removal of these proteins. Lipoproteins were removed from serum by ultracentrifugation, albumin by affinity chromatography and orosomucoid by immunoprecipitation. Removal of the lipoproteins did not affect the serum binding of the acidic (phenytoin) and neutral (digitoxin) drugs tested, nor the basic drugs disopyramide, quinidine or propranolol. A reduction in binding of amitryptyline, nortriptyline, doxepin and desmethyldoxepin was observed. Removal of albumin did, with some exception for nortriptyline, not affect the serum binding of the basic drugs tested. A pronounced reduction in the binding of phenytoin and digitoxin was observed. Removal of orosomucoid did not affect the binding of the acidic and neutral drugs tested. A reduction in the binding of all the basic drugs tested was observed, especially for disopyramide whose binding almost disappeared. Quinidine, propranolol, phenytoin and digitoxin all bound to isolated lipoproteins, but the removal of lipoproteins had no effect on the total serum binding for these drugs. Hence, the use of deficient sera provides valuable information as to the quantitative role of the various proteins in drug binding, whereas studies using purified proteins are often necessary to examine the mechanisms of the drug protein interactions.

Humans↗
PubMed1996

Transport and epithelial secretion of the cardiac glycoside, digoxin, by human intestinal epithelial (Caco-2) cells.

1. Human intestinal epithelial Caco-2 cells have been used to investigate the transepithelial permeation of the cardiac glycoside, digoxin. 2. Transepithelial basal to apical [3H]-digoxin flux exceeds apical to basal flux, a net secretion of [3H]-digoxin being observed. At 200 microM digoxin, net secretory flux (Jnet) was 10.8 +/- 0.6 nmol cm-2 h-1. Maximal secretory flux (Jmax) of vinblastine was 1.3 +/- 0.1 nmol cm-2 h-1. Cellular uptake of digoxin was different across apical and basal cell boundaries. It was greatest across the basal surface at 1 microM, whereas at 200 microM, apical uptake exceeded basal uptake. 3. Net secretion of [3H]-digoxin was subject to inhibition by digitoxin and bufalin but was not inhibited by ouabain, convallatoxin, and strophanthidin (all 100 microM). Inhibition was due to both a decrease in Jb-a and an increase in Ja-b. Uptake of [3H]-digoxin at the apical surface was increased by digitoxin and bufalin. All cardiac glycosides decreased [3H]-digoxin uptake at the basal cell surface (except for 100 microM digitoxin). 4. The competitive P-glycoprotein inhibitors, verapamil (100 microM), nifedipine (50 microM) and vinblastine (50 microM) all abolished net secretion of [3H]-digoxin due to both a decrease in Jb-a and an increase in Ja-b. Cellular accumulation of [3H]-digoxin was also increased across both the apical and basal cell surfaces. I-Chloro-2,4,-dinitrobenzene (10 microM), a substrate for glutathione-S-transferase and subsequent ATP-dependent glutathione-S-conjugate secretion, failed to inhibit net secretion of [3H]-digoxin. The increase in absorptive permeability Pa-b (= Ja-b/Ca) and cellular [3H]-digoxin uptake upon P-glycoprotein inhibition, showed that the intestinal epithelium was rendered effectively impermeable by ATP-dependent extrusion at the apical surface. 5. A model for [3H]-digoxin secretion by the intestinal epithelium is likely to involve both diffusional uptake and Na(+)-K+ pump-mediated endocytosis, followed by active extrusion at the apical membrane.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Modulation of pump function by mutations in the first transmembrane region of Na(+)-K(+)-ATPase alpha 1-subunit.

The Cys in the first transmembrane region of the Na(+)-K(+)-adenosinetriphosphatase (ATPase) alpha 1-subunit has been shown to be a critical determinant of cardiac glycoside binding. To study the role of this Cys on ion transport activity, we measured pump currents in HeLa cells expressing wild-type or mutant alpha 1-subunit cDNAs. The endogenous ouabainsensitive Na(+)-K(+)-ATPase was selectively inhibited by growing the cells in 0.1 microM ouabain. A Cys-to-Tyr substituted mutant exhibited decreased sensitivity to digitoxin but not digoxin compared with wild type. The decreased affinity for digitoxin was due to a faster dissociation rate. In contrast, the Cys-to-Ala substitution did not significantly alter the sensitivity to digitoxin or digoxin. Both wild-type and mutant cells displayed marked external K(+)-dependent pump currents; however, the affinity for K+ was reduced by the mutations. The decrease in K+ affinity was due to a slower association rate. The results show that the Cys that interacts with cardiac glycosides also participates in the sensitivity of the pump to external K+.

Amino Acid Sequence↗
PubMed1991

[Metabolic fate of bufalin and cinobufagin].

In the course of study of the metabolic fate of "Kyushin", a traditional medicine containing toad venom, the metabolic fates of bufalin and cinobufagin, main constituents of toad venom, have been studied. Six metabolites were detected in the extracts from incubation mixture of rat liver slice with bufalin, and one main metabolite shown by mass spectroscopy and high performance liquid chromatography (HPLC) to be 3 alpha-bufalin. Serum levels of bufalin and 3 alpha-bufalin were determined by HPLC after oral administration of 2000 micrograms/kg of bufalin, and both compounds appeared in the rat serum. On the other hand, only 3 alpha-bufalin appeared after administration of 20 or 200 micrograms/kg. 3 alpha-Bufalin levels increased dose dependently. Serum levels of cinobufagin and its metabolites and digitoxin were compared after repeated intravenous administration (5 h interval) of cinobufagin or digitoxin. Although digitoxin was accumulated in the rat serum, cinobufagin and its metabolites were not. Inhibitory activities of metabolites of bufalin and cinobufagin on (Na+ + K+)-adenosine triphosphatase were less than those of original compounds.

Administration, Oral↗
PubMed1984

Relationship between the inotropy speeds in guinea-pig myocardium and lipophilic character of cardenolides and ericaceous toxins.

Interrelation between lipophilic characters and speeds of positive inotropic effect (PIE) of cardenolides and ericaceous toxins was studied by determining both parameters of lipophilicity and inotropy speeds. The lipophilic characters of 8 kinds of cardenolides, evaluated from Rm or log k' values by means of thin layer chromatography (Rf) or high performance liquid chromatography (retention time), increased in the order of ouabain, digoxin, digitoxigenin, digitoxigenin-monodigitoxoside, digitoxigenin-bis-digitoxoside, digitoxin, alpha-acetyl-digitoxin, triacetyl-digitoxin. Lipophilic character, evaluated from Rm values of 6 kinds of ericaceous toxins, was in decreasing order of 10S-grayanotoxin II, 6-acetyl grayanotoxin I, asebotoxin I, grayanotoxin I, asebotoxin III, asebotoxin X. The speed with which PIE developed was evaluated from the time to half maximum PIE (T50) of cardenolides and ericaceous toxins at a pD2 concentration. The speed of positive inotropy of cardenolides was independent of their concentration tested in the range from half to twice the concentration of pD2, while the speeds of PIE of ericaceous toxins depended on their concentration in the same range used in case of cardenolides. Inotropy speed of these two classes of cardiotoxins correlated well with the lipophilic character: a) In the case of cardenolides, a positive and close correlation (r = 0.98) was observed between T50 and Rm. The more lipophilic the cardenolides, the more time was required to reach the fully development of PIE. b) In contrast, a negative correlation (r = -0.82, between Rm and T50) was obtained in the case of ericaceous toxins; Toxins with more lipophilic nature caused faster development of PIE. The present results can be interpreted to mean that the PIE receptor for cardenolides in myocardial cells is located on the outer surface of the sarcolemma, while that for ericaceous toxins is located on the inside of the myocardial cell.

Animals↗
PubMed1984

Comparison of the affinity of human, beef and cat heart (Na+ + K+)-ATPase for different digitalis derivatives.

The potencies of eight digitalis derivatives, including two new derivatives of digitoxin, were determined on heart (Na+ + K+)-ATPase or erythrocytes from three digitalis-sensitive species, beef, cat and human. Three methods were used: inhibition of 3H-ouabain binding to give the dissociation constant (KD-value), or inhibition of (Na+ + K+)-ATPase activity or 86Rb+-uptake into human erythrocytes to give the IC50-values. The same order of potency was observed with all methods. The slopes of the concentration-response curves were similar for all compounds. For all compounds, the concentrations which inhibited 3H-ouabain binding by 50% caused about a 50% inhibition of (Na+ + K+)-ATPase activity. All three methods are suitable for determining the potency of new semisynthetic digitalis derivatives. The two new derivatives of digitoxin, 3"'-dehydrodigitoxin oxime and 3"'-dehydrodigitoxin methyloxime, were less potent than digitoxin but were of similar potency to ouabain.

Animals↗
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↗
PubMed1996

Binding characteristics of KNI-272 to plasma proteins, a new potent tripeptide HIV protease inhibitor.

The binding characteristics of KNI-272, a potent and selective human immunodeficiency virus (HIV) protease inhibitor, were evaluated in rat and human plasma, and in solutions of human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA). The unbound fractions (Fu) of KNI-272 were 12.13 and 2.24% in rat and human plasma, respectively, at the drug concentration of 1.0 microgram mL-1. Although KNI-272 binds to both AAG and HSA, the Fu of KNI-272 in AAG solution was 1.83%, and only one-quarter of that in HSA solution (Fu = 6.78%). Binding displacing agents, such as disopyramide, warfarin, diazepam, and digitoxin, were used to determine the binding site of KNI-272 on these plasma proteins. The Fu of KNI-272 in AAG solution increased 14-fold when disopyramide was added to the AAG solution. In addition, warfarin, diazepam, and digitoxin were added to HSA solution as representative drugs bound to distinct binding sites on HSA, namely sites I, II, and III, respectively. The Fu values of KNI-272 in HSA solution significantly increased when warfarin and diazepam were added. In particular, with the addition of warfarin to HSA solution, the Fu of KNI-272 increased to 16%. The modified Scatchard plots of KNI-272 binding to AAG and HSA both showed biphasic curves, and the KNI-272 binding sites at low concentration range on AAG and HSA disappeared with the addition of disopyramide and warfarin, respectively. Therefore, it is considered that KNI-272 binds to the identical site as disopyramide on AAG and site I on HSA in the low KNI-272 concentration range. By comparing the KNI-272 binding parameters obtained in human plasma and these protein solutions, we can assume that KNI-272 binding at low concentration in human plasma is mainly concerned with the binding on AAG. As KNI-272 concentration in plasma increases, HSA becomes concerned with KNI-272 binding.

Animals↗