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PubMed1997

Involvement of a peripheral mechanism in the emesis induced by cardiac glycosides in Suncus murinus.

The ability of three cardiac glycosides, ouabain, digitonin and digitoxin, to induce emesis and their mechanism(s) of action were investigated in Suncus murinus. The intraperitoneal injection of ouabain but not digitonin nor digitoxin caused vomiting in a dose-dependent manner. However, the administration of ouabain into the cerebroventricle did not cause emesis. Ouabain-induced emesis was partly prevented by surgical abdominal vagotomy. Pretreatment with tropisetron, a selective 5-HT3 (5-hydroxytriptamine) receptor antagonist, did not affect the emetic response evoked by ouabain. These results suggest that ouabain exerts emetic effects via peripheral mechanism(s), but 5-HT3 receptors are not involved in the pathway.

Animals↗
PubMed2005

Application of fluorescence correlation spectroscopy to hapten-antibody binding.

Two-photon fluorescence correlation spectroscopy 2P-FCS has received a large amount of attention over the past ten years as a technique that can monitor the concentration, the dynamics, and the interactions of molecules with single molecule sensitivity. In this chapter, we explain how 2P-FCS is carried out for a specific ligand-binding problem. We briefly outline considerations for proper instrument design and instrument calibration. General theory of autocorrelation analysis is explained and straightforward equations are given to analyze simple binding data. Specific concerns in the analytical methods related to IgG, such as the presence of two equivalent sites and fractional quenching of the bound hapten-fluorophore conjugate, are explored and equations are described to account for these issues. We apply these equations to data on two antibody-hapten pairs: antidigoxin IgG with fluorescein-digoxin and antidigitoxin IgG with Alexa488-digitoxin. Digoxin and digitoxin are important cardio glycoside drugs, toxic at higher levels, and their blood concentrations must be monitored carefully. Clearly, concentration assays based on IgG rely on accurate knowledge of the hapten-IgG binding strengths. The protocols for measuring and determining the dissociation constants for both IgG-hapten pairs are outlined and discussed.

Animals↗
PubMed1979

A critical appraisal of a further three new commercial digoxin radioimmunoassay kits with reference to cross-reacting substances.

A further 3 digoxin radioimmunoassay (RIA) kits have been evaluated for performance and cross-reaction with digitoxin, spironolactone, canrenone and furosemide (Lasix-Hoechst). Effects of serum protein concentrations have also been tested. The kits tested were from the following manufacturers: A) Diagnostic Products Corporation Digoxin RIA Kit. B) Byk-Mallinckrodt SPAC Digoxin Kit. C) Boehringer-Mannheim Digoxin RIA Kit. All kits used a 125I-labelled tracer. Kit A used a conventional liquid phase system using double-antibody separation for bound and free drug, Kits B and C used a solid-phase antibody coated tube method. All kits showed a lower cross-reaction to digitoxin than quoted by the manufacturer. Cross-reaction to spironolactone (Aldactone--Boehringer-Mannheim) was less than 1.50 nmol/l at a serum concentration of 125 mg/l Aldactone in all 3 kits. The cross-reaction to canrenone was somewhat higher, 5.2 nmol/l "digoxin" being measured in one kit at a serum canrenone concentration of 125 mg/l. There was no cross-reaction with furosemide in any kit, even at a serum concentration of 5 g/l. The coated-tube assays were affected by serum albumin and globulin concentration changes, one kit showing a difference of over 50% binding in the range 1--20% albumin. The double-antibody kit did not show dependence on the concentration of these proteins. All kits measured digoxin with good reproducibility in the range 0.40--10.0 nmol/l.

Blood Proteins↗
PubMed1976

The effect of digitalis on regional ischaemia of the rat small intestine.

Research in recent years has shown that under certain conditions digitalis has a strong vasoconstrictive effect in the splanchnic region. This may imply that in cases of mesenteric ischaemia, digitalization may inhibit a collateral circulation necessary for restoration of the intestinal function. In this investigation the effect of digitoxin on the exchange circulation of the small bowel mucosa was studied in rats with induced regional ischaemia of the intestine. On analysis 30 min after establishment of the ischaemia a statistically significant negative effect of digitoxin was observed.

Animals↗
PubMed1987

Demonstration and characterization of two classes of cardiac glycoside binding sites to rat heart membrane preparations using quantitative computer modeling.

Cardiac glycoside binding to rat heart membrane preparations was measured by rapid filtration technique. The binding data were analyzed using quantitative computer analysis. The experimental results using [3H]-ouabain as the labeled ligand were consistent with a model in which cardiac glycoside specific binding occurs at two independent classes of sites. The high affinity sites were characterized by a dissociation constants of 40 nM, 50 nM, and 61 nM for ouabain, digoxin and digitoxin, respectively, with a binding capacity of 1.3 pmoles/mg protein. The lower affinity sites for ouabain were characterized by dissociation constants of 2.3 microM, 67 nM and 71 nM for ouabain, digoxin and digitoxin, respectively, with a binding capacity of 3 pmoles/mg protein. Potassium ions inhibit [3H]-ouabain binding in a dose dependent manner with an IC50 of 500 microM. Quantitative computer modelling indicated that potassium inhibits ouabain binding at both binding sites.

Animals↗
PubMed1976

Differential species sensitivity to the inhibitory effect of cardiac glycosides on 3H-1-noradrenaline accumulation by tissue slices.

Effects of three cardiac glycosides on the accumulation of 3H-1-noradrenaline (3H-1-NA) by slices of heart and spleen were studied. Ouabain, digitoxin and digoxin, all produced a concentration dependent inhibition of 3H-1-NA uptake in both types of tissue slices. The maximum amount of 3H-1-NA accumulated as well as the rate of uptake was decreased. Digitoxin and ouabain were equipotent; however, digoxin was significantly less potent. Tissues from different mamalian specis did not exhibit the same degree of sensitivity to the inhibitory effect of cardiac glycosides on 3H-1-NA accumulation. Dogs were most sensitive and guinea-pigs an order of magnitude less sensitive. Rats were least sensitive by roughly two orders of magnitude when compared with guinea-pigs. The relationship of the effect of digitalis on 3H-1-NA accumulation to digitalis-induced cardiac arrhythmias is discussed. Finally, the pattern of species sensitivity found here is compared with that observed in relation to inhibition of Na+-K+-ATPase by cardiac glycosides.

Animals↗
PubMed2001

Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells.

PURPOSE: Digitalis or cardiac glycosides have been noted to induce tumor static or oncolytic effects in various types of cancer. We evaluated the effects and underlying mechanisms of cardiac glycosides, including digoxin, digitoxin and ouabain, on the proliferation of hormone dependent and independent prostate cancer cell lines. MATERIALS AND METHODS: Cell proliferation of the 3 human prostate cancer cell lines LNCaP, DU145 and PC3 was measured by 3-(4,5-dimethylthiazol-2-yle)2,5-diphenyltetralozium bromide (Sigma Chemical Co., St. Louis, Missouri) colorimetric assay. The cytotoxic effects of digitalis on prostate cancer cells were determined by lactate dehydrogenase measurements of the culture medium. Intracellular Ca2+ was measured by a dual wavelength spectrometer system. The percent of apoptotic cells after digitalis treatment was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling and flow cytometry. RESULTS: Digoxin, digitoxin and ouabain significantly inhibited the proliferation of LNCaP, DU145 and PC3 cells at a dose of 1 or 10 microM. after 1 to 4 days of culture. Cytotoxicity of digitalis on the DU145 and LNCaP cells was dose dependent but cytotoxicity was not obvious in PC3. Digitalis (1 microM.) significantly increased intracellular Ca2+ in LNCaP and DU145 after 12 hours of culture but PC3 cells needed a 24-hour treatment to show any effect. In the apoptosis measurement digitalis at a dose of 1 and 10 microM. also significantly increased the percent of apoptotic cells in the LNCaP, DU145 and PC3 cell lines. Normal control human glomerular epithelial cells showed no response to digitalis treatment at all tested doses. CONCLUSIONS: Digitalis may inhibit the proliferation of prostate cancer cell lines, although the 3 cell lines showed varied sensitivity to digitalis. These effects are possibly the result of a mechanism involving sustained elevation of the concentration of intracellular Ca2+ and of apoptosis.

Apoptosis↗
PubMed1975

[Studies on metabolism and pharmacokinetics of alpha-acetyldigitoxin in man (author's transl)].

3H-alpha-Acetyl-digitoxin was administered to 5 patients i.v. and 3 patients p.o. The half-life of label in the plasma was 8.5 +/- 1 (i.v.) and 8.8 +/- 1 (p.o.) days. 20.9 +/- 3.6% (i.v.) and 21.3 +/- 2.9% (p.o.) of the radioactive dose were excreted into the urine in 6 days. Two patients excreted within 18 days 14.3 and 16.1% of the given dose with the stool. After oral administration 22.3% of the orally administered 3H-activity were eliminated into the feces by one patient. 63% (i.v.) and 53% (p.o.) of the chlorofrom-extracted 3H-activity in the urine could be attributed to digitoxin by means of thin-layer chromatography. The volatile content of plasma radioactivity was 4.07 +/- 0.1% (i.v.) and 6.78 +/- 0.2% (p.o.). The protein binding of a 4%. Albumin solution was 83 +/- 0.54%, for plasma 80.8 +/- 2%.

Acetyldigitoxins↗
PubMed1976

Correction of protein binding defect in uremic sera by charcoal treatment.

Protein binding of numerous drugs, primarily organic acids, is decreased in sera from uremic patients. The defect in binding is (1) greater than can be accounted for by hypoalbuminemia alone; (2) unchanged by prolonged in vitro dialysis; (3) transferred in the protein but not the ultrafiltrate fraction of uremic serum; and (4) not reproduced by addition of low and middle molecular weight compounds known to accumulate in uremia. However, treatment with activated charcoal at pH3 was found to significantly increase drug protein binding in uremic sera. This effect was studied with six different drugs in sera from groups of 6 normal subjects and 8 patients on chronic hemodialysis. The percentage of sulfamethoxazole, dicloxacillin, diphenylhydantoin, salicylate, and digitoxin bound to protein in normal sera (65.9, 97.1, 93.1, 96.7, and 92.7, respectively) was unchanged by charcoal treatment. In contrast, charcoal treatment significantly (p less than 0.01) increased the percentage of drug bound to protein in uremic sera from 41.7 to 59.0 for sulfamethoxazole, 90.7 to 96.3 for dicloxacillin, 84.3 to 90.8 for diphenyhydantoin, 86.4 to 93.8 for salicylate, and 89.5 to 90.9 for digitoxin. Charcoal treatment significantly (p less than 0.05) reduced penicillin protein binding in normal sera and failed to correct the binding defect for penicillin in uremic sera. The effect of charcoal can be explained by removal of an inhibitor which accumulates in uremia and (1) occupies the binding site of certain drugs, (2) changes the configuration of the albumin molecule, or (3) both. Free fatty acid (FFA) concentrations in uremic patients were similar to those in normal subjects and were not the cause of the binding defect.

Blood Proteins↗
PubMedDate not supplied

Differences in cardiodepressant effects of halothane and isoflurane after inotropic stimulation in guinea-pig papillary muscles.

The effects of halothane and isoflurane on action potentials and force of contraction were studied in guinea-pig isolated papillary muscles in order to investigate the cardiodepressant action of the anesthetics in the presence of clinically relevant inotropic drugs. In control conditions, equipotent concentrations of the two volatile anesthetics depressed force of contraction to a similar degree. Halothane (2%) slightly shortened the action potential duration, whereas isoflurane (2.8%) did not influence the shape of the action potential. The muscles were then treated with three different inotropes, digitoxin, amrinone and 3-isobutyl-1-methylxanthine (IBMX) prior to exposure to the anesthetics. After pretreatment with digitoxin and amrinone, halothane was significantly more cardiodepressant than isoflurane. With IBMX, no difference in negative inotropic effect was observed. Neither volatile anesthetic significantly changed the action potential duration after pretreatment with the inotropic drugs. We suggest that halothane is more cardiodepressant than isoflurane in the presence of drugs which enhance force of contraction both by an increase in calcium influx and calcium release because it impairs force of contraction not only via inhibition of the calcium current but also via interference with calcium release.

1-Methyl-3-isobutylxanthine↗
PubMed1976

[Influence of roentgen rays on electrolyte changes and metabolism of the myocardium. VII. Radiation-induced inhibition of the sodium- and potassium--activated microscomal-trasport ATPase].

The behavior of a Mg2+-dependent microsomal ATPase, which may be activated by Na+ and K+, was investigated in the myocardium of Guinea pigs after local irradiation. The part which can be activated by Na+ and K+ (transport-ATPase) is already slightly inhibited thirty minutes after a dose of 250 R; the inhibition rate with 1500 R amounts to about 60%, the maximal inhibition effect with a dose of 3000 R was about 70%. Four hours after a local irradiation with 1500 R, a restitution of the inhibition effect occurs with overshoot reaction; 15 and 24 hours following irradiation, a significant inhibition of the transport-ATPase activity can again be verified. The k-strophanthidine and digitoxin are inhibiting within the concentration ranges analyzed (2 X 10(-5), 2.5 X 10(-7), 5 X 10(-7) M) the activity of the transport-ATPase. The above-mentioned radiation-induced inhibition effect upon the ATPase activated by Na+ and K+ is additively increased by adding k-strophanthidine (2 X 10(-5) M) and digitoxin (2.5 X 10(-7) M).

Adenosine Triphosphatases↗
PubMed1977

Digitalis toxicity: lack of marked effect on brain na+,k+-adenosine triphosphatase in the cat.

Effect of digitalis on central sympathetic neurons have been proposed to alter sympathetic influences on the heart and to contribute to the induction of arrhythmias. Recently, however, we have presented evidence which indicates that the involvement of a direct central action of digitalis is negligible in the alteration of sympathetic nerve activity after i.v. administration of the drug. Thus, a group of experiments were designed to determine if central drug concentrations or biochemical events in the brain would suggest a central action of the drug. Tritiated digoxin (20 microng/kg) was injected i.v. into cats every 15 minutes until ventricular fibrillation occurred. The concentrations of digoxin in cerebrospinal fluid and serum increased linearly with time as the cumulative dose of digoxin was increased. At the mean arrhythmic dose, 140 microng/kg, cerebrospinal fluid contained approximately 10 nM digoxin whereas free digoxin concentration in serum was approximately 30 nM and total digoxin concentration in serum was approximately 120 nM. Since inhibition of Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) is often associated with the pharmacological effects of digitalis, effects of nanomolar concentrations of digoxin on Na+,K+-ATPase activity were determined in vitro. The concentration of digoxin faund in cerebrospinal fluid at arrhythmia inhibited Na+,K+-ATPase only slightly (5-10%). Activity of Na+,K+-ATP-ase was also examined in brains of cats which had died in ventricular arrhythmias due to treatment with lethal dose of digitoxin. After ventricular fibrillation, the cat brains were removed and Na+,K+-ATPase activity and ouabain binding were determined in eight areas. No reduction in Na+,K+-ATPase activity or [3H]ouabain binding was observed in any area. Thus, it appeared that toxic doses of digitalis did not cause sail to provide evidence for central effects of toxic doses of digoxin or digitoxin.

Adenosine Triphosphatases↗
PubMed1989

[Suicidal digitalis poisoning: considerations concerning treatment strategy with antibodies].

Suicidal digitalis poisoning is life-threatening and often has a fatal outcome. The treatment and clinical course of acute poisoning with 250 mg digitoxin in a depressive male patient aged 48 years are reported. Marked elevation of serum digitoxin level (360 nmol/l 8 hours after ingestion) and initial hyperkalemia (5.7 mmol/l) as well as the history of excessive dose intake, pointed toward severe intoxication. Mainstays of management with favourable outcome were vomiting and gastric lavage, followed by administration of repeated doses of digoxin-specific Fab antibody fragments. Evaluation of severity of poisoning and recommended supportive measures in digitalis overdose suicide victims are summarized and practical features of antibody preparations are discussed.

Digitoxin↗
PubMedDate not supplied

[Guidelines for prescription of the assay of digitalis glycosides by immunologic methods].

Digoxin, digitoxin and acetyldigitoxin are the most widely prescribed of cardiotonic glycosides. Analytical exploration can be performed by a single assay when only one compound is prescribed or by multiple assays in cases of imprecise prescription or when several glycosides are given concomitantly. In addition, the metabolic transformation of digitoxin into digoxin and the presence of endogenous "digitalis-like compounds" mean that a number of precautions must be taken during prescription. These examples underline the ambiguity of the so-called "digitalinaemia" prescriptions and the need for biologists to be supplied with maximum information by clinicians.

Acetyldigitoxins↗
PubMed1985

Pharmacokinetics and pharmacodynamics of muzolimine in chronic heart failure.

The aim of the present study was to investigate muzolimine pharmacokinetics and pharmacodynamics in chronic heart failure. We report preliminary results from 6 patients, aged 64.2 years (range 54-73), in chronic heart failure (NYHA class III). All patients had lowered ejection fraction determined by echocardiography, and increased heart volume determined by cardiac X-ray. They were under treatment with long-term digitoxin with serum digitoxin concentrations within or below the therapeutic range. We investigated muzolimine pharmacokinetics on day 1 of treatment and after 28 days. Heart rate and rhythm were monitored with 24 hours ECG recording and analyzed on an Avionics Arrhythmia Analyzer. Heart rate, cardiac volume, ejection fraction and laboratory findings were not significantly changed between day 1 and day 28 of treatment. The time for peak absorption ranged between 1.5 and 6 hours on day 1 and 1.0 and 3 hours on day 28. The peak concentration was significantly higher on day 28. No significant difference was found in the areas under the concentration curves, serum elimination half-lives and renal clearances after acute and chronic administration. In the first 4 patients studied, we found ventricular and supraventricular arrhythmias before treatment and after 28 days on muzolimine. These preliminary data indicate a change in the pharmacokinetics of muzolimine on chronic dosing with more rapid absorption, higher peak concentrations, and increased area under the other plasma concentration curves.

Aged↗
PubMed1977

[Synthesis and characterization of some cardenolide glucuronides and sulphates (author's transl)].

Cardenolide glucuronides are synthesized in the following way: firstly cardenolide glucosides are prepared by the reaction with acetobromglucose; secondly the hydroxymethyl group of the glucose moiety is oxydized in presence of a platinum catalyst to the carboxyl group of the final glucuronic acid. Glucuronides of the following cardenolides are prepared and described: digoxin, digoxigenin, digitoxin, digitoxigenin-monodigitoxoside, digitoxigenin, and 3-epi-digitoxigenin. Sulphates of digoxigenin, digitoxigenin, and 3-epi-digitoxigenin are prepared by direct reaction of these cardenolides with chlorosulphonic acid in pyridine. The assumed structure of some conjugates has been confirmed by n.m.r. spectroscopy. A high water solubility (6.7-65.1 g/l), a minute chloroform solubility (0.0002-0.0005 g/l), and a low octanol/polar nature of these compounds. Inotropic or toxic cardiac activities of the conjugates are examined on isolated guinea pig papillary muscles and by the Hatcher method on cats. Conjugates with at least one digitoxose show cardioactivities comparable to digoxin or digitoxin. In contrast to that the conjugated genins indicate decreased activities which are at least one-tenth of the potency of the unconjugated glycosides.

Animals↗
PubMed1977

Studies on digitalis. XIV. Is there any correlation between hypomagnesemia and digitalis intoxication?

In a prospective study on digitalis intoxication, low serum magnesium was found in 90 patients, while 388 patients had values above 1.5 mEq/l. Hypomagnesemia was more frequent in women than in men, in those with low body weight and in those with advanced heart failure. More patients with hypomagnesemia than those without had nausea, anorexia, fatigue, flickering of vision and atrial tachycardia with block. Patients with hypomagnesemia also had lower serum potassium than normomagnesemic patients. There was, however, no significant difference in the prevalence of digitalis intoxication or in serum digitoxin concentration. Nor was there any correlation between serum digitoxin and serum magnesium levels.

Body Weight↗
PubMed1981

Correlations between adrenal weight and heart weight in rats with a cardiac overload.

A significant positive correlation between heart weight and adrenal weight was found in rats with myocardial hypertrophy induced by experimental hyperthyroidism or ligation of the abdominal aorta. The simultaneous administration of digitoxin partly inhibited myocardial hypertrophy after ligation of the abdominal aorta, but not after experimental hyperthyroidism. Digitoxin also inhibited adrenal hypertrophy after ligature of the abdominal aorta but, again, not after experimental hyperthyroidism. The possible existence of an endogenous cardiotropic hormone participating in the development of cardiac hypertrophy from overloading is discussed.

Adrenal Glands↗