Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Digitoxin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1977

[Affinity of polar digoxin and digitoxin metabolites for digoxin and digitoxin antibodies].

The affinities of some polar and non-polar digoxin and digitoxin metabolites to the related antibodies are largely dependent on the structure of their genin parts. Metabolites with unchanged genins show high cross reactivities towards their related antibodies when compared to the original immunogenic cardenolides. Towards the digoxin antibody the following cross reactivities were found: digoxin-16'-glucuronide 50%, digoxigenin 89.5%, and digoxigenin-3-glucuronide 85%. Values of the same order of magnitude were found with the corresponding digitoxin metabolites and the digitoxin antibody. In contrast, there is a marked decrease in cross reactivity caused by only minor changes in the genin part. With the digitoxin antibody the following cross reactivities are found: digoxin (i.e. 12-OH-digitoxin) 9.1%, 3-epi-digitoxigenin 5.6% and 3-epi-digitoxigenin-3-sulphate 1%. Bcause 12-hydroxylation has been reported to be one of several possible ways of digitoxin metabolisation in man, from a theoretical point of view erroneous results in the clinical digitoxin estimation by radioimmuno-assay are possible. In the case of all of the other metabolites the alterations in positive inotropic activity and cross reactivity run largely parallel.

Antibody Specificity↗
PubMed1977

Studies on digitalis. X. Digitoxin metabolites in human myocardium and relationship between myocardial and serum concentrations of digitoxin in patients on maintenance treatment.

The levels of digitoxin and cardioactive metabolites were measured in 42 atrial biopsies with a 86Rb method modified for analysis of myocardial samples. The mean value was 91.0 ng/gm wet weight (SD 54.4). Myocardial and serum concentrations were compared in 23 patients; there was no significant correlation. The ratio of total drug concentration in myocardium and serum ranged from 1 to 38 with a mean value of 5.4. Calculated from the free drug concentrations, the mean myocardial serum ratio was 200, which reflects the high affinity of digitoxin and cardioactive metabolites to the myocardium. The metabolic pattern of cardioactive and inactive metabolites (conjugates with glucuronic and sulfuric acid) was studied in autopsy samples from left ventricular myocardium from 7 patients. Significant differences between the myocardial and serum patterns of cardioactive and inactive metabolites were demonstrated. The myocardium contained less unchanged digitoxin (25.7%) and more hydrolyzed (55.4%) and conjugated (54.1%) metabolites than serum (57.6%, 31.0%, and 33.1%, respectively). Hydroxylated metabolites in myocardium (15.8%) were not significantly changed compared to serum (10.0%).

Adult↗
PubMed1976

Correlation between myocardial and plasma concentration of digitoxin and its metabolites with special reference to digitoxin radio-immunoassay.

According to our prevous study, the metabolites of digitoxin show nearly dentical affinity with digitoxin antibody. The present study reveals relatively constant ratio of heart to plasma in total 3H-counts, and the concentration of metabolites are ver similar between the two throughout the time investigated which indicates digitoxin concentration of plasma as determined by radioimmunoassay reflects well that of myocardium, although it may contain metabolites.

Animals↗
PubMed1977

Reversal of advanced digitoxin toxicity and modification of pharmacokinetics by specific antibodies and Fab fragments.

The effects of Fab fragments of high-affinity specific antibodies have been studied in a canine experimental model of lethal digitoxin toxicity. Selected antiserum from sheep immunized and boosted with a digoxin-serum albumin conjugate contained antibodies that cross-reacted with digitoxin with an average intrinsic association constant of 1.4 x 10(10) M(-1) as determined by equilibrium dialysis. Rapid second-order association kinetics (k(f) = 3.7 x 10(6) M(-1) per s) and slow dissociation kinetics (k(r) = 1.9 x 10(-4) per s) were documented for the antibody-digitoxin complex. Eight dogs given 0.5 mg/kg digitoxin intravenously developed ventricular tachycardia after 23+/-4 (SEM) min. Control nonspecific Fab fragments were then given. All animals died an average of 101+/-36 min after digitoxin administration. Another eight dogs given the same digitoxin dose similarly developed ventricular tachycardia after 28+/-3 min. This group then received a molar equivalent dose of specific Fab fragments intravenously over 3 min, followed by a 30-min infusion of one-third of the initial dose. All dogs survived. Conducted sinus beats reappeared 18+/-4 min after initial Fab infusion, and stable normal sinus rhythm was present at 54+/-16 min. Plasma total digitoxin concentrations increased threefold during the hour after initial Fab infusion, while plasma free digitoxin concentration decreased to less than 0.1 ng/ml. Effects on digitoxin pharmacokinetics of these Fab fragments and the antibody population from which they were derived were further investigated in a primate species. Unlike common laboratory animals previously studied, the rhesus monkey was found to have a prolonged elimination half-life, estimated at 135 and 118 h by radioimmunoassay and [(3)H]digitoxin measurements, respectively, similar to man and thus providing a clinically relevant experimental model. Intravenous administration of 2 mol of specific Fab fragments per mole of digitoxin 6 h after 0.2 mg of digitoxin produced a rapid 4.3-fold increase in plasma total digitoxin concentration followed by a rapid fall (t((1/2)) 4 h) accompanied by a 14-fold enhancement of urinary digitoxin excretion over control values during the 6-h period after Fab was given. Analytical studies were consistent with increased excretion of native digitoxin rather than metabolites, and the glycoside was found in equilibrium dialysis studies to be excreted in the urine in Fab-bound form. Administration of 2 mol of specific antibody binding sites per mole of digitoxin as intact IgG caused a greater and more prolonged increase in plasma total digitoxin concentration, peaking 13-fold above control levels. In contrast to the effects of Fab, however, specific IgG reduced the rate of urinary digitoxin excretion substantially below control values. We conclude that Fab fragments of antibodies with high affinity for digitoxin are capable of rapid reversal of advanced, otherwise lethal digitoxin toxicity, and are capable of reducing the plasma half-life and accelerating urinary excretion of digitoxin.

Animals↗
PubMed1992

Interactions between digitoxin and some antiarrhythmic drugs.

In the present study the pharmacokinetic interactions between digitoxin and the antiarrhythmic drugs amiodarone, mexiletine and propafenone have been examined. Experiments were performed on rabbits in which serum digitoxin concentration was used as indicator to detect drug interactions. The radioimmunoassay "Coat-A-Count" procedure of DPC was used for the quantitative measurement of digitoxin. It was determined that in order to achieve a considerable level of serum digitoxin, it was necessary to administer a multiple dose rather than the one tolerated by humans. It was also observed that serum contained digitalis like immunoreactive factor(s) (DLIF) measured as digitoxin. The mean (+/- SE) digitoxin equivalent value of the DLIF, measured by the "Coat-A-Count" radioimmunoassay in the serum of rabbits (n = 34) was 4.15 +/- 0.059 ng/ml. Each of the three antiarrhythmic drugs increased serum digitoxin levels; its values were almost double in relation to the control group where only digitoxin was administered. This increased digitoxin value was detected one hour after administration of the first dose of the antiarrhythmic drug and remained at a higher level than that of the control group for 6-8 hours. Rabbits given a single high dose of digitoxin and some of the antiarrhythmic drugs and those given a small dose of digitoxin for only four days, presented a retrogressive increase of digitoxin level in serum 5-6 days later. This mechanism needs to be further investigated.

Amiodarone↗
PubMed1977

Studies on digitalis. XI. Digitoxin metabolism in patients with impaired renal function.

The metabolic pattern of cardioactive and conjugated digitoxin metabolites was studied in 10 uremic patients on maintenance treatment with digitoxin 24 hr after the last dose (mean dose, 0.060 mg/day). Urine was collected over 24 hr. The mean serum digitoxin level was 9.4 ng/ml, and urine level was 6.8 ng/ml. The metabolic pattern of cardioactive metabolites was studied in 5 patients on hemodialysis. Their mean serum digitoxin level was 6.3 ng/ml and urine level was 7.3 ng/ml, on a digitoxin dose of 0.072 mg/day. Unchanged digitoxin was the main cardioactive substance present in both serum and urine of uremic patients. Uremic patients had significantly less unchanged digitoxin and had more hydroxylated (DG-3) and hydroxylated and hydrolyzed (DG-2, DG-1, and DG-0) metabolites than control patients. The extent of conjugation was the same in the two groups. Our data suggest that uremic patients produce more digitoxose than control patients and that digitoxin elimination is more rapid in uremic patients. The altered pattern of digitoxin metabolites is most consistent with uremia-induced changes in hydroxylation and hydrolysis. The hemodialysis group had a pattern of digitoxin and cardioactive metabolites similar to control patients, indicating that patients on hemodialysis differ from other uremic patients with respect to digitoxin metabolism.

Biotransformation↗
PubMedDate not supplied

Effect of cardiopulmonary bypass with heparin administration on digitoxin pharmacokinetics, serum electrolytes, free fatty acids, and renal function.

In 14 patients investigated before, during, and after extracorporeal circulation, serum digitoxin concentration fell significantly during bypass but returned to preoperative values within 24 hr. Both changes occurred in parallel with changes in hematocrit. Serum magnesium concentration fell markedly just before and during bypass and returned to preoperative values on the third and fourth postoperative days. Urine digitoxin concentration fell on the day of operation and remained low in the postoperative period, with a concomitant reduction in the renal excretion of digitoxin. Creatinine and digitoxin clearances decreased on the day of operation and returned slowly to control values during the postoperative period. In 5 other patients, serum digitoxin protein binding decreased significantly during bypass due to heparinization and was normalized by administration of protamine sulfate. Free fatty acids increased significantly immediately before bypass and returned to normal toward its end. The marked changes in digitoxin serum levels during cardiopulmonary bypass can be explained by hemodilution. Acute deterioration of renal function does not lead to accumulation of digitoxin. Heparin administration causes major changes in free fatty acids and serum digitoxin protein binding without important changes in the free digitoxin concentration. Digitoxin can thus be safely administered to patients undergoing cardiac surgery with extracorporeal circulation.

Aged↗
PubMed1979

Some observations on serum concentrations of digitoxin and digoxin.

Serum concentrations of digitoxin and digoxin were measured in 145 cases with various heart diseases receiving maintenance doses of digitalis. Digitalis toxicity was seen in only 2 cases (1.4%). Day-to-day variation of serum concentration while taking the same daily dose was small in digitoxin therapy (13.8%), but a considerable variation was seen in digoxin therapy (24.4%). Serum concentrations of both digitoxin and digoxin were measured in the patients receiving digitoxin, and there was a positive correlation between the two (r = 0.66, p less than 0.001). This fact suggested that the effect of digitoxin was the sum of the effects of digitoxin and its metabolite, digoxin. In the patients taking digoxin, digitoxin was not detected in the serum. Serum digitoxin level had a significantly positive correlation to serum albumin level, presumably because digitoxin was retained in serum in the bound form to albumin. Minimal effective level, 10 ng/ml, was however obtained with higher daily dose of digitoxin in patients with lower serum albumin.

Adolescent↗
PubMed1976

Studies on digitalis. V. The influence of impaired renal function, hemodialysis, and drug interaction on serum protein binding of digitoxin and digoxin.

The aim of the present investigation is to study digitoxin and digoxin protein binding in patients with normal renal and hepatic function, in patients with uremia, and in patients under treatment with hemodialysis for renal failure. The binding of digitoxin and cardioactive metabolites to serum proteins was studied using equilibrium dialysis (an in vitro chemical assay) alone and in combination with a modified 86Rb method. The following values for protein binding were found: DT-3 (digitoxin), 95.7%; DT-2 (digitoxigenin-bis-digitoxoside), 96.5%; DT-1 (digitoxigenin-mono-digitoxoside), 98.7%; DT-0 (digitoxigenin), 92.7%; DG-3 (digoxin), 21.2%; DG-2 (digoxigenin-bis-digitoxoside), 16.3%; DG-1 (digoxigenin-mono-digitoxoside), 18.5%; and DG-0 (digoxigenin), 13.3%. In vitro addition of procainamide, phenytoin, heparin, and rifampicillin did not influence the in vitro binding of digitoxin. Protein binding of digitoxin showed small individual variations in patients with normal renal and hepatic function. Uremia per se did not influence the in vitro binding of digitoxin. There were marked changes in digitoxin and digoxin protein binding during an 8-hr hemodialysis, digitoxin binding decreasing from 97.1% to 93.7% (p less than 0.0025) and digoxin binding from 23.5% to 15.4% (p less than 0.05). In the uremic patient the metabolic pattern of digitoxin tended toward a decrease in protein-bound metabolites.

Blood Proteins↗
PubMed1992

Evidence for the involvement of a distinct form of cytochrome P450 3A in the oxidation of digitoxin by rat liver microsomes.

The preceding paper (B. Gemzik, D. Greenway, C. Nevins, and A. Parkinson (1992). Regulation of two electrophoretically distinct proteins recognized by antibody against rat liver cytochrome P450 3A1. J. Biochem. Toxicol., 7 (43-52).) described the regulation of two rat liver microsomal proteins (50- and 51-kDa) recognized by antibody against P450 3A1. It was also shown that changes in the levels of the 51-kDa 3A protein were usually paralleled by changes in the rate of testosterone 2 beta-, 6 beta-, and 15 beta-hydroxylation. The present study demonstrates that age- and sex-dependent changes in the 50-kDa protein were paralleled by changes in the rate of digitoxin oxidation to digitoxigenin bisdigitoxoside. Induction or suppression of the 50-kDa protein by treatment of rats with various xenobiotics were also paralleled by changes in the rate of digitoxin oxidation. These results suggest that, contrary to previous assumptions, the conversion of digitoxin to digitoxigenin bisdigitoxoside and the conversion of testosterone to 2 beta-, 6 beta-, and 15 beta-hydroxytestosterone are primarily catalyzed by different forms of P450 3A. Further evidence for this conclusion was obtained from studies in which the suicide inhibitor, chloramphenicol, was administered to mature female rats previously treated with pregnenolone-16 alpha-carbonitrile (PCN), which induces both the 50-kDa and the 51-kDa protein. Treatment of mature female rats with PCN alone caused a marked increase (16- to 18-fold) in the 6 beta-hydroxylation of testosterone and the rate of digitoxin oxidation. Treatment of PCN-induced rats with chloramphenicol caused a approximately 70% decrease in liver microsomal testosterone 6 beta-hydroxylation, but had no effect on the rate of conversion of digitoxin to digitoxigenin bisdigitoxoside. The oxidation of testosterone by purified 3A1 (a 51-kDa protein) was also inhibited by chloramphenicol in a time- and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent manner. In addition to testosterone and chloramphenicol, purified 3A1 also metabolized troleandomycin, but it was unable to convert digitoxin to digitoxigenin bisdigitoxoside. Testosterone inhibited the microsomal oxidation of digitoxin, but digitoxin did not inhibit testosterone oxidation. This suggests that testosterone is a substrate for the 3A enzyme that metabolizes digitoxin, but that this form of P450 3A does not contribute significantly to testosterone oxidation by rat liver microsomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1977

[Kinetics of digitoxin during antirheumatic therapy with azapropazone (author's transl)].

The effect of chronic therapy with 5-dimethylamino-9-methylamino-9-methyl-2-propyl-1H-pyrazolo[1,2-a] [1,2,4] benzotriazine-1,3-(2H)-dione-dihydrate (azapropazone-dihydrate; Prolixan 300) on the elimination of a single i.v. dose of digitoxin was studied in 8 patients with rheumatoid arthritis and osteoarthritis using a crossover design. 0.5 mg digitoxin were injected i.v. alone and together with a chronic oral therapy of azapropazone starting 3 weeks before digitoxin was given. Digitoxin plasma levels were determined by radioimmunoassay over a period of 19 days. The half-life for plasma digitoxin was 6.4 +/- 0.5 days after digitoxin alone and 7.0 +/- 0.6 days during azapropazone treatment. In two patients the half-life of digitoxin was increased by about one-third during azapropazone therapy. The areas under the plasma digitoxin curve were 2592 +/- 262 ng/ml X h and 2615 +/- 273 ng/ml X h, respectively. None of the differences were statistically significant. It was concluded that there was no clinically significant interaction between azapropazone and a single dose of digitoxin.

Adult↗
PubMed1975

Intestinal transport of 3H-digitoxin in vitro incompatible with simple diffusion.

On everted jejunal segments of mice the transfer and tissue uptake of 3H-digitoxin, over a concentration range from 2 times 10(-10)--1 times 10(-4)M, was investigated from the mucosal ("m") to the serosal ("s") side as well as in the opposite direction. 1. The time course of the absorption of 3H-digitoxin and some other compounds investigated (glucose, urea, p-aminohippurate) gave evidence of functional integrity throughout the 75 min-periods of the experiments. 2. When 3H-digitoxin was applied to the mucosal side the permeability coefficient showed a dose-dependent increase but returned to lower values at higher concentrations. When 3H-digitoxin was administered to the serosal side the permeability coefficient showed a dose-dependent decrease at high concentrations. The ratio of both coefficients "m" leads to "s"/"s" leads to "m" increased dose-dependently from 0.4--2.6. 3. The uptake of 3H-digitoxin--applied on the serosal side--into the tissue was independent of dose. However, having administered 3H-digitoxin on the mucosal side the tissue accumulation was 2--5 fold higher and the tissue/medium (T/M) ratio increased within the concentration range from 3.0-9.0 4. Under DNP (1 mM) the asymmetry and dose dependence of the permeability and tissue uptake up 3H-digitoxin observed in controls were almost abolished. Therefore it is likely that the transfer of 3H-digitoxin in the intact intestine involves a mechanism more complex than simple diffusion. The existence of more than a two compartment system and/or the contribution of an active transport mechanism is suggested.

Aminohippuric Acids↗
PubMed1992

Measurement of digitalis-glycoside levels in ocular tissues: a way to improve postmortem diagnosis of lethal digitalis-glycoside poisoning? II. Digitoxin.

Postmortem digitoxin levels in the choroid-retina and vitreous humor of patients who had undergone digitoxin therapy (therapeutic group) and in one case of suicidal digitoxin poisoning were measured and compared with levels in femoral vein blood, myocardium, kidney and liver. The results were interpreted in light of the medical history of each patient. The digitoxin level in the choroid-retina of the single case of suicidal poisoning was far higher than the choroid-retinal levels in the therapeutic group. In the latter, variation in choroid-retinal levels was comparable to that in the other tissues. In cases where the choroid-retina of the right and left eyes were examined, digitoxin levels in both eyes were essentially equal. There was no indication of significant changes in choroid-retinal levels due to postmortem diffusion of digitoxin into the vitreous body. Based on these results, determination of digitoxin levels in the choroid-retina could contribute to improving postmortem diagnosis of lethal digitoxin poisoning.

Adult↗
PubMedDate not supplied

Correlation between pharmacokinetics and intropic and electrophysiologic responses to digitoxin in the intact dog.

We attempted to correlate inotropic and eletrophysilogic digitoxin effects with serum digitoxin concentrations during 8 hr after a single dose. Eight pentobarbital-anesthetized Labrador dogs were given 2.0 mg digitoxin intravenously. Left heart catheterization and His bundle registration were performed. acing and programed electrical stimulation were used to determine heart rate-independant changes in dP/dt, intra-atrial, atrioventricular (AV), His-Purkinje, and intraventricular conduction velocity. The effective (A-ERP) and functional (A-FRP) refractory periods of the atrium and the functional nodal refractory period (AV-FRP) were measured. Serum digitoxin concentrations were determined by radioimmunoassay. Median serum digitoxin half-time was 5.7 hr. The dP/dt increased after digitoxin, with maximum values after 2 hr. Digitoxin concentration correlated with the inotropic response after 4 hr. Heart rate fell significantly within 2 min and remained below control values for the 8 hr observation period concimitant with an increase in AV-nodal conduction time and AV-ERP increased significantly in the late elimination phase, while A-FRP increased slightly initially and remained high. No consistent correlation was found between the electrophysilogic variables and serum concentrations. We conclude that the two main effects of digitoxin, the inotropic and electrophysiologic, are dissociated in the elimination phase after a single dose.

Animals↗
PubMed1978

Quantitative studies on acid hydrolysis of digitoxin.

Hydrolysis of 3H(G)-digitoxin by hydrochloric acid and human gastric juice is described. Incubation temperatures of 37 degrees C and 22 degrees C were chosen for electrolyte solutions, and 37 degrees C for the experiments with gastric juice. After dichloromethane extraction, the radioactive metabolites were separated by thin-layer chromatography, localized and quantified by a radiochromatogram scanner. The degradation products separated by TLC were digitoxigeninbis-digitoxoside, digitoxigenin-mono-digitoxoside, and digitoxigenin. After 10 min of incubation at pH 1, digitoxin amounted to 38.6% of the total radioactivity in electrolyte solution and 37.6% in gastric juice. After 60 min, the percentage of digitoxin decreased to 5.9% and 0%, respectively. After 120 min at 22 degrees C, amounts of unhydrolyzed digitoxin were: at pH 1 55%; and at pH 2 84%. After 10 min at pH 1, and 60 min at pH 2, digitoxin was hydrolyzed to such an extent that bioavailability should have been significantly reduced. Absorption of digitoxin (liquid) from the stomach was studied during gastroscopy in five patients. Among them, significant differences in absorption kinetics and bioavailability existed, as revealed by radioimmunological measurements of the digitoxin blood levels.

Chemical Phenomena↗