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PubMed1989

[Therapeutic drug monitoring of digitoxin--results of 3 years' experience].

Between 1986 and 1988 within our therapeutic drug monitoring plasma concentrations were estimated in 1,442 plasma samples by radioimmunoassay. Plasma levels between 0 and 84.2 ng.ml-1 with a mean of 20.8 ng.ml-1 were measured. If the maintenance dose was reduced from 0.1 to 0.07 mg the frequency distribution of the plasma samples was shifted to the left, and the mean value decreased by 5.8 ng.ml-1 (23.5 vs. 17.7 ng.ml-1). The physician's assumptions underdosage?, optimum dosage schedule? or overdosage? were confirmed by the laboratory results in 22.3, 63.6, or 23.0% of the requests, respectively. In 61.2% of all plasma samples were digitoxin concentrations in the range between 10 and 30 ng.ml-1, i.e. in the optimum therapeutic range. Main reasons for the divergent results are non-compliance of the patients and inter-individual differences in the pharmacokinetics of digitoxin. Furthermore, incomplete filling of the forms by the physicians aggravates the assessment of the results. Therefore, a permanent dialogue between clinician and clinical pharmacologist is necessary for an improvement of digitalis therapy.

Adolescent↗
PubMedDate not supplied

In vitro digitoxin metabolism. Rate-limiting step and alteration following spironolactone pretreatment.

The biotransformation of digitoxin was considered as a linear transformation comprised of dual deoxy sugar cleavages culminating with product conjugation to glucuronic acid. Digitoxin and two metabolites, digitoxigenin bisdigitoxoside and digitoxigenin monodigitoxoside, were each incubated for 1 hr with rat liver slices. Measurements of amounts of various metabolites allowed determination of rate constants, showing the cleavage of the terminal sugar from digitoxigenin bisdigitoxoside to be the rate-limiting step. The inductive action of spironolactone predominately affected the rate-limiting step.

Animals↗
PubMed1985

[Digitoxin-induced thrombopenia with recurrence after accidental reexposure].

One case of digitoxin-induced thrombopenia with relapse upon reexposure is reported. Cytopenia was each time rapidly reversible upon withdrawal of the medication. During the two episodes, blood digitoxin was superior to the generally accepted value. No thrombopenia was caused by administration of digoxin. The criteria for diagnosis and the difficulty of causal demonstration are discussed. Up to the present the literature has reported 11 cases of cardiotonic-induced thrombopenia. The features of these observations are reviewed.

Digitoxin↗
PubMedDate not supplied

Metabolism of digitoxin in the isolated perfused rat liver. Effect of spironolactone pretreatment.

Livers from either control or spironolactone-treated rats were perfused for a 90-min period with 30% rat blood and 3H-digitoxin. At several time periods throughout perfusation, bile was collected and a sample of blood was removed from the perfusate. Extractions were performed on both blood and bile to determine amount of polar and nonpolar metabolites at 60 min. Polar metabolites were cleaved with beta-glucuronidase and high-pressure liquid chromatography was used to separate the resultant nonpolar metabolites from blood and bile cleaved with beta-glucuronidase. Biliary excretion and perfusate disappearance of 3H-digitoxin were significantly increased in livers taken from spironolactone-pretreated animals. Both polar and nonpolar metabolites in bile were significantly increased in pretreated animals. The majority of polar metabolites produced by livers from both treated and nontreated animals were readily cleaved with beta-glucuronidase. Both biliary excretion and metabolic pattern, obtained from these studies in an isolated perfused rat liver, mimic those seen in the intact rat. Thus, the isolated perfused rat liver can be used as a model for in vivo studies of cardiac glycoside metabolism.

Animals↗
PubMed1984

Role of electrolytes and digitalis-like activity in hypertension: effects of digitoxin, sodium, potassium and magnesium on blood pressure.

The purpose of the present study was to test the hypothesis that an increased digitalis-like activity, induced by excessive intake of Na, is involved in the development and maintenance of hypertension. In normotensive rats prolonged administration of digitoxin alone induced only a mild and transient rise of blood pressure. Increased intake of NaCl did not affect the blood pressure of these rats. However, simultaneous administration of both digitoxin and NaCl produced a sustained elevation of blood pressure. In SHR the effect of the addition (6% of the weight of the pellets) of 1) NaCl or 2) a mixture containing 50% NaCl and 50% KCl or 3) a mixture containing 65% NaCl, 25% KCl, and 10% MgSO . 7H2O, was examined. A marked fall of blood pressure occurred during the use of the mixtures containing K and Mg. The results suggests that both an increased intake of Na and an increased digitalis-like activity are needed for the development of hypertension. The results on SHR confirm the previous findings demonstrating that the use of salt mixtures in which a part of the NaCl is replaced by K and Mg salts is beneficial compared to the use of NaCl. Furthermore, since K and Mg are effective antagonists of digitalis the results could suggest the involvement of an increased digitalis-like activity in the maintenance of hypertension.

Animals↗
PubMed1984

[Gitoformate and digitoxin as alternatives to kidney-dependent glycosides in the therapy of cardiac insufficiency].

Kidney independent glycosides offer a high measure of therapeutic safety in comparison with kidney dependent glycosides. The intoxication rate lies between 4 and 6%. The pharmacokinetic properties of pentaformylgitoxin (INN: gitoformate) are comparable with those for digitoxin. The active glycoside 16-formylgitoxin (INN: gitaloxin) is formed by rapid deformylation of the formyl residue on the sugar chain. The maintenance dose of 0.06 mg daily, based on the half-life, produces therapeutic concentrations in the range 6-30 ng/ml. The required loading dose, as for digitoxin, amounts to 10 times the maintenance dose.

Cardiac Glycosides↗
PubMed1978

Appropriateness of the use of serum digoxin and digitoxin assays.

The use of 145 digoxin and digitoxin assays was studied in a teaching hospital to determine if performance of assays was appropriate and therapeutically beneficial. Patient charts (121) were randomly selected from a list of all patients for whom digoxin or digitoxin assays were performed. Charts were compared with established criteria to determine whether the assay was indicated and performed correctly and whether dosage was adjusted correctly based on assay results. Of the assays reviewed, 49% were performed for irrational indications; 86% were performed appropriately under steady-state conditions; and 96% used serum samples appropriately drawn more than six hours after administration of the last digitalis glycoside dose. Of the assays performed at appropriate times in relation to dose and at steady-state plasma concentrations (120), 31 should have and 89 should not have resulted in a dosage change. Of the latter, 98% were evaluated correctly. Of the former, 36% were not evaluated correctly (i.e., indicated dosage adjustments were not made). Control of the use of digitalis glycoside assays is needed. Pharmacists should become involved in monitoring drug assays to assure appropriateness of assay request, interpretation and follow-up.

Digitoxin↗
PubMed1996

Digitoxin intoxication with lethal outcome.

A 65-year old woman with known history of reactive depression and failed suicide attempts ingested 7 mg digitoxin at 09.00 h. After vomiting 4 hours later, she reported the drug intake to her husband who thereupon summoned a physician. Arriving at 16.00 h, the physician was informed about the suicide attempt, but failed to initiate any specific measures. After a second doctor's visit at 22.00 h, the patient was rushed to hospital in a moribund state. In spite of a gastric lavage, treatment with activated charcoal and insertion of a transvenous pacemaker, the patient died at 23.45 h with signs of total atrioventricular block. Digitalis fab fragments could not be administered in time. A calculation based on the plasma digitoxin concentration of 212 ng.ml-1 measured at 23.00 h indicated that nearly the entire ingested dose had been absorbed. Thus, neither the vomiting nor the gastric lavage eliminated significant amounts of the drug which had left the stomach without delay. Under these circumstances, the failure to initiate timely therapy with specific digitalis fab fragments ultimately contributed to the lethal outcome.

Aged↗
PubMed1976

Digitoxin plasma half-life in the dog after administration of toxic doses.

Digitoxin plasma levels were determined in the dog by radioimmunoassy after i.v. infusion of this cardenolide in toxic amounts (388 +/- 13 mug/kg). Plasma values found immediately after the administration of this dose were 588.5 +/- 91 ng/ml and attained very low levels (10 ng/ml) 96 h later. The dominant half-life of digitoxin in the dog was found to be 49.6 +/- 6.5 h, but this value was attained only in the final part of our study. The results found are compared with previous data and controversial aspects are discussed.

Animals↗
PubMed1978

Cross reactivity of digitoxin and spironolactone in two radioimmunoassays for serum digoxin.

We measured the cross reactivity of two medications--digitoxin and spironolactone--in two digoxin radioimmunoassay (liquid and solid-phase) kit procedures. Both tests showed similar average percentages of cross reactivity with digitoxin (7.2 and 8.9% for intravenous, and 11.9 and 10.9% for oral administration), but no cross reactivity with spironolactone or its metabolites after equal intravenous or oral doses.

Cross Reactions↗
PubMed1988

Laser desorption/fourier transform ion cyclotron resonance mass spectrometry: digoxin, digitoxin, and their reduced and sugar-hydrolyzed metabolites.

Mass spectra of digoxin and digitoxin (the most widely prescribed drugs for treatment of congestive heart failure) and a complete set of their 14 dihydro- and sugar-hydrolyzed metabolites have been obtained via laser desorption/ionization with a Fourier transform ion cyclotron resonance (LD/FT/ICR) mass spectrometer. The most intense peak is typically the pseudomolecular [M + K]+ ion, but fragment ions corresponding to loss of 1-3 sugars and hydroxyls are also observed. LD/FT/ICR mass spectra for all 16 compounds were produced with a single set of sample and spectrometer parameters. No matrix peaks are present. Finally, LD/FT/ICR provides dynamic mass accuracy within approximately 5 ppm throughout a mass range of 404 less than m/z less than 819.

Digitoxin↗
PubMed2006

Mechanisms of digoxin and digitoxin on the production of corticosterone in zona fasciculata-reticularis cells of ovariectomized rats.

Previous studies have indicated that digoxin (DG) inhibits testosterone production by rat testicular interstitial cells through both in vivo and in vitro experiments. DG and digitoxin (DT), but not ouabain, inhibit the progesterone, pregnenolone, and corticosterone secretion by rat granulosa cells, luteal cells, and zona fasciculata-reticularis (ZFR) cells, respectively. However, the effect of DG and DT on the enzyme kinetics of cytochrome P450 side chain cleavage enzyme (P450scc), the protein expression of P450scc and steroidogenic acute regulatory protein (StAR), and mRNA expression of StAR are unclear. ZFR cells were prepared from adrenocortical tissues of ovariectomized rats, and then challenged with adrenocorticotropin (ACTH), 8-Br-cAMP, forskolin, A23187, cyclopiazonic acid (CPA), nicotinic acid adenine dinucleotide phosphate (NAADP), trilostane, 25-OH-Cholesterol, progesterone, or deoxycorticosterone in the presence of DG, DT, or ouabain for 1 h. Enzyme kinetics of P450scc, protein expression of acute regulatory protein (StAR) and P450scc, and mRNA expression of StAR were investigated. DG and DT but not ouabain suppressed basal and other evoked-corticosterone release significantly. DG and DT also inhibited pregnenolone production. The Vmax of the DG and DT group was the same as the control group, but the Km was higher in DG- and DT-treated group than in control group. DT and ouabain significant suppressed mRNA expression of StAR. DG and DT had no effect on the P450scc and StAR protein expression at basal state, but diminished ACTH-induced StAR protein expression to basal level. These results indicated that DG and DT have an inhibitory effect on corticosterone production via a Na+, K+-ATPase-independent mechanism by diminishing actions on cAMP-, Ca2+-pathway, competitive inhibition of P450scc enzyme and reduction of StAR mRNA expression.

Adrenal Cortex↗
PubMed1977

Polynitro aromatic compounds in analytical chemistry I: reaction with ouabain and digitoxin.

By the use of NMR spectroscopy, the highly colored reaction products formed by ouabain or digitoxin in with 1,3,5-trinitrobenzene or 2,4,6-trinitroanisole in the presence of alkali (as used for the determination of these glycosides) are shown to be Meisenheimer complexes. The complexes are produced by attachment of a carbon of the butenolide ring to an aromatic carbon of the nitro compound with formation of a charge-delocalized cyclohexadienate anion.

Anisoles↗
PubMed1979

Differential thermal, solubility, and aging studies on various sources of digoxin and digitoxin powder: biopharmaceutical implications.

Unlike most organic compounds, both digoxin and digitoxin melted over a wide temperature range, with the widest range being 88 and 33 degrees for both compounds, respectively. Furthermore, the melting ranges varied markedly among several untriturated powders obtained from commercial sources and after recrystallization. Trituration produced dramatically sharper and generally lower melting temperatures. Apparent equilibrium solubility also varied considerably among different untriturated compounds. Correlation between solubility and final melting temperature was found. Results from dynamic solubility studies were used to explain the failure of trituration to enhance the apparent equilibrium solubility in certain samples. Storage at room temperature increased the melting points and decreased aqueous solubilities. Several reasons such as the presence of polymorphic and amorphous forms, crystal defects, impurities, and solvate formation were postulated to explain the findings. In a preliminary study, the in vitro dissolution rates of two commercial tablet products stored at elevated temperatures for 4-8 weeks progressively decreased. Biopharmaceutical implications and areas for further studies are discussed.

Biopharmaceutics↗
PubMed1992

Hydroxysteroid sulfotransferase and a specific UDP-glucuronosyltransferase are involved in the metabolism of digitoxin in man.

In vitro experiments were performed with cytosolic and microsomal fractions of human liver specimens in order to investigate which enzyme forms of sulfotransferase (ST) and UDP-glucurosyltransferase (GT) are involved in the metabolism of digitoxin (dt-3) and/or its cleavage products. It was found that the cytosolic STs preferentially react with digitoxigenin (dt-0) whereas microsomal GTs conjugate digitoxigenin-monodigitoxoside (dt-1) and in traces the bisdigitoxoside (dt-2). Dt-3 and dt-0 cannot be glucuronidated. By separation of different sulfotransferases it was found that the hydroxysteroid-ST is responsible for dt-0 and 3-epidigitoxigenin (epi-dt-0) sulfation. The hydroxysteroid-ST could be purified and characterized (apparent Km and Vmax for dt-0 sulfation: approx. 17 mumol/l and 2.7 nmol/min mg protein, respectively). Of various model substrates and endogenous compounds (steroids, bilirubin) none caused a competitive inhibition of the microsomal dt-1 glucuronidation except dt-2 and dt-3. Therefore it can be supposed that a new GT form catalyses this reaction. It is characterized by an extraordinarily high affinity towards dt-1 with Km values ranging between 0.7 and 27 mumol/l.

Binding, Competitive↗
PubMed1978

Increased digitoxin cleavage by liver microsomes of spironolactone-pretreated rats.

Pretreatment of rats with spironolactone caused an fourfold increased cleavage rate of the sugar chain of digitoxin (dt-3) in vitro yielding digitoxigenin-bis-digitoxoside. This was due to an enhanced, cyt. P450 dependent, formation of 15'-dehydro-dt-3, the intermediate which has to be formed before the terminal sugar can be split off. The second reaction catalysed by microsomal monoxygenases, the 12-beta-hydroxylation, was only increased by a factor 2. In contrast to the effects of spironolactone no increase of metabolism could be observed after phenobarbital pretreatment. From our results it may be concluded that the enhanced dt-3 metabolism in vivo is mainly caused by spironolactone inducible monoxygenases which catalyse the oxidation of the terminal sugar.

Animals↗
PubMed1979

Pharmacokinetics of dihydrodigitoxin in the cat. A comparison with digitoxin.

Pharmacokinetics of digitoxin (DGT) and its derivative hydrogenated at the unsaturated lactone ring have been studied using the 3H-labelled compounds in cats. Blood level data could be described by an open three compartment body model. The biological half-lives of dihydrodigitoxin (DH-DGT) and DGT are rather similar (0.12, 0.48, 20.4 h, and 0.11, 0.43, 31.8 h, respectively), whereas the volume of distribution of DH-DGT is about 1/10 from that of DGT (0.241 versus 2.581). Especially in myocardial tissue a significantly lower DH-DGT concentration was measured, indicating the loss of affinity to cardenolide binding sites by hydrogenation. Dihydrodigitoxinic acid was detected as the main metabolite of DH-DGT.

Animals↗