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Wiener Klinische Wochenschrift 1993A 82-year-old woman was admitted to hospital because of heart failure, vomiting, and pain in the right upper abdomen. During the past three months she had received...
A 82-year-old woman was admitted to hospital because of heart failure, vomiting, and pain in the right upper abdomen. During the past three months she had received treatment with 0.07 mg digitoxin twice daily. The ECG showed sinus bradycardia with intermittent complete sinoatrial block. On the basis of the history, clinical presentation and ECG findings digitalis intoxication was suspected. Digitoxin level was 65.23 ng/ml--far beyond the therapeutic range. Laboratory examinations revealed a marked thrombocytopenia (25,000/microliters). The patient was placed on cholestyramine (4g three times daily) to accelerate intestinal excretion of digitoxin. As there were no life-threatening complications there was no indication for treatment with digitalis-specific antibodies. On the 6th day after discontinuation of digitoxin treatment the platelet count showed a marked rise and returned to normal values as from the 12th day.
Topics: Aged; Aged, 80 and over; Bradycardia; Digitoxin; Electrocardiography; Female; Heart Block; Heart Failure; Humans; Thrombocytopenia
PubMed: 8212711
DOI: No ID Found -
Deutsche Medizinische Wochenschrift... Feb 1992Because she felt unwell, an 80-year-old woman who was receiving treatment with digitoxin (0.07 mg daily) raised the dose on her own initiative to twice or three times...
Because she felt unwell, an 80-year-old woman who was receiving treatment with digitoxin (0.07 mg daily) raised the dose on her own initiative to twice or three times the previous level. She then experienced faintness, visual abnormalities and bradyarrhythmia (rate about 40/min). The ECG showed 2 degrees AV block. The digitoxin level was 70.8 ng/ml--far above the upper limit of the therapeutic range (7.5-25 ng/ml). One striking abnormality was thrombocytopenia (33,000/microliters), though the white and red cell counts were normal. Petechiae were not present and there was no evidence of internal bleeding. As the AV block had not produced any critical fall in ventricular rate, there was no need to start treatment with digitalis-binding antibody fragments (Fab fragments). Instead, the patient was given cholestyramine 4 g three times daily with the aim of interrupting the enterohepatic circulation of digitoxin. From then on the rise in platelet count paralleled the fall in digitoxin level. Seven days after discontinuing digitoxin the platelet count reentered the normal range (147,000/microliters). However, the digitoxin level (39.5 mg/ml) was still well above the therapeutic range.
Topics: Aged; Aged, 80 and over; Cholestyramine Resin; Diagnosis, Differential; Digitoxin; Electrocardiography; Female; Humans; Poisoning; Thrombocytopenia
PubMed: 1544354
DOI: 10.1055/s-2008-1062317 -
American Heart Journal Feb 1972
Topics: Digitoxin; Digoxin; Drug Interactions; Humans; Liver; Phenobarbital; Stimulation, Chemical
PubMed: 5058316
DOI: 10.1016/0002-8703(72)90148-2 -
Biochemical Pharmacology Mar 2014Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by...
Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, digitoxin and several of its novel synthetic derivatives, such as α-l-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50=11.9 nM) than digitoxin (IC50=90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3β signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.
Topics: Anoikis; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Culture Techniques; Cell Line, Tumor; Digitoxin; Humans; Lung Neoplasms; Myeloid Cell Leukemia Sequence 1 Protein
PubMed: 24231508
DOI: 10.1016/j.bcp.2013.10.027 -
Science (New York, N.Y.) May 1969Spironolactone (Aldactone(R)) protects the rat against the production of myocardial necroses and other manifestations of digitoxin poisoning.
Spironolactone (Aldactone(R)) protects the rat against the production of myocardial necroses and other manifestations of digitoxin poisoning.
Topics: Animals; Digitoxin; Female; Heart; Rats; Spironolactone
PubMed: 5767787
DOI: 10.1126/science.164.3881.842 -
Electrophoresis May 2022Cardiac glycosides digoxin and digitoxin are used in therapy for the treatment of congestive heart failure. Moreover, these compounds can be responsible for intoxication...
Development of a new ultra-high-performance liquid chromatography-tandem mass spectrometry method for the determination of digoxin and digitoxin in plasma: Comparison with a clinical immunoassay.
Cardiac glycosides digoxin and digitoxin are used in therapy for the treatment of congestive heart failure. Moreover, these compounds can be responsible for intoxication cases caused by fortuitous ingestion of leaves of Digitalis. Due to the narrow therapeutic range of these drugs, therapeutic drug monitoring is recommended in the clinical practice. In this context, immunoassays-based methods are generally employed but digoxin- and digitoxin-like compounds can interfere with the analysis. The aim of this study was to develop and validate an original UPLC-MS/MS method for the determination of digoxin and digitoxin in plasma. The method shows adequate sensitivity and selectivity with acceptable matrix effects and very good linearity, accuracy, precision, and recovery. A simple liquid-liquid extraction procedure was used for sample clean-up. The method was applied for the analysis of n = 220 plasma samples collected in two different clinical chemistry laboratories and previously tested by the same immunoassay. The statistical comparison showed a relevant negative bias of the UPLC-MS/MS method versus the immunoassay. These results are consistent with an immunoassay overestimation of digoxin plasmatic levels due to cross-reaction events with endogenous digoxin-like substances.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Digitoxin; Digoxin; Immunoassay; Tandem Mass Spectrometry
PubMed: 35132652
DOI: 10.1002/elps.202100290 -
Deutsche Medizinische Wochenschrift... Sep 1983Serum digitoxin levels were measured during maintenance treatment with digitoxin, 0.1 mg daily i.v., in 12 patients under intensive postoperative care who had...
Serum digitoxin levels were measured during maintenance treatment with digitoxin, 0.1 mg daily i.v., in 12 patients under intensive postoperative care who had hepatorenal failure resulting from multiple organ failure. Thirteen patients in intensive care with comparable basic diseases served as controls; they had developed predominantly renal failure. Serum digitoxin levels in the two groups were no different and remained within therapeutic range during the total period of observation of 8-40 days. During this time toxic serum digitoxin levels were measured in 2.9% of patients in renal failure and 2.7% of patients with hepatorenal failure. The pathogenesis of the liver failure and the severity of the underlying disease did not influence serum digitoxin levels. Digitoxin was tolerated similarly in the two patient groups.
Topics: Adult; Aged; Digitoxin; Female; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Shock; Shock, Septic
PubMed: 6617500
DOI: 10.1055/s-2008-1069770 -
The Journal of Clinical Investigation Dec 1977The effects of Fab fragments of high-affinity specific antibodies have been studied in a canine experimental model of lethal digitoxin toxicity. Selected antiserum from...
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.
Topics: Animals; Antibodies; Antigen-Antibody Complex; Cross Reactions; Digitoxin; Dogs; Half-Life; Heart; Immune Sera; Immunoglobulin Fab Fragments; Kinetics; Tachycardia
PubMed: 914999
DOI: 10.1172/JCI108889 -
The Journal of Organic Chemistry Dec 2011Digitoxin, a clinically important cardiac trisaccharide, was assembled efficiently from digitoxigenin and 3,4-di-O-tert-butyldiphenylsilyl-d-digitoxosyl...
Digitoxin, a clinically important cardiac trisaccharide, was assembled efficiently from digitoxigenin and 3,4-di-O-tert-butyldiphenylsilyl-d-digitoxosyl o-cyclopropylethynylbenzoate in 9 steps and 52% overall yield via alternate glycosylation and protecting group manipulation. The present synthesis showcases the advantage of the gold(I)-catalyzed glycosylation protocol in the synthesis of glycoconjugates containing acid-labile 2-deoxysugar linkages.
Topics: Benzoates; Catalysis; Digitoxin; Glycosides; Gold; Molecular Conformation
PubMed: 22054226
DOI: 10.1021/jo201850z -
Methods and Findings in Experimental... Jun 1992In the present study the pharmacokinetic interactions between digitoxin and the antiarrhythmic drugs amiodarone, mexiletine and propafenone have been examined....
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.
Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Digitoxin; Drug Interactions; Female; Male; Mexiletine; Propafenone; Rabbits; Radioimmunoassay
PubMed: 1513190
DOI: No ID Found