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[en] Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents
[en] This study was performed to outline the different MDR-1 (Multi-Drug Resistance-1) genotypes in a sample of 37 Egyptian patients, suffering from atrial fibrillation (AF) and/or congestive heart failure (CHF) and is using digoxin, to assess the role of MDR-1 genotypes polymorphism in affecting steady state serum digoxin therapeutic levels, and studying the consequences on patient's clinical outcome. Two venous blood samples were drawn from each patient; the 1st sample was taken, on admission, for DNA extraction and genotyping and the 2nd was taken, 6 hours post dose after reaching steady state concentration, for serum digoxin assay. Serum digoxin levels were assayed using EMIT 2000 analyzer, and MDR-1 genotyping was done using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Twenty patients (54.1%) showed serum digoxin levels within the therapeutic range, 12 patients (32.4%) showed serum digoxin levels under the minimum effective concentration (<0.9 ng/ml), while 5 patients (13.5%) showed serum digoxin levels over maximum safety concentration (>2 ng/ml), with P value of 0.0001 among three groups. MDR-1 genotyping revealed ten patients (27%) carrying the homozygous mutant TT genotype, 27 patients (73%) carrying the heterozygous mutant CT genotype, with no patient showing the wild CC genotype Allelic distribution showed 42% for the wild type C allele while 58% for the homozygous mutant C allele. Patients carrying the homozygous mutant TT genotype showed significantly lower serum digoxin levels compared with those carrying the heterozygous mutant CT genotype (P value: 0.009). Patients with significant improvement carried the CT genotype and had serum digoxin levels within the therapeutic range. In conclusion, patients with different MDR-1 genotypes had variations in their serum digoxin levels and identification of MDR-1 variations was found useful in predicting therapy outcome. We recommend further extensive work on large samples to study the important role of MDR-1 gene in affecting the disposition of different substrates, to be able for individualizing them according to the patient's genetic profile in order to improve drug therapy and reduce inter-patient variability. (author)
[en] Objective: To examine the outcome of ASD closure in adults and the effect of patients age on drug therapy, symptoms and incidence of atrial fibrillation. Results: There were no deaths. Five patients from early in the series were lost to follow-up. Large defect size was associated with patch rather than direct closure but there was extensive crossover. Analysis by age showed that patients over 49 had more postoperative atrial fibrillation (P 0.001), more chest pain (P>0.0001), more postoperative dyspnea (p = 0.021), greater use of diuretics (p = 0.20) and longer hospital stay (10.1 plus minis 2.6 vs. 8.5 plus minis 1.6 days; p = 0.007) than patients under 49. Conclusion: Operation for atrial septal defects in adults can be performed with no mortality and low morbidity. The age at which complications appear more frequent suggests that closer analysis of these patients is required. (author)
[en] Cardiotonic steroids (CTS) are compounds which bind to the Na,K-ATPase, leading to its inhibition and in some cases initiating signaling cascades. Long utilized as a treatment for congestive heart disease, CTS have more recently been observed to inhibit proliferation and cause apoptosis in several cancer cell lines. A synthetic derivative of the CTS digoxin, called 21-benzylidene digoxin (21-BD), activates the Na,K-ATPase rather than cause its inhibition, as its parent compound does. Here, the mechanism behind the unique effects of 21-BD are further explored. In HeLa cancer cells, low (5 µM) and high (50 µM) doses of 21-BD activated and inhibited the Na,K-ATPase, respectively, without altering the membrane expression of the Na,K-ATPase. While digoxin did not affect HeLa membrane cholesterol or phospholipid content, 50 µM 21-BD increased both lipids via a mechanism reliant on an intact cell. Afterwards, the direct action of 21-BD was evaluated on erythrocyte membranes; however, no effect was observed. As CTS may generate reactive oxygen species (ROS) which can affect plasma membrane fluidity and therefore Na,K-ATPase activity, several markers involved in ROS generation were analyzed such as, lipid peroxidation (TBARS), reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD). GSH content and catalase activity were unaffected by digoxin or 21-BD. Surprisingly, TBARS and SOD activity was decreased with digoxin and with 50 µM 21-BD. Thus, 21-BD and digoxin altered components involved in ROS generation and inhibition in a similar fashion. This study suggests alterations to the Na,K-ATPase and membrane lipids by 21-BD is not reliant on ROS generation.
[en] Endogenous factors crossreacting with antidigoxin antibodies (digoxin-like immunoreactive substances=DLIS) have been found in several tissues and body fluids of animals and humans, using commercially avaiable digoxin RIA or EIA methods. Detectable DLIS concentration were found in blood and urine extracts of adults (normal healthy controls, hypertensive patients and salt loaded healthy subjects), while higher levels were generally observed in plasma samples of pregnant women, newborns and patients with renal insufficiency. The chemical characteristics of this endogenous factor are, at present, unknown, although it has been suggested that DLIS could be a substance with low molecular weight. Experimental studies and theoretical consideration suggest that DLIS, in addition to reacting with antibodies, might also bind to the specific cellular receptor of the cardiac glycosides and thus inhibit the membrane Na+/K+ ATPase (sodium pump). Therefore, it has been suggested that DLSI is an endogeneous modulator of the membrane sodium-potassium pump and it could play a role in the regulation of fluid and electrolytes muscular tone of myocardial and also in pathogenesis of hypertension
[en] Highlights: • The digoxin MIP-sensor was developed. • The device can detect digoxin in the serum samples without pretreatment. • The detection is simple, inexpensive, fast, precise, sensitive and label free. • The linear relationship between the digoxin concentration and the current is 1.28–128 Nm. • A detection limit is 1.28 nM. The detection time is less than 5 min. -- Abstract: A novel biosensor (the synthetic receptor sensor) employing the molecular imprinted technology for the digoxin analysis is investigated. The molecularly imprinted polymer (MIP) modified electrode can specifically bind to the analyte in the sample without sample pretreatment. The digoxin analyzed by the MIP sensor was carried out in 1 mM K3Fe(CN)6 solution with the cyclic voltammetry. In the system, the K3Fe(CN)63−/Fe2(CN)64− redox couple was taking place. When the solution contains the digoxin, the MIP on the electrode will bind the digoxin. Further the redox system is interrupted and the peak current is decreased according to the digoxin concentration increasing. Digoxin is a glycosylated steroid-like drug. It is important for the heart disease treatment. However, since the digoxin toxic level is low, the drug remains in the blood sample must be monitored frequently. The device possesses many advantages, such as high specific recognition properties, good chemical and mechanical stability, simplicity and low cost of preparation, sensitive and label free determination. The reproducibility is good (CV < 5). The linear relationship between the digoxin concentration and the current is 1.28–128 nM, and a detection limit of 1.28 nM is achieved. The detection time is less than 5 min
[en] Mechanisms of digitoxin-inhibited cell growth and induced apoptosis in human non-small cell lung cancer (NCI-H460) cells remain unclear. Understanding how digitoxin or derivate analogs induce their cytotoxic effect below therapeutically relevant concentrations will help in designing and developing novel, safer and more effective anti-cancer drugs. In this study, NCI-H460 cells were treated with digitoxin and a synthetic analog D6-MA to determine their anti-cancer activity. Different concentrations of digitoxin and D6-MA were used and the subsequent changes in cell morphology, viability, cell cycle, and protein expressions were determined. Digitoxin and D6-MA induced dose-dependent apoptotic morphologic changes in NCI-H460 cells via caspase-9 cleavage, with D6-MA possessing 5-fold greater potency than digitoxin. In comparison, non-tumorigenic immortalized bronchial and small airway epithelial cells displayed significantly less apoptotic sensitivity compared to NCI-H460 cells suggesting that both digitoxin and D6-MA were selective for NSCLC. Furthermore, NCI-H460 cells arrested in G(2)/M phase following digitoxin and D6-MA treatment. Post-treatment evaluation of key G2/M checkpoint regulatory proteins identified down-regulation of cyclin B1/cdc2 complex and survivin. Additionally, Chk1/2 and p53 related proteins experienced down-regulation suggesting a p53-independent cell cycle arrest mechanism. In summary, digitoxin and D6-MA exert anti-cancer effects on NCI-H460 cells through apoptosis or cell cycle arrest, with D6-MA showing at least 5-fold greater potency relative to digitoxin. -- Highlights: ► Digitoxin and synthetic analog D6-MA induced apoptotic morphologic changes in NCI-H460 cells in a dose-dependent manner. ► Apoptotic cell death induced by analog was 5-fold more potent when compared to digitoxin. ► NCI-H460 cells arrested in G(2)/M phase following digitoxin (≥ 5 nM) and analog (≥ 1 nM) treatment. ► Digitoxin inhibited the expression of cyclin B1/cdc2 complex and survivin at sub-therapeutic concentrations. ► D6-MA was 4-fold more potent than digitoxin.
[en] The Gammaflow automated radioimmunoassay system is described. The complete automation of radioimmunoassay makes results of analyses available in minutes rather than in hours or days. Results of a serum digoxin assay are given as an example
[en] Double-antibody radioimmunoassays in which tritium is used for labeling were adapted for emergency determinations of serum drug concentrations. In the cases of digoxin and gentamicin, the first and second antibody incubations may be carried on simultaneously, minimizing incubation times (10 and 27 min, respectively). Counting the bound radioactivity in solubilized immunospecific precipitates decreases variability in the composition of the phase counted and markedly decreases problems of quenching and chemiluminescence. Logit-log transformation of the sigmoidal standard curve results in a straight line, which can be described by its slope and intercept and which remains constant if assay conditions and critical reagents are held constant. Because the slope and intercept of the standard curve are characteristic of a given assay system, it is possible to calculate the theoretical standard curve for a specific assay system by using the means of previously observed slopes and intercepts. Thus, a separate standard curve need not be prepared for each subsequent assay run. Total time required for drug determinations is now less than 1 h. When unknown samples were measured by both the conventional radioimmunoassay method and the new rapid radioimmunoassay method, the values correlated well (r = 0.99) for both digoxin and gentamicin. (U.S.)