-
The Cochrane Database of Systematic... Oct 2006Cardenolides are naturally occurring plant toxins which act primarily on the heart. While poisoning with the digitalis cardenolides (digoxin and digitoxin) are reported... (Review)
Review
BACKGROUND
Cardenolides are naturally occurring plant toxins which act primarily on the heart. While poisoning with the digitalis cardenolides (digoxin and digitoxin) are reported worldwide, cardiotoxicity from other cardenolides such as the yellow oleander are also a major problem, with tens of thousands of cases of poisoning each year in South Asia. Because cardenolides from these plants are structurally similar, acute poisonings are managed using similar treatments. The benefit of these treatments is of interest, particularly in the context of cost since most poisonings occur in developing countries where resources are very limited.
OBJECTIVES
To determine the efficacy of antidotes for the treatment of acute cardenolide poisoning, in particular atropine, isoprenaline (isoproterenol), multiple-dose activated charcoal (MDAC), fructose-1,6-diphosphate, sodium bicarbonate, magnesium, phenytoin and anti-digoxin Fab antitoxin.
SEARCH STRATEGY
We searched MEDLINE, EMBASE, the Controlled Trials Register of the Cochrane Collaboration, Current Awareness in Clinical Toxicology, Info Trac, www.google.com.au, and Science Citation Index of studies identified by the previous searches. We manually searched the bibliographies of identified articles and personally contacted experts in the field.
SELECTION CRITERIA
Randomised controlled trials where antidotes were administered to patients with acute symptomatic cardenolide poisoning were identified.
DATA COLLECTION AND ANALYSIS
We independently extracted data on study design, including the method of randomisation, participant characteristics, type of intervention and outcomes from each study. We independently assessed methodological quality of the included studies. A pooled analysis was not appropriate.
MAIN RESULTS
Two randomised controlled trials were identified, both were conducted in patients with yellow oleander poisoning. One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect. The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81). Other benefits were also noted in both studies and serious adverse effects were minimal. Studies assessing the effect of antidotes on other cardenolides were not identified. One ongoing study investigating the activated charcoal for acute yellow oleander self-poisoning was also identified.
AUTHORS' CONCLUSIONS
There is some evidence to suggest that MDAC and anti-digoxin Fab antitoxin may be effective treatments for yellow oleander poisoning. However, the efficacy and indications of these interventions for the treatment of acute digitalis poisoning is uncertain due to the lack of good quality controlled clinical trials. Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides. Unfortunately cost limits the use of antidotes such as anti-digoxin Fab antitoxin in developing countries where cardenolide poisonings are frequent. More research is required using relatively cheap antidotes which may also be effective.
Topics: Acute Disease; Antidotes; Cardenolides; Cardiac Glycosides; Charcoal; Humans; Phytotherapy; Poisoning; Randomized Controlled Trials as Topic; Thevetia
PubMed: 17054261
DOI: 10.1002/14651858.CD005490.pub2 -
Deutsches Arzteblatt International Apr 2018
Topics: Digitoxin
PubMed: 29739499
DOI: 10.3238/arztebl.2018.0285b -
Journal of the American College of... May 1985Digoxin, the cardiac glycoside most frequently used in clinical practice in the United States, can be given orally or intravenously and has an excretory half-life of 36... (Review)
Review
Digoxin, the cardiac glycoside most frequently used in clinical practice in the United States, can be given orally or intravenously and has an excretory half-life of 36 to 48 hours in patients with serum creatinine and blood urea nitrogen values in the normal range. Since the drug is excreted predominantly by the kidney, the half-life is prolonged progressively with diminishing renal function, reaching about 5 days on average in patients who are essentially anephric. Serum protein binding of digoxin is only about 20%, and differs markedly in this regard from that of digitoxin, which is 97% bound by serum albumin at usual therapeutic levels. Digitoxin is nearly completely absorbed from the normal gastrointestinal tract and has a half-life averaging 5 to 6 days in patients receiving usual doses irrespective of renal function. The bioavailability of digoxin is appreciably less than that of digitoxin, averaging about two-thirds to three-fourths of the equivalent dose given intravenously in the case of currently available tablet formulations. Recent studies have shown that gut flora of about 10% of patients reduce digoxin to a less bioactive dihydro derivative. This process is sensitive to antibiotic administration, creating the potential for important interactions among drugs. Serum or plasma concentrations of digitalis glycosides can be measured by radioimmunoassay methods that are now widely available, but knowledge of serum levels does not substitute for a sound working knowledge of the clinical pharmacology of the preparation used and careful patient follow-up.
Topics: Absorption; Biological Availability; Cardiac Glycosides; Cost-Benefit Analysis; Digitoxin; Digoxin; Half-Life; Humans; Kinetics; Radioimmunoassay; Time Factors
PubMed: 3921586
DOI: 10.1016/s0735-1097(85)80462-9 -
ACS Medicinal Chemistry Letters Apr 2014Cardiac glycosides are potent inhibitors of cancer cell growth and possess antiviral activities at nanomolar concentrations. In this study we evaluated the...
Cardiac glycosides are potent inhibitors of cancer cell growth and possess antiviral activities at nanomolar concentrations. In this study we evaluated the anticytomegalovirus (CMV) activity of digitoxin and several of its analogues. We show that sugar type and sugar length attached to the steroid core structure affects its anticytomegalovirus activity. Structure-activity relationship (SAR) studies identified the l-sugar containing cardiac glycosides as having improved anti-CMV activity and may lead to better understanding of how these compounds inhibit CMV replication.
PubMed: 24900847
DOI: 10.1021/ml400529q -
Canadian Medical Association Journal Jul 1969
Topics: Adrenal Cortex Hormones; Animals; Digitalis Glycosides; Digitoxin; Drug Tolerance; Female; Glucocorticoids; Rats; Steroids
PubMed: 5793358
DOI: No ID Found -
Canadian Medical Association Journal Feb 1964
Topics: Bradycardia; Delirium; Digitalis; Digitalis Glycosides; Digitoxin; Digoxin; Gynecomastia; Humans; Lanatosides; Male; Neuritis; Paresthesia; Tachycardia; Thrombocytopenia; Toxicology; Trigeminal Neuralgia; Urticaria
PubMed: 14122470
DOI: No ID Found -
Medicine International 2022The alpha subunits (ATP1A1-3) of Na/K-ATPase binds digitoxin with varying affinity. The expression levels of these subunits dictate the anticancer effects of digitoxin....
The alpha subunits (ATP1A1-3) of Na/K-ATPase binds digitoxin with varying affinity. The expression levels of these subunits dictate the anticancer effects of digitoxin. In the present study, three pancreatic cancer cell lines, AsPC-1, Panc-1 and CFPAC-1, were used to investigate the effects of digitoxin in relation to the expression of the subunits ATP1A1 and ATP1A3. Cell viability and intracellular calcium concentrations was measured in relation to the gene and protein expression of ATP1A1 and ATP1A3. Digitoxin was used to treat the cells at concentrations of 1-100 nM, and the intracellular calcium concentrations increased in a concentration-dependent manner in the Panc-1 and in the CFPAC-1 cells with treatment at 100 nM. In the AsPC-1 cells only the supraphysiological concentration of digitoxin (100 nM) resulted in a decrease in the number of viable cells (unviable cells increased to 22%), whereas it had no effect on intracellular calcium levels. The number of viable Panc-1 and CFPAC-1 cells decreased after digitoxin treatment at 25-100 nM (unviable Panc-1 cells increased to 33-59%; unviable CFPAC-1 cells increased to 22-56%). Digitoxin treatment also affected the transcriptional expression of the and subunits. In Panc-1 cells, gene expression was negatively associated with the digitoxin concentration (25-100 nM). In the AsPC-1 and CFPAC-1 cells, the expression of the gene increased in the cells treated with the 100 nM digitoxin concentration. The protein expression of ATP1A1 and ATP1A3 was not altered with digitoxin treatment. The basal protein expression of ATP1A1 was high in the AsPC-1 and CFPAC-1 cells, compared to the Panc-1 cells, in contrast to the basal expression of ATP1A3, which was higher in the Panc-1 cells, compared to the other pancreatic cancer cells used. On the whole, the present study demonstrates that the high expression of ATP1A3 renders pancreatic cancer cells more susceptible to digitoxin-induced cell death. The findings suggest that the expression of ATP1A3 may be used as a marker for tumor sensitivity to digitoxin treatment, where a high expression of ATP1A3 is favorable for the anticancer effects of digitoxin.
PubMed: 36698913
DOI: 10.3892/mi.2022.52 -
Journal of Molecular Modeling Jun 2021The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process....
The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor.
Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Animals; Antiviral Agents; Binding Sites; COVID-19; Drug Discovery; Drug Repositioning; Glycyrrhizic Acid; Host-Pathogen Interactions; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Receptors, Virus; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Structure-Activity Relationship; Virus Internalization; COVID-19 Drug Treatment
PubMed: 34169390
DOI: 10.1007/s00894-021-04816-y -
Journal of Cellular Biochemistry Dec 2021Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na /K -ATPase to induce anti-neoplastic effects; however, these cardiac glycosides...
Cardiac glycosides, such as digoxin and digitoxin, are compounds that interact with Na /K -ATPase to induce anti-neoplastic effects; however, these cardiac glycosides have narrow therapeutic index. Thus, semi-synthetic analogs of digitoxin with modifications in the sugar moiety has been shown to be an interesting approach to obtain more selective and more effective analogs than the parent natural product. Therefore, the aim of this study was to assess the cytotoxic potential of novel digitoxigenin derivatives, digitoxigenin-α-L-rhamno-pyranoside (1) and digitoxigenin-α-L-amiceto-pyranoside (2), in cervical carcinoma cells (HeLa) and human diploid lung fibroblasts (Wi-26-VA4). In addition, we studied the anticancer mechanisms of action of these compounds by comparing its cytotoxic effects with the potential to modulate the activity of three P-type ATPases; Na /K -ATPase, sarco/endoplasmic reticulum Ca -ATPase (SERCA), and plasma membrane Ca -ATPase (PMCA). Briefly, the results showed that compounds 1 and 2 were more cytotoxic and selectivity for HeLa tumor cells than the nontumor cells Wi-26-VA4. While the anticancer cytotoxicity in HeLa cells involves the modulation of Na /K -ATPase, PMCA and SERCA, the modulation of these P-type ATPases was completely absent in Wi-26-VA4 cells, which suggest the importance of their role in the cytotoxic effect of compounds 1 and 2 in HeLa cells. Furthermore, the compound 2 inhibited directly erythrocyte ghosts PMCA and both compounds were more cytotoxic than digitoxin in HeLa cells. These results provide a better understanding of the mode of action of the synthetic cardiac glycosides and highlights 1 and 2 as potential anticancer agents.
Topics: Cell Membrane; Digitoxigenin; HeLa Cells; Humans; Plasma Membrane Calcium-Transporting ATPases; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Potassium-Exchanging ATPase
PubMed: 34553411
DOI: 10.1002/jcb.30150 -
European Journal of Pharmaceutical... Apr 2024In this communication, the solubility of digitoxin drug in supercritical CO was studied at different operating conditions (311 < T (K) < 343, 120 < P (bar) < 300). The...
In this communication, the solubility of digitoxin drug in supercritical CO was studied at different operating conditions (311 < T (K) < 343, 120 < P (bar) < 300). The results revealed digitoxin drug solubility (in mole fraction) was between 0.095 × 10 to 1.12 × 10. In the case of thermodynamic solubility modeling, cubic and non-cubic equation of states i.e. SAFT (statistical associating fluid theory), SRK (Soave-Redlich-Kwong) and sPC-SAFT (simplified perturbed chain SAFT) EoSs and six density-based correlations (Chrastil, Kumar-Johnston (KJ), Mendez-Santiago-Teja (MST), Garlapati and Madras (GM), Bartle et al. and Sung-Shim models) were considered. All used equations indicated reasonable behavior with appropriate accuracy for the solubility of the digitoxin drug. Meanwhile, sPC-SAFT EoS and Kumar-Johnston correlation with AARD% set to 8.96 % and 6.25 %, respectively exhibited greater accuracy in fitting the solubility data. Moreover, total, solvation and vaporization enthalpies of the digitoxin/supercritical carbon dioxide binary mixture were calculated based on KJ, Chrastil and Bartle et al. models.
Topics: Carbon Dioxide; Solubility; India; Thermodynamics
PubMed: 38387711
DOI: 10.1016/j.ejps.2024.106731