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World Journal of Gastroenterology Mar 2023Repurposing of the widely available and relatively cheap generic cardiac gly-coside digoxin for non-cardiac indications could have a wide-ranging impact on the global... (Review)
Review
Repurposing of the widely available and relatively cheap generic cardiac gly-coside digoxin for non-cardiac indications could have a wide-ranging impact on the global burden of several diseases. Over the past several years, there have been significant advances in the study of digoxin pharmacology and its potential non-cardiac clinical applications, including anti-inflammatory, antineoplastic, metabolic, and antimicrobial use. Digoxin holds promise in the treatment of gastrointestinal disease, including nonalcoholic steatohepatitis and alcohol-associated steatohepatitis as well as in obesity, cancer, and treatment of viral infections, among other conditions. In this review, we provide a summary of the clinical uses of digoxin to date and discuss recent research on its emerging applications.
Topics: Humans; Digoxin; Non-alcoholic Fatty Liver Disease; Fatty Liver, Alcoholic; Obesity; Anti-Inflammatory Agents
PubMed: 37032732
DOI: 10.3748/wjg.v29.i12.1824 -
Cancers Dec 2020Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease...
Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as 'anti-estrogen'-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.
PubMed: 33352737
DOI: 10.3390/cancers12123840 -
Cell Calcium Mar 2020Ever since British Physician William Withering first described the use of foxglove extract for treatment of patients with congestive heart failure in 1785, cardiotonic... (Review)
Review
Ever since British Physician William Withering first described the use of foxglove extract for treatment of patients with congestive heart failure in 1785, cardiotonic steroids have been used clinically to treat heart failure and more recently atrial fibrillation. Due to their ability to bind and inhibit the ubiquitous transport enzyme sodium potassium pump, thus regulating intracellular Na concentration in every living cell, they are also an essential tool for research into the sodium potassium pump structure and function. Exogenous CTS have been clearly demonstrated to affect cardiovascular system through modulation of vagal tone, cardiac contraction (via ionic changes) and altered natriuresis. Reports of a number of endogenous CTS, since the 1980s, have intensified research into their physiologic and pathophysiologic roles and opened up novel therapeutic targets. Substantive evidence pointing to the role of endogenous ouabain and marinobufagenin, the two most prominent CTS, in development of cardiovascular disease has accumulated. Nevertheless, their presence, structure, biosynthesis pathways and even mechanism of action remain unclear or controversial. In this review the current state-of-the-art, the controversies and the remaining questions surrounding the role of endogenous cardiotonic steroids in health and disease are discussed.
Topics: Animals; Cardiac Glycosides; Cardiovascular Diseases; Humans; Models, Biological; Signal Transduction; Sodium-Potassium-Exchanging ATPase
PubMed: 31896530
DOI: 10.1016/j.ceca.2019.102156 -
American Journal of Physiology. Heart... Dec 2022Cloning of the "Na pump" (Na,K-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal... (Review)
Review
Cloning of the "Na pump" (Na,K-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal discoveries regarding EO and its NKA receptor in cardiovascular function and the pathophysiology of heart failure (HF) and hypertension. Cardiotonic digitalis preparations were a preferred treatment for HF for two centuries, but digoxin was only marginally effective in a large clinical trial (1997). This led to diminished digoxin use. Missing from the trial, however, was any consideration that endogenous CTS might influence digitalis' efficacy. Digoxin, at therapeutic concentrations, acutely inhibits NKA but, remarkably, antagonizes ouabain's action. Prolonged treatment with ouabain, but not digoxin, causes hypertension in rodents; in this model, digoxin lowers blood pressure (BP). Furthermore, NKA-bound ouabain and digoxin modulate different protein kinase signaling pathways and have disparate long-term cardiovascular effects. Reports of "brain ouabain" led to the elucidation of a new, slow neuromodulatory pathway in the brain; locally generated EO and the α2 NKA isoform help regulate sympathetic drive to the heart and vasculature. The roles of EO and α2 NKA have been studied by EO assay, ouabain-resistant mutation of α2 NKA, and immunoneutralization of EO with ouabain-binding Fab fragments. The NKA α2 CTS binding site and its endogenous ligand are required for BP elevation in many common hypertension models and full expression of cardiac remodeling and dysfunction following pressure overload or myocardial infarction. Understanding how endogenous CTS impact hypertension and HF pathophysiology and therapy should foster reconsideration of digoxin's therapeutic utility.
Topics: Digitalis; Cardiac Glycosides; Ligands; Heart Failure; Hypertension
PubMed: 36367691
DOI: 10.1152/ajpheart.00362.2022 -
American Journal of Medicine Open Dec 2023Studies show that digoxin use is declining but is still prevalent. Recent data on digoxin prescription and characteristics of digoxin prescribers are unknown, which can...
BACKGROUND
Studies show that digoxin use is declining but is still prevalent. Recent data on digoxin prescription and characteristics of digoxin prescribers are unknown, which can help understand its contemporary use.
METHODS
Using Medicare Part D data from 2013 to 2019, we studied the change in number and proportion of digoxin prescriptions and digoxin prescribers, overall and by specialty. Using logistic regression, we identified prescriber characteristics associated with digoxin prescription.
RESULTS
From 2013 to 2019, total digoxin prescriptions (4.6 to 1.8 million) and proportion of digoxin prescribers decreased (9.1% to 4.3% overall; 26.6% to 11.8% among General Medicine prescribers and 65.4% to 48.9% among Cardiology). Of digoxin prescribers from 2013 practicing in 2019 (91.2% remained active), 59.1% did not prescribe digoxin at all, 31.7% reduced, and 9.2% maintained or increased prescriptions. The proportion of all digoxin prescriptions that were prescribed by General Medicine prescribers declined from 59.7% to 48.2% and increased for Cardiology (29% to 38.5%). Among new prescribers in 2019 ( = 85,508), only 1.9% prescribed digoxin. Digoxin prescribers when compared to non-digoxin prescribers were more likely male, graduated from medical school earlier, were located in the Midwest or South, and belonged to Cardiology (all < .001).
CONCLUSIONS
Digoxin prescriptions continue to decline with over half of 2013 prescribers no longer prescribing digoxin in 2019. This may be a result of the increasing availability of newer heart failure therapies. The decline in digoxin prescription was greater among general medicine physicians than cardiologists, suggesting a change in digoxin use to a medication prescribed increasingly by specialists.
PubMed: 38213879
DOI: 10.1016/j.ajmo.2023.100048 -
ACS Omega May 2023Digoxin is a cardiac glycosylated steroid-like drug with a positive inotropic effect and has been widely used in treating congestive heart failure, atrial fibrillation,...
Digoxin is a cardiac glycosylated steroid-like drug with a positive inotropic effect and has been widely used in treating congestive heart failure, atrial fibrillation, atrial flutter, and other heart diseases. Digoxin is also a dangerous drug, which can cause drug poisoning at a low blood drug concentration (2.73-3.9 nmol/L, i.e., 2.14-3.05 ng/mL). Therefore, the timely detection of a patient's blood drug concentration plays a significant role in controlling blood drug concentration, reducing the occurrence of drug poisoning events, and maximizing the role of drug therapy. In this study, a DNA vector for the expression of the antidigoxin antibody Fab fragment was constructed. With the vector, Fab was expressed in and purified, and 1.2 mg of antibodies was obtained from 100 mL of culture. An immunofluorescent sensor based on the mechanism of photoinduced electron transfer was constructed by labeling additional cysteines in the heavy chain variable region and light chain variable region of the antibody Fab fragment with fluorescent dyes. The assay for digoxin with the immunosensor could be finished within 5 min with a limit of detection of 0.023 ng/mL, a detectable range of 0.023 ng/mL to 100 μg/mL, and an EC of 0.256 ng/mL. A new approach for the rapid detection of digoxin was developed and will contribulte to therapeutic drug monitoring.
PubMed: 37151524
DOI: 10.1021/acsomega.3c00571 -
Molecular Neurobiology Jan 2023Astrocyte reaction is a complex cellular process involving astrocytes in response to various types of CNS injury and a marker of neurotoxicity. It has been abundantly...
Astrocyte reaction is a complex cellular process involving astrocytes in response to various types of CNS injury and a marker of neurotoxicity. It has been abundantly studied in rodents but relatively poorly in human cells due to limited access to the brain. Astrocytes play important roles in cerebral energy metabolism and are also key players in neuroinflammation. Astroglial metabolic and inflammatory changes have been reported with age, leading to the hypothesis that mitochondrial metabolism and inflammatory responses are interconnected. However, the relationship between energy metabolism and astrocyte reactivity in the context of neurotoxicity is not known. We hypothesized that changes in energy metabolism of astrocytes will be coupled to their activation by xenobiotics. Astrocyte reaction and associated energy metabolic changes were assessed by immunostaining, gene expression, proteomics, metabolomics, and extracellular flux analyses after 24 h of exposure of human ReN-derived astrocytes to digoxin (1-10 µM) or TNFα (30 ng/ml) used as a positive control. Strong astrocytic reaction was observed, accompanied by increased glycolysis at low concentrations of digoxin (0.1 and 0.5 µM) and after TNFα exposure, suggesting that increased glycolysis may be a common feature of reactive astrocytes, independent of the triggering molecule. In conclusion, whether astrocyte activation is triggered by cytokines or a xenobiotic, it is strongly tied to energy metabolism in human ReN-derived astrocytes. Increased glycolysis might be considered as an endpoint to detect astrocyte activation by potentially neurotoxic compounds in vitro. Finally, ReN-derived astrocytes may help to decipher mechanisms of neurotoxicity in ascertaining the ability of chemicals to directly target astrocytes.
Topics: Humans; Astrocytes; Central Nervous System; Digoxin; Energy Metabolism; Tumor Necrosis Factor-alpha; Cells, Cultured
PubMed: 36223047
DOI: 10.1007/s12035-022-03057-1 -
Children (Basel, Switzerland) May 2023Antiarrhythmic drugs represent a mainstay of pediatric arrhythmia treatment. However, official guidelines and consensus documents on this topic remain scarce. There are... (Review)
Review
Antiarrhythmic drugs represent a mainstay of pediatric arrhythmia treatment. However, official guidelines and consensus documents on this topic remain scarce. There are rather uniform recommendations for some medications (including adenosine, amiodarone, and esmolol), while there are only very broad dosage recommendations for others (such as sotalol or digoxin). To prevent potential uncertainties and even mistakes with regard to dosing, we summarized the published dosage recommendations for antiarrhythmic drugs in children. Because of the wide variations in availability, regulatory approval, and experience, we encourage centers to develop their own specific protocols for pediatric antiarrhythmic drug therapy.
PubMed: 37238395
DOI: 10.3390/children10050847 -
Journal of Medicine and Life Apr 2023Cancer is a major public health problem, and chemotherapy plays a significant role in the management of neoplastic diseases. However, chemotherapy-induced cardiotoxicity... (Review)
Review
Cancer is a major public health problem, and chemotherapy plays a significant role in the management of neoplastic diseases. However, chemotherapy-induced cardiotoxicity is a serious side effect secondary to cardiac damage caused by antineoplastic's direct and indirect toxicity. Currently, there are no reliable and approved methods for preventing or treating chemotherapy-induced cardiotoxicity. Understanding the mechanisms of chemotherapy-induced cardiotoxicity may be vital to improving survival. The independent risk factors for developing cardiotoxicity must be considered to prevent myocardial damage without decreasing the therapeutic efficacy of cancer treatment. This systematic review aimed to identify and analyze the evidence on chemotherapy-induced cardiotoxicity, associated risk factors, and methods to decrease or prevent it. We conducted a comprehensive search on PubMed, Google Scholar, and Directory of Open Access Journals (DOAJ) using the following keywords: "doxorubicin cardiotoxicity", "anthracycline cardiotoxicity", "chemotherapy", "digoxin decrease cardiotoxicity", "ATG7 activators", retrieving 59 articles fulfilling the inclusion criteria. Therapeutic schemes can be changed by choosing prolonged infusion application over boluses. In addition, some agents like Dexrazoxane can reduce chemotherapy-induced cardiotoxicity in high-risk groups. Recent research found that Digoxin, ATG7 activators, Resveratrol, and other medical substances or herbal compounds have a comparable effect on Dexrazoxane in anthracycline-induced cardiotoxicity.
Topics: Humans; Resveratrol; Cardiotoxicity; Dexrazoxane; Anthracyclines; Digoxin; Polyketides; Antineoplastic Agents
PubMed: 37305823
DOI: 10.25122/jml-2022-0322 -
World Journal of Gastrointestinal... May 2022Cardiac and hepatic functionality are intertwined in a multifaceted relationship. Pathologic processes involving one may affect the other through a variety of...
BACKGROUND
Cardiac and hepatic functionality are intertwined in a multifaceted relationship. Pathologic processes involving one may affect the other through a variety of mechanisms, including hemodynamic and membrane transport effects.
AIM
To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.
METHODS
Twelve adult rats were included in this study; baseline hepatic and renal laboratory values and digoxin pharmacokinetic (PK) studies were established before evenly dividing them into two groups to undergo bile duct ligation (BDL) or a sham procedure. After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction. Data were analyzed using SigmaStat 3.5. Means between pre-surgery and post-surgery in the same experimental group were compared by paired -test, while independent test was employed to compare the means between sham and BDL groups.
RESULTS
Digoxin clearance was decreased and liver function, but not renal function, was impaired in BDL rats. BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine. Organic anion transporting polypeptides (OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL. OATP4C1 expression was markedly increased in the kidney following BDL.
CONCLUSION
The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis. These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.
PubMed: 35720166
DOI: 10.4291/wjgp.v13.i3.73