digoxin and Obesity

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: Anti-Inflammatory Agents; Digoxin; Fatty Liver, Alcoholic; Humans; Non-alcoholic Fatty Liver Disease; Obesity

ACC Stage C heart failure includes those patients with prior or current symptoms of heart failure in the context of an underlying structural heart problem who are primarily managed with medical therapy. Although there is guideline-based medical therapy for those with heart failure with reduced ejection fraction (HFrEF), therapies in heart failure with preserved ejection fraction (HFpEF) have thus far proven elusive. Emerging therapies such as serelaxin are currently under investigation and may prove beneficial. The role of advanced surgical therapies, such as mechanical circulatory support, in this population is not well defined. Further investigation is warranted for these therapies in patients with Stage C heart failure.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cardiac Resynchronization Therapy; Cardiotonic Agents; Coronary Artery Bypass; Defibrillators, Implantable; Diet, Sodium-Restricted; Digoxin; Diuretics; Exercise Therapy; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Mitral Valve Insufficiency; Obesity; Patient Compliance; Patient Education as Topic; Sleep Apnea, Obstructive; Vasodilator Agents

Diastolic heart failure is predominantly a disease of the elderly: at the age of 70 years, almost half of all patients with heart failure have diastolic heart failure. Hypertension and obesity are common underlying disorders in patients with diastolic heart failure. Patients with diastolic heart failure have an equal, or only slightly better, prognosis in terms of mortality compared to patients with systolic heart failure. Echocardiography can distinguish diastolic heart failure from systolic heart failure. Patients with heart failure and a normal ejection fraction almost certainly have a diastolic dysfunction. There is a lack of reliable data about the optimal medicinal treatment strategy for patients with diastolic heart failure. Angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and (non-dihydropyridine) calcium antagonists have therapeutic potential. Digoxin may be contraindicated.

Topics: Adrenergic beta-Antagonists; Age Factors; Angiotensin-Converting Enzyme Inhibitors; Diastole; Digoxin; Echocardiography; Heart Failure; Humans; Hypertension; Obesity; Prognosis

Endogenous factors cross-reacting with antidigoxin antibodies have been found in several tissues and body fluids of animals and humans, using commercially available digoxin radioimmunoassay or enzyme immunoassay methods. The chemical characteristics of these endogenous factors are, at present, unknown, although it has been suggested that they could be substances with low molecular weight. Experimental studies and theoretical considerations indicate that endogenous digitalis-like factors (DDLFs), in addition to the ability to react 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, EDLF can be an endogenous modulator of the membrane sodium-potassium pump and several authors have suggested that EDLF could play a role in the regulation of fluids and electrolytes, muscular tone of myocardial and also in the pathogenesis of arterial hypertension. In this review, the authors discuss the hypothesis that, in metabolic diseases such as diabetes mellitus, obesity and acromegaly, the sodium retention and volume expansion, possibly due to exaggerated sodium intake, and/or exogenously induced peripheral hyperinsulinemia and high levels of growth hormone, could trigger a sustained release of EDLF, which in turn increases the blood pressure.

Topics: Acromegaly; Blood Proteins; Cardenolides; Cardiac Glycosides; Diabetes Mellitus; Digoxin; Humans; Hypertension; Natriuresis; Obesity; Saponins

Digitalis glycosides continue to place high on the list of prescribed drugs. Digoxin is 8th on prescriptions written in the United States in 1980, digitoxin 16th, and digitalis leaf 23rd. There is little doubt that most physicians continue to believe these drugs are useful. The application of more definite indications, smaller doses, and the recognition of the role of pharmacokinetics and drug interactions make use of the glycosides more challenging than ever before in 1985.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Age Factors; Anti-Arrhythmia Agents; Antihypertensive Agents; Arrhythmias, Cardiac; Biological Availability; Bretylium Tosylate; Deslanoside; Digitalis Glycosides; Digitoxin; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Heart Failure; Humans; Injections, Intramuscular; Injections, Intravenous; Intestinal Absorption; Kidney Failure, Chronic; Lidocaine; Metabolic Clearance Rate; Myocardial Infarction; Obesity; Phenytoin; Potassium; Pulmonary Heart Disease; Thyroid Diseases

Topics: Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Heart Failure; Humans; Hyperthyroidism; Hypothyroidism; Intestinal Absorption; Kidney Failure, Chronic; Molecular Conformation; Obesity

Topics: Administration, Oral; Aged; Digitalis Glycosides; Digitoxin; Digoxin; Feces; Heart Atria; Heart Failure; Humans; Injections, Intramuscular; Injections, Intravenous; Intestinal Absorption; Kidney Diseases; Liver Diseases; Malabsorption Syndromes; Obesity; Tachycardia; Thyroid Diseases; Tritium; Water-Electrolyte Balance

Topics: Age Factors; Arrhythmias, Cardiac; Calcium; Child; Coronary Care Units; Digitalis Glycosides; Digoxin; Electric Countershock; Electrocardiography; Endocrine System Diseases; Heart Diseases; Heart Failure; Heart Rate; Heart Valve Diseases; Humans; Kidney Failure, Chronic; Liver Diseases; Lung Diseases; Magnesium; Obesity; Ouabain; Poisoning; Potassium; Psychophysiologic Disorders; Pulmonary Heart Disease; Thyroid Diseases; Time Factors

Overnutrition causes obesity, a global health problem without any effective therapy. Obesity is characterized by low-grade inflammation, which predisposes individuals to metabolic syndrome via unknown mechanisms. Here, we demonstrate that abolishing the interleukin-17A (IL-17A) axis in mice by inhibition of RORγt-mediated IL-17A production by digoxin, or by ubiquitous deletion of IL-17 receptor A (Il17ra), suppresses diet-induced obesity (DIO) and metabolic disorders, and promotes adipose-tissue browning, thermogenesis and energy expenditure. Genetic ablation of Il17ra specifically in adipocytes is sufficient to completely prevent DIO and metabolic dysfunction in mice. IL-17A produced in response to DIO induces PPARγ phosphorylation at Ser273 in adipocytes in a CDK5-dependent manner, thereby modifying expression of diabetogenic and obesity genes, which correlates with IL-17A signalling in white adipose tissues of individuals with morbid obesity. These findings reveal an unanticipated role for IL-17A in adipocyte biology, in which its direct action pathogenically reprograms adipocytes, promoting DIO and metabolic syndrome. Targeting the IL-17A axis could be an efficient antiobesity strategy.

Topics: Adipocytes; Adipose Tissue, Brown; Animals; Cyclin-Dependent Kinase 5; Diet; Diet, High-Fat; Digoxin; Energy Metabolism; Feces; Gene Deletion; Interleukin-17; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 1, Group F, Member 3; Obesity; Overnutrition; Phosphorylation; PPAR gamma; Thermogenesis

To evaluate the effect of Roux-en-Y gastric bypass surgery (RYGB) on the pharmacokinetics of midazolam (a CYP3A4 substrate) and digoxin (a P-glycoprotein substrate).. Prospective, nonblinded, longitudinal, single-dose pharmacokinetic study in three phases: presurgery baseline and postoperative assessments at 3 and 12 months.. Twelve obese patients meeting current standards for bariatric surgery.. At each study visit, patients received a single dose of oral digoxin and midazolam at 8 a.m. Blood samples were collected at regular intervals for 24 hours after dosing. Continuous 12-lead electrocardiogram (EKG), heart rate, blood pressure, and respiratory rate were monitored, and pharmacokinetic parameters from the three visits were compared. The peak plasma concentration (Cmax ) of midazolam increased by 66% and 71% at 3- and 12-month post-RYGB (p=0.017 and p=0.001, respectively), whereas the median time to peak concentration (Tmax ) was reduced by 50%. The mean Cmax for 1'-hydroxymidazolam increased by 87% and 80% at 3 and 12 months (p=0.001 and p<0.001, respectively). However, neither the area under the concentration-time curve (AUC) for midazolam nor the metabolite-to-parent AUC ratio changed significantly over time. For digoxin, the median Tmax decreased from 40 minutes at baseline to 30 and 20 minutes at 3 and 12 months, respectively. The mean AUC for digoxin, heart rate, and EKG patterns were similar across the three study phases.. Contemporary proximal RYGB increases the rate of drug absorption without significantly changing the overall exposure to midazolam and digoxin. The Cmax of a CYP3A4 substrate with a high extraction ratio was substantially increased after RYGB.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Digoxin; Female; Gastric Bypass; Gastrointestinal Absorption; Humans; Longitudinal Studies; Male; Midazolam; Middle Aged; Obesity; Pilot Projects; Prospective Studies

Placental P-glycoprotein (P-gp) plays a significant role in controlling digoxin transplacental rate. Investigations on P-gp regulation in placenta of women with different pregnant pathology are of great significance to the individualized transplacental digoxin treatment for fetal heart failure (FHF). This study aimed to explore the effect of maternal obesity on the expression and functionality of placental P-gp both in human and in mice.. Placenta tissues from obese and lean women were collected. Female C57BL mice were fed with either a normal chow diet or a high-fat diet for 12 weeks before mating and throughout pregnancy. Maternal plasma glucose, HDL-C, LDL-C, TC, TGs, insulin, IL-1β, IL-6 and TNF-α concentrations was detected. Placental ABCB1/Abcb1a/Abcb1b/IL-1β/IL-6/TNF-α mRNA and P-gp/IL-1β/IL-6/TNF-α protein expression were determined by real-time quantitative PCR and western-blot, respectively. Maternal plasma and fetal-unit digoxin concentrations were detected by a commercial kit assay.. Both ABCB1 gene mRNA and protein expression of obesity group was significantly lower than that of control group in human. The high-fat dietary intervention resulted in an overweight phenotype, a significant increased Lee's index, higher levels of plasma glucose, HDL-C, LDL-C, insulin and TGs, increased peri-renal and peri-reproductive gland adipose tissue weight, and larger size of adipose cell. Compared with control group at the same gestational day (E12.5, E15.5, E17.5), placental Abcb1a mRNA and P-gp expression of obese group were significantly decreased in mice, while digoxin transplacental rates were significantly increased. Higher maternal plasma IL-1β/TNF-α concentrations and placental IL-1β/TNF-α expression were observed in obesity groups in comparison with control group at the same gestational age.. Maternal obesity could inhibit placental P-gp expression and its functionality both in human and in mice, which might be resulted from a heightened inflammatory response.

Topics: Adult; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiotonic Agents; Case-Control Studies; Digoxin; Disease Models, Animal; Female; Fetal Diseases; Heart Failure; Humans; Mice, Inbred C57BL; Obesity; Placenta; Precision Medicine; Pregnancy; Pregnancy Complications; Random Allocation

Our object was to evaluate the effects of regular mild exercise on blood pressure and on circulating level of ouabainlike factors (OLF) and of nitrate anion, an endproduct of nitric oxide (NO) in humans. We measured plasma ouabainlike immunoreactivity (OLI) and nitrate ions (NO3.) before and after mild exercise for 3 months' duration in 16 patients with essential hypertension, diabetes mellitus, obesity, or hyperlipidemia. Plasma OLI was measured using an amplified ELISA system with anti-ouabain antibody and biotinyl-tyramide. Serum NO3. was measured with high-performance liquid chromatography (HPLC) with an anion-exchange column. With the reverse phase HPLC system with an octa decylsilyl silicagel column, the elution volume of plasma OLI of a healthy volunteer matched that of authentic ouabain in a gradient elution system of acetonitrile/H2O. Plasma OLI levels decreased significantly by about 34% after mild exercise, and NO3. levels tended to be within the reference interval in normal volunteers. Body weight, diastolic and systolic blood pressure, serum triglyceride and acetylcholine esterase (a marker of the fatty liver) were significantly decreased (p < 0.01) after 3 months of regular mild exercise. The plasma OLI level was significantly correlated with plasma NO3., there was a trend toward a correlation with diastolic blood pressure (p = 0.06) before and after regular exercise. Regular mild exercise led to a decrease in plasma levels of OLI, and acetylcholine esterase activity and blood pressure in adult patients. Results suggest that changes in OLF production contribute to the blood pressure regulation seen in patients who exercise regularly.

Topics: Adult; Aged; Blood Pressure; Cardenolides; Chromatography, High Pressure Liquid; Diabetes Mellitus; Digoxin; Enzyme-Linked Immunosorbent Assay; Exercise; Female; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Nitrates; Nitric Oxide; Obesity; Ouabain; Saponins

The role of endogenous digitalis-like factors in the pathogenesis of the hypertension associated with impaired glucose tolerance was investigated by measuring plasma digoxin-like immunoreactivity (DLI). Mean blood pressure correlated significantly with the obesity index, serum insulin-like immunoreactivity (IRI), and plasma DLI concentrations in subjects with impaired glucose tolerance (IGT). Plasma DLI concentrations also correlated significantly with the obesity index and serum IRI concentrations. Because increased insulin has been proposed to promote sodium reabsorption, sodium retention in turn has presumably caused an increase of natriuretic, digitalis-like factors reflected by the increased plasma DLI concentrations in patients with IGT. Consequently, increased DLI may contribute to the elevated arterial pressure in patients with hyperinsulinemia.

Topics: Adult; Aged; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypertension; Insulin; Middle Aged; Obesity; Regression Analysis; Saponins; Sodium-Potassium-Exchanging ATPase

Hypertensive obese subjects with glucose intolerance have hyperinsulinaemia, insulin resistance and intracellular cation imbalance resulting in increased sodium content. The aim of our study was to assess in these patients plasma levels of endogenous digoxin-like factor (EDLF), an inhibitor of the sodium-pump mechanism. We studied 14 hypertensive and 12 normotensive subjects with obesity and glucose intolerance for fasting blood glucose, and plasma insulin, C-peptide and EDLF levels: the two groups were matched for age and BMI and were studied after a 2-week wash-out period from hypotensive drugs. Compared with normotensives, hypertensive subjects had higher plasma insulin levels, a greater immunoreactive insulin/C-peptide ratio, a lower glucose/insulin ratio and higher plasma EDLF levels. Our results confirm that among obese people with glucose intolerance, hypertensives are more hyperinsulinaemic and insulin-resistant than normotensives and indicate that the intracellular cation imbalance in these patients may be attributable, at least in part, to EDLF.

Topics: Blood Glucose; Blood Proteins; C-Peptide; Cardenolides; Digoxin; Female; Glucose Tolerance Test; Humans; Hyperglycemia; Hypertension; Insulin; Insulin Resistance; Male; Middle Aged; Obesity; Saponins; Sodium-Potassium-Exchanging ATPase

Topics: Blood Proteins; Cardenolides; Catecholamines; Diabetes Mellitus; Diabetic Neuropathies; Diabetic Retinopathy; Digoxin; Erythrocyte Membrane; Humans; Hypertension; Insulin; Obesity; Saponins; Sodium-Potassium-Exchanging ATPase

We assessed the role of circulating digitalis-like substance(s) on the blood pressure regulation in patients with essential hypertension, cardiac diseases, diabetes mellitus and renal diseases by measuring digoxin-like immunoreactivity (DLI). Plasma DLI concentrations tended to correlate with blood pressure in all patient groups. Plasma DLI correlated to plasma aldosterone concentration in patients with essential hypertension, which suggested close interrelationship between DLI and electrolytes metabolism with adrenal steroids. Serum immunoreactive insulin (IRI) levels significantly correlated with blood pressure. Because plasma DLI levels correlated with serum IRI, increased levels of insulin could have induced sodium retention leading to increased DLI levels. Digitalis-like substance, but not insulin, would have directly increased blood pressure in patients with abnormal glucose tolerance. Plasma DLI levels significantly correlated with the severity of renal insufficiency in patients with renal diseases. Plasma DLI highly correlated with amounts of plasma proteins, particularly with albumin, which would be due to the binding of DLI with albumin in plasma. Because the level of non-binding DLI is extremely low when assayed with a digoxin-radioimmunoassay, it was impossible to assess the level of a free-form of DLI, i.e., active DLI. That could be a reason why the correlation between the DLI and the other parameters was not highly significant. Collectively, these findings suggest that the DLI is one of the major determinants of blood pressure rises, regardless of any cause.

Topics: Adult; Aged; Blood Pressure; Blood Proteins; Cardenolides; Diabetes Mellitus; Digoxin; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Obesity; Saponins

Topics: Adult; Age Factors; Arrhythmias, Cardiac; Biological Availability; Digoxin; Dosage Forms; Drug Interactions; Eating; Female; Humans; Infant, Newborn; Kidney Diseases; Male; Obesity; Pregnancy; Radioimmunoassay; Specimen Handling

Possible involvement of an endogenous digitalislike substance (EDLS) in blood pressure regulation was investigated using a Japanese population. Mean arterial pressure (MAP) significantly correlated with urinary excretion of the EDLS, age, and the obesity index. The plasma EDLS correlated with urinary EDLS. Urinary EDLS excretion well correlated with the inhibitory activity on Na+,K+-ATPase, and also with the urinary excretion of NaCl. Obesity index correlated with the Na+,K+-ATPase inhibition and arterial pressure. Although plasma content of atrial natriuretic polypeptide correlated with the urinary Na+,K+-ATPase inhibition, it did not correlate with the rest of all parameters. Plasma vasopressin level did not correlate with these parameters either. These results clearly indicate that the circulating EDLS (ie, Na+,K+-ATPase inhibitor) is implicated in the hypertension associated with an excess intake of sodium, aging and obesity.

Topics: Adult; Aged; ATPase Inhibitory Protein; Blood Pressure; Blood Proteins; Cardenolides; Digoxin; Female; Humans; Japan; Male; Middle Aged; Obesity; Proteins; Proteinuria; Saponins

Na+-K+-ATPase activity, as measured by erythrocytic 86Rb uptake and number Digoxin Binding Sites were evaluated in 34 obese patients and in 39 control subjects. No differences were found in 86Rb uptake and Digoxin Binding Sites between obese and controls. Likewise no differences were found between obese patients on their spontaneous caloric intake and those studied during various hypocaloric regimens. Finally, no relationship between thyroid hormone serum concentrations and ATPase activity was found in the group of obese patients.

Topics: Adult; Binding Sites; Diet, Reducing; Digoxin; Energy Intake; Erythrocytes; Female; Humans; Male; Middle Aged; Obesity; Rubidium; Sodium-Potassium-Exchanging ATPase

Topics: Body Weight; Digoxin; Humans; Obesity

Digoxin pharmacokinetics were studied in 16 obese (mean +/- SD weight, 100.2 +/- 36.8 kg) and 13 control (64.6 +/- 10.5 kg) subjects. All subjects had normal renal function and no other coexisting disease. After administration of 0.75 mg digoxin by intravenous infusion, multiple plasma samples obtained over the 96 hours following infusion were analyzed for digoxin concentration by radioimmunoassay. Pharmacokinetic parameters were determined by weighted iterative nonlinear least squares regression analysis. Elimination half-life (t 1/2) was not different between obese and control groups (35.6 +/- 10.5 vs 41.2 +/- 16.7 hours). Absolute volume of distribution (Vd) also was not different (981 +/- 301 vs 937 +/- 397 liters), nor was total clearance of digoxin (328 +/- 82 vs 278 +/- 87 ml/min). Elimination t 1/2 was significantly negatively correlated with clearance among all subjects (r = -0.46; p less than 0.01). Using percent ideal body weight (IBW) as a measure of obesity, no correlation was found between percent IBW and Vd (r = 0.03). Thus digoxin is similarly distributed into IBW in obese and normal weight subjects, and there is no significant distribution of digoxin into excess body weight over IBV. In addition, there is no difference in total metabolic clearance or elimination half-life between obese and control subjects. Digoxin loading and maintenance dosage should be calculated on the basis of IBW, which reflects lean body mass, rather than TBW, which reflects adipose tissue weight in addition to lean body mass.

Topics: Adult; Body Weight; Digoxin; Female; Half-Life; Humans; Kinetics; Male; Obesity; Regression Analysis

Seven subjects who underwent jejunoileal bypass surgery for massive obesity participated in a study to examine the relative bioavailability of digoxin before and one to two months after surgery. They were given a loading dose of 1 mg digoxin in divided oral doses followed by oral maintenance doses of 0.5 mg daily. There were no significant differences in the area under the serum concentration time curve, steady state serum levels or 24 hour steady state excretion of digoxin before and after surgery. We conclude that the bioavailability of digoxin from the Lanoxin tablets employed is not impaired in these patients, although urinary d-xylose and 24 hour fecal fat excretion indicated moderate to severe malabsorption after surgery.

Topics: Digoxin; Female; Humans; Ileum; Jejunum; Kinetics; Male; Obesity; Time Factors

Topics: Biological Availability; Cardiac Glycosides; Creatinine; Deslanoside; Digitalis Glycosides; Digitoxin; Digoxin; Drug Interactions; Humans; Hypokalemia; Kidney Diseases; Liver Diseases; Malabsorption Syndromes; Obesity; Ouabain; Thyroid Diseases

The pharmacokinetics of digoxin, the most frequently used digitalis preparation, are reviewed. The dominate serum turnover time is about 34 hours, and is not affected by the route of administration. Excretion is largely as unchanged digoxin in the urine and this excretion is compromised in renal failure. Serum levels of digoxin (determined by radioimmunoassay) are generally available and are useful clinically in assessment of both toxicity and the state of underdigitalization, even though significant overlap exists. Special problems are presented in patients with myocardial infarction, pulmonary heart disease, and thyroid disease.

Topics: Acute Kidney Injury; Aging; Digitalis Glycosides; Digoxin; Heart Rate; Kidney; Kinetics; Myocardial Contraction; Myocardial Infarction; Obesity; Pulmonary Heart Disease; Structure-Activity Relationship; Thyroid Diseases; Water-Electrolyte Balance

Topics: Administration, Oral; Aged; Arrhythmias, Cardiac; Digitalis Glycosides; Digitoxin; Digoxin; Heart Block; Heart Diseases; Heart Failure; Humans; Hyperthyroidism; Injections, Intravenous; Kidney Failure, Chronic; Middle Aged; Obesity; Ventricular Fibrillation

Topics: Brain Diseases; Chemoreceptor Cells; Chronic Disease; Diagnosis, Differential; Diazepam; Digoxin; Furosemide; Humans; Hydrochlorothiazide; Hypercapnia; Hypoventilation; Hypoxia; Lung Diseases, Obstructive; Male; Obesity; Respiratory Center; Respiratory Function Tests

Topics: Angiography; Cardiac Catheterization; Digoxin; Female; Heparin; Humans; Lung; Middle Aged; Obesity; Obesity Hypoventilation Syndrome; Pulmonary Embolism; Respiratory Function Tests

Topics: Adipose Tissue; Adult; Body Weight; Digoxin; Female; Humans; Injections, Intravenous; Male; Obesity; Tritium