digoxin and Metabolic-Diseases

Na,K-ATPase (sodium pump; EC 3.6.1.37) is present in the membrane of most eukaryotic cells and controls directly or indirectly many essential cellular functions. Regulation of this enzyme (ion transporter) and its individual isoforms is believed to play a key role in the etiology of some pathological processes. The sodium pump is the only known receptor for the cardiac glycosides. However, endogenous ligands structurally similar to digoxin or ouabain may control the activity of this important molecular complex. Here we review the structure and function of Na,K-ATPase, its expression and distribution in tissues, and its interaction with known ligands such as the cardiac glycosides and other suspected endogenous regulators. Also reviewed are various disorders, including cardiovascular, neurological, renal, and metabolic diseases, purported to involve dysfunction of Na,K-ATPase activity. The escalation in knowledge at the molecular level concerning sodium pump function foreshadows application of this knowledge in the clinical laboratory to identify individuals at risk for Na,K-ATPase-associated diseases.

Topics: Cardiac Glycosides; Cardiovascular Diseases; Digoxin; Fetus; Humans; Lung Diseases; Metabolic Diseases; Nervous System Diseases; Sodium-Potassium-Exchanging ATPase; Structure-Activity Relationship

Topics: Adult; Amino Acids; Cardiac Output; Cardiovascular System; Cells; Digoxin; Energy Intake; Energy Metabolism; Female; Heart Diseases; Humans; Infections; Intubation; Metabolic Diseases; Multiple Organ Failure; Myocardium; Positive-Pressure Respiration; Probability; Respiratory Insufficiency; Vascular Resistance

Following the development of methods for eliciting and purifying digoxin-specific Fab fragments with high affinity and specificity for cardiac glycosides, clinical studies were undertaken as a multicenter, open-label trial to test safety and efficacy in patients with advanced and potentially life-threatening digitalis toxicity that failed to respond to conventional therapeutic measures. One-hundred fifty such patients were treated with digoxin-specific antibody fragments purified from immunoglobulin G (IgG) produced in sheep. Doses of Fab were equivalent to the amount of digoxin or digitoxin in the patient's body, as estimated from the medical history or serum concentration measurements. Of 150 patients included in this trial, detailed information is available on 148. One-hundred nineteen (80%) had resolution of all signs and symptoms of digitalis toxicity following specific Fab fragment infusions, 14 (10%) improved, and 15 (10%) showed no response. Among 14 patients with adverse events possibly or probably caused by Fab, the most common events were development of hypokalemia and exacerbation of congestive heart failure. Analysis of the available clinical data indicates that a treatment response was observed in at least 90% of patients with convincing evidence of advanced and potentially life-threatening digitalis toxicity. The data from this multicenter trial have been augmented by findings from an observational surveillance study conducted to monitor the safety and effectiveness of treatment with digoxin immune Fab (ovine) following commercial availability. In this experience, 74% of patients were judged to have a complete or partial response to treatment, and 12% no response. The response for the remaining 14% was not reported or reported as uncertain. In this clinical experience, digoxin-specific Fab was generally well tolerated and clinically effective in patients with potentially life-threatening digitalis toxicity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Child; Child, Preschool; Digoxin; Female; Humans; Immunoglobulin Fab Fragments; Infant; Infant, Newborn; Infusions, Intravenous; Male; Metabolic Diseases; Middle Aged; Poisoning; Product Surveillance, Postmarketing

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 determine the prevalence of adverse drug reaction (ADR)-related hospital admissions in an older population, to describe the most common clinical manifestations and drugs most frequently responsible for ADR-related hospital admissions, and to identify independent factors predictive of these ADRs.. Multicenter pharmacoepidemiology survey conducted between 1988 and 1997.. Eighty-one academic hospitals throughout Italy.. Twenty-eight thousand four hundred eleven patients consecutively admitted to participating centers during the survey periods.. For each suspected ADR at admission, a physician, who coded description, severity, and potentially responsible drugs, completed a questionnaire.. Mean age +/- standard deviation of the patients was 70 +/- 16. One thousand seven hundred four ADRs were identified upon hospital admission. In 964 cases (3.4% of all admissions), ADRs were considered to be the cause of these hospital admissions. Of these, 187 ADRs were coded as severe. Gastrointestinal complaints (19%) represented the most common events, followed by metabolic and hemorrhagic complications (9%). The drugs most frequently responsible for these ADRs were diuretics, calcium channel blockers, nonsteroidal antiinflammatory drugs, and digoxin. Female sex (odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.10-1.54), alcohol use (OR = 1.39, 95% CI = 1.20-1.60), and number of drugs (OR = 1.24, 95% CI = 1.20-1.27 for each drug increase) were independent predictors of ADR-related hospital admissions. For severe ADRs, age (OR = 1.50, 95% CI = 1.01-2.23 for age 65-79 and OR = 1.53, 95% CI = 1.00-2.33 for age > or =80, respectively), comorbidity (OR = 1.12, 95% CI = 1.05-1.20 for each point in the Charlson Comorbidity Index), and number of drugs (OR = 1.18, 95% CI = 1.11-1.25 for each drug increase) were the only predisposing factors.. The most important determinant of risk for ADR-related hospital admissions in older patients is number of drugs being taken. When considering only severe ADRs, risk is also related to age and frailty.

Topics: Aged; Alcohol Drinking; Anti-Inflammatory Agents, Non-Steroidal; Calcium Channel Blockers; Comorbidity; Digoxin; Diuretics; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Hemorrhage; Humans; Male; Metabolic Diseases; Patient Admission; Risk Factors; Sex Factors; Surveys and Questionnaires

Because global T wave inversion has not been specifically characterized, 100 electrocardiograms (ECGs) with this pattern (frontal plane T vector -100 degrees to -170 degrees with precordial T inversion) were prospectively collected from approximately 30,000 consecutively interpreted ECGs and analyzed blindly. There was a striking female predominance (82 women vs. 18 men; p less than 0.0005) despite an essentially equal number of female and male hospital admissions. There was a single statistically significant ECG correlate: a more vertical QRS axis in women (+14.1 degrees +/- 45.3 degrees vs. -5.6 degrees +/- 31.3 degrees; p = 0.034). The T waves were basically symmetric (68%), the influence of this factor usually altering the characteristically asymmetric T wave inversions of right bundle branch block (4 of 5) and left ventricular hypertrophy (21 of 36). Asymmetry was mainly associated with digoxin therapy (21 of 32 patients taking digoxin; p less than or equal to 0.0005) and a corrected QT (QTc) interval (0.433 +/- 0.095) shorter than with symmetric T wave inversions (0.507 +/- 0.074; p less than or equal to 0.0005) though not reaching the degree of shortening expected for digitalization. Twenty-eight patients admitted for acute myocardial infarction and 23 for a central nervous system disorder accounted for the majority of patients with symmetric T wave inversion. Fifteen of 18 patients who had coronary angiography had some degree of coronary artery disease: 3 had angiographically normal coronary arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Bundle-Branch Block; Cardiomegaly; Central Nervous System Diseases; Digoxin; Electrocardiography; Female; Gastrointestinal Diseases; Heart; Humans; Lung Diseases; Male; Metabolic Diseases; Myocardial Infarction; Sex Factors

Topics: Adult; Age Factors; Aged; Body Weight; Carbon Dioxide; Creatinine; Digoxin; Diuretics; Electrocardiography; Female; Humans; Kidney Diseases; Magnesium; Male; Metabolic Diseases; Middle Aged; Radioimmunoassay; Sex Factors