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Despite controversy over their use and the potential for toxic side effects, cardiac glycosides have remained an important clinical component for the treatment for congestive heart failure (CHF) and supraventricular arrhythmias since the effects of Digitalis purpurea were first described in 1785. While there is a wealth of information available with regard to the effects of these drugs on their pharmacological receptor, the Na(+), K(+)-ATPase, the exact molecular mechanism of digitalis binding and inhibition of the enzyme has remained elusive. In particular, the absence of structural knowledge about Na(+), K(+)-ATPase has thwarted the development of improved therapeutic agents with larger therapeutic indices via rational drug design approaches. Here, we propose a binding mode for digoxin and several analogues to the Na(+), K(+)-ATPase. A 3D-structural model of the extracellular loop regions of the catalytic alpha1-subunit of the digitalis-sensitive sheep Na(+), K(+)-ATPase was constructed from the crystal structure of an E(1)Ca(2+) conformation of the SERCA1a and a consensus orientation for digitalis binding was inferred from the in silico docking of a series of steroid-based cardiotonic compounds. Analyses of species-specific enzyme affinities for ouabain were also used to validate the model and, for the first time, propose a detailed model of the digitalis binding site.
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Pretreatment with calcium channel blocker may improve the efficacy by reversing the so-called "electric remodeling" phenomenon, also related to overload in cytosolic calcium.
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The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of sotalol in the treatment of fetal tachycardia.
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Supraventricular tachycardia is the most common pediatric arrhythmia, but there is no consensus and little evidence to guide its treatment. We sent a questionnaire to pediatric cardiologists in North America to assess the current practice pattern. Of 1534 surveys mailed, 352 (23%) were returned and 295 (19%) had complete data for analysis. In the acute setting, 11 different medications were chosen. The most commonly used in the infant without preexcitation were digoxin (42%), procainamide (21%), esmolol (13%), propranolol (10%), and amiodarone (8%). In the infant with preexcitation, propranolol (34%), procainamide (23%), esmolol (17%), amiodarone (11%), and digoxin (6%) were used. In the chronic setting, 8 different medications were chosen. The most commonly used in this scenario were digoxin (52%), propranolol (33%), amiodarone (4%), and sotalol (3%). In the infant with preexcitation, propranolol (70%), amiodarone (6%), digoxin (6%), atenolol (6%), and flecainide (5%) were used. Medication choices were influenced by additional electrophysiology training and preexcitation. Digoxin was used less in the setting of preexcitation. There are no comparative trials to explain the different medication choices. Although a number of medications may be efficacious, a randomized clinical trial is needed to offer further guidance.
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The predictive risk factors concerning severe acute digoxin poisoning are profuse vomiting, hyperkalaemia and bradycardia. The predictive risk factors of fatal outcome are age over 65 years associated with primary disease, vomiting and bradycardia.
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Intravenous digoxin induces constriction of normal and stenotic coronary arteries in patients with coronary artery disease, which may lead to ischemic complications. We found that pretreatment with oral nisoldipine and intracoronary nitroglycerin neutralizes this digoxin-induced effect.
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A substantial proportion of older adults on high-risk medications do not recall receiving instructions for the use of their medications and do not take advantage of existing systems for organizing medication regimens. Improved patient education and delivery of medication organization systems are immediate opportunities to potentially reduce the risk of medication errors in older people.
This study tested the hypothesis that endogenous digitalis-like factor (DLF) is involved in the development of alcohol dependence in rats. In 33 male Wistar rats in conditioned place preference (CPP) experiment, ethanol evoked increase in time spent in the ethanol-associated compartment (702+/-82 in ethanol-treated vs. 426+/-86 sec in the controls). Digoxin pretreatment (125 microg/kg, i/p) did not affect the time spent in the water-associated compartment (476+/-80 sec), but prevented the acquisition of ethanol CPP (385+/-112 sec in ethanol-paired side, P<0.05). In a two bottle choice test, where rats (n=6 per group) chose between drinking water and 9% ethanol, immunization against two putative DLFs, marinobufagenin and ouabain (MBG and OLC) resulted in a 60% increase of ethanol consumption. Acute intragastric administration of 9% ethanol to the rats was associated with increased OLC in cerebrospinal fluid, and stimulated urinary excretion of MBG and OLC. Thus, in rats, digoxin, which mimics the effects of DLFs, suppresses the free choice of alcohol, while immunization against DLFs is associated with alcohol seeking behavior.
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Estimated number of and risks for emergency department visits for adverse drug events involving Beers criteria medications and other medications.
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Hamsters fed a Mg-deficient diet (MD) develop a cardiomyopathy (CM) with foci of myocardial necrosis, calcification, and modest mononuclear and giant cell infiltration. We hypothesize that the lesions are secondary to Ca overload following an increase in myocardial Na due to inhibition of (Na.K)-ATPase and secondary Na-Ca exchange. Nifedipine and digoxin were selected as agents to test this hypothesis. Hamsters were given nifedipine, digoxin, or placebo as sustained release subcutaneous pellets the same day they were started on the MD diet. Animals were killed after 14 days, and MD lesions were quantified in H&E stained slides. Regression analysis showed that nifedipine produced a dose-dependent reduction in lesion abundance (p less than .005) and diameter (p less than .05), while digoxin produced a dose-dependent increase in lesion abundance (p less than .005) and diameter (p less than .005). These results support the hypothesis that MDCM is secondary to Ca overload coupled to inhibition of (Na.K)-ATPase of cardiac myocytes.
Digoxin poisoning still remains a common cause of morbidity and mortality. Fortunately, digoxin-specific Fab fragments are commercially available as an antidote. However, these Fab fragments are several thousand dollars per vial. There is a standardized formula to calculate appropriate Fab fragment dosage based on the serum digoxin concentration. This can greatly reduce the amount of Fab fragment administered. There is also an empiric dosing guideline recommending 6-10 vials be given; however, this may result in higher amounts of Fab fragments being administered than required. We performed this study to assess the amounts of digoxin-specific Fab fragments administered in the treatment of digoxin poisonings recorded in a poison control system database from January 1, 2000, to December 31, 2009, in which digoxin serum concentrations were available. This was a retrospective study of 278 patients, 107 with acute poisonings (group A) and 171 following chronic poisoning (group B). In group A, the calculated Fab dose was higher than the calculated dose based on available concentrations in 39 (36%) of group A and 15 (9%) of group B patients. The average wholesale price cost of the excessive dosages ranged from $4818 to as high as $50,589 per patient. Our data suggests that clinician education on digoxin poisoning and the use of the standardized formula to calculate the Fab dose may decrease over utilization and decrease costs associated with the administration of digoxin-specific Fab fragments in the treatment of digoxin poisonings.
(1) One minute after i.c. injection, the plasma peak of digoxin was 40 times higher (p < 0.01) after injection with norepinephrine than after injection with vasodilators. (2) There was a statistically significantly (p < 0.01) higher plasma digoxin level 5, 6, 10 and 15 min after injection in the 30 patients presenting an abnormal cavernosometry than in the 30 patients presenting a normal one.