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At least 19 recordsLinked to original sources
PubMed1988

Digitalis, digitalis antibodies, digitalis-like immunoreactive substances, and sodium homeostasis: a review.

Most pharmacokinetic and biologic attributes of digitalis are age dependent. They are determined in great measure by the chemical structure of the specific cardiac glycoside being used. These effects differ in the intact normal circulation and in heart failure because of the altered autonomic nervous system and hormonal control that exist in the latter. Digitalis is effective only in the presence of myocardial dysfunction, but in a clinical setting, cardiac performance may be difficult to gauge; improved tools are needed for this purpose. The dosages of digoxin recommended for infants and children have been steadily reduced in the past decade, and there is no good evidence that more favorable risk-to-benefit ratios are achieved when higher doses are used or when higher plasma concentrations are sought. Massive digitalis toxicity is a serious, often fatal, complication in young infants, especially when the drug is given parenterally; it may be difficult to diagnose early. The only reliable deterrent for this complication is the adoption of careful safety standards whenever the drug is employed. Experience with digoxin antibodies is still scarce in children, especially in infancy, but their use generally has been associated with a favorable outcome. Endogenous substances that interfere with the digoxin radioimmunoassay (DLIS) occasionally yield clinically relevant, erroneously high, plasma digoxin concentration readings in neonates. An interesting hypothesis currently being investigated is the physiologic and pathologic role of these compounds in sodium hemostasis; they may be part of a putative endogenous NaK-ATP-ase inhibitor involved in the pathogenesis of hypertension and renal diseases.

Cross Reactions↗
PubMed1975

Serum digitalis measurements in the assessment of digitalis resistance and sensitivity.

Antibodies to digitalis glycosides have been elicited in experimental animals and have been utilized in the development of rapid, sensitive, specific and convenient radioimmunoassay methods for the clinical measurement of digoxin and other cardiac glycosides in man. The use of these assay methods has supplemented earlier studies with radiolabeled digitalis preparations and has made it possible to obtain much new information concerning factors which may contribute to the well known patient to patient variability in digitalis dosage requirements and in sensitivity to the toxic effects of cardiac glycosides. In some patients with a poor clinical response to digitalis, the finding of a serum concentration which is relatively low for the dose prescribed may suggest that true digitalis resistance is not present and may raise questions of poor patient compliance, tablet inadequacies, intestinal malabsorption, increased metabolic degradation or hyperthyroidism; if the cause of the low serum level cannot be identified or corrected, serial serum measurements should enable safe and rational upward adjustment of dosage. In some patients with digitalis toxicity, the finding of a serum level which is relativity high for the dose prescribed may suggest that the patient is not sensitive to digitalis but rather is excreting it slowly; in such instances in elderly patients (with decreased glomerular filtration rates) and in patients with renal disease, serial digitalis measurements are useful adjuncts to clinical observation in determining optimal digitalis dosage schedules. A knowledge of serum digitalis concentrations should enable us to develop sound principles for a more rational approach to the clinical administration of cardiac glycosides, especially in patients with unusually high dosage requirements or with unusual sensitivity to relatively small doses of digitalis.

Animals↗
PubMed1992

Digitalis and heart failure: does digitalis really produce beneficial effects through a positive inotropic action?

Although digitalis was introduced to medicine long ago, the drug is still extensively used in clinical practice today. Opinions on its mechanism of action have undergone much change in the course of time, and the way in which cardiovascular effects are produced is still not completely clear. Limitations and contraindications for the use of digitalis substances are reported, especially in the treatment of ischemic heart disease. Preliminary data regarding the effects of digitalis on the diastolic phase are unfavorable, although the relationship between digitalis and diastolic function ought to be studied in greater depth in various clinical conditions. In spite of many recent trials, the old question of the usefulness of digitalis in the chronic treatment of patients in sinus rhythm and heart failure is still debated. An important clinical benefit in the chronic use of digitalis appears restricted to a relatively small proportion of patients with severe congestive heart failure, while in the majority of chronically treated subjects the effects of the drug are scanty or insignificant. The beneficial effect of digitalis used chronically is essentially believed to be due to its positive inotropic action. Since the vagomimetic and the antiadrenergic effects of digitalis have been demonstrated to be independent from its inotropic action, they could be considered determinants of the clinical benefits of digitalis. These indirect effects may be useful in the control of the negative neuroendocrine response developing during congestive heart failure. Thus the statement that digitalis is essentially an inotropic agent seems restrictive; its definition should reflect the favorable effects obtained in some cases of congestive heart failure rather than its various and contrasting underlying mechanisms of action.

Contraindications↗
PubMed1977

[Digitalis intoxication: specifity and significance of cardiac and extracardiac symptoms. part II. Patients with extracardiac symptoms of digitalis intoxications (author's transl)].

In 1148 cases the serum digoxin concentration (SDC) was correlated with the extracardiac signs of digitalis intoxication. There is a considerably overlap of SDC levels of patients with and without extracardiac signs of toxicity even though the mean SDC's of these two groups differ significantly. An increasing percentage of clinical intoxicated patients with increasing SDC levels was found at digoxin concentrations of 2.0 ng/ml and higher. At lower SDC levels patients with and without extracardiac signs of digitalis intoxication did not differ significantly in their mean SDC but in mean age and in mean creatinine concentration indicating that at least part of the symptoms in these patients might be due to a more severe illness. We could show that many of the extracardiac signs of digitalis intoxication are also seen in patients with impaired kidney function at low SDC levels and may lead to a wrong diagnosis. The most common complaint in patients with SDC's of 2.0 ng/ml and more is nausea (39.4%), followed by tiredness (30.4%), dizzyness (23.7%), vomiting (23.1%), headache (16.0%), visual disturbances (13,5%), colour (yellow) seeing (6;7%), diarrhea (4.2%) and severe neuro-psychiatric disturbances (3.8%). In patients with digitalis-induced arrhythmias the sequence of symptoms is the same only with a somewhat higher percentage rate. Only about one half of the patients with digitalis-induced arrhythmias and SDC values up to 2.5 ng/ml showed also extracardiac signs of intoxication. Therefore these signs are not to be taken as early symptoms of digitalis intoxication. Divided into subgroups (patients with/without digitalis-induced arrhythmias, patients with SDC values of more/less than 2.0 ng/ml) the patients with and without extracardiac signs of digitalis toxicity are compared with each other in regard to: mean body height and weight, concentration of digoxin, potassium and creatinine, digoxin dosage and mean age. The greatest differences were found between patients with combined cardiac and extracardiac signs of intoxication and patients with neither cardiac nor extracardiac signs of intoxication: These intoxicated patients are of significantly higher mean age and lower body weight, their mean concentration of digoxin and creatinine and the digoxin dosage administered are significantly greater, but there is no significant difference in potassium concentration. An important group of patients, namely the elderly with impaired kidney function, are especially prone to develop digitalis intoxication. In this group, however, the extracardial symptoms are of little benefit in the diagnosis of digitalis intoxication. In these patients rhythm disturbances and intoxication-like symptoms are frequently caused by other reasons. In most cases the SDC value can clarify the diagnosis without withdrawal of the drug.

Age Factors↗
PubMed1976

The serum digitalis concentration--does it diagnose digitalis toxicity?

We propose that an investigation of the serum digitalis concentration as a test for digitalis toxicity should (1) study patients with similar toxic manifestations, (2) obtain control concentrations from nontoxic patients with symptoms suggesting toxicity, (3) define criteria for toxicity and nontoxicity, (4) select representative patients, (5) describe the study population and (6) analyze how much diagnostic information the serum digitalis concentration provides that cannot be inferred from other observations. To determine if available evidence validates the digitalis concentration as a test for toxicity 27 reports were reviewed. No investigation employed symptomatic controls. Of five studies most consistent with points 1-5 only three demonstrated higher mean serum digitalis concentrations in toxic patients. Whether knowledge of the digitalis concentrations was diagnostically more useful than knowledge of the digitalis dosage, renal function, serum potassium concentration and cardiac status was not determined in any study. The usefulness of the serum digitalis concentration as a test for digitalis toxicity is therefore not established.

Adult↗
PubMed1977

[Digitalis intoxication: specifity and significance of cardiac and extracardiac symptoms. part I: Patients with digitalis-induced arrhythmias (author's transl)].

In 1164 cases clinical and electrocardiographical findings were correlated with serum digoxin concentrations (SDC). The diagnosis of digitalis intoxication was based on rhythm disturbances which disappeared on withdrawel of the drug. The mean SDC for patients with digitalis-induced arrhythmias was 3.07 ng/ml compared to 1.02 ng/ml for patients with normal Ecg's and 1.01 ng/ml for patients with rhythm disturbances of other origin. Taking 2.0 ng/ml as the lower limit of digitalis intoxication a more than 85% coincidence was found between the diagnosis based on serial Ecg's and on SDC levels. No signs of cardiac toxicity were found in patients with SDC's less than 1.6 ng/ml, some patients, however, showed normal Ecg's despite SDC's up to 4.5 ng/ml. Patients with SDC's greater than 1.9 ng/ml and normal Ecg's were significantly younger than patients with digitalis-induced arrhythmias at comparable SDC's. Although no definite diagnosis of cardiac toxicity could be established in 327 cases, the clinical data of patients with SDC's of 2.0 ng/ml and greater resemble closely those with digitalis-induced arrhythmias while patients with SDC's less than 2.0 ng/ml showed close resemblance to patients with no cardiac evidence of toxicity with regard to: mean age, kidney function, mean digoxin dosage and mean body weight. Patients with elevated SDC's showed a 45% incidence of severely impaired kidney function in contrast to 28% of the patients with SDC's less than 2.0 ng/ml. Even in patients with normal kidney function the correlation between the orally administered digoxin dosage and SDC levels was poor. The correlation was significantly better when dogoxin was administered intravenously. Therefore knowing the amount of digoxin taken (according to the patient's statement) seems of little benefit in the evaluation of digitalis toxicity. In patients with digitalis-induced arrhythmias mean age and mean body weight were significantly lower, mean creatinine concentration and the incidence of severe cardiac insufficency and of typical ST-T-changes were significantly higher. There was no significant difference in mean potassium concentration and incidence of coronary artery disease compared to nontoxic patients. Compared to patients with cardiac arrhythmias of other origin there were no significant differences in mean age, mean potassium and creatinine concentrations and cardiac insufficiency while the incidence of coronary artery disease was significantly higher among patients with rhythm disturbances of other origin. Every type of rhythm disturbance can be digitalis-induced. Among our patients the incidence of digitalis-induced second-degree atrioventricular block (Wenckebach), ventricular bigeminy, nonparoxysmal nodal tachycardia and PAT with block was significantly higher while patients with rhythm disturbances of other origin showed an equally high incidence of PVB's and prolongation of PQ interval...

Arrhythmias, Cardiac↗
PubMed1989

[Estimation of intracellular free calcium concentration in patients undergoing digitalis treatment and in patients presenting digitalis toxicity].

Delayed afterdepolarizations occur under conditions in which there are large increase in the intracellular Ca and may be considered as one of the important mechanisms for digitalis-induced arrhythmias. Intraplatelet free calcium (Ca2i+) was measured in 25 patients, using the fluorescent indicator Quin-2. The patients included 15 with glycosides treatment (Group A) and 10 with arrhythmias indicating the presence of digitalis intoxication (Group B). The average Ca2i+ level in Group A was higher than the normal value but did not reach a statistical significance (170.8 +/- 9.09 vs 161.6 +/- 30.2, NS). The Ca2i+ level during digitalis toxicity in Group B was significantly higher than that in Group A (201.7 +/- 17.65 vs 170.18 +/- 91.09, P less than 0.01) as well as the normal value (P less than 0.01). With the disappearance of digitalis toxicity the Ca2i+ level was significantly decreased from 201.7 +/- 17.65 to 171.4 +/- 14.08 (P less than 0.001). Following the elimination of digitalis toxicity the increased digoxin concentration also declined. However, the decline of digoxin concentration did not correlate well with the decline of Ca2i+ (r = -0.57, P greater than 0.05). There is a close association between digitalis-induced arrhythmias and the change of Ca2i+ level, compatible with the tentative mechanism of delayed after depolarization (triggered activity). The poor correlation between the Ca2i+ level and digoxin concentration during the process of digitalis toxicity may suggest the presence of factors other than glycosides concentration to cause increased Cai2+ and arrhythmias.

Adult↗
PubMed1987

Differential inactivation of inotropic and toxic digitalis receptors in ischemic dog heart. Molecular basis of the deleterious effects of digitalis.

When applied to ischemic hearts digitalis exhibits depressed inotropic effect and increased toxicity. The molecular basis of these effects was investigated at the level of the digitalis receptors characterized by Na,K-ATPase assays and [3H]ouabain-binding measurements. In sarcolemma obtained from dog hearts rendered ischemic for 15, 30, and 60 min (left anterior descending), two populations (high and low affinity) of digitalis receptors were detected. The apparent affinity (KD, 300 nM) and the binding capacity of the low-affinity sites (responsible for toxicity) remained constant and similar to those found in normal hearts. The KD value of the high-affinity sites, "responsible for inotropy," remained unchanged (2 nM), but the site number sharply decreased (up to 90%). These inotropic sites that account for 66% of the total binding in normals are gradually inactivated, as the duration of ischemia increases. This inactivation would occur in situ since it was detectable in homogenates and was not depressed by the isolation procedure per se. The loss of function of the inotropic sites and the increased contribution of the low-affinity toxic sites represent the setting of a new distribution of the digitalis receptors in the ischemic heart before reperfusion is instituted. This constitutes the molecular basis of the deleterious pharmacological effects observed with digitalis.

Animals↗
PubMed1979

Species restriction of the mitogenicity induced by lanatoside C. Lymphocyte activation by digitalis glycosides is confined to cells from digitalis resistant species.

Activation of Na+, K+-ATPase has previously been suggested to be the triggering signal in mitogen-induced cell activation. Using a digitalis glycoside known to be a potent polyclonal B-cell activator, this hypothesis could be tested since digitalis activates ATPase at different concentrations in various species, depending on the degree of sensitivity to the toxic effects of glycosides. Lanatoside C was found to stimulate lymphocytes from glycoside resistant species such as rat, mouse and hamster. The possible involvement of Na+, K+-ATPase was made less likely by the similarity in dose--response profile in these cells although they have been reported to display varying degrees of glycoside resistance. Furthermore, using lymphocytes from digitalis-sensitive species such as man, guinea-pig or rabbit, no mitogenicity could be recorded, strongly suggesting a lack of correlation between glycoside-induced effects on Na+, K+-ATPase and cell activation.

Adenosine Triphosphatases↗
PubMed1977

Studies on digitalis. XIV. Is there any correlation between hypomagnesemia and digitalis intoxication?

In a prospective study on digitalis intoxication, low serum magnesium was found in 90 patients, while 388 patients had values above 1.5 mEq/l. Hypomagnesemia was more frequent in women than in men, in those with low body weight and in those with advanced heart failure. More patients with hypomagnesemia than those without had nausea, anorexia, fatigue, flickering of vision and atrial tachycardia with block. Patients with hypomagnesemia also had lower serum potassium than normomagnesemic patients. There was, however, no significant difference in the prevalence of digitalis intoxication or in serum digitoxin concentration. Nor was there any correlation between serum digitoxin and serum magnesium levels.

Body Weight↗
PubMed1990

Digitalis receptor sugar binding site characteristics: a model based upon studies of Na+, K(+)-ATPase preparations with differing digitalis sensitivities.

The structure-activity relationships of the genin moieties of digitalis glycosides are commonly elucidated by determining the inhibitory potency of a variety of genins toward the plasma membrane Na+, K(+)-ATPase; qualitatively these relationships appear to be fairly independent of the specific Na+, K(+)-ATPase preparation utilized for the analysis. To determine whether this is the case with regard to the sugar moieties of glycosides, the inhibitory effects of 12 monoglycosides of digitoxigenin toward four Na+, K(+)-ATPase preparations of different origin were measured. It was found that while recognition of the major structural determinants of sugar activity appeared to be independent of enzyme source, recognition of the minor structural determinants of activity showed some source dependence. It was also observed that the intrinsic sensitivity to sugar potentiation may be source dependent and unrelated to intrinsic sensitivity to inhibition by digitoxigenin. These observations are compatible with a model of the Na+, K(+)-ATPase sugar binding site(s) in which intrinsic sensitivity to sugar attachment as well as recognition characteristics (for sugar structural features) both determine the extent to which a sugar moiety may contribute to the activity of monoglycosides. Further, in these studies one of the Na+, K(+)-ATPase preparations employed was obtained from rat brain, a tissue known to contain a mixture of ouabain sensitive and insensitive isoforms. We have observed that the rigorous purification techniques employed appear to have selectively removed from or denatured the less ouabain sensitive alpha 1 isoform found in this enzyme preparation.

Animals↗
PubMed1992

Measurement of digitalis-glycoside levels in ocular tissues: a way to improve postmortem diagnosis of lethal digitalis-glycoside poisoning? I. Digoxin.

Prompted by animal studies reporting the accumulation of digitalis-glycosides in ocular tissues, we investigated whether measurement of digoxin levels in human ocular tissues can improve the postmortem diagnosis of lethal digoxin intoxication. Digoxin was measured in the vitreous humor and choroid-retina of patients who had received in-patient treatment with digoxin prior to death (therapeutic group) and in a single case of suicidal intoxication. The results were compared with the digoxin levels in the femoral vein blood, myocardium, kidney and liver, and evaluated in light of the medical history of each patient. In the therapeutic group the mean digoxin level was higher in the choroid-retina than in other tissues and body fluids. The range of variation in levels in the choroid-retina following therapeutic doses was comparable to that in the other tissues. An extremely high level of digoxin was present in the choroid-retina in the case of suicidal intoxication. In all cases, levels in the vitreous humor were very low compared to those in the choroid-retina. Hence, it is unlikely that significant distortion of choroid-retinal levels occurs due to postmortem diffusion of digoxin into the vitreous body. Our results indicate that measurement of digoxin levels in the choroid-retina can aid the postmortem diagnosis of lethal digoxin intoxication.

Aged↗
PubMed1978

Correlative studies of serum digitalis levels and the arrhythmias of digitalis intoxication.

Correlative studies of serum digoxin levels, cardiac rhythm and related clinical laboratory data were carried out in 114 patients. Seventy-three patients who presented with 79 episodes of arrhythmias typical of digitalis intoxication could be separated into a normokalemic group of 55 patients whose serum digoxin level was 6.68 +/- 0.17 ng/ml (mean +/- standard error of the mean), and a hypokalemic group of 24 with a mean serum digoxin level of 1.13 +/- 0.04 ng/ml (P less than 0.001). Of 45 consectutive normokalemic patients with a high serum digoxin level (more than 2 mg/ml) who underwent serial studies, 17 had arrhythmias. Serial studies in 10 hypokalemic patients revealed an inconsistent relation between presence of arrhythmia and serum digoxin level. During repletion of serum potassium in seven of these patients with an arrhythmia, the arrhythmia disappeared without a significant change in serum digoxin level in four patients. A group of seven patients had 16 episodes of serum digoxin level greater than 2.2 ng/ml, but an arrhythmia occurred during only 3 of these episodes. A sharp border between toxic and therapeutic serum digoxin values was not found in these groups of study patients. The serum digoxin level at which arrhythmias occurred appeared to be variable for both groups and individual patients. However, correlative studies utilizing serum digoxin levels can define existing thresholds for therapeutic and toxic effects and may often be more useful than isolated observations.

Aged↗
PubMed1976

[Digitalis poisoning, risk factors and digitalis intolerance].

It was established by means of radioimmunoassay that the blood concentration of Digoxin in patients with congestive heart failure depends not only on the dose of the drug given, but also on the stage of cardiac insufficiency. With equal daily doses, higher Digoxin concentrations were observed in patients with more severe cardiac insufficiency. The analysis of the obtained data has demonstrated that in 75% of the patients with signs of digitalis intoxication the concentration of Digoxin in blood exceeded 2.5 ng/ml. In animal experiments it was established that a distinct reduction of the toxic threshold took place in rabbits with acute myocardial infarction, acute pulmonary embolism, congestive cardiac failure, this threshold being determined by the amount of intravenously injected Strophantin that causes persistent ventricular tachycardia.

Digoxin↗