beta-acetyldigoxin and Arrhythmias--Cardiac

Topics: Acetyldigoxins; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrioventricular Block; Bradycardia; Contrast Sensitivity; Diagnosis, Differential; Dose-Response Relationship, Drug; Electrocardiography; Emergencies; Humans; Male; Medication Errors; Middle Aged; Scotoma; Vision Disorders; Visual Field Tests

The aim was to compare the binding characteristics of a highly purified digoxin specific antigen binding fragment (digoxin immune Fab: DIGIBIND) with digoxin and with two commonly used derivatives of digoxin, beta methyl digoxin and beta acetyl digoxin, and to assess its ability to abolish the arrhythmogenic effects of these digitalis glycosides.. The binding characteristics of DIGIBIND with digoxin, beta methyl digoxin, and beta acetyl digoxin were assessed in vitro by measuring their ability to inhibit the binding of DIGIBIND to 3H-digoxin. From these studies the affinities of the interactions between DIGIBIND and these glycosides, and the binding capacity of DIGIBIND for each of these glycosides, could be measured. The ability of DIGIBIND to abolish the arrhythmogenic effects of digoxin, beta methyl digoxin, and beta acetyl digoxin was assessed using an in vivo anaesthetised guinea pig model (n = 36, weight 300-400 g), in which these glycosides were infused intravenously (50 micrograms.kg-1 x min-1) until the onset of ventricular arrhythmias, at which point the total amount of glycoside given was calculated. A single bolus dose of either vehicle or DIGIBIND was then given intravenously, and the time to restoration of normal cardiac rhythm noted. After the administration of DIGIBIND, a second infusion of the same glycoside was given to reinitiate the ventricular arrhythmias. The time to onset of the arrhythmias was noted, and the additional amount of glycoside given calculated.. In vitro studies showed the binding of DIGIBIND to 3H-digoxin to be inhibited by digoxin and by the two derivatives. The affinities of these interactions with DIGIBIND were significantly different, that for digoxin being some twofold greater than that for beta methyl digoxin and beta acetyl digoxin. The ED50 concentrations were 14.1 (95% CI 12.2, 15.2), 29.2(26.1, 32.7), and 36.2(33.0, 39.8) nM, respectively. However, there were no significant differences between these glycosides in their binding capacities. The in vivo studies showed that intravenous infusion of digoxin, beta methyl digoxin, or beta acetyl digoxin induced similar ventricular arrhythmias. The onset of the arrhythmias was clearly discernible, and required a significantly lower dose of digoxin compared with that of beta methyl digoxin and beta acetyl digoxin. These doses were 667(SEM 55), 868(33), and 854(40) nmol.kg-1, respectively. Termination of the infusion had no effect on the arrhythmias, and in those animals which received a bolus intravenous injection of saline there was no return to normal cardiac rhythm. By contrast, in animals which received a bolus intravenous injection of DIGIBIND, there was complete abolition of the arrhythmias within 4-6 min. Although the dose of DIGIBIND given to abolish digoxin induced arrhythmias was approximately 25% less than that given to abolish beta methyl digoxin and beta acetyl digoxin induced arrhythmias (p < 0.05), the time to restoration of normal cardiac rhythm after DIGIBIND was not significantly different for digoxin compared with beta methyl digoxin and beta acetyl digoxin, at 4.6(0.9), 4.9(0.8), and 5.7(0.8) min, respectively. To reinitiate the arrhythmias in those animals which had received DIGIBIND, a dose of glycoside was required which was not significantly different from that given prior to the DIGIBIND. This observation therefore confirmed the stoichiometric relationship between DIGIBIND and each of the glycosides in respect of the neutralising action of DIGIBIND in abolishing the arrhythmogenic effects of these agents.. Although there is some small difference in the affinities of the binding interactions, there is no difference in the binding capacities of DIGIBIND for digoxin, beta methyl digoxin, or beta acetyl digoxin in vitro. These binding interactions are manifest as the ability of DIGIBIND to abolish the arrhythmogenic effects of digoxin and the two derivatives in vivo.

Topics: Acetyldigoxins; Animals; Antigen-Antibody Reactions; Arrhythmias, Cardiac; Digoxin; Guinea Pigs; Immunoglobulin Fab Fragments; Male; Medigoxin

A retrospective study of two groups of patients with a different plasma digoxin level (Group A: digoxin greater than or equal to 2 ng/ml, n = 32, Group B: digoxin less than 2 ng/ml, n = 34; total n = 66) showed a significantly lower creatinine clearance (p less than 0.05) in group A. This group also showed a weak correlation between the digoxin level and the length of observation (R = + 0.31, p less than 0.05, n = 29). Furthermore, a weak correlation between digoxin level and the ratio of average daily dosage to creatinine clearance was found for the total sample (R = + 0.30, p less than 0.05, n = 66). Patients treated for less than 7 days and with a higher digoxin level also had a higher dosage and worse renal function (p = 0.05, p = 0.01, respectively). A weak correlation also existed between the digoxin level and creatinine clearance and body weight for the whole sample (R = -0.29, p less than 0.05; R = -0.29, p less than 0.01, respectively; n = 66). The latter correlation was also found within each group. Apart from renal function, the medication taken and body weight seem to be useful variables in predicting impending elevation of the digoxin level. In this study these variables were found to be better suited for the said purpose than the ECG. These conclusions remain to be confirmed by means of a prospective study.

Topics: Acetyldigoxins; Age Factors; Arrhythmias, Cardiac; Body Weight; Creatinine; Digoxin; Dosage Forms; Dose-Response Relationship, Drug; Drug Administration Schedule; Electrocardiography; Female; Humans; Kidney Function Tests; Male; Medigoxin; Risk

To date, 16 patients with severe glycoside poisoning have been treated with Fab as part of the clinical trial for efficacy and tolerance. The ages of the patients ranged from 4 to 77 years. In 13 cases, the substance was taken with suicidal intent. The following were considered to be indications for the use of Fab: the appearance of life-threatening arrhythmias as high-grade atrioventricular conduction disorders, multifocal ectopic beats, ventricular tachycardia, and relapsing ventricular fibrillation in 5 cases. Serum digoxin concentrations were between 3.8 and 78 ng/ml before the start of treatment. The amount of Fab administered was 240-800 mg, in the majority of cases 480 mg. Regression of the arrhythmias was seen in all patients during or shortly after the Fab infusion. There was a rapid fall in the free digoxin in the serum to levels that were no longer measurable and a marked rise in bound digoxin with a simultaneous intensive excretion of bound digoxin in the urine. Fab therapy is considered to be a major advance in the treatment of severe, previously fatal, glycoside poisoning. No notable side effects were observed, nor were there any allergic reactions to foreign protein.

Topics: Acetyldigoxins; Adolescent; Adult; Aged; Antibodies; Arrhythmias, Cardiac; Child, Preschool; Digoxin; Dose-Response Relationship, Drug; Female; Humans; Immunoglobulin Fab Fragments; Male; Medigoxin; Metabolic Clearance Rate; Middle Aged; Suicide, Attempted

The potency of 17 derivatives of 16 alpha-gitoxin was tested in the isolated atrium and heart of the guinea pig and the contractility-increasing activity of the 16 alpha-gitoxin 16 alpha-acetate was compared with that of 16 alpha-gitoxin in the anesthetized dog. The potency of 16 alpha-gitoxin was increased by the substitution of 16 alpha-OH for 16 alpha-methyl ether, 16 alpha-acetate and 16 alpha-nitrate. Substitution of the 16 alpha-acetyl group for substituents with a higher molar volume diminished this enhanced potency. Variation in the digitoxose moiety caused an increase or decrease in potency depending on the position and number of the substituted OH groups. In spite of changes in 16 alpha-OH, the low influence on rhythmicity persisted, as was found in experiments in the dog.

Topics: Acetyldigoxins; Animals; Arrhythmias, Cardiac; Cardiac Glycosides; Digoxin; Dogs; Dose-Response Relationship, Drug; Female; Guinea Pigs; Heart; Heart Rate; Isomerism; Male; Myocardial Contraction; Stimulation, Chemical; Structure-Activity Relationship

The inotropic and arrhythmogenic effects of 16-acetyl-gitoxin and digoxin were studied in isolated cardiac preparations and in anaesthetized dogs. ECG alteration-producing and lethal doses of both glycosides were determined in anaesthetized cats. In the isolated guinea-pig atrium, the properties of 16-acetyl-gitoxin are identical with those of ouabain, and in the isolated guinea-pig heart they are equal to those of digoxin, while gitoxin and penta-acetyl-gitoxin produce equieffective reactions at higher glycoside concentrations. In the cat, 75% of lethal doses of 16-acetyl-gitoxin and digoxin provoke ECG changes (qrs complex prolongation). The ratio of the lethal doses amounts to 1:2.8 and 1:3.5 (digoxin:16-acetyl-gitoxin). In case of equal contractile increment, the ratio of glycoside doses in dogs amounts to 1:1.3, while the percentages of rhythm disturbances following both glycosides are identical. Apart from slight deviations of the doses used, the cardiac properties of 16-acetyl-gitoxin are equal to those of digoxin.

Topics: Acetyldigoxins; Animals; Arrhythmias, Cardiac; Atrial Function; Cats; Digoxin; Dogs; Female; Guinea Pigs; Heart; Heart Rate; Isomerism; Male; Myocardial Contraction; Ouabain; Species Specificity; Structure-Activity Relationship