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Successful treatment of oleander intoxication (cardiac glycosides) with digoxin-specific Fab antibody fragments in a 7-year-old child: case report and review of literature.

UNLABELLED: A 7-year-old girl presented six hours after ingestion of a yellow oleander seed (Thevetia peruviana) with severe emesis, change in colour vision and complete heart block. Initial treatment with phenytoin and isoprenalin infusion led to intermittent supraventricular and ventricular tachycardia. The patient was then treated with two intravenous doses of 190 mg of digoxin-specific Fab antibody fragments (Digibind). Subsequently the patient's rhythm reverted to sinus rhythm and the symptoms resolved within 2 hours. CONCLUSION: administration of digoxin-specific Fab antibody fragments in an otherwise healthy child after oleander intoxication is safe and without adverse reactions.

Cardiac Glycosides↗

Submolecular mechanisms underlying in vitro and in vivo effect of cardiac glycosides on contractile activity of myocardial myofibrils during heart failure.

The development of severe heart failure associated with toxicoallergic myocarditis is accompanied by profound structural and conformational changes in the outer domain of actin (major protein in a thin filament of cardiomyocyte sarcomere). These changes were revealed in subdomains 1 (Cys374 and Cys10) and 2 (Lys61 and Tyr69). Structural and conformational changes in the monomer and protomer of the actin thread during heart failure were energetically forbidden. Variations in the distance between amino acid residues exceeded 0.26 nm. They were partly or completely reversible in vivo under the influence of cardiotropic drug refracterin with high antihypoxic activity, as well as in vitro after treatment with digitalis preparations optimizing the concentration of ATP.

Acetyldigoxins↗

Some substances with proposed digitalis-like effects evaluated on platelet functions sensitive for cardiac glycosides.

1. The effects of progesterone, corticosterone 21-acetate, chlormadinone acetate, dehydroepiandrosterone 3-sulfate and lysophosphatidylcholine were tested on 86Rb-uptake, 3H-5-HT-uptake, ADP-induced aggregation and 5-HT-induced shape change in human platelets. Ouabain and digoxin were used for reference. 2. Ouabain and digoxin 10(-5) M inhibited 86Rb-uptake by more than 85%, and chlormadinone acetate 10(-5) M by 20%. The other substances had no effects. 3. Ouabain and digoxin were potent inhibitors on 3H-5-HT-uptake, whereas chlormadinone acetate had no effect. 4. Ouabain and digoxin increased ADP-induced aggregation but chlormadinone acetate decreased it. 5-HT-induced shape change was decreased by ouabain and digoxin, and to a lesser extent by chlormadinone acetate and its vehicle (ethanol 1.0%).

Blood Platelets↗

Cardiac glycosides: 2. Synthesis of glucose and galactose analogs.

Five cardioactive steroid genins 1a to 5a of widely varying C17 beta-side groups were converted by modified Koenigs-Knorr reactions into the corresponding beta-D-glucosides 1c to 5c and beta-D-galactosides 1e to 5e. The genins included digitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta-card-20-(22)-enolide, 1a); (20R)-20, 22-dihydrodigitoxigenin (3 beta, 14-dihydroxy-5 beta, 14 beta, 20R-cardanolde, 2a); 3 beta, 14-dihydroxy-22-methylene-5 beta, 14 beta, 20S-cardanolide (3a); methyl 3 beta, 14-dihydroxy-5 beta, 14 beta-pregn-20(E)-ene-21-carboxylate (4a); and methyl 3 beta, 14-dihydroxy-21-methylene-5 beta, 14 beta-pregnane-21-carboxylate (5a).

Cardiac Glycosides↗

Na,K-ATPase from placenta of women with pregnancy-induced hypertension exhibits an increased affinity for cardiac glycosides.

Microsomes were prepared from placentas of normotensive women and of patients suffering from pregnancy-induced hypertension (PIH). Activity of Na,K-ATPase (estimated as ATP hydrolysis) from the hypertensive tissue was lower than from tissue of normotensive women, even if the number of Na,K-ATPase molecules (monitored by anthroyl ouabain binding) was actually greater in the hypertensive tissue. The affinity of Na,K-ATPase for anthroyl ouabain was about four times higher in plasma membranes of hypertensives, indicating some structural change in the Na,K-ATPase or in its vicinity. Assuming the presence of an endogenous digitalis-like factor, the results suggest a simple way of explaining not only the lower Na,K-ATPase activity in the placental membranes of hypertensives but also the different extent of enzyme inhibition in different tissues of PIH patients.

Anthracenes↗

Protein binding of cardiac glycosides in disease states.

Digitoxin in 97% bound to serum albumin and digoxin only to the extent of 24%. Hypoalbuminaemia significantly changes the protein binding of digoxin in Kwashorkor serum and the binding of digitoxin in patients with chronic active hepatitis and the nephrotic syndrome. Sprue patiens with normal albumin values have normal binding of digitoxin. Preliminary data in patients with thyrotoxicosis and myxoedema show digitoxin binding within the normal range. The effect of uraemia per se on digitoxin binding is controversial as both normal and slightly decreased values have been reported. In uraemic patients on treatment with haemodialysis, heparin administration has been shown to be a powerful serum binding displacing agent for both digitoxin and digoxin, the mechanism probably being a heparin-induced release of free fatty acids. Patients with a significant decrease in serum protein binding of digitoxin or digoxin should be maintained on a total serum concentration lower than usually considered within the therapeutic range.

Blood Proteins↗

Comparative pharmacokinetics and pharmacodynamics of cardiac glycosides.

1 The pharmacokinetics and pharmacodynamics of ouabain, digoxinn and beta-methyl digoxin (medigoxin) have been investigated in a crossover study in four normal healthy volunteers. 2 Pharmacokinetics were studied using [3H]-labelled glycosides and the shortening of the left ventricular ejection time (LVET) was used as a measure of the effect of the drugs. A graded exercise protocol was used to correct for the effects of heart rate on LVET. 3 In three of the four subjects, both digoxin and beta-methyl digoxin produced a shortening in the LVET, but no such change could be detected with ouabain in any of the four subjects. 4 There was a good linear correlation between the shortening of the LVET and the amounts of digoxin or beta-methyl digoxin present in the body tissues. 5 One subject who showed no drug-related LVET shortening had greatly enhanced clearances of all three drugs studied.

Adult↗

Characterization of (Na+ + K+)-ATPase-liposomes. III. Controlled activation and inhibition of symmetric pumps by timed asymmetric ATP, RbCl, and cardiac glycoside addition.

Inside-out as well as right-side-out oriented (Na+ + K+)-ATPase molecules reconstituted in liposomes are activated successively by timed asymmetric addition of ATP to the internal and external liposome compartment; this presents the first functional confirmation of the symmetric pump-orientation in cholate-dialysed preparations revealed previously by the equal distribution of intramembrane particles on the concave and convex surface of freeze-fractured (Na+ + K+)-ATPase-liposomes. The initial transport rates of the symmetrically oriented pump populations are regulated by varying the bilateral K or Rb ion concentrations; ATP, ouabain, digoxin or vanadate are used to activate or block selectively the right-side-out, inside-out or both (Na+ + K+)-ATPase populations. Finally, these liposomes of the second generation present a new tool to evaluate the membrane-permeability as well as the effects of receptor-ligands or other probes in a single preparation.

Adenosine Triphosphate↗

Human hypertensive placenta contains an increased amount of Na,K-ATPase with higher affinity for cardiac glycosides.

Placentas of women suffering from pregnancy-induced hypertension (PIH) were found to contain a greater amount of Na,K-ATPase molecules, estimated from anthroyl ouabain binding, than normotensive individuals. Both the microsomal fraction of placental cells and purified Na,K-ATPase showed an increased affinity for the specific inhibitor ouabain which, in the case of the microsomes, bound with a dissociation constant of 0.9 nM as compared with 3.4 nM in the controls. Likewise, the dissociation constant of the ouabain complex with purified Na,K-ATPase was about 3.5 times lower in the hypertensive patients. The differences are apparently caused by a different microenvironment of the ouabain-binding site, as reflected in the quantum yield of bound anthroyl ouabain. If an endogenous digitalis-like factor is present in the body fluids to regulate Na,K-ATPase activity, the present results render its role quite plausible.

Adult↗

Antidotes for acute cardenolide (cardiac glycoside) poisoning.

BACKGROUND: Cardenolides are naturally occurring plant toxins which act primarily on the heart. While poisoning with the digitalis cardenolides (digoxin and digitoxin) are reported worldwide, cardiotoxicity from other cardenolides such as the yellow oleander are also a major problem, with tens of thousands of cases of poisoning each year in South Asia. Because cardenolides from these plants are structurally similar, acute poisonings are managed using similar treatments. The benefit of these treatments is of interest, particularly in the context of cost since most poisonings occur in developing countries where resources are very limited. OBJECTIVES: To determine the efficacy of antidotes for the treatment of acute cardenolide poisoning, in particular atropine, isoprenaline (isoproterenol), multiple-dose activated charcoal (MDAC), fructose-1,6-diphosphate, sodium bicarbonate, magnesium, phenytoin and anti-digoxin Fab antitoxin. SEARCH STRATEGY: We searched MEDLINE, EMBASE, the Controlled Trials Register of the Cochrane Collaboration, Current Awareness in Clinical Toxicology, Info Trac, www.google.com.au, and Science Citation Index of studies identified by the previous searches. We manually searched the bibliographies of identified articles and personally contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials where antidotes were administered to patients with acute symptomatic cardenolide poisoning were identified. DATA COLLECTION AND ANALYSIS: We independently extracted data on study design, including the method of randomisation, participant characteristics, type of intervention and outcomes from each study. We independently assessed methodological quality of the included studies. A pooled analysis was not appropriate. MAIN RESULTS: Two randomised controlled trials were identified, both were conducted in patients with yellow oleander poisoning. One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect. The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81). Other benefits were also noted in both studies and serious adverse effects were minimal. Studies assessing the effect of antidotes on other cardenolides were not identified. One ongoing study investigating the activated charcoal for acute yellow oleander self-poisoning was also identified. AUTHORS' CONCLUSIONS: There is some evidence to suggest that MDAC and anti-digoxin Fab antitoxin may be effective treatments for yellow oleander poisoning. However, the efficacy and indications of these interventions for the treatment of acute digitalis poisoning is uncertain due to the lack of good quality controlled clinical trials. Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides. Unfortunately cost limits the use of antidotes such as anti-digoxin Fab antitoxin in developing countries where cardenolide poisonings are frequent. More research is required using relatively cheap antidotes which may also be effective.

Acute Disease↗

Vagal role in potentiation by Ca2+ ions of the action of cardiac glycosides on the atrial specialised tissue.

The combined effects of digoxin and hypercalcaemia were studied in the canine heart in situ on the sinoatrial (SA) and atrioventricular (AV) nodes. Measurements were made of heart rate, of conduction time in the AV node by the endocavitory recording of the His bundle potentials, and of the effective refractory period of this node by the extrastimulus method. In the presence of acetylcholine released by vagal endings or infused into the coronary blood, an increase in plasma calcium concentration from 2.50 to 4.60 mmol/l after a 80 micrograms/kg dose of digoxin considerably depressed conduction in the AV node and automatism in the SA node. In the absence of acetylcholine, no bradycardia occurred under the influence of digoxin alone or digoxin and hypercalcaemia, and hypercalcemia enhanced to a lesser extent digoxin-induced depression of conduction in the AV node. These results evidence a potentiation by acetylcholine of the combined effects of digoxin and hypercalcaemia on the SA and AV nodes.

Acetylcholine↗

Cardiac glycosides. 6. Gitoxigenin C16 acetates, formates, methoxycarbonates, and digitoxosides. Synthesis and Na+,K+-ATPase inhibitory activities.

A series of 17 gitoxigenin 16 beta-formates, acetates, and methoxycarbonates was synthesized, including their 3 beta-acetates, formates, and digitoxosides. A 16 beta-formate group was generally found to increase activity 30 times, a 16 beta-acetate group 9-12 times, while a 16 beta-methoxycarbonate decreased activity by two-thirds. 3 beta-Formates and acetates had little effect on activity by themselves, but sometimes reduced the activity-increasing properties of 16 beta-formates and acetates. A 3 beta-digitoxoside increases the activity of gitoxigenin by 15 times, but the effect is less if the 16 beta-group is esterified. And finally, a 16-one decreases activity dramatically. These data suggest an important role for C16 esters and possibly the presence of a separate binding site on Na+,K+-ATPase corresponding to the cardenolide C16 position.

Animals↗

The acute changes seen in cardiac glycoside receptor sites, 86rubidium uptake and intracellular sodium concentrations in the erythrocytes of patients during the early phases of digoxin therapy are not found during chronic therapy: pharmacological and therapeutic implications for chronic digoxin therapy.

1 Measurements of the binding of 12-alpha-[3H]-digoxin to the membranes of intact erythrocytes, erythrocyte 86rubidium uptake and intraerythrocytic sodium concentrations have been made in the red cells of various groups of patients--those who have not received digoxin, those during the early phases of treatment, those during chronic (greater than 2 months) treatment, and those toxic. 2 The values of those measurements in the patients in the early phases of therapy and in the toxic patients differed significantly from those of the untreated patients. 3 However, the values in the chronically treated patients were not different from those of the untreated patients. 4 The results suggest that the biochemical pharmacological effects of digoxin which occur during the early phases of therapy do not persist in the long-term. 5 The possible clinical significance of these observations is discussed.

Aged↗

[Cardiac glycosides in complex treatment of patients with heart failure and supraventricular arrhythmias].

The authors of the article studied potential of various drug combinations (atenolol + enalapril + indapamide, and celanid + enalapril + indapamide) in complex treatment of patients with heart failure (HF) and supraventricular arrhythmias. The subjects were 106 patients, of whom 74 had coronary heart disease, of whom 51 had old myocardial infarction, and 18 had undergone coronary artery bypass grafting. Dilatation cardiomyopathy was found in 8, aortomitral valvular disease--in 18, and combined mitral valvular disease--in 6 patients. 36 subjects had permanent atrial fibrillation, 48--a paroxysmal form of ciliary arrhythmia, 22--paroxysms of atrial tachycardia. NYHA functional class (FC) II HF was diagnosed in 64 patients, NYHA FC III HF--in 42 patients. According to what treatment regimen was applied, the patients were divided into two groups, comparable in the main clinical and functional characteristics. Two-month therapy resulted in improvement of hemodynamics, increase of activity tolerance and improvement of life quality in both groups. The combination celanide + enalapril + indapamide in individual doses was effective in FC II-III HF with supraventricular arrhythmias. The cost of treatment with celanid is lower.

Aged↗

Interactions of diphenylhydantoin and cardiac glycosides on atrial potassium.

Effects of diphenylhydantoin (DPH) on amphibian atrial myocardium K were investigated using a method which permits both total tissue K and tension response to be monitored continuously. In normal (nondigitalized) preparations, DPH caused a decrease in average K efflux, a net gain of tissue K, and negativeinotropy at low perfusate K concentrations. However, the DPH-induced gain of tissue K was abolished at high perfusate K concentrations while marked negative inotropy was still observed. It is concluded that a gain of tissue K is not the cause of DPH-induced negative inotropy. When digitalis-induced inotropy was associated with tissue K loss, DPH reversed tissue K loss and positive inotropy and caused a decrease in average K efflux. In the presence of toxic effects of digitalis, DPH reversed the K loss and the contracture, but the loss of developed tension was not reversed by DPH. Transmembrane resting potentials and action potential duration were reduced by digitalis and were returned to or above control levels in the presence of DPH. The present findings are consistent with the hypothesis that the therapeutic effect of DPH in digitalis toxicity is brought about by an inhibition of K efflux. This would tend to minimize the loss of tissue K which results from sodium pump inhibition.

Animals↗

[The comparative efficacy and differences in the molecular mechanism of the inotropic action of cardiac glycosides and nonglycoside cardiotropic agents on the contractile protein system of the myocardium].

The in vitro study on an isolated system of myocardial contractile proteins determined optimal concentrations of the positive inotropic action and biological activity ranges of beta-methyldigoxin (beta-MD), strophanthin K, K-strophantozide, beta-acetyldigoxin (beta-AD), milrinone, and amrinone. Optimal concentrations of the beta-MD and strophanthin K (10(-2) and 10(-6) M, respectively) significantly increased qualitatively and quantitatively the economy and thermodynamic efficiency, altered the energy transformation in the contractile protein system under the isometric contraction, whereas the beta-AD produced only the quantitative effect. However, the beta-MD and strophanthin K at concentrations exceeding the optimal one by one order lost the ability to produce the qualitative effect, retaining only the quantitative one in the actomyosin ensemble. The strophanthin K significantly increased the economy of a single actomyosin ensemble in the force generation phase and the beta-MD in the tension maintenance phase. Unlike the strophanthin K, the beta-MD did not slow down (did not worsen) the relaxation process. This provides grounds to conclude that the beta-MD produces most favorable effect on the energy transformation by myocardial contractile proteins.

Animals↗

Structural insights into the binding of cardiac glycosides to the digitalis receptor revealed by solid-state NMR.

Several biologically active derivatives of the cardiotonic steroid ouabain have been made containing NMR isotopes ((13)C, (2)H, and (19)F) in the rhamnose sugar and steroid moieties, and examined at the digitalis receptor site of renal Na(+)/K(+)-ATPase by a combination of solid-state NMR methods. Deuterium NMR spectra of (2)H-labeled inhibitors revealed that the sugar group was only loosely associated with the binding site, whereas the steroid group was more constrained, probably because of hydrogen bonding to residues around the K(+)-channel region. Crosspolarization magic-angle spinning NMR showed that chemical shifts of inhibitors (13)C-labeled in the sugar group moved downfield by 0.5 ppm after binding to the digitalis site, suggesting that the sugar was close to aromatic side groups. A (19)F, (13)C- rotational-echo double-resonance NMR strategy was used to determine the structure of an inhibitor in the digitalis receptor site, and it showed that the ouabain derivatives adopt a conformation in which the sugar extends out of the plane of the steroid ring system. The combined structural and dynamic information favors a model for inhibition in which the ouabain analogues lie across the surface of the Na(+)/K(+)-ATPase alpha-subunit with the sugar group facing away from the surface of the membrane but free to move into contact with one or more aromatic residues.

Carbohydrate Conformation↗

Effect of digoxin and amino sugar cardiac glycoside (ASI-222) on plasma antidiuretic hormone activity.

Digoxin acts at central neural (CNS) as well as peripheral sites after intravenous administration. In contrast, the analog, 3-beta-O(4-amino-4,6-dideoxy-beta-D-galactopyranosyl)-digitoxigenin (ASI-222), cannot cross the blood-brain barrier so it acts only at sites outside the CNS. The effects of these two agents on plasma antidiuretic hormone activity (ADH) were investigated in conscious dogs. Despite previous evidence that digoxin produces reflex decreases in sympathetic nerve activity by activating ventricular receptors with vagal afferents, no decreases in ADH were detected when either digoxin (25 and 50 micrograms/kg) or ASI-222 (38.5 micrograms/kg) were administered intravenously even with preexisting high levels of plasma ADH. In contrast, both digoxin (50 micrograms/kg) and ASI-222 (38.5 micrograms/kg) resulted in increased ADH levels, but only in association with emesis and behavioral changes suggestive of nausea. Cerebroventricular (IVT) injections of digoxin were given, starting with a dose of 0.1 microgram, that were intended to produce a comparable cerebrospinal fluid (CSF) concentration to that associated with the 50 micrograms/kg intravenous dose. Only the highest dose of digoxin, 1 micrograms, but not 0.1 and 0.3 micrograms, produced increases in ADH and emesis when given into the lateral cerebral ventricle. This is further evidence that a site accessible to blood but not to CSF was involved. These results suggest that digoxin and ASI-222 may activate pathways in the area postrema and produce increases in ADH as well as emesis.

Animals↗