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PubMed2001

[Augmentation of left ventricular outflow tract gradient by digitalis glycosides in a case of cardiac (AL-) amyloidosis].

HISTORY AND CLINICAL FINDINGS: A 61-year-old man suffering from histologically confirmed amyloidosis associated with coagulation disturbances presented with exercise induced shortness of breath and symptoms of cardiac asthma after four cycles of chemotherapy with melphalan and prednisolone. As a result, treatment with digitoxin was initiated. In addition furosemide and an oral nitrate were administered. INVESTIGATIONS: Disparity between electrocardiogram and echocardiographic findings was observed in that, while the electrocardiogram showed loss of 'R wave in precordial leads V(2 - 4), excessive thickening of both left and right ventricular wall was shown in the echocardiogram. Doppler-echocardiography revealed a left ventricular outflow tract obstruction at rest with a peak pressure gradient of 64 mm Hg which rose to 145 mm Hg during Valsalva manoeuvre. Colour Doppler presented a moderate mitral insufficiency and the transmitral Doppler flow studies detected a restrictive left ventricular filling pattern. DIAGNOSIS, TREATMENT AND COURSE: Digitalis therapy was stopped because of the outflow tract obstruction complicating cardiac amyloidosis. Cardiac symptoms abated over the following weeks. This improvement was reflected in a significant reduction of the outflow tract gradient, the gradients now being 16 mm Hg under resting conditions and a maximum of 36 mm Hg during the Valsalva manoeuvre. The transmitral Doppler flow pattern showed a pseudonormalisation and the mitral regurgitation regressed nearly completely. The patient was free from cardiac complaints until his sudden death 21 months after the diagnosis of cardiac amyloidosis. CONCLUSION: Cardiac amyloidosis can present with left ventricular outflow tract obstruction mimicking hypertrophic obstructive cardiomyopathy. This fact must be borne in mind to avoid therapy with preload-reducing or positive inotropic drugs and especially glycosides.

Amyloidosis↗
PubMed1984

[Epidemiology of digitalis medication. Results of the Munich blood-pressure study].

As part of a blood-pressure survey in Munich, some of its inhabitants aged 30-69 years were asked by questionnaire about any digitalis medication. Chemically defined glycosides were taken by 127 of 1827 persons (7%), two-thirds of them older than 60 years, for clinically compensated chronic heart failure. Using the equation of Cockcroft and Gault to calculate creatinine clearance, it was below 80 ml/min and thus indicative of early impairment of renal function in more than 50%. In 44% the prescribed daily dose of glycoside corresponded to the calculated maintenance dose, 29% had less and 27% had taken more. None had clinical signs of digitalis intoxication. ECG changes possibly due to digitalis were much less common than had been expected. Sinus rhythm was present in 93%. More than 50% did not know why they were taking digitalis and 80% were taking two or more drugs at the same time. Since more than half had signs of early renal function impairment, creatinine clearance should be taken into account when determining the dosage of a digoxin preparation especially in elderly patients; alternatively, digitoxin should be prescribed. The survey also showed that a large number of persons on glycoside medication did not take the drug regularly.

Acetyldigoxins↗
PubMed1982

Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases.

Purified Fab fragments of digoxin-specific antibodies obtained from sheep were used to treat 26 patients with advanced, life-threatening digoxin (23 cases) or digitoxin (3 cases) toxicity. These patients had advanced cardiac arrhythmias, and in some cases hyperkalemia, which were resistant to conventional treatment. All patients had an initial favorable response to doses of Fab fragments calculated (in most cases) to be equivalent, on a molar basis, to the amount of cardiac glycoside in the patient's body. In four patients treated after prolonged hypotension and low cardiac output, death ensued from cerebral or myocardial hypoperfusion. In one case the available Fab fragment supply was inadequate to reverse a massive suicidal ingestion of digoxin, and the patient died after recurrent ventricular arrhythmias. In the remaining 21 patients, cardiac rhythm disturbances and hyperkalemia were rapidly reversed, and full recovery ensued. There were no adverse reactions to the treatment. We conclude that the use of purified digoxin-specific Fab fragments is a safe and effective means to reverse advanced, life-threatening digitalis intoxication.

Adolescent↗
PubMed1992

The use of digoxin-specific Fab fragments for severe digitalis intoxication in children.

BACKGROUND: Because life-threatening digitalis intoxication is unusual in children, treatment with digoxin-specific-antibody Fab fragments (Fab) has rarely been reported. We describe the efficacy of Fab in the treatment of children with severe digitalis intoxication. METHODS: Twenty-nine children with intoxication due to digoxin (28) or digitoxin (1) received Fab at 21 participating hospitals between 1974 and 1986. Data were gathered about the patients' medical illnesses, doses and serum concentrations of digitalis, responses to Fab therapy, and outcomes. RESULTS: In the infants and young children with acute digoxin intoxication, the digoxin doses ranged from 0.30 to 0.96 mg per kilogram of body weight; two adolescents had severe intoxication after doses of only 0.20 and 0.26 mg per kilogram. The serum digoxin concentrations ranged from 3.0 to greater than 100 ng per milliliter (mean, 13.8). Atrioventricular block (present in 22 patients [76 percent]) was the most common sign of toxicity. All the patients in this series had severe disturbances of cardiac rhythm, hyperkalemia (mean serum potassium concentration, 5.4 mmol per liter), or both. In 27 patients (93 percent), digitalis toxicity resolved after the administration of Fab. Of the 19 patients for whom data were available on the timing of the response to Fab, 15 responded within 180 minutes. Three patients required retreatment with Fab. Seven died of complications unrelated to the administration of Fab. CONCLUSIONS: We recommend that Fab be used in the treatment of digitalis poisoning in infants and young children who have ingested greater than or equal to 0.3 mg of digoxin per kilogram, who have underlying heart disease, or who have a serum digoxin concentration of greater than or equal to 6.4 nmol per liter (greater than or equal to 5.0 ng per milliliter) in the elimination phase; and who also have a life-threatening arrhythmia, hemodynamic instability, hyperkalemia, or rapidly progressive toxicity. Adolescents, who are more sensitive to the toxic effects of digoxin than younger children, may require treatment with Fab after ingesting lower doses.

Acute Disease↗
PubMed2005

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization.

Glycosylated natural products are reliable platforms for the development of many front-line drugs, yet our understanding of the relationship between attached sugars and biological activity is limited by the availability of convenient glycosylation methods. When a universal chemical glycosylation method that employs reducing sugars and requires no protection or activation is used, the glycorandomization of digitoxin leads to analogs that display significantly enhanced potency and tumor specificity and suggests a divergent mechanistic relationship between cardiac glycoside-induced cytotoxicity and Na+/K+-ATPase inhibition. This report highlights the remarkable advantages of glycorandomization as a powerful tool in glycobiology and drug discovery.

Animals↗
PubMed1997

In vitro scanning saturation mutagenesis of an antibody binding pocket.

We have combined PCR mutagenesis with in vitro transcription/translation and ELISA for the rapid generation and characterization of antibody mutants. The PCR products are used directly as the template for the in vitro transcription/translation reactions and because no cloning steps are required, the in vitro saturation mutagenesis of one residue can be completed in duplicate within a week by a single investigator. In vitro scanning saturation mutagenesis was used to analyze the role and plasticity of six key contact residues (H:Tyr-33, H:Asn-35, H:Tyr-50, H:Trp-100, L:Val-94, and L:Pro-96) in the binding pocket of a single chain Fv antibody derived from the 26-10 monoclonal antibody. A total of 114 mutant antibodies were produced; all 19 substitutions at each of the 6 chosen positions. The mutants were analyzed for binding to digoxin, digitoxin, digoxigenin, and ouabain resulting in the generation of a comprehensive data base of 456 relative affinity values. Excellent agreement between the relative affinity values obtained with in vitro synthesized mutant antibodies and equilibrium affinity data obtained with previously reported purified mutant monoclonal antibodies was observed. Approximately 75% of the single amino acid mutants exhibited significant binding to one or more of the digoxin analogs. Mutations that alter and, in some cases, reverse specificity for the different digoxin analogs were identified. In vitro scanning saturation mutagenesis represents a new tool for protein structure-function and engineering studies and can be interfaced with laboratory automation so that an even higher throughput of protein mutants can be constructed and analyzed.

Binding Sites, Antibody↗
PubMed1999

Interspecies differences in cancer susceptibility and toxicity.

One of the most complex challenges to the toxicologist represents extrapolation from laboratory animals to humans. In this article, we review interspecies differences in metabolism and toxicity of heterocyclic amines, aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and related compounds, endocrine disrupters, polycyclic aromatic hydrocarbons, tamoxifen, and digitoxin. As far as possible, extrapolations to human toxicity and carcinogenicity are performed. Humans may be more susceptible to the carcinogenic effect of heterocyclic amines than monkeys, rats, and mice. Especially, individuals with high CYP1A2 and 3A4 activities and the rapid acetylator phenotype may be expected to have an increased risk. Striking interspecies variation in susceptibility to aflatoxin B1 carcinogenesis is known, with rats representing the most sensitive and mice the most resistant species, refractory to dietary levels three orders of magnitude higher than rats. An efficient conjugation with glutathione, catalyzed by glutathione S-transferase mYc, confers aflatoxin B1 resistance to mice. Extremely large interspecies differences in TCDD-induced toxicity are known. The guinea pig is the most susceptible mammal known, with an LD50 in the range 1-2 micrograms TCDD/kg, whereas the hamster is the most resistant species with an LD50 greater than 3000 micrograms/kg. A number of experts have pointed out to the fact that humans appear to be less sensitive to TCDD than most laboratory animals. Human exposure to background levels of TCDD is not likely to cause an incremental cancer risk. A clear cause--effect relationship has been shown between environmental endocrine-disrupting contaminants and adverse health effects in wildlife, whereas the effects seem to be less critical for humans. Studies on DNA adduct formation and metabolism of the nonsteroidal antiestrogen tamoxifen indicate that rats and mice are orders of magnitude more susceptible than humans.

Aflatoxin B1↗
PubMed1983

The cardiac glycoside-receptor system in the human heart.

Specific binding sites have been demonstrated to exist in the heart for several drugs and hormones such as beta-blocking agents, cardiac glycosides, catecholamines, insulin, glucagon and acetylcholine. The specific binding sites for cardiac glycosides in the human heart have certain properties which make it likely that they are the pharmacological receptors for the therapeutic and toxic actions of digitalis glycosides: they are located in the cell membrane and bind cardioactive steroids reversibly with high affinity: half-maximal receptor binding occurs at approximately 2 nM (approximately 1.5 ng/ml) for digoxin; potassium decreases receptor affinity, calcium increases it; specific binding of ouabain, digoxin or digitoxin is related to inhibition of (Na+ + K+)-ATPase activity--which is supposed to be the receptor enzyme for cardiac glycosides. Human left ventricle contains approximately 1.5 x 10(14) binding sites/g wet weight, right ventricle approximately 0.9 x 10(14). In disease the number of receptors may decrease (hypothyroid states, myocardial infarction) or increase (hyperthyroidism, chronic hypokalaemia). Certain drugs (such as phenytoin) or different temperatures or pH changes cause a change in digitalis-receptor affinity. Thus, the number of receptors and possibly their properties are subject to regulation in clinically relevant situations. Further investigations will probably reveal those pathophysiological states, which allow the explanation of toxicity or digitalis refractoriness.

Animals↗
PubMed2004

A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor.

Spinobulbar muscular atrophy is a neurodegenerative disorder caused by expansion of a CAG triplet repeat sequence encoding a polyglutamine tract in the androgen receptor. It has been shown that the mutant protein is toxic in cell culture and triggers an apoptotic cascade resulting in activation of caspase-3. We developed an assay of caspase-3 activation in cells expressing the mutant androgen receptor. This assay was used to screen 1040 drugs, most of which are approved for clinical use. Drugs that inhibit polyglutamine-dependent activation of caspase-3 were subjected to follow-up screens to identify compounds that reproducibly prevent polyglutamine-induced cytotoxicity. Four drugs satisfied these criteria. Three of these (digitoxin, nerifolin and peruvoside) are structurally and functionally related compounds of the cardiac glycoside class and known inhibitors of Na(+)K(+)-ATPase. The fourth compound, suloctidil, is a calcium channel blocker.

Apoptosis↗
PubMed1980

Hemoperfusion with Amberlite resin in the treatment of self-poisoning.

Ten patients with various intoxications were treated with resin hemoperfusion. Three of four patients with grade IV coma due to tricyclic antidepressant (TCA) poisoning could be extubated during or on termination of hemoperfusion. Clearance values of 135--185 and 190--200 ml/min were obtained for amitriptyline and nortriptyline, respectively. One patient with severe chloral hydrate poisoning could be extubated after less than one hour's hemoperfusion. A clearance of 140 ml/min was obtained in a uremic patient with AV block II due to digitoxin intoxication. Four patients with mushroom poisoning were treated with combined hemoperfusion-hemodialysis. A transient fall in platelet count was seen in all patients. Resin hemoperfusion is of definite value in selected, severe cases of self-poisoning with psychotropic drugs such as TCA and possibly in cases of mushroom poisoning where the prognosis with hemodialysis and supportive therapy is doubtful.

Adult↗
PubMed1987

Alpha 1-acid glycoprotein and serum binding of drugs in healthy and diseased dogs.

Inter-individual variation in drug serum protein binding was studied in healthy dogs and in dogs with inflammatory diseases for lidocaine, oxprenolol and propranolol, which bind mainly to alpha 1-acid glycoprotein (alpha 1-AGP), and for diazepam, digitoxin and phenytoin, which bind mainly to albumin. For the drugs mostly bound to alpha 1-AGP, in both groups of dogs binding varied considerably, and it was markedly higher in dogs with inflammatory disease. For the other drugs, the variation in binding was smaller and did not differ between the two groups of dogs. In both groups of dogs, the alpha 1-AGP concentration varied widely; it was higher in the serum of the dogs with inflammation, while the concentration of albumin was lower in these animals. There was a significant negative correlation between percentage free lidocaine, oxprenolol or propranolol and alpha 1-AGP concentration, suggesting that the inter-individual variation in binding of these drugs is due to the variation in alpha 1-AGP concentration. There was a marked intra-individual variation in lidocaine binding and in serum alpha 1-AGP concentration, studied over a period of 3 weeks in healthy dogs; a significant negative correlation between percentage free lidocaine and alpha 1-AGP concentration was obtained.

Animals↗
PubMed2005

Acute digoxin loading reduces ABCA8A mRNA expression in the mouse liver.

Human ABCA8, a new member of the ATP binding cassette (ABC) transporter family, transports certain lipophilic drugs, such as digoxin. To investigate the roles of this transporter, we cloned a mouse homologue of ABCA8, from a mouse heart cDNA library, named ABCA8a. The deduced mouse ABCA8a protein is 66% identical with that of human ABCA8 and possesses features common to the ABC superfamily. It was found that ABCA8a was mainly expressed in the liver and heart, similar to human ABCA8. We further evaluated the effect of acute digoxin (a substrate for ABCA8) intoxication on the mRNA expression of ABCA8 using northern blotting with a 3' non-coding region as a probe to avoid cross-hybridization with other ABCA genes. Following acute digoxin infusion, the mRNA expression of ABCA8 was significantly reduced in the liver 12-24 h after injection (14.7% of vehicle treatment), but not in the heart and kidney. Real-time quantitative polymerase chain reaction analysis confirmed the reduction in ABCA8a mRNA. Similar reductions in ABCA5, ABCA7, ABCA8b and ABCA9 mRNA were also observed. A comparable amount of digitoxin did not affect ABCA8a mRNA expression in the liver. The results suggest that ABCA8 may play a role in digoxin metabolism in the liver.

ATP-Binding Cassette Transporters↗
PubMed1959

The duration of action of some cardiac glycosides and aglycones in the guinea-pig.

A method is described for determining the duration of action of cardiac glycosides and aglycones in the guinea-pig. It is based on their property of potentiating the cardiac response to adenosine. The method is particularly suitable for those drugs with a short duration of action, whereas previous methods are more suitable for those drugs with longer durations of action. The duration of action of one-fifth of the lethal dose has been found for: digoxigenin, lanatoside C, ouabain, digitoxigenin-3-one, digitoxin, 3-acetyldigitoxigenin, digoxin, digitoxigenin, lanatoside A; these drugs are arranged in order of increasing duration of action. The possible relationship between the elimination of these drugs and their duration of action can provide an estimate of their rates of elimination.

Biological Transport↗
PubMed1969

Effect of spironolactone and norbolethone on the toxicity of digitalis compounds in the rat.

1. In the rat, both spironolactone (an antimineralocorticoid) and norbolethone (an anabolic steroid) inhibit the characteristic neuromuscular disturbances and the mortality produced by digitoxin, gitalin, proscillaridin, digoxin and digitalin. The corresponding effects of strophanthin K, ouabain and digitoxigenin could not be prevented.2. It may be concluded that, in our experimental conditions, both spironolactone and norbolethone counteract the toxicity of some, but not all, digitalis compounds tested and that both the protective steroids affect the toxicity of the same digitalis derivatives.3. This antidigitalis effect is not merely a secondary consequence of either antimineralocorticoid or anabolic potency because spironolactone lacks anabolic and norbolethone lacks antimineralocorticoid properties. Indeed, it appears that the ability to antagonize the toxicity of digitalis compounds represents a pharmacological property independent of all known steroid hormone actions, since spironolactone is virtually devoid of these.

Anabolic Agents↗
PubMed1970

The uptake of cardiac glycosides by intestinal smooth muscle of the guinea-pig in relation to digitalis receptors.

1. The accumulation and release of (3)H-digitoxin, (3)H-digoxin and (3)H-ouabain by isolated guinea-pig intestinal smooth muscle has been studied and compared with a pharmacological action due to inhibition of the sodium pump.2. The uptake of labelled cardiac glycosides can be described by means of an exponential function. The t of uptake was similar for the three compounds and did not depend on the concentration.3. Analysis of the curve relating the uptake of cardiac glycosides at equilibrium to the bath concentration enabled a non-saturable and a saturable binding site to be distinguished.4. In contrast to the uptake observations, the onset of the pharmacological effect was dependent on the concentration, and furthermore the t((1/2)) for this effect was shorter.5. The release of cardiac glycosides proceeded more slowly than the uptake.6. The uptake of a labelled glycoside was reduced in the presence of another glycoside. The amount of displaceable glycoside was nearly equivalent to the capacity of the saturable binding site.7. The significance of these results is discussed.

Animals↗
PubMed1987

Visualization of ouabain binding in bovine cornea.

In these experiments, the binding of ouabain, a specific inhibitor of NA,K-ATPase is visualized in bovine cornea using an immunohistochemical method. Due to cross-reactivity between ouabain and digitoxin antiserum, the ouabain binding is demonstrated after an immunological labelling with fluorescein. As shown in the corneal tissue sections and in the epithelial and endothelial cell preparations, a bright fluorescence of the endothelial cell membranes is observed in corneae incubated in 10(-5)-10(-3) mol/l ouabain. In the epithelium, only a weak binding of the ouabain is observed at the basolateral membrane after incubation in 10(-3) mol/l ouabain.

Animals↗
PubMed1970

The difference in sensitivity to cardiac steroids of (Na++K+)-stimulated ATPase and amino acid transport in the intestinal mucosa of the rat and other species.

1. The effect of various cardioactive steroids on the activity of a microsomal (Na(+) + K(+))-activated ATPase from rat intestinal mucosa has been studied and compared with their effects on L-phenylalanine and D-galactose transport by rings of rat intestine in vitro. A similar comparison between the sensitivities to ouabain of microsomal (Na(+) + K(+))-ATPase and of phenylalanine transport in the intestines of the mouse, guinea-pig and toad has been made.2. The rat intestinal enzyme is 50% inhibited by a concentration of 1 x 10(-4)M ouabain, 1 x 10(-5)M scillaren A and 4 x 10(-6)M scilliroside. At concentrations which almost completely inhibit the (Na(+) + K(+))-ATPase activity, these steroids have no effect on the transport of phenylalanine or galactose by the rat intestine. Only at concentrations of 1 x 10(-3)M are scillaren A and scilliroside able to reduce phenylalanine accumulation significantly, the same concentration of ouabain being effective only in the absence of external potassium ions. Digitoxin, 1 x 10(-4)M, a comparatively apolar glycoside, had no action on phenylalanine transport in the rat intestine.3. The effect of ouabain on the (Na(+) + K(+))-ATPase and phenylalanine transport system in the mouse intestine is completely analogous to its effect on these parameters in the rat.4. A half-maximal inhibition of guinea-pig intestinal (Na(+) + K(+))-ATPase by ouabain occurs at an inhibitor concentration of 2 x 10(-6)M, but phenylalanine transport by this tissue is only half-maximally reduced at a concentration of 3 x 10(-5)M. Similarly, in the rabbit intestine, there appears to be a difference of an order of magnitude between the sensitivities of the two parameters.5. In the toad, 50% inhibition of the enzymic activity is observed at a concentration of 3 x 10(-5)M ouabain, whereas a concentration of 8 x 10(-4)M is required to reduce phenylalanine accumulation by one half.6. These findings are consistent with the suggestion that an (Na(+) + K(+))-stimulated ATPase is not the only enzyme in the epithelial cells of the intestinal mucosa that is responsible for sodium extrusion (the mechanism for sodium extrusion being intimately coupled with the mechanism for active amino acid transport); therefore, a second, as yet unidentified, enzyme system must be postulated to account for bulk sodium flow through the intestine.

Adenosine Triphosphatases↗