digoxin and gitaloxin

Gitaloxin is a digitalis glycoside used for the same indications as digoxin and digitoxin. The successful outcome for a 2 1/2-year-old boy who accidentally ingested 3 mg of gitaloxin (100 times the normal therapeutic dose) is reported. At admission the child presented with irregular heart rhythm. He subsequently started vomiting, even after continuous gastric feeding. Only 48 h after ingestion of gitaloxin he became somnolent and developed bradyarrhythmia. The symptoms disappeared 96 h later; the bradyarrhythmia, however, (second-degree atrioventricular block) decreased progressively only after 120 h. The initial clinical presentation of gitaloxin poisoning may be misleading and careful observation in a pediatric intensive care unit is mandatory. A cross-reaction between the fluorescence polarization immunoassay for digitoxin and the radioimmunoassay for gitaloxin was found and was used as a helpful, but rough, estimate of the severity of gitaloxin poisoning, in the absence of a specific measurement of gitaloxin.

Topics: Bradycardia; Child, Preschool; Critical Care; Digoxin; Electrocardiography; Fluorescence Polarization Immunoassay; Humans; Male; Poisoning; Vomiting

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.

Topics: Animals; Cardenolides; Cardiac Glycosides; Digitalis Glycosides; Digoxin; Magnetic Resonance Spectroscopy; Sodium-Potassium-Exchanging ATPase; Structure-Activity Relationship; Swine

The inhibitory effect of formylated cardiac steroids (gitaloxin and its derivatives) on guinea-pig heart Na, K-ATPase was compared to that of other cardiac steroids with various hydroxy substituents. The decreasing order of potency of aglycones at equilibrium was as follows: gitaloxigenin greater than digitoxigenin greater than ouabagenin greater than digoxigenin greater than gitoxigenin greater than diginatigenin. This sequence was different to the sequence of drugs hydrophobic character. The compounds with hydroxy groups in the vicinity of the lactone ring (gitoxigenin, diginatigenin) were less potent than the hydrophilic compound ouabagenin. We propose that intramolecular bounding between 16 beta-OH and the lactone ring contributes to the relatively low potency of gitoxigenin and diginatigenin. The formylation of 16 beta-OH increased the potency of gitoxigenin by a factor of 41. The formylated compound (gitaloxigenin) was 5-fold more potent than digitoxigenin. The 3 beta-glycosylation of digoxigenin lead to pseudo-irreversible inhibitors of Na, K-ATPase. The half-time to achieve the equilibrium (for 5 mumol/l) was equal to 54 s, 90 s and 108 s respectively for digoxigenin monodigitoxoside, digoxin and desacetyllanatoside C. However, at equilibrium the three glycosides were equipotent, suggesting the existence of steric effects at the sugar site of the receptor. The sequence of potency observed for monodigitoxosides, monodigitalosides and tridigitoxosides after 60 min incubation was similar to that observed for the corresponding aglycones. These results suggest that the strongly negative inductive group 16 beta-OCHO is tightly bound to Na, K-ATPase, possibly to the same receptor site than that which is thought forming hydrogen and ionic bonds with the lactone ring. They show that the high toxicity of gitaloxin in guinea-pig heart is likely due to its high potency as Na, K-ATPase inhibitor.

Topics: Animals; Digitalis Glycosides; Digoxin; Guinea Pigs; In Vitro Techniques; Models, Molecular; Myocardium; NAD; Sodium-Potassium-Exchanging ATPase; Time Factors

Rat and guinea-pig hearts were perfused with gitoxin and gitaloxin at various concentrations. Simultaneously, the amplitude of myocardial contractions was recorded. In the case of guinea-pig, digoxin and digitoxin were studied, too. After perfusion, the amount of cardiac glycoside taken up by each heart was determined. The uptakes of gitoxin and gitaloxin by rat hearts were similar and directly proportional to the glycoside concentration in the perfusion medium. In guinea-pig hearts, the sequence in binding amount of digoxin less than gitaloxin less than gitoxin less than or equal to digitoxin. The positive inotropic effects of the four glycosides in guinea-pig hearts were similar; the toxicity, however, increased in the sequence: gitoxin less than gitaloxin congruent to digoxin less than digitoxin. Briefly, gitoxin is bound to the guinea-pig heart muscle much more than its positional isomer, digoxin; though it shows a similar positive inotropic effect on guinea-pig hearts, gitoxin appears to be markedly less toxic than the three other glycosides.

Topics: Animals; Digitoxin; Digoxin; Extracellular Space; Female; Guinea Pigs; Heart; In Vitro Techniques; Male; Myocardial Contraction; Myocardium; Rats; Species Specificity

Topics: Animals; Digitalis Glycosides; Digitoxin; Digoxin; Guinea Pigs; Heart; In Vitro Techniques; Isomerism; Myocardial Contraction; Myocardium

Topics: Cardiotonic Agents; Digitalis; Digitalis Glycosides; Digoxin; Drug Therapy; Heart Failure; Plant Extracts

Topics: Digitalis; Digitalis Glycosides; Digoxin; Plant Extracts