Rapid detection of convallatoxin using five digoxin immunoassays.

CONTEXT: Cardiac glycosides of plant origin are implicated in toxic ingestions that may result in hospitalization and are potentially lethal. The utility of commonly available digoxin serum assays for detecting foxglove and oleander ingestion has been demonstrated, but no studies have evaluated the structurally similar convallatoxin found in Convallaria majalis (lily of the valley) for rapid laboratory screening, nor has digoxin immune Fab been tested as an antidote for this ingestion. OBJECTIVE: We aimed to (1) evaluate multiple digoxin assays for cross-reactivity to convallatoxin, (2) identify whether convallatoxin could be detected in vivo at clinically significant doses, and (3) determine whether digoxin immune Fab could be an effective antidote to convallatoxin. MATERIALS AND METHODS: Cross-reactivities of purified convallatoxin and oleandrin with five common digoxin immunoassays were determined. Serum from mice challenged with convallatoxin was tested for apparent digoxin levels. Binding of convallatoxin to digoxin immune Fab was determined in vitro. RESULTS: Both convallatoxin and oleandrin were detectable by a panel of commonly used digoxin immunoassays, but cross-reactivity was variable between individual assays. We observed measurable apparent digoxin levels in serum of convallatoxin intoxicated mice at sublethal doses. Convallatoxin demonstrated no binding by digoxin immune Fab. CONCLUSION: Multiple digoxin immunoassays detect botanical cardiac glycosides including convallatoxin and thus may be useful for rapid determination of severe exposures, but neutralization of convallatoxin by digoxin immune Fab is unlikely to provide therapeutic benefit.

[Comparative study of the antiarrhythmic activity of L-, D-and DL-stereoisomers of potassium magnesium aspartate].

Injection forms of potassium (K) and magnesium (Mg) aspartate (Asp) were compared in preventing cardiac disorders caused by electrolytic disturbances, primarily low K and Mg levels (e.g. caused by the treatment with cardiac glycosides and diuretic drugs). Widely used K- and Mg-Asp preparations (asparkam, panangin, pamaton) are synthesized from aspartic acid representing a racemic mixture of L- and D-stereoisomers. Differences in metabolism and utilization of D- and L-amino acids probably influence the pharmacological properties of K and Mg L- and D-aspartates. Moreover, the pharmacologically effective doses of Mg and K salts can induce toxicity, which depends on the nature of anions. The aim of this study was to compare of antiarrhythmic action of K and Mg L-, D-, and DL-Asp stereoisomers using calcium chloride (CaCl2) and aconitine induced arrhythmia models in rats and strophanthin-K induced arrhythmia model in guinea pigs. It was found that intravenously administered K- and Mg-L-Asp exhibited higher activity compared to K- and Mg-D- and DL-Asp on the strophanthin-K, CaCl2, and aconitine induced arrhythmia models. Indeed, K- and Mg-L-Asp more effectively decreased the incidence of arrhythmias, increased the time to onset of the first arrhythmia, decreased percentage loss of rats, and increased the survival life of animals after the first arrhythmia onset in rats with arrhythmias induced by strophanthin-K and CaCl2 as compared to K and Mg-D- and DL-Asp. At the same time K- and Mg-L-Asp was better than D- and DL-Asp with respect to acute toxicity (LD50), effective dose (ED50) and antiarrhythmic (therapeutic) ratio (LD50/ED50) in rats with aconitine-induced arrhythmia model.

Potassium channels in the cardiovascular system.

In vitro and in vivo studies suggest that opening of ATP-sensitive potassium channels following ischaemia enhances recovery of myocardial contraction, dilates blood vessels and has an antiarrhythmic effect. Different sulphonylurea compounds that block the ATP-sensitive potassium channels exert different effects on cardiac functions. Glibenclamide decrease, arrhythmogenesis during acute myocardial infarction in rats and reduces strophanthin cardiotoxicity in rabbits. Other sulphonylurea compounds, but not glibenclamide, increase arterial blood pressure and myocardial contractility. These effects may be partly secondary to blockade of ATP-sensitive potassium channels and partly due to independent cardiac and extracardiac actions. Glimepiride may have a more advantageous cardiovascular effect than glibenclamide. The studies suggest the hypothesis that deleterious cardiovascular effects of some hypoglycaemic sulphonylurea drugs may contribute to the high cardiovascular mortality rate in diabetes mellitus. An observational study suggested glibenclamide decreased the incidence of fatal myocardial infarction and development of ventricular fibrillation in patients suffering from acute myocardial infarction. Glibenclamide may also decrease the incidence of ventricular ectopic beats in digitalized patients compared with other sulphonylurea compounds. The studies suggested the survival of subjects treated with glibenclamide, insulin, or diet alone after the first attack of angina pectoris or after first acute myocardial infarction may be longer compared with those on other sulphonylurea therapies. Further large scale prospective, randomised studies are needed to determine whether the reported effects can be verified and are sufficiently large to affect clinical prescribing.

Adaptogenic and cardioprotective action of Galleria mellonella extract in rats and frogs.

Pharmacological and metabolic effects of Galleria mellonella larvae extract used in Russian folk medicine to treat cardiovascular and senile diseases were studied. It was shown that the extract possesses adaptogenic, cardiotropic, cardioprotective, and hypocoagulant properties. The extract possesses low toxicity and does not cause significant changes in biochemical parameters in the blood serum of laboratory animals. Increase in catecholamine content in the heart and aortic tissues and their decrease in adrenal glands are unfavourable effects of high doses of the extract.

[The influence of kordaron on the pharmacodynamic effects of strophanthin in experiments on isolated myocardial preparations and in the modelling of heart failure]. / Vliianie kordarona na farmakodinamicheskie éffekty strofantina v éksperimentakh na izolirovannykh preparatakh miokarda i v usloviiakh modelirovaniia serdechnoi nedostatochnosti.

The experiments with isolated rat atria isometrically contracting and those with simulated rat heart failure were performed to study the effects of the alpha-, beta-, and X-blocker cordarone on the pharmacodynamic effects of strophanthin. Cordarone was demonstrated to greatly decrease the toxicity of the cardiotonic in circulatory decompensation, without causing negative effects of cardiac inotropic function. Cordarone in combination with strophanthin slightly diminished the magnitude of the negative chronotropic effect of the cardiac glycoside and slowed down the rate of its cardiotonic effect.

Retinal toxicity in albino rabbits induced by intravitreal injection of strophanthin-K.

Time course and extent of strophanthin-K induced disturbances of flash electroretinogram (F-ERG) has been observed in 12 albino rabbits treated by a single dose of 1, 3 and 9 ug/0.1 ml of intravitreal injection. A phenomenon of the dependence of a- and b-wave amplitude changes on dosage was demonstrated. A 9 ug/0.1 ml dose caused a flat a- and b-wave showing the F-ERG wave could be completely suppressed by larger dose of strophanthin-K. Two parameters of "attenuation kinetics" are proposed to identify the pharmacodynamics and toxic kinetics on retina as time profile is concerned: 1) B (the slope of attenuation curve); 2) Et1/2 (half attenuative time). B and Et1/2 are helpful in making a tentative identification of the target cells on retina and in demonstrating a synergism or antagonism between drugs if any. The a-wave of F-ERG, having a steeper slope, is more sensitive than b-wave in terms of strophanthin-K toxicity bringing forth a quantitative criterion in visual pharmacology. The attenuation of amplitude in a-wave may therefore be considered as an early response to this drug. The direct pupillary response test were also done pre- and post-strophanthin-K, and the results of this test support that of F-ERG.

Chronopharmacology of strophanthin and inderal: an experimental study.

Chronopharmacological investigations were performed in 54 guinea pigs and 126 white mice to explore their tolerance to arrhythmogenic and lethal doses of strophanthin, and changes in sensitivity to threshold antiarrhythmic dose of inderal during 24 hours. The investigations were carried out at a 4-hour interval, i.e., six times in 24 hours. The data obtained were processed using the approximation method to determine sinusoid fluctuations with an initially given period (cosinor analysis) and with an unknown period (non-linear least-square method in combination with the method of gradual approximation) on an EC 1045 computer and a DZ 28 microcomputer. It was found that strophanthin toxicity in guinea pigs and white mice reaches a maximum in the late evening, night and early morning hours. The acrophases of circadian rhythms of chronotolerance to the threshold arrhythmogenic dose of strophanthin, and those of chronosensibility to inderal are virtually identical.

[Changes in the myocardium damaged by strophanthin]. / Izmeneniia miokarda, povrezhdennogo strofantinom.

The mechanism of intoxication, produced with strophanthin (10 mg/kg) has been studied in myocardium of white rats. Area, perimeter and factor of form in mitochondria, ratio of the mitochondrial surface area with injured external membranes to the whole mitochondrial area, agranular sarcoplasmic network and T-system area, changes in myofilaments, Z-lines, length of sarcomeres have been estimated. Changes in succinate dehydrogenase, lactate dehydrogenase and in reduced forms of nicotinamide coenzymes activity has been investigated histochemically. Adenosine triphosphate (ATP) prevents appearance of ultrastructural and histochemical disturbances, produced with strophanthin. However, the protective effect of ATP is not sufficient. Adenosine monophosphate, penetrating across the cell membrane, is supposed to produce a greater curative effect.

[Influence of kordaron, anaprilin, dimedrol and riboxin on the hemodynamic effects of strophanthin in experimental heart failure]. / Vliianie kordarona, anaprilina, dimedrola i riboksina na gemodinamicheskie éffekty strofantina pri éksperimental'noi serdechnoi nedostatochnosti.

In experiments on 183 rats it was shown that cordarone, anapriline, dimedrol and riboxine increasing in experimental cardiac insufficiency tolerance to the cardiotoxic effect of strophanthin differ significantly by their influence on the hemodynamic effects of this cardiac glycoside. Cordarone increased intensity of the hemodynamic effects of strophanthin and accelerated their development. Under the action of anapriline and dimedrol the stimulating effect of strophanthin on hemodynamics decreased to a much lesser degree than its cardiotoxicity. Riboxine virtually abolished the hemodynamic effects of strophanthin.

[Effect of strophanthin and digoxin on the activity of an experimental epileptogenic focus in the frog hippocampus]. / Vliianie strofantina i digoksina na aktivnost' éksperimental'nogo épileptogennogo ochaga v gippokampe liagushki.

It has been shown on frogs with epileptogenic focus induced by the injection of penicillin (1000 U in 0.4 ml) into the hippocamp that preinjection (or injection on the background of the functioning epileptogenic focus) of strophanthin (1.8 and 0.18 microgram/g) or digoxin (1.2 micrograms/g) into spinal lymphaticus sac led to a sharp increase in interparoxysmal epileptiform discharges and electrographic correlates of fits on the ECG. The influence of cardiac glycosides upon the epileptized cerebral neurons is thought to be associated with the capacity of these drugs to inhibit Na+, K+-ATPase of neurons and their axons resulting in the disturbance of cerebral mediator activity.

Effects of computer controlled submaximal glucose utilization on myocardial energy potential and on survival time during acute strophantin intoxication in dogs.

We checked the effect of a 4 hourly computer controlled submaximal glucose utilization (CCSGU) of 12.01 +/- 1.19 mg/kg min under normoglycaemic conditions and of a simultaneous diminishing of myocardial NEFA supply on trigger mechanism of ventricular fibrillation during acute strophantin intoxication (4 micrograms/kg min) in 17 mongrel dogs. Dogs treated with CCSGU (protective group, n = 8) showed a nearly 30% (p less than 0.01) major survival time (47.6 +/- 3.6 min) before ventricular fibrillation occurred in comparison to a control group (33.1 +/- 3.7 min, n = 9). CCSGU induced a 90% higher left ventricular hydraulic work (5.18 +/- 0.57 Nm/g heart weight) during strophantin infusion compared to controls (2.75 +/- 0.47). No significant myocardial NEFA extraction was evident in the protective group. During CCSGU myocardial oxygen extraction was on a lower level in rest (15.8 +/- 1.0%, p less than 0.01) as well as during strophantin infusion (11.3 +/- 2.6%, p less than 0.01) compared to controls. In dogs treated with CCSGU nearly equal myocardial levels of HEP and lactate were found compared to controls in spite of a major survival time and higher left ventricular hydraulic work. A higher myocardial glycogen content was observed in the protective group (45.1 +/- 6.7 mumol/g w.w.) in comparison to controls (28.1 +/- 2.9, p less than 0.05). Our results prove that CCSGU using the device system GLUCON induces a shift in substrate utilization from NEFA to glucose, decreases myocardial oxygen extraction, increases myocardial glycogen content, enlarges heart work and protects against strophantin induced ventricular fibrillation.

[Anti-arrhythmia and antifibrillatory properties of dibenzazepine derivatives]. / Antiaritmicheskie i antifibrilliatornye svoistva proizvodnykh dibenzazepina.

Antiarrhythmic and antifibrillation properties of bonnecor, a derivative of dibenzepin, were studied in comparison with ethmozine, quinidine and novocainamide, using various experimental arrhythmia models. Bonnecor activity was somewhat smaller than that of ethmozine, and much greater than that of quinidine and novocainamide in the mixed atrioventricular arrhythmia model simulated in aconitin-treated rats and the ventricular arrhythmia model simulated by two-degree coronary occlusion in dogs. Intravenous 1 mg/kg and oral 6 mg/kg bonnecor doses prevented ventricular fibrillation caused by acute coronary occlusion in rats, while ethmozine showed no such effect.

[Effect of diuretics on the course of experimental arrhythmias]. / Vliianie diuretikov na techenie éksperimental'nykh aritmii.

The protective effect of triamterene was demonstrated on aconitine (rats) and strophanthin (cats) models of arrhythmias. Furosemide potentiates the antiarrhythmic effects of calcium chloride (rats) and strophanthin, ethacrynic acid potentiates the arrhythmogenic action of all agents used.

[Glycoside poisoning in experimental heart failure and its drug correction]. / Glikozidnaia intoksikatsiia pri éksperimental'noi serdechnoi nedostatochnosti i ee lekarstvennaia korrektsiia.

It has been demonstrated in experiments on 420 rats that antiadrenergic, antihistamine, antihypoxic, anabolic, antiarrhythmic and diuretic agents have different effects on the cardiotoxicity of strophanthine K for intact animals and in experimental heart insufficiency of different genesis. The pharmacological analysis revealed some risk factors capable of provoking glycoside intoxication in circulatory failure. Approaches to the goal-oriented drug correction of the risk factors are proposed.