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Protective action of nifedipine (Bay a 1040, Adalat) in cardiac arrhythmias was tested in digitalis-intoxicated cats. Animals of both sexes weighing from 1.4 to 3.2 kg were anesthetized with sodium pentobarbital (35 mg/kg i.p.) heparinized (500 U/kg i.v.) and mechanically ventilated. Mean intracarotid blood pressure and heart rate were recorded. Two study groups were compared with a control group. Group I (N = 19): nifedipine (6.25; 12.50 or 25 micrograms/kg/min) was given in a 10-min infusion into the femoral vein of the cat, before a fast intravenous injection of lanatoside C (0.15 mg/kg). Group II (N = 19): cats intoxicated with lanatoside C were treated with nifedipine in the same doses and conditions described for Group I. The calcium antagonist was administered as soon as cardiac arrhythmias appeared. Control group (N = 10): lanatoside C was given as the only drug. In each group the observation period was maintained from 60 to 180 min after the administration of the last drug (nifedipine or lanatoside C). Results showed that pre-treatment with nifedipine inhibited digitalis arrhythmias in 10 out of 19 cats and prevented death in the majority of cases (16 out of 19). When given after lanatoside C, nifedipine was unable to suppress cardiac arrhythmias but improved the survival rate (8 out of 19). In lethal cases, the time of death of nifedipine-treated animals was earlier compared with the control group (p less than 0.05). It is concluded that nifedipine prevents and, in a minor proportion, protects from the toxic effects of digitalis.
6 patients with severe digitalis intoxication were studied while hospitalised in a coronary care unit. 2 and 4 patients had ingested high doses of lanatosid C and digoxin, respectively. In three cases ventricular arrhythmias, in one of these and two further cases SA blocking and an additional A-V-block in one case were observed. Maximum blood levels of digoxin between 3.4 and 20 ng/ml were determined several hours after the ingestion. The maximal blood levels were achieved in one patient only 52 h after ingesting lanatosid C and in one patient taking digoxin after 12.5 h. Potassium concentrations in plasma were elevated in 4 patients. Antiarrhythmic and electrolyte therapy is discussed and the usefulness of a stomach lavage for diminishing the quantity of absorbed lanatosid C is shown in one patient who had a maximal blood level of 3.4 ng/ml after taking 23.7 mg of lanatosid C. Cumulative urinary excretion of this patient was 0.68 mg within 5.5 days. This result confirms the minimal enteral absorption under the therapy chosen.
We sought to determine whether digitalis augments cardiopulmonary baroreflex control of forearm vascular resistance in normal young men. Cardiopulmonary baroreceptor input was reduced with lower body negative pressure (LBNP) at 10 and 20 mm Hg, which decreased central venous pressure but did not alter blood pressure or heart rate. Decreases in forearm blood flow and increases in forearm vascular resistance with LBNP were greater after administration of lanatoside C (Cedilanid) than before, and the slope of the regression line relating changes in central venous pressure and those in forearm vascular resistance was steeper after lanatoside C. Vasoconstrictor responses to the cold pressor test did not differ before and after lanatoside C, which suggested that augmented responses to LBNP after the drug were not caused by a generalized change in reflex control. These results suggest that lanatoside C augments the tonic inhibitory influence of cardiopulmonary baroreceptors in normal men.
An original method based upon high-performance liquid chromatography coupled to ionspray mass spectrometry (HPLC-ISP-MS) has been developed for the identification and quantification in plasma of several cardiac glycosides, namely digoxin, digitoxin, lanatoside C and acetyldigitoxin. After single-step liquid-liquid extraction by chloroform-2-propanol (95:5, v/v) at pH 9.5 using oleandrin as an internal standard, solutes are separated on a 4 microm NovaPak C18 (Waters) column (150x2.0 mm, I.D.), using a gradient of acetonitrile-2 mM NH4COOH, pH 3 buffer (flow-rate 200 microl/min, post-column split 1:3). Detection is done by a Perkin-Elmer Sciex API-100 mass analyzer equipped with an ISP interface. In most instances the major ion observed is not [M+H]+ as expected, but [M+NH4]+. The mean retention times (min) are: lanatoside C, 5.74; digoxin, 6.00; digitoxin, 8.08, oleandrin, 8.30, acetyldigitoxin, 8.66 and 9.01 (isomers alpha and beta, respectively). The lower limits of detection in single ion monitoring mode range from 0.15 ng/ml (alpha- and beta-acetyldigitoxin) to 0.60 ng/ml (lanatoside C), making the method less sensitive than radioimmunoassay, whereas it is much more specific.
In Czechoslovakia, drug utilization studies showed that oral forms of digoxin and lanatoside C are traditionally the most prescribed cardiac glycosides. Our study of the relative bioavailability of the oral form of lanatoside C revealed that the drug has a low and irregular bioavailability making use of this frequently prescribed drug non-rational. The above data definitely contributed to a sharp decrease in the use of the oral form of lanatoside C in our country, which is in agreement with consumption trends in other European countries. However, the use of only drug forms with a good bioavailability is one aspect of new approaches applied in pharmacotherapy with cardiac glycosides resulting in gradual decrease of their consumption as a pharmacological group. Clinical pharmacological evaluation of individual drug forms and postgraduate education in clinical pharmacology of cardiac glycosides contribute significantly--apart from other regulatory measures--to a more rational use of cardiac glycosides in Czechoslovakia.
The effect of lanatosid C on the peripheral vascular system was studied in a randomized double-blind cross-over study. 1 mg lanatosid C in saline or a corresponding volume of saline were applied intravenously for 30 min to healthy subjects. A significant drop of 28% in blood flow and an increase of peripheral vascular resistence at rest of 44% during and after the application of the cardiac glycoside could be seen while the placebo effect was minimal.
A rapid extraction method followed by high-performance liquid chromatographic assay was developed for the quantitative determination of the cardioactive glycosides of Digitalis lanata. The leaf samples were extracted with water or aqueous alcohols. The simple extraction method gives a better yield than the methods described previously. Lanatoside C and its metabolites have been separated on a reversed-phase column with various mixtures of acetonitrile, methanol, and water as mobile phases for isocratic elution. Extraction and quantitative determination of lanatoside C and digoxin from a leaf sample require not more than 30 min.