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1. 1. Circulation and ventilatory studies before and one hour after the administration of 1.6 mg. of lanatoside C to nine patients with chronic pulmonary disease are reported. 2. 2. Clinical improvement occurred in only three cases. 3. 3. The most consistent effect of the digitalis glycoside was an increase in the work of the heart as manifested by a rise in systemic blood flow and ventricular systolic pressure. 4. 4. Deleterious effects occurring in some cases were an increase in right atrial mean and right ventricular end-diastolic pressures, an increase in functional residual capacity, and a decrease in arterial blood oxygen saturation. 5. 5. The causes of these effects and their relation to therapy are discussed.

Using the method of Lowenstein and Corrill modified by the authors the relationship between measured plasma digitalis concentrations and symptoms and signs of toxicity was studied in cases of suicide and accidental poisoning. Direct relationship could not be detected between plasma levels and clinical symptoms. Severe toxic symptoms occured only in the presence of high levels. Nevertheless, patients with high plasma levels may be symptom-free. Parallelism was observed between a fall in the digitalis level and the disappearance of clinical symptoms.

SummaryCassaine sulfate produced emesis in cats when given by intracerebroventricular (0.02 mg in 0.20 ml) and intravenous (0.5 mg/kg) injection with an average latency of 6 min in either case. The emesis elicited through both routes of administration was eliminated after chronic ablation of the chemoreceptor trigger zone in the area post-rema of the medulla oblongata. The emetic response to intravenous cassaine was blocked by pretreatment with intraventricular cassaine. Intravenous deslanoside only partially blocked the emetic activity of intraventricular cassaine. These results indicate that the emetic receptors of the chemoreceptor trigger zone are accessible to cassaine from the blood as well as from the cerebrospinal fluid, and that identical receptor elements are stimulated by the drug through both routes of administration. This lack of directional selectivity of cassaine stands in contrast to the known selectivity of the cardiac glycosides.

The hemodynamic effects of cardiac glycosides were studied in 13 patients with cardiogenic shock. Intravenous administration of ouabain, deslanoside, or digoxin produced a prompt pressor effect which was characterized by increases in systemic vascular resistance and tension time index and no change or increase in right atrial pressure (RAP) and left ventricular enddiastolic pressure (LVEDP). Acute pulmonary edema developed during this period in one patient. During the later phase, 15 to 60 minutes after infusion of digitalis, there were increases in the maximum rate of rise of left ventricular pressure (LV dp dt ), mean systolic ejection rate, and left ventricular stroke work usually with a fall in RAP or LVEDP. Despite the evidence of improved myocardial function, cardiac output (CO) was not significantly increased and was always lower than that attained during infusion of isoproterenol. It is concluded that digitalis is not very effective by itself in restoring blood flow in cardiogenic shock and that the early peripheral vasoconstrictor effect following intravenous administration may be deleterious in some patients.

1. 1. Three patients on the first day of an acute myocardial infarction with heart block, two complete and one incomplete, and associated congestive heart failure were successfully treated with digitalis preparations. 2. 2. It is possible to conjecture that the digitalis reversed the heart failure and the heart block within 24 hours. 3. 3. When digitalis is indicated, there is no contraindication.

The purpose of our study was to determine whether a toxic arrhythmogenic dose of digitalis administered to an in vivo preparation would affect the neuronal uptake of norepinephrine, serotonin and dopamine in brain tissue and norepinephrine in cardiac tissue. This was investigated by intoxicating anesthetized cats with deslanoside, removing cardiac and brain tissue at the onset of ventricular fibrillation, and examining the ability of brain tissue to accumulate [ 3 H]-NE, [ 3 H]-5-HT and [ 3 H]-DA and cardiac tissue to accumulate [ 3 H]-NE. It was found that deslanoside inhibited uptake of [ 3 H]-NE into the left ventricle and [ 3 H]5-HT into the area postrema. These selective effects may reflect greater blood flow to these regions or different sensitivities of the transport mechanisms for these amines. This inihibition of uptake into both left ventricular tissue and area postrema may contribute to some of the cardiovascular and emetic effects seen with digitalis drugs.

In acute experiments on anesthetized cats with artificial respiration and isolated autohemoperfusion of the cerebral vessels by the pump of stabilized capacity (heparin was injected intravenously), cerebral ischemia was evoked by the stopping of the perfusion pump for 15 minutes. In the postischemic period (after perfusion resumption), 2 phases of the perfusion pressure (PP) changes were noted: at the beginning the PP lowering followed by the long-term increase (above the basic level). It is assumed that the PP changes reflect the time course of the development of suggestive postischemic cerebrovascular phenomena: hyper- and hypoperfusion. Preliminary intravenous injection (40-90 min before ischemia) of strophanthine and celanide (0.05 and 0.1 mg/kg) enhanced and extended the first phase and hampered the development of the second phase PP changes. Administration of strophanthine 90-120 min after ischemia (during the PP increase phase) did not alter the cerebrovascular resistance to the blood flow. Under these conditions the response of the cerebral vessels to strophanthine decreased as compared to that in intact (non-ischemized) cats.

Lanatoside C, a digitalis glycoside, has previously been shown to be a potent polyclonal B cell activator for mouse lymphocytes. Since the chemical structure of lanatoside C is well defined we investigated the effect of different chemical modifications on the mitogenic properties of the glycoside in order to determine the molecular basis of B cell activation. The presence of an OH- group at C12 in the steroid nucleus proved to be essential for activation to occur in serum-free medium. Likewise, an intact carbohydrate side chain at C3 appeared to be necessary for retaining mitogenic properties. In serum-supplemented cultures, however, a much more complex response pattern was observed where the prerequisites for activation were not as distinct as in serum-free medium.

Resistography was used in acute experiments on anesthetized cats to demonstrate that cardiac glycosides, particularly celanide, often cause phasic (constrictive-dilative) responses of the perfused vessels and general arterial pressure. The constrictive response of the perfused vessels did not depend on the concentration of calcium ions in the blood and was not prevented by preliminary administration of dihydroergotoxin. However, glycosides prolonged the vasoconstrictive effect of noradrenaline. The vasodilative response to glycosides was reversed by atropine. It is assumed that the constrictive response is myotropic, whereas the dilative one is cholinergic in nature.

The purpose of our study was to determine whether deslanoside administered in vivo results in inhibition of the active transport of [3H]-serotonin into blood platelets. Experiments were performed in cats and arterial blood samples were taken prior to initiating deslanoside infusion and at the point when it appeared from the ECG that ventricular fibrillation was imminent. Toxic arrhythmogenic doses of deslanoside were found to produce a significant reduction in the uptake of [3H]-serotonin into platelets. This increase in free serotonin in plasma caused by inhibition of uptake may play a role in the cardiotoxicity of deslanoside.

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.

In pediatrics it is difficult to define indications of drug therapy, appropriate dosage and therapeutic reliability of drugs because experimental pharmacology in this age group has many obstacles. To provide information on optimal drug selection 83 pediatric clinics were asked to define their choice of drug treatment for particular purposes. The results were compared with an investigation of 1969. Trends of pediatric drug treatment during the last decade can be recognized.

Streptomyces purpurascens transforms primary and secondary 12-deoxycardenolids into digoxin, 7 beta-hydroxy-digitoxin and 7 beta-hydroxy-digoxin, respectively. A metabolic pathway is proposed for cardenolid transformations and the enzymes participating in it are investigated. The substrate concentration in the medium can be increased by using a water-miscible solvent of electron donor character. The newly developed procedure yields 0.5 g/1(-1) of digoxin in a five-day fermentation.