Experiments with calculated therapeutic and toxic doses of digitalis: I. Effects on the myocardial cellular structure

Abstract

No microscopic pathologic changes were found in the myocardiums or coronary arteries of the control animals. No evidence of histologic changes was found in the myocardiums of the experimental animals after the administration of calculated therapeutic amounts of digitalis (30 per cent of minimal lethal dose) in single or divided doses, given over a period of forty-eight hours. The histologic studies were made after a minimum of six days and a maximum of fifty-six days. Myocardial lesions were not produced in our experimental animals when they were digitalized rapidly with a calculated therapeutic dose of digitalis, and were then given daily maintenance doses of the drug which were estimated to correspond to either 1 or 2 cat units for a man weighing 70 kg. The histologic studies were made after a minimum of nineteen days and a maximum of sixty days. In our experiments, 60 per cent of the minimal lethal dose was the smallest amount of digitalis which, when given as a single dose, produced definite evidence of myocardial lesions. This dose of digitalis is in the toxic range. The frequency with which myocardial lesions occurred increased as the size of the single dose of digitalis was increased to 80 per cent of the minimal lethal dose. Myocardial lesions were not found until five or more days after the single toxic doses of digitalis had been administered. Histologic changes were not observed in the hearts of all the animals which had received toxic amounts of digitalis, even when the quantity of the drug was 80 per cent of the minimal lethal dose. Histologic changes were produced in the myocardium when the animals were digitalized rapidly with a calculated therapeutic dose of digitalis, and were then given daily quantities of the drug which were estimated to correspond to 3, 4, 5.5, or 6 cat units for a man weighing 70 kg. The equivalent of 3 cat units daily of parenterally administered digitoxin caused myocardial lesions within five days in one animal, whereas the same amount of orally administered tincture of digitalis produced myocardial lesions within eleven days in another animal. The digitalized animals in this group which received daily doses of digitalis in the toxic range had their myocardiums examined microscopically after a minimum of five days and a maximum of thirty days. Histologic changes in the heart were produced by digitalis whole leaf or by crystalline products of digitalis (digitoxin, lanatoside A, lanatoside B, and lanatoside C). The sequence of pathologic changes in the myocardium after the administration of toxic doses of digitalis was studied. The observations of Levitski 1 and Bu¨chner 3 were confirmed. The myocardial lesions were focal in distribution, and were more frequent in the papillary muscles and in the left ventricular wall than in other regions. This also confirmed the observations of Levitski and Bu¨chner. Animals which survived the toxic doses of digitalis recovered completely in three or more weeks. Animals which had myocardial scars produced by digitalis (healed lesions) appcared entirely normal after three to four or more weeks. Myocardial lesions were more prone to develop in old animals after the administration of digitalis than in young ones. This difference in sensitivity to the drug was not related to arteriosclerosis, for no evidence of this disease was found in the cardiac arteries or arterioles of any of the cats. Experimental hyperthyroidism increased the sensitivity of the animals to digitalis. Myocardial lesions were found after the administration of calculated therapeutic doses of digitalis to hyperthyroid cats. No evidence of anatomic changes was seen in the skeletal musculature or the smooth musculature of any of the animals which had received digitalis in therapeutic or toxic quantities.