Experiments with calculated therapeutic and toxic doses of digitalis: IV. Effects on the cellular structure of the central nervous system

Abstract No significant cellular changes were observed in the brain and spinal cord after the administration of calculated therapeutic amounts of digitalis (30 per cent of the minimal lethal dose) in single or in divided doses. The histologic studies were made after a minimum of six days and a maximum of fifty-six days. No cellular changes were produced in our experimental animals when they were digitalized rapidly with a calculated therapeutic dose of digitalis and then were given 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 which, when given as a single dose, produced definite evidence of cellular degeneration in the cerebral cortex. This dose of digitalis was in the toxic range. The frequency with which lesions of the central nervous system occurred increased as the size of the single dose of digitalis was increased to 80 per cent of the minimal lethal dose. Cerebral lesions were not observed until six or more days after single toxic doses of digitalis had been administered. Histologic changes were not observed in the central nervous systems of all of 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. Degenerative changes were produced in the central nervous system when the animals were digitalized rapidly with a calculated therapeutic dose of digitalis and then were 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 lesions in the brain and spinal cord within five days in one animal, and a corresponding daily dose of orally administered tincture of digitalis produced cellular changes in the central nervous system within eleven days in one animal. The central nervous systems of the digitalized animals in the group which had received daily doses of digitalis in the toxic range were examined microscopically after a minimum of five days and a maximum of thirty days. The cellular changes in the brain after the administration of digitalis were not specific. The following cellular alterations were observed in the large and small pyramidal cells of the cerebral cortex: swelling of the cell body; vacuolization of the cytoplasm; varying grades of cytoplasmic and nuclear degeneration, up to complete liquefaction of the cell; pyknosis of the cells; and cellular degeneration plus satellitosis. The cerebral changes often occurred in localized zones, with normal cortical cells in the surrounding tissue. The lesions were at times diffuse when large doses of digitalis had been administered. Old animals were more prone than young ones to manifest cerebral lesions after the administration of digitalis. This difference of sensitivity to the drug was not related to arteriosclerosis; at least no evidence of this disease was observed in any of the arteries or the arterioles of the central nervous system. Drowsiness and spastic reflexes were observed in the animals which were markedly intoxicated with digitalis. Animals which survived the administration of the toxic doses of digitalis recovered completely in three to four weeks.