Effects of short-term and long-term theobromine administration to male dogs

Thirty-three dogs were each given a single oral dose of theobromine which ranged from 15 to 1000 mg/kg. Three dogs died, one each given theobromine 300, 500, and 1000 mg/kg. Ten dogs were continued on theobromine (75 to 150 mg/kg/day) for periods of 21 or 28 days; seven died and the others were killed with pentobarbital sodium. None had thymic or testicular atrophy, as has been reported in rats, but a degenerative, fibrotic cardiomyopathy limited to the right atrial appendage occurred in 6 of these 10 dogs. Theobromine was given to two groups of dogs for 1 year in doses of 25 and 50 mg/kg/day, respectively. Other dogs were given theobromine 25 or 50 mg/kg/day for 4 months and the dose was then increased to 100 or 150 mg/kg/day for 8 months. Three dogs (one each at 50, 100, and 150 mg/kg/day) died during the course of the year. The right atrial appendage of one, the dog at 100 mg/kg/day, was obliterated by fibrosis, but no heart lesions were found in the other two dogs. At the end of 1 year all surviving dogs including controls were killed and subjected to complete necropsies. As in the short-term study, the only gross and microscopic change associated with theobromine was a fibrotic lesion in the right atrium of the heart, in three of five dogs given theobromine 150 mg/kg/day and in two of the four dogs given 100 mg/kg/day. Plasma theobromine concentrations were determined during the last 2 months of the year. While right atrial cardiomyopathy occurred in dogs given theobromine 100 or 150 mg/kg/day, a clear relationship between dose, plasma concentration, frequency, and severity of the lesion could not be determined.