The toxicity of
temelastine 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid+ ++-3-yl) methyl]-4-
pyrimidone a potent, selective, competitive
histamine H1-receptor antagonist was examined in dogs and rats. The major toxicological response seen in the dog was marked, but intermittent and reversible, increases in the plasma activity of a number of liver-associated
enzymes, viz
alanine aminotransferase (ALT),
glutamate dehydrogenase (GLDH), and
alkaline phosphatase (ALP). The increases first seen in two male dogs treated for 30 consecutive days at a dose of 300 mg/kg became apparent at lower doses, i.e., 100 and 33.3 mg/kg/day, in 6- and 12-month studies. Although the increases were suggestive of hepatotoxicity, the only histological changes were increases in hepatocellular
lipofuscin pigment and foci of macrophages seen in dogs treated at 300 mg/kg for 12 months. Rats treated for up to 12 months at doses as high as 300 mg/kg/day showed no treatment-related increases in plasma
enzymes although increases in liver weights and hepatocellular
lipofuscin pigment together with centrilobular
hypertrophy were seen in the 300 mg/kg/day treatment group. To investigate differences in hepatic responsiveness between species dogs, rats, and monkeys were exposed to high concentrations of
temelastine by continuous 24-hr
intravenous infusion. The results of the study showed the dog to be most sensitive to the hepatic effects of
temelastine. The major toxicological effect of
temelastine in the rat was a histopathological lesion of the thyroid gland characterized by agglomeration and depletion of
colloid, follicular epithelial
hypertrophy and reduced follicular size. The no-effect dose for this lesion was between 10 and 33.3 mg/kg/day. These histopathological changes, characteristic of a "TSH-driven" thyroid gland, were not seen in the thyroid glands of dogs.