© 1990 Oxford University Press
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Comparative Toxicology of Temelastine
A Novel H1 Antagonist in Dog, Rat, and Monkey
Smith Kline & French Research Ltd. The Frythe, WelwynALb 9AR, England, United Kingdom
Received December 16, 1988; accepted June 8, 1989
Comparative Toxicology of Temelastine: A Novel H, Antagonist in Dog, Rat, and Monkey. POOLE, A., BETTON, G. R., SALMON, G., SUTTON, T., AND ATTERWILL, C. K. (1990). Fundam. Appl. Toxwol. 14, 71–83. The toxicity of temelastine 2-[4-(5-bromo-3-methylpyrid-2-yl)butyl-amino]-5-[(6-methylpyTid-3-yl) methyl]-4-pyrimidone a potent, selective, competitive hista-mine Hrreceptor antagonist was examined in dogs and rats. The major toxicologjcal 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 dehydro-genase (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.