Comparative toxicology of temelastine. A novel H1 antagonist in dog, rat, and monkey.
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.
Poole
A
A
Smith Kline & French Research Ltd., Frythe, England, United Kingdom.
Betton
G R
GR
Salmon
G
G
Sutton
T
T
Atterwill
C K
CK
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D004285:Dogs; D005260:Female; D005969:Glutamate Dehydrogenase / Q000097:blood; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D011744:Pyrimidinones / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology
D006634:Histamine H1 Antagonists; D011744:Pyrimidinones; C049054:temelastine; D005969:Glutamate Dehydrogenase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase