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TH9507, an analogue of human growth hormone-releasing factor (hGRF(1-44)NH 2 ) minimally modified by addition of a trans -3-hexenoyl moiety to Tyr 1 of the amino acid sequence, was found to be resistant to dipeptidyl aminopeptidase-IV deactivation. Compared to natural hGRF(1-44)NH 2 , the modification slowed the in vitro degradation of the peptide in rat, dog and human plasma and prolonged the in vivo plasma elimination kinetics of immunoreactive TH9507. Plasma growth hormone and insulin-like growth factor-1 (IGF-1) markedly increased in pigs, rats and dogs after daily repeat intravenous or subcutaneous injections of TH9507 at doses up to 600 µ g /kg. Subchronic toxicity studies in rats and dogs with TH9507 treatment for up to 4 months showed a significant, but not dose-related, increase in body weight gain associated with increased biomarker response. Although TH9507 was well tolerated by both rats and dogs, a more pronounced anabolic effect and more evident (reversible) adverse effects (liver and kidney findings, anaemia, clinical chemistry changes, organ weight effects) were observed in dogs after repeat daily subcutaneous injections, which were attributed to prolonged exposure to supraphysiological levels of growth hormone and/or IGF-1. In both rats and dogs, toxicokinetic evaluations indicated that exposure to immunoreactive TH9507 was dose related after both routes of administration. The apparent elimination t 1/2 in dogs ranged from 21 to 45 min. In conclusion, TH9507 is a modified hGRF peptide having enhanced potency and duration of action. The adverse treatment-related effects in dogs appear to be associated with sustained exposure to supraphysiological levels of growth hormone and IGF-1 induced by prolonged TH9507 treatment.

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Male and female cynomolgus monkeys (Macaca fascicularis), equally divided as to sex, were fed, up to 24 wk, diets which contained 20% by weight of either soybean oil or Brassica napus cv. Tower rapeseed oil which contained 0.2% erucic acid. Long-chain monoenes appeared to accumulate in the cardiac lipids of both sexes fed Tower rapeseed oil. Histochemical studies suggested no myocardial damage associated with the feeding of either diet. Histopathological examination of the hearts of monkeys fed the two diets showed that only two male monkeys fed soybean oil for 24 wk had myocardial lesions, and these were multiple small foci of mononuclear cells. The results indicate that Tower rapeseed oil is indistinguishable from soybean oil in its nutritional and pathological properties.

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