The Effects of Prolactin on Aspects of Carbohydrate, Lipid and Amino Acid Metabolism in the Goldfish Carassius Auratus

Unlike other pituitary hormones, prolactin affects a broad spectrum of physiological systems. Of the over 100 reported actions of prolactin, a majority are related to the involvement of this hormone in reproduction, growth and development. In teleost fishes, as in other non-mammalian species, seasonal reproductive cycles involve dramatic changes in carbohydrate and lipid metabolism. The hormonal control of these seasonal, reproductively related, metabolic shifts remains to be elucidated. As prolactin has been implicated in the control of carbohydrate and lipid metabolism throughout most classes in the vertebrate group, this study examines the effects of prolactin on specific aspects of carbohydrate and lipid metabolism in fish. In view of the fact that prolactin and growth hormone are structurally similar, and since overlap in activities are commonly noted, the action of these hormones on carbohydrate, lipid and amino acid metabolism were compared. Since prolactin has been reported to have growth-promoting effects in all vertebrates except the fishes, the examination of the effects of prolactin on growth and amino acid metabolism is of particular interest

Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780

Alzheimer’s disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-β peptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aβ production. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβ peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aβ1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aβ1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects