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But, as we saw with Avandia and as we see with all the “likely”s and “maybe”s that come with the manipulation of molecular pathways in the body, this is a risky endeavor. Harno and White propose some potential ways to reduce the risk of upregulating the adrenal gland– using tissue-specific 11β-HSD1 inhibitors, for example, to focus on tissues that are shown to have less of an effect on the feedback loop up to the adrenal gland; or reducing cortisol levels only during certain times of the day, at advantageous places within the natural circadian rhythm– but they also point out that more study of the cortisol pathway is needed, especially in long-term clinical trials on human patients. It seems clear to me, too, that variation in patient responses should be analyzed in terms of genetic profiles, given the differing responses in genetically disparate mouse models.