11βHSD1 inhibitor use in human disease- a systematic review and narrative synthesis, page-9

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09/05/20

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Post #: 44523343
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Originally posted by krispi: ↑

Okay I'm surprised you guys have so much confidence in the mechanism of action because from my search of the literature, chronically raised cortisol isn't 100% confirmed to cause cognitive decline of the Alzheimer's type. However, if you can link me some papers or evidence that suggests otherwise I'd be interested to take a look

Most of the human evidence linking high serum or CSF cortisol to Alzheimer's is only correlative in nature, and not causative. On the other hand animal evidence suggests 11BHSD1 inhibition might help or reverse cognitive changes in animal models, but the challenge really is whether or not it can be replicated in people, which hasn't been done yet conclusively.

Another point that I'm not sure has been fully explored is why Xanadu failed at 10 mg. If markers of cortisol inhibition were increased by a good 20-40% (androstenedione, ACTH), then why didn't we observe any changes in cognition? Ketelbey would like you to believe that it's the dosage, but if the lower dose produced these dramatic alterations in cortisol regulation, why didn't we see an effect in cognition? In XanaHES we saw changes from as early as 4 weeks, but why is it that with significant pharmacodynamic effects we didn't observe a single statistically significant parameter in Xanadu?

It's easy when your money is on the line to only see the positive sides of a complicated issue - it's human nature. But it's dangerous to think in absolutes, to see things the way that you would like rather than what is actually there.

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I agree that Dr Ketelbey is always careful to say "associated with", not "causes".

I don't think it's productive to speculate precisely why a once daily low dose of a drug with a known half life of 10-14 hours failed to significantly improve cognition over placebo. Maybe the low dose and wrong frequency couldn't beat the powerful placebo? Better to just move on, as ACW is doing.

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11βHSD1 inhibitor use in human disease- a systematic review and narrative synthesis, page-9

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11βHSD1 inhibitor use in human disease- a systematic review and narrative synthesis, page-9

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