The Winning Combination for ANAVEX 2-73 and is it all about inflammation?

Sorry, I hasn’t been in condition to write anything but I think I am back at least for some time. Beside, I have tendency to miss certain things and home on others with the grace of single-minded heat seeking missile as I have explained myself before with all my problems.  I have just finished reading the transcripts from the Q2 2018 Conference Call.   There was a part which gave me the impression that my approach with slicing and dicing the ANAVEX 2-73 data was corroborated.  Namely, mention of the combination of  SIGMAR1 variant, COMT variant, above 20 MMSE and High Concentration of ANAVEX 2-73.  They were never put explicitly together in one paragraph and this is the killer application for Alzheimer suffers, at least at this moment.  In the High Concentration Cohort about 50% were responders, and other 50% declined faster rate than average so the only conclusion can be reached about this group is that there was something innate what made them decline faster.  Actually, we don’t know much about this group at all save that the five patients did not behave like average set of patients. But do we have a reason to expect it?  So my previous reasoning might be faulty. It leads nowhere.

The reasoning for SIGMAR1 seems straightforward as it is first object to be affected in a cascade triggered by ANAVEX 2-73.  COMT variants have something to do, at least as cognition is involved, with trade-off between attention and ability to perform under stress.  In some references there are hints of connections between mental stress and inflammation of CNS.

Beyond the existence of the plaque theory the most encompassing is the inflammation theory.  All other therapy targets look at isolated links in the chains of cause and effect, at least that is what it seems to me (lol).

Returning to inflammation, I looked at description of murine model of Alzheimer used by AVXL. it is called 3xTg. Its description can be found on ALZFORUM. Reference

3xTg Murine Model of AD.png

It seems to me that the cognitive impairment starts at 4 months but the Aβ plaque appears at 6 months earliest.  Would that genetic model engender inflammation which would later lead to Alzheimer?

I had received  communication from AVXL IR on the mouse model with plots for two opposing sexes of mice.  If I correctly remember the therapeutic effect was more pronounced in female mice.  ANAVEX 2-73 “cured” 3xTg mouse from the cognitive impairment placed on them by the model.  It seems that women are more prone to suffer from autoimmune diseases than men (immune reaction – inflammation to one’s own body).  Reference1   What differentiate men’s and women’s immune systems is the pregnancy where women’s bodies have to “accommodate” in their system a “foreign body”.   The paper I am going to reference here points to chronic neuroimflammation,  taking place in CNS with certain genetic markers, which leads to all those the bells and whistles of fully fledged Alzheimer disease.  Possibilities here are endless (exaggeration), but is the action of ANAVEX 2-73 alleviating the damage done by chronic inflammation or it abates inflammation itself? It could do both at the same time.   Reference2

In Reference3 when considering the natural agonist for SIGMAR1 progesterone was named as the most likely.  This hormone is related to preparation for pregnancy.

 

I can’t do detailed analysis on both grounds; I know only buzzwords and mentally I lack of the attention needed to do detailed study.

 

 

 

 

 

 

 

 

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