Replies to post #36803 on Anavex Life Sciences Corp (AVXL)

[tob999]

Well compiled and literally a work of literary art!

Anavex simply needs to expand the clinical trials to include greater numbers of patients with more stringent controls (blinding, etc…).

Bring on the next results n phases!

[OB_WEALTH_INC]

I AGREE with everything you wrote..i even double checked references. ALL OK!

PS. Even spell check was 99.9999% correct. I disagree with a position of couple "dots". Other than that..good job!

[twiz0019]

Wow, hooperg, just WOW...awesome post! Thanks for your insight!!!

[cjstocksup]

Now that is some great AVNX DD.

[MMMQA]

Awsome post!Thanks for the hard work and insight.

[jimmy667]

$AVXL This is our time. These are our people. God bless those that use one's intellect for the greater good.

[Diamondhands45]

Great Post. Thank you so much for all the work.

[Tony888]

Dr H,

Great article. Why don't you publish this in Seeking Alpha? It is very easy to get published there. Just follow the link below;
http://seekingalpha.com/page/become-a-seeking-alpha-contributor

[Dan_P]

Excellent

[orveko_inc]

Excellent write ups.

One possible correction: I think you mixed up ANAVEX 2-73 and ANAVEX 3-71 with regard to their muscarinic receptor affinities.

So, how does A2-73, which is an agonist of muscarinic (M1-2-3-4) receptors, namely M1—the most common muscarinic receptor in the brain, important in motor control, sleep-wake cycle regulation, memory, and attention—presume to do any better than Donepezil [10]? I can only speculate. Given that the M1 receptor is coupled to a 7-transmembrane G-protein, activating it directly must have more longevity downstream than simply making more acetylcholine available in the synaptic cleft, but the literature is quite clear that M1 activation alone has promise in the field of Alzheimer’s therapy. Coupled with the hypothesis in early A2-73 literature that suggests a possible synergistic effect with S1/M1 receptor agonism, and the possibilities, in my opinion, favorably expand [11].

In the above section, you cited a work by Dr. Abraham Fisher, the inventor of ANAVEX 3-71 (formerly AF710B). A3-71 is indeed an agonist of the M1 receptor, but A2-73 is more mixed. A2-73 does seem to be an agonist of M1 but it is an antagonist of M2 and M3 (unsure about M4). This antagonism of the M2 and M3 receptors is seemingly what makes it such a good match for donepezil.

This is from Dr. Alexandre Vamvakides (inventor of A2-73) in his original Greek patent application for what is now ANAVEX PLUS (A2-73 + donepezil):

Indeed, all these aminotetrahydrofurans are antagonists of the M2 and M3 muscarinic receptors which originate the cholinergic side effects of Rivastigmine, Galantamine and Donepezil.

More importantly, the increase of acetylcholine on presynaptic muscarinic M2 auto-receptors, induced by the IACEases (Rivastigmine, Galantamine or Donepezil) is deleterious for the cholinergic neurons and for all the neuronal systems modulated by the extrasynaptic M2 receptors (especially in AD and in ageing, where these M2 auto-receptors are hyper-activated by neurotoxins and soluble amyloids) and could be the most important factor explaining the absence of the therapeutic effects of these drugs on the evolution of AD and also their weak effects against the AD symptoms. Indeed the high concentrations of acetylcholine, induced by the IACEases Galantamine, Rivastigmine and Donepezil, hyper-stimulated the M2 auto-receptors which exerced high inhibition of the released acetylcholine and severe hypo-activity of the presynaptic cholinergic neurons therefore inducing, in a first phase, the diminution of the cholinergic effect on Ml and nicotinic receptors (insufficient symptomatic benefit) and, in a second phase, degeneration of hypoactive cholinergic neurons (absence of therapeutic effects on the evolution of AD and, possibly, even worsening)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014155138&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Basically, A2-73's agonism of sigma-1 and M1 receptors may work to alter the progression of AD, while its antagonism of the M2 and M3 receptors may work to improve the affects of donepezil on the symptoms of the disease.

[frrol]

Thank you for the explanations. Great to be co-investing with you.

[bigstocksnbonds]

Thank you So Much!! Excellent best post of all of them!! AVXL $$$$$$$$

[GuiNoir]

On the PBS Newshour a physician was speculating that Robin Williams had a rare form of dementia, Lowry's Body something. When you start seeing little fury animals, you might have it. Fortunately mice are not fury, except yak mice. Our Himilayan is very familiar with them

[pbar]

Wonderful post. Thank you.

[Jockimo]

Dr. H - what is your background, degree, experience in the field?

Thanks for sharing your thoughts on the science.

[Mikesc]

Great post...We need to tell the world.

Thanks Doc.