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What if....
What if Anavex buys a few cages of the new COVID-19 test mice and then (in a careful, proper study) tests both blarcamesine and Anavex 3-71 against the disease in the mice?
It's not a lengthy or difficult trial to run. Mice have short life spans; easy to study. Easy to have control and experimental treatment arms (populations), at various dosage regimens. A team of biology grad students could run the study in a few months.
Then, what would be the results of such a story: "Anavex Life Sciences Corp Finds Two Drugs That Stop COVID-19?"
New SARS-CoV-2 Mouse, for testing.
The breeding of ...a new mouse model of infection that may help facilitate testing of COVID-19 vaccines and therapeutics... was just announced.
https://eurekalert.org/pub_releases/2020-07/aaft-pas073020.php
Now, Anavex can dose these COVID-19-suffering mice with blarcamesine or Anavex 3-71, to see if there are any prophylactic or treatment efficacies.
Must always start with an animal model. It's now available.
Kodachrome Chemistry....
ER Stress (Dysfunction) a Major COVID-19 Factor
Someone posted earlier this new Anavex PDF:
https://hub.bio.org/system/files/2020-04/AV2-73%20Sigma-1%20Receptor%20COVID-19%20April%202020.pdf
I could not find it on the Anavex corporate website; the note "confidential 2020" appears in the lower right corner of the title page. What that means or signifies is unknown to me.
From the title, the question instantly arises, could blarcamesine be a prophylactic or therapy for COVID-19? The title of the website, Modulation with ANAVEX®2-73 as Potential Therapy for COVID-19, states the matter clearly.
How might this be so? How could the Anavex sigma-1 receptor agonist (Anavex 2-73, AKA blarcamesine) actually be a COVID-19 therapy? What would be its biochemical mechanism(s)?
It is now well understood that blarcamesine activates or restores the proper functions of the sigma-1 receptor protein. With that (among other things), mitochondrial and endoplasmic reticular functions are restored or supported. Below, for those who wish to read the papers closely, are the titles and URLs of six papers noted in the Anavex PDF.
(I read the abstracts.)
Coronavirus infection, ER stress, apoptosis and innate immunity
https://www.frontiersin.org/articles/10.3389/fmicb.2014.00296/full
The Endoplasmic Reticulum Stress Sensor IRE1a Protects Cells from Apoptosis Induced by the Coronavirus Infectious Bronchitis Virus
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248946/
Regulation of the ER Stress Response by the Ion Channel Activity of the Infectious Bronchitis Coronavirus Envelope Protein Modulates Virion Release, Apoptosis, Viral Fitness, and Pathogenesis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992538/
Modulation of the Unfolded Protein Response by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1563899/
Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Regulates Cell Stress Response and Apoptosis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197621/
The expanding roles of endoplasmic reticulum stress in virus replication and pathogenesis
https://pubmed.ncbi.nlm.nih.gov/25168431/
Most important is this. A central factor in these papers is the dysfunction of the endoplasmic reticulum (ER), ER stress, in viral infections. Normally, supported by contact of the associated mitochondrion, the ER properly folds proteins (including enzymes), which then go on to catalyze virtually all of the cellular reactions in the cell. Disrupt ER function (by a virus, for example) and all sorts of pathologies ensue (the case in cells infected with the SARs-CoV-2 virus, the cause of COVID-19 disease).
Ok, then, is it reasonable to hypothesize that blarcamesine might properly activate sigma-1 receptor proteins, which in turn would allow both mitochondria and endoplasmic reticula to function normally; obviating COVID-19?
Consider this. Children, by and large, are virtually immune to lethal cases of COVID-19. Most kids apparently never even develop COVID-19 symptoms. They may have the disease asymptomatically for short, uneventful periods. But at the other end, people in their 60s, 70s, and 80s are at rather significant risk of dying from COVID-19.
Could this be the involved age-related factor? Kids have fully functioning sigma-1 receptors, mitochondria, and endoplasmic reticula. Proteins are properly and effectively folded into a host of functioning enzymes, against which the SARS-CoV-2 virus then cannot replicate. But not the case in the elderly. By then, certain cellular mechanisms have begun to wear out or weaken. The sigma-1 receptor/mitochondria/endoplasmic reticulum mechanism has weakened with age. Proteins are not properly or sufficiently folded into functioning enzymes. Viral replication can prevail, and tissues become inflamed (particularly pulmonary tissues). Death ensues.
If this is so, it is very plausible that early (or even late?) administration of blarcamesine would restore the homeostatic processes of the mitochondria and endoplasmic reticula. As in the case of children with normally functioning, youthful cells, viral infection or replication would be terminated. The elderly patient lives. For most, COVID-19 is then no longer a lethal threat.
Very reasonable and plausible.
Pulmonary Inflammation Is Cause of Most COVID-19 Deaths
Again, the future veterinary factor.
Animal Models for Blarcamesine Against COVID-19
Speculation regarding blarcamesine (Anavex 2-73) in its function as a sigma-1 receptor agonist to moderate or prevent the severe, even lethal outcomes of a SARS-CoV-2 infection (the COVID-19 disease) must be resolved first in animals that can harbor the disease.
Sure, it would be wonderful to just give to patients suffering from COVID-19 doses of blarcamesine. See what happens.
Of course, that's not how testing of drugs is allowed. First, always, is safety. Do no harm. So, first dose animals, usually murines (lab rats and mice). Check for harm. Adust doses to minimize harm.
Then, dose transgenic rats or mice that have had inserted into their genomes the genes that cause susceptibility to a SARS-CoV2 infection, resulting in the COVID-19 disease. With such animals in hand, dose 'em with both with the SARS-CoV-2 virus and blarcamesine and see if lethal cytokine storms can be prevented or moderated. Do the little rodents with COVID-19 survive better with blarcamesine?
If so, would the discovery and posting of this positive outcome be of much significance? Let the reader discern.
Apparently (as of March; probably much further along now), transgenic mice with genes for COVID-19 susceptibility are being grown.
Rhesus macaques, real primates, are also being bred for use as COVID-19 drug test animals.
https://www.nature.com/articles/d41586-020-00698-x
Time and again, I've claimed that Anavex Life Sciences Corp has almost surely, but very privately, undertaken a wide diversity of murine studies with their sigma-1 receptor agonists against a host of human pathologies resident in transgenic rats and mice. Such testing takes tens of thousands of dollars, not the millions for testing in humans.
Would Anavex allow the posting of this new slide show, implicating a possible blarcamesine efficacy against the SARS-CoV2 virus (COVID-19 disease) without at least some evidence of efficacy in model murines?
https://hub.bio.org/system/files/2020-04/AV2-73%20Sigma-1%20Receptor%20COVID-19%20April%202020.pdf
We'll be watching (as will the stock market).
Later, no chickens.
Especially if they lay golden eggs.
But for only parts of the year....
D-3
My Hope.
The Will There Be Enough Question
The How Long Question
Magic not at play.
Anavex drugs for multiple CNS diseases.
I have a mild case of hereditary spastic paraplegia (HSP), caused by one of >200 genes that are presently known to bring on the symptoms of HSP. It is a very rare central nervous system (CNS) disease. As in my case, symptoms are usually absent until their onset in middle age, or later. Before my early 60s, I could walk and run with normal, expected facility. Today (I'm 72), my legs are, typically, spastic (leg adductor muscles continually tense). The spasticity also disrupted normal bladder functions; so, through a created stoma I must use an indwelling suprapubic catheter.
This morning, I closely followed a live webinar of HSP researchers, telling in some detail new understandings of the complicated genetics and pathologies of the many forms of the disease, and most importantly, new understandings of the various pathological mechanisms causing the symptoms. I won't deliberate on any of that here, except for the following; which is very significant, I believe.
As it happens, the root causes, the upstream mechanisms that cause HSP symptoms, as one presenter clearly pointed out, rather closely parallel or are found in a variety of CNS diseases. (Here it is, the Anavex connection.) Can you believe? It's mitochondrial dysfunction.
Mitochondrial dysfunction is known to be involved, at least to some degree (in most cases, to a significant or exactly-causing degree) in amytrophic lateral sclerosis (ALS, 'Lou Gehrig's Disease'), Parkinson's disease, Alzheimer's disease, HSP, frontotemporal dementia (FTP), and forms of multiple sclerosis (among others).
For Anavex (and me), here's what I find applicable. In the majority of cases with people having these CNS diseases, they were not entirely, or in any way debilitated in their younger years. With rare exceptions, this is the known case with ALS, Parkinson's, Alzheimer's, my HSP, and other CNS diseases. Debilitating symptoms appear later in life. Earlier, the CNS worked normally.
This is extremely significant. Ponder (and explain) this. For some time, at least during youth, these CNS diseases yield no symptoms in the first part of life. Nerves function rather well. The aberrant genetics that cause the CNS disease may be present, but don't get expressed until later in life — perhaps when mitochondria begin to malfunction. With that, the pathogenic mechanisms of the disease genes get expressed.
What, then, if either blarcamesine or Anavex 3-71 would be administered before, or at the exact appearance of the symptoms of any of these CNS diseases? Very clearly, it is known that activation of the sigma-1 receptor protein enhances or restores both mitochondrial and downstream cellular functions. With that, might either of the Anavex drugs be broad-spectrum CNS disease therapies; either alone, or with complementary adjunct drugs?
Already, Anavex is conducting clinical trials on Parkinson's and Alzheimer's. New trials involving Anavex 3-71 against frontotemporal dementia (FTD) were recently announced.
http://www.anavex.com/anavex-life-sciences-announces-initiation-of-first-in-human-phase-1-study-of-anavex3-71-af710b/
As a biologist, I am adequately conversant in the involved deep molecular biology. It's all too complicated to lay out here; and wouldn't be comprehended by most readers; so I won't further elaborate on the topic. But what I heard the HSP researchers explaining about their new findings in HSP and its closely-related CNS diseases made clear the rather central involvement of mitochondrial dysfunction in all of the mentioned diseases.
Simply, if the Anavex sigma-1 receptor agonists can return diseased neurons back to earlier, more normalized youthful stages of function, various CNS diseases cannot produce their pathological symptoms. The Anavex drugs: yielding neuron youth restoration; preventing CNS disease symptoms before they can appear.
Reasons to buy or sell AVXL shares.
I have a moderate AVXL position (a few thousand shares) purchased incrementally in the last five years (mostly four and five years ago). I read and consider closely almost all of the messages posted on this board.
I ponder the reasons people have purchased or sold Anavex shares. In most cases, they differ widely from the reasons I took and hold my AVXL position. Let me see if I can categorize the various reasons people or parties buy AVXL shares.
But first, there are two major ownership categories, are there not?
A. Institutional Investors. This is a broad category, is it not, ranging from mutual funds to hedge funds? And, the individual reasons for buying some AVXLs includes all of the categories enumerated below.
B. Retail Investors. These would be individuals, taking personally-owned AVXL positions.
Ok, then, how are the AVXL positions played or viewed? What are the various stock investment perspectives of owners of AVXL shares, both institutional and retail?
1. Long-term Buy and Hold Investors. These people (of which I'm one) understand that Anavex Life Sciences Corp is a new, start-up pharmaceutical, with potentially phenomenal new and novel drug therapies for a number of central nervous system (and other) diseases. It is recognized that until Anavex gains authority to commercially sell at least one of their new drugs, the AVXL share price will wonder, never attaining any price approaching anything of significance. Morever, there is the possibility, however remote, that all clinical trials fail and the company goes bust. But the science is strong and the likelihood of clinical success is high. The long wait, then, will be richly rewarding. Buy and hold investors think in decadal, not quarterly or yearly time frames. Rewards will be in eventual strong dividends and share values.
Most such investors have intelligently not bet the ranch on their AVXL positions. They may be lost. But with any sort of clinical success, they will be richly rewarded. If that takes a few more years, so be it. Patience is a virtual for this investment perspective.
2. Fear-of-Missing-Out (FOMO) Momentum Players. In this case, it is noted that from time to time the AVXL share price steeply ascends. FOMO players want to get in quick and early, then liquidate at a high price, thereby taking rewarding profits. FOMO players may not be much different from Day Traders, No. 3.
3. Day Traders. Simply, try to discern price variations during typical days. Buy low and sell slightly higher. Do this with consistent success and considerable accumulated gains can be reaped.
4. Technical Analysis (TA) Traders. In this case, learn to plot and discern share price trends over various time periods. "Charting" is another name for this stock investment perspective. Pay little attention to stock fundamentals. Stay focused on what the various share price and volume charts reveal.
Whatever one's AVXL investment perspective might be, I wish the best for all. My thanks for posters who have explained each of these perspectives for Anavex Life Sciences Corp equities.
Antibiotics, including fluoroquinolones, damage mitochondria.
If <40ng/ml vitamin D, you are deficient.
Single drug; multiple therapies for multiple diseases.
End of 2023
So, with PD, too, early treatment is required.
The authors of the paper make this claim, "These data suggest that a pharmacological stimulation of Sig-1R could be useful to slow down the progression of PD only when started in the early stages of the disease."
Again with Parkinson's, as probably with Alzheimer's, the Anavex sigma-1 receptor agonists most likely will function best as prophylactics; drugs that prevent the onset of disease symptoms, or prevent their progression at early disease stages.
Retroactive treatments, after either Parkinson's or Alzheimer's are fully developed, may not be fully provide disease-state reversal. Too little, too late.
But, eventually Anavex 3-71.
Yes, concentrations of ingested blarcamesine (Anavex 2-73) apparently do not strictly comport in all cases with serum or intracellular concentrations. Taking 50 mg apparently can result in rather variable serum or cytosol concentrations between individuals. Effective dosing for individual patients may require some titration (dosage adjustments resulting from tested serum concentrations or therapeutic results).
Regardless, the Anavex end-game for Alzheimer's may well be Anavex 3-71. From murine and in vitro data it appears to offer far greater efficacies, but at much lower concentrations; perhaps by an order of magnitude or more. Let's see if therapeutic outcomes are more consistent and more universally controlled by specific dosages of that powerful drug.
This is a crucial question.
After debilitating accumulations of waste proteins (amyloids and tau tangles) have disabled neurons for lengthy periods, when Alzheimer's pathologies are fully present (dementia, etc.), could blarcamesine facilitate or cause the clearance of these proteins, and thereby restore normalized neuron functions?
Perhaps. But probably not, inasmuch as blarcamesine does not directly react with or connect or clear waste proteins.
The key test would be this. Provide two critical measures in blarcamesine therapy for Alzheimer's.
First, yet to be precisely determined, administer an adequate dose of the drug. Without enough of it (inside neurons), there is no way it could work.
But equally important would be the early administration of the drug; BEFORE the waste proteins that cause Alzheimer's symptoms have begun to profusely accumulate; before they essentially crystalize or otherwise agglutinate in neurons and nerves. With early, first-indication dosing, the drug's ability to restore normalized waste-clearing neuron chemistries can be effective. The amyloid and tau wastes are cleared before they further accumulate --- exactly as in the case of people who don't yet have any Alzheimer's symptoms. Protein wastes are generated in all neurons, at all ages. Properly functioning neurons have chemical mechanisms to clear those wastes before they accumulate. By its activation of the sigma-1 receptor, blarcamesine can facilitate all of the normal, downstream chemical pathways that normally clear protein wastes.
This slides blarcamesine into the category of an Alzheimer's prophylactic; a drug that prevents the untoward development or progression of the disease.
The applicable phrase? Enough, early on!
Are these two factors being effectively implemented in any Alzheimer's/blarcamesine trial? Until they are, the determinative answers to blarcamesine efficacies against Alzheimer's will not be known.
Exactly.
Well, great!
Hope the mothers can keep quiet.
Good to see that the first girl with Rett syndrome is now enrolled in the new study; will soon be taking a daily dose of blarcamesine.
Crucial to such studies is the absolute hiding of any therapeutic results until the study is completed, the all-party blindedness. Nobody, doctors, nurses, parents, relatives, or patients themselves, are to know or reveal any sort of therapeutic outcomes. If any are detected by anyone before official results are released, they are to be kept secret, unrevealed to anyone. Share with no one any observations or perceptions of trial participant behaviors, good, bad, or indifferent.
Little girls with Rett syndrome display a number of quite obvious debilities. It's good to know that to preserve the integrity and validity of this new clinical trial mothers and friends of the affected girls will be particularly attentive in not sharing a whisper of anything they see during the trial.
(???)
But, that's body temp in the stomach.
Yes, but not a competitor.
Please, tell.
A million shares traded.
For whatever it's worth, my Schwab account screen posted the 1 million share breakthrough today at 3:30:05, showing a trade total for the day at that time of 1,003,055, at a trade price $4.2699.
With 58,660,000 AVXL share outstanding (in trade), the traded 1,003,055 shares was 1.71% of the outstanding shares.
Of any significance? Not to me, inasmuch as technical analysis makes no sense to me. Not my thing (which doesn't in any way mean it doesn't have it's applications).
The interesting thing is that this is first time daily trades have broken a million, in some good number of weeks. March?
So, more shares have been purchased, at higher than recent prices. Let's see if this one-day trend continues in the coming days.
Nope, not a word shared.
What will the New York Times report?
For the AVXL share price, after any sort of clinical results are reported, the major factor controlling it will be how those results get headlined in major news outlets. Which might be a likely headline?"
New Drug Shows Success Against a CNS Disease
Or,
New Drug Shows No Promise
I Said Nothing
My dear father suffered, then died from Alzheimer's. My mother, an accomplished geriatric-practice nurse, saw and detected the onset before any of us.
Because she was a practicing nurse dealing with older patients with Alzheimer's at her facility, she learned that some new drug was to be tested there in an FDA Phase 3 clinical trial. Early on, she got my dad enrolled, and she monitored his progress until the day he died, a number of years later.
During the course of the clinical trial, over several years, with dozens of behavioral and physiological monitoring tests, my mother and I closely observed Dad. No doubt, he had Alzheimer's; a valid test subject for the clinical trial.
Well, then, how did the drug work for Dad? I'm a biologist, therefore I understand that clinical results, especially of particular individuals should never be revealed. Trial blindedness, both ethically and biologically, must be maintained. Therefore, I will not reveal whether or not my mother and I rather accurately determined if Dad was in the placebo arm, and/or the test arm, and what his outcomes were (other than death).
(But secretly, we knew rather early whether or not Dad was getting a placebo, or if he had the real deal and was getting any benefit or not. Secrets will never be revealed. Normal humans don't share such thoughts and information with anyone else. And, at the edge of the world, gravity disappears, so the oceans don't drain off.)
But, the MOAs?
Hope this is acceptable:
The superiority of Anavex against the other Alzheimer's treatments needs to be understood.
Ok, a new candidate drug is going to solve the Alzheimer’s problem, not by focusing on amyloid plaques or tau tangles, but by, somehow, improving the function of synapses (contact points between neurons).
Parties “are backing a drug — NDX-1017 — that bypasses the whole toxic plaque debate and focuses on another familiar strategy: the frayed synaptic network in the brain that erodes with the disease. Boost the network and you can stop, possibly reverse, the damage that corrodes cognition. For awhile.”
Well and good — if positive results appear with this new drug. But since the drug in no way addresses root causes of Alzheimer’s, which is the pathogenic non-clearance of wastes in neurons and nerves (the amyloid and tau proteins) those will continue to accumulate.
Understand, all sorts of potentially toxic wastes are continually produced by living cells, tissues, and organisms. Think not? Then don’t use a toilet for 24 hours; see how that works out.
This is where the mechanisms of action (MOA) of the Anavex sigma-1 receptor agonists separate themselves from all the other Alzheimer’s treatment approaches. Each of them (there are but a few), as with this new proposed drug, try to reduce only symptoms. For a period, this, to a degree, can happen. But sooner or later (usually sooner) the biochemical mechanisms of symptomatic suppression are overwhelmed. Fatal.
The real problem is the inability of neurons and nerves with Alzheimer’s to efficiently clear the biochemical wastes, before they can pathogenically accumulate. Here’s an analogy.
Your furnace, in winter, produces toxic waste gases, including carbon dioxide and carbon monoxide. Your furnace, normally and properly, voids these wastes out of the chimney. Well and good.
But how do you “treat” your furnace if a carbon monoxide sensor in your hallway goes off? “Whoa, something’s wrong.” Carbon monoxide is both odorless and fatal (in high concentrations). So, you turn off your furnace, and call the HVAC contractor to fix the problem.
But you could have dealt with it like the current Alzheimer’s drugs do. Treat the symptoms, not the causes of them. Very simple. Just open the windows to allow enough fresh air into the room so as to sufficiently dilute the carbon monoxide. That would work, would it not? Well, until it got really cold.
The solution to both problems, Alzheimer’s and a furnace leaking carbon monoxide into the heating airstreams of a house, is to fix the root cause. In the case of the furnace, find the corroded gap in the fire chamber, and replace it with a new one (or, an entire new furnace). Problem solved.
In the case of Alzheimer’s, biochemically arrange for the restoration of the normalized clearance of wastes. With that, Alzheimer’s is impossible. No pathological accumulation of wastes; neither beta-amyloids or tau tangles. Nerves function normally.
How, then, is this arranged? But ingesting (orally) small amounts of blarcamesine, AKA Anavex 2-73. By its activation of the sigma-1 receptor protein (among other things) this proprietary molecule allows the cell to resume normalized function. “Homeostasis” (feedback-controlled cell processes) is restored. Wastes cannot accumulate. Before they do, their increasing concentration is detected by the cell which, then, turns on increased waste-clearance processes (the cell uses the toilet frequently, as it were).
Essential to all homeostatic processes (and many others) in the cell (especially with age) is the proper folding of proteins into fully functioning enzymes. Blarcamesine causes this. With that, wastes can be enzymatically rendered and compartmentalized into waste-clearing structures before they are pathogenic. Problem solved.
Anavex solves the Alzheimer’s problem at the top, at the start of the cascade of processes that result in the disease. All of the other treatment approaches deal, ever so inadequately or briefly, with only “downstream” factors. The problems continue.
Anavex is way better.
I'm done. No further postings. Enough.
I use the Vitacost quercetin, the version which includes bromelain, which enhances absorption.
Very good. A real study with zinc.
Thank you for finding this study, on the other side of the world. It's just getting underway, in Tunesia, at the Military Hospital of Tunis.
Those Tunesian military physicians seem to be way out in front of American researchers on the (presently) putative value of zinc as an essential co-factor with hydroxychloroquine as an effective treatment or prevention of COVID-19.
The study ends at the end of July, this year. In August, let's see what they find.
If the results are negative, showing that zinc wasn't effective, how the study will be reported here is very clear. "New study proves zinc is not useful, just as American experts said from the beginning."
On the other hand, ponder the possible comments by American experts if the study does show zinc efficacy; particularly in reference to all of the previous warnings about about hydroxychloroquine and zinc.
The sociology of the topic wil be interesting, even revealing; however it turns out.
But inasmuch as hydroxychloroquine is not likely a zinc ionophore as strong as quercetin, I'll still keep in mind my intention to fund a similar study involving quercetin and zinc (after or if my moderate AVXL position becomes valued at several million).
Good news. Thanks.