From falconer66a on IHUB, Fletch falconer66a

From falconer66a on IHUB,
Fletch


falconer66a Thursday, March 5, 2020 10:52:23 AM
Re: McMagyar post# 239885 Post # of 239912
"How important to Blarcamesine’s effectiveness IS it’s S1r metabolite?"

Well, to answer that would require a year’s work of intense lab work with murine and human cells, etc. — conducted by a team of qualified experts.

Personally, I have no good idea just how blarcamesine and its metabolites specifically work their favorable cell health outcomes. It’s biochemistry and cellular physiology beyond my comprehension.

But as an accomplished biology instructor (advanced placement biology, retired) I understand the essential elements of how blarcamesine works its apparent magic — in great contrast with a host of other therapeutic molecules treating a multitude of diseases and conditions. Most drugs used to treat nerve-centered diseases treat the symptoms of those diseases, not the diseases themselves. Something’s wrong, genetically or chemically, in the nerve cells. Bad things then happen, so the drug aims to turn off the bad outcomes, the symptoms. This can be done by a variety of mechanisms; would take a textbook chapter or two to just touch on them.

But this is where blarcamesine (Anavex 2-73) is SO different. Most drugs aren’t even allowed inside nerve cells (neurons). The nervous system has the almost impenetrable blood-brain barrier. With this physical and chemical mechanism, only allowed chemicals are permitted to pass into the neuron proper. Neurons expend a lot of energy moderating and controlling this.

Blarcamesine, however, rather freely crosses the blood-brain barrier. It readily gets inside neurons (and other cells) where it can attach to the sigma-1 receptor protein. And that’s where things start to so favorably happen. In short, this small Anavex molecule (to use the company’s term) “activates” the sigma-1 receptor protein. With that, all sorts of “downstream” biochemical reactions favorably occur. “Homeostasis” is restored.

It would take another chapter’s text (well, more properly an entire textbook itself) to fully describe all of the status detection and feedback loops involved in cellular homeostasis; particularly those in neurons.

But this comes to mind. I’ve never explained blarcamesine’s unique efficacies this way. (Pretty good, if I say so myself.)

A house has a homeostatic mechanism, whereby in the winter the temperature is maintained at the setting on the thermostat on the wall. When it gets below that setting, the thermostat turns on the furnace; the house warms up. When warm enough, the thermostat turns off the furnace. That’s thermostatic homeostasis.

Now here’s how most nerve-acting drugs would work, in this case with the thermostat/furnace interaction. Something goes wrong. The thermostat fails to detect elevated room temperatures. It fails to send a turn-off signal to the furnace. The room and house get way too hot. The house has a disease; hyperthermia.

Here’s how most drugs would work. They would then try to turn on the air conditioner. The furnace anomalously pours out too much heat. The air conditioner gets turned on to HIGH and the room is cooled back to normal. All is well then, right?

Yes, until the air conditioner or furnace fails; or until the homeowner sees the fuel bills to run both of these appliances at the same time.

The air conditioner “treatment” treated the symptom, too much heat from the heat ducts. It didn’t turn off the furnace. It remained “diseased.” The dysfunctional furnace/thermometer feedback loop, the temperature homeostasis, was never repaired.

But here’s how the blarcamesine model would have worked. It would have gone right inside the thermostat and blew out the dust contaminating the contacts in there. All of a sudden, it worked again; when it got warm enough in the house, it turned off the furnace. Blarcamesine restored normalized thermostatic homeostasis. This is the Anavex Big Deal. It fixes things at the start of the problem; not ‘downstream.’

Ok, then, what about blarcamesine “metabolites?” First, what is a metabolite? Inside a cell, there are thousands of chemicals eager and able to react; often to digest waste or invasive molecules; to get rid of them. They get “metabolized,” chemically processed, making them easier to be expelled as the wastes most of them are.

In the case of blarcamesine, after it’s been worked over by the waste-processing and waste-clearing chemicals in the cell, it takes on new configurations, molecular architectures. And, the Big Thing, these metabolites are also bioactive, able to modulate, activate, or promote other homeostatic processes in the cell — many of which, until fixed by the created metabolites, are pathogenic, disease-causing.

Blarcamesine works to activate the sigma-1 receptor protein. With that, the dysfunctional (diseased) cell can once again properly fold proteins into reaction-controlling enzymes. With those, cellular chemistry is restored; the cell is no longer diseased.

But metabolites of blarcamesine are able to facilitate other homeostatic restorations. Just how? I don’t know. That ignorance (on anyone’s part) is not important. The only important things are the positive outcomes rendered by blarcamesine metabolites — the topic of intense murine research by Anavex, I’m certain.

Understand, the exact chemistry of a drug’s mechanism of action (MOA) does not have to be known to gain regulatory approval for sale and clinical use. Three things have to be demonstrated: 1) the drug is efficacious; provides desired treatment outcomes, 2) the drug is safe; side effects are not severe, and 3) the drug matches or exceeds existing standard of care (SOC) drugs or treatments.

For what will prove to be an ever-expanding list of human diseases and conditions, the Anavex sigma-1 receptor agonists will provide innovative, effective treatments — by the Anavex drugs themselves, or their metabolites.


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