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All Medicines Are Poisons (in large enough doses)!
I hope that things would be so simple as just calculating IC50 and blood concentration and then passing a judgement on the therapeutic effect of the drug. Things happen in time, there is the liver, Brain Blood Barrier, intestines, stomach juices all contributing to the level of SIGMAR1 occupation. I do not know in detail what happens when SIGMAR1 is occupied by Anavex2-73. What is the the timing of the response. I do not know at what rate SIGMAR1 receptors are produced. In light of this sort of ignorance, demanding that 100% occupation of SIGMAR1 receptors by molecules of Anave2-73 for emerging therapetic effect is surprising.
Anavex2-73 is not simply an inhibitor of a single point in a pathway as is the case with Donezepil. SIGMAR1 agonist set in motion complexity way beyond the four operation of arithmetic. On my blog I presented number of papers describing hypotetical mechanisms of action for the SIGMAR1 agonists. When I studied biology in preparation for medical school, I had to make the discovery that pathways or cascades leading to some physiological mechanism had sometimes negative feedback loops. You overstimulate them, they shut down. Many cascades would be like conjoined twins, feeding into others. That is why there is always a considerable risk of serious side effect in drug development. You cure the disease but cause another,. Therapeutic effect might not be connected to occupancy as much as sensitivity and specificity. In some cases you want occupancy to be as large as 100% but in others cases this can lead to serious side effects.
The concept of homeostasis is experienced in its simplest form in the existence of balance between stimulating and inhibiting compounds. Example of that can be the homeostatic balance between GABA and Glutomate, both neurotrasmitters of opposing action. The complexity of these interdependencies can be seen in scientific papers. Hey, we inhibit (or otherwise increase or exite) something and let’s see how it will cascade into changes in a number of places, hopefully desirable.
For every 11 drugs in development only one gets approved. Had the process been without surprises and serendipity I guess four arithmetic operation would suffice. Complexity makes things impossible by arithmetic, at least in biology, possible. One of the most interesting scientific mysteries is the emergence of life and its thermodynamics which eludes the one taught in engineering schools for running power plants. The term homeostasis was invented to describe this thermodynamic impossibility, that is life. Had Mr Brodkin been talking about shutting production of a mutated toxic protein I would gladly agree to concure. Yet, this is a receptor setting in motion large number of processes improving cellular homeostasis. Could it possibly overstimulate the cells? This possibility exists.
Long time ago, Anavex2-73 was used to dose healthy volunteers so that maximum safe dose could be established. At certain level headaches and vomitting was induced. This was recognized as a sign that the drug crossed Brain Blood Barrier and was occuping the SIGMAR1 receptors. The later studies on mice confirmed this.
Let’s again review Mr Brokin’s numbers. So, I calculated that at the 6 nanog/milliLiter (the highest concentration in patient) is equivalent to 30milligrams. Let’s look at another fact, the highest concentration in a patient was almost double that i.e. 60 milligrams. These values correspont to highest level for some time and do not represent doses. These can be approximated or estimated by intergrating the concentration curve over time. The highest dose given to the patients is 50milligrams per kg. If you weight 70 kg you recieve 3,500 milligrams into your stomach. The the slide of corporate presentation I can see that occupancy is just about 70% for 30milligrams per kg. Anavex does not provide information for 50milligrams per kg. Is 70% occupancy sensitive enough to induce a therapeutic effect? We find our soon.
Mr Brodkin gave the occupancy range between 1/100 and 1/10. Unfortunately, his calculations do not agree with the experimental data as he made wrong assumptions about the dose delivered by confusing concentration with dose.
For a scientist it is hard to not understand the difference between peak concentration and the area under the curve of concentration over time that is the cumulative dose. I hope, Mr. Brodkin that you will update your tweet as soon as possible. This would benefit the investing public,thank you!
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