As promised I’d like to address the scientific issues you raised in your post.
My original post made the points that:
1. There are many animal models of AD and those models are often used to assess many different compounds. There are a number of compounds in clinical use that have been assessed in animal models and it would be useful to assess their performance relative to 2-73 when there is overlap. I encouraged all to seek out these situations. The implication being that if the models are valid it would give some indication of relative clinical performance which is far more valuable/weighty than just showing an effect.
2. The Goguadze article I cited does what is noted in #1. It looks at 2-73 relative to a number of other S1R agonists in a number of models relevant to oxidative stress. What it showed is that S1R agonists do have a number of beneficial effects vs. oxidative stress. What it also showed was that the performance of 2-73 for these measures was certainly no better than and typically worse than for the other S1R agonists including DZP. As I noted in a prior post, my description was “underperform”. For some aspects the Goguadze article authors noted 2-73 as “ineffective” or “not effective” and those are the only times I also used those terms.
Sokol states: “This study OFP cited actually concludes that AVXL 2-73 is neuroprotective…OFP cited part of this study…to argue that AVXL 2-73 is ineffective in treating AD disease.” Also later in your post you note where the Goguadze authors state “These data confirmed the direct mitochondria protective effect of s1R agonists. “
First, the authors were not specific about identifiying 2-73 as neuroprotective for data related to this study but instead made a general statement that S1R agonists are protective which I recognized IN MY ORIGINAL POST by “Thus, in a generic sense S1R agonism helps”. What you are missing is that in the data that leads to the statement regarding a S1R agonist benefit is that 2-73 underperforms. If you are looking for a reasons to say 2-73 can do something that other S1R agonists cannot (and I know you are) then you are not finding them in this study.
Sokol states: “Apparently, the authors of the above study, Tangui Maurice Included, observed that some agonists like donepezil increase beneficial and non-beneficial oxidative stress. However, AVXL 2-73 may not increase the non-beneficial type of stress. The way I, and maybe others…understand it, some degree of physiological oxidative stress is beneficial and other oxidative stress such as pathological oxidative stress is not.”
There is a model showing that most S1R agonists promote physiologic oxidative stress (which Sokol refers to as “beneficial”) and this was discussed in my original post. 2-73 was ineffective in that setting and while it’s not encouraging that 2-73 was inactive I also noted in my original post that it is “not the end of the world”. It is not the end of the world because we’d expect combating pathologic oxidative stress to be more important. Unfortunately, 2-73 underperforms in the pathologic models as well.
Sokol states: “As Lane Simonian has pointed out in the comments section of his SA article”… The Seeking Alpha author has an extraordinarily confused response. He cites Phase 2a data which represents an entirely different misunderstanding of indication for 2-73 efficacy but is utterly unrelated to the article discussed. He then goes on to restate that the article discusses physiologic and pathophysiologic oxidative phenomenon with absent elucidation or relevance. Then he goes on to state “…sigma 1 agonists such as Aricept only slow the further production of oxidants; they do not scavenge or reverse the damage done by oxidants. Korean red ginseng, various herbs in conjunction with conventional therapy, and Anavex 2-73 may limit the production of oxidants, scavenge oxidants, and reverse part of their damage”.
Thus, in the face of evidence that 2-73 underperforms in this setting he introduces the idea that 2-73 “may limit production of oxidants, scavenge oxidants” which the study under consideration offers contrary evidence or may “reverse their damage” a highly dubious statement for which he offers no evidence. His scattered references to KRG and herbs are very frustrating and utterly irrelevant. He does not really have "another way to look at it" he's just answering with contradiction, hope, and distraction.
Sokol states: “Again, as the title of the above OFP cited article indicates ”Sigma-1 Receptor Agonists Induce Oxidative Stress in Mitochondria and EnhanceComplexIActivityinPhysiological Condition but Protect Against Pathological Oxidative Stress”, sigma-1 receptor agonists -- especially AVXL 2-73, which may provide the right kind and degree of stress to help contribute to restoration of mitochondrial physiology that ignites the spark so to speak.”
Well, 2-73 does not provide the physiologic inducement as you’d hope and underperforms in reducing the pathologic…as discussed above.
So how does 2-73 compare to other S1R agonists in promoting homeostasis in the realm of oxidative function and pathophysiology? We’d like to see it promote mitochondrial activity when needed “beneficial” oxidation and we’d like to see it reduce pathologic oxidative stress when needed. The Goguadze study suggests it fails in the former and underperforms in the latter. For this area, this suggests other S1R agonists are better homeostats.
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