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Posted On: 02/25/2021 3:26:13 PM
Post# of 148902
I can't find anywhere in Dr. Yang's paper where he measures the concentration of leronlimab in his patients, let alone offers any commentary on efficacy vs. blood concentratoin.
The only reference in Dr. Yangs paper as to 45ug/mL that I could find is the following:
"Binding of leronlimab to CCR5 on cells not only blocks HIV-1 entry, but also prevents CCL5-mediated calcium flux with an IC50 of about 45 μg/mL [8] and is therefore a potent inhibitor of CCR5- mediated chemotaxis."
I think Dr. Yang is simply repeating the original PRO140 mouse data from the article cited by midwesthedgie.
Midwesthedgie's tweet has some obvious problems that suggest the guy is clueless. He substitues freely "micrograms" for "milligrams" so whatever numbers he offers in his tweet are obviuosly wrong.
However, the thrust of midwesthedgies argument is more interesting, although it probably does not apply to covid.
Midwesthedge says he is short because the original PRO 140 mouse work, linked by midwesthedgie's tweet, suggests that a blood concentration of 45 micrograms per milliliter is need to get LL to work.
Midwesthedgie goes on to say that measured blood levels of LL in human patients never reach 45 micrograms per milliliter, and that is shown in midwesthedgie's linked article on human LL trials.
Midwesthedgie is right about one thing: Human trial blood levels have never reached 45 micrograms per milliliter.
If you look at the preclinicalLL HIV trial human trial results, subcutaneously injected LL never gets much above 25 micrograms per milliliter. (The plots from the below article max out at 10mg/mL on the 324mg HIV dose, but its very linear so extrapolating 20ug/mL at 700mg dose is reasonable.)
https://academic.oup.com/jid/article/201/10/1...login=true
The inability of subcutaneous LL injection to get above 45 micrograms per milliliter is hardly suprising. If 700mg were injected instantaneously into the average human with 5 liters of blood, the blood concentration would be 140ug/mL. Subcutaneous just cant go in that fast so the peak LL concentration is much lower, around 20-25 mg/mL for a 700mg subcutaneous injection, and the peak is obtained about 48 hours after the injection as shown in other PRO140 HIV human trial data.
So midwesthedgie is right that LL never hits the 45ug/mL level delineated in the original PRO140 mouse experiments and then repeated in Dr. Yang's recent paper.
Unfortunately, the significance of IC50 for calcium channels in mice has never been demonstrated. What's the point? No one knows.
Patterson has demonstrated near 100% CCR5 receptor occupancy at blood concentration levels far below 45ug/mL, although I don't think Patterson measured LL levels in blood.
So what's the deal? Is IC50 for calcuim channel inhibition the critical point or is receptor occupancy the critical point?
LL is certainly working for some covid patients at levels well below 45ugmL.
And LL works for almost all HIV patients at levels well below 45ug/mL.
It would be great if Cytodyn had benn doing some R&D to get a handle on this, but probs going forward they will have an opportunity.
Those PRO140 guys were completely wrong for decades in their often repeated claim that "PRO140 does not effect CCR5 signalling." Completely and totally wrong for decades.
In the podcast, midwesthedgie says, "Leronlimab is a very old asset, 25 years old. The big pharma companies are not stupid, if it was important they would have figured it out."
So that's midwesthedgie's argument, 1) LL never gets to 45ug/mL, and 2) if it was good for anything someone would have figured it out. He throws in there that Cytodyn is "too promotional" and the moderator responds, "Yes, even their name Cytodyn sounds weird."
I think there are some test tube experiment reports that measure some chemotaxis effects as a fuction of LL concentration, but my quick google scholar search was unable to track them down.
The only reference in Dr. Yangs paper as to 45ug/mL that I could find is the following:
"Binding of leronlimab to CCR5 on cells not only blocks HIV-1 entry, but also prevents CCL5-mediated calcium flux with an IC50 of about 45 μg/mL [8] and is therefore a potent inhibitor of CCR5- mediated chemotaxis."
I think Dr. Yang is simply repeating the original PRO140 mouse data from the article cited by midwesthedgie.
Midwesthedgie's tweet has some obvious problems that suggest the guy is clueless. He substitues freely "micrograms" for "milligrams" so whatever numbers he offers in his tweet are obviuosly wrong.
However, the thrust of midwesthedgies argument is more interesting, although it probably does not apply to covid.
Midwesthedge says he is short because the original PRO 140 mouse work, linked by midwesthedgie's tweet, suggests that a blood concentration of 45 micrograms per milliliter is need to get LL to work.
Midwesthedgie goes on to say that measured blood levels of LL in human patients never reach 45 micrograms per milliliter, and that is shown in midwesthedgie's linked article on human LL trials.
Midwesthedgie is right about one thing: Human trial blood levels have never reached 45 micrograms per milliliter.
If you look at the preclinicalLL HIV trial human trial results, subcutaneously injected LL never gets much above 25 micrograms per milliliter. (The plots from the below article max out at 10mg/mL on the 324mg HIV dose, but its very linear so extrapolating 20ug/mL at 700mg dose is reasonable.)
https://academic.oup.com/jid/article/201/10/1...login=true
The inability of subcutaneous LL injection to get above 45 micrograms per milliliter is hardly suprising. If 700mg were injected instantaneously into the average human with 5 liters of blood, the blood concentration would be 140ug/mL. Subcutaneous just cant go in that fast so the peak LL concentration is much lower, around 20-25 mg/mL for a 700mg subcutaneous injection, and the peak is obtained about 48 hours after the injection as shown in other PRO140 HIV human trial data.
So midwesthedgie is right that LL never hits the 45ug/mL level delineated in the original PRO140 mouse experiments and then repeated in Dr. Yang's recent paper.
Unfortunately, the significance of IC50 for calcium channels in mice has never been demonstrated. What's the point? No one knows.
Patterson has demonstrated near 100% CCR5 receptor occupancy at blood concentration levels far below 45ug/mL, although I don't think Patterson measured LL levels in blood.
So what's the deal? Is IC50 for calcuim channel inhibition the critical point or is receptor occupancy the critical point?
LL is certainly working for some covid patients at levels well below 45ugmL.
And LL works for almost all HIV patients at levels well below 45ug/mL.
It would be great if Cytodyn had benn doing some R&D to get a handle on this, but probs going forward they will have an opportunity.
Those PRO140 guys were completely wrong for decades in their often repeated claim that "PRO140 does not effect CCR5 signalling." Completely and totally wrong for decades.
In the podcast, midwesthedgie says, "Leronlimab is a very old asset, 25 years old. The big pharma companies are not stupid, if it was important they would have figured it out."
So that's midwesthedgie's argument, 1) LL never gets to 45ug/mL, and 2) if it was good for anything someone would have figured it out. He throws in there that Cytodyn is "too promotional" and the moderator responds, "Yes, even their name Cytodyn sounds weird."
I think there are some test tube experiment reports that measure some chemotaxis effects as a fuction of LL concentration, but my quick google scholar search was unable to track them down.
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