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That depends on if he is needed there. But it would be uncomfortable situation if Leo would be the one answering possible questions about Brilacidin mechanism of action.
I assume if and when Brilacidin gets into FDA review process potential mechanisms of action and certainly transient paraesthesia (MOA etc.) need to be addressed. Those are in DeGrado's bailwick.
Yes, B has been studies as anti-infective in eye. Conclusions so far:
Not only that, Karin.
It looks like certain people here miss some pertinent points. One being the fact that there are multiple ways how a drug can be tripped in FDA review.. Some being questions that arise in chemistry review, pharmacology review, microbiology review i.e. not only in medical a.k.a. trial review. DeGrado is probably the best person to answer any questions on those fields.
example link for ribavirin FDA approval page.
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-511_Copegus.cfm
Take your time, people,and read some of the stuff there.
Long, long time ago when a computer game named Thief was brand new there was a message board dedicated to it. Within the board was a section called Nuthaus dedicated to imaginative and definitely absurd discussions. I am delighted to see that this board is getting there.
And, although the question was not addressed to me, I somehow feel compelled to answer: No, I haven't used penis bone to find water or anything else. Don't even have one.
TIAB, Degrado's compensation at the University of California in 2019 was 433,580.00. Maybe in your neck of the woods that's considered just pittance.
Try PBI-05204. Cancer: quick check did shown nothing past failed p2 trials. Maybe I missed some.
Talk about anti SARS-Cov-2 activity is probably based on this article:
https://www.biorxiv.org/content/10.1101/2020.07.15.203489v1.full
If reported results hold in human cells (the article is ALL Vero cells), then... maybe.
Empiricst1, You can relax. D614G mutation has been here since June, at least. It probably originated in Europe, traveled here and is now scaring ill informed people in Asia. What we have here is Covid-19 intercontinental ping-pong. China lobbed a soft one over to Europe. Europe added some spikes and slammed a hard one back, but missed a bit.
see
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310631/
P.S. no evidence that it is deadlier than original; more infectious, yes.
Possibility is that we get some price movement with the pre-print. It depends what assays were done and with which compounds. I expect to see price up-swing if the article has any human cell line data favoring B over remdesevir.
Count it as a misunderstanding on my part. I do it a lot, even with myself :)
Well, that was educational! You are right, strange looking dose response curve. I have seen occasional inverted U shaped response curves when there has been two affected processes with opposite effects and different thresholds. But nothing like this.
Thanks. Somehow I feel better now :)
Because I started the conversation you are protesting,I claim the privilege to answer: Not looking for the next play, but exchanging information. This board was once famous for it. Times change, I guess.
Thanks for clarification KMBJN.
I am hoping that word polypeptide in articles about aviptadil will turn associative light bulbs on in certain, important heads. We'll see.
No argument, it is frustrating. And now for something totally different...
Interesting link to aviptadil, until now an intracavernosally injected (ouch!) erectile dysfunction drug. (No one can make this stuff up). FDA did approve IND for covid-19 few days ago. Thankfully for inhaled form.
There is additional irony: aviptapil is synthesized human polypeptide, stuff that Brilacidin was designed to mimic. This fact, when digested in proper places may end up helping B, who knows.
Funny. I wondered the same thing about Polymedix's data. It may have been that they intended to publish, but financial woes preempted that effort. Just a guess, but sad development, if true. A nice paper in well respected journal... one wonders what could have been.
In a way you are correct, it's authors intent. RBL and Leo desire to publish. Most, and practically all well regarded, medical journals do required original, novel content, because it brings subscribers (See it here first!). End result: some meaningful data will be held back until publication.
See, for instance, what medical heavyweight journal New England Journal of Medicine requires. Of interest, heading: No Prior Publication
https://www.nejm.org/about-nejm/editorial-policies
"Posting a manuscript on a non-profit preprint server for feedback from the scientific community" is allowed. That seems to be what RBL is intending to do.
NOTE: My example DOES NOT IMPLY that NEJM would be the publication receiving RBL's manuscript. Not likely. There are better suited journals for in-vitro studies.
Okay, you got me. I went and checked press releases. Some Brilacidin concentration levels in human kidney cells are given in ug/mL. For instance, 85 % inhibition for Brilacidin concentration 100 ug/mL. That 100ug/mL is roughly equivalent to 100 uM (if my quick calculation is correct. Don't count on it). No concentrations were given for Brilacidin inhibition values in human lung cells - the later press release that mentions remdesevir.
There might be a method in mental flagellants' toolbox that would allow us to develop wild estimates if we combine all IPIX press releases. I am NOT going to go there. I already have a headache and unpleasant hallucinations. I give up [PP goes to corner of his study and assumes fetal position]
Let's hope that the awareness will spread to right places. Twitter and Wired are not exactly pharma references, great as it is to see the discussion over there. Now, if Dr. Seema Yasmin would utter something about Vero cells and Brilacidin on CNN...
Well, while it is not The Lancet, NEJM, JAMA or Nature, this one is getting there
https://www.infectioncontroltoday.com/view/new-study-hydroxychloroquine-works-in-monkeys-not-humans
LR, if the concentration is expressed in Mols, as I think it is in this case (10 uM keeps coming in mind) then it would mean that both B and R have the same number of molecules per unit of volume AND biologists could say:
".. B is more effective in the inhibition of the coronavirus relative to an equal amount of R"
That's the beauty of using Mols.
Now, If Leo & Co are using something like weight/volume then the situation is a tad different. In this case you have equal weights per same volume. That is equality in, say, on scale used to calculate shipping cost, but not in biological sense.
I always make sense, don't I. Clear as day etc
In sane world Vero cell quandary should benefit Brilacidin.
Downfall of hydroxy
As I said before (tooting... post #317698) it looks like the only thing hydroxy might do is preventing corona virus from entering blood, provided that one takes it in time, preferably from birth. This, however, does not prevent one from dying of Covid-19. The final exit just comes different way, suffocation due failing lungs instead of heart attack, or kidneys quitting. Ah, choices...
Pretender in Trouble?
ViralClear's merimepodib, the one that scored 98 % viral inhibition, may have the same problem as hydroxy. As far as I can find stuff[1], in vitro was done with Vero cells. Furthermore, it looks to me that the process inhibited by merimepodib [2] results in proton release [3]. [SWIKAI STARTS] My questionable memories from high school chemistry classes are telling me that adding proton should change pH level, a la hydroxy. It all depends how important IMP to XMP process itself is for viral proliferation - pH level maybe meaningless in case of merimepodib.[SWIKAI ENDS]
Be it as may, this late enlightenment about Vero cells should strengthen the case for Brilacidin.
[1] https://f1000research.com/articles/9-361
[2] Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes the nicotinamide-adenine dinucleotide (NAD+)-dependent oxidation of inosine 5'-monophosphate (IMP, 1) to xanthosine 5'-monophosphate (XMP, 3), the first committed and rate limiting step in the biosynthesis of guanosine monophosphate
source:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810100/
[3] https://en.wikipedia.org/wiki/Inosine-5%E2%80%B2-monophosphate_dehydrogenase
SWIKAI: Speculation With Insufficient Knowledge And Intelligence
Farrel, are you sure about the name? My source says THE official name is Belorussian Academy for Deception, Anonymous Computer Networking and Exhortation {BADACNE} He should know. He is the head of Business Infiltration Group in Deceptive Informatics Center at Kent State.
Good weekend to you all. I go and wrestle some fence posts. If nothing is heard of me by Monday morning I will be like a big raisin on the road side. I would appreciate if somebody will come and deliver me to nearest commercial dumpster.
These come to mind:
ViralClear has merimepodib which registered 98 % inhibition. And, of course, hydroxychloroquine. Unfortunately in both cases results are for Vero E6 (green monkey kidney) cell line, which is not a good representative for human lung cells, for instance. Questions remain.
There are bound to be others.
Thanks, LR. I guess that settles it. Thou here you never know.
Ahhh, My, Canned Heat!
In support of KarinCA’s assertion I decided to do the forbidden and unthinkable, never done before thing: voice a non-professional opinion on weighty medical matter: does hydroxychloroquine (HCQ from now on) have benefit in treatment of Covid-19? I will treat in-vitro studies as if they were verified, which they are not. BTW: All that follows has been said here before. Maybe not in a single entry.
Step and Reference 1:
“Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro” a.k.a. The Chinese letter to Cell Research / Nature
In-vitro study using Vero E6 (green monkey kidney) cells showed that HCQ inhibits corona virus proliferation by about 50 to 80 % depending on test used. This was markedly better result than obtained with current favorite, Remdesevir.
At this point is seems that HCQ has something going for it, and more so than Remdesevir. But…
Step and Reference 2:
“Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2” a.k.a. German accelerated paper in Nature.
Looks like Germans have totally opposite opinion on HCQ to that of Chinese. Well, actually not. This needs some explaining. An edited quote from the German paper follows:
“Chloroquine and hydroxychloroquine elevate endosomal pH and inhibit viruses that depend on low pH for cell entry. SARS-CoV-2 can employ pH-dependent and pH-independent pathways for entry into cells. Thus, SARS-CoV-2 spike protein (SARS-2-S), which mediates viral entry, is activated by the endosomal pH-dependent cysteine protease cathepsin L (CatL) in certain cell lines. In contrast, entry into airway epithelial cells, which express low levels of CatL depends on the pH-independent, plasma membrane resident serine protease TMPRSS2. Importantly, TMPRSS2 activity is essential for viral spread and pathogenesis in the infected host.”
It turns out that SARS-Cov-2 entry into Vero E6 cells is facilitated by CatL pathway which is, as stated above, pH depended. When alternate pathway is present ie. TMPRSS2 is activated in Vero E6 cells (engineered Vero-TMPRSS2+ cell line) HCQ does not inhibit viral entry into cell. So, German’s did not disagree with the Chinese, they pointed out limitations, so to speak.
Lofty conclusion based on pre-clinical data, or who needs clinical studies anyway!
Here the story gets iffy, I start to rely on my own brain power, which is like my late dad’s beloved Ericsson outboard motor – sputtering. I went surfing and found some evidence that fits nicely to above findings – reference 3, tissue expression of TMPRSS2. This link has a pretty table showing our current knowledge of TMPRSS2 tissue expression. Notice that according the table TMPRSS2 is not expressed in blood. Okay, it is somewhat dangerous to say that. The table is, as I said, OUR CURRENT UNDERSTANDING. Who knows, maybe tomorrow, somebody publishes a paper firmly showing that TMPRSS2 is expressed all over blood cells. But, for now, I proceed as my current knowledge dictates. No TMPRSS2 in blood.
And here we are. It is plausible that hydroxychloroquine prevents viral entry into blood by altering endosomal pH level in blood cells. That would render Covid-19 to be something akin to bad pneumonia. Treatment wise there are some caveats.
1. To be effective HCQ needs to be administered really, really early in the disease progression. If SARS-Cov-2 gets a good foothold in blood the game is probably over.
2. Because viral infection in lungs is not affected by HCQ patients are still infectious. Plus, serious scarring of lung tissue is still possible.
All this is, of course, my opinion and as such… But, details in pro-HCQ clinical findings so far (and they are very anecdotal and scientifically flimsy, whatever the Good Doctor at Yale says) seem to support it. We should know better before the end of this year. There are number of well-designed (about time!) studies on-going.
Meanwhile, I do as all lonely, self-appointed geniuses do – become ornery and retire in my bedroom to wait my inevitable, posthumous Nobel award (which will never come, Nobels are bestowed only on living)
Here are the links.
1. https://www.nature.com/articles/s41422-020-0282-0
2. https://www.nature.com/articles/s41586-020-2575-3
3. https://www.proteinatlas.org/ENSG00000184012-TMPRSS2/tissue
And the paper by the Good Doctor at Yale (who did not read my reference 2 before writing his opinion. It is that new)
https://academic.oup.com/aje/article/doi/10.1093/aje/kwaa093/5847586
Very interesting. Thanks for finding these.
Happened more than 30 years ago. Clear of fungus since.
From personal experience I fully agree with this:
Didn't watch it. I doubt that he did, it would be all over the press now.
If you mean Moleculin Biotech and their WP1122 drug I went thru their recent press releases and did not find any clear data. Instead I encountered significant verbiage to explain SEC imposed trading halts. There was one sentences, which when interpreted the most beneficial way ("5 to 10 fold inhibition...") could mean about 90 % inhibition at best. Even that is guess work.
Maybe somebody else can see what I can't, meaning facts.
I agree. Thanks for clarifying.
I have an inkling that the reported inhibition was at one half of molarity for maximum inhibition. At least that was what was used for remdesevir in the paper referenced.
Excellent. Thanks.
I suspect that for effective surveillance testing we would need some kind of 15 minutes or less test. Do we have any?
Brilacidin capsule for CV is not viable. Brilacidin's systemic uptake is negligible, which makes a B. capsule intriguing for UC/P and IBS, but useless for treating anything via blood circulation.
Failures in vaccine for respiratory syncytial virus in anything between fetus and old geezer. Failed vaccines for Ebola and SARS. And that's as far as my memory serves. BUT they DO have a spiffy method of producing viral proteins - speedy moths.
No disagreement. Not even about Sweden. I only tried to point out that it was not that smooth sailing in Sweden, some hard decisions may have been made because of government policy. They may have missed the optimal approach, probably not by much.
P.S. Great to read well written posts. Thank you.
KMBJN, about Sweden protecting elderly, according linked study Sweden avoided overloading ICU units, among other measures, by this example of 'Nordic pragmatism':
I am not an expert on PCR. That said, his idea is plausible. PCR amplification is tremendous as far as I know. Hence, it is possible that PCR results get misread as having a (repeat) infection instead of having beaten an infection. If he is right, it is good news - maybe I get to go and see my niece and nephew this fall.
The thing is: how often PCR test is used? I don't know.
Interesting find, SS, thanks. It presents, among other conclusions, maybe the best explanation, so far, for covid induced Kawasaki syndrome in children. Still many, many questions remaining.