Amyloid fibril formation

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I've seen topics and posts going both ways on this.

It seems like PH needs to be under around 4-4.5 exactly to be considered safe for this.

However, a lot of people don't seem to think it's a risk either way and this is overblown etc.

Would love to know your thoughts on this.

I have some I got for free I'm considering stacking with my current tirz dose, but still researching.
 
personally I think it's fear mongering.

on another place where conversation exists... this was discussed. I think you were there.

1730691939568.png


Smart people mechanically stressed the peptide to force the formation of these demons and had little success.

Amilyn has a natural tendency to form fibrils. Cagri is an amylin analogue specifically designed to resist fibril formation.

That snippet above describes the mechanical stress they applied to Cagri to force the formation.

45 hours at high temp in a centrifuge

source: https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00565

bring this up to mega and he starts in on some proprietary formulation not found in research peps. Novo dual injectors with some magic ingredient... and other nonsense.

Personally, I will stick with peptides that are approved. I may cross the bridge to Reta, and hopefully it is approved by the FDA by then... but until then prices for Reta remain high and what I have is working.

Overall, I think this is an often unspoken risk of "research". China is shipping all these trial drugs and peptides to us. And we're like SLU-PP-332? Sweet! Almost no human trials (at least none I could find) and only research in mice... but gimme "exercise in a pill".

Just wait for them to be at least approved in some first world nation with modern healthcare. A conservative approach.
 
I did a fair amount of reading on this and I came to the conclusion that even if cagri could form these fibrils, it doesn't seem like they could work their way into the brain.
 
My sarcasm isn't pointed at anyone, but isn't NN in phase 3 trials for CagriSema? But supposedly it's well known that the cagrilinitide part causes fibrils.

I get that NN doesn't give a crap about us, but I'm sure they care about the bottom line. The study costs are already significant but the lawsuits would be enormous if they moved forward with Cagrilinitide knowing it would do harm.

Note, don't take cagrilinitide, while sitting in a sauna spinning around in circles. You'll die /s
 
ImSW1 said:
My sarcasm isn't pointed at anyone, but isn't NN in phase 3 trials for CagriSema? But supposedly it's well known that the cagrilinitide part causes fibrils.
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Can you point to any papers or studies confirming this?
 
@brentm What do you need a citation for? That NN is doing phase 3 trials of CagriSema or the "it's well known that the cagrilinitide part causes fibrils." because I don't believe it does create fibrils except under very extreme circumstances. 👍
 
ImSW1 said:
@brentm What do you need a citation for? "it's well known that the cagrilinitide part causes fibrils." because I don't believe it does create fibrils except under very extreme circumstances. 👍
Click to expand...

This... The fibril formation.
 
brentm said:
personally I think it's fear mongering.

on another place where conversation exists... this was discussed. I think you were there.

View attachment 3394

Smart people mechanically stressed the peptide to force the formation of these demons and had little success.

Amilyn has a natural tendency to form fibrils. Cagri is an amylin analogue specifically designed to resist fibril formation.

That snippet above describes the mechanical stress they applied to Cagri to force the formation.

45 hours at high temp in a centrifuge

source: https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00565

bring this up to mega and he starts in on some proprietary formulation not found in research peps. Novo dual injectors with some magic ingredient... and other nonsense.

Personally, I will stick with peptides that are approved. I may cross the bridge to Reta, and hopefully it is approved by the FDA by then... but until then prices for Reta remain high and what I have is working.

Overall, I think this is an often unspoken risk of "research". China is shipping all these trial drugs and peptides to us. And we're like SLU-PP-332? Sweet! Almost no human trials (at least none I could find) and only research in mice... but gimme "exercise in a pill".

Just wait for them to be at least approved in some first world nation with modern healthcare. A conservative approach.
Click to expand...

Thank you for continuing to circulate this source because the random people talking out of their a** about this subject when we have actual science is infuriating.

Cagri was designed to RESIST fibril formation and researchers did a lot of testing to make sure that was actually how it worked. You don't have to take Cagri if you're concerned, especially given that there are plenty of other options, but don't run around lying and trying to scare people
 
Megalith's arguing style is not the type that I find persuasive - I agree that there is a huge volume of words being blasted out, only a portion of it being well referenced, and then the rest of the messages being things we're supposed to take at face value just because some other portion is backed up by some documentation.

However, I do think it's important to clarify that while it is true that Cagri was designed to resist fibril formation, Novo Nordisk does still do it at specific PH levels as part of this process - PH levels I do not know if we are at in the grey market.

Now, it's possible that NN is just being careful keeping the pH at ~4 for their clinical trials with Cagri/CagriSema and that the other work is enough. But their patent for Cagri does state that it must be formulated between 3.5 and 4.5. https://patents.google.com/patent/WO2021144476A1/en

The ThT Assay stuff I find persuasive. But I also am curious as to why NN is adamant about the low pH. I'm not educated enough here to come to a strong enough personal conclusion, so I've decided to skip cagri for now.
 
brentm said:
This... The fibril formation.
Click to expand...

I think you've read my sarcasm wrong 😂. I'm in full agreement with you on the Cagri and fibrils subject.

Basically, if Cagri created fibrils, why would NN be doing phase 3 trials with the stuff.
 
hexagonal said:
Megalith's arguing style is not the type that I find persuasive - I agree that there is a huge volume of words being blasted out, only a portion of it being well referenced, and then the rest of the messages being things we're supposed to take at face value just because some other portion is backed up by some documentation.

However, I do think it's important to clarify that while it is true that Cagri was designed to resist fibril formation, Novo Nordisk does still do it at specific PH levels as part of this process - PH levels I do not know if we are at in the grey market.

Now, it's possible that NN is just being careful keeping the pH at ~4 for their clinical trials with Cagri/CagriSema and that the other work is enough. But their patent for Cagri does state that it must be formulated between 3.5 and 4.5. https://patents.google.com/patent/WO2021144476A1/en

The ThT Assay stuff I find persuasive. But I also am curious as to why NN is adamant about the low pH. I'm not educated enough here to come to a strong enough personal conclusion, so I've decided to skip cagri for now.
Click to expand...

This is where I'm coming to with it. From what I understand, the PH needs to be exactly between 3.5-4.5 or it runs the risk of forming.

It seems like they are running phase 3 trials with it because they are able to manufacture it at a specific PH. We aren't really able to do that on the research side. From my understanding, part of the fibril formation resistance that was designed in is based on the PH balance.
 
When you do a scientific trial you have to make sure conditions are exactly the same, to see if the medicine works in a pattern, so you saying them doing this one specific thing makes all your concerns over forming amyloid fibril true. Unless the study says the reason they hit that Ph is specifically due to fibril forming. They didn't.

You are just speculating
 
normal said:
This is where I'm coming to with it. From what I understand, the PH needs to be exactly between 3.5-4.5 or it runs the risk of forming.
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Can gray market researchers simply adjust the PH with SB or AA to get into this range? 3.5 ph sounds like a spicy shot!
 
LaughingDuck said:
When you do a scientific trial you have to make sure conditions are exactly the same, to see if the medicine works in a pattern, so you saying them doing this one specific thing makes all your concerns over forming amyloid fibril true. Unless the study says the reason they hit that Ph is specifically due to fibril forming. They didn't.

You are just speculating
Click to expand...
The patent explicitly states the pH must be a 3.5 to 4.5 for physical and chemical stability.

Instability is, from my understanding, what would cause the fibrils to form - see the details in the ThT Assay bit posted above where it also explicitly says they are testing the stability properties.
 
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GimmeABreak said:
Can gray market researchers simply adjust the PH with SB or AA to get into this range? 3.5 ph sounds like a spicy shot!
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This would help if the pH does need to be that low for stability, in that new fibrils shouldn't form. But my limited understanding from googling seems to indicate that amyloid-like fibrils would survive lyophilization, so if the the raw material pH was too high to prevent fibril formation they would likely still be present upon reconstitution.

But I am not a chemist and no one here should be taking my word as anything but my own layperson's extremely limited understanding. All I really know is that NN indicates in the patent that they formulate it at 3.5 to 4.5 for stability reasons. I have no real idea if there is any concern around fibrils forming, or if any fibrils that may form are actually harmful. Perhaps NN is just taking a 'better safe than sorry' approach. Or perhaps there are real concerns.

I want to be quite explicit in that I don't know the answer here, and I recommend everyone come to their own conclusions based on the information available, at least unless we get actual experts chiming in.
 
LaughingDuck said:
When you do a scientific trial you have to make sure conditions are exactly the same, to see if the medicine works in a pattern, so you saying them doing this one specific thing makes all your concerns over forming amyloid fibril true. Unless the study says the reason they hit that Ph is specifically due to fibril forming. They didn't.

You are just speculating
Click to expand...

In the patent for the drug, they mention hitting that ph specifically due to fibrils forming.

Of course I'm speculating, this is a research forum isn't it? Lol. I don't think we're gonna have any of the actual scientists jumping in here to discuss.
 
So I worked doing a scientific project and we were super strict, so it's why I'm saying if the test don't bring up fibril it's most likely just keeping the same standard for medication.

For example I would use the same tempture, from the same water source everyday during the scientific study we did, why? Eliminate any reasons for skewed results. Less things to blame.

They say stability, but does that mean Fibrosis happens if it's not or does it just mean they want to now it's the exact age, reconstitution, pH, tempture etc?

Like I said not saying "don't be questioning" this, it's not approved, but so far I haven't had anything say otherwise.
 
LaughingDuck said:
So I worked doing a scientific project and we were super strict, so it's why I'm saying if the test don't bring up fibril it's most likely just keeping the same standard for medication.

For example I would use the same tempture, from the same water source everyday during the scientific study we did, why? Eliminate any reasons for skewed results. Less things to blame.

They say stability, but does that mean Fibrosis happens if it's not or does it just mean they want to now it's the exact age, reconstitution, pH, tempture etc?

Like I said not saying "don't be questioning" this, it's not approved, but so far I haven't had anything say otherwise.
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The linked design document talks about them testing a wide variety of formulations with different salt bridges, etc., at two different pH levels specifically because of trying to strike a balance between solubility, efficiency, and resistance to fibril formation. They have data on fibril formation at a pH of 7.5 - the study specifically looked at it. They could have chosen that as the 'standard' for the final version.

But the final patent specifies a pH of 3.5 to 4.5
 
clayd said:
I know not everyone is a scientist but if you are injecting this into your own body and this is a concern, you really should try to read and understand this: https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00565

maybe ask chatgpt to help explain the parts to you that you don't understand.
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That doesn't sound like a good solution. The bottom-line question is whether something is safe enough to try. I wouldn't trust ChatGPT on any question involving safety.
 
Is there anything I can squirt into my already reconstituted vial to uhh… make the ph lower/negate potential fibrils?
 
I have 9 vials of 10mg cagri from QSC that I am looking to sell as well. It works for me but the fatigue I get from it is too much. Thinking about just stacking sema with reta to help with appetite suppression instead.
 
echohunter said:
I have 9 vials of 10mg cagri from QSC that I am looking to sell as well. It works for me but the fatigue I get from it is too much. Thinking about just stacking sema with reta to help with appetite suppression instead.
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stacking sema and reta is just going to give you worse results than just using reta. they are competing for the same receptor.
 
zpped said:
stacking sema and reta is just going to give you worse results than just using reta. they are competing for the same receptor.
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According to some chart I’ve seen on this forum, Reta has very low GLP-1 activity, compared to Sema. Anecdotally people have said Reta doesn’t provide as much appetite suppression as Sema, or even Tirz. Using Sema to make up for Reta’s lower GLP-1 activity seems to make sense to me.
 
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echohunter said:
According to some chart I’ve seen on this forum, Reta has very low GLP-1 activity, compared to Sema. Anecdotally people have said Reta doesn’t provide as much appetite suppression as Sema, or even Tirz. Using Sema to make up for Reta’s lower GLP-1 activity seems to make sense to me.
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You (and many others) are making it out to be much simpler than it is. Adding in the sema just kicks the reta off the receptor and you're not using the reta to its full effect. They mix with albumin and cause completely unstudied interactions. Do whatever you want though, it's probably not dangerous but almost certainly less effective. There is a reason they picked the balance for reta that they did.
 
Yeah. If fibrils are forming, It won't do anything to existing fibrils, but it should help prevent additional ones.

I would get the PH to 4.0 and filter after if I was going to use cagri. Stop new growth and potentially get any that had clumped together enough for the filter to catch.
 
zpped said:
You (and many others) are making it out to be much simpler than it is. Adding in the sema just kicks the reta off the receptor and you're not using the reta to its full effect. They mix with albumin and cause completely unstudied interactions. Do whatever you want though, it's probably not dangerous but almost certainly less effective. There is a reason they picked the balance for reta that they did.
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This is why I think people stacking reta with anything else are on a fool's quest. Yes, they might be seeing results that make them happy, but it was designed the way it is for a reason and if they just followed the dosing schedule to a high enough dose they'd likely see better results on reta alone. Sanofi designed a triple agonist that was completely balanced and they stopped development. Seems to me a lot of people stack with Reta because it sucks at appetite suppression at the lower doses, and many of us trying to lose weight are (understandably) afraid of eating. I plan on trying it for maintenance, because my impression of it is that it's for upping your metabolism, not suppressing your appetite. I want to be able to enjoy pizza during maintenance😉
 
In order to prevent any possibility of harm to our bodies, I think we should even consider stopping breathing 🤣
 
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