MESO-Rx
Anabolic Steroids
what's your gh dosaging?
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Trenbolonetax
Well-known Member
@Ghoul I know you're an advocate for once weekly dosing of the GLP1s due to mimicking the studies. What do you make of this study that utilizes daily microdosing of Semaglutide?
It was 2018, so is it old news and we have learned since then of immunogenicity concerns thus prompting once weekly dosing in most (if not all) studies moving forward?
Ghoul
Well-known Member
There is significant anecdotal, and increasingly, observational evidence by clinicians.
The mechanism is likely immunogenicity, that is, the immune response nearly all peptides induce.
This response "trains" the immune system how to quickly respond to and eliminate the drug.
Provided this response is kept low and stable, it's often clinically insignificant.
However, many factors can cause it to rise to problematic levels. Contaminants (particularly aggregates which form after reconstitution), dosing frequency, and others. UGL peptides are particularly prone to inducing immunogenic reactions.
The stop/start problem is likely due to another immunogenic boosting factor, "Reexposure". This is caused after a "vacation" from a protein therapeutic. Upon resumption, the immune system has a type of memory, and responds more forcefully than if there was "continuous exposure". It's a broadly observed phenomenon with pharma protein therapeutics and various strategies have been developed to deal with it.
A good analogy for all of this are vaccines, which are proteins designed to induce immunogenicity. Many are administered in multiple doses, with a gap between each. This is intended to maximize the immune system's response to the substance being vaccinated against by using this "reexposure" effect.
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Ghoul
Well-known Member
Unfortunately the public data for that study doesn't go into adverse events and immunogenicity.
The thing to bear in mind is immunogenicity isn't binary. It's not on or off. It's a sliding scale. A little is often no problem, as long as it doesn't rise over time. At lower levels, site reactions like pain and redness are common. At higher levels the drug starts to lose effectiveness as you become "immune" to it. Worst case, you develop immunity to the natural hormones the peptides are mimicking.
When we see pharma trials. they're using a finished product that's been engineered and tweaked to minimize immunogenicity. Everything from manufacturing the peptide, the excipient ingredients used in the formulation, to the packaging it's contained in.
For instance, pharma uses the recombinant method, producing Sema and Tirz with yeast that's had its DNA reprogrammed, vs the synthesized type UGL uses. Recombinant peptides appear more "natural" to the immune system vs the "alien" synthesized alternatives which trigger stronger immune reactions.
The specific formulation, tightly controlling things like PH also contribute greatly to keeping immune reactions down. Something no one pays attention to with UGL peptides.
If you took a pharma peptide, and intentionally did everything you could to make it as immunogenic as possible, you'd end up with something similar to what UGL peptides are today.
So with this in mind, as an end user, doing everything you can with the factors in your control to minimize immunogenicity is a wise course, Weekly dosing induces a lower immunogenicity reaction than daily, Reconstituting properly. Filtering.
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songsofpyramids
Well-known Member
@Ghoul do you think using low dose glp1, like .25-.5mg sema for a 4 month stint, would drastically impact the drugs efficacy in the future if using the salts/synthetic version assuming filtering and all that? It’s my most major hangup for hopping on glp1 is I don’t want the efficacy for me to be crap out for me.
Part of me is thinking of starting and staying on low dose glp1 for the neuroprotective and anti-inflammatory aspects of the drug more than anything to do with weight. I just fear the immunogenicity component of these drugs as there’s zero way I’ll get my hands on pharma in a way I won’t feel like a jackass paying full price for. I just don’t want them to loose efficacy if they’re something that could improve my qol later in life.
Part of me is thinking of starting and staying on low dose glp1 for the neuroprotective and anti-inflammatory aspects of the drug more than anything to do with weight. I just fear the immunogenicity component of these drugs as there’s zero way I’ll get my hands on pharma in a way I won’t feel like a jackass paying full price for. I just don’t want them to loose efficacy if they’re something that could improve my qol later in life.
Ghoul
Well-known Member
I think that if you take reasonable precautions to minimize immunogenicity, ie don't recklessly hop on and off, avoid protocols wildly different from pharma, reconstitute to the correct dilution ratios, use pharma grade BAC, filter, and commit yourself to "continuous exposure" by staying on and just altering the dose as necessary, I think the incredible and growing list of health benefits far, far outweigh the risks.
songsofpyramids
Well-known Member
This is the conclusion I’m starting to come to as well. My crp is continuously high no matter what interventions I do (diet clean as fuck including removing foods that tests showed cause inflammation for me, alcohol on rare special occasions only, regular gym, supps for it, etc) due to what is likely an as of yet undiagnosed (due to not being far along enough to diagnose) autoimmune issue. As I get older it has increasingly caused me grief.
Doing research I kept getting contradicting information on the dose necessary for insulin protection and autoimmune protection. Do you think the lowest dose of sema or tirz would be effective at reducing inflammation?
Ghoul
Well-known Member
Every dose lowers systemic inflammation.
The higher the dose, the greater the benefit. One irony is that those most responsive to the appetite suppression effect, limiting the maximum "maintainance dose" they can use, are actually at a disadvantage vs those who can tolerate a high dose without dropping to too low of a weight.
Since the studies almost exclusively use overweight or diabetic subjects, some people, understandably, assume the benefits are entirely related to improving those conditions. They absolutely aren't, as GLP receptors are present in many tissues, but it's not easy to untangle the direct benefits. It's been shown in animal studies and in the petri dishes with human tissues for decades.
But I came across one of the few human studies that demonstrates direct GLP effects on tissue. Stopping and reversing neurodegeneration is probobly the most exciting, because who doesn't want to keep a maximally functioning brain for a lifetime?
When GLP is applied topically to the eyes of subjects with retinopathy, the condition stops worsening, the nerves begin to heal, and microscopic blood vessels rebuild themselves and stop leaking.
Topical administration of GLP-1 eyedrops improves retinal ganglion cell function by facilitating presynaptic GABA release in early experimental diabetes - PubMed
Diabetic retinopathy is a prominent cause of blindness in adults, with early retinal ganglion cell (RGC) loss contributing to visual dysfunction or blindness. In the brain, defects in y-aminobutyric acid (GABA) synaptic transmission are associated with pathophysiological and neurodegenerative...
pubmed.ncbi.nlm.nih.gov
MA11
Member
Each time I think I closed a door behind me, I feel like two new doors opened in front of me.
Anyways, interesting to follow your conversation.
Anyways, interesting to follow your conversation.
songsofpyramids
Well-known Member
1) thank you for such a thorough response! I will read up on this! 2) yes absolutely to the quote above you! I watched my grandmother slowly wither and die from dementia due to Alzheimer’s. To this day it remains one of the saddest things I’ve watched in life and I’ve spent considerable time in war zones. Thus far the research on these drugs for treating dementia and Alzheimer’s it appears to be *the* treatment for it, vastly outpacing other drugs in terms of reducing the damage done. It is wild stuff and I honestly can’t believe it is not getting more attention.
I am increasingly convinced. If my crp is high still on bloods next week after months living like a boring af monk I will be hoping on the sema or tirz train.
Ghoul
Well-known Member
Research capacity is maxed out. There are too many health benefits for science to pursue at once. So as expected, those with greatest profit potential will get attention first as drug companies seek FDA approval for using their GLP to treat various conditions, which opens the door to insurance coverage.
There's more good news about GLPs, literally, every single day.
Evidence Mounts for Potential of GLP-1s in Alzheimer’s Disease
The darlings of the weight loss and diabetes spaces, GLP-1 receptor agonists have shown promise against Alzheimer’s in recent studies—with Phase III results expected next year from Novo Nordisk.
www.biospace.com
Trenbolonetax
Well-known Member
Do you have the study handy that shows direct impact on neurodegeneration independent of weight loss? I believe it, because it improves insulin sensitivty independent of weightloss, I would just like to read it!Research capacity is maxed out. There are too many health benefits for science to pursue at once. So as expected, those with greatest profit potential will get attention first as drug companies seek FDA approval for using their GLP to treat various conditions, which opens the door to insurance coverage.
There's more good news about GLPs, literally, every single day.
Evidence Mounts for Potential of GLP-1s in Alzheimer’s Disease
The darlings of the weight loss and diabetes spaces, GLP-1 receptor agonists have shown promise against Alzheimer’s in recent studies—with Phase III results expected next year from Novo Nordisk.
To elaborate on my curiousity, alzheimers essentially type 3 diabetes so it doens't surprise me that giving diabetic folks GLP1 that then subsequently lose weight helps reverse their neurodegeneration.
I've seen the mouse studies on Tirz and Sema where you can sus out direct improvement in fasting insulin + insulin sensitivity + glucose clearance. I know those things all will positively impact neurodegeneration.
I would just like to see the study showing the direct impact on neurodegeneration if that makes sense
Think I found it (one of them?)
Unlocking the Potential: Semaglutide’s Impact on Alzheimer’s and Parkinson’s Disease in Animal Models - PMC
Semaglutide (SEM), a glucagon-like peptide-1 receptor agonist, has garnered increasing interest for its potential therapeutic effects in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). This review provides ...
pmc.ncbi.nlm.nih.gov
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songsofpyramids
Well-known Member
There really is and it is honestly wild to watch. Anyone who thinks the benefits are limited to weight loss aren’t following the science. It honestly does look like these drugs are miraculous when you start really diving into the literature on them,
malfeasance
Well-known Member
This is where I keep getting confused. HRV is not measured in anything that would say 30.
30 milliseconds.
Maybe we are talking about two different things.
readalot
Member
songsofpyramids
Well-known Member
What Heart Rate Variability Means on Your Fitness Tracker
Cardiologists explain what heart rate variability is, and why it is and isn't an important health metric to pay attention to.
You are correct its milliseconds.
Ghoul
Well-known Member
The operative term is "variability".
The HRV score is not a single static measurement in milliseconds of the interval between heartbeats, it's the variability between highest and lowest over many heartbeats.
A higher level of variability is positively associated of fitness, a lower level with a lack of fitness.
So a master athlete could have a very small interval, and then a very large interval a number of heartbeats later. This wide range is a measure of the heart's ability to quickly adapt.
With age, loss of fitness and illness, this range shrinks.
malfeasance
Well-known Member
So if my heart beats 70 bpm
that is 857 milliseconds
and I drive it up to 168 on cardio
that is 337 milliseconds
so . . . 520 milliseconds?
What am I missing?
that is 857 milliseconds
and I drive it up to 168 on cardio
that is 337 milliseconds
so . . . 520 milliseconds?
What am I missing?
songsofpyramids
Well-known Member
It’s a measure over time not in a moment, and I think it is taken by watches and such when you’re asleep and have reached resting heart rate. It’s a measure done at rest I believe.
malfeasance
Well-known Member
Ah, ok, thanks
