Are there more side effects with higher peak dosing? @Olafurpall For example, 5 mg one time a week reaching higher peaks than 1 mg EOD. 10 mg two times a month is higher… 20 mg one time a month, etc.
I hate anecdotes like this but Blagosklonny was focusing on higher peak dosing and he got an aggressive cancer according to some early in life.
Also if you read these forums, there are a lot of reports of skin infections including Kaeberlein himself in people that are weekly dosing. There is a lot that we still don’t know.
I suspect there may need to be a need for periodization in the dosing. For example, a period of loading dose and period of maintenance dosing or no dosing. Some people are already starting to do that, cycling on and off.
I would point out the Mannick study is over cited and conclusions made from this often exceed what was demonstrated. Ultimately this short duration study has value, in looking at immune response to a vaccine, which certainly is part of aging - but not entirely the same thing.
Jumping on the bandwagon of trough levels, I understand why - it’s because this is what they measured - but it is not in any way logically or pharmacologically the active ingredient in safety or dosing - but instead is a proxy for % of time at a therapeutic level - which is what they should have measured.
The trough levels are simply a proxy for time at a therapeutic level where mTORC1 is highly inhibited. If you had patients maintained at 0.1, 0.4, and 0.8 troughs by microdosing - there would almost certainly be absolutely no difference between them – as all would likely have essentially no activity in any fashion - beneficial or harmful. None would be active - as the trough is not the active ingredient. Treating it as such is a misunderstanding of pharmacology.
I appreciate that this is a standard measure in pharmacology, and understand why they did this. It would be more precise, and meaningful to have assessed the % of time in a therapeutic level on a weekly basis. That logically is the active ingredient, and also would relate to risk of adverse outcomes and benefits.
I see no situation in which I would care what the trough is, as it is a less precise way to look at what the real issue is - how strongly inhibited is mTORC1 and for what % of the time. That being said, my approach will result in a low trough before repeat dosing.
This is a great question. The answer is, it depends. Taking very high single doses, instead of spreading the same dose throughout a week or few, comes with certain risks. While rapamycin is generally very safe, the risk of side effects increase with higher doses. The high peak levels seen when taking a lot in a single dose will increase the risk of certain rare side effects. There are individuals that are susceptible to strange side effects, and for those people, a high single dose could be risky. Note that this is not comon. I’ve seen a ton of anecdotes on rapamycin and know of only one case where an individual got a serious adverse reaction right after taking a single high dose of rapamycin, which required a visit to the ER. That individual supposedly did not have adverse reactions to lower doses, so this is a case where high peak levels might have been causing negative effects. This is why one should always ramp up the doses slowly and start small and increase it a little bit every week or few to see if one tolerates it.
On the other hand, chronic mTORC inhibition by rapamycin does tend to inhibit mTORC2, which causes side effects like impaired insulin sensitivity and elevated blood lipids. This can be largly avoided by intermittent dosing, but taking a large dose every one or two weeks can often prevent this effect almost completely, while the same dose spread out into more frequent smaller doses will inhibit mTORC2 and cause more side effects. In this respect, intermittent doses have less adverse effects, despite higher peak levels.
Overall we have a case where the dose makes the poison and overall for most people the side effects are likely minimized with intermittent doses (every one or two weeks) as opposed to chronic daily or every other day doses. People just need to be careful and ramp up the doses slowly to test their tolerance levels.
Regarding Blagosklonny, the reason he was focusing on higher peak dosing is, if I recall, the idea that higher peak levels are necessary for rapamycin to cross the blood-brain barrier. I think this is one reason he eventually stopped taking rapamycin weekly and started taking double the dose every two weeks instead. I doubt this dosing strategy had anything to do with him getting cancer.
Can you please elaborate on what this means? Do you mean that you were able to get a physician to write you a script for Sirolimus using Push Health, and then said prescription can be sent electronically to CostPlusDrugs?
Yes, I do not use CostPlusDrugs.
The prescription was sent electronically to the pharmacy of my choice.
Well that’s very good to know. Under what kind of premise did you request Sirolimus if I may? Were you upfront about what you wanted it for?
I had a PharmD, Henry Dunklau, contact me from MidTown Express Pharmacy in Nashville, TN. Their number is 615.320.8410 and website is www.midtownexpresspharmacy.com
He has coated tablets of Rapamycin 2 mg x 30 for $90 or 2 mg x 90 for $240.
Yes, they need an Rx - but he can send them to 43 states - cannot send to CA, OK, Kansas, Arkansas, SC, WV or NH.
Seems like this could be a good U.S. based resource for some folks!
how do you buy from india? Any reputable sources? Or for that matter, any sources. On brazil medications are usually very cheap, 1/5 of US price, yet rapamicyn (60 pills 1mg) cost 600 dollars as generic companies do not produce them (even though the patent expired long ago).
See the information on this page, about importing, and pricing and list of reliable India pharmacies: How to Get Rapamycin, Where to get a Prescription
Recommend both apple pharmaceuticals and Shivansh trade!
Just create a Indianmart account and then start quoting and you will then get quite a response from the many pharmaceutical companies in India!
Payment is easy via wise.com and product quality is good as well! You can negotiate the best possible price as well!
I got some some discounts!
Yeah I don’t love rapamycin becoming more mainstream before there is enough acceptance in the medical community that it can be prescribed freely.
A clampdown on the gray market before the traditional medical world accepts it would make things difficult.
Have you actually tried to use Mark Cuban’s? I haven’t used it, but I would have thought that they would have a way to upload a scan of a hardcopy script. Unless someone here says they don’t do that, it seems worth a shot …
I’m just now starting to have patients use this who are in California - my other patients get it through the pharmacy in Nashville that has a very sensible deal and sends to the other states for the most part.
It looks like 30x1 mg is ~$2/mg, and 30 x 2 mg is a bit below that.
I’m putting through my first Rx right now and will let everyone know how it goes once I get feedback from my patient with CostPlusDrugs
Yes, I’ve tried to use my hardcopy Rx with both Mark Cuban’s site and Amazon Pharmacy. Both were no-go. They need to get the Rx from the doctor directly - if the doctor hasn’t worked with them before, the Doc will have to do some paperwork to get into their system, so some Docs (like mine) just aren’t going to do that.
Yes - I’ve done their paperwork. It is a hassle. But it is a one off hassle and then no problems from there.
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Okay - have had my first Rx go through - really was a need for patient to sign up. On my side, all I had to do was fax or electronically transmit a prescription. Nothing fancy at all.
They do require that I put the patient’s email in with the Rx. Don’t really see this should be any impediment at all for any prescribing physician with Cost Plus. I put through 30 x 2 mg.
Cost for patient delivered, I think was $112.
Or about $1.80 per mg.
Mark Cuban’s Cost Plus provides a fillable form (https://costplusdrugs.com/PrescriptionRequestForm.pdf) that can be completed and saved by patients, then forwarded to the doctor, saving the doctor some time. Maybe try that.
Thanks Daph, I appreciate the idea. However my Doc has made it very clear he’s only going to provide hardcopy/paper prescriptions, and not do business with online pharmacies. So I’m not going to push the issue at this time. I can make do with my current situation.
Don’t underestimate the Indian sources. They may be meds made in India or elsewhere. I’ve researched the manufacturer of what I’ve bought and every time they are quality manufacturers. Shipping time on what we’re looking for is not usually an issue. I’ve bought overseas since 2010 and have never had an issue–those days are gone if it’s written up properly as a prescribed med and is less than 90-days supply. I’ve never seen evidence of a package that was opened and inspected.
The above being said, here is a possible example: Metformin from
Well, that was who made the MDMA contaminated Metformin, See:
https://www.healthcentral.com/condition/type-2-diabetes/metformin-recall
“The 2020 metformin tablet recall was a voluntary one from Marksans Pharma Limited, which issues metformin tablets marketed as Time-Cap Labs Inc. Some 178 lots of metformin hydrochloride were recalled in total from various manufacturers.”
Note: “Various manufacturers.” Various manufacturers that sold at pharmacies in America, these were not mail-order shipped from India, so there is risk even if you buy it from CVS. Supposedly “brand” drugs are safer but consider: Virtually all drugs/feedstock come from China, so in reality either the med came from China, or feedstock that went into making the finished med originated in China.
Just something to think about.