I have been on doxycycline for my acne before rapamycin but rapa makes it much worse. The only antibiotic that works to cure the acne is bactrim. Works every time within a day or 2.
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I don’t know if the with food effect with intestinal SGLT1i with cana matters or not since the ITP tested it with all meals yet cana is generally used at the start of the day. I believe some other chap mentioned it here already. Empa is much more selective SGLT2i so it may not have the same effect as cana. Both have potential for side effects in the long run that are not necessarily noticeable right away. Especially older adults in general.
There is no long-term safety data on the effects of chronic glucosuria on the urinary tract, but the FDA has initated postmarketing studies due to these risks from immune dysfunction to bladder cancer from a somewhat significant number of case reports. Hence, I personally only do intermittent cana (I’m trying to keep uric acid down to right under 5.8 while keeping well hydrated among other reasons).
If the core hypothesis is true on hyperglycemic environments - significant amounts of SGLT2i induced glycosuria seems to be potentially particularly problematic especially when we jump into urogenital infections that may accelerate aging phenotype even with the assumption of no urosepsis (or rare Fournier’s gangrene).
We already know that glycosylation of uroplakins (presumably from glycosuria) can be a potential part of immune dysfunction as it’s the main “barrier” for the bladder. There is a bladder-associated microbiome and perhaps the possibility of some rough threshold exists or some preexisting precancer lesions seems plausible in animal studies - particularly with empa over cana. On the other hand, the most common infectious agents - gram-negative bacteria ie E coli and P mirabilis produce nitrosamines where metabolites are known carcinogens. Chronic UTIs can be asymptomatic - with the molecular inflammatory subtype tending towards the more aggressive deadly form of bladder cancer.
There is more than enough evidence for a bidirectional relationship between UTI and new onset dementia.
Not worth doing the full deal for me or empa entirely for me until there is more data for certainty on some threshold, even if it potentially results in no life extension effect (which is not yet really evidenced much in the first place for healthy) for now. Trying to balance cardiorenal, immune, and pancreas/metabolic systems and those tend to age faster first with very high impact on mortality.
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Presumably the montelukast is functioning to block leukotriene receptors on microglia, which are basically brain-resident macrophages. As with other macrophages, this presumably helps to prevent/limit M1 polarization of the neuroglia, which in turn would help to calm down an inflammatory situation.[Edit: Also, my understanding is that when there’s significant inflammation going on, the BBB may be substantially more permeable to many drugs than it normally would be.]
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Canaglilozin looks good to me.
Mabe Canaflizon is a better choice for smokers and the elderly?
Possible increase in bladder infections, but no increase in cancer for Canaglifozin.
In fact, it might prevent or fight cancer.
“These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells.”
"The current findings provide novel evidence and demonstrate that CANA effectively inhibits the growth of pancreatic cancer in addition to its anti-diabetic role. CANA is capable of suppressing pancreatic cancer growth by inhibiting glycolysis.
“A Review on the Relationship between SGLT2 Inhibitors and Cancer”
“No increased risk of overall bladder or breast cancer was noted for canagliflozin”
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Yes, I’m aware of the “no increased risk” studies but keep in mind they are in the short term.
I’m talking about long-term exposures where animal studies still support the possibility as well as several plausible mechanisms of known shorter-term effects of SGLT2i from human studies on common infectious agents that are known to produce carcinogens or increase risk for bladder cancer.
Your same study also says “Relationship between SGLT2 inhibition and cancer formation is still inconclusive and studies with larger sample size, longer exposure duration, and different ethnicities are warranted” - we don’t know if canaglifozin over long-term studies may show some effect.
That’s why I said “There is no long-term safety data on the effects of chronic glucosuria on the urinary tract” and even the FDA is interested in postmarketing survelliance
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“There is no long-term safety data”
That is true of many of the supplements we take.
In many of the studies, I have looked at, it seems dapagliflozin, not canagliflozin is the risk factor. There seems to be some other factor than just SGLT2 inhibition.
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That’s partly why the supplements I take are generally well within the upper limit of what a diet in a studied subpopulation takes - i.e. creatine monohydrate (specifically Creapure), preferably in how it is typically absorbed as a very general heuristic. Most people are in fact taking things that do not have long-term safety data and have a real very likely potential for harm i.e. lead or other heavy metals that exceeds the limits by many times. One might not notice it in the short-term but there is strong potential for real likely long-term harm in excessive lead amounts, as an example.
I very sparingly make exceptions if there is a very compelling case, even then I’d carefully consider any individual factors or situations, the entire manufacturing process and quality control process, and what I’d like to test for or monitor. This might be surprising to some, but plenty of “third party” test results are bogus (supplement companies generally go extra cheap-o and/or false and misleading on testing regardless of one’s brand perception) and one can only easily figure it out by reading the fine print and whether it makes sense given enough context.
A lot of people like to go the “kitchen sink” route and don’t think about evaluating patient safety in depth on a case by case basis, mechanistic basis for these compounds, drug interactions, how it may affect pathophysiology, or all the possible interactions and such. There may not be apparent harm in the short-term - but the multivitamin and antioxidant studies showing increased mortality over the long run in “gold standard” Cochrane reviews give us more than enough pause for what was previously widely considered “safe”.
Now one can have very high risk tolerance and very high levels of optimism on an individual level - not necessarily anything inherently wrong with that assuming one is well informed of the risks.
Personally, I have a low risk tolerance that is only relatively overcome to some extent by the risk of doing nothing, while balancing the risks of over-interventionalism with cautious levels of optimism.
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Would you please share which supplements you do take?
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See @tongMD supplement stack here: Can you share your Longevity / HealthSpan Regime? - #68 by tongMD
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I’ve changed exactly what I’m taking somewhat and currently not taking rapamycin as I’ve developed symptoms that may be related with 6 mg/week - mild polyarthalgias (intermittent, 1-2/10, symmetric in the extremities) and positive serology that may or may not be a false positive. Normal hs-CRP/ESR. (Stopped in a few days right after it was clear not an one-off mild polyarthralgia)
If it is induced by rapamycin, it may take months to recover from what is possibly reversible drug-induced arthralgias, and we shall see. It seems to be related to rapa and is a common symptom in transplant patients. Or it could be “pre-RA”/“pre-lupus” unrelated to or indirectly associated with rapa, but my rheumatologist thinks either is possible and we came to believe that an infectious agent (ie rare but possible unconfirmed parvo B19 chronic arthalgia) causing false positive is also plausible, but not an easy way to distinguish when false positives are possible with none of the high specificity tests turning positive. These are very mild symptoms that don’t affect my daily life, but if it is indeed a rheumatoid disease - prognosis probably isn’t particularly horrible either when early DMARDs are started. Just better to get the right diagnosis first before revisiting whether to continue perhaps very low dose rapa.
I’ll eventually detail in a separate blog, along with my clinical reasoning involved for each selection in detail
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For the non-medical professionals in the crowd (like myself) who need to look up these things:
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What supplements do you think are particularly worrisome for lead/heavy metal contaminants?
It varies so much and can be in many different supplements. Toxic heavy metals at significantly excessive amounts above the limits are just one of many concerns. I just gave one example that is incredibly easy to discern (and fairly common) without one having to already learn knowledge on the pharma and supplement industry (my dad is an expert at it).
Even generic medications aren’t guaranteed 100% to be completely safe with USP grade although it’s not to the point where it’s as bad as the overall supplement industry - some of these Indian manufacturing options can have excessive levels of carcinogens ie nitrosamines such that there are voluntary recalls or recall with lawsuits for outright systemic fraudulent documentation. Generic Drug Manufacturer Ranbaxy Pleads Guilty and Agrees to Pay $500 Million to Resolve False Claims Allegations, cGMP Violations and False Statements to the FDA | OPA | Department of Justice
So if I’m taking anything long-term, especially if the meds were intended for developing or third-world countries, I am very wary. Even for the ones ending up for the US or other developed countries with slightly better laws, I am wary about anything non-brand name (“authorized generics” can be acceptable) even if the risk is relatively low, and it’s generally not cost-effective to switch from generics to brand name in most situations - the generics side is just based on my low risk tolerance.
Of course, it’s far less common than the issues regarding supplements - unless you figure out how to get insurance to cover the brand name (which I often can - especially for certain psych meds with documentation and pre-auths especially with my “Cadiliac health plan” - @DrM might be able to chime in better as it’s more common in psychiatry to actually happen) it’s probably not worth it in most cases, but it can be for supplements since almost all of them aren’t USP grade or at least close to equivalent.
The FDA barely even has any oversight on international manufacturers and they still do pre-announced inspections (instead of the abandoned surprise inspections done in 2014-2016 partly due the frauds getting so bad, especially starting with the 1984 Hatch-Waman Act which changed incentives towards cutting a lot more corners) with a dearth of staff qualified to do so. When I see enough bogus third party testing reports on the supplement side or especially the wide majority has lack thereof, along with the rates of testing by relatively legitimate enough third-party testers ie ConsumerLab and supplement-induced liver issues far higher than USP grade meds in certain comparable cases - it’s more than enough to be concerned.
You can read about the FDA accountability issues on international generic manufacturers here at a very recent GAO report:
“GAO’s concerns about FDA’s ability to oversee the increasingly global drug supply chain led it to designate the issue as a high-risk area in 2009.”
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To get brand names prescribed, the doctor must be persistent, it takes quite a bit of your and the front office time to respond to every denial that managed care gives. My experience is that they wear down if you keep trying, often you eventually prevail.
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Unfortunately, that is the case for most insurers - the better the stock price the worse they are in general it seems…but I guess the bright side is if one can get the right type of “Cadillac plan” (my SO is an engineer in big tech where it’s easy for them to negotiate on the best possible plans - but it still varies somewhat) as an example - they covered Concerta XR for me easily instead of generic methylphenidate ER. No back and forth - simple pre auth approved - and not just psych meds. I heard a lot of insurance cos make it so hard from my psych for brand name meds - and it’s hard for patients to tell which ones are gonna play hardball.
Btw I’ve tried the generic before a few times blinded (may not have been perfectly blinded on a true standard, since my SO helped me choose a day “pseudo-randomly”) - was such a noticeable difference in effect and duration, multiple times. I think the generics had to drop the bioequivalence claims at some point?
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I have just developed shingles. I also have a suspicion this is from Rapamycin. I took a small break from Rapa (as I ran out), and just recently started up again around 3 weeks ago. Now I have shingles. I have no recollection of getting this except since my childhood. Nothing too serious, I’m not even totally sure it was because of Rapa, just thought it was worth noting.
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The half-moon shape at the base of your fingernail is known as a lunula. Lunulae cover the bottom of your nail, just above
Apparently a common denominator of people who are suffering from long Covid is that they no longer have lunula on their fingers (just their thumbs). I’ve never had Covid and certainly don’t have long Covid, but it gave me occasion to look at my fingers for the first time. And I have none!
It could be a sign of anemia or other issues. I don’t think I have that either. So I wondered if other people taking rapamycin have lunulae?
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Funny… I know that I use to have half moons on my fingernails… now none… not even on my thumbs. All gone.
Does rapamycin cause that? On rapamycin for 2.5 years… or is it something else?
Obviously gone before I caught covid for the first time last month.
Since I trim my nails frequently… I did think since being on Rapamycin…my fingernails and toenails are healthier… great color. They actually might be a bit thinner…upon closer inspection. They seem to grow faster. Trimming… weekly.
What does no lunula means? Link: No half-moon on nails: What does it mean?
And one more reason - you are taking rapamycin.
I have been taking rapamycin for over a year and I have zero lunulae. I really don’t know when they disappeared, but I do remember having them in the past.
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Solutions to canker sores? Yes. Colgate Total (cetylpyridinium Chloride mouthwash).
Rince at night, sore gone by morning. Works every time.
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