Azithromycin (Zithromax) as senolytic; a note of caution

This is the problem with "cell studies." The authors who found this result decided to look at what they called a "low dose" of azithromycin (AZM) on cells. They found that 50 uM did nothing, and they needed 100 uM for senolytic effects in their assay.

https://www.aging-us.com/article/101633/text

That sounds low, but it's not for serum. The MW of AZM is 749 u so 100 uM is basically 75 mg/L (remember this as the senolytic concentration we might shoot for).  That's far, far over normal therapeutic serum levels of AZM, which hit Cmax of a few TENTHS of a mg/L on a standard Z-pak dose of 250 mg a day (5 mg/kg a day).

In mice 200 mg/kg AZM results in Cmax concentrations of 15 mg/L, which is only 1/5th of 75 mg/kg. (Girard, et al 2005). If the results scale linearly (no guarantees), it would take a dose of 1 gram/kg AZM to get to the senolytic 75 mg/L in the serum. This  would be 50 grams AZM for a 50 kg person, which is 200 standard 250 mg AZM pills. That's a ridiculous amount.

Fortunately, AZM concentrations in tissues are up to 100 times those in serum (now we're back to 2 pills taken at once, at best), but unfortunately this varies by the tissue. For example in rectal tissues, a 1 g dose of AZM (4 standard pills = about 20 mg/kg) resulted in a mean Cmax of 133 mg/kg concentration in tissue. This is almost 1.8 times the theoretical senolytic concentation.

https://www.ncbi.nlm.nih.gov/pubmed/28350806

So a 20 mg/kg dose might be enough for senolytic effects in some other tissues, but we can't simply push the dose of AZM arbitrarily, as it has a cardiac proarrythmic side effect.

https://www.ncbi.nlm.nih.gov/pubmed/28408648

In humans, 30 mg/kg (a dose of about 6 pills or 1.5 g at once) is about the limit people have used in 1-dose treatment of STDs and ear infections. That's probably right at the edge of what we are looking for and the cardiac effects limit much exploration of higher doses.

That's probably not coincidence!  The cardiac toxicity is probably due to high tissue concentration and inhibition of cardiac mitochrondria-- exactly what is happening in senolytic therapy and anti-cancer-stem cell therapy. We can probably expect that the therapeutic window of all drugs that work this way, is not that large. At doses a few times what kills cancer stem cells and senile cells, we start to get effects on normal cells. If that's in your heart, it's not something you can tolerate for a few days, like cancer "chemo." Instead you might be dead from just momentary problems.

14replies Oldest first
  • Oldest first
  • Newest first
  • Active threads
  • Popular
  • is 30 mg/kg unlikely to cause heart problems? 

    I’m thinking of taking 2400mg (30mg/kg x 80kg) once and see what happens

    Like
  • Warning: I wouldn't touch any antibiotics unless necessary for an infection, and certainly not based on this idea. My wife had a UTI a few weeks ago and was prescribed a antibiotic which is related to Azithromycin, and she's still dealing with the consequences weeks after discontinuing. Joint and muscle pain, there are many reports of a percentage of people having this side effect, to the degree the FDA has black labeled this drug. It was developed back in the 50's before modern test standards, which might be an issue. 

     

    So we have a big problem we're dealing with on this one - don't be cavalier with any drug, they all have side effects. I wish I could go back and tell her not to take it in the first place. 

    Like
    • Dan What was the antibiotic?

      Like
      • Karl
      • Karl.1
      • 1 yr ago
      • Reported - view

      Dan I respect your personal experiences, but in a group of people taking Metformin, Rapamycin, Dasatinib, and Navitoclax, I don’t think Zithromax will be their biggest risk.

      Like
      • Danmoderator
      • skipping my funeral
      • dantheman
      • 1 yr ago
      • Reported - view

      Karl Thanks, however the group isn't here to promote one approach but to explore alternatives, there are plenty of posts warning about contraindications. Indeed several of our posters are concerned about taking off the shelf supplements, not to mention pharmaceuticals. All negative experiences and warnings are welcome to add to our body of knowledge and experience. 

      Like
  • Thanks for the note of caution. However, to summarize, at what min oral dose AZ becames senolytic and at what min oral dose can be used for CSC therapy along with doxycycline and vit C? 

    Like
  • Hi Steve, thanks for the excellent analysis.

    Buried in the paper that announced senolytic effects of azithromycin (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286845/) was a mention that for skin fibroblasts, 50µm was sufficient to create strong senolytic effects (100µm was for lung).

    Unfortunately, skin cell uptake of AZM is low, lower than serum - normal dosing regimens of AZM lead to only about 25ng/ml, around 2000x too low.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623349/

    So what about topical AZM?  I haven't yet found data for humans, but in this murine study of topical AZM, every mouse exceeded 100mg/L from a single 5% topical AZ dose (some hit 750mg/L).

    https://academic.oup.com/jac/article/66/12/2814/696535

    Stopping SASP in the skin and hair could have cosmetic benefits as well as head off skin cancers.  There are a lot of variables here - does murine skin absorb AZM better than human skin, will topical AZM actually reach specifically the fibroblasts in sufficient concentration, etc - but possibly worth a shot with a small test region initially, and then perhaps left hand vs right hand test before applying elsewhere.

    Like
  • It would appear that you can safely get the senolytic effects from AZM if you drop the dose and combine with doxycycline. Looks like you can do ~50x less dosage. 

    Like
      • Karl
      • Karl.1
      • 1 yr ago
      • Reported - view

      uzoma iwuagwu interesting data. Do you have a link?

      Like
  • https://europepmc.org/article/PMC/6520007

    What would be interesting is to make a topical with the AZM DOX C combo.

    Karl

    Like 1
    • uzoma iwuagwu Karl Steve Harris awaiting the dosage for the DAV triple combo as the article mentioned that it should translate to less than therapeutic doses. 

      Like
  • I tried this combination 3 days ago. I developed my own 7-day protocol, but unfortunately I had to interrupt it on the second day :( The cause was severe low back and chest pain, which alerted to a heart and kidney problem.

    In fact, I'm very surprised by this seemingly harmless combination. The effects seem to be exactly what a senolytic expects. Before I try again, I will do some blood tests.

    Like
      • Karl
      • Karl.1
      • 2 mths ago
      • Reported - view

      Spasov it’s a combination that could cause stomach irritation.

      Like
  • Everyone forgot that Vitamin C is also part of this stack.  It enhances bioavailability and other things and was used in initial study.  So I am taking 1,000 mg AZH every two weeks + Vitamin C., 1,000 mg.  Dr. Blagoslonny just added an antibiotic (Doxycyclin) taken 1-2 times a month to his longevity formula.  Doxycyclin instead of Azh probably because of heart side-effects for some people.            

    [08:11, 9/25/2021] Van: NEW ANTI-AGEING FORMULA FROM DR. BLAGOSKLONNY
    TWITTER SEPT. 25TH. 2021 https://twitter.com/Blagosklonny/status/1441539123349790720

     

    4/5 
    Rapamycin high dose intermittently
    Low-Carb or Low Carb/Cal diets, time-restricted, IF 
    Physical exercise daily
    Sun, Sunbath/Vit D3
    Metformin low/medium dose  
    Angiotensin II inhibitors 
    Aspirin low dose
    Lithium low dose
    DHEA, L-Ornithine
    NAD boosters
    PDE5 inhibitor

    5/5 Other agents to consider:
    Alpha-estradiol for men when become clinically available
    Acarbose  (if cannot adhere to Low carb diet)
    Fisetin
    Doxycyclin (once/twice a month)
    And other compounds depending on conditions
     Van: Goes on to say evidence on NAD boosters, and Fistein is weak, but will not hurt you except for pocketbook
    Van: Notice high dose rapa change

     


    Van: He also states, "These recommendations are for medical doctors to consider for there patients."  He does not make recommendations directly to people because not practicing medicine.

    Like
Like5 Follow
  • 5 Likes
  • 1 mth agoLast active
  • 14Replies
  • 1202Views
  • 14 Following