#20

I think it is mechanistic. There are quite a few case reports. Angioedema is an accepted rare side effect from high dose rapa.

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#21

I posted pictures of my hives in the side effects topic. This is a type of angioedema.

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#22

I thought I would do a bit more research. There clearly is an interaction between ACE inhibitors and Rapamycin. (or mTOR inhibitors more generally).

These individuals experienced life-threatening tongue angioedema while concurrently being treated with a daily regimen of 5 mg sirolimus and 5 mg ramipril. Intriguingly, the onset of angioedema occurred approximately 1 month after initiating ramipril, despite prior uneventful usage of ramipril in the absence of sirolimus. It is noteworthy that all five patients exhibited relatively elevated sirolimus blood levels ranging from 16 to 20 ng/mL. The complete resolution of angioedema transpired following the discontinuation of ramipril. Subsequently, ramipril was reintroduced, albeit at reduced doses of 2.5 mg, for all patients. This was meticulously executed while maintaining sirolimus levels within the range of 8–12 ng/mL. Remarkably, this re-administration was devoid of any adverse effects, suggesting a potential dose-dependent influence of both drugs on the development of angioedema [14].

Now 5mg daily is equivalent to a single dose of 20mg. Hence anyone on ramipril has to be careful with Rapamycin although it took a while for symptoms to develop.

There is also another paper, but when I posted the link it seemed to go wrong, but from the paper

Angioedema without urticaria occurred a mean of 5 times in 12/80 (15%) RTRs taking sirolimus. It was predominantly located on the face (83%), with mucous membrane involvement in 7 (58%) patients, and was life threatening in 1

Identified triggers for angioedemas included: walnut ingestion, physical activity, enalapril, mango ingestion.

I am particularly interested in getting clarity on the risks for angioedema because I think the benefits of Rapamycin arise mainly from getting maximum serum concentration, but also the risks will lie in that.

Angioedema can be life threatening and people need to be aware of that.

5 Likes
#23

  1. ACE inhibitors are the most common inducers of angioedema with incidence of 0.5%. So ANYONE taking an ACE inhibitor is at risk for angioedema and it can occur at any time, even years of taking the drug. In fact 40 million people take ACE inhibitors world-wide, that’s potentially 200,000 cases of angioedema. Ask @KarlT or @DrFraser how many cases of ACE induced angioedema they see monthly.

  2. The case studies you posted involve patients are extremely sick (post-transplantation) and taking high doses of sirolimus… which are hardly applicable to those that take low dose sirolimus and are relatively healthy like people in these forum

There is just no reason to fear-monger. There are potentially serious side effects with even low dose sirolimus like bacterial infection but life threatening angioedema with low dose sirolimus is less likely than Haitians eating your cat.

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#24

Urticaria can present with histaminergic angioedema which is rarely life threatening. Urticaria is extremely common, 20% life time chance of having it in your life time.
However angioedema can have other pathophysiology like complement deficiency, bradykinin, or autoimmune associated. These usually present without urticaria, can be life threatening and are are very rare.

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#25

Actually we know this is not true. Daily rapamycin creates a very different feedback loop in the mTORC pathways, specifically with regard to inhibiting mTORC2. we know this. Just like taking 100mg of rapamycin is not like taking 20mg per day for a week: Attempted suicide by rapamycin (but was fine) - Case Report

The pharmacokinetics of rapamycin taken daily is very different from weekly dosing, so I would not conflate the two at all, nor conflate the side effects that daily cancer/organ transplant patients see with what we see in longevity / pulsed weekly (or longer) dosing periods.

Please don’t mislead people. We have lots of reports on what the side effect profiles are in the longevity use cases, and bad side effects are rare:

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#26

Let’s face it, something wonky is going on in the translation of rapamycin effects in mice to humans. We all know the ITP rapa results in mice. We know that mice were fed rapa daily and continuously (i.e. no rapa holidays) to superlative overall effect.

We also know that the rate of metabolism is much faster in mice vs humans (roughly x4), obviously different body weight surface area etc. There are generally accepted formulas for translating dosages from mice to humans, and RapAdmin has frequently posted the relevant tables.

If we were to go by those tables, the rapa dosages in humans would be quite high. Daily. And no holidays. The lived experience in great number of people seems to say that at those doses and indeed much smaller doses, the side effects can be unacceptable. That includes the paper I referenced in another thread (wrt. Crohn’s disease) and the comments from several members were that 2mg/day is quite high (LaraPro says she can’t even tolerate 1mg/day, and she is possibly the longest rapa taking member here).

So while the mice data is very interesting, something isn’t translating quite right, despite those official dosage equivalents commonly used by researchers. Rapa seems to be different. Perhaps mice are not a good model for humans when it comes to rapa, and if so, perhaps the benefits might not translate the same way either.

The marmoset study needs to come out, but it too seems to have used quite high doses in human equivalents. Dogs are closer, so maybe that’s something to look at (as well as the cat study).

Translating from animals to humans as we all know is always a fraught affair. In the end, it appears that we have to find our human way by trial and error when it comes to rapa, including individual differences as always.

Try for yourself, there’s no other option at this time. Establish baseline biomarkers and criteria, and then experiment and measure.

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#27

I think the only way rapamycin could be useful in humans is if high doses only needed to be taken intermittently, like once every two weeks or once a month. If mTOR activity needs to be continuously suppressed to achieve lifespan extensions of 15%, that’s just not feasible.

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#28

As I’ve not every seen nor heard of a case anywhere I worked over the last 30 years of a verified feline meal by a Haitian or Sirolimus induced angioedema; I can not speak to their relative frequencies. Both things seem pretty rare, although I’d be more privy to the sirolimus arm of this question.

Yes Ace-inhibitor angioedema is fairly common, and can be a real mess when it goes bad, requiring things like fiberoptic placement of airway or surgical airway. Those cases aren’t too often, but are very memorable.

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#29

I accept that the mode of action is different. I think it is worthwhile trying to identify a safety threshold for single intermittent doses.

#30

I used to take 20mg weekly with GFJ which allows my max level to shoot above 50ng/mL … and it seems to work for some strange reason… anyway, I thought it was a bit high, and now I take 10mg ever 2 weeks … and after 3.5 days my level is like 4.4 - 4.7 ng/mL. I am tempted to increase it back to 20mg but I will see how it affects me for another 3 to 6 months. Feels like my psoriasis is creeping back slightly or is it just my imagination?

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#31

Your psoriasis is probably creeping back as it is an autoimmune disease which Rapamycin acts against.

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#32

Will see how it goes for the next 3 months, maybe more is better… anyway I am going to add 15ml of MCT with my 15ml Hemp oil daily and take 600mg of poly-phenol which should help with my weight loss.

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#33

It seems he has decided to take 1mg weekly. Yes, rapamisin is a strong mTOR inhibitor. Even 1mg per week is effective.

#34

I believe Rapamycin at that dose (1 mg a week) is ineffective and in fact counterproductive. There are reports that dosing at this level actually stimulates MTOR instead of deactivating it which defeats the purpose of taking it

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#35

I think the starting point is around 4mg… If you have a lot of issues like me, try to tolerate as much as you can … once all those issues are resolved, drop back down to 3ng/mL after day 4.

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#36

I read John_Hemming’s post to be referring to use of sirolimus in combination with an ACE inhibitor, which is what the case reports involved, rather than alarming folks to sirolimus being a serious standalone risk of angiodema. I think this is relevant for those on an ACE inhibitor who are also taking sirolimus, in case you might be bumping up the .5% risk any higher. In the case reports, the angiodema occurred relatively early in sirolimus introduction, which suggests you don’t need to start inhibiting mTORC2 to see this side effect. While the paper discussed organ recipients taking sirolimus daily, the risk isn’t clear for let’s say sirolimus 6mg weekly while taking an ACE inhibitor.

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#37

There are hundreds of factors that can have a much bigger effect on elevating the risk of angioedema with ACE inh use …like having an respiratory infection, high level of stress or cancer like lymphoma… that could probably elevate the risk to 1% or higher.

Ok… but you have these case studies, not AEs obtained from any interventional data, from gravely ill people taking high doses of sirolimus… BUT let’s humor your concerns

so let’s assume we elevate the risk to from 0.5 % to 0.500005% of having angioedema with sirolimus in low doses used by relative healthy patients in this forum

How exactly is that clinically significant ?

1 Like
#38

@noahdoc is right that I was referring to a combination particularly with an ACE inhibiitor. You are also right that this is perhaps more about the ACE inhibitor than rapamycin.

However,

a) There are case reports of angioedema without ACE inhibitors - but in a large dose potentially by mistake.
b) A lot of people use ACE inhibitors.

Because I am working on a broader protocol I wish to understand all the risks with Rapamycin.

The normal dosage for a healthy person on this forum even at 6mg with GFJ does not as far as I can see put people in risk of angioedema. However, I personally think the benefit arises more from the peak of the serum concentration than the area under the curve.

If someone is taking 6mg plus GFJ and is also on an ACE inhibitor I am not sure I would be that comfortable about whether or not there is an added risk. Possibly either way. It is something that seems to build up, but with a 60 hour half life there is time for something to build up.

Hence I think it is worth considering where such risks which can be acute risks may occur.

Remember that my own personal last dose was 22mg plus accelerator perhaps around 75mg-80mg equivalent enteric coated. This has interesting effects on blood glucose that I am measuring with a CGM.

As far as I personally am concerned I think the interaction with ACE inhibitors is something that needs to be taken in account. Quite a lot of people take ACE inhibitors.

Why I am I concerned about this risk?

Is angioedema fatal?

For some people, allergic angioedema can cause anaphylaxis — severe swelling of the airways and lungs. People with this life-threatening condition should carry injectable epinephrine (EpiPen®, Auvi-Q®, Adrenaclick® and other brand names) to treat severe allergic reactions. Angioedema that affects the airways, no matter what the cause, is always a medical emergency and you should seek treatment immediately. Sometimes a tracheostomy, an opening in the windpipe/trachea, is performed to help people breathe.

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#39

I had allergic angioedema that caused anaphylaxis while on ACE inhibitor twice. It was before I had kidney transplant or started rapamycin. So it was not connected with rapamycin at all.

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