The study posted by MAC. This looks like a nice study compare with and w/o GFJ. But it raises questions to me.
The data show that sirolimus alone at 20 mg had more side effects overall than when admin with grapefruit juice at 20 mg. GFJ is supposed to increase intake by 350%, thus the GFJ dose was equal to 70 mg without the juice.
It is unfortunate that the study did not run equal doses of Sirolimus alone and Sirolimus with GFJ, so the nearest straight comparison is at 20 mg, which for us is way high. And also be useful to start the trail at a bit lower dose…say 5 mg with and without.
It seems that one would want to determine how much the low doses of sirolimus are affected by GFJ as they do with keto and even there the sirolimus and keto added doses are not comparable at lower doses.
Yep…other anomalies here too. Big disconnect in what we assume on this. Given all the other work on GFJ and drugs it seems that the boost is real. How much is the issue and timing, etc. I started using it to boost an 8 mg weekly dose with zero side effects (which now seems low compared to other reporting).
I take 8 oz fresh squeezed with pulp 2 hours before. Still no side effects. going to park here.
I figure if at max it increases 3.5 x then that’s a lot (equal to 28 mg) but also build in the fact that it might really be 2x for lots of reasons reasons…so that 16 OK too. at least for now.
Final note…the effect of GFJ varies widely by drug. I think for the 3.5x we are using some other drug as the base (one of the statins I think). Anybody have this multiplier specifically for Rapa?
“I will add that I have serious reservations about the use of Sirolimus for general prophylactic purposes, since the drug can cause both serious interstitial lung disease, as well as anemia due to impaired iron utilization”.
Has Dr Green given this adverse effect warning?
Also, on elevated glucose and lipids…“that’s how you know it’s working”. I’ve not even reached this state yet, so I have runway.
He provided no references to the lung disease assertion/context other than I assume his clinical practice. I donate blood every 8 weeks to expressly dump iron, whilst taking Rapamycin, and have zero side effects to date. I would be classified as iron deficient without anemia (self-induced), although my hemoglobin is normal. (But I’m also homozygous H63D…so maybe I have deep cellular iron storage reserves not captured in blood tests)
Regarding Interstitial Lung Disease (ILD) and mTOR inhibitors:
“In February 2017, after completion of chemotherapy she was started on Sirolimus 2mg daily. The level was maintained at 5–10 ng/ml. In July 2017, the patient presented with dry cough, fever and dyspnea on exertion for six weeks. In November 2017, sirolimus was discontinued and she was switched to everolimus at 0.75 mg twice daily. The level was maintained at 4–8 ng/ml. Within one week the patient experienced improvement in her symptoms and she was back to her baseline level of activity after two months”
Here’s another:
“The literature review identified 57 publications on ILD in solid organ TxR receiving everolimus or sirolimus. ILD presented months or years after mTORi initiation and symptoms were nonspecific and insidious. The event was more frequent in patients with a late switch to mTORi. In most cases, ILD was reversed after prompt mTORi discontinuation. ILD induced by mTORi is an uncommon and potentially fatal event warranting early recognition and drug discontinuation. Out of the 1,473 de novo TxR receiving everolimus in Phase III trials, everolimus-related ILD was confirmed in six cases (one kidney, four heart, and one liver TxR) representing an incidence of 0.4%”
ILD wasn’t even a noted adverse event in the Sirolimus/GFJ trial, only anemia (DLT in only 5 of 138 persons)? It appears to be something associated with chronic daily Sirolimus administration and some significant length of time (malignant cancer/transplant setting), you can feel it coming on, and thus, backing off dosing, reversible.
I am not perturbed in an intermittent dose model. As long as you closely monitor blood markers and side effects, whenever it reaches tolerance levels, you just back off. The effects of Rapamycin are reversible, hundreds of studies have shown this.
You’ve said “20mg, which for us is way high”, and “max increases 3.5X, then that’s a lot (equal to 28mg”. Define high and a lot?
Unless you do your own n=1 experiment, monitoring blood markers and side effects, you just don’t know your limit, whatever that target might be for YOU. We don’t even know what level of mTOR suppression in humans reaches high percentile to flatten the aging curve?The GFJ study gives some insight for cancer target (and it’s higher than what most of us take)…is this “the” target for longevity?
Genetic predisposition to CYP3A4 enzyme polymorphisms/expression, mTOR polymorphisms, GFJ type/dose, gastric processing, base levels of nutrient signalling, timing, etc will all have major impacts on your personal pharmacokinetics/response. Different cell lines/organs have varying degrees of mTOR suppression.
GFJ/drug interaction is highly specific. GFJ can have a HUGE impact on some statins.
“In a randomized cross-over study with two phases, 10 healthy volunteers ingested grapefruit juice 200 ml or water (control) for 3 days. On day 3, a single 40-mg dose of simvastatin was administered with grapefruit juice 200 ml or water. Plasma concentrations of simvastatin and simvastatin acid were determined up to 24 h. Grapefruit juice increased the area under the plasma concentration–time curves from 0 to 24 h [AUC(0–24)] of simvastatin 3.6-fold and that of simvastatin acid 3.3-fold (range 2.1–5.6-fold; respectively. The peak concentrations (Cmax) of simvastatin and simvastatin acid were increased 3.9-fold and 4.3-fold (range 2.7–7.9-fold;
by grapefruit juice.”
“This crossover study consisted of 5 study days, during which 10 healthy volunteers ingested 40
mg simvastatin with water (control), with “high-dose” grapefruit juice (200 mL double-strength grapefruit juice three times a day for 3 days), or 1, 3, and 7 days after ingestion of “high-dose” grapefruit juice. For safety reasons, the study was performed in three parts to allow simvastatin-free days between the study days. Serum concentrations of simvastatin and simvastatin acid were measured by liquid chromatography–tandem mass spectrometry up to 12 hours. When simvastatin was taken with grapefruit juice, the mean peak serum concentration (Cmax) and the mean area under the serum concentration-time curve [AUC(0-∞)] of simvastatin were increased 12.0-fold (P < .001) and 13.5-fold (P < .001), respectively, compared with control. When simvastatin was
administered 24 hours after ingestion of the last dose of grapefruit juice, the Cmax and AUC(0-∞) were increased 2.4-fold (P < .01) and 2.1-fold (P < .001), respectively, compared with control. When simvastatin was given 3 days after ingestion of grapefruit juice, the Cmax and AUC(0-∞) were increased 1.5- fold (P = .12) and 1.4-fold (P = .09), respectively, compared with control”
“In a randomized, four-phase crossover study, eight healthy subjects consumed either GFJ or water t.i.d. for 4 days in each trial. On each final day, a single dose of 4 mg pitavastatin or 20 mg atorvastatin was administered. GFJ increased the mean AUC 0-24 of atorvastatin acid by 83% (95% CI 23–144%)and that of pitavastatin acid by 13% (-3 to 29%).”
“We determined the validity of current medical advice to avoid grapefruit juice consumption while taking 3 widely used statins. A daily glass of grapefruit juice increases blood levels of simvastatin and lovastatin by about 260% if taken at the same time (about 90% if taken 12 hours apart), and atorvastatin by about 80% (whenever taken). Simvastatin 40 mg, lovastatin 40 mg, and atorvastatin 10 mg daily reduce low-density lipoprotein (LDL) cholesterol levels in a 60-year-old man with an LDL cholesterol of 4.8 mmol/L by 37%, reducing ischemic heart disease risk by 61%. When simvastatin or lovastatin are taken at the same time as grapefruit juice, the estimated reduction in LDL cholesterol is 48%, and in heart disease is 70%. If the juice is taken 12 hours before these statins, the reductions are, respectively, 43% and 66%, and for atorvastatin, 42% and 66%. The increased rhabdomyolysis risk from grapefruit juice consumption due to the increased effective statin dose is minimal compared with the greater effect in preventing heart disease. Grapefruit juice should not be contraindicated in people taking statins.”
Am I missing something? In the data tables shows the gfj portion with higher, not lower starting sirolimus levels than sirolimus alone. Would you not think if concerned about high levels with gfj the dose there would start at 5 mg or so…not 15 which is higher than the sirolimus alone low dose.
I did read lots on the lung disease side effects. Worrisome at first but reading the detail gets me over that.
As far as my comments on dosing and 20 mg weekly being “high” I base that on reports from users which is about the only thing to go on right now. Even with all of your testing you are not sure you are on the best dose for results. So I am hedging side effects against results…not the live to 110 years results but the health extension ones…aches, performance,etc. I have no big “obvious” problems to overcome so cannot measure on that. Green got into this with 6 mg and great results. That seems a good
starting point…until we have real trials…a long time away….this type of estimation is about all we have to go on. Blood tests every month are great but not necessary. You can drive yourself crazy doing all that and still not have it figured out.
My results so far. Eight weeks in. Got rid of a few nagging but not really debilitating aches and stiffness in shoulder. Maybe imagination. Some facial aging blemishes seem to have almost cleared. Have no noticed an increase in “fitness” as some report and nothing with weight…need to lose 15 lbs. This on 8 mg….last 2 weeks did with gfj. This is the 28 mg I refer to…8 plus 3.5 multiplier with the juice. So seems to be moving in the right direction. Will continue to ten weeks and the a break.
Great. Slow and steady. At minimum, unless you reach one or more side effects, you are probably not pushing mTOR down sufficiently. I am trending slowly and methodically to try and trigger some of these, whilst trying to tease out “improvements”. Blood markers, how I feel, and the study adverse table summary will serve as my guide.
I personally think you are getting much more than 350% increase taking 16 oz of GFJ. The GFJ protocol is as important as the dose of rapa when posting results. The more GFJ you take = the more bioavailability of Sirolimus. Most studies used 240 cc appx. 8 oz GFJ. I adjusted my personal protocol to 250 cc GFJ, 30 minutes before ingestion of SIrolimus and feel that I am getting 300-350%.
Have there been any studies on varying amounts of GFJ (or ketoconazole or the like) for inhibiting drug clearance? It stands to reason that more GFJ would give more inhibition, but probably only up to some maximum? 8oz? 16? 32?
So this is my current thinking. The Mannick paper showed a decrease in immune response with 20mg/wk of everolimus. We also know that everolimus is less effective than rapamycin so let’s put the dose equivalent at 80%. That would mean 20mg everolimus is the equivalent of ~16mg rapamycin. That further suggests that the optimum dosage for rapamycin (at least for immunity) is somewhere between 4 and 16mg/wk? Do those taking an effective dose above 16mg/wk (eg 6mg plus GF) have concerns around lower immunity?
One unknown from the study I would like to know is body weight. If the participants were small women for example then of course their mg/kg would be higher.
I thoroughly investigated pulmonary fibrosis before starting rapamycin and was convinced that it was an issue in immunosuppressed patients who had been on potent post transplant drugs and then switched over to rapamycin. A very select group.
The concern for rapamycin would be a suppression of the innate immune system leading to bacterial infections, so neutropenia, not lymphopenia, would be the red flag. Of course, we still want the range to be normal for both.
Also not concerned about iron deficiency. I take IP6 with inositol on top of rapamycin and my ferritin level is totally fine.
I’ve been on rapamycin for 5 years now at weekly doses. My ophthalmologist told me last week that I have the eyes of a 40 year old. I also had renal testing and my GFR is essentially the same as 15 years ago. I’m 67.
One concern, I’ve been free of all infections for the pas t5 years, but this past month, for the first time, I switched from 9 mg/ week to 12 mg every other week and caught this virus from hell, not Covid . Going back to weekly.
Relates to a more general point about the onset of side effects being an indicator of an efficacious dose. In other words, the idea that you push dose until you get side effect and then back off a bit and you will be at your “best” dose. Some posters allude to the idea (their thoughts, not verified) that if you don’t hit a side effect you are not at the dose which does any/much good. So, in theory that makes a good indicator of what your dose should be.
I disagree as does the data. Rapamycin has a very high therapeutic index…(great big difference in toxic dose and therapeutic dose …determined in phase 1 clinical trials)…which also would indicate that there can be a big difference in the therapeutic dose and the dose at which side effects occur. This varies a lot by person and is shown in various clinical trials.
Bottom line is cannot determine the efficacious dose from the onset of side effects. Nice thought, but does not work.
I have worked up to 9 mg/week with 9 oz GFJ and no sides. Thats about as far as I will go and seems to be at the top of the range for using amount us human lab rats. Guess I will break down and get tested for Rapamycin level post admin. Planning to time it for 2 hours post.
As I have pointed out…9 weeks into this and no really obvious changes. Then again, I had no big deal issues coming in…except visceral fat…so difficult to measure effect. Gonna keep using and see what happens in another cycle of 8 weeks with no break in-between.
I’m 76 and have been using rapamycin for 8 months, with grapefruit or grapefruit juice from the beginning. I started with 6 mg every ten days (thinking it was 3.5 times that, or 21 mg, accounting for the grapefruit) and quickly went to 12 mg (thinking it was 42 mg) every two weeks. I walk a few miles most days, but don’t do any other form of exercise. There have been no side effects and no noticeable benefits. If were more vigilant, I might have noticed something, but I haven’t.
Thanks to this forum, I decided to get a blood test to check my peak. It cost $108 through Ulta Labs. I ate a grapefruit the evening before, ate another at 8:30 a.m. and ate another at 11:00 a.m. when I took the 12 mg of rapamycin. The blood was drawn at 1:00 p.m. It tested at 68 ng/mL with a note that it had been retested. A representative from Ulta called to tell me that that level was critically high. I don’t find that worrisome since they would have been considering it in its role as an anti-rejection drug taken daily.
It did tell me what I wanted to know - whether the pills were the real thing. They are. I bought them from Pravin Lahoti at Varun Medicals in India. The cost, including shipping, was about $1.13 per mg for 1mg Zydus brand pills. I wanted to pay with PayPal, but he doesn’t accept that. I had to wire the money to his bank. The package of 83 strips of 6 pills took about a month to get here, with tracking showing lengthy stops at customs in Mumbai and New Jersey. The return address said Varun Medicals and the box didn’t appear to have been opened.