731 replies to this topic

[Alpharius]

What seems to be consensus with the D+Q combo? The results don't seem to be life changing but is it still worthwhile to use? I know quercetin is now suspect with recent studies. Have we abandoned navitoclax because of the cost plus the potential testicular toxicity?

Do you have a source for the testicular toxicity?
 

Another possible danger is killing off and depleting stem cells. Again, the very old would be vulnerable.

Do you have also a source on a possible negative impact of senolytics on stem cells? There was one publication with MSCs in vitro, where only Navitoclax did kill the senescent ones.

[Alpharius]

Ok I have found it. http://ar.iiarjourna.../34/7/3739.full

The equivalent dose used in those experiments would be 30 mg for humans. As far as I understand the wording, in dogs after prolonged usage the testicular germ cell depletion was so severe, that they could not regenerate, but 4 week duration of Navitoclax treatment was reversible.
Any comments on this one guys?

Non-clinical toxicity profiles of navitoclax. Navitoclax is not genotoxic. The main effects of navitoclax were testicular toxicity, thrombocytopenia and lymphopenia. Both thrombocytopenia and lymphopenia were dose-dependent, reversible, and monitorable. Dose-dependent testicular toxicity was observed in both rats and dogs. After 4 weeks of once daily dosing, the NOAEL was 3 mg/kg/day in the rat, with less severe effects at the end of a 4-week recovery period suggestive of reversibility, and 1 mg/kg/day in the dog, with minimal, non-adverse effects at the end of a 4-week recovery period. There was no evidence of reversibility with 13 weeks of dosing and a 13-week recovery period. Minor navitoclax effects were observed on the rat ovary (decreased in ovarian weights in all studies; ovarian atrophy at the highest dose level, 100 mg/kg/day, in the chronic, 6-month study). However, these effects were considered not to be adverse due to the absence of associated histopathologic findings or effects on fertility. The HED of 30 mg was based on the NOAEL of 1 mg/kg/day for platelet and lymphocyte count reductions and for testicular germ cell depletion in the dog at dosing durations up to 13 weeks. This provided a conservative estimate of the non-adverse navitoclax dose level as determined from toxicology studies.

[abefij]

First human trial of D+Q by Dr. Kirkland in the Lancet:

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

https://www.ebiomedi...0629-7/fulltext

Abstract

Background

Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.

Methods

A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.

Findings

Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).

Interpretation

Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases.

ClinicalTrials.gov identifier: NCT02874989 (posted 2016–2018).

 

Edited by abefij, 10 January 2019 - 11:43 PM.

[roguereason]

 

First human trial of D+Q by Dr. Kirkland in the Lancet:

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study

https://www.ebiomedi...0629-7/fulltext

Abstract

Background

Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.

Methods

A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.

Findings

Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).

Interpretation

Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases.

ClinicalTrials.gov identifier: NCT02874989 (posted 2016–2018).

 

 

They used "quercetin phytosome" haven't researched the bio-availability yet, but worth noting.

[Izan]

we need a separate sub-group for this.

[steven acoca]

For support,

Dasatinib potently inhibits BCL-2 (anti-apoptotic) and induces BAX (pro-apoptotic).

• “The Achilles' heel of senescent cells: from transcriptome to senolytic drugs” (2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531078/
• "Philadelphia chromosome"), Src, c-Kit, ephrin receptors, and several other tyrosine kinases. “Targeting BCL-2 and ABL/LYN in Philadelphia chromosome–positive acute lymphoblastic leukemia” (2016) http://stm.sciencemag.org/content/8/354/354ra114.full
• “Bcl-xl and Mcl-1 are the major determinants of the apoptotic response to dual PI3K and MEK blockage” (2015) https://www.spandidos-publications.com/ijo/47/3/1103

Honokiol potently inhibits BCL-XL (anti-apoptotic).

• “Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells” (2002) https://drive.google.com/open?id=0B_pfWfFEQDILeUw1NHBsQXV5LUU

A good pictorial overview of the relationship between apoptosis effectors is shown in Figure 1A of “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging” (2017) http://www.cell.com/cell/fulltext/S0092-8674(17)30246-5


Modulating the BAX/BCL ratio has long been a target for inducing apoptosis.

• “Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association” (2004) https://www.ncbi.nlm.nih.gov/pubmed/14712090

Dasatinib doesn’t target BCL-2 and does nothing for the bax/bcl-2 ratio. Reread your own references!!

[alexfedorov]

Hey guys, does any of you sell Dasatinib? My email is 79850605415@ya.ru. 

[PAMPAGUY]

I ordered my Dasatinib and Fisetin powders from the following Alibaba supplier.  https://hhdpharm.en....TpH#top-nav-bar.  Used Emily.  This is the same supplier that furnished Rapa for other members in this forum.  Need to make sure that you get 98% Fisetin vs 50%.  Both are sold.  Dasatinib is 99% only, I believe.  I paid $245 for 5 grams Dasatinib, and 50 grams of Fisetin.  That includes $50 Fedex shipping.  So cost is Dasatinib = 120/5= $24 gram Fisetin   =  120/50 = $2.40 gram.  This includes shipping.  Saved on shipping by ordering both at same time.  This does not include Visa CC charge of 3% = $7.20 which is really the cheapest way to pay, and you have CC guarantees.  Will update group once I receive it.  Noticed that Fisetin on line is starting to get expensive vs just a few months ago.  The word is getting out.  It takes around 5 grams for one quarterly dose of Fisetin, so those little 30 tab bottles (100mg) they sell are worthless, and expensive.  I had no problem with receiving my Rapa order from China which was only a business size envelope delivered by Fedex, but this one is going to be larger.  Will have to wait and see.  For those without experience using powders, this is the way to go.  Buy a jewelers scale that measures to .001 gm. = 1 mg. for about $30.  Usually includes calibration weights.  The lower the max weight, the more accuracy you get.  Mine has a max weight of 20 grams, but goes to 1/1000.  You only need to weigh once a week for Rapa and quarterly for  senolytics.

I was suspect of China also at the beginning until I read an article that most of the drug manufactures in US order there raw materials from China.  They were running out of reagents for testing for Covid-19.  The reagents came from China.  If it is good enough for Merck and Pfizer, it's good enough for me.  Alibaba which is bigger than Amazon guarantees that you will get the product you order and they take CC.   I ordered by Rapa from China and I got exactly what I ordered at a very reduced price.  Remember China is 4 x the size of US and has 1,000 of companies competing for your dollars.

 

There is no mixing powders here.  You simply weigh the grams/milligrams that you are taking and put in glass, add water, mix, and drink it.  Not too difficult.  My Rapa was a little more complex, but not applicable here.

 

[OlderThanThou2]

I ordered my Dasatinib and Fisetin powders from the following Alibaba supplier.  https://hhdpharm.en....TpH#top-nav-bar.  Used Emily.  This is the same supplier that furnished Rapa for other members in this forum.  Need to make sure that you get 98% Fisetin vs 50%.  Both are sold.  Dasatinib is 99% only, I believe.  I paid $245 for 5 grams Dasatinib, and 50 grams of Fisetin.  That includes $50 Fedex shipping.  So cost is Dasatinib = 120/5= $24 gram Fisetin   =  120/50 = $2.40 gram.  This includes shipping.  Saved on shipping by ordering both at same time.  This does not include Visa CC charge of 3% = $7.20 which is really the cheapest way to pay, and you have CC guarantees.  Will update group once I receive it.  Noticed that Fisetin on line is starting to get expensive vs just a few months ago.  The word is getting out.  It takes around 5 grams for one quarterly dose of Fisetin, so those little 30 tab bottles (100mg) they sell are worthless, and expensive.  I had no problem with receiving my Rapa order from China which was only a business size envelope delivered by Fedex, but this one is going to be larger.  Will have to wait and see.  For those without experience using powders, this is the way to go.  Buy a jewelers scale that measures to .001 gm. = 1 mg. for about $30.  Usually includes calibration weights.  The lower the max weight, the more accuracy you get.  Mine has a max weight of 20 grams, but goes to 1/1000.  You only need to weigh once a week for Rapa and quarterly for  senolytics.

I was suspect of China also at the beginning until I read an article that most of the drug manufactures in US order there raw materials from China.  They were running out of reagents for testing for Covid-19.  The reagents came from China.  If it is good enough for Merck and Pfizer, it's good enough for me.  Alibaba which is bigger than Amazon guarantees that you will get the product you order and they take CC.   I ordered by Rapa from China and I got exactly what I ordered at a very reduced price.  Remember China is 4 x the size of US and has 1,000 of companies competing for your dollars.

 

There is no mixing powders here.  You simply weigh the grams/milligrams that you are taking and put in glass, add water, mix, and drink it.  Not too difficult.  My Rapa was a little more complex, but not applicable here.

 

You didnt have problems with the customs? I am in France and I would like to order Dasatinib from China as well. When you say you use Emily, is that the name of the person you talked to? Thank you.

[mhillgizmo]

As stated in some of the above "interested" posts, if international mailing's to the U.S. is not an issue I'm in for 5 grams 

[aribadabar]

You didnt have problems with the customs? I am in France and I would like to order Dasatinib from China as well. When you say you use Emily, is that the name of the person you talked to? Thank you.

 

French customs are one of the lax ones, comparatively speaking. You most probably will be fine getting it through.

[OlderThanThou2]

French customs are one of the lax ones, comparatively speaking. You most probably will be fine getting it through.

 

Hopefully it will work out if they put the dasatinib in an enveloppe without saying what it is. If it works maybe I'll buy more products from them. I am not sure I would trust them on peptides though since they're harder to manufacture. I'd like to get some FOXO4-DRI when the next version is available, but that will be hard to obtain it in France. Perhaps we'll be able to arrange a group purchase from the legit company that made it for the trials.