[GRG] wrap up: 50mg Dasatinib+500mg Quercetin gerotrial ?

Hello,

Attempt to keep focus and go forward:

First a recap (please rectify if misunderstood):

— Treatment: one oral dose of {500 mg Quercetin and 50 mg Dasatinib} (/slightly less) ; or placebo

— Length: one year

— Inclusion: ideally “healthy aged persons” eg at age 65. Should we do a spirometry test? for inclusion? see below. The sufficient number of participants should be estimated once measures are defined.

— Treatment cost: about 800$ per participant

— Measures?:  what would we typically measure to make an aggregate health indicator and to measure cell senescence and regeneration? how much would it typically cost?

— Logistics?: should participants be US based/more restrictive/less restrictive? Should they each be followed by their personal doctor?

— Alternative: a skin treatment. (*Personally* I would very much prefer to transpose the article highlighted here by Johnny; killing senescent cells looks very big against general aging)

Then about the main concern: Dasatinib likely to cause pulmonary hypertension?

a) After browsing dasatinib+pulmonary on pubmed it seems quite clear (in the sense of repeated reports) that long term administration of 140 mg dasatinib/day creates cases of pulmonary hypertension that are reversible when the treatment is stopped. 

— Example: http://ift.tt/1G4UWOa

“A 23-year-old female with chronic myelogenous leukemia was treated with dasatinib at a dosage of 140 mg/d”… “after 35 months (…) PAH related to dasatinib was diagnosed and dasatinib was permanently discontinued. The symptom of dyspnea disappeared quickly after withdrawal of dasatinib. The heart structure and pulmonary arterial pressure completely recovered after 7 months of dasatinib discontinuation”

— Example: http://ift.tt/1G4UWOe

“Similar to other studies, this study too found that dasatinib administered at 140 mg/day for the treatment of advanced SqCC of thelung is associated with excess adverse events, so is not recommended in unselected patients” //reversion after discontinuation was not checked in this study

— Example: http://ift.tt/1G4UWOf

“a 50-year-old man, diagnosed with chronic myeloid leukemia in August 2003, who developed pulmonary arterial hypertension after > 4 years of treatment with dasatinib. The complete remission of pulmonary arterial hypertension following dasatinib discontinuation”

— and many other examples of reversible PPH with Dasatinib. eg http://ift.tt/1G4UWOh

b) A Phase I was stopped due to pulmonary toxicity with 70 mg/day dasatinib

The full text is available: http://ift.tt/1EMJVEa

However is was in combination with chemoradiation which causes lung toxicity, and it was before the studies above

c) Quercetin is is reported to reverse pulmonary toxicity in rats http://ift.tt/1G4UVdg

10 mg/kg/d per os during 10 days. The human equivalent (http://ift.tt/1G4UVdi : 37/6) would be 70kg*10/(37/6) = 113 mg/day so a smaller dose than what would be done here over one day, more about a week but at the same time there is elimination => if it transposes to human (total guess) it would help further reduce the risk

d) Conclusion?

I am not a medical doctor but I would think that the risk it very small (or rather reversible after the single dose) and to be secure I would personnally suggest a spirometry test to include patients as it is merely blowing it a little thing http://ift.tt/1G4UWOo excludes many risks.

IF there was still wonder I would try to ask around, but I can’t promise the result (it happens that I have worked on pulmonary hypertension, in mice, rats and patients, but that’s more that a decade ago).

Of note,

– I haven’t gone though clinicaltrials.gov to see if there is more than what I found on pubmed.

– My analysis though pubmed is rather rapid (~2h). One might want to go through it too.

Then about the theoretical wonder about why some mice did not appear tolive longer.

The famous mice that were ‘rapidly aging’ due to an excess of senescent cells and went back to an appearently normal health state when those excessive senescent cells were killed, did not apearently lived longer than normal (not published I believe).

…In my view this is totally logic (which is impressive because with our general lack of knowledge, in various areas biology is not logic): they still have a ‘standard’ dose of senescent cells compared to their ‘wild-type’ controls: why would they age less.

I am not aware of any lifespan result yet of mice with a system that makes them have less senescent cells than their standard ‘wild-type’ control. My guess is that the effects (on health at least) were so obvious on models so far that we are on something robust in terms of extrapolation to ‘standard aging’: to me the approach discussed here is likely to improve health and lifespan.

Cheers

Edouard

De : Mike Darwin À : Dr. Harold Katcher ; Gerontology Research Group Cc : edebonneuil Envoyé le : Jeudi 12 mars 2015 11h00Objet : Re: [GRG] Dasatinib + Quercetin gerotrial?…

Hi Howard,

Quercetin is not associated with PPH, to the best of my knowledge. Rather, it’s dasatanib, which is a prescription drug used primarily in the treatment of cancer. Dasatnib is an oral oral Brc Abl tyrosine kinase inhibitor. It was U.S. FDA approved in 2006, however because of its high cost, there is not a lot of experience with it.

I don’t know if dasatanib+quercetin will be effective in humans at doses that are “safe”, or even if reducing the burden of senescent cells will extend lifespan. However, as you point out, it is likely that reducing the number of senescent cells will improve the health-span. Moreover, if this combo works topically, or as an oral-topical combination then it may substantially rejuvenate the skin. Senescent and hyperplasia cells in skin are a major cause of skin aging.  I suppose I should patent this idea, because whoever develops AND successfully markets the first truly effective skin anti-aging cream/nostrum is going to be richer than Bill and Melinda Gates, LOL! Photodamaged cells form large colonies of both senescent and actinic (hyperplastic) cells. A recently developed UV photography technique shows just how bad, how early, and how nearly invisible this pathology is:

There are several treatments to eliminate the actinic fraction of these photodamaged areas, most notably the cytotoxic chemotherapeutic agent  5-fluorouracil, administered as a 5% cream. The 5-FU causes inflammatory necrosis of the actinic cells, as can be seen in the photos below:

This red, raw inflammatory response starts after a few days of application. The recommended duration of treatment is 3-4 weeks and the redness persists for a couple of weeks following the cessation of Tx. Once Tx is complete, the risk of skin cancer is greatly reduced, most of the hyperpigmented, freckled, liver-spotted areas are gone, and the skin generally looks much younger. However, you have to go around looking like the people in the photos above for onto two months: http://ift.tt/1EMJTw1 to say, many patients simply refuse to have this Tx! [As a relevant aside, age spots or liver spots are NOT due to lipofuscin containing cells, nor are they remediated by centrophenoxine.]

There is another Tx for actinic keratosis which does not cause this inflammatory response, imiquimod, which is a topical medication that up-regulates a variety of cytokines that provoke a nonspecific immune response (interferons, natural killer cells) and a specific immune response (T cells). It is applied 2-3 times a week for up to 4 months, although generally one month of Tx is sufficient, with the notable downside being that it costs about $800 for a course of treatment. 

If you look at the photos above, it makes you wonder what the interior of our aging/aged bodies look like with respect to senescent cells. It should also give pause to the systemic application of dasatinib+quercetin without first evaluating the effect of inducing apoptotic death in a significant fraction of the body’s cells locally. This is in part why I suggest a cutaneous trial, first. 

Since I discovered the ability of imiquimod to selectively destroy actinic cells in the skin, I’ve thought about the possibility of finding a way to do the same thing with senescent cells systemically. Dasatinib+quercetin may be the answer. Even if it can only be used topically, that may prove advantageous from a cosmetic standpoint – which is no small thing.

Mike Darwin 

 

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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