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Question about PBN, Tempol and Parkinson's disease

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 Posted 4/15/2014 9:04:46 AM
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My father has been treating his Parkinson's disease with supplements, herbs and antioxidants to limit the free radical damage.  He is only on two prescription medications, Deprenyl and extremely low dose zonisimide (which at a low dose helps make gluathione).  He also gets weekly IV glutathione pushes.

Many of his symptoms ceased when he started these treatments -- but as Parkinson's is a proressive disease. he sought out other therapies.  

Based on the information in Mitochondria-targeted antioxidants for treatment of Parkinson's disease: Preclinical and clinical outcomes.  http://www.ncbi.nlm.nih.gov/pubmed/24060637  he started the protocol for the nitroxide spin trap known as Tempol.  He has been on this treatment for about 6 weeks with marked improvement - which again got him out of his wheel chair and has kept the choking and shaking at bay in between his IV treatments.  However, his doctor thought he would see even more improvement given that the treatment works on a cellular level.  Maybe there will be more improvements in the future -- but searching the term brought me to a post on the older life extension forum. http://forum.lef.org/default.aspx?f=37&m=16851

The post mentions another spin trap.  I was wondering if the members who posted the information are still around on this forum.  If so, can you please tell me about your experience with PBN (n-tert-butyl phenyl aplha nitrone), n-tert-butyl hydroxylamine hydrochloride (or plain hydroxylamine hydrochloride) or 2-deoxy-d-glucose (which has been shown to mimic the effects of CR)?

It looks like PBN has a slightly different mode of action -- although it still works on the mitochondrial level.

Here is a repost in the event that the old forum is ever taken off-line -

charles grashow
Registered Member


Date Joined Jan 2001
Total Posts : 15
Posted 6/1/2001 3:15 PM (GMT -4)
The following 3 chemicals have exhibited, in laboratory tests, potent life-extension results

1) n-tert-butyl hydroxylamine hydrochloride (or plain hydroxylamine hydrochloride)

2) 2-deoxy-d-glucose (which has been shown to mimic the effects of CR)

3) PBN (n-tert-butyl phenyl aplha nitrone)

I have obtained (rather easily) hydroxylamine hydrochloride which I intent start taking at a dosage of 50mg/da.

The other 2 chemicals are available from chemical suppliers but the ones I have contacted will not sell to individuals!!

As a libertarian, I find this offensive as these substances are non-hazardous, legal substances.

::Actually, since hazardous is a matter of relative defintion (the dose makes the poison), saying they are non-hazardous is not a logically supportable statement. The LD50 for hydroxylamine chloride in mice is 408 mg/kg orally which scales to about 2800 mg for a human which is not an extremely large amount (although still 20 times more than you are considering). ::

My question is, does anyone know of a reputable supplier who is willing to sell the above chemicals to me as an individual?

Any input would be greatly appreciated
Charles Grashow

::While I totally agree with your libertarian viewpoint (these companies are under duress from governments to require legitimate experimental use before sale), it is actually reasonably easy to get around this problem by faking being a research company for your order, although you may have to construct a research protocol to satisfy some of them.
As for using them as supplements, unless one is in a desperate situation (is terminal or has a terminal loved one), IMO it is rather foolish to take the first two of these for life extension purposes at this time (PBN has been around longer and is better tested). If you wish to get the benefits of CR then simply have the will and courage to do CR. Lots of people do. It is not that difficult. In addition, I have been in correspondence with someone taking N-tert-butyl-hydroxylamine regarding dosage and, IMO, a much safer daily dosage of the lighter hydroxylamine hydrochloride to start with would be 10 mg and then work up to 50 as observations and tests suggest.::
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Chris Allen
Registered Member


Date Joined Dec 2000
Total Posts : 112
Posted 10/8/2001 10:50 AM (GMT -4)
>1) n-tert-butyl hydroxylamine hydrochloride (or plain hydroxylamine hydrochloride)
{snip}
>I have obtained (rather easily) hydroxylamine hydrochloride which I
>intent start taking at a dosage of 50mg/da.

I just ordered it (n-tert-butyl hydroxylamine hydrochloride) easily from Springfield Scientific. My 5g order should be coming in this week.

http://springfieldsci.com
1-800-344-2047
I ordered n-tert-butyl hydroxylamine hydrochloride
by Pfaltz & Bauer
CAS# 57497-39-9
formula C4H12CINO

When they asked for my company name and phone #, I gave them my own personal name and phone #. If anyone who wants to order this stuff thinks this is a bad idea, then make up a company name in advance, of course.

::How much are they charging you for it? Others have been paying $135.00 for 5 grams of the TCI brand. I have just written to TCI asking for bulk pricing and I will be doing the same for Pfaltz & Bauer.::

One concern I have, though, is the 97% purity. What do you suppose, Tom, might be in the other 3%? Is this something to worry about?

::Both the sources show 98% purity in their chemical information. I imagine that most of the impurity is leftover solvent, but you would be best to ask your supplier directly about it.::

-Chris
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Chris Allen
Registered Member


Date Joined Dec 2000
Total Posts : 112
Posted 10/9/2001 3:57 PM (GMT -4)
>::How much are they charging you for it? Others have been
>paying $135.00 for 5 grams of the TCI brand.::

Im pretty sure it was around $135. Ill have specific details for you about the order after I get it -- later this week, hopefully.

>::Both the sources show 98% purity in their chemical information.::

Oh. I see that on their website now. IIRC sciquest reported 97%.

-Chris
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steve
Registered Member


Date Joined Dec 2000
Total Posts : 98
Posted 10/10/2001 9:08 AM (GMT -4)
I have obtained the same quantity (5 grams) from TCI America (through an intermediary which I cant remember at the moment) for $106.45 which purports to be 100% pure. TCI, as I recall, wont deal directly with individual customers.

::Actually, on their online catalog page (http://tciamerica.com - catalog search) for that product (CAS# 57497-39-9), it states that the Purity (Method) is 98 % T. I dont know what the T implies.
Two days ago I sent email to them asking for bulk pricing, but they have not replied. Perhaps I will also have to either invent a company or go through an already established company.::
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tomcarter_99
Registered Member


Date Joined Dec 2000
Total Posts : 35
Posted 10/28/2001 12:15 PM (GMT -4)
>The following 3 chemicals have exhibited, in laboratory tests, potent life-extension
>results
>
>1) n-tert-butyl hydroxylamine hydrochloride (or plain hydroxylamine hydrochloride)
>
>2) 2-deoxy-d-glucose (which has been shown to mimic the effects of CR)
>
>3) PBN (n-tert-butyl phenyl aplha nitrone)
>
>I have obtained (rather easily) hydroxylamine hydrochloride which I intent start
>taking at a dosage of 50mg/da.
>
>The other 2 chemicals are available from chemical suppliers but the
>ones I have contacted will not sell to individuals!!
>
>As a libertarian, I find this offensive as these substances are
>non-hazardous, legal substances.
>
>::Actually, since hazardous is a matter of relative definition (the dose
>makes the poison), saying they are non-hazardous is not a
>logically supportable statement. The LD50 for hydroxylamine chloride in mice
>is 408 mg/kg orally which scales to about 2800 mg
>for a human which is not an extremely large amount
>(although still 20 times more than you are considering). ::
>
>My question is, does anyone know of a reputable supplier who
>is willing to sell the above chemicals to me as an individual?
>
>Any input would be greatly appreciated
>Charles Grashow
>
>::While I totally agree with your libertarian viewpoint (these companies are
>under duress from governments to require legitimate experimental use before
>sale), it is actually reasonably easy to get around this
>problem by faking being a research company for your order,
>although you may have to construct a research protocol to
>satisfy some of them.
>As for using them as supplements, unless one is in a
>desperate situation (is terminal or has a terminal loved one),
>IMO it is rather foolish to take the first two
>of these for life extension purposes at this time (PBN
>has been around longer and is better tested). If you
>wish to get the benefits of CR then simply have
>the will and courage to do CR. Lots of people
>do. It is not that difficult. In addition, I have
>been in correspondence with someone taking N-tert-butyl-hydroxylamine regarding dosage and,
>IMO, a much safer daily dosage of the lighter hydroxylamine
>hydrochloride to start with would be 10 mg and then
>work up to 50 as observations and tests suggest.::

Hi,
You may be better off without the other two.

N-t-butyl hydroxylamine, a hydrolysis product of alpha-phenyl-N-t-butyl nitrone, is more potent in delaying senescence in human lung fibroblasts.
Atamna H, Paler-Martinez A, Ames BN.
Division of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3202, USA.

Alpha-phenyl-N-t-butyl nitrone (PBN), a spin trap, scavenges hydroxyl radicals, protects tissues from oxidative injury, and delays senescence of both normal human lung fibroblasts (IMR90) and senescence-accelerated mice. N-t-butyl hydroxylamine and benzaldehyde are the breakdown products of PBN. N-t-Butyl hydroxylamine delays senescence of IMR90 cells at concentrations as low as 10 microM compared with 200 microM PBN to produce a similar effect, suggesting that N-t-butyl hydroxylamine is the active form of PBN. N-Benzyl hydroxylamine and N-methyl hydroxylamine compounds unrelated to PBN were also effective in delaying senescence, suggesting the active functional group is the N-hydroxylamine. All the N-hydroxylamines tested significantly decreased the endogenous production of oxidants, as measured by the oxidation of 2, 7-dichlorodihydrofluorescin and the increase in the GSH/GSSG ratio. The acceleration of senescence induced by hydrogen peroxide is reversed by the N-hydroxylamines. DNA damage, as determined by the level of apurinic/apyrimidinic sites, also decreased significantly following treatment with N-hydroxylamines. The N-hydroxylamines appear to be effective through mitochondria; they delay age-dependent changes in mitochondria as measured by accumulation of rhodamine-123, they prevent reduction of cytochrome C(FeIII) by superoxide radical, and they reverse an age-dependent decay of mitochondrial aconitase, suggesting they react with the superoxide radical.
PMID: 10702229 Full text available.

In the full text the authors say that the other breakdown product of PBN, benzaldahyde, is toxic. I recently read somewhere that the effective dose and the toxic dose of 2-deoxy-glucose are very close to each other. (I may have read it in this very article) Note that the concentrations given are expressed in moles and are not therefore due to the molecular weights.

::In vitro concentrations are always expressed in moles per liter since nothing else makes as much sense to compare. The lower concentration of NTBH than PBN needed to have the same effect is probably due to the need for PBN to disassociate to NTBH and benzaldehyde before it is as effective. That kind of metabolic conversion would be less efficient in vitro than in vivo, I think. ::

This stuff is very powerful and very untested, but with perhaps the greatest potential to slow aging of any existing product.

::I agree and I have been watching reports of it and those taking it for several months now. I still have reservations about its lack of long range safety testing, but for those over forty or in a more desperate state, I think it may be worth trying in small dosages. I will soon be starting to take it myself, and I am asking for input from anyone who might also be interested in taking it with a view to arranging lower bulk price purchasing. ::

Good luck and let us know how you do on it. Beware of anything Tom is afraid to take because he takes just about everything. :>Wink I will probably end up taking this stuff just a few months after he does. Tom, I wonder if you think this stuff would potentiate (by sparing) other non-enzymatic intracellular anti-oxidants that you and take and to what extent?

::I expect that it would. However, my biggest aging damage concern at this time is with the mitochondria, so the effect of NTBH that I am most interested in derives from its relationship to PBN and the proven result that PBN reduced mitochondrial ROS and their damaging effects back to youthful levels even while ALC was increasing mitochondrial energy output back to youthful levels.::

Thomas

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SuperDave
Registered Member


Date Joined Apr 2001
Total Posts : 3
Posted 10/28/2001 7:34 PM (GMT -4)
I have also recently ordered and obtained some N-(tert-Butyl)hydroxylamine HCl, and would like to know how people are administering their doses as a practical matter. I have been storing it in the freezer (have not yet even broken seal on bottle). Since I plan on starting with a very small amount (10 mg/day), it would be a real hassle to remove the bottle from storage, weigh out 10 mg, and put in a capsule (or whatever) nearly every single day. Perhaps of greater concern, would be the inherent repeated exposure of the chemical to the air and moisture at RT, when weighing out the dose.

Does anyone know how stable the stuff is in an aqueous solution? Perhaps it would work to dissolve an amount sufficient for ~ week in water, and keep refrigerated.

Any ideas/suggestions?

Thanks.

::I agree that it should not be opened and closed every day. For one thing, that will cause it to attract water and you will loose that ability to measure it accurately if not causing it to be unstable. If you keep it in a brown bottle (or zip-lock bag placed inside a brown bottle that would be best. At least one person who has been taking NTBH has been diluting/disolving it in water and it does not appear to be unstable if kept in the refrigerator (dark and cool) for a few weeks at a time.
My preferred method for all powders is to keep the original stock sealed, out of light and not warn while opening it only periodically to make up my currently being used supply. The currently being used supply (2-3 weeks worth) is then mixed with all the other powders which are currently being used. Thus, I mix up (actually Kitty does it for both of us) 2-3 weeks worth of all powders at one time. See our regimens at http://morelife.org/personal for details.
Either of these dilution methods have the advantage that the original stock is opened only infrequently and measurement of tiny amounts (potentially inaccurate and tedious) is avoided. ::

-Dave
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SuperDave
Registered Member


Date Joined Apr 2001
Total Posts : 3
Posted 10/29/2001 11:18 PM (GMT -4)
>I have obtained the same quantity (5 grams) from TCI America
>(through an intermediary which I cant remember at the moment)
>for $106.45 which purports to be 100% pure. TCI, as
>I recall, wont deal directly with individual customers.

Mine came from TCI as well, and the label on the bottle lists the purity at 100%.

>::Actually, on their online catalog page (http://tciamerica.com - catalog search) for
>that product (CAS# 57497-39-9), it states that the Purity (Method)
>is 98 % T. I dont know what the T
>implies.::

I assume the T refers to titration.

Dave
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Tim
Registered Member


Date Joined Jul 2001
Total Posts : 71
Posted 10/30/2001 8:34 AM (GMT -4)
Tom
From the article I cited on the PBN thread on diethylhydroxylamine, Heicklen found it was very unstable in tap water due to dissolved oxygen therein. He autoclaved the water and found the DEHA had a half-life of about three days. A pressure cooker can be used as a crude autoclave to rid the water of oxygen. This would be somewhat labor intensive and I think probably unnecessary given the fact that hydroxylamines redox cycle in the mitochondria. So its oxidized form is probably as effective as the reduced form.

Tim

::If the same oxidation which happens during in vivo operation of the chemical is all that happens to it in water, then I agree that should not reduce its effectiveness.::
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tomcarter_99
Registered Member


Date Joined Dec 2000
Total Posts : 35
Posted 11/1/2001 3:45 PM (GMT -4)
Here is some more info I missed first time around. I now have almost 1,000 pages of archives which I regret not having organized better from the start. This indicates that nitrone-related therapeutics and something called Ebselen may have some effects that the hdroxylamines dont. And further more that well tested compounds may be only about two years away.

::Then, by definition almost, it is questionable how well-tested they are. We must always bear in mind the limited length of time for which most of these new compounds have been tested on any mammal, let alone on complex and long-lived humans.::

This is referenced in the Ames article listed above and it shows that in some circumstances PBN (a nitrone is effective when Hydoxylamines are not. Perhaps because of lack of effect on H2O2. http://www.jbc.org/cgi/content/full/275/43/33585 Nitrones are in phase II trials in 2001.
FROM AN ARTICLE IN 2001 ( I dont know from where)
Centaur has long since moved beyond PBN to entire new classes of compounds, which the company refers to collectively as NRTs (for nitrone-related therapeutics) and for which it holds patents. Centaur has NRTs for three brain- related indications -- acute stroke (in collaboration with AstraZeneca), Parkinsons disease, and AIDS dementia complex -- in Phase II clinical trials and is preparing to move into final pivotal studies for all of these indications this year. Frenzel says the company has relatively advanced preclinical programs in arthritis and inflammatory bowel disease as well as Alzheimers. Cutanix, a Centaur spin-off, focuses on dermatological applications of NRTs. (Lawrence Berkeleys Campisi is engaged in a collaboration with Cutanix.)

Centaur doesnt call its molecules anti-aging compounds. But a new NRT appears to have extended the life spans of lab mice, according to a talk company scientists gave at the annual meeting of the American Aging Association in Seattle last June. Although Floyd says the study needs further validation, it seems to confirm oxidative stress key role in the aging of not only invertebrates but mammals.
Recently, Ames then-postdoc, Tory Hagen, perfected a way to assess mitochondrial function in intact rat-liver cells, avoiding the artifact inherent in more rough-and-tumble isolation procedures that destroy fragile older mitochondria. The team observed significant age-related reduction in mitochondrial transmembrane potential, the driving force for ATP synthesis.
Moreover, says Hagen, now a biochemistry professor at Oregon State University in Corvallis, we found that acetyl carnitine (ALCAR), orally administered in the rats drinking water, could completely reverse that decline. We also found that ALCAR reversed a more than 50 percent age-related decline in cardiolipin, an important mitochondrial-membrane phospholipid that governs many protein functions.
After one month on ALCAR, Ames says, the rats mitochondrial metabolism kicked into high gear. Those old rats got up and did the macarena. They looked, acted, moved, behaved like younger ones and showed improved performance on a rat IQ test.
However, the treated rats reinvigorated liver mitochondria also seemed to be generating more free radicals. We were concerned about that, says Hagen. We were increasing mitochondrial function but were not necessarily making the mitochondria more efficient. Its like an untuned car engine. Step on the gas and the car will go faster, but you get lots of hideous exhaust fumes. So we decided to see whether we could tune up the cells antioxidant levels.
When they gave the rats PBN in addition to ALCAR, oxygen radical production dropped. Then, in place of PBN, they substituted alpha-lipoic acid, which is both fat- and water-soluble, easily crosses the blood-brain barrier (as does PBN, but not vitamin E), and, unlike PBN, can be taken orally with good absorption and is freely available in health-food stores. The ALCAR-lipoate combination worked like a charm. When we combine them, we have the best of both worlds. Were improving mitochondrial function without an attendant increase in oxygen radicals, says Hagen.

::It is unfortunate that he never published this result to make it scientifically valid, accessable and reproducible. ::

Cautious observers are reserving their applause pending studies designed to see if ALCAR-lipoate-treated rats actually outlive controls. Ames has received an NIH grant to do just that. Meanwhile, he and Hagen are scientific cofounders of a company, tentatively named Juventa, to exploit potential uses of the ALCAR-lipoate mitochondrial tonic. (Juventa has just hired an acting CEO, Allan Prager.)

There is also the well known Eukarion story:
Eukarion, Inc., a privately held biopharmaceutical company located in Bedford, MA, is developing small molecule drugs primarily for the treatment of degenerative and age-related disorders. The companys principal focus is on its patented synthetic catalytic scavenger (SCS) technology for the treatment of conditions associated with oxidative stress. In addition to its SCS technology, Eukarion is developing proprietary technology to adapt monoclonal antibodies for intracellular use. For more information, visit http://www.eukarion.com. For updates on the progress of their products

Should a 60 year in good health wait for better tested products that might be just around the corner? Or should we jump on the theory that the probable impending launch of similar products mitigates safety concerns? I would really like to go with about 10mg of NTBH while continuing to monitor developments. It seems more exciting than watchful waiting.

::Even after approval, all these chemicals would almost certainly only be available by expensive prescriptions for limited purposes, however. Moreover, I think that is it more important to carefully read the papers and hear the reports of those who have already jumped in (for emergency purposes mostly) than it is to rely on the impending launch. But for NtBHA, yes, I think the situation looks good for most people over 50 from the point of view of safety and effectiveness and I am planning to soon begin taking small amounts (10-20 mg) daily as soon as I get some. I will also be investigating Ebselen.::

Thomas

::I am checking interest in making a bulk purchase of NtBHA (mnemonic used by Ames latest paper) from a chemical supplier to make it more easily available. If anyone is interested contact me at: tom@morelife.org ::
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axolotl
Registered Member


Date Joined Feb 2001
Total Posts : 16
Posted 11/12/2001 8:04 AM (GMT -4)
This bothers me, hope-wise. Are these new antioxidants like PBN, etc. unique in function so as to slow aging in ways that natural antioxidants cannot? We can safely take large amounts of a wide variety of natural antioxidants - unlike some of these newer chemicals. Is the evidence clear that these new substances are potent where others are not?

axolotl

::I had very nice long explanatory answer to your question and lost it all, so I am afraid you will just have to do with a shorter one. Sorry.
The answer is basically, yes. Just as with many exogenous chemicals which we now take which are not part of our natural foods, say ginkgo biloba, these other chemicals have certain properties and penetrate to certain places in the body which other exogenous chemicals do not. Some of them even exceed the capabilities in certain special ways of chemicals which the body makes itself (other than enzymes).
Since our bodies are currently far from perfect, it is certainly going to take *something* unnatural to make them better and to greatly extend human lifespan.
Besides, there is no reason to suppose that chemicals which are man-made are any more likely to be harmful than those which are made by plants or animals, but which are not consumed as food by humans. Both are equally as foreign to the body. Both need to be tested thoroughly for safety before human consumption and taken in very small dosages to start.::
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Chris Allen
Registered Member


Date Joined Dec 2000
Total Posts : 112
Posted 11/13/2001 9:24 AM (GMT -4)
I wrote:
>Im pretty sure it was around $135. Ill have specific details
>for you about the order after I get it --
>later this week, hopefully.

Its more than a month later now and, after checking with springfieldsci to see if my order had come in _yet_ and being told no, I cancelled.
{sourgrapesmode}
They charge too much anyway.
{/sourgrapesmode}

-Chris

::I checked their online catalog and it does not even contain NtBHA. Then I emailed them and all they said was: Yes, you are right, it is not in our catalog. Perhaps it has another name. Currently, I am not sure how anyone has managed to buy it from them.::
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tomcarter_99
Registered Member


Date Joined Dec 2000
Total Posts : 35
Posted 11/18/2001 5:48 PM (GMT -4)
Does N-tert-butyl-hydroxylamine (NtBHA) break ages too?

FASEB J 2001 Nov;15(13):2415-22
Changes in myosin structure and function in response to glycation.
Ramamurthy B, Hook P, Jones AD, Larsson L.
Noll Physiological Research Center, University Park, Pennsylvania 16802, USA.

Nonenzymatic glycosylation (glycation) is recognized as an important post-translational modification underlying alterations of structure and function of extracellular proteins. The effect of glycation on intracellular proteins is, on the other hand, less well known despite the vital importance of intracellular proteins for cell, tissue, and organ function. The aim of this study was to explore the effects of glycation on the structure and function of skeletal muscle myosin. Myosin was incubated for up to 30 min with glucose and subsequently tested for structural and functional modifications by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and a single-fiber in vitro motility assay, respectively. MALDI spectra revealed glycation-related structural alterations as evidenced by the disappearance of specific Lys-C proteolysis products and the appearance of higher mass peaks that are attributed to cross-linking by glucose. This change was paralleled by a significant reduction in the in vitro motility speed, suggesting a structure-related decline in myosin mechanics in response to glucose exposure. Further evidence that early glycation products form in the regulatory regions of the myosin molecule is derived from the fact that there is complete reversal of motility speed after reaction with the Schiff base-cleaving agent hydroxylamine hydrochloride. Thus, glycation of skeletal muscle myosin has a significant effect on both the structural and functional properties of the protein, a finding that is important in understanding the mechanisms underlying the impairment in muscle function associated with aging and diabetes.
PMID: 11689466

::Thanks for the interesting abstract. However, I think it does not imply anything about *breaking* crosslinks. The Schiff base is merely the first product of glycation which can also spantaneously reverse to throw off the sugar attachment. The irreversibility comes only after the Schiff base converts to an Amadori product. Even then there is as yet no crosslinking, but only solid sugar attachment. Cross-linking only occurs when the other end of the sugar also attaches somewhere else.
However, there may be more going on than is theorized in this abstract. The full paper bears reading here.::

Thomas
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tomcarter_99
Registered Member


Date Joined Dec 2000
Total Posts : 35
Posted 11/21/2001 4:33 PM (GMT -4)
Hi,
I believe Tom has made it quite clear that no young people should experiment with this type of supplement. The below abstract emphasizes this point for premenopausal women. I also post it to get Toms response to the curious fact that the affect was prevented by another anti-oxidant.
Thomas

Teratology 2000 Nov;62(5):346-55
Hydroxylamine moiety of developmental toxicants is associated with early cell death: a structure-activity analysis.
DeSesso JM, Jacobson CF, Scialli AR, Goeringer GC.
Mitretek Systems, McLean, Virginia 22102, USA. jdesesso@mitretek.org

BACKGROUND: Cellular debris, an indicator of cell death, appears in limb buds of gestational day 12 rabbit embryos 4 hr after either a subcutaneous injection
of hydroxyurea to pregnant rabbits or an injection of hydroxyurea into the exocoelomic cavities of the embryos. This episode of early cell death appears to be central to the teratogenic action of hydroxyurea. Several chemicals that are structurally related to hydroxyurea, and that possess a terminal hydroxylamine moiety (-NHOH), also produce limb abnormalities.
METHODS: To investigate whether the hydroxylamine moiety is responsible for early cell death and, therefore, is likely to be associated with teratogenesis, five structurally related hydroxylamine-bearing chemicals (hydroxylamine hydrochloride,
N-methylhydroxylamine hydrochloride, hydroxyurea, acetohydroxamic acid, and
hydroxyurethane) were administered at equimolar doses to rabbits either by
subcutaneous (8.55 mmol/kg) or intracoelomic (2.66 micromol/embryo) injection on gestational day 12. Five additional chemicals, structurally similar to the
hydroxylamine-bearing compounds, but possessing a terminal amino group
(-NH(2)) (ammonium hydroxide, methylamine, urea, acetamide, and urethane), were
tested at equimolar or higher doses by an identical protocol. In a subsequent experiment, the antioxidant propyl gallate (3.0 mmol/kg or 1.30 micromol/embryo) was co-administered with the hydroxylamine-bearing compounds to determine its effect on early cell death. Embryos were harvested 4 or 8 hr after treatment and analyzed by light microscopy.
RESULTS: Cellular debris was obvious in forelimb buds from embryos treated with the hydroxylamine-bearing compounds; however, none of the amino compounds produced an early episode of embryonic cell death. In all cases, the antioxidant propyl gallate prevented or delayed the early episode of cell death observed after treatment with the hydroxylamine-bearing compounds.
CONCLUSIONS: These results are consistent with the concept that the rapidly occurring embryonic cytotoxicity induced by hydroxylamine-bearing compounds involves a free radical mechanism that requires the presence of a terminal hydroxylamine group for initiation.

::It is too bad that they did not use NtBHA as one of the hydroxylamines tested. It appears to be less toxic than some of the others. Still the result probably would have been the same. The first thing that needs to be stated is that the method of administration is highly non-physiological and bypasses all digestive and systemic safeguards. Secondly, the dosage (377 mg/kg equivalent) is over 250 times what is suggested for a human life extensionist (using a rabbit/human metabolic weighting factor of 3). Therefore, the study does not imply that the result would be the same if the rabbits were fed either similar dosages of NtBHA or the equivalent to what a human using this should responsibly take. Even so, yes, this study is an example of why, to be completely safe, premenonpausal females should take nothing strange beyond excellent dietary nutrition prior to and during pregnancy and lactation, perhaps bolstered by a few extra well known vitamins and nutrients.

I think the answer to the fact that propyl gallate prevented or delayed the effect is found in the conclusion to the abstract. All antioxidant, in the right millieu are capable of causing free radical generation. In this case, propyl gallate was just the kind of antioxidant required to prevent that. A previous example of this kind of thing which was first brought to my attention by an article in LEF Magazine, is the fact that vitamin E can be highly pro-oxidant in certain body areas and that alpha lipoic acid is highly valuable in preventing any harm done there.

Free Radic Res Commun 1992;16(1):51-64
Ultraviolet light-induced generation of vitamin E radicals and their recycling. A possible photosensitizing effect of vitamin E in skin.
Kagan V, Witt E, Goldman R, Scita G, Packer L.
Department of Molecular and Cell Biology, University of California, Berkeley 94720.

Vitamin E (alpha-tocopherol) is the major lipid-soluble chain-breaking antioxidant of membranes. Its UV-absorbance spectrum (lambda max 295 nm) extends well into the solar spectrum. We hypothesize that in skin alpha-tocopherol may absorb solar UV light and generate tocopheroxyl radicals. Reduction of tocopheroxyl radicals by other antioxidants (e.g. ascorbate, thiols) will regenerate (recycle) vitamin E at the expense of their own depletion. Hence, vitamin E in skin may act in two conflicting manners upon solar illumination: in addition to its antioxidant function as a peroxyl radical scavenger, it may act as an endogenous photosensitizer, enhancing light-induced oxidative damage. To test this hypothesis, we have illuminated various systems (methanol-buffer dispersions, liposomes and skin homogenates) containing alpha-tocopherol or its homologue with a shorter 6-carbon side chain, chromanol-alpha-C6 with UV light closely matching solar UV light, in the presence or absence of endogenous or exogenous reductants. We found that: (i) alpha-tocopheroxyl (chromanoxyl) radicals are directly generated by solar UV light in model systems (methanol-water dispersions, liposomes) and in skin homogenates; (ii) reducing antioxidants (ascorbate, ascorbate dihydrolipoic acid) can donate electrons to alpha-tocopheroxyl (chromanoxyl) radicals providing for vitamin E (chromanol-alpha-C6) recycling; (iii) recycling of UV-induced alpha-tocopheroxyl radicals depletes endogenous antioxidant pools (accelerates ascorbate oxidation); (iv) beta-carotene, a non-reducing antioxidant, is not active in alpha-tocopherol recycling, and its UV-dependent depletion is unaffected by vitamin E.
PMID: 1325398

Once again, no one thing is all good or all bad! ::


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 Posted 4/15/2014 9:39:32 AM
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While this doesn't answer your question, Life Extension does have information concerning PD at http://www.lef.org/protocols/neurological/parkinsons_disease_01.htm

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 Posted 4/16/2014 3:47:43 AM
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Spectator:  I must commend you for doing this amount of research on PD; you probably know more about this than anyone on this forum!
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 Posted 4/20/2014 9:45:03 AM
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One other possible treatment to try is electrical brain stimulation using a device like Alpha-Stim.
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