R-alpha-lipoic acid
Nelson J. Navarro
R-alpha-lipoic acid?
The problem is it costs about $1 per gram, and the minimum buy is 1 kg.
Let me know.
Regards,
Nelson Navarro
Tom Kobzina
Why should we be interested in an enantiomer?
How do you justify the cost?
"Nelson J. Navarro" <nnav...@adelphia.net> wrote in message news:<BgFK7.223$cs3....@news1.news.adelphia.net>...
Nelson J. Navarro
Ever since I've heard "through the grapevine" that Bruce Ames will not take
the ALA racemic mixture (I don't know if it's actually true), I've been sort
of concerned that the "S" enantiomer might be not only inert, but possibly
detrimental in some manner.
The following studies seem to indicate some negative effects of the
S-enantiomer with regard to insulin levels and mitochondrial membrane
fluidity.
There are also some recent U.S. patents that point out differential effects.
For example, in patent #6,284,787 recently issued to Lester Packer et al.
(Assignee: Asta Medica Aktiengesellschaft (Dresden, DE) ), the inventors
state:
"The finding that specifically R-(+)-.alpha.-lipoic acid is suitable for the
treatment of diabetes mellitus and insulin resistance, while the
S-(-)-.alpha.-lipoic acid practically is not usable for this, is new and
unexpected and not inferable by those skilled in the art. Our own
investigations have shown that, in animal experiments, the key enzyme,
pyruvate dehydrogenase, surprisingly was inhibited by the
S-(-)-.alpha.-lipoic acid."
In patent #6,271,254 also assigned to Asta Medica, the inventors state:
"It has now surprisingly been found that, in the case of the purely optical
isomers of .alpha.-lipoic acid (R- and S-form, i.e. R-.alpha.-lipoic acid
and S-.alpha.-lipoic acid), unlike the racemate, the R-enantiomer mainly has
an anti-inflammatory activity and the S-enantiomer mainly has an
antinociceptive activity, the anti-inflammatory activity of the R-enantiomer
also, for example, being stronger by a factor of 10 than that of the
racemate. The antinociceptive (analgesic) activity of the S-enantiomer is
for example stronger by a factor of 5 to 6 than that of the racemate. The
enantiomers therefore constitute very much more specific and stronger acting
active substances than the racemate.
The following differences exist in particular in comparison to
.alpha.-lipoic acid, i.e. to the racemate:
The R-enantiomer acts mainly as an anti-inflammatory and the S-enantiomer
mainly as an analgesic, the optical isomers of .alpha.-lipoic acid being a
number of times stronger (for example by at least a factor of 5) than the
racemate of -lipoic acid."
****************************************************************
Am J Physiol 1997 Jul;273(1 Pt 1):E185-91 Books, LinkOut
Differential effects of lipoic acid stereoisomers on glucose metabolism in
insulin-resistant skeletal muscle.
Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ.
Department of Physiology, University of Arizona, Tucson 85721-0093, USA.
The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances
insulin-stimulated glucose metabolism in insulin-resistant humans and
animals. We determined the individual effects of the pure R-(+) and S-(-)
enantiomers of ALA on glucose metabolism in skeletal muscle of an animal
model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese
Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100
mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or
50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake],
glycogen synthesis, and glucose oxidation were determined in the
epitrochlearis muscles in the absence or presence of insulin (13.3 nM).
Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05),
whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA
treatment significantly reduced plasma insulin (17%) and free fatty acids
(FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment
further increased insulin (15%) and had no effect on FFA. Insulin-stimulated
2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, whereas
S-(-)-ALA administration resulted in only a 29% improvement. Chronic
R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen
synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No
significant increase in these parameters was observed after S-(-)-ALA
treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic
R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with
S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the
antioxidant ALA enhances insulin-stimulated glucose transport and
non-oxidative and oxidative glucose metabolism in insulin-resistant rat
skeletal muscle, with the R-(+) enantiomer being much more effective than
the S-(-) enantiomer.
PMID: 9252495 [PubMed - indexed for MEDLINE]
********************************************************************
J Mol Cell Cardiol 1995 Sep;27(9):1895-903 Related Articles, Books, LinkOut
Dose/response curves of lipoic acid R-and S-forms in the working rat heart
during reoxygenation: superiority of the R-enantiomer in enhancement of
aortic flow.
Zimmer G, Beikler TK, Schneider M, Ibel J, Tritschler H, Ulrich H.
Gustav-Embden-Zentrum, Biologischen Chemie, Universitatsklinikum, Frankfurt
am Main, Germany.
Micromolar concentrations of lipoic acid racemate added to a working rat
heart during hypoxia have been previously found to improve aortic flow
during subsequent reoxygenation. Since the R-form represents the naturally
occurring form of lipoic acid, and the S-form does not reveal a positive
influence on ATP synthesis in isolated mitoplasts, a dose/response curve of
both enantiomers has been performed in working rat hearts. After the end of
perfusion mitochondria were isolated and further analysed. At a
concentration of 0.05-0.1 mumol of the R-enantiomer, aortic flow rises
precipitously during reoxygenation, reaching over 70% of normoxic values
compared to 50% of the controls. By contrast, with the S-enantiomer a value
of about 60% is attained at 1 mumol, only. Accordingly, ATPase activity in
mitochondria isolated from rat hearts previously treated with 0.05-0.1 mumol
of the R- or S-enantiomer was significantly decreased or increased
respectively. Consequently, whereas mitochondrial ATP synthesis was
increased when the R-enantiomer was previously added to the working heart at
0.05-0.1 mumol concentration, with the S-enantiomer ATP synthesis remained
within the control range. Mitochondrial membrane fluidity, measured with
diphenylhexatriene, revealed a trend towards increase with the R- and
decrease with the S-enantiomer. The total amount of thiol added at 0.1 mumol
concentration is consistent with a value of 2 nmol/mg mitochondrial protein.
This value has previously been found to be connected with -SH groups which
add oligomycin-sensitivity to the ATPase complex. It is suggested that
oligomycin-sensitive mitochondrial -SH groups contribute to the overall
efficiency of low concentrations of lipoic acid R-enantiomer to enhance
aortic flow.
PMID: 8523450 [PubMed - indexed for MEDLINE]
In light of this, I'm going to stop taking the racemate and only take the R
enantiomer.
Regards,
Nelson Navarro
"Tom Kobzina" <tkob...@msn.com> wrote in message
news:2cc7ec87.01112...@posting.google.com...
Chris Allen
> R-alpha-lipoic acid?
> The problem is it costs about $1 per gram, and the minimum buy is 1 kg.
Well, one would take less of it than the racemate, right? If that's
the case, the cost shouldn't be too much higher. Someone taking 1g/day
of BAC's racemate lipoic acid is paying $0.38/day. 0.5g/day of rectus
lipoic acid would cost $0.50/day. One might even want to take less
than that.
How much were you thinking of taking?
-Chris
Nelson J. Navarro
Right now, I take about 900 mg. per day. I plan on cutting down to about 300
mg. per day when I get the R-ALA.
As of right now, I have one other buyer, and I still need to find buyers for
another 700 grams.
Regards,
Nelson Navarro
"Chris Allen" <cal...@efn.org> wrote in message
news:698c89aa.01112...@posting.google.com...
Chris Allen
> As of right now, I have one other buyer, and I still need to find buyers for
> another 700 grams.
I just did some reading on medline. Most studies show the rectus is
superior to the sinister on a particular metric, effective where the
sinister has no effect, or has an opposite effect of the sinister. The
rest of the studies show equal or better efficacy for the racemate
compared to the rectus with both being better than the sinister
(except for one showing sinister and rectus equivalence on a
particular metric). Even these studies say it is the rectus that is
doing the work, but I'm not sure how they come to that conclusion if
the racemate shows greater effectiveness.
Based on its effectiveness on glucose metabolism alone, it seems to be
worth it. I would like to be counted in for 100g, if that's not too
small a quantity.
Thanks,
-Chris
Te...@aor.ca
Ever since I've heard "through the grapevine" that Bruce Ames will not take
the ALA racemic mixture (I don't know if it's actually true), I've been sort
of concerned that the "S" enantiomer might be not only inert, but possibly
detrimental in some manner.
I just did some reading on medline. Most studies show the rectus is
superior to the sinister on a particular metric, effective where the
sinister has no effect, or has an opposite effect of the sinister. The
rest of the studies show equal or better efficacy for the racemate
compared to the rectus with both being better than the sinister
(except for one showing sinister and rectus equivalence on a
particular metric). Even these studies say it is the rectus that is
doing the work, but I'm not sure how they come to that conclusion if
the racemate shows greater effectiveness.
Google Search:
We share these concerns with the racemic compound. So do many key lipoic acid researchers. Here are some recent comments:
“We're finding - and others are, too - that the R(+)-form - the natural
form - is much more
powerful than the racemic mixture ... Hopefully ... companies are going
to be producing on more of a clinical scale the R(+)-form of lipoic acid,
because we're finding very significant effects using this, as opposed to
the racemic mixture."
Dr. Tory Hagen, in Mitochondrial Decay in Aging.
"We have presented in this study new information indicating that this
enhancement of glucose
metabolism is sterospecific, with the R(+)-enantiomer being much more
effective than the S(-)-
enantiomer."
Dr. Ryan Streeper and colleagues, in The American Journal of Physiology.
"Lipoic acid sold in a health food store is a synthetic mixture, a racemic
mixture. And R[+]- is the
natural form and S[-]- is an unnatural one ... And in our hands R[+]-
works and S[-]- doesn't."
Dr. Bruce Ames, at Strategies for Engineered Negligible Senescence.
"R[+]-LA [that is, R(+)-lipoic acid], and not a racemic mixture of R[+]-and
S[-]- LA, should be
considered a choice for therapeutic applications."
Dr. Lester Packer and colleagues, in Free Radical Biology and Medicine.
"The S[-]-enantiomer … part of the racemate, which is present as about
a 50% impurity, needs to
be eliminated."
Dr. Guido Zimmer and colleagues, in Methods in Enzymology.
See also the full text of this critical article from Dr. Hagen and Dr. Ames, entitled "(R)-alpha-Lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate."
FASEB J. -- HAGEN et al. 13 (2): 411
AOR has now privately contracted the mass-scale production of pharmaceutical grade R(+)-lipoic acid, and will make it available shortly. The material is consistently >97% R(+)-enantiomer, with the remainder as the S(-)-form.
We received our first shipment of the material in August, but have been experimenting with a new sustained-release delivery system. We believe that we have now perfected the scaling up of this process to mass production. If this works, we will bring it out in this form. If not, we will use simple vegetarian capsules.
In any case, we will have the product available in a month. We are currently exploring our options for a distributor in the USA.
The following is a summary of a detailed article to appear on a separate website shortly:
Many molecules used by the body have a specific "handedness" (chirality).
For
example, alpha-tocopherol, or essential fatty acids. In some cases,
synthetic
versions of these molecules have a different "handedness" than the
natural molecule.
You're probably familiar with some examples of this phenomenon, such
as natural d-
vs. synthetic dl-alpha-tocopherol, or natural cis- vs. unnatural
trans-fatty
acids.
Some of these artificial molecules are merely less potent than the natural
forms, such
as in the case of dl-alpha-tocopherol. But others are actually harmful
- for example,
trans-fatty acids.
Unless they specify otherwise, "lipoic acid" supplements are a 50/50
mixture of
the natural R(+)-lipoic acid, and the synthetic S(-)-lipoic acid.
These mixtures
are called "racemates." In some cases, S(-)-lipoic acid - or the racemate
- is simply
less effective than R(+)-lipoic acid. But in other cases, the S(-)-form
actually acts
in opposition to the
Glucose Metabolism
•Insulin resistance, in which the cells of the body stop responding
properly to
the hormone insulin, happens to some degree in almost all of us as
we age.
•Insulin resistance causes higher levels of insulin, blood sugar, and
free fatty
acids, all of which are threats to your health.
•Lipoic acid has been used to support healthy blood sugar metabolism.
Scientists have compared the effects of the two "lipoic acid" molecules
seperately.
•R(+)-lipoic acid has emerged as the active ingredient in the racemate.
•R(+)-lipoic acid fights all of the major effects of insulin resistance.
The
S(-)-form either does not help in these areas, or even makes things
worse.
Antioxidant Defenses
•Lipoic acid is known as a powerful and versatile antioxidant .
•R(+)-lipoic acid is more easily absorbed and taken into the cells
than
S(-)-lipoic acid.
•Both forms of lipoic acid can be made more powerful by "charging"
them up
into their DHLA form. R(+)-lipoic acid is "upgraded" much more rapidly
than
S(-)-lipoic acid.
•Many studies have found that R(+)-lipoic acid provides much more effective
protection than S(-)-lipoic acid or the racemate. In some cases, the
S(-)-lipoic acid actually counteracts the effects of R(+)-lipoic acid.
Neurological Health
•Lipoic acid is known for its ability to protect brain and nerve cells
from free
radicals and toxins.
•Excessive levels of "transition metals" such as iron, copper, and
cadmium are
believed to play an important role in many neurological disorders.
Having too
much free iron in a key part of the brain has been implicated as a
cause of
Parkinson's disease, for example.
•An animal study using R(+)-lipoic acid found that it was able to significantly
reduce age-related buildup of iron in the brain. Other studies suggest
that
S(-)-lipoic acid will not work as well.
Mitochondrial Function
•The biggest source of free radicals in your body are your cellular
"power
plants," the mitochondria. They are both the origin, and the target,
of most of
the free radical damage in the body.
•As we age, our mitochondria become less and less efficient, generating
less
and less energy while creating more and more free radicals.
•R(+)-lipoic acid, in animal experiments and in test-tube studies,
makes
mitochondria more efficient, so that they produce more energy and create
fewer free radicals.
•S(-)-lipoic acid does not have these effects, and may antagonize the
action
of R(+)-lipoic acid.
•These benefits have a real impact on the organism. Animals undergoing
a
simulated heart attack recover heart function more rapidly when infused
with
•R(+)-lipoic acid; S(-)-lipoic acid has no effect.
•Old animals supplemented with lipoic acid look better and are more
active.
S(-)-lipoic acid does not have these effects.
Fundamental Aging
•Nearly all researchers into the biology of aging agree that the decay
of
mitochondrial function is a major engine of the aging process.
•Caloric restriction, with adequate nutrition, is the only proven way
to slow
down the fundamental aging process in mammals.
•Many of the benefits of R(+)-lipoic acid closely mimic those of caloric
restriction. R(+)-lipoic acid's effects on mitochondrial function are
its most
striking and unique parallel with caloric restriction.
•A study in a short-lived strain of mouse demonstrated that R(+)-lipoic
acid
can dramatically increase its lifespan. Neither S(-)-lipoic acid, nor
the
racemate, had any significant effect.
•The National Institutes on Aging are currently funding studies to
see if lipoic
acid can truly slow down the aging process.
The Bottom Line
Common "lipoic acid" supplements are thus like a house at war with
itself. The
S(-)-form should be removed from supplements in favor of pure R(+)-lipoic
acid.
Selected References:
Streeper RS, Henriksen EJ, Jacob S, et al. Differential effects of
lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal
muscle. Am J Physiol. 1997 Jul;273(1 Pt 1):E185-91.
Hagen TM, Vinarsky V, Wehr CM, Ames BN. (R)-alpha-lipoic acid reverses
the
age-associated increase in susceptibility of hepatocytes to
tert-butylhydroperoxide both in vitro and in vivo. Antioxid Redox
Signal. 2000
Fall;2(3):473-83.
Lockhart B, Jones C, Cuisinier C, et al. Inhibition of L-homocysteic acid and buthionine sulphoximine-mediated neurotoxicity in rat embryonic neuronal cultures with alpha-lipoic acid enantiomers. Brain Res. 2000 Feb 14;855(2):292-7.
Suh J, Rocha A, Shigeno E, Frei B, Hagen TM. (R)-alpha-lipoic acid
supplementation of old rats decreases age-dependent accumulation of
iron
and ascorbate depletion in brain. AGE. 1999 Jul; 22(3):121(Abs
19).
Hagen TM, Ingersoll RT, Lykkesfeldt J, et al. (R)-alpha-lipoic acid-supplemented
old rats have
improved mitochondrial function, decreased oxidative damage, and increased
metabolic rate. FASEB J. 1999 Feb;13(2):411-8.
Freisleben HJ, Neeb A, Lehr F, Ackermann H. Influence of selegiline
or lipoic
acid on the life expectancy of immunosuppressed mice. Arzneim Forsch.
1997 Jun;47(6):776-80.
Ames BN. Damage to mitochondria. Strategies for Engineered Negligible
Senescence. 2000 Oct 1;Children's Hospital of Oakland Research Institute,
Oakland, CA.
Lykkesfeldt J, Hagen TM, Vinarsky V, Ames BN. Age-associated decline
in
ascorbic acid concentration, recycling, and biosynthesis in rat
hepatocytes-reversal with (R)-alpha-lipoic acid supplementation. FASEB
J.
1998 Sep;12(12):1183-9.
AOR
--
ADVANCED ORTHOMOLECULAR RESEARCH is Canada's most advanced supplement
line. AOR was the first to make SAMe, Pantethine, anti-aging Carnosine,
and Prostaphil defined pollen extract, available to Canadians. http://www.holisticinternational.com
http://www.R-Lipoic.com
Thomas Carter
Every year at this time I buy most of my year's supply of nutrients
taking advantage of LEF's super sale and keeping my medicine from
storage in hot warehouses during the summer months. It seems a good
time to investigate pure R-ALA. Some conclusions seem possible.
1. The R is a natural product and is much more effective for most
cases.
2. The S is a Xenobiotic substance. Technically a drug.
3. The racemate is probably safe, but S may interfere with R
4. If R is freed from S's putative inhibition toxic doses may be taken
by some due to lack of info as to the degree of the effect, or some
may take inappropriately small doses.
5. To change, or not to change? A close call in my opinion.
Some details, building on the fine references already provided:
Te...@AOR.ca wrote in message news:<3C02A45C...@AOR.ca>...
> "Nelson J. Navarro" wrote:
>
> > Ever since I've heard "through the grapevine" that Bruce Ames will not take
> > the ALA racemic mixture (I don't know if it's actually true), I've been sort
> > of concerned that the "S" enantiomer might be not only inert, but possibly
> > detrimental in some manner.
My search found no evidence of harm from the racemate, and virtually
none from the S
snip
> We share these concerns with the racemic compound. So do many key lipoic acid
> researchers. Here are some recent comments:
>
> “We're finding - and others are, too - that the R(+)-form - the natural form -
> is much more
> powerful than the racemic mixture ... Hopefully ... companies are going to be
> producing on more of a clinical scale the R(+)-form of lipoic acid, because
> we're finding very significant effects using this, as opposed to the racemic
> mixture."
> Dr. Tory Hagen, in Mitochondrial Decay in Aging.
This is a plea for clinical availability, not commercial
availability.
> "We have presented in this study new information indicating that this
> enhancement of glucose
> metabolism is sterospecific, with the R(+)-enantiomer being much more effective
> than the S(-)-
> enantiomer."
> Dr. Ryan Streeper and colleagues, in The American Journal of
> Physiology.
>
This is true in most cases, but it is not a comparasion of the
racemate with the R form.
> "Lipoic acid sold in a health food store is a synthetic mixture, a racemic
> mixture. And R[+]- is the
> natural form and S[-]- is an unnatural one ... And in our hands R[+]- works and
> S[-]- doesn't."
> Dr. Bruce Ames, at Strategies for Engineered Negligible
> Senescence.
The full quote idicates that the L is effective in the cytoplasm and
the R is in the mitochondria, which is also indicated by other
references of mine below. The phrase "in our hands" means in the
mitochondria which is what they are studying. Here's the full quote:
So: Lipoic acid sold in a health food store is a synthetic mixture, a
racemic mixture. And R is the natural form and S is some unnatural
one. R is reduced in mitochondria, S is reduced in the cytoplasm. And
in our hands R works and S doesn't.
So why does this work? From
http://research.mednet.ucla.edu/pmts/sens/transframe.htm
> "R[+]-LA [that is, R(+)-lipoic acid], and not a racemic mixture of R[+]-and
> S[-]- LA, should be
> considered a choice for therapeutic applications."
> Dr. Lester Packer and colleagues, in Free Radical Biology
> and Medicine.
He's selling the stuff.
> "The S[-]-enantiomer … part of the racemate, which is present as about a 50%
> impurity, needs to
> be eliminated."
> Dr. Guido Zimmer and colleagues, in Methods in Enzymology.
Reference? Is it PMID: 7651214? There is no abstract. Is it a study or
a letter? Do you have a more complete quote with context?
> See also the full text of this critical article from Dr. Hagen and Dr. Ames,
> entitled "(R)-alpha-Lipoic acid-supplemented old rats have improved
> mitochondrial function, decreased oxidative damage, and increased metabolic
> rate."
>
> FASEB J. -- HAGEN et al. 13 (2): 411
This study used only the R form and has to relevance as a comparasion
of it with the L or racemate. Niether the abstract nor the text of the
article mentions what two tables clearly show, that the R form was
related with a slight increase in free radicles per mole of O2 and
with a doubling (marginaly significant) of MDA levels in young rat
liver cells. MDA is a marker of lipid peroxidation. If the
relationship is causal and if it was caused by the higher
mitochondrial membrane potential in the young rats, the effect could
carry over to older mammals co-supplemented with ALCAR. See my
reference #4 below.
Trans-fatty acids are not an example of chirility. They are simply
another form of conjugation of the double carbon bonds nothing more.
(If you want call transpostion of the bond from one side of the chain
to other conjugation.)
> Unless they specify otherwise, "lipoic acid" supplements are a 50/50 mixture of
> the natural R(+)-lipoic acid, and the synthetic S(-)-lipoic acid. These mixtures
>
> are called "racemates." In some cases, S(-)-lipoic acid - or the racemate - is
> simply
> less effective than R(+)-lipoic acid. But in other cases, the S(-)-form actually
> acts
> in opposition to the
>
> Glucose Metabolism
No reference of yours supports this statement. Only the first comes
close. See my reference #6 for the abstract. And note that they used
more of the S form than they did of the R. And that there was no
comparison of R with racemate.
This is especially invalid since the S form is only absorbed by humans
at 60% the rate of the R. Which would be an argument againse paying
extra to throw out something you don't absorb well anyway. See my ref
#3
> •Insulin resistance, in which the cells of the body stop responding properly to
> the hormone insulin, happens to some degree in almost all of us as we age.
> •Insulin resistance causes higher levels of insulin, blood sugar, and free fatty
>
> acids, all of which are threats to your health.
> •Lipoic acid has been used to support healthy blood sugar metabolism.
> Scientists have compared the effects of the two "lipoic acid" molecules
> seperately.
> •R(+)-lipoic acid has emerged as the active ingredient in the racemate.
> •R(+)-lipoic acid fights all of the major effects of insulin resistance. The
> S(-)-form either does not help in these areas, or even makes things worse.
Again no reference of yours supports this. See my argument above and
again at the end of this post.
> Antioxidant Defenses
> •Lipoic acid is known as a powerful and versatile antioxidant .
> •R(+)-lipoic acid is more easily absorbed and taken into the cells than
> S(-)-lipoic acid.
> •Both forms of lipoic acid can be made more powerful by "charging" them up
> into their DHLA form. R(+)-lipoic acid is "upgraded" much more rapidly than
> S(-)-lipoic acid.
> •Many studies have found that R(+)-lipoic acid provides much more effective
> protection than S(-)-lipoic acid or the racemate. In some cases, the
> S(-)-lipoic acid actually counteracts the effects of R(+)-lipoic acid.
Nonsense. They are both anti-oxidants. Did you make this up?
> Neurological Health
> •Lipoic acid is known for its ability to protect brain and nerve cells from free
>
> radicals and toxins.
> •Excessive levels of "transition metals" such as iron, copper, and cadmium are
> believed to play an important role in many neurological disorders. Having too
> much free iron in a key part of the brain has been implicated as a cause of
> Parkinson's disease, for example.
> •An animal study using R(+)-lipoic acid found that it was able to significantly
> reduce age-related buildup of iron in the brain. Other studies suggest that
> S(-)-lipoic acid will not work as well.
>
So what? Not a reason the throw the S out.
> Mitochondrial Function
> •The biggest source of free radicals in your body are your cellular "power
> plants," the mitochondria. They are both the origin, and the target, of most of
> the free radical damage in the body.
> •As we age, our mitochondria become less and less efficient, generating less
> and less energy while creating more and more free radicals.
> •R(+)-lipoic acid, in animal experiments and in test-tube studies, makes
> mitochondria more efficient, so that they produce more energy and create
> fewer free radicals.
> •S(-)-lipoic acid does not have these effects, and may antagonize the action
> of R(+)-lipoic acid.
It barely if at all reaches the mitochondrial matrix. Give a
reference.
> •These benefits have a real impact on the organism. Animals undergoing a
> simulated heart attack recover heart function more rapidly when infused with
> •R(+)-lipoic acid; S(-)-lipoic acid has no effect.
Reference? My #13 shows otherwise.
> •Old animals supplemented with lipoic acid look better and are more active.
> S(-)-lipoic acid does not have these effects.
So what? Reference?
> Fundamental Aging
> •Nearly all researchers into the biology of aging agree that the decay of
> mitochondrial function is a major engine of the aging process.
> •Caloric restriction, with adequate nutrition, is the only proven way to slow
> down the fundamental aging process in mammals.
> •Many of the benefits of R(+)-lipoic acid closely mimic those of caloric
> restriction. R(+)-lipoic acid's effects on mitochondrial function are its most
> striking and unique parallel with caloric restriction.
> •A study in a short-lived strain of mouse demonstrated that R(+)-lipoic acid
> can dramatically increase its lifespan. Neither S(-)-lipoic acid, nor the
> racemate, had any significant effect.
I find nothing on this. Did you make it up?
> •The National Institutes on Aging are currently funding studies to see if lipoic
>
> acid can truly slow down the aging process.
>
> The Bottom Line
> Common "lipoic acid" supplements are thus like a house at war with itself. The
> S(-)-form should be removed from supplements in favor of pure R(+)-lipoic
> acid.
>
> Selected References:
> Streeper RS, Henriksen EJ, Jacob S, et al. Differential effects of lipoic acid
> stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J
> Physiol. 1997 Jul;273(1 Pt 1):E185-91.
>
> Hagen TM, Vinarsky V, Wehr CM, Ames BN. (R)-alpha-lipoic acid reverses the
> age-associated increase in susceptibility of hepatocytes to
> tert-butylhydroperoxide both in vitro and in vivo. Antioxid Redox Signal. 2000
> Fall;2(3):473-83.
>
> Lockhart B, Jones C, Cuisinier C, et al. Inhibition of L-homocysteic acid and
> buthionine sulphoximine-mediated neurotoxicity in rat embryonic neuronal
> cultures with alpha-lipoic acid enantiomers. Brain Res. 2000 Feb
> 14;855(2):292-7.
>
> Suh J, Rocha A, Shigeno E, Frei B, Hagen TM. (R)-alpha-lipoic acid
> supplementation of old rats decreases age-dependent accumulation of iron
> and ascorbate depletion in brain. AGE. 1999 Jul; 22(3):121(Abs 19).
Not listed in Medline.
> Hagen TM, Ingersoll RT, Lykkesfeldt J, et al. (R)-alpha-lipoic acid-supplemented
> old rats have
> improved mitochondrial function, decreased oxidative damage, and increased
> metabolic rate. FASEB J. 1999 Feb;13(2):411-8.
>
> Freisleben HJ, Neeb A, Lehr F, Ackermann H. Influence of selegiline or lipoic
> acid on the life expectancy of immunosuppressed mice. Arzneim Forsch. 1997
> Jun;47(6):776-80.
>
> Ames BN. Damage to mitochondria. Strategies for Engineered Negligible
> Senescence. 2000 Oct 1;Children's Hospital of Oakland Research Institute,
> Oakland, CA.
>
> Lykkesfeldt J, Hagen TM, Vinarsky V, Ames BN. Age-associated decline in
> ascorbic acid concentration, recycling, and biosynthesis in rat
> hepatocytes-reversal with (R)-alpha-lipoic acid supplementation. FASEB J.
> 1998 Sep;12(12):1183-9.
>
> AOR
Nelson wrote:
>Ever since I've heard "through the grapevine" that Bruce Ames will
not take
>the ALA racemic mixture (I don't know if it's actually true), I've
been sort
>of concerned that the "S" enantiomer might be not only inert, but
possibly
>detrimental in some manner.
Maybe its because he's getting the R free. :>)
The two abs provided by Nelson are covered by my arguments above. The
Patents are legal issues, not medical documents. The patent
applications are legal briefs written by lawyers and in the manner of
lawyers make any claim, untrue, reasonable, or other wise it is up to
the lawyer trying to break the patent to expose them. This is an
honorable legal practice. (it really is, in legal circles).
Their first claim states: the key enzyme,
>pyruvate dehydrogenase, surprisingly was inhibited by the
>S-(-)-.alpha.-lipoic acid."
True, but it was also inhibed by the R form. See my #2 ref
Their second claim states: >"It has now surprisingly been found that,
in the case of the purely optical
>isomers of .alpha.-lipoic acid (R- and S-form, i.e. R-.alpha.-lipoic
acid
>and S-.alpha.-lipoic acid), unlike the racemate, the R-enantiomer
mainly has
>an anti-inflammatory activity and the S-enantiomer mainly has an
>antinociceptive activity, the anti-inflammatory activity of the
R-enantiomer
>also, for example, being stronger by a factor of 10 than that of the
>racemate. The antinociceptive (analgesic) activity of the
S-enantiomer is
>for example stronger by a factor of 5 to 6 than that of the racemate.
The
>enantiomers therefore constitute very much more specific and stronger
acting
>active substances than the racemate.
They probably got this from my ref. #15. If so, a lie, if not probably
a slie.
Below I list 16 references that come from the search string: .
((alpha lipoic acid OR thiotic acid) AND (racemic OR racemate)) OR
R-lipoic acid OR S-lipoic acid
Slightly off topic but very interesting is my #5. Synergism between
ALA and CLA. Tom Matthews might be especially interested in this.
My findings were that R is a better all around anti-oxidant (1). S
slightly decreases decarboxylation of Pyruvatedehydrogenase
(interferes with ATP formation) in cultured liver cells. (note that
most of the study was on naked membranes, not entact cells.) (2) Both
R and S increase sugar uptake in diabetic rats, but S increased
insulin by 15%. (6) Life expectancy of immunosuppressed mice was
helped slightly more by R than S. (7) Racemate was better than R in
cataract reduction. (9), but (12) indicates otherwise. R and S equal
in prevention of oxidative stress in neurons. (10) R and S were
synergistic in increasing membrane fluidity of red blood cells. (11)
S is about twice as effective as R in the cytoplasm of cells, while R
is 18 times as effective in the mitochondria, note that lipoamide is
the form of lipoic acid after it is attached and active in the
mitochondria. (14) both forms protected rat muscle cells (that
overexpress glucose transporter 4) equally from oxidative stress.
(16)
My guess is that both forms, racemic and R will turn out to be
equally effective in appropriate ratios. The racemic has been studied
longer and is safer from that point of view. The appropriate ratio is
not known and to switch now could be a risk for that reason. For now I
will stay with the racemate.
Thomas
1: Antioxid Redox Signal 2000 Fall;2(3):473-83 (R)-alpha-lipoic acid
reverses the age-associated increase in susceptibility of hepatocytes
to tert-butylhydroperoxide both in vitro and in vivo. Hagen TM,
Vinarsky V, Wehr CM, Ames BN. Department of Molecular and Cell
Biology, University of California at Berkeley 94720, USA. Hepatocytes
were isolated from young (3-5 months) and old (24-28 months) rats and
incubated with various concentrations of tert-butylhydroperoxide
(t-BuOOH). The t-BuOOH concentration that killed 50% of cells (LC50)
in 2 hr declined nearly two-fold from 721 +/- 32 microM in cells from
young rats to 391 +/- 31 microM in cells from old rats. This increased
sensitivity of hepatocytes from old rats may be due, in part, to
changes in glutathione (GSH) levels, because total cellular and
mitochondrial GSH were 37.7% and 58.3% lower, respectively, compared
to cells from young rats. Cells from old animals were incubated with
either (R)- or (S)-lipoic acid (100 microM) for 30 min prior to the
addition of 300 microM t-BuOOH. The physiologically relevant (R)-form,
a coenzyme in mitochondria, as opposed to the (S)-form significantly
protected hepatocytes against t-BuOOH toxicity. Dietary
supplementation of (R)-lipoic acid [0.5% (wt/wt)] for 2 weeks also
completely reversed the age-related decline in hepatocellular GSH
levels and the increased vulnerability to t-BuOOH as well. An
identical supplemental diet fed to young rats did not enhance the
resistance to t-BuOOH, indicating that antioxidant protection was
already optimal in young rats. Thus, this study shows that cells from
old animals are more susceptible to oxidant insult and (R)-lipoic
acid, after reduction to an antioxidant in the mitochondria,
effectively reverses this age-related increase in oxidant
vulnerability. PMID: 11229361
2 Free Radic Biol Med 1999 Mar;26(5-6):685-94 The inhibitory effects
of lipoic compounds on mammalian pyruvate dehydrogenase complex and
its catalytic components. Hong YS, Jacobia SJ, Packer L, Patel MS.
Department of Biochemistry, School of Medicine and Biomedical
Sciences, State University of New York at Buffalo, 14214-3000, USA. To
examine the stereospecific effects of lipoic compounds on pyruvate
metabolism, the effects of R-lipoic acid (R-LA), S-lipoic acid (S-LA)
and 1,2-diselenolane-3-pentanoic acid (Se-LA) on the activities of the
mammalian pyruvate dehydrogenase complex (PDC) and its catalytic
components were investigated. Both S-LA and R-LA markedly inhibited
PDC activity; whereas Se-LA displayed inhibition only at higher
concentrations. Examination of the effects on the individual catalytic
components indicated that Se-LA inhibited the pyruvate dehydrogenase
component; whereas R-LA and S-LA inhibited the dihydrolipoamide
acetyltransferase component. The three lipoic compounds lowered
dihydrolipoamide dehydrogrenase (E3) activity in the forward reaction
by about 30 to 45%. The kinetic data of E3 showed that both R-LA and
Se-LA are used as substrates by E3 for the reverse reaction.
Decarboxylation of [1-14C]pyruvate via PDC by cultured HepG2 cells was
not affected by R-LA, but moderately decreased with S-LA and Se-LA.
These findings indicate that (i) purified PDC and its catalytic
components are affected by lipoic compounds based on their
stereoselectivity; and (ii) the oxidation of pyruvate by intact HepG2
cells is not inhibited by R-LA. The later finding with the intact
cells is in support of therapeutic role of R-LA as an antioxidant.
PMID: 10218658
3 Eur J Pharm Sci 1999 Apr;8(1):57-65 Dose-proportionality of oral
thioctic acid--coincidence of assessments via pooled plasma and
individual data. Breithaupt-Grogler K, Niebch G, Schneider E, Erb K,
Hermann R, Blume HH, Schug BS, Belz GG. Center for Cardiovascular
Pharmacology, Mathildenstrasse 8, 55116, Mainz, Germany. Thioctic acid
(TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid,
acts as a powerful lipophilic, free-radical scavenger and is used in
the treatment of diabetic neuropathy. This trial investigated the
dose-linearity of enantiomer pharmacokinetics following the oral
administration of single doses of 50 to 600 mg TA (formulation
provided by ASTA (Medica)) in healthy volunteers. TA enantiomer
concentrations in individual and pooled plasma samples were determined
using enantioselective, high-performance liquid chromatography. TA was
rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations
(Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of
the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml
S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA;
geometric means). The decline observed in the plasma concentration was
steep (t1/2, 0.5 h). The dose-linearity and proportionality of
pharmacokinetic parameters could be demonstrated on an
intra-individual basis and for the group geometric means. An analysis
of pooled plasma samples proved to be a suitable means for deriving
reliable first-sight results prior to individual assessments.
Publication Types: Clinical Trial PMID: 10072479
4 FASEB J 1999 Feb;13(2):411-8 (R)-alpha-lipoic acid-supplemented old
rats have improved mitochondrial function, decreased oxidative damage,
and increased metabolic rate. Hagen TM, Ingersoll RT, Lykkesfeldt J,
Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB. Department of
Molecular and Cell Biology, University of California at Berkeley,
Berkeley, California 94720, USA. A diet supplemented with (R)-lipoic
acid, a mitochondrial coenzyme, was fed to old rats to determine its
efficacy in reversing the decline in metabolism seen with age. Young
(3 to 5 months) and old (24 to 26 months) rats were fed an AIN-93M
diet with or without (R)-lipoic acid (0.5% w/w) for 2 wk, killed, and
their liver parenchymal cells were isolated. Hepatocytes from
untreated old rats vs. young controls had significantly lower oxygen
consumption (P<0. 03) and mitochondrial membrane potential. (R)-Lipoic
acid supplementation reversed the age-related decline in O2
consumption and increased (P<0.03) mitochondrial membrane potential.
Ambulatory activity, a measure of general metabolic activity, was
almost threefold lower in untreated old rats vs. controls, but this
decline was reversed (P<0.005) in old rats fed (R)-lipoic acid. The
increase of oxidants with age, as measured by the fluorescence
produced on oxidizing 2',7'-dichlorofluorescin, was significantly
lowered in (R)-lipoic acid supplemented old rats (P<0.01).
Malondialdehyde (MDA) levels, an indicator of lipid peroxidation, were
increased fivefold with age in cells from unsupplemented rats. Feeding
rats the (R)-lipoic acid diet reduced MDA levels markedly (P<0.01).
Both glutathione and ascorbic acid levels declined in hepatocytes with
age, but their loss was completely reversed with (R)-lipoic acid
supplementation. Thus, (R)-lipoic acid supplementation improves
indices of metabolic activity as well as lowers oxidative stress and
damage evident in aging. PMID: 9973329 full text available The
abstract fails to mention that the R form almost doubles the MDA
content of the cells. Border line significant in young rats
5 Diabetologia 1998 Apr;41(4):390-9 Effects of alpha-lipoic acid on
neurovascular function in diabetic rats: interaction with essential
fatty acids. Cameron NE, Cotter MA, Horrobin DH, Tritschler HJ.
Department of Biomedical Sciences, University of Aberdeen, Scotland,
UK. Elevated oxidative stress and impaired n-6 essential fatty acid
metabolism contribute to defective nerve conduction velocity (NCV) and
perfusion in diabetic rats, which may be corrected by free radical
scavenger and gamma-linolenic acid (GLA) treatments. Alpha-lipoic acid
(LPA) has antioxidant actions and both LPA racemate (racLPA) and GLA
treatments produced benefits in clinical neuropathy trials. The aims
were to study LPA action on neurovascular function in diabetic rats
and to investigate potential interactions for co-treatment with GLA
and other essential fatty acids. After 6 weeks of diabetes, 2 weeks of
racLPA treatment corrected 20% sciatic motor and 14% saphenous sensory
NCV deficits. The ED50 for motor NCV restoration was approximately 38
mg kg(-1) day(-1). racLPA also corrected a 49% diabetic deficit in
sciatic endoneurial blood flow. R and S-LPA enantiomers were
equipotent in correcting NCV and blood flow deficits. Treatment of
diabetic rats with low doses (20 mg kg(-1) day(-1)) of racLPA and GLA,
while having modest effects on their own, showed evidence of marked
synergistic action in joint treatment, completely correcting motor NCV
and blood flow deficits. This was also noted for the novel compound,
SOC0150, which contains equimolar proportions of LPA and GLA (ED50 9.3
mg kg(-1) day(-1), containing 3.5 mg LPA). NCV effects also showed
marked synergism when racLPA:GLA ratios were varied over a 1:3-3:1
range. In contrast, a compound containing LPA and the n-3 component,
docosahexaenoic acid, showed similar activity to LPA alone. Thus,
LPA-GLA interactions yield drug combinations and compounds with an
order of magnitude increase in efficacy against experimental diabetic
neuropathy and are worthy of consideration for clinical trials. PMID:
9562342
6 Am J Physiol 1997 Jul;273(1 Pt 1):E185-91 Differential effects of
lipoic acid stereoisomers on glucose metabolism in insulin-resistant
skeletal muscle. Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt
R-(+) enantiomer being much more effective than the S-(-) enantiomer.
PMID: 9252495
7 Arzneimittelforschung 1997 Jun;47(6):776-80 Influence of selegiline
and lipoic acid on the life expectancy of immunosuppressed mice.
Freisleben HJ, Neeb A, Lehr F, Ackermann H. Gustav-Embden-Zentrum der
Biologischen Chemie, Laboratorium fur Mikrobiologische Chemie,
Frankfurt/Main Germany. Ten groups of 14 immunosuppressed NMRI-mice
(nu/nu) were raised and kept under germ-reduced conditions. The
control animals were fed a germ-reduced diet, nine other groups
received the same diet with selegiline (CAS 14611-51-9, Deprenyl) or
lipoic acid (thioctic acid, CAS 62-46-4) admixed at various amounts.
The 50% survival rate, the total life span of each group and the areas
under the curves were determined to evaluate life expectancy as
compared to the controls. The racemate of lipoic acid at high dosage
(350 mg/kg body weight) reduced the life span significantly. The
S(-)-enantiomer of lipoic acid (75 mg/kg body weight) increased the
50% survival rate, whereas the physiologic R(+)-enantiomer (9 mg/kg
body weight) expanded the total life span of its group. Alteration of
only one out of three parameters was not considered significant. All
other groups except for one did not differ from controls: only animals
which obtained 75 micrograms selegiline per kg of body weight and per
day exerted increased life expectancies by all three parameters. This
group exhibited also in statistical evaluation a significantly (p <
0.05) prolongated survival time up to about 200% as compared to the
control animals. PMID: 9239459
8 Diabetes 1996 Dec;45(12):1798-804 Stimulation of glucose uptake by
the natural coenzyme alpha-lipoic acid/thioctic acid: participation of
elements of the insulin signaling pathway (Says R better than L,
similar to one I have above) . PMID: 8922368
9 Biochem Biophys Res Commun 1996 Apr 16;221(2):422-9 Stereospecific
effects of R-lipoic acid on buthionine sulfoximine-induced cataract
formation in newborn rats. Maitra I, Serbinova E, Tritschler HJ,
Packer L. Department of Molecular and Cell Biology, University of
California, Berkeley, 94720-3200, USA. This study revealed a marked
stereospecificity in the prevention of buthionine sulfoximine-induced
cataract, and in the protection of lens antioxidants, in newborn rats
by alpha-lipoate, R- and racemic alpha-lipoate decreased cataract
formation from 100% (buthionine sulfoximine only) to 55% (buthionine
sulfoximine + R-alpha-lipoic acid) and 40% (buthionine sulfoximine +
rac-alpha-lipoic acid) (p<0.05 (Racemate better than R alone)
compared to buthionine sulfoximine only). S-alpha-lipoic acid had no
effect on cataract formation induced by buthionine sulfoximine. The
lens antioxidants glutathione, ascorbate, and vitamin E were depleted
to 45, 62, and 23% of control levels, respectively, by buthionine
sulfoximine treatment, but were maintained at 84-97% of control levels
when R-alpha-lipoic acid or rac-alpha-lipoic acid were administered
with buthionine sulfoximine; S-alpha-lipoic acid administration had no
protective effect on lens antioxidants. When enantiomers of
alpha-lipoic acid were administered to animals, R-alpha-lipoic acid
was taken up by lens and reached concentrations 2- to 7-fold greater
than those of S-alpha-lipoic acid, with rac-alpha-lipoic acid reaching
levels midway between the R-isomer and racemic form. Reduced lipoic
acid, dihydrolipoic acid, reached the highest levels in lens of the
rac-alpha-lipoic acid-treated animals and the lowest levels in
S-alpha-lipoic acid-treated animals. These results indicate that the
protective effects of alpha-lipoic acid against buthionine
sulfoximine-induced cataract are probably due to its protective
effects on lens antioxidants, and that the stereospecificity exhibited
is due to selective uptake and reduction of R-alpha-lipoic acid by
lens cells. PMID: 8619871
10 Free Radic Biol Med 1996;21(5):631-9 Alpha-lipoic acid:
antioxidant potency against lipid peroxidation of neural tissues in
vitro and implications for diabetic neuropathy. Nickander KK, McPhee
BR, Low PA, Tritschler H. Department of Neurology, Mayo Foundation,
Rochester, MN 55905, USA. Nerve lipid peroxidation is increased in
experimental diabetic neuropathy, and alpha-lipoic acid will prevent
the deficits in nerve blood flow, oxidative stress, and distal sensory
conduction. Because these alterations can occur by mechanisms other
than augmenting lipid peroxidation in vivo, and because both
pro-oxidant and antioxidant effects of the agent have been reported,
we undertook studies of in vitro lipid peroxidation of brain and
sciatic nerve using an in vitro lipid peroxidation model with an
ascorbate-iron-EDTA system. We evaluated the effectiveness of the
R(+)-, S(-)-enantiomers, and racemate of alpha-lipoic acid in reducing
thiobarbituric acid reactive substances (TBARS) generation in rat
brain and sciatic nerve. Studies were also done in an incubation
medium containing 20 mM glucose, which increased lipid peroxidation up
to fourfold. A dose-dependent and statistically significant reduction
in lipid peroxidation was seen with both tissues with similar
potencies for both enantiomers. This effect was unassociated with any
reduction in the loss of alpha-tocopherol. PMID: 8891666
11 Arch Biochem Biophys 1995 Dec 1;324(1):85-92 Decrease of red cell
membrane fluidity and -SH groups due to hyperglycemic conditions is
counteracted by alpha-lipoic acid. Hofmann M, Mainka P, Tritschler H,
Fuchs J, Zimmer G. Gustav-Embden-Zentrum der Biologischen Chemie,
Universitatsklinikum Frankfurt, Frankfurt am Main, Germany. Human red
cell membranes (ghosts) were treated by 5 min of incubation with
fasting or hypo- and hyperglycemic concentrations of D-glucose. This
simulation of nondiabetic or diabetic conditions revealed an influence
on membrane fluidity and on protein -SH reactivity. Protein -SH
groups, measured with Ellman's reagent, generally behave in the same
way as membrane fluidity determined with diphenylhexatriene. Maximal
values were obtained with 5 mM D-glucose, whereas decrease was
observed above 10 mM D-glucose. Addition of alpha-lipoic acid (4
nmol/mg protein) resulted in a significant increase in membrane
fluidity and titratable -SH groups at glucose concentrations of 10 mM
and above. Dithiothreitol diminished titrable-SH groups and did not
restore membrane fluidity. 2-Mercaptopropionylglycine was only
effective in restoration of -SH groups. By contrast to D-glucose,
other sugars such as L-glucose, D-fructose, or sucrose revealed no
comparable changes on membrane fluidity and titratable membrane -SH
groups between concentrations of 5 and 10 mM. The hyperglycemic
effects of D-glucose were corroborated with isolated, reconstituted
membrane proteins and erythrocyte glucose carrier, indicating that, in
general, the observed divergent biochemical/biophysical changes of the
red cell membrane are influenced by the glucose transport protein
GluT1. The natural R-form and the S-form of alpha-lipoic acid were
compared with racemic R-/S-forms for their efficiencies in alterations
of red cell membrane fluidity. Decreased fluidities in presence of 10
mM glucose were found to be influenced in differentiated ways: the
S-form was highly active in increasing fluidity at 4 nmol/mg and
increasingly less active up to 20 nmol/mg protein. By contrast the
R-form of lipoic acid was moderately efficient in increasing fluidity
through a larger concentration range between 4 and 80 nmol/mg protein.
PMID: 7503564
12 Biochem Mol Biol Int 1995 Oct;37(2):361-70 Modelling cortical
cataractogenesis 17: in vitro effect of a-lipoic acid on
glucose-induced lens membrane damage, a model of diabetic
cataractogenesis. Kilic F, Handelman GJ, Serbinova E, Packer L,
Trevithick JR. Dept. of Biochemistry, University of Western Ontario,
London, Canada. The effect of R, S, and racemic forms of a-lipoic acid
was tested on the formation of opacity in normal rat lenses incubated
with 55.6 mM glucose, as a model for in vivo diabetic
cataractogenesis. Control lenses, incubated 8 days with 5.56 mM
glucose, did not develop opacities. Formation of lens opacities in
vitro was correlated with lactate dehydrogenase (LDH) leakage into the
incubation medium. Opacity formation and LDH leakage, resulting from
incubation in medium containing 55.6 mM glucose to model diabetes,
were both suppressed by the addition of 1 mM R-lipoic acid. Addition
of 1 mM racemic lipoic acid reduces these damaging effects to the lens
by one-half, while S-lipoic acid potentiated LDH leakage, consistent
with the hypothesis that R-lipoic acid is the active form. Although
HPLC analysis demonstrated that both stereoisomers of lipoic acid were
reduced to dihydrolipoate at comparable rates by the intact lens, the
mitochondrial lipoamide dehydrogenase system (An enzyme that
regenerates lipoamide from the reduced form dihydrolipoamide
lipoamide is The functional form of lipoic acid in which the carboxyl
group is attached to protein by an amide linkage to a lysine amino
group ) is highly specific for reduction of exogenous R-lipoic to
dihydrolipoic acid. Therefore, stereospecific protection against this
opacity is consistent with specific reduction of R-lipoic acid in
mitochondria of the vulnerable cells at the lens equator where the
first globular degeneration is seen in glucose cataract. PMID: 8673020
13 J Mol Cell Cardiol 1995 Sep;27(9):1895-903 Dose/response curves of
connected with -SH groups which add oligomycin-sensitivity (A
bacterial toxin inhibitor of oxidative phosphorylation that acts on a
small subunit of the F1 ATPase)
to the ATPase complex. It is suggested that oligomycin-sensitive
mitochondrial -SH groups contribute to the overall efficiency of low
concentrations of lipoic acid R-enantiomer to enhance aortic flow.
PMID: 8523450
14 Biochem Biophys Res Commun 1995 Jan 17;206(2):724-30 Glutathione
reductase and lipoamide dehydrogenase have opposite
stereospecificities for alpha-lipoic acid enantiomers. Pick U,
Haramaki N, Constantinescu A, Handelman GJ, Tritschler HJ, Packer L.
Department of Biochemistry, Weizman Institute, Rehovot, Israel. The
reduction of exogenous alpha-lipoic acid to dihydrolipoate by
mammalian cells and tissues confers additional antioxidant protection
to the cell. Both (R+) and (S-) isomers of alpha-lipoic acid were
analyzed as substrates with glutathione reductase from several sources
and with mammalian lipoamide dehydrogenase. Mammalian glutathione
reductase catalyzed faster reduction of (S)-lipoic acid (1.4-2.4-fold
greater activity) than of (R)-lipoic acid, whereas lipoamide
dehydrogenase had a very marked preference for (R)-lipoic acid
(18-fold greater activity) over (S)-lipoic acid. Mammalian glutathione
reductase showed better affinity for (S)-lipoic acid substrate; Km
values were 3.5 mM for (S)-lipoic acid and and 7 mM for (R)-lipoic
acid. Glutathione reductase from yeast reduced lipoic acid less
efficiently than the mammalian enymes, had a Km for both stereoisomers
of about 10 mM, and showed little stereospecificity. Although
(S)-lipoic acid is not formed in nature, these findings indicate that
exogenous (S)-lipoic acid may have a useful role as an antioxidant for
mammalian systems. PMID: 7826393
15 Skin Pharmacol 1994;7(5):278-84 Antioxidant inhibition of skin
inflammation induced by reactive oxidants: evaluation of the redox
couple dihydrolipoate/lipoate. Fuchs J, Milbradt R. Department of
Dermatology, University Hospital, Frankfurt, FRG. Reactive oxygen
species play an important role in mediating skin inflammation, and
antioxidants may provide protection. We investigated the
anti-inflammatory activity of natural antioxidants, such as superoxide
dismutase, catalase, trolox (a water-soluble tocopherol analog) and
the redox couple dihydrolipoate/lipoate in skin. Furthermore we
compared the anti-inflammatory potency of natural R and racemic
dihydrolipoate, as well as R and S lipoate. Skin inflammation in
hairless mice was induced by intradermal injection of the hydrogen
peroxide producing enzyme glucose oxidase (GOD) or by topical
application of the prooxidant drug anthralin. Intradermal injection of
the antioxidants inhibited skin inflammation caused by GOD (catalase,
dihydrolipoate) and anthralin (trolox, superoxide dismutase,
dihydrolipoate). There was no statistically significant difference
between the anti-inflammatory activity of the natural R and racemic
dihydrolipoate. R or S lipoate did not inhibit skin inflammation when
injected intradermally. In feeding experiments, however, R lipoate
significantly inhibited GOD-mediated skin inflammation, while S
lipoate was only marginally protective. We conclude that (1) several
natural antioxidants such as catalase, superoxide dismutase and
dihydrolipoate have anti-inflammatory properties in dermatitis induced
by reactive oxidants, (2) lipoate (oxidized dihydrolipoate) has skin
anti-inflammatory activity when administered orally and (3) naturally
occurring R lipoate is a more potent anti-inflammatory agent than the
non-physiological S lipoate. PMID: 8054210
16 Diabetes 2001 Feb;50(2):404-10 Protection against oxidative
stress-induced insulin resistance in rat L6 muscle cells by mircomolar
concentrations of alpha-lipoic acid. Maddux BA, See W, Lawrence JC Jr,
Goldfine AL, Goldfine ID, Evans JL. Diabetes Research Laboratory,
Mount Zion Hospital, San Francisco, California 94143-1616, USA.
bma...@itsa.ucsf.edu In diabetic patients, alpha-lipoic acid (LA)
improves skeletal muscle glucose transport, resulting in increased
glucose disposal; however, the molecular mechanism of action of LA is
presently unknown. We studied the effects of LA on basal and
insulin-stimulated glucose transport in cultured rat L6 muscle cells
that overexpress GLUT4. When 2-deoxy-D-glucose uptake was measured in
these cells, they were more sensitive and responsive to insulin than
wild-type L6 cells. LA, at concentrations < or = 1 mmol/l, had only
small effects on glucose transport in cells not exposed to oxidative
stress. When cells were exposed to glucose oxidase and glucose to
generate H2O2 and cause oxidative stress, there was a marked decrease
in insulin-stimulated glucose transport. Pretreatment with LA over the
concentration range of 10-1,000 pmol/l protected the insulin effect
from inhibition by H2O2. Both the R and S isomers of LA were equally
effective. In addition, oxidative stress caused a significant decrease
(approximately 50%) in reduced glutathione concentration, along with
the rapid activation of the stress-sensitive p38 mitogen-activated
protein kinase. Pretreatment with LA prevented both of these events,
coincident with protecting insulin action. These studies indicate that
in muscle, the major site of insulin-stimulated glucose disposal, one
important effect of LA on the insulin-signaling cascade is to protect
cells from oxidative stress-induced insulin resistance. PMID: 11272154
Nelson J. Navarro
"Thomas Carter" <tcar...@elp.rr.com> wrote in message
news:a7b55247.01112...@posting.google.com...
Well, one study (and Packer's patent, for what it's worth) found that S
decreases insulin sensitivity; in my view, that's significant, and that's
bad.
<snip>
Well, yes, they are legal documents. That doesn't automatically mean they
are uninformative or misleading. A well written patent will usually provide
references and/or describe experimental results in support of such
statements. You have to be circumspect and take it for what it's worth.
In any case, I would think that people (especially subject matter experts
like Packer) usually do not go through the trouble and expense of filing a
patent unless they feel they have something worthwhile.
The patent
> applications are legal briefs written by lawyers and in the manner of
> lawyers make any claim, untrue, reasonable, or other wise it is up to
> the lawyer trying to break the patent to expose them.
Actually, the I believe the lawyers are mainly concerned with the scope of
the "claims"; the substance has to come from the inventors.
This is an
> honorable legal practice. (it really is, in legal circles).
> Their first claim states: the key enzyme,
> >pyruvate dehydrogenase, surprisingly was inhibited by the
> >S-(-)-.alpha.-lipoic acid."
>
> True, but it was also inhibed by the R form.
Well, take a look at the patent before you decide how much weight to give
it. The inventors' experimental procedures and results are described.
See my #2 ref
> Their second claim states: >"It has now surprisingly been found that,
> in the case of the purely optical
> >isomers of .alpha.-lipoic acid (R- and S-form, i.e. R-.alpha.-lipoic
> acid
> >and S-.alpha.-lipoic acid), unlike the racemate, the R-enantiomer
> mainly has
> >an anti-inflammatory activity and the S-enantiomer mainly has an
> >antinociceptive activity, the anti-inflammatory activity of the
> R-enantiomer
> >also, for example, being stronger by a factor of 10 than that of the
> >racemate. The antinociceptive (analgesic) activity of the
> S-enantiomer is
> >for example stronger by a factor of 5 to 6 than that of the racemate.
> The
> >enantiomers therefore constitute very much more specific and stronger
> acting
> >active substances than the racemate.
>
> They probably got this from my ref. #15. If so, a lie, if not probably
> a slie.
Go here and check it out: http://patft.uspto.gov/netahtml/srchnum.htm
The numbers are 6,284,787 and 6,271,254.
>
>
>>
> My guess is that both forms, racemic and R will turn out to be
> equally effective in appropriate ratios. The racemic has been studied
> longer and is safer from that point of view. The appropriate ratio is
> not known and to switch now could be a risk for that reason. For now I
> will stay with the racemate.
> Thomas
I'm most interested in insulin sensitivity and mitochondrial function.
And it appears to me that S decreases insulin sensitivity and is at best
neutral wrt mitochondria, so I'm going to switch to R as soon as I can get
some.
Nelson J. Navarro
>
> "Thomas Carter" <tcar...@elp.rr.com> wrote in message
> news:a7b55247.01112...@posting.google.com...
I forgot to mention, on page four of Packer's patent #6,284,787, he
describes an experiment where S significantly increased the mortality of
diabetic rats, whereas R decreased mortality, relative to controls. S also
increased "glycosilated hemoglobin" wrt controls whereas R decreased it,
etc.
Regards,
Nelson Navarro
RK
The racemic form is prescribed in Germany for control of diabetes, so
the effect of the R- may very probably overwhelm the effect of the S-
isomer in this case.
Still, the R- should ultimately be cheaper (less required) and more
effective (no inhibiting isomer present). But if only the racemic
form is available, I would think it's better than nothing,
particularly if one is also taking acetyl l-carnitine.
Nelson J. Navarro
"RK" <rj...@my-deja.com> wrote in message
news:993db82c.01113...@posting.google.com...
> "Nelson J. Navarro" <nnav...@adelphia.net> wrote in message
news:<BhDN7.220$kC6....@news1.news.adelphia.net>...
> > "Nelson J. Navarro" <nnav...@adelphia.net> wrote in message
> > news:EOCN7.200$kC6....@news1.news.adelphia.net...
> > >
> > > "Thomas Carter" <tcar...@elp.rr.com> wrote in message
> > > news:a7b55247.01112...@posting.google.com...
> >
> > I forgot to mention, on page four of Packer's patent #6,284,787, he
> > describes an experiment where S significantly increased the mortality of
> > diabetic rats, whereas R decreased mortality, relative to controls. S
also
> > increased "glycosilated hemoglobin" wrt controls whereas R decreased it,
> > etc.
> >
>
> The racemic form is prescribed in Germany for control of diabetes, so
> the effect of the R- may very probably overwhelm the effect of the S-
> isomer in this case.
I think so too. I think the net effect is positive.
Being the way I am, however, I don't want to settle for a 5% increase in
insulin sensitivity if I can get 15%, for example.
>
> Still, the R- should ultimately be cheaper (less required) and more
> effective (no inhibiting isomer present). But if only the racemic
> form is available, I would think it's better than nothing,
> particularly if one is also taking acetyl l-carnitine.
I certainly hope so; but I must admit, the fact that LEF seems so reluctant
to release the results of their life span studies with ALC and racemate ALA
doesn't exactly leave me with a warm and fuzzy feeling about it.
Regards,
Nelson
tintinet
I'd also go for 100 grams.
Te...@aor.ca
> "Nelson J. Navarro" <nnav...@adelphia.net> wrote in message news:<BhDN7.220$kC6....@news1.news.adelphia.net>...
> > "Nelson J. Navarro" <nnav...@adelphia.net> wrote in message
> > news:EOCN7.200$kC6....@news1.news.adelphia.net...
> > >
> > > "Thomas Carter" <tcar...@elp.rr.com> wrote in message
> > > news:a7b55247.01112...@posting.google.com...
> >
> > I forgot to mention, on page four of Packer's patent #6,284,787, he
> > describes an experiment where S significantly increased the mortality of
> > diabetic rats, whereas R decreased mortality, relative to controls. S also
> > increased "glycosilated hemoglobin" wrt controls whereas R decreased it,
> > etc.
> >
>
> The racemic form is prescribed in Germany for control of diabetes, so
> the effect of the R- may very probably overwhelm the effect of the S-
> isomer in this case.
But taking pure medicine is preferrable to taking medicine with a little added poison. And the mitochondrial effects
"antioxidant network" effects are nearly exclusive to R(+)-lipoic acid.
>
>
> Still, the R- should ultimately be cheaper (less required) and more
> effective (no inhibiting isomer present). But if only the racemic
> form is available, I would think it's better than nothing,
> particularly if one is also taking acetyl l-carnitine.
Better than nothing, we agree. However, R(+)-lipoic acid will be available shortly from AOR.
AOR
--
ADVANCED ORTHOMOLECULAR RESEARCH is Canada's most advanced supplement line. AOR was the first to make SAMe,
Pantethine, anti-aging Carnosine, and Prostaphil defined pollen extract, available to Canadians. Watch for the
world's first R(+)-lipoic acid!
Thomas Carter
SNIP
> I'm most interested in insulin sensitivity and mitochondrial function.
> And it appears to me that S decreases insulin sensitivity and is at best
> neutral wrt mitochondria, so I'm going to switch to R as soon as I can get
> some.
Hi Nelson and all,
In attempting to give an all around discussion of the various issues
involved, I probably did not give enough explicit attention the very
important insulin effects. I attach below the abstract Nelson gave
with another one by the very same researchers on the very same muscles
of the very same rats with the very same doses giving the very same
results for the R form and the racemate. (Note that this means 30 mg
of racemate compared with 30 mg of R form indicating that 15 mg of R
had the same affect if accompanied by 15 mg of S. Even Nelson's
abstract taken in isolation does not indicate insulin resistence for
the S form if read carefully. Insulin resistence is not measured by
peak insulin levels, but by the IR index, which is to say the insulin
resistence index, which is the product of the area under the curves
(in the GTT test) of the plasma insulin and gulcose levels vs time.
(see PMID: 11723064 for an example.) While the change in the IR index
was not given in Nelson's abstract, it was probably slightly favorable
for the S form and certainly not significantly unfavorable as judging
by the 17% increase in peak insulin and the 29% increase in glucose
uptake.
Since Germans have been taking the racemate form for years for
diabetes and since we now do not even have any spurious data
indicating the R form is better than the racemate for diabetes, I
think we can rest assured on this matter.
As far as some sort of hinderence of the R by the S in the
mitochondria, I note that no one as been able to find any evidence so
far. I for one have looked thouroughly. I looked for the two most
pertenant references in Lester Packer's patent app. and they do not
exist in medline. I gave up looking for the others for lack of time
and interest. I will repeat once more, we should make our supplemental
decisions based on good firm, peer reviewed scientific documents, not
lawyers' briefs.
Finally I will say that the many positive benefits of the S form
detailed in my 16 references in the previous post should not be
overlooked.
Diabetes 1996 Aug;45(8):1024-9 The antioxidant alpha-lipoic acid
enhances insulin-stimulated glucose metabolism in insulin-resistant
rat skeletal muscle. Jacob S, Streeper RS, Fogt DL, Hokama JY,
Tritschler HJ, Dietze GJ, Henriksen EJ. Department of Physiology,
University of Arizona College of Medicine, Tucson, USA.
Insulin resistance of muscle glucose metabolism is a hallmark of
NIDDM. The obese Zucker (fa/fa) rat--an animal model of muscle insulin
resistance--was used to test whether acute (100 mg/kg body wt for 1 h)
and chronic (5-100 mg/kg for 10 days) parenteral treatments with a
racemic mixture of the antioxidant alpha-lipoic acid (ALA) could
improve glucose metabolism in insulin-resistant skeletal muscle.
Glucose transport activity (assessed by net 2-deoxyglucose [2-DG]
uptake), net glycogen synthesis, and glucose oxidation were determined
in the isolated epitrochlearis muscles in the absence or presence of
insulin (13.3 nmol/l). Severe insulin resistance of 2-DG uptake,
glycogen synthesis, and glucose oxidation was observed in muscle from
the vehicle-treated obese rats compared with muscle from
vehicle-treated lean (Fa/-) rats. Acute and chronic treatments (30
mg.kg-1.day-1, a maximally effective dose) with ALA significantly (P <
0.05) improved insulin-mediated 2-DG uptake in epitrochlearis muscles
from the obese rats by 62 and 64%, respectively. Chronic ALA treatment
increased both insulin-stimulated glucose oxidation (33%) and glycogen
synthesis (38%) and was associated with a significantly greater (21%)
in vivo muscle glycogen concentration. These adaptive responses after
chronic ALA administration were also associated with significantly
lower (15-17%) plasma levels of insulin and free fatty acids. No
significant effects on glucose transporter (GLUT4) protein level or on
the activities of hexokinase and citrate synthase were observed.
Collectively, these findings indicate that parenteral administration
of the antioxidant ALA significantly enhances the capacity of the
insulin-stimulatable glucose transport system and of both oxidative
and nonoxidative pathways of glucose metabolism in insulin-resistant
rat skeletal muscle. PMID: 8690147
Thomas
Nelson J. Navarro
From: "Thomas Carter" <tcar...@elp.rr.com>
Newsgroups: sci.life-extension
Sent: Thursday, December 06, 2001 2:09 AM
Subject: Re: R-alpha-lipoic acid
> "Nelson J. Navarro" <nnav...@adelphia.net> wrote in message
news:<EOCN7.200$kC6....@news1.news.adelphia.net>...
> SNIP
>
> > I'm most interested in insulin sensitivity and mitochondrial function.
> > And it appears to me that S decreases insulin sensitivity and is at best
> > neutral wrt mitochondria, so I'm going to switch to R as soon as I can
get
> > some.
>
> Hi Nelson and all,
> In attempting to give an all around discussion of the various issues
> involved, I probably did not give enough explicit attention the very
> important insulin effects. I attach below the abstract Nelson gave
> with another one by the very same researchers on the very same muscles
> of the very same rats with the very same doses giving the very same
> results for the R form and the racemate. (Note that this means 30 mg
> of racemate compared with 30 mg of R form indicating that 15 mg of R
> had the same affect if accompanied by 15 mg of S.
That's the "very same" racemate I take right now, and that's why I take it,
albeit somewhat apprehensively.
Even Nelson's
> abstract taken in isolation does not indicate insulin resistence for
> the S form if read carefully.
No, it doesn't, but I wasn't taking it in isolation. I've been trying to get
you to look at Packer's patent.
Insulin resistence is not measured by
> peak insulin levels, but by the IR index, which is to say the insulin
> resistence index, which is the product of the area under the curves
> (in the GTT test) of the plasma insulin and gulcose levels vs time.
> (see PMID: 11723064 for an example.) While the change in the IR index
> was not given in Nelson's abstract, it was probably slightly favorable
> for the S form and certainly not significantly unfavorable as judging
> by the 17% increase in peak insulin and the 29% increase in glucose
> uptake.
Unfortunately, I don't have access to the full paper. But here's what
happens according to Packer et al.:
Glucose Assimilation in Muscle Cells (pmol/mg x min)
Incubation
Time
Control R S
15 15.1 .+-. 0.4 16.7 .+-. 0.6 16.3 .+-. 0.3
30 12.1 .+-. 0 15.9 .+-. 0.9 14.8 .+-. 0.7
60 16.5 .+-. 0.4 26.1 .+-. 0.9 21.6 .+-. 0.4
120 15.7 .+-. 0.6 27.0 .+-. 0.4 20.5 .+-. 0.8
Glucose Assimilation in Muscle Cells with Insulin (200 nM)
Control R Insulin
Insulin + R
15 20.0 .+-. 0.9 23.2 .+-. 0.5 24.7 .+-. 0.9 25.1 .+-. 0.6
30 18.1 .+-. 0.6 21.1 .+-. 0.4 21.6 .+-. 0.4 21.1 .+-. 0.2
60 18.0 .+-. 0.6 25.7 .+-. 0.5 23.7 .+-. 0.5 26.2 .+-. 0.7
Control S Insulin
Insulin + S
15 14.5 .+-. 0.3 14.8 .+-. 0.4 17.7 .+-. 0.3 16.0 .+-. 0.4
30 13.8 .+-. 0.5 13.3 .+-. 0.4 16.3 .+-. 0.5 15.7 .+-. 0.3
60 15.6 .+-. 0.5 16.0 .+-. 0.2 22.3 .+-. 0.5 19.8 .+-. 1.1
If this data is accurate, and I have no reason to think it isn't, then it's
clear that S inhibits insulin action somewhat.
> Since Germans have been taking the racemate form for years for
> diabetes and since we now do not even have any spurious data
> indicating the R form is better than the racemate for diabetes, I
> think we can rest assured on this matter.
LOL! R-ALA has not been widely available until now (actually it still
isn't).
So, I think it's rather premature to come to that conclusion.
> As far as some sort of hinderence of the R by the S in the
> mitochondria, I note that no one as been able to find any evidence so
> far. I for one have looked thouroughly. I looked for the two most
> pertenant references in Lester Packer's patent app. and they do not
> exist in medline. I gave up looking for the others for lack of time
> and interest. I will repeat once more, we should make our supplemental
> decisions based on good firm, peer reviewed scientific documents, not
> lawyers' briefs.
Hey, I wish I had a bunch of full papers in front of me which carefully
elucidate the differences between the two. Unfortunately, I don't.
> Finally I will say that the many positive benefits of the S form
> detailed in my 16 references in the previous post should not be
> overlooked.
According to Packer, S increases insulin resistance, increases glycosylated
hemoglobin, inhibits translocation and reduces content of GLUT4 glucose
transporters, and helps diabetic rats die faster.
Maybe it doesn't matter to you, but I'd rather not ingest that poison if I
don't have to.
RK
> ----- Original Message -----
> Glucose Assimilation in Muscle Cells with Insulin (200 nM)
>
> Control R Insulin
> Insulin + R
> 15 20.0 .+-. 0.9 23.2 .+-. 0.5 24.7 .+-. 0.9 25.1 .+-. 0.6
> 30 18.1 .+-. 0.6 21.1 .+-. 0.4 21.6 .+-. 0.4 21.1 .+-. 0.2
> 60 18.0 .+-. 0.6 25.7 .+-. 0.5 23.7 .+-. 0.5 26.2 .+-. 0.7
>
> Control S Insulin
> Insulin + S
> 15 14.5 .+-. 0.3 14.8 .+-. 0.4 17.7 .+-. 0.3 16.0 .+-. 0.4
> 30 13.8 .+-. 0.5 13.3 .+-. 0.4 16.3 .+-. 0.5 15.7 .+-. 0.3
> 60 15.6 .+-. 0.5 16.0 .+-. 0.2 22.3 .+-. 0.5 19.8 .+-. 1.1
>
>
> If this data is accurate, and I have no reason to think it isn't, then it's
> clear that S inhibits insulin action somewhat.
>
> > Since Germans have been taking the racemate form for years for
> > diabetes and since we now do not even have any spurious data
> > indicating the R form is better than the racemate for diabetes, I
> > think we can rest assured on this matter.
>
> LOL! R-ALA has not been widely available until now (actually it still
> isn't).
> So, I think it's rather premature to come to that conclusion.
>
But one can conclude that the racemate is improving the situation for
German diabetics. The question, which cannot be answered from any
data I've seen, is does the R form in the racemate overwhelm any
inhibitory action of the S for, so one can obtain the same result as
taking the R form, by taking more racemate? I believe Tom Mathews
espoused that view when the subject of R-lipoic acid came up in this
newsgroup last year.
If this is the case, then it's a simple matter of cost as to whether
to take the racemate or the R form. (I can get a kilo of the racemic
alpha lipoic acid, encapsulated, for about $40 from kilosports.com.
What is your cost for the R-lipoic powder?) With L-carnitine versus
the racemic carnitine, it has been shown that the D form and the
racemate cause problems (muscular myopathy, I think.) But that is not
necessarily the case with lipoic acid.
If one is into all risk aversion, one would take the R form only. But
the evidence against the racemate is weak to nonexistent, and the
evidence in favor of the racemate seems stronger, but still far from
certain.
.....
>
> According to Packer, S increases insulin resistance, increases glycosylated
> hemoglobin, inhibits translocation and reduces content of GLUT4 glucose
> transporters, and helps diabetic rats die faster.
>
But what about the overall effect of the racemic mixture? Does the
R-enantiomer in racemic lipoic acid overwhelm the negative effect of
the S-enantiomer, or is the negative effect significant with the
racemate? We do not have a peer-reviewed answer to this question, nor
do we really seem to have one in the patent application. By nature a
patent application is self-serving; though one can glean inferences
from a patent, one cannot rely on the information.
> Maybe it doesn't matter to you, but I'd rather not ingest that poison if I
> don't have to.
Agreed, better safe than sorry. But the benefits of racemic lipoic
acid are many, and well documented. The risk appears to be low.
Nelson J. Navarro
I'm confused as to the use of R vis-a-vis racemate in Germany. I'm trying to
find out.
The question, which cannot be answered from any
> data I've seen, is does the R form in the racemate overwhelm any
> inhibitory action of the S for, so one can obtain the same result as
> taking the R form, by taking more racemate? I believe Tom Mathews
> espoused that view when the subject of R-lipoic acid came up in this
> newsgroup last year.
IMHO, that question can only be definitively answered by a study comparing
the effect of each on life span.
Somewhere I heard that Bruce Ames is presently doing such a study with
R-ALA. Once the outcome of that study is available, and if (a big if) LEF
ever releases the data from study they allegedly funded, which I believe
involved the racemate, then we'll have some useful data.
By the way, I must say that LEF's apparent reluctance to release the results
of their life span studies with various substances really makes me
suspicious. I mean, if something they tested increased max lifespan, do you
suppose they'd keep it a secret?
I don't think they would.
>
> If this is the case, then it's a simple matter of cost as to whether
> to take the racemate or the R form. (I can get a kilo of the racemic
> alpha lipoic acid, encapsulated, for about $40 from kilosports.com.
> What is your cost for the R-lipoic powder?) With L-carnitine versus
> the racemic carnitine, it has been shown that the D form and the
> racemate cause problems (muscular myopathy, I think.) But that is not
> necessarily the case with lipoic acid.
>
> If one is into all risk aversion, one would take the R form only. But
> the evidence against the racemate is weak to nonexistent, and the
> evidence in favor of the racemate seems stronger, but still far from
> certain.
The way I look at it is like this: you only get one chance at life
extension, and the stakes are high; so I prefer to err on the side of
caution.
>
> .....
>
> >
> > According to Packer, S increases insulin resistance, increases
glycosylated
> > hemoglobin, inhibits translocation and reduces content of GLUT4 glucose
> > transporters, and helps diabetic rats die faster.
> >
>
> But what about the overall effect of the racemic mixture? Does the
> R-enantiomer in racemic lipoic acid overwhelm the negative effect of
> the S-enantiomer, or is the negative effect significant with the
> racemate? We do not have a peer-reviewed answer to this question, nor
> do we really seem to have one in the patent application. By nature a
> patent application is self-serving; though one can glean inferences
> from a patent, one cannot rely on the information.
Well, here's how I see it. Packer is undoubtedly an authority on alpha
lipoic acid.
I'm guessing that the data he presents in the patent is data collected from
his many studies on the subject.
I have to give that data considerable weight. In other words, if he claims
that S-ALA increases the mortality of diabetic rats, I believe it.
>
> > Maybe it doesn't matter to you, but I'd rather not ingest that poison if
I
> > don't have to.
>
>
> Agreed, better safe than sorry. But the benefits of racemic lipoic
> acid are many, and well documented. The risk appears to be low.
In my mind, the "risk" of taking the racemate is that I'm possibly
shortchanging myself; sort of like taking synthetic vitamin E when I could
be taking a natural tocopherol mixture, for example.
Tom Matthews
>
> "Nelson J. Navarro" <nnav...@adelphia.net> wrote in message news:<m2VP7.125$O42....@news1.news.adelphia.net>...
> > > Since Germans have been taking the racemate form for years for
> > > diabetes and since we now do not even have any spurious data
> > > indicating the R form is better than the racemate for diabetes, I
> > > think we can rest assured on this matter.
> >
> > LOL! R-ALA has not been widely available until now (actually it still
> > isn't).
> > So, I think it's rather premature to come to that conclusion.
> >
>
> But one can conclude that the racemate is improving the situation for
> German diabetics. The question, which cannot be answered from any
> data I've seen, is does the R form in the racemate overwhelm any
> inhibitory action of the S for, so one can obtain the same result as
> taking the R form, by taking more racemate? I believe Tom Mathews
> espoused that view when the subject of R-lipoic acid came up in this
> newsgroup last year.
Since I was brought into this discussion here, I thought I should add my
current opinion.
Basically, I agree with Nelson's position on this, and I thank him for
his dilligent study and presentation.
Many (most?) non-natural stereoisomers of natural chemicals appear to
not have any biological effects and thus to be just so much "filler" if
included with the active form. However, there are sufficiently many that
do have biological effects (some of them quite different or even
contrary to the effects of the natural form), that I rather think the
lack of such proven effects may be more a sign of lack of yet finding
them. Until such xenobiotic forms have been thoroughly studied, I would
prefer to stay away from them. To do so, I am certainly willing to pay
more then double the price of the racemic form for the pure natural
enantiomeric form.
As for improving things for diabetics, let's realize that diabetics have
life-shortening disease for which many things that healthy people would
not take are appropriate. This is similar to people with cancer or any
other life-threatening disease. So we are talking about what heathly
people should do, not what those with terminal diseases should do.
I certainly have been taking the alpha lipoic racemate and I would
continue if it was not possible to purchase the pure R(+) form, because
I think that even for healthy life-extenders it is beneficial. However,
this is just a guess based on the evidence of benefits and the dearth of
research on the xenobiotic form. I would gladly switch to the R(+) form
even at several times the cost, if I could get it.
> If this is the case, then it's a simple matter of cost as to whether
> to take the racemate or the R form. (I can get a kilo of the racemic
> alpha lipoic acid, encapsulated, for about $40 from kilosports.com.
Are you sure? That is far cheaper than BAC's straight powder ($19 for 50
grams) I also know a wholesaler who thinks he has a very good price at
$170/kg for powder.
I would be extremely suspicious of any alpha lipoic acid that you get
for $40/kg!
> What is your cost for the R-lipoic powder?) With L-carnitine versus
> the racemic carnitine, it has been shown that the D form and the
> racemate cause problems (muscular myopathy, I think.) But that is not
> necessarily the case with lipoic acid.
How do you know what will yet be found? Little research has been done on
the xenobiotic forms of most natural chiral chemicals. With
phenylalanine the d-form has quite different effects.
> If one is into all risk aversion, one would take the R form only. But
> the evidence against the racemate is weak to nonexistent, and the
> evidence in favor of the racemate seems stronger, but still far from
> certain.
Nonsense! There is no evidence for the *racemate*, there is only
evidence for alpha lipoic acid of *any* form. And where comparative
studies have been conducted, the R form always comes out way ahead.
Thus, all evidence for the racemate is almost certainly only evidence
for the R form, with the S form, at best, only dead weight. Well, just
as with artificial sweeteners of fats, I for one do not wish to ingest
any dead weight, which might just turn out down the road to be harmful
weight! At least, not I there is a choice of better.
I will leave the rest to Nelson who appears to have very well researched
this topic.
--Tom Matthews
The LIFE EXTENSION FOUNDATION - http://lef.org
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***
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RK
> RK wrote:
> >
> (I can get a kilo of the racemic
> > alpha lipoic acid, encapsulated, for about $40 from kilosports.com.
>
> Are you sure? That is far cheaper than BAC's straight powder ($19 for 50
> grams) I also know a wholesaler who thinks he has a very good price at
> $170/kg for powder.
> I would be extremely suspicious of any alpha lipoic acid that you get
> for $40/kg!
My mis-recollection. Price is $69.95 per 1000 capsules of 100 mg
each. https://ssl-000.9netave.com/~ux15f112/cgi-bin/secure/alphalipoicacid.html
They mostly supply powders, and typically include an independant lab
analysis of the material.
> > What is your cost for the R-lipoic powder?) With L-carnitine versus
> > the racemic carnitine, it has been shown that the D form and the
> > racemate cause problems (muscular myopathy, I think.) But that is not
> > necessarily the case with lipoic acid.
>
> How do you know what will yet be found? Little research has been done on
> the xenobiotic forms of most natural chiral chemicals. With
> phenylalanine the d-form has quite different effects.
>
> > If one is into all risk aversion, one would take the R form only. But
> > the evidence against the racemate is weak to nonexistent, and the
> > evidence in favor of the racemate seems stronger, but still far from
> > certain.
>
> Nonsense! There is no evidence for the *racemate*, there is only
> evidence for alpha lipoic acid of *any* form. And where comparative
> studies have been conducted, the R form always comes out way ahead.
> Thus, all evidence for the racemate is almost certainly only evidence
> for the R form, with the S form, at best, only dead weight.
I don't quite follow your reasoning here; most ALA studies, which
generally show some benefit, have been done with the racemate. Either
thr S enantiomer is dead weight, or its inhibitory powers are
overwhelmed by the R form, or the S enantiomer has positive effects,
too. Only more recent studies have tested enantiomers separately.
All the early studies were witht he racemic form.
Nelson is trying to make R-lipoic acid available at a cost of $1 per
gram ($1000 to split a bulk order ofone kilogram). This is a good
thing. Some of us have limited budgets for supplements, though.
There should be something left over for things like food and clothing.
How much lower can the price get, with bulk orders greater than one
kilogram?
Chris Allen
> > to take the racemate or the R form. (I can get a kilo of the racemic
> > alpha lipoic acid, encapsulated, for about $40 from kilosports.com.
> Are you sure? That is far cheaper than BAC's straight powder ($19 for 50
> grams) I also know a wholesaler who thinks he has a very good price at
> $170/kg for powder.
kilosports.com sells racemic alpha Lipoic Acid for $700/kilo. BAC
sells it for $380/kilo.
-Chris
RK
ans S-lipoic acids. Though otherwise similar, "Decarboxylation of
[1-14C]pyruvate by intact HepG2 cells was significantly increased with
R-LA, and decreased by ... S-LA ." I believe this supports Nelson's
position.
Stereospecific effects of lipoic acids on mammalian pyruvate
dehydrogenase complex
M.S. Patel, Y.S. Hong, S.J. Jacobia, and L. Packer
Department of Biochemistry, State University of New York, Buffalo, NY
14214 and Department of Molecular and Cell Biology, University of
California, Berkeley, CA 94720
Mammalian pyruvate dehydrogenase complex (PDC) plays a pivotal role in
the oxidation of pyruvate derived from hexoses and some aminoacids.
R-Alpha-lipoic acid (natural enantiomer) serves as a covalently linked
prosthetic group for two components of PDC, namely the
dihydrolipoamide acetyltransferase (E2) component and the
dihydrolipoamide dehydrogenase (E3)-binding protein (E3BP).
Additionally, of the three catalytic sites of the pyruvate
dehydrogenase (E1), E2 and E3 components, two active sites (E2 and E3)
also recognize free lipoic acid. Since R-lipoic acid is increasingly
used as an anti-oxidant, we investigated the stereospecific effects of
lipoic compounds (R-lipoic acid, R-LA; S-lipoic acid, S-LA;
diseleno-lipoic acid, Se-LA) on PDC catalytic activities as well as on
pyruvate oxidation by cultured HepG2 cells. Both R-LA and S-LA
inhibited overall PDC activity at a concentration of 1 mM; whereas
Se-LA displayed less inhibition than either enantiomer. Examination of
the effects of LAs on the individual catalytic components of PDC
indicated that Se LA significantly inhibited E1 activity; whereas both
enantiomers of LA inhibited E2 activity. These lipoic compounds
reduced E3 activity (forward reaction) by about 30 to 45% due most
likely to the reoxidation of NADH by its reverse reaction. Kinetic
analyses of E3 showed that both R-LA and Se-LA are used as substrates
for the reverse reaction. Decarboxylation of [1-14C]pyruvate by intact
HepG2 cells was significantly increased with R-LA, and decreased by
either S LA or Se-LA. These findings indicate that (i) PDC and its
catalytic components are affected by lipoic compounds based on their
stereospecificity, and (ii) the oxidation of pyruvate by HepG2 cells
is not inhibited by R-LA, suggesting that R-LA does not accumulate in
mitochondria at a sufficient level toexert any inhibitory effect on
PDC activity. Since R-LA enhances the decarboxylation of pyruvate by
cultured HepG2 cells, it would enhance the flux of glucose-carbon via
PDC reaction.
Tom Matthews
> PDC activity. Since R-LA enhances the decarboxylation of pyruvate by
> cultured HepG2 cells, it would enhance the flux of glucose-carbon via
> PDC reaction.
It sure does. Here is another. Perhaps it was posted before, but note
the significance of the highlighted sentence.
Do you really want a lot of oxidized S-LA to be sitting around?
I think it is a very powerful argument for the R-Form that it will be
reduced back to its active state so much faster rather than remain in an
oxidative state.
Free Radic Biol Med 1997;22(3):535-42
Cytosolic and mitochondrial systems for NADH- and NADPH-dependent
reduction of alpha-lipoic acid.
Haramaki N, Han D, Handelman GJ, Tritschler HJ, Packer L.
Department of Molecular and Cell Biology, University of California at
Berkeley 94720-3200, USA.
In cellular, tissue, and organismal systems, exogenously supplied
alpha-lipoic acid (thioctic acid) has a variety of significant effects,
including direct radical scavenging, redox modulation of cell
metabolism, and potential to inhibit oxidatively-induced injury. Because
reduction of lipoate to dihydrolipoate is a crucial step in many of
these processes, we
investigated mechanisms of its reduction. The mitochondrial
NADH-dependent dihydrolipoamide dehydrogenase exhibits a marked
preference for R(+)-lipoate, whereas NADPH-dependent glutathione
reductase shows slightly greater activity toward the S(-)-lipoate
stereoisomer. Rat liver mitochondria also reduced exogenous lipoic acid.
The rate of reduction was stimulated by substrates which increased the
NADH content of the mitochondria, and was inhibited by
methoxyindole-2-carboxylic acid, a dihydrolipoamide dehydrogenase
inhibitor. In rat liver cytosol, NADPH-dependent reduction was greater
than NADH, and lipoate
reduction was inhibited by glutathione disulfide. In rat heart, kidney,
and brain whole cell-soluble fractions, NADH contributed more to
reduction (70-90%) than NADPH, whereas with liver, NADH and NADPH were
about equally active.
***An intact organ, the isolated perfused rat heart, reduced R-lipoate
six to eight times more rapidly than S-lipoate,***
consistent with high mitochondrial dihydrolipoamide dehydrogenase
activity and results with isolated cardiac mitochondria. On the other
hand, erythrocytes, which lack mitochondria, somewhat more actively
reduced S- than R-lipoate. These results demonstrate differing
stereospecific reduction by intact cells and tissues. Thus, mechanisms
of reduction of alpha-lipoate are highly tissue-specific and effects of
exogenously supplied alpha-lipoate are determined by tissue glutathione
reductase and dihydrolipoamide dehydrogenase activity.
PMID: 8981046
Tom Matthews
>
> Tom Matthews <t...@morelife.org> wrote in message news:<3C120487...@morelife.org>...
> > RK wrote:
> > >
> > (I can get a kilo of the racemic
> > > alpha lipoic acid, encapsulated, for about $40 from kilosports.com.
> >
> > Are you sure? That is far cheaper than BAC's straight powder ($19 for 50
> > grams) I also know a wholesaler who thinks he has a very good price at
> > $170/kg for powder.
> > I would be extremely suspicious of any alpha lipoic acid that you get
> > for $40/kg!
>
> My mis-recollection. Price is $69.95 per 1000 capsules of 100 mg
> each. https://ssl-000.9netave.com/~ux15f112/cgi-bin/secure/alphalipoicacid.html
Then that is $0.70 per gram. Far more than BAC ($0.38 per gram).
The R-Form will likely come in at about $1.50 per gram in small
quantities.
> > > What is your cost for the R-lipoic powder?) With L-carnitine versus
> > > the racemic carnitine, it has been shown that the D form and the
> > > racemate cause problems (muscular myopathy, I think.) But that is not
> > > necessarily the case with lipoic acid.
> >
> > How do you know what will yet be found? Little research has been done on
> > the xenobiotic forms of most natural chiral chemicals. With
> > phenylalanine the d-form has quite different effects.
> >
> > > If one is into all risk aversion, one would take the R form only. But
> > > the evidence against the racemate is weak to nonexistent, and the
> > > evidence in favor of the racemate seems stronger, but still far from
> > > certain.
> >
> > Nonsense! There is no evidence for the *racemate*, there is only
> > evidence for alpha lipoic acid of *any* form. And where comparative
> > studies have been conducted, the R form always comes out way ahead.
> > Thus, all evidence for the racemate is almost certainly only evidence
> > for the R form, with the S form, at best, only dead weight.
>
> I don't quite follow your reasoning here; most ALA studies, which
> generally show some benefit, have been done with the racemate.
Actually, there is no evidence that this is true. Some recent studies
clearly state that they used the DL- or racemate form, but dozens of
earlier studies state nothing. Given that until it was synthesized
(1986), all lipoic acid was extracted from natural sources and the names
thioctic acid, thioctacid, protogen A, valeric acid, Thioctan, Tioctan,
etc. all meant the R-Form only, I even think that it is most likely that
most studies are using the natural (R) form and simply don't think they
need to report that.
> Either thr S enantiomer is dead weight, or its inhibitory powers are
> overwhelmed by the R form, or the S enantiomer has positive effects,
> too.
Those are not the exclusive possibilities.
The S enantiomer may (and does) have *different* effects.
Furthermore, "overwhelmed" is not the way things work in biology. A
chemical's effects can be reversed in one type of tissue and not in
another by the same dosage of reversing chemical.
With R and S ALA, studies show just this difference between erythrocytes
and cells with mitochondria.
> Only more recent studies have tested enantiomers separately.
> All the early studies were witht he racemic form.
See my reasoning above why this is likely false.
> Nelson is trying to make R-lipoic acid available at a cost of $1 per
> gram ($1000 to split a bulk order of one kilogram). This is a good
> thing. Some of us have limited budgets for supplements, though.
Then you will just have to make more money or do without.
> There should be something left over for things like food and clothing.
> How much lower can the price get, with bulk orders greater than one
> kilogram?
Since the R-form is clearly much more than twice as beneficial as the
racemate, why should it need to sell for any less.
In fact, the only reason why Nelson (who did a great deal of work to
find and make it available) was willing to sell at cost was because he
very much wanted some for himself. Any ongoing sale of the R-form must
pay for the time and other costs of operation, and the work that went
into setting things up.
BTW, I am using the past tense because Nelson's source did not come
through and he is no longer offering it for sale. Instead, I have found
a source and will be offering it for sale in 50 gram quantities for
US$75.00 as soon as I get it in stock. Anyone who was considering
purchasing from Nelson, should now contact me instead.
--Tom Matthews
RK
the following somewhat puzzling:
On the other
> hand, erythrocytes, which lack mitochondria, somewhat more actively
> reduced S- than R-lipoate. These results demonstrate differing
> stereospecific reduction by intact cells and tissues. Thus, mechanisms
> of reduction of alpha-lipoate are highly tissue-specific and effects of
> exogenously supplied alpha-lipoate are determined by tissue glutathione
> reductase and dihydrolipoamide dehydrogenase activity.
> PMID: 8981046
>
So erythrocytes reduce S- more actively than R-lipoate. The net
effects are unclear given the complexity of the mechanisms involved.
Tom Matthews
It all depends on the purposes for which you are looking to aLA for
benefits.
IMO, for life-extension purposes our main concern should be
mitochondrial health, especially in post-mitotic cells.
The RLA is far more effective there.
There are lots of other antioxidants to help erythrocytes and they only
last a few months anyway. New pristine ones are being constantly reborn.
Thomas Carter
Tom Matthews <t...@morelife.org> wrote in message news:<3C135803...@morelife.org>...
Snip
> > > Nonsense! There is no evidence for the *racemate*, there is only
> > > evidence for alpha lipoic acid of *any* form. And where comparative
> > > studies have been conducted, the R form always comes out way ahead.
> > > Thus, all evidence for the racemate is almost certainly only evidence
> > > for the R form, with the S form, at best, only dead weight.
I find it somewhat peculiar that the exclamation "Nonsense!" so
frequently precedes nonsensical arguments. No evidence for racemate?
Only evidence for ALA of any form??
If this thread is not heavily laced with just such evidence citing and
comparing racemate, R and S by name I need an eye transplant.
The R form always comes out way ahead? Have you read the thread,
Tom?
PMID: 8619871, and my ref.#9 in the fith post of this thread, a
study done by Nelson's patron saint Lester Packer clearly shows the
racemate reducing cataracts by 15% more that R. and states that
racemate maintained glutathione, vit C and vit. E as well as R.
My ref #16 Shows both forms equally effective against oxidative stress
in rat muscle cells that over express Glut 4. PMID: 11272154
This is from the 11th post of this thread: " I attach below the
abstract Nelson gave with another one by the very same researchers on
the very same muscles of the very same rats with the very same doses
giving the very same
results for the R form and the racemate. (Note that this means 30 mg
of racemate compared with 30 mg of R form indicating that 15 mg of R
had the same affect if accompanied by 15 mg of S"
Here's a direct quote from my ref. #15: "There was no
statistically significant difference between the anti-inflammatory
activity of the natural R and racemic dihydrolipoate." PMID: 8054210
> > > Thus, all evidence for the racemate is almost certainly only evidence
> > > for the R form, with the S form, at best, only dead weight?
From my ref.#10: A dose-dependent and statistically significant
reduction in lipid peroxidation was seen with both tissues with
similar potencies for both enantiomers. This effect was unassociated
with any reduction in the loss of alpha-tocopherol. PMID: 8891666
My post #11 shows synergistic softening of red blood cells for R and
S. I note that This is critical for circulation since the RBC's have
to pass thru capillaries that are smaller in diameter than the cells
themselves. PMID: 7503564
> > I don't quite follow your reasoning here; most ALA studies, which
> > generally show some benefit, have been done with the racemate.
>
> Actually, there is no evidence that this is true. Some recent studies
> clearly state that they used the DL- or racemate form, but dozens of
> earlier studies state nothing. Given that until it was synthesized
> (1986), all lipoic acid was extracted from natural sources and the names
> thioctic acid, thioctacid, protogen A, valeric acid, Thioctan, Tioctan,
> etc. all meant the R-Form only, I even think that it is most likely that
> most studies are using the natural (R) form and simply don't think they
> need to report that.
No evidence where? In the thread? There is now.
From a 1995 study:
"rac-a-Lipoic acid (CAS 62-46-4, thioctic acid) is used in human
therapy
PMID: 7741788"
It took me just ten minutes to find the above and a half dozen others.
Since the number given is the Common Market drug number for racemic
ALA any full text with that number listed in the materials section is
for the racemate. This is frequently not mentioned in the abstracts.
When someone has an opinion that is markedly at variance with the
common belief, it is incombent upon him to give facts, not opinions.
> > Either thr S enantiomer is dead weight, or its inhibitory powers are
> > overwhelmed by the R form, or the S enantiomer has positive effects,
> > too.
>
Snip the sophmoric debate, Micheal Rae is not involved.
RK wrote:
>
> I found an abstract of a paper that elucidates the biochemistry of R-
> ans S-lipoic acids. Though otherwise similar, "Decarboxylation of
> [1-14C]pyruvate by intact HepG2 cells was significantly increased with
> R-LA, and decreased by ... S-LA ." I believe this supports Nelson's
> position.
>
> Stereospecific effects of lipoic acids on mammalian pyruvate
> dehydrogenase complex
>
> either S LA or Se-LA. These findings indicate that (i) PDC and its
> catalytic components are affected by lipoic compounds based on their
> stereospecificity, and (ii) the oxidation of pyruvate by HepG2 cells
> is not inhibited by R-LA, suggesting that R-LA does not accumulate in
> mitochondria at a sufficient level to exert any inhibitory effect on
> PDC activity. Since R-LA enhances the decarboxylation of pyruvate by
> cultured HepG2 cells, it would enhance the flux of glucose-carbon via
> PDC reaction.
Tom wrote "It sure does."
No it doesn't, in fact it is not even the abstract of the paper it
purports to summarize. It would be interesting to know where you got
it from, RK. Here is the true abstract:
A careful reading of the two shows a slightly more favorable
treatment for the R form in the phoney abstract. Possibly by one of
the authors, Lester Packer. It is hard to remain objective about one's
products one is trying to sell them.
This post is getting rather long, so I will explain only briefly
that the pyruvate hydrogenase complex is a very large enzyme in the
mitochndria, that feeds acetyl Co A to the krebs cycle which feeds
NADH to the electron transport chain (ETC) which is the major source
of free radicles. It has at least five allosteric moieties that exist
for the very purpose of its being activated and inhibited. It's
inhibition is necessary when there is insufficient oxygen for the ETC
to prevent runaway production of free radicles. Thus a "moderate
inhibition which is all that was shown by the true abstract should act
as an *antioxidant* in times of stress. I note that epinephrine
accelerates the complex and that fish oil attenuates the tendency.
>Here is another. Perhaps it was posted before, but note
>the significance of the highlighted sentence.
>Do you really want a lot of oxidized S-LA to be sitting around?
Of course you do! the essence of ALA is that it is recycled. Here is a
quote from Lester Packer before he started trying to sell the pure R
form:
" Although (S)-lipoic acid is not formed in nature, these findings
indicate that exogenous (S)-lipoic acid may have a useful role as an
antioxidant for mammalian systems." PMID: 7826393
>I think it is a very powerful argument for the R-Form that it will be
>reduced back to its active state so much faster rather than remain in
an
>oxidative state.
Free Radic Biol Med 1997;22(3):535-42
Cytosolic and mitochondrial systems for NADH- and NADPH-dependent
reduction of alpha-lipoic acid.
Haramaki N, Han D, Handelman GJ, Tritschler HJ, Packer L.
Department of Molecular and Cell Biology, University of California at
Berkeley 94720-3200, USA.
activity and results with isolated cardiac mitochondria. On the other
hand, erythrocytes, which lack mitochondria, somewhat more actively
reduced S- than R-lipoate. These results demonstrate differing
stereospecific reduction by intact cells and tissues. Thus, mechanisms
of reduction of alpha-lipoate are highly tissue-specific and effects
of
exogenously supplied alpha-lipoate are determined by tissue
glutathione
reductase and dihydrolipoamide dehydrogenase activity.
PMID: 8981046
> BTW, I am using the past tense because Nelson's source did not come
> through and he is no longer offering it for sale. Instead, I have found
> a source and will be offering it for sale in 50 gram quantities for
> US$75.00 as soon as I get it in stock. Anyone who was considering
> purchasing from Nelson, should now contact me instead.
>
> --Tom Matthews
>
> MoreLife for us all - http://morelife.org
> Reality based tools for More Life in quantity & quality
These last few posts of Tom's are not up to the high standards we have
come to expect of him. I have come to respect and admire Tom for his
unequaled intelligence, objectivity, and knowledge that he brings to
this group and others. I expect that when the final tally is in his
work will have "extended" many lives. I challange him to, and have
confidence that he will maintain this trust that he has so rightfully
earned as he embarks on his fledgling attempts to branch out in other
endevors.
Thomas
Tom Matthews
approach. There are a very few people on this group who use this
technique. IMO, if you can't say something simply and succinctly then it
is questionable that you know what you are talking about.
Relevant to this thread, I received agreement today from Sigma-Aldrich
that their website has contained an error for many years in the CAS#
which identified their product number T28606. It turns out the they have
been identifying it as CAS#62-46-4 which is the number for the R(+)
enantiomer of alpha lipoic acid (see:
http://webbook.nist.gov/cgi/cbook.cgi?Units=SI&cTG=on&cIR=on&cTC=on&cMS=on&cTP=on&cES=on&cTR=on&cPI=on&cDI=on&ID=C62464
and http://chemfinder.cambridgesoft.com/result.asp?mol_rel_id=62-46-4),
but in fact, T28606 is a racemic mixture just like their three other
alpha lipoic acid products.
The correct CAS# for the racemate is 1077-28-7 (see:
http://webbook.nist.gov/cgi/cbook.cgi?Units=SI&cTG=on&cIR=on&cTC=on&cMS=on&cTP=on&cES=on&cTR=on&cPI=on&cDI=on&ID=C1077287
and http://chemfinder.cambridgesoft.com/result.asp?mol_rel_id=1077-28-7)
Since most researchers in the US appear to buy their research chemicals
from Sigma-Aldrich which is deemed to be the most credible and quality
source (and charges for it too!), I am wondering just how many research
studies of alpha lipoic acid will be invalidated by this error!
Actually, the confusion extends much further than Sigma-Aldrich. The
chemical community all over the net is rife with inconsistencies on the
CAS numbers. Even the two Cambridgesoft websites http://chemfinder.com
and http://chemACX.com are inconsistent with each other on this issue.
Currently, I am waiting for a reply from Sigma-Aldrich concerning
whether they intend to inform all those who have bought product number
T28606 about this error. If they do not then I intend to inform as many
as I can find.
BTW, an inconsistency in the melting point data between the Merck Index
and the Sigma-Aldrich website was what alerted me to this error. Of
course, as is usual when dealing with large companies, I got waived off
a
few times and had to really *convince* them.
This is an example of what I have been spending my time on.
Tom Matthews
[snip]
> BTW, an inconsistency in the melting point data between the Merck Index
> and the Sigma-Aldrich website was what alerted me to this error.
I hasten to give credit to my good friend Nelson Navarro who alerted me
to the differences in the melting points between RLA and the racemate,
as we were both searching for a source for purchase of RLA (not yet
found at any reasonable price).
Max Watt
>
> Since most researchers in the US appear to buy their research chemicals
> from Sigma-Aldrich which is deemed to be the most credible and quality
> source (and charges for it too!), I am wondering just how many research
> studies of alpha lipoic acid will be invalidated by this error!
>
Yes, indeed. One wonders how many studies finding a difference
between he R- enantiomer and the racemate, were in fact comparing the
same chemical.
Thomas Carter
effect not only supplemental choices of people in this group, but
world wide scientific literature thus adding significantly to our
knowledge of ALA. I suspect 99% of the people would have overlooked or
ignored that tiny bit of data. I know I would have.
Tom Matthews <t...@morelife.org> wrote in message news:<3C172F59...@morelife.org>...
> Enormously long posts remind me of a kind of "baffle them with bullshit"
> approach. There are a very few people on this group who use this
> technique. IMO, if you can't say something simply and succinctly then it
> is questionable that you know what you are talking about.
I do apologize for my long post. I will try to keep them shorter in
the future. It may help if someone would point out how I could have
done so and still corrected all of Tom's mistakes.
Max wrote:
>Yes, indeed. One wonders how many studies finding a difference
between he R- >enantiomer and the racemate, were in fact comparing the
same chemical.
I don't expect to see many of these, since what brought me into the
thread in the first place was to clear up the mistaken view that there
were such studies. As of now no one has found and posted any. I for
one have searched high and wide. The burning question is about the
studies that found no difference. Were they infact comparing racemate
and R? Or were the mistakenly comparing racemate with itself? If so my
conclusions will certainly be invalidated along with the studies. We
must keep an open mind depending on the results of Tom's
investigation. I'm sure he will keep us informed. Hopefully there were
no invalid studies. That would be my gut-feeling.
Thomas
Tom Matthews
Related to the above, I never received any further reply from
Sigma-Aldrich and have now sent the following message to the alpha
lipoic acid researchers for whom I could find email addresses.
--Tom Matthews
MoreLife for us all - http://morelife.org
Reality based tools for More Life in quantity & quality
-------- Original Message --------
From: - Sat Jan 26 17:01:34 2002
Date: Sat, 26 Jan 2002 17:01:26 -0500
From: Tom Matthews <t...@morelife.org>
Organization: MoreLife
To: Balz Frei <balz...@orst.edu>, CK Sen <ck...@socrates.berkeley.edu>, CK Sen <se...@medctr.osu.edu>, John K Lodge <joh...@socrates.berkeley.edu>, JS Coombes <jcoo...@hms.uq.edu.au>, M Podda <Po...@em.uni-frankfurt.de>,
"sash...@violet.berkeley.edu" <sash...@violet.berkeley.edu>, Tetsuya Konishi <kon...@niigata-pharm.ac.jp>
CC: Cyndi Lembke <cle...@sial.com>
Subject: Sigma-Aldrich Product Number T28606 -Thioctic Acid
Dear Thioctic Acid Research Scientist,
This message is being sent to you because I found an error in the
Sigma-Aldrich description of their product number T28606 which they have
yet to rectify since I notified them over 6 weeks ago. Furthermore,
Sigma-Aldrich never even replied to the last message below which I sent
them. For such a large and reputable company, this sort of behavior is
surprising and, of course, it is totally unacceptable.
I am concerned that some of you may have purchased this product which
incorrectly has CAS# 62-46-4, thinking that it was the pure R(+)
enantiomer (natural form) of Thioctic acid. Whereas it is in fact the
racemic mixture and should be CAS# 1077-28-7, just as are all the other
Thioctic acid products of Sigma-Aldrich.
I have not been able to find email contact information for all those who
have done research with this chemical and I ask that you attempt to
inform others of this potential problem. I am concerned that this error
may invalidate some important research results on this chemical.
I uncovered this error while searching for a source of the pure R(+)
enantiomer for the purpose of human consumption by myself and a
limited number of people who appreciate its advantage over the easily
available racemic mixture. If any of you know of a source where I can
secure supplies, please let me know.
Thank you for your attention to this important matter,
--Tom Matthews
MoreLife for us all - http://morelife.org
Reality based tools for More Life in quantity & quality --
-------- Original Message --------
From: - Tue Dec 11 18:40:23 2001
Date: Tue, 11 Dec 2001 18:40:17 -0500
From: Tom Matthews <t...@morelife.org>
Organization: MoreLife
To: cle...@sial.com
Subject: Re: T28606
Hi Cyndi,
Thank you for resolving this error.
However, CAS#62-46-4 is *not* discontinued. It is the number for the
pure R-enantiomer of alpha lipoic acid.
I expect that Sigma-Aldrich will now inform all those who have purchased
product number T28606 that it is not CAS#62-46-4 and that it is a
racemic mixture. When you do, I would appreciate it if you would inform
them that I was I who brought this error to your attention. You may also
give them my email address.
I have a desire to make contact with those doing research on alpha
lipoic acid and this will expedite that process.
Please let me know if Sigma-Aldrich will inform them or not, since if
you are not going to inform them, then I will attempt myself to write to
all those who have published research on alpha lipoic acid and buy their
products from Sigma-Aldrich and inform them myself.
It would be a enormous disservice to the accuracy and veracity of
scientific research if such informing of possible errors does not take
place.
--Tom Matthews
cle...@sial.com wrote:
>
> Hi,
> It looks like we had the product listed under a discontinued
> CAS number. It should be the 1077-28-7. Our product is a
> racemic mixture.
> Best Regards,
> Cyndi
>
>
> Tom Matthews
> <tom@morelife. To: cle...@sial.com
> org>
> Subject: Re: T28606
> 12/08/2001
> 02:46 AM
>
>
>
> Dear Cyndi,
>
> Now I am really confused! If product number T28606 shown at
> URL:
>
>
http://www.sigma-aldrich.com/sacatalog.nsf/Prod?OpenFrameSet&*=/sacatalog.nsf/ProductLookup/AldrichT28606?OpenDocument^
>
> is the dl-Form then why does it have CAS# 62-46-4?
>
> According to Chemfinder.com this is the CAS# for the pure d
> or R(+)
> enantiomer.
> See
> http://chemfinder.cambridgesoft.com/result.asp?mol_rel_id=62-46-4
>
> Whereas the racemate which you list with three product
> numbers: T5625,
> T1395 and 6230, is CAS# 1077-28-7
> see
> http://chemfinder.cambridgesoft.com/result.asp?mol_rel_id=1077-28-7
>
> There is some major inconsistency going on here.
> Do you not have the pure enantiomer R(+)-alpha lipoic acid
> available at
> all?
>
> Please clarify.
>
> --Tom Matthews
>
> cle...@sial.com wrote:
> >
> > Dear Tom,
> > Thank you for your email. The product number T28606,
> > thioctic acid, from Aldrich is actually the DL form,
> > therefore the melting point would be 59-61 degree C.
> Thank
> > you for your interest.
> > Best Regards.
> > Cyndi Lembke
> > Chemist, Technical Service
> >
> > Name: Tom Matthews
> > Customer Number:
> > Account Name:
> > Department:
> > Building / Room:
> > Street:
> > Mail Stop / Code:
> > City:
> > State / Province:
> > Zip / Postal Code:
> > Country of Residence: Canada Ontario
> >
> > Phone Number: 416-968-6291
> > Fax Number:
> > E-Mail Address: t...@morelife.org
> > Product Number: T28606
> > Product Name: T28606
> > Brand: Aldrich
> >
> > Intended Use of Product: Research
> > My Question: Why is this product's melting point
> > equal to that
> > listed for the dl-Form in the Merck Index, whereas Merck
> > lists the d-Form
> > (which should be equal to this product) as having a
> melting
> > point of 46-48
> > deg C?
>
> --
> --Tom Matthews
>
> The LIFE EXTENSION FOUNDATION - http://lef.org
> Life Extension Forums - http://forum.lef.org
> Information to help you live longer and healthier
> ***
Tom Matthews
From: - Mon Jan 28 10:19:31 2002
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Subject: Re: Sigma-Aldrich Product Number T28606 -Thioctic Acid
I just received the following from Sigma-Aldrich:
-------------------------------------------------------
To: Tom Matthews <t...@morelife.org>
Cc: Balz Frei <balz...@orst.edu>, CK Sen
<ck...@socrates.berkeley.edu>, JS Coombes <jcoo...@hms.uq.edu.au>,
John K Lodge <joh...@socrates.berkeley.edu>, Tetsuya Konishi
<kon...@niigata-pharm.ac.jp>, M Podda <Po...@em.uni-frankfurt.de>,
"sash...@violet.berkeley.edu" <sash...@socrates.berkeley.edu>, CK
Sen <se...@medctr.osu.edu>
From: cle...@sial.com
Date: Mon, 28 Jan 2002 09:07:55 -0600
Hello to all,
Sigma-Aldrich is aware of the incorrect CAS number listed,
and it will be changed in the upcoming catalog.
Best Regards,
Cyndi Lembke
Aldrich Technical Service
-----------------------------------------------------
Tom Matthews
I just received the following from Sigma-Aldrich:
-------------------------------------------------------
To: Tom Matthews <t...@morelife.org>
Cc: Balz Frei <balz...@orst.edu>, CK Sen
<ck...@socrates.berkeley.edu>, JS Coombes <jcoo...@hms.uq.edu.au>,
John K Lodge <joh...@socrates.berkeley.edu>, Tetsuya Konishi
<kon...@niigata-pharm.ac.jp>, M Podda <Po...@em.uni-frankfurt.de>,
"sash...@violet.berkeley.edu" <sash...@socrates.berkeley.edu>, CK
Sen <se...@medctr.osu.edu>
From: cle...@sial.com
Date: Mon, 28 Jan 2002 09:07:55 -0600
Hello to all,
Sigma-Aldrich is aware of the incorrect CAS number listed,
and it will be changed in the upcoming catalog.
Best Regards,
Cyndi Lembke
Aldrich Technical Service
-----------------------------------------------------
--Tom Matthews
Dave
Good catch man. Looks like some of the scientists contacted Aldrich after
receiving your emails on the matter.
DB
Tom Matthews
I think you have it the wrong way around.
Yes, this message from them came as a result of my contacting some
scientists, but I also copied Sigma-Aldrich with my open message to
them. The above was an attempt by Sigma-Aldrich to save face by assuring
the scientists that action was being taken.
Here is a response from one of the scientists contacted:
----------------------------------------------
Thank you very much, this is important information indeed.
Sincerely,
Alan Pollock
Scary stuff. Nex
Max Watt
corporate fogging. It sounds like they are going to change to CAS
number to that of the mixed isomer form but continue to sell it as
R-lipoic acid.
Tom Matthews <t...@morelife.org> wrote in message news:<3C5574A8...@morelife.org>...
Rodney Reid
a process chemist with maybe 10 others, and believe me, he has the know-how
to seperate lipoic acid isomers and test the results, drunk, at 3am.
I'll mention this next week to him when I travel there and see what he
says.
...Rodney
"Max Watt" <maxwa...@yahoo.com> wrote in message
news:870a5d01.02013...@posting.google.com...
Kitty Antonik Wakfer
hours - about separating the R from the mixed isomer form of LA?
--
**Kitty Antonik Wakfer
Associate of Tom Matthews
***
MoreLife for us all - http://morelife.org
Reality based tools for more life in quantity and quality