R-ALA... Is polymerization really a factor, or are we just being scammed?

[NO HYPE]

With the more stable/expensive versions (K and Na) becoming more and more popular, this is a subject that needs more attention. Mike McCandless and I recently had a discussion about RALA polymerization, and how he feels that it's not much of a problem at all.... but unfortunately due to the fact that Mike runs a respectable company, his comments were limited.

My thoughts, I feel that polymerization occurs, but that it completely depends on a few key points.

1. The source/manufacturing procedures of the raw material.

2. The environmental conditions at the site of production, storage and/or shipping.

3. The environmental conditions once the product seal has been broken.

Provided that the bottle is refrigerated after opening, I would think that any possible polymerization of R-ALA, would be more attributed to environmental conditions at the site of production/storage.

I remember the people that used to say regular R-ALA would degrade into almost nothing.

Yeah I definitely noticed the exaggeration as well, but still though, the polymerization factor cannot be denied.

Funny how when I had an independent lab test some of my old 1fst r-ala, that was over two years old and sent to them via ground ups during a 100 degree summer, it still had 97mg per 100mg cap. Yet, there were some people pushing R-ala that swore if it wasn't shipped to you via 2nd day air that it would literally degrade in transport.

I would have to assume the results would have been different if the seal was broke.

Back in those days I was selling the material out of a jug sitting on a table. That thing saw more open air space than you can imagine back then. That is the material that was used to make the product that tested out 2 years after manufacturing and being exposed to ungodly levels of heat.

To some degree I'm sure it happens. To make it sound like the material goes to crap is BS. There is one company that has convinced everyone this stuff goes to crap unless you buy it from them because they take "special" care of it. There is a big surprise. Go to walmart and buy a basic marketing book, I think this is the first chapter.

I agree however, bioavailability would be affected.

Just a reminder for anyone following....

Polymerization = Forming large molecules, from small molecules.

I had an independent lab test some of my old 1fst r-ala

Mike, I am curious and I truly want to know your thoughts (serious). Did you send them any raw material, or was it only capsules?

Did they run a TLC test for polymer content?

You're drawing off 2.5 years ago of memory. So I don't remember all of the details. Gerenova called me claiming they had the best R-ala material and how I needed to buy this "new" stuff. They kept claiming how regular R-ala goes to crap in no time, blah blah blah. I said I have a bottle sitting here that has been here for 2 years, from one of the first runs I did. He asked if there were any other products to test, I said sure, sent him a bottle of R from syntrax (which tested perfectly fine). I told him I'd send it to him via ground ups so it'd get nice and hot. Both syntrax and mine came back fine. The third brand that was choosen, was about 40% short. Gerenova bought it and tested it, not me. I'm not sure what the testing conditions were from so long ago. The results were sent to me, I posted them on the testing website and then I got sued by the company that failed, eventhough I had ZERO to do with the testing. It was just funny, the company that kept claiming how all these special things had to be done to prevent these problems, had the very problems they warned against. Yet, syntrax and myself were fine. It cost me about 12k, but the case obviously got thrown out of court.

Just to re-emphasize, I have a feeling that when polymerization does occur, the majority of it happens with the raw material, in unfavorable conditions during production, storage, and/or shipping (depending on source).

I still disagree and I had the tests to prove it . You couldn't get more unfavorable. I don't care what papers say, I know what my own products tested at. Marketing baby, marketing.

Mike, no disrespect here (I definitely get your point about it being exaggerated), but might you be implying that within the industry, polymerization is simply, not occuring?

I tell ya what, since I have to run a company these days, I'll hold off making any more comments. My legal team keeps telling me message boards are bad, mmmmmkkk.

I should go back into the online business, it was lot easier to run my mouth.

So if anyone has any evidence that polymerization is occuring (be it scientific or anecdotal evidence), please share your thoughts.

[NO HYPE]

Now you will notice Mike's mentioning of a company (i.e. Geronova) who is well known/well respected, and who basically brought the subject of polymerization to the table. I got the impression that someone feels as if this particular company has merely made a mountain out of a molehill, but I cannot speak for this person here. In any case, here is more info on polymerization, from Geronova....



Polymerization, G.I. Absorption and Bioavailability. Polymerization and Instability in Dosage Forms

Racemic Lipoic Acid is a relatively unstable molecule due its propensity to form polymeric chains. There are significant stability problems, especially with the pure enantiomers which have a lower melting point and polymerize more readily than the racemic mixture. It is not surprising that some people doubt our claims concerning this problem on a product that has only been commercially available as a nutritional supplement for a few years.

Most supplement companies have no experience with the actual doing of the chemistry on the products they manufacture. Consumers and supplement manufacturers are bombarded with so much hype that suspicion is a natural result. It can be difficult to discriminate between scientific fact and "marketing hype". Since most people do not have the time to dig out old chemistry journals, we decided to publish what we have discovered from both the library and the laboratory.

Hands-on Experience
R-Lipoic Acid derived products are our specialty and we have gained significant experience working with this compound in the laboratory and in production during the last four years. At times, we have literally been "up to our elbows" in RLA polymer, and process 100's of kilograms of RLA at a time. We have gained considerable hands on experience in dealing with this "sticky rubber" which is unavoidable and all too real.

GeroNova did not invent the problem of RLA polymerization as a marketing ploy, although we have been frequently accused of this. In fact, we were shocked, and dismayed when we discovered (several years ago) that our very first batch of capsules (made from 99.5% enantiomerically pure RLA) contained 22% polymer! Subsequent research revealed that what was new to us is actually a well known characteristic of disulfides and was observed from the very first laboratory preparations of racemic ALA in the early 50's. (see JACS references below and Characterization and Stability of Cyclic Disulfides and Cyclic Dimeric Bis (Disulfides) Tetrahedron 45, 91 (1989).

It is also important to recognize the new USP 27 monolog of rac- ALA (p.2019, which incidently shows a molecular diagram of RLA, not rac- ALA) has a simple (and approximate) TLC test for polymer content in the raw material (but not the capsules or tablets) limiting it to NGT 2%. When we adapted the method to tablets and capsules of previously assayed ALA, the polymer content grew 5-10 fold over the raw material, showing that polymerization is also a potentially significant problem with dosage forms of racemic ALA, and why the allowable ranges of ALA content is 90-115% label claim.

Novel, Patented Methods of Stabilization
While vitamin resellers are still largely unaware of the the stability problems of RLA, primary manufacturing companies know all too well about its reality. Asta Medica (now Viatris), BASF, Degussa, Labochim and Antibioticos, have developed novel methods of dealing with this annoying property of an otherwise valuable supplement.

Asta Medica [US Patent 5,455,264] modified the usual isolation and crystallization of ALA or RLA to yield a product with a novel crystalline structure, characterized by a novel x-ray diffraction pattern and dissolution profile. It was also easy to isolate the product from polymeric starting materials.

The next Asta Medica invention [US Patent 5,994,393] utilized a special resolution technique to alter the R/S ratio. The resulting products have varying melting points depending on the how much of the S isomer is present. The more SLA present, the higher the melting point, so that a R/S mixture of 65.8 % RLA: 34.2% SLA has a melting point of 54-58 degrees C and is less prone to polymerize. Labochim (Italy) has a dosage form commercially available containing a 70:30 mixture of RLA: SLA and that is more stable and less prone to polymerization than the usually encountered RLA.

BASF jumped in on the act [US 6,441,024] and developed a process (similar to Asta Medica's) utilizing a mixed solvent system and precise temperature control which modified the crystalline structure and physical properties of RLA.

Polymerization Problems in Commercial RLA Products
GeroNova did not set out to gain a market advantage over our competitors by publicizing this problem. We actually set out to discover what they were doing that we were not in order to prevent polymerization. This sticky elastomer was the cause of many sleepless nights, and two years of subsequent R&D to develop a stable/heat resistant dosage form. It was only after testing competitors products (by third party HPLC analysis) that we discovered that not only were most companies not doing anything to prevent polymerization, but were obviously also not doing any quality control on their finished products, since they were not delivering anything close to their label claims.

Commercial RLA products tested had polymer contents ranging from 13-64%
We brought the issue of RLA instability and our test results to the attention of vitamin companies as well as to the public in an attempt to raise the quality of products reaching the consumer. While many companies choose to deny any problem exists, we reported it from the beginning and have subsequently discovered novel ways to overcome the limiting physical properties.

Our K-RALA? and Na RALA, while effective, is not novel. The processing of a carboxylic acid into its salt is a standard process in industrial chemistry and pharmaceutical technology. While conceptually simple, the practical achievement is a formidable task presenting many challenges when done on a large commercial scale. Even the salts can retain significant quantities of polymer, resulting in a sticky, hygroscopic tablets and capsules with poor dissolution profiles.

Since we believe the old philosophy of business (bashing your competitors) is outdated, GeroNova endorses any of our "competitors" involved with this fascinating molecule, and support them in their attempts to bring it to the public, as long as they are delivering what they claim. Since we believe that every living, breathing human being needs RLA, there is room for quite a few good RLA companies, and we believe RLA will outgrow CoQ10 and Vitamin E within 10 years.

On the other hand, it makes no sense to report all the health benefits of RLA if you cannot deliver it into the body in a usable form. GeroNova will not endorse companies selling products containing largely polymerized RLA, with poor dissolution properties and low bioavailability, even at discount prices. If you are using a cheap RLA product, with no mention of the polymer content, or if the companies that produce finished tablets and capsules deny the reality of RLA instability, you may be better off to use or take high quality racemic ALA.

According to Asta Medica, [6,348,490] RLA tablets were characterized by poor disintegration and dissolution profiles, such that RLA was only 9% dissolved in simulated gastric juice after 30 minutes, whereas racemic ALA was 100 % dissolved after 30 minutes. This means that unless the product has been stabilized and is not polymeric, use racemic ALA.

This also suggests the possibility that the insoluble polymer may accumulate in the GI tract over time, since it is essentially insoluble in water or gastric juice. In the lab it is insoluble in strong acids or any of the common organic solvents (even powerful solvents like DMF and DMSO). Strong base will depolymerize it in time and under forceful conditions but requires much more heat and alkalinity than what is found in the intestinal environment. This could be significant for diabetics, Alzheimer's sufferers, MS patients or the HIV infected who take high daily doses (up to 6 gm per day).

Revolutionary Research
Many people consider Bruce Ames the guru of Lipoic Acid. The revolutionary research (and subsequent media coverage) of Bruce Ames, Lester Packer and Tory Hagen has been largely responsible for the consumer demand for Lipoic Acid products in the US (which consumes most of the Lipoic Acid in the world).

Ames' group has shown the role of mitochondrial decay in age-related disease and how it can be reversed with ALC, Lipoic Acid, and the "spin trap", PBN. Dr Ames has recently filed a patent called:

"Stability of Lipoic Acid" (US Application 20040044046, March 4, 2004) [0011] LA suffers from certain disadvantages, however. In particular, the natural form R-LA is unstable above 40? C., so it can degrade under some warehousing conditions. Also LA is hygroscopic. What is needed is stabilization of this natural form of LA with a natural salt.

The natural salt in the patent is a salt pair formed by reacting RLA with nicotinamide. This was an example of a fortuitous discovery that may ultimately be commercially successful. As an incidental note, the salt was actually made by a famous local organic chemist and friend of Ames who found it in a vial on a lab shelf 17 months after he synthesized it. He decided to re-test it utilizing IR spectrophotometry and realized that the spectral data was identical to the original, indicating that it was stable. He then reported his finding to Ames.

[NO HYPE]

According to Juvenon (the patent holder of Ames' ALC / ALA cocktail) RLA is not used in their formulas, even though the research was done with the R-form because,

"The R form can be purified from the S form. However, the major problem with this compound, when separated from the S form, is stability. The compound deteriorates relatively rapidly at room temperature. The R form is also significantly more expensive. Work is ongoing to solve the stability problem, and when we feel this is complete to our satisfaction, Juvenon will offer a product containing only the R form.

Here are a few more patents mentioning the polymer problem, innovative solutions, the problems of RLA tablet dissolution, poor bioavailability and the enhanced bioavailability of the salt forms.

Alpha-Lipoic Acid with Novel Modification. (US Patent 5,994,393 Nov 30, 1999 ) "The melting range of the pure enantiomers of thioctic acid (47-49? C) is lower compared to the racemic compound (58-61? C). In the production of solid galenic formulations, the use of pressure on the material is indispensable so that on the one hand a heating and on the other hand a melting of thioctic acid takes place. Concentrated solutions of thioctic acid or its melts polymerize immediately and can no longer be converted into a crystalline form by cooling."

According to "Method of Producing Flowable R, S-Thioctic Acid, R,S-Thioctic Acid and its Use" (US Patent 5,705,192 Jan 6, 1998 )

...it is possible to make a thioctic acid form available which does not adhere to the pressing tool or exhibit a tendency to form fissures on the tablet, even when tablets with 600mg or more active substance content are prepared."

According to "Dosage Forms containing thioctic acid or solid salts of thioctic acid with improved release and bioavailability" ( US Patent 6,348,490)

"In contrast with dosage forms prepared from free R-thioctic acid, the dosage forms prepared from salts of R-Thioctic acid have not only the advantage of better release and bioavailability of the active ingredient, but are moreover more easily produced."

According to the article "Disulfide Polymers of DL-alpha-Lipoic Acid" by Thomas and Reed (JACS 78, 6148 (1956)

"The ease with which ALA polymerizes has been noted. The several Lipoic Acids described in this paper polymerized to various extents during their distillation and recrystallisation. The liquid esters of Lipoic Acid polymerized with extreme ease".

The previous note referred to by Reed was reported by his group at the University of Texas in JACS 77, 416 (1955) and about the same time by a team from Merck Sharp & Dohme [JACS 78, 5079 (1956)]. The polymer problem was recognized from the very first laboratory preparations of Lipoic Acid because the oxidation of DHLA produced not only the disulfide (ALA ) but also an insoluble chain of oligomeric disulfides.

This polymer is the same polymer found in commercial dosage forms of RLA
It is important to realize that Reed was working with the racemic ALA, i.e. DL-Lipoic Acid and not RLA, which was not yet available in any sizeable quantities. (In 1957 he isolated RLA by classical resolution in 60% yield).

The optical isomers were first made by Merck in 1955 [JACS 77, 416 (1955)] and later by DuPont [JACS 79, 6483 (1957)].

HEAT AND POLYMER FORMATION
Extreme heat is NOT a necessary requisite for polymer formation, as indicated in the above patents and the citation by Reed. Reed heated the product to 65?C because he knew heat would accelerate the polymerization, but in the case of RLA this occurs instantly at 46?C.

A key point that needs recognition is that even the so called "stable" ALA used extensively in the nutritional supplement industry is still prone to polymerization, and is also hygroscopic, although more heat stable than RLA. Anyone that has worked with this material knows how sticky it gets during its conversion into solid dosage forms. The pure enantiomers are even more unstable since they melt at a lower temperature, lose crystallinity and form a non-recrystallizable glass. Technically, a "glass" is an amorphous substance, i.e. without crystallinity. The isolation of crystalline R-Lipoic is a formidable problem during commercial production, and one of the key factors influencing the cost of the product. Even processed under high vacuum and below room temperature, it is very common to get a pot of "rubber" rather than "golden crystals".

Melting Point Test, Polymeric Structure
The best methods to prove the structure of the polymer conclusively is by x-ray diffraction, and by UV spectrophotometry which has a spectral profile distinct from the crystalline forms [JACS 78, 5079 (1956)].

The heat of friction during encapsulation and the compression of tableting are sufficient to initiate this process. Polymerization is also catalyzed by light and acid, and de-polymerized by strong base and more heat. The rate of polymerization is slower in acid than by light or heat.

"In the solid state ALA appears to be stable. In the cases noted above the instability of the compound was apparent only when it was in a dissolved or fluid state. It appears therefore that once the crystal lattice of ALA is broken the molecules tend to polymerize under certain conditions. These conditions must provide for the opening the 1,2 dithiolane ring of Lipoic Acid. The necessary energy for opening or at least loosening the disulfide bond comes from the absorption of light in the visible or on the edge of the visible spectrum. Once these bonds are activated, the molecules in a non rigid state tend to polymerize." [JACS 78, 5079 (1956)]

Dissolution
While ALA is more stable in the solid form than in solution, the hygroscopic nature of ALA initiates polymerization. Even a partially polymerized product can pose significant problems in the manufacturing and stability of a dosage form. The polymer reduces dintegration, dissolution of tablets or capsules, GI absorption and lowers the bioavailability, since it is so poorly absorbed from the GI tract.

We placed RLA capsulesof known RLA and Polymer contents in simulated gastric juice in a dissolution tester, and tested concentrations of active RLA over time by HPLC. In five runs, the amount of detectable RLA was significantly less than the assay result of the same dosage forms, suggesting that the polymer is trapping active material.

The results of our experiment supported our intuitive hunches, i.e. even if the entire dosage form has not become polymeric, the stickiness of the material will limit the dissolution, absorption and bioavailability of RLA.

The fact that the product has not been completely polymerized, and that there is some material still available to enter the circulation can account for the positive (albeit limited) results obtained with the preparations.

Baffling Molecular Behaviour
It should also be realized that the peculiar behavior of RLA which drives pharmaceutical technologists crazy is related to the ring strain of the dithiolane ring, imparting unique reactivity to the disulfide/dithiol bonds, the same phenomena that imparts RLA with unique and beneficial biological properties!

http://www.geronova.com/products/in_...ailability.php

[NO HYPE]

Here is more interesting information that pertains to a different supplier....



I have been delving deeply into the research and manufacturing of R(+) alpha lipoic acid for some time now (see my webpage on this chemical at: http://morelife.org/supplements/RLA.html) and from time to time I have posted much of the information which I have found on the newsgroup sci.life-extension. (This can be accessed via a newsreader or through http://groups.google.com/groups?hl=e...life-extension) However, I recently visited the manufacturing facility of my own supplier, LaboChim during a holiday in Northern Italy after attending the Sixth International Symposium on Neurobiology and Neuroendocrinology of Aging in Bregenz, Austria.

In the light of the current information which I have acquired and the growing number of sources of RLA as a supplement product on the North American market, I decided to update and extend the information which I have found (besides the peer reviewed studies described on my website which refer only to the effects of the different pure forms).

9. Manufacturing of Pure Alpha Lipoic Acid Enantiomers

The process of manufacture of RLA is quite time consuming and requires very careful monitoring of temperatures and times of processing for each of the 13 steps involved (10 for the racemic and 3 additional for the RLA). The final steps of separation into pure enantiomers are the most critical and Labochim has a special patented process which they would not tell me (it could be that patents are not publicly accessible in Italy as they are in the US). I do know that (for reasons detailed below) Labochim takes special measures to do the final separation of enantiomers and the drying processes (necessary to remove solvents) at
a low temperature. I am not easily "impressed" but I was certainly pleasantly surprised by the manufacturing methods of Labochim, particularly with the care, documentation and analysis which was done at each and every step of the manufacturing process of each of their products. This is a company which is fully approved to make pharmaceuticals for the US and European markets and they use the same careful methods in the manufacture of lipoic acid and pure RLA. Because of the complexity of the production, I am now convinced that high purity and quality RLA is unlikely to be available soon in product forms as inexpensive as are regular vitamins. At Labochim's required selling price (even in quantity), RLA could likely not be sold profitably in capsule form for less than $3.00 per gram retail. Since a reasonable capsule size would be 100 mg (3 or more per day), this translates to a daily price of just under $1.00 which only the most serious life extensionists are likely to embrace.

On the other hand, because the Labochim product is so expensive (and before I understood why) I was, like many others, scouring the world for other manufacturers. I have so far only found these in Germany (one only which has provided the RLA used by many of the researchers) and China (several). The German company wrote to me: "R(+)-alpha-lipoic acid is currently not available for commercial purposes." Some of the Chinese manufacturers tried to sell me racemic LA as RLA and others did not know the correct name or the CAS number for RLA. After much searching I did find one or two Chinese companies which appeared to have the right chemical at a price which is a little less than half that which Labochim is charging. However, after my recent visit to Labochim and the analyses that I have seen of product from other sources, I am no longer looking beyond Labochim for this chemical.

10. While the racemate does not seem to have this problem, the pure enantiomer forms (both R(+) and S(-)) have a tendency to polymerize (attach together forming long chains). This is especially strong at any temperature above about 25'C. It may still happen that the polymerized form is absorbed and beneficial after being depolymerized into its previous chemical form by the digestive system. However, no one knows whether this depolymerization will, in fact, take place or whether the polymer will be absorbed, be of any benefit, or even might be harmful! All that we know is that if the tests for presence of the molecule are run periodically when it is being stored at a high temperature, the concentration decreases over time (Labochim provided me with the data from such tests) because of formation of the polymer. Labochim strongly suggests that the pure enantiomers should be stored under refrigeration (or even in a freezer for very long-term storage). I keep my supply stored in the freezer of my refrigerator.

11. I also purchased a bottle of the Advanced Orthomolecular Research product, Lot# 040012-0, Exp date 02/2005 and sent 10 of the capsules to Labochim for analysis (btw, the bottle said nothing about storage temperature - although I have been told now that I have informed AOR of this potential problem they are labeling their bottles with a warning to keep refrigerated). Labochim takes pains to keep track of the world supply and has very sophisticated testing facilities (needed for custom synthesis and high quality manufacturing). They had already tested some Chinese samples and found them lacking. Here are their results for the AOR product (bearing in mind some limitations because they did not have the raw RLA which went into the capsules).

a) The average content of RLA per capsule assayed to 119 mg (instead of the 150mg stated on the label).

b) The purity of the ALA in the capsules was: R(+)LA - 91%, S(-)LA - 9% (instead of 100% RLA).

c) The total contents of the capsules weighed from 140-150 mg (including 100 ug of biotin + microcrystalline cellulose as stated on the label).

It is possible that some of the missing RLA is due to polymerization (before I sent them) because none of the suppliers or retail stores are taking any special measures to keep them at low temperature (and we had very hot weather in Canada this spring and summer). (Again, I have been told that AOR has now advised their retailers to keep this product under refrigeration.) The polymerization could not have occurred after I purchased the product since I kept it in my refrigerator and sent the capsules by expedited delivery to Labochim. Labochim stated that this analysis was similar to what they had seen in RLA from Chinese sources, but they also said that the purity of Chinese material appears to vary greatly from one batch to another, likely because of insufficient process control procedures and in-process testing.

From all this information, it appears to be almost certain that the products numbered 1) and 3) above are from Chinese sources and may be inferior product. Jarrow, which was going to market this RLA obtained from AOR in the USA, has apparently discontinued their plans to do so, perhaps because of the variable purity of the product. The product numbered 2) above, is 4 times the price of the others per gram of RLA which could reflect either a quality product or a very high mark-up. Until it is analyzed we cannot really tell which.

Another choice:

After seeing the quality of the facilities at Labochim and considering the whole situation, I decided to purchase from them 5 kilograms of RLA powder. A Certificate of Analysis of this product from Labochim (batch number 123013) shows that it is between 99.4% (by HPLC assay) and 99.1% (by titrimetric assay) pure RLA with less that 10 ppm heavy metals, each impurity less than 0.02% and impurity total less than 0.02%.This new purchase is now in my possession, being stored under refrigeration and available for sale to interested parties. I have packaged it in 40 gram quantities of powder placed in a polypropylene zip-lock bag inside another polyethylene protector zip-lock bag. These will be sent in a padded envelope with a diskette by first class mail at no extra charge. The diskette serves the dual purpose of keeping the package stiff and allowing the receiver to determine if the package has been irradiated (since the disk would then be unreadable). The product usage instructions are in text and MSWord files on the diskette. My price for this product is US$100 for 40 grams of pure powder. (If you wish other forms of delivery, you will have to pay extra.) If you wish to take advantage of this offer, email me with your order (including
full name, mailing address, phone number, and any special shipping requirements) and I will tell you by reply how payment should be made. The delivery address given should *not* be one in which the mail will sit at high temperature. For dosage estimating purposes, my suggestion based on the references at my website is to take from 4-8 mg/kg body weight daily. Therefore 40 grams should last most people 3 to 5 months depending on weight and dosage taken. Suggestions on usage will be included with the package. Since lipoic acid competes with biotin, you should certainly take at least an extra 1 mg of biotin daily with the RLA, which you might want to get that ahead of time. Since biotin is available cheaply from many good sources, I have no wish to supply it.

Some may think this is pure commericalism and forbidden on this venue, however in view of the information that I have found and presented, I think of it more as a service to help others have a quality source of RLA at a reasonable price. Once there is proven quality product available in the marketplace at a reasonable price, I will be very happy to stop providing RLA and spend my time on the many things which I value more highly such as my website. I am only supplying it to ensure that I (and my wife) have a source of quality product at a reasonable price (Labochim will not sell less than 1 kg which is too much for two people to use
in a timely manner).

--Tom Matthews (Paul Wakfer)

http://forum.lowcarber.org/showthread.php?t=62322

[NO HYPE]

I will PM androgenic an Mike on this matter.

[cakedonkey]

This patent is rather telling:

On the other hand, the intensified pharmacology research had indicated that R-(+)-α-Lipoic Acid had poor heat stability, and susceptible to be polymerized if given adequate oxygen, and be insoluble to the water. Overall, such factors would more or less affect its storage and bioavailability. Therefore, it is desirable to prepare the R-(+)-α-LA into metal-salt form, or organic alkali salt form to improve the stability, solubility as well as the bioavailability for satisfying the demanding request of the medical market.

[Method of preparing R-(+)-alpha-lipoic acid and its salt, U.S. Patent 20070015926]

Likewise, this paper lends credence to the superiority of K/ Na forms:

Due to its tendency to polymerize, RLA is relatively unstable
and suffers poor aqueous solubility, leading to poor absorption
and low bioavailability. A preliminary study demonstrated the
stability and bioavailability were improved by converting RLA
to its sodium salt (NaRLA) and pre-dissolving it in water. The
current study extends earlier findings from this laboratory and
presents PK data for the 600-mg oral dosing of 12 healthy adult
subjects given NaRLA. In addition, the effect of three consecutive
doses was tested on a single subject relative to a one-time
dosing in the same subject to determine whether plasma
maximum concentration (Cmax) and the area under the plasma
concentration versus time curve (AUC) values were comparable
to those in animal studies and those achievable via intravenous
infusions in humans. METHODS: Plasma RLA was separated
from protein by a modification of a published method.

[Altern Med Rev 2007;12(4):343-351]

[Rodzilla]

very good read.

[NO HYPE]

this paper lends credence to the superiority of K/ Na forms:

Awesome cake. That is what I like to see.

[NO HYPE]

I'm wondering if anyone has ever found any evidence of this in their RALA supplements?

[Zachattack43]

I will PM androgenic an Mike on this matter.

dont forget Dinoiii

Subscribed to read after class

[Nsaladino]

subbed. Thanks for sharing this info here.

[NO HYPE]

dont forget Dinoiii

Subscribed to read after class

Done.... hopefully he will stop by.

[Zachattack43]

Done.... hopefully he will stop by.

it might take some time due to the horrible family tradegy

[NO HYPE]

I am truly saddened by this news.... I pray for a full recovery. Stay strong Dana.

[NO HYPE]

It looks as if anyone who is supplementing R-ALA.... is unaware of the truth.

So either way, we are getting scammed????



Results

Baseline levels of RLA (Limit of Detection ~50-250 ng/mL) could be detected by liberation from plasma proteins with mobile phase using a modification of the method of Chen et al. (46) Although previous studies indicate rac-LA does not accumulate in blood or tissues, (17) in the present study baseline RLA was detected only in subjects who are regular users of a mixture of RLA and R-DHLA, even subsequent to a three-day washout period at levels of 0.05-0.25 mcg/mL. Analysis of the plasma concentration-time curves in a preliminary study with two subjects revealed that 600 mg pure RLA yields low Cmax and bioavailability (as measured by AUC) values, significantly lower than an equivalent weight of rac-LA. (43) The preliminary study provided the first published PK values for NaRLA. The Cmax and AUC values for NaRLA in the male subject were 25.86 and 3.3 times higher, respectively, than RLA. In the female subject, NaRLA produced Cmax and AUC values 17.9 and 2.67 times higher, respectively, than pure RLA. (43) RLA (100 mg; commonly found in nutritional supplements) is barely distinguishable from baseline, presumably due to poor absorption (data not shown). As expected, use of RLA as the pre-dissolved sodium salt resulted in significant increases in Cmax and AUC in all 12 subjects (Figure 2; Table 2). The average dose was 8.25 mg/kg, generating a mean Cmax of 16.03 mcg/mL (range: 10.6-33.8 mcg/mL), median Tmax of 15 minutes (range: 10-20 minutes), and mean AUC of 441.59 mcg min/mL (7.36 mcg hr/mL). The plasma concentration time profile had negligible effect on plasma glucose levels measured at each time point. Subject 3 consumed three 600-mg doses of RLA (as NaRLA) (Figure 3), resulting in a Cmax of 21.9 mcg/mL, AUC of 1,049 mcg min/mL (17.48 mcg x hr/mL), and extended the Tmax out to 45 minutes. An unexpected finding of this study was that, at plasma concentrations as high as 30 mcg/mL (~150 [micro]M) (Cmax subject 6), negligible free RLA was detected.


Discussion

Although the clinical significance of baseline RLA (0.05-0.25 mcg/mL) is not fully characterized, previous trials have correlated low baseline RLA with a variety of disease states. (7,10,49-52) It has been suggested that the presence of RLA in plasma may function to maintain the plasma redox status, which shifts to a more oxidized state with age and in numerous diseases. (53,54) The current study and previous findings from this laboratory conclude that pure RLA is not suitable for use in nutraceutical or pharmaceutical products. Rather, it should be treated as raw material for further processing into stable, bioavailable dosage forms. PK data reveals pure RLA is significantly less bioavailable than RLA found as a 50-percent component of rac-LA; and RLA in a salt form is considerably more bioavailable than an equivalent dose of racLA (RLA + SLA). This indicates SLA may function as a competitive inhibitor in the absorption of RLA.

Different forms of RLA produce dramatically different PK values. Recently, RLA was compared to NaRLA in humans using a simple crossover design. (43) This study compared Cmax and AUC values of a pre-dissolved aqueous solution containing 600 mg RLA (as NaRLA) to those of 600 mg RLA in the same subjects. In a single male (subject 1), NaRLA produced Cmax of 14.1 mcg/mL; whereas, RLA resulted in a Cmax of 0.7 mcg/mL (increase of 25.86x). The AUC in the same subject was 5.18 mcg hr/mL for NaRLA versus 1.56 mcg hr/mL for RLA (increase of 3.3x). In a single female (subject 4), Cmax was 18.1 mcg/mL for NaRLA versus 1.01 mcg/mL for RLA (increase of 17.9x) and the AUC was 5.71 mcg hr/mL for NaRLA compared to 2.14 mcg hr/mL for RLA (increase of 2.67x).

The data shows Cmax and relative bioavailability as measured by AUC for the aqueous solution of three doses of 600 mg RLA (as NaRLA) taken at 15-minute intervals is similar to those reported for a 20-minute I.V. infusion of 300 mg rac-LA. (55) Cmax and AUC values were significantly increased over the one-time dose. Cmax values reached 21.9 mcg/mL versus 12.9 mcg/mL and AUC values increased from 376.2 mcg min/mL (6.27 mcg hr/mL) to 1,049 mcg min/mL (17.48 mcg min/mL).

Based on the mean values from eight human PK studies utilizing 600 mg rac-LA, the current authors suggest the threshold of activation of the therapeutic effects of LA is equal to Cmax of 4-5 mcg/mL (~20-25 [micro]M) and AUC equal to 2.85 mcg hr/mL. (17,45,46,55-59) More consistent therapeutic results may be achieved at plasma concentrations of 10-20 mcg/mL (~50-100 [micro]M) of the natural enantiomer, RLA. (17,60) The upper limit of the human therapeutic concentration range is ~50 mcg/mL (~250 [micro]M). (41)

A basic principle of pharmacology states that free drug (not bound to plasma proteins) is more biologically active than plasma protein-bound drug and mostly responsible for the therapeutic action. (61-63) Most PK studies and assays for LA have measured the total LA content in serum or plasma rather than differentiating the concentrations of free and bound LA. Many different techniques with varying degrees of efficiency have been utilized to determine the total LA concentrations. In vitro, rac-LA spiked into human plasma is not measurable in "free" form until plasma protein binding is saturated at ~4-5 [micro]M (0.825-1.030 mcg/mL). (64) In rats, it was reported only 20 percent (~0.8 mcg/mL) of the total plasma RLA (~4 mcg/mL) was free (using the Centrisart ultrafiltration device). The level of free/unbound RLA was concentration independent and temperature dependent. The "free" value corresponded to the amounts of RLA found in skeletal muscle by micro-dialysis and was extrapolated to account for plasma protein binding in humans. (17) Since the therapeutic efficacy of a compound is associated with the "free" levels and levels of "free" drug concentration differ from species to species (and even wide inter-individual differences are known), the decision was made to test the levels of "free" RLA in each subject's plasma.

This is the first study to demonstrate negligible amounts of "free" RLA, even at Cmax. This indicates that a re-assessment of a fundamental principle of pharmacology (i.e., the therapeutically active form of a drug or nutrient is correlated to the amount of "free" versus unbound drug) relative to the mechanisms of transport and action of LA is necessary.

http://relentlessimprovement.com/inc..._lipoic_PK.pdf

[NO HYPE]

I would really appreciate a response from Mike McCandless on any of the above posts.

[CognitiveNutrition]

I like R-Dihydrolipoic acid. Just saying.

[NO HYPE]

I would really appreciate a response from Mike McCandless on any of the above posts.

I tell ya what, since I have to run a company these days, I'll hold off making any more comments. My legal team keeps telling me message boards are bad, mmmmmkkk.

Note: I am really not being a smart-ass here (until recently, I used RALA myself), it's just that Mike really painted a different picture about what's going on in the industry, and I wish he could comment without legalities being an issue.

[NO HYPE]

I like R-Dihydrolipoic acid. Just saying.

Yeah I have a few bottles around myself.... 'suspected' pro-oxidation is the reason I have been holding off. I'll check my files, and elaborate.

[NO HYPE]

'suspected' pro-oxidation =

the DHLA form, which is very potent and if not used correctly can be pro-oxidant.

From what I've gathered, R-ALA is effectively reduced via mitochondrial lipoamide dehydrogenase, as opposed to DHLA.

I was hoping you might have some inside knowledge as to the antioxidant and/or prooxidant likelihood of R-dihydro (in vivo). I still have a few bottles of LEF's version left that I'm just not sure about.

DHLA. I didn't want to uncover this one here. I am a life-extensionist first and foremost, so you're talking my talk here. I've got in to this one before. Let me go on record and say 1. LEF is a good company. 2. They tried to hire at excellent pay 3. In this case they are dead wrong. They shouldn't sell DHLA alone. Geronova, who makes the Na-R-ALA and K-R-ALA for the whole industry has the research on lock and DHLA while the next step is readily pro-oxidant when not balanced 50:50 by R-ALA. If you're going to use it do this with a 50:50 balance...otherwise avoid it. Surely, there is synergy, especially from the perspective of antioxidant power...the best really. As for the benefit acutely for the athlete with DHLA, I am not sure. Geranova hasn't dug into that. They do tons of research and are the leaders in the area. I believe geronova patented it and hence LEF trying to capitilize on "a new superior form" (they kind of feel like Biotest with all their products this way). LEF is wrong. AOR recommends against DHLA altogether, due its potential swing toward pro-oxidation, then again they are smart to say this as they can't sell the balanced one. AOR is TRULY superior to LEF in every conceivable way, much better formulations and quality control.

[DRP7]

this is why I still prefer to go to my local pharmacy and purchase the good old ALA with mixed enantiomers, in light-proof bottles and tablets with oxidation-resistant coating.

[NO HYPE]

this is why I still prefer to go to my local pharmacy and purchase the good old ALA with mixed enantiomers, in light-proof bottles and tablets with oxidation-resistant coating.

Nice.

With results like "25.86 higher".... NaRLA is my new choice. I would assume NaRLA would be superior to KRLA, due to the fact that Na has a lighter molecular weight than K (i.e. 22.990 vs. 39.098).

[NO HYPE]

1. I have not found evidence suggesting that polymerization is merely a myth, generated by the industry.

2. NaRLA appears to be the most bioavailable form.

3. Even if the polymerization of RALA was not an issue, the scam appears to be on us.

[B1CEPS]

I had a old bottle of 100mg r-ala capsules which had been in by bedroom for the past 1-2 years and in temperatures above 26oC at times (summer time)..... i opened a few capsules just to find a slightly soft white powder. main ingredients apart from r-ala was cellulose. Ponit im making is that there wasnt any evidence of any sticky , goo substance !

[NO HYPE]

I had a old bottle of 100mg r-ala capsules which had been in by bedroom for the past 1-2 years and in temperatures above 26oC at times (summer time)..... i opened a few capsules just to find a slightly soft white powder. main ingredients apart from r-ala was cellulose. Ponit im making is that there wasnt any evidence of any sticky , goo substance !

Thanks for your response.

[NO HYPE]

Provided the manufacturer's supply of raw materials is pure and standard manufacturing procedures are adhered to, I would think that once RALA is encapsulated, the chances of polymerization are slim. I am curious to know how often polymerization of the raws (prior to encapsulation) occurs.

[DRP7]

ALA is particularly sensitive to light. I don't know whether it polymerize or just oxidize or what happens but I know that infusions with ALA need to be protected with aluminum foil.
therefore, regardless of NaALA/kALA/RALA, I would not purchase ALA from supplement companies but rather from the pharmacy. sorry, I know that such statements will not really increase my sympathy points here in the supp forum, but with regards to ALA, i truly believe that procedures like those described above by Mr.McCandless (letting the powder staying aroudn without ANY protection) will most likely decrease the quality. not necessarily polymerization may occur, but oxidation probably will!

[dinoiii]

Admittedly, I have not read this whole thing yet - it will have to take place this evening or weekend (have to go to hospital after seeing 3 more clients and the afternoon gets a bit more sticky with my return for meetings).

In any event, I am simply taking note for now and will try and get Shawn in here - he is bigger into DHLA (of which, I think is completely unnecessary and am more along the lines supportive of the same suggestion as AOR rather than LEF and/or Gernova and the conversion of ALA into DHLA is just fine without ingesting this).

As far as the original question posed - I can tell you this for now: When we test people's blood work, there is NOT precipitous difference between those running R-ALA and the sodium -and/or- potassium salts when considering blood glucose levels. And I think that would be the bottom line, the clinical effect - no?


I have bookmarked for return and sent Shawn an email in regards to this one. Should prove to be an interesting discussion.


D_

[Bane]

I would not purchase ALA from supplement companies but rather from the pharmacy.

Just remind me where you wnat me to put you the money

[40-Yard Dash_2]

As far as the original question posed - I can tell you this for now: When we test people's blood work, there is NOT precipitous difference between those running R-ALA and the sodium -and/or- potassium salts when considering blood glucose levels. And I think that would be the bottom line, the clinical effect - no?


D_

I would certainly think so.