Also see the reply to this letter from the advertiser.

Editor:
I have to object to the advertisement for Benfotiamine on page 132 of your June issue, since the statements designed to promote it are inaccurate. I wish to put the record straight concerning the derivatives of thiamine that have been extremely well studied in Japan. Very little research has been reported about these important vitamers in recent years, but with the awakening of information concerning heavy metal poisoning it becomes important for us to know about the proper use of thiols in therapy.

First, a little history is necessary. The enzyme known as thiaminase was being studied in the 1940s by members of the University-based Vitamin B Research Committee of Japan. As a byproduct of these studies, Fujiwara discovered a derivative of thiamine that was more active biologically than the original thiamine. After many years of further research into this phenomenon, they produced a book in English, published in Tokyo in 1965 and obviously hard to obtain. The authors were particularly concerned that there was considerable ignorance in the West about the massive amount of research that surrounds the versatile therapeutic properties of thiamine and its many derivatives.

The following information is extracted from this book. Fujiwara called the new byproduct of thiamine by the name of allithiamine to indicate that it was found in garlic bulbs and other members of the allium plant genus. Subsequently, it was found that allithiamine was a disulfide derivative of thiamine formed only when an enzyme within the plant acted on thiamine. This action occurs when the garlic bulb is crushed or cut and allithiamine is one of the many thiols that produce some of the diverse therapeutic properties of garlic. The advertisement refers to Benfotiamine as being a member of a group of allithiamines and that is simply not true. There is only one allithiamine and that is the one that occurs naturally in the allium plants as described above. Thiamine tetrahydrofurfuryl disulfide (TTFD), the synthetic counterpart of allithiamine is presently sold as Allithiamine. Note the capital A, for this product is not to be confused with the naturally occurring disulfide in garlic.

Fujiwara and his colleagues then went on to do a vast amount of research that is detailed in the book referenced at the end of this letter. They went on to synthesize a whole series of thiamine derivatives and performed animal and human subject studies. Much of this experimental work was performed with thiamine propyl disulfide (TPD), the forerunner of the most modern derivative, TTFD. Both of these "fat soluble" thiamines have the same biologic properties. Other molecules, synthesized and studied later, are known as S-acyl-thiamine derivatives. They included O, S-diacetyl thiamine (DAT), O,S-dibenzoyl thiamine (DBT) and S-benzoylthiamine monophosphate (BTMP), the last one now known as Benfotiamine and obviously a trade name.

I would like to quote from a chapter in the book that was written by Fujiwara: "While S-acyl-thiamine derivatives are readily absorbed from the intestinal canal at a rate comparable to allithiamine, they are devoid of that marked property of allithiamine (and its synthetic derivatives), i.e. penetration into blood cells." Later in the text: “S-acyl-thiamine derivatives are devoid of the preventive effect against the intoxication of various types which characterize allithiamine: this difference may be ascribed to the absence of the S-S bond in S-acyl-thiamine derivatives."

To enlarge on this, experiments in animals showed that TPD partially protected mice against experimental cyanide poisoning by stimulating the enzyme rhodanese that is responsible for converting toxic cyanide ions to non-toxic thiocyanate. They were also able to show that TPD protected animals from experimentally administered carbon tetrachloride, to mention but two of the many animal studies that were performed by this group of investigators.

Generally, they said, allithiamine and its synthetic derivatives are very easily reducible to thiamine in the presence of cysteine or glutathione, an extremely important part of their biologic action. On the other hand, S-acyl-thiamine derivatives resist such a simple reduction. They are first reduced to thiamine only after they are acted on enzymatically in the liver or kidney. This very important difference needs further explanation, since it affects their biologic properties.

Both the disulfide and S-acyl-thiamine derivatives are formed by opening the thiazolium ring of thiamine and attaching a prosthetic group to the sulfur atom of the thiazolium. The disulfide bond is the key and the S-acyl-thiamine derivatives are not disulfides. For this reason they cannot be referred to as "fat soluble." The only reason for calling TPD or TTFD "fat soluble" is because they enable the passage of thiamine across the lipid barrier of the cell membrane. In fact, TTFD is water soluble and can be given intravenously. The disulfide is reduced and the prosthetic group (the tetrahydrofurfuryl mercaptan) is left outside the cell. The opened thiazolium ring closes in the cell to become an intact molecule of thiamine. This non-enzymatic transport enables the import of the thiamine moiety into the cell where it is then capable of building up high concentrations of thiamine pyrophosphate and triphosphate, the active forms of the vitamin. The ordinary water soluble salts of thiamine rely on a transport system across cell membranes that makes the absorption of the thiamine moiety into cells limited. It would appear that BTMP is subject to the same natural transport mechanisms by the release of an intact thiamine molecule outside the cell.

Lastly, the mercaptan prosthetic group of TTFD has been very well studied, its sequential enzymatic breakdown known, and it is non-toxic. The prosthetic group from BTMP has not, to my knowledge, been studied and is an important part of the biochemical transaction that takes place when the molecule is split into its two factions. Animal studies have shown that thiamine causes lead to be excreted via the bile duct and kidney. Since lead is SH-reactive, like mercury, arsenic and cadmium, it is very probable that it is the SH reactivity that is linked to this and it obviously needs to be explored in the wake of the increasing knowledge of the toxicity of these heavy metals. If intracellular thiamine is required for this effect, then it is apparent that TTFD would be superior to BTMP or water-soluble salts in any other form.

Derrick Lonsdale, MD
Preventive Medicine Group
24700 Center Ridge Road
Westlake, Ohio 44145 USA
440-835-0104
Fax 440-871-1404
dlonsdale@pol.net

Reference
1. Fujiwara M. Absorption, excretion and fate of thiamine and its derivatives in [the] human body. Chapter in: Shimazono N, Katsura, eds: Beriberi and Thiamine. 1965, Tokyo, Igaku Shoin Ltd. pp.179-213.