Beriberi

Editor:

I read the response of Dr. Nibber to my original letter (Townsend Letter August/September 2004) with interest. Both my letter and the response raise some important issues that go beyond the mere fact of whether blood concentrations are increased by any one of the many thiamine derivatives. The most important of these issues is which one of these derivatives has the best therapeutic record. Readers that may not be familiar with the obscure literature on this subject should be aware that the original biochemical research was carried out in Japan in mid-20th century. These investigators performed detailed biochemical studies and tested the clinical effects of many thiamine derivatives in animal and human subjects. This resulted finally in the choice of thiamine tetrahydrofurfuryl disulfide (TTFD) as the best one for clinical use and it has been marketed for years as Alinamin F (Odorless). It is made by Takeda Chemical Industries in Osaka, Japan. Its patent expired years ago but it has never been picked up for manufacture in the USA because it is generally regarded as a way of administering thiamine for vitamin deficiency rather than considering its use as an extremely valuable therapeutic agent. It is an orphan drug "looking for a disease to treat." Much of the original work was performed with thiamine propyl disulfide (TPD) that has the same properties as TTFD, but is associated with a powerful garlic odor when metabolized. It was for this reason that TTFD was synthesized since the odor was not associated with its use.

There was a hiatus in research news on the subject until the recent papers from Germany appeared on the superiority of benfotiamine. This derivative, whose chemical name is S-benzoyl thiamine monophosphate (BTMP) is produced commercially as "Ankermann" by Worwag Pharma in Germany who provided financial support for at least one research paper that compared benfotiamine with fursultiamin (TTFD). (1) This work was performed on "seven healthy volunteers between 25 and 49 years" and it should be clear to discerning readers that a statistical analysis for differences in transketolase (the test for intracellular thiamine activity), which the authors claimed, are irrelevant with such numbers, added to the fact that the subjects were described as healthy volunteers who should have a normal transketolase anyway.

The original Japanese investigators stated that "all of the S-acylthiamine derivatives (they tested O,S diacetyl thiamine, O,S-dibenzoyl thiamine, and S-benzoylthiamine monophosphate) were absorbed from the intestine far more readily than thiamine and at a rate comparable to TPD." On the other hand, they found that they were "devoid of the marked property of allithiamine in penetration into blood cells." (2)

Neither did BTMP, or any of the alkyl derivatives, have the same therapeutic properties against cyanide, carbon tetrachloride or carageenan induced paw edema in animal studies. (2) It must be clearly stated that each and every one of these derivatives represents a way of introducing thiamine into the cell where its actions are required. At least part of the therapeutic benefit is dependent on the buildup of its active forms to stimulate oxidative metabolism. We know, for example, that TTFD increases the concentration of thiamine triphosphate (TTP) in guinea pig heart muscle (3) and that this probably is an extremely important phenomenon in treatment of cardiac disease. (4) I have successfully treated idiopathic dilated cardiomyopathy with TTFD (Lonsdale D. Unpublished observations). Reducing the molecule before entry into cells gives rise to thiamine that has to be absorbed through the cell membrane transport system that normally operates for this vitamin. It is not possible, therefore, to assess bioavailability (1) unless the cellular concentration of thiamine and its biologic effect as an enzyme cofactor are assessed.

Dr. Nibber stated in his letter that "benfotiamine is first taken up across the gut mucosa through dose-proportional passive diffusion. Only at this point is S-benzoylthiamine finally subject to intracellular reduction to biologically active thiamine" for which he quotes a reference. That is not disputed and agrees essentially with the observations made by the original investigators. The mechanism of reduction is an essential part of the transaction and TTFD is easily reduced in the presence of cystine or glutathione whereas the alkyl derivatives require enzymatic reduction in liver or kidney (2) as I stated in my original letter.

The next important item is what happens to the prosthetic group after reduction and this has been well studied for TTFD. (5-9) At the present time we do not know whether the prosthetic group produces any drug action in its own right. It is a mercaptan and may be instrumental in removal of SH-reactive metals from the body. From experimental work in animals we do know that thiamine has been shown to remove lead via the bile and urine. (10) The question remains as to whether thiamine derivatives are better in this respect. In a pilot study my colleagues and I have demonstrated clinical improvement in 8 of 10 autistic spectrum children (ASD) who demonstrated increased concentrations of SH-reactive metals in urine related to their treatment, given by rectal suppository. (11) We agree, however, that this needs further study, using a double blind, controlled approach. Yamamoto and Kaneda (12) performed experimental administration of cadmium contaminated rice to 6 men with concurrent treatment with BTMP, followed by TTFD. Their results, based on increase in cadmium in moustache hair, are unconvincing for BTMP and the results of TTFD administration are not presented. They do, however, quote references by Yamamoto and associates, on which they comment as follows: "examination was made of the excretion of intracorporeal methylmercury into body hair (Yamamoto, 1990) by the administration of thiamin tetrahydrofurfuryl disulfide (TTFD) which caused significant increase in mercury content in human mustache. The thiamin derivative, S-benzoylthiamin monophosphate (BTMP) (Yamamoto, 1988) failed to have such effect. The mechanism of mercury excretion is thus based on the side chain structure of TTFD, mercaptan."

Radioactivity and thiamine concentration in blood cells and plasma of rabbits following injection of (35) S labeled TPD in a dose of 10 mg.

I do not claim that these issues are by any means settled. My interest in TTFD dates back to 1973 when I was granted an IND for clinical studies. Because of the extraordinary resistance to vitamin therapy for most of those years, it has been virtually impossible to publish work in major journals. If any reader wishes further details concerning therapeutic value of thiamine and TTFD, a review was published in the September issue of Medical Science Monitor (13) (www.medsciencemonit.com), an on-line journal that is indexed in Index Medicus. There is no doubt that thiamine is a most reactive molecule and plays a huge part in the control of many different aspects of energy metabolism. Its therapeutic potential is largely untapped. The choice of the best derivative to achieve this needs much more study.

References

1. Greb A. Bitsch R. Comparative bioavailability of various thiamine derivatives after oral administration. Int J Clin Pharmacol Ther 1998;36(4):216-221.

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

3. Iida S. Rapid formation of thiamine triphosphate in heart muscle after administration of disulfide derivatives of thiamine. Biochem Pharmacol 1966;15:1139-1145.

4. Shinozaki H Cardiac action of thiamine derivatives in guinea pig atria J Nutr Sci Vitaminol 1976;22:29-34.

5. Fujita T, Suzuoki Z. Enzymatic studies on the metabolism of the tetrahydrofurfuryl mercaptan moiety of thiamine tetrahydrofurfuryl disulfide. I. Microsomal S-transmethylase. J Biochem 1973;74:717-722.

6. Fujita T, Suzuoki Z, Kozuka S. Enzymatic studies on the metabolism of the tetrahydrofurfuryl mercaptan molety of thiamine tetrahydrofurfuryl disulfide. II. Sulfide and sulfoxide oxygebases in microsomes. J Biochem 1973;74:723-732.

7. Fujita T, Suzuoki Z. Enzymatic studies on the metabolism of the tetrahydrofurfuryl mercaptan moiety of thiamine tetrahydrofurfuryl disulfide. III. Oxidative cleavage of the tetrahydofuran moiety. J Biochem 1973;74:733-738.

8. Fujita T, Teraoka A, Suzuoki Z. Enzymatic studies on the metabolism of the tetrahydrofurfuryl mercaptan moiety of thiamine tetrahydrofurfuryl disulfide. IV. Induction of microsomal S-transmethylase, and sulfide and sulfoxide oxygenases in the drug-treated rat. J Biochem 1973;74:739-745.

9. Kikuchi S, Nishikawa K, Suzuoki Z. The metabolism of thiamine tetrahydrofurfuryl disulfide in the rat, rabbit and man. Eur J Pharmacol 1970;9:367-373.

10. Olkowski AA, Gooneratne SR, Christenson DA. The effects of thiamine and EDTA on biliary and urinary lead in sheep. Toxicol Lett 1991;59:153-159.

11. Lonsdale D, Shamberger R J, Audhya T. Treatment of autistic spectrum children with thiamine tetrahydrofurfuryl disulfide:a pilot study. Neuroendocrinol Lett 2002;23:303-308.

12. Yamamoto J, Kaneda Y. Excretion of intracorporeal cadmium with S-benzoylthiamin monophosphate. Bull Environ Contam Toxicol 1995;54:745-750.

13. Lonsdale D. Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent Med Sci Monit 2004;10(9): RA 199-203.

Derrick Lonsdale, MD

dlonsdale@pol.net

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