616/TIN PDR FOR NUTRITIONAL SUPPLEMENTS Pekelharing HL, Lemmens AG, Beynan AC. Iron, copper and PHARMACOKINETICS zinc status in rats fed on diets containing various concentrations Much is unknown about the pharmacokinetics of tiratricol in of tin. Br J Nutr. 1994; 71: 103-109. humans. The pharmacokinetics of tiratricol appears to be Yokoi K, Kimura M, Itokawa Y. Effect of dietary tin similar to those of thyroxine and triiodothyronine. Tiratricol deficiency on growth and mineral status in rats. Bioi Trace is absorbed from the small intestine following ingestion. Elem Res. 1990; 223-231. Distribution of tiratricol in the body has not been fully elucidated. Most of this substance appears to be bound to serum proteins, including thyroxine-binding protein and albumin. It appears to be less firmly bound to serum proteins Tiratricol (TRIAC) than are T4 and T3' The liver appears to be the major site of degradation of tiratricol. Tiratricol appears to be conjugated FDA warns against consuming dietary supplements with glucuronic acid and sulfuric acid and excreted in the containing Tiratricol. bile. Mainly because it is less tightly bound to serum proteins, tiratricol has a shorter half-life than T4 or T3, DESCRIPTION INDICATIONS AND USAGE Tiratricol is an orphan drug for use in combination with The FDA has warned consumers not to purchase tiratricol- levothyroxine to suppress thyroid stimulflting hormone containing dietary supplements due to risk of serious health (TSH) in patients with well-differentiated thyroid cancer consequences, including heart attacks and strokes. Tiratricol who are intolerant to adequate doses of levothyroxine alone. should be used only under a 'physician's supervision. Tiratricol is a metabolite of the thyroid hormone triiodothy- Tiratricol is currently used by some as a supplement to burn ronine (T3) and has thyroid hormone activity. fat. The doses required to achieve this effect pose significant Tiratricol is also marketed as a dietary supplement for health risks. weight-loss purposes. In November 2000, the Food and Drug Administration (FDA) warned against consuming dietary RESEARCH SUMMARY supplements containing tiratricol. This was based on reports Tiratricol is an orphan drug. The FDA has determined that it of individuals using tiratricol developing side effects, such as should not be used as a dietary supplement due to serious fatigue, lethargy, profound weight loss and severe diarrhea. potential health risks including heart attack and stroke. They were also found to have abnormal thyroid function tests. Further action by the FDA is being considered. CONTRAINDICATIONS,, PRECAUTIONS, ADVERSE REACTIONS CONTRA INDICA TIONS Tiratricol is also known as triiodothyroacetic acid, TRIAC, Tiratricol is contraindicated in those with untreated thyrotox- 3,5,3' -triiodothyroacetic acid and [4-(4-hydroxy-3-iodophe- icosis of any etiology and in those with uncorrected adrenal noxy)-3,5-di-iodophenyl]acetic acid. Its molecular formula is insufficiency. Thyroid hormones increase tissue demands for C14H91304,and its molecular weight is 621.9 daltons. adrenocortical hormones and may thereby precipitate acute adrenal crisis. Tiratricol is also contraindicated in those who ACTIONS AND PHARMACOLOGY are hypersensitive to any component of a tiratricol-contain- ACTIONS ing product. FDA warns against consuming dietary supple- Tiratricol has thyroid hormone activIty, including various ments containing tiratricol. metabolic effects. It also inhibits the secretion of thyroid- stimulating hormone (TSH) by the pituitary gland. Tiratricol PRECAUTIONS is a product of triiodothyronine or T3 metabolism, derived by Tiratricol should only be used for specific approved indica- deamination and oxidative decarboxylation of the alanine tions and only under strict medical supervis~on. Tiratricol chain. In humans, tiratricol production by the liver and other should not be used as a treatment for obesity. Tiratricol tissues accounts for about 14% of T3 metabolism and is should be used with extreme caution in those with cardiovas- increased under certain physiological conditions, such as , cular disorders (including flngina, coronary artery disease fasting. Tiratricol may play a role in regulat.ing energy and hypertension) and in the elderly who have a greater balance. likelihood of occult cardiac disease. Concomitant use of MECHANISM OF ACTION tiratricol and sympathomimetic agents in those with coronary The mechanism by which thyroid hormones exert their artery disease may increase the risk of coronary insufficien- various actions has not been completely elucidated. Tiratri- cy. Use of tiratricol in those with concomitant diabetes col is known to act as a feedback inhibitor of TSH secretion mellitus, diabetes insipidus or adrenal cortical insufficiency by the pituitary gland. may aggravate the intensity of their symptoms. SUPPLEMENT MONOGRAPHS TOCOTR IENOLS /617 FDA warns against consuming dietary supplements contain- a child with thyroid hormone resistance. Thyroid. 1997;7:775- ing tiratricoI. 778. Takeda T, Suzuki S, Uu RT, et al. Triiodothyroacetic acid has ADVERSE REACTIONS unique potential for therapy of resistance to thyroid hormone. J Reported adverse reactions include fatigue, lethargy, pro- Clin Endocrinol Metab. 1995;80:2033-2040. found weight loss and severe diarrhea. Tir~tricol has also been reported to cause abnormal thyroid function tests. INTERACTIONS DRUGS Tocotrienols Anticoagulants (oral). The hypoprothrombinemic effect of DESCRIPTION anticoagulants, such as warfarin, may be potentiated. Tocotrienols comprise one of the two groups of molecules Sympathomimetic agents. There is a possible increased risk belonging to the vitamin E family, the other group being the of coronary insufficiency in those with coronary artery tocopherols. Tocotrienols and tocopherols are sometimes disease. collectively called tocols. Just as there are four natural tocopherols, alpha-, beta-, gamma- and delta-tocopherol, Thyroid drugs (levothyroxine, tr,iiodothyronine, thyroid). there are also four natural tocotrienols, alpha-, beta-, gamma- Concomitant use of tiratricol with the~e thyroid drugs is and delta-tocotrienoI. The tocotrienols differ from the likely to produce additive effects. tocopherols in the chemical nature of the side chain or tail. Tocopherols have a saturated phytyl side chain, whereas LABORATORY TESTS tocotrienols have an unsaturated isoprenoid or farnesyl side Tiratricol is likely to alter thyroid function tests, including chain ,possessing three double bonds. TSH, 'f,4 and T3' OVERDOSAGE The major source of tocotrienols are plant oils, and the There have been no reports of overdosage with tiratricoI. richest sources are palm oil, rice bran oil, palm kernel oil and Excessive doses of tiratricol theoretically may result in a coconut oil. Tocotrienols are also found in such cereal grains hyperrnetabolic state indistinguishable from thyrotoxicosis. as oat, barley and rye. Vegetable oils, such as those from canola, cottonseed, olive, peanut, safflower, soybean and DOSAGE AND ADMINISTRATION sunflower, contain little to no tocotrienols. However, those Tiratricol is not recommended for use as a dietary oils do contain tocopherols. Corn oil has small amounts of supplement. tocotrienols. LITERATURE All of the natural tocotrienols are fat-soluble, water-insoluble Anon. FDA warns against consuming dietary supplements oils. The tocotrienols, as well as the tocopherols, possess containing tiratricol. FDA Talk Paper. Nov. 21, 2000. chain-breaking, peroxyl radical scavenging activities. In Bracco D, Morin 0, Schutz Y, et al. Comparison of the contrast to tocopherols, tocotrienols inhibit the rate- metabolic effects of 3,5,3' -triiodothyroacetic acid and thyroxine. limiting enzyme of the cholesterol biosynthetic pathway J Clin Endocrin Met. 1993;77:221-228. beta-hydroxy-beta-methylglutaryl-coenzyme A (HMG-CoA) Darendeliler F, Ba F. Successful therapy with 3,5,3'- reductase. triiodothyroacetic acid (TRIAC) in pituitary resistance to thyroid hormone. J Pediatr Endocrinol Metab. 1997;10(5):535-538. The four natural tocotrienols are characterized by the number of methyl groups and their position in the chromanol ring. Iglesias P, Dfez 11. [Therapeutic possibilities in patients with Alpha-tocotrienol has three methyl groups located on posi- selective pituitary resistance to thyroid hormones.] [In Spanish.] Med Clin (Barc). 2008;130(9):345-350. tions 5, 7 and 8 of the chromanol ring; beta-tocotrienol has two methyl groups located on positions 5 and 8 of the ring; Medina-Gomez G, Calvo RM, Obregon MJ. Thermogenic eff~ct gamma-tocotrienol has two methyl groups located on posi- of triiodothyroacetic acid at low doses in rat adipose tissue tions 7 and 8 of the ring and delta-tocotrienol has one methyl without adverse side effects in the thyroid axis. Am J Physiol Endocrinol Metab. 2008;294(4):E688-697. group located on position 8 of the ring. Pisarev MA, Brenta G, Schnitman M, et al. [Triiodothyroacetic While tocopherols have three chiral centers, tocotrienols acid in euthyroid goiter. New data on its mechanisms of action. have only one chiral center. Therefore, each tocotrienol has Comparison with L-thyroxin.] [In French.] Bull Acad Natl Med. two stereoisomeric possibilities in comparison with eight 2007;191(8):1705-1715; discussion 1715. such possibilities for each of the tocopherols. The natural Radetti G, Persani L, Molinaro G, et al. Clinical and hormonal tocotrienols exist as d-stereoisomers: d-alpha-tocotrienol, d- outcome after two years of triiodothyroacetic acid treatment in beta-tocotrienol, d-gamma-tocotrienol and d-delta-tocotrien-.