1. Field of the Invention
The present invention relates to novel pharmaceutical compositions and methods of treatment that utilize or comprise tetrac (3,3xe2x80x2,5,5xe2x80x2-tetraiodothyroacetic acid), a natural metabolite of the thyroid hormone T4 (L-thyroxine). Pharmaceutical compositions of the invention are capable of suppressing the secretion of thyroid stimulating hormone (TSH) while reducing or avoiding the thyromimetic stimulation of peripheral tissues as compared to an equivalent TSH-suppressive dose of L-thyroxine.
2. Background
The thyroid is a bilobal gland located at the base of the neck in front of the windpipe. It produces a variety of hormones that regulate body metabolism and organ function and thus affects such things as heart rate, cholesterol level, body weight, energy level, muscle strength and skin condition, among other things. The thyroid hormones bind to protein receptors closely associated with DNA in the nucleus of the cells of the body thereby regulating the transcription of DNA and the translation of RNA. Therefore, the metabolic effects of the thyroid hormones derive from their ability to regulate the turnover of enzymes and proteins in the body.
The amount of thyroid hormone present in the body is carefully regulated by a feedback mechanism involving the hypothalamus, pituitary and thyroid glands. The hypothalamus produces thyrotropin releasing hormone (TRH) which causes the pituitary to produce thyroid stimulating hormone (TSH). TSH stimulates the thyroid to produce T4 (thyroxine) and T3 (3,3xe2x80x2,5-triidodothyronine), the two major thyroid hormones (FIG. 1). The levels of T4 and T3 in the blood are monitored by the pituitary which will produce more TSH if the thyroid hormone levels are too low and less TSH if the levels of T3 and T4 are too high.
T4 is the principal secretory product of the thyroid gland while T3 is the most potent thyroid hormone due to its high binding affinity for the thyroid hormone nuclear receptors. Secretion of TSH from the pituitary gland is exquisitely sensitive to inhibition by T3. Although T3 is only secreted by the thyroid gland in small amounts, its principle source in the pituitary gland is through the local conversion of T4 to T3 by the pituitary specific enzyme, monodeiodinase type II. The control of pituitary TSH secretion therefor depends on the activity of this monodeiodinase. As the circulating concentrations of T4 approach normal levels, T4 suppresses the activity of the pituitary specific monodeiodinase type II thus reducing T3 generation and effectively releasing the pituitary from further suppression. The ability of T4 to control the suppression of TSH secretion accounts for the feedback regulation of T4 on its own secretion and the normal set-point of the thyroid-pituitary axis.
The presence of too much or too little thyroid hormone in the body leads to abnormalities which can become life-threatening if left untreated. The presence of too much thyroid hormone leads to hyperthyroidism. Hyperthyroidism, or overactivity of the thyroid gland, has several causes and amongst other symptoms causes anxiety, insomnia, weight loss and rapid heart rate. Hyperthyroidism is treated by destruction of all or part of the thyroid gland by surgical removal, treatment with radioiodine, or both, and with drugs that block the synthesis of the thyroid hormones.
The presence of too little thyroid hormone leads to hypothyroidism which is more common than hyperthyroidism. Hypothyroidism, or underactivity of the thyroid gland, has several causes and amongst other symptoms causes lassitude, weakness, weight gain and slow heart rate. Hyperthyroidism is treated by lifelong replacement with synthetic thyroid hormones, usually L-thyroxine.
Abnormal growths or cancers of the thyroid gland are presently treated by surgical removal of the gland followed by radioiodine to destroy any remaining thyroid tissue. This is followed by chronic treatment with supraphysiologic doses of T4 to suppress the secretion of TSH from the pituitary gland, thereby preventing stimulation of residual thyroid cancer cells expressing the TSH receptor. These supraphysiologic suppressive doses of T4 unavoidably lead to mild hyperthyroidism.
Other metabolites of the thyroid hormones are tetrac (3,3xe2x80x2,5,5xe2x80x2-tetraiodothyroacetic acid) and triac (3,3xe2x80x2,5-triiodothyroacetic acid) which are produced by the deamination of T4 and T3, respectively (FIG. 1). Tetrac is a prohormone of triac and is converted by two enzymes, the same monodeiodinase type II found in the pituitary and to some extent elsewhere in the brain and at low expression in the heart and thyroid gland and monodeiodinase type I found in the liver and other peripheral tissues that converts T4 to T3. Triac is also a potent inhibitor of TSH secretion and has been investigated as a substitute for T4 in treating thyroid patients after thyroidectomy. However, because of its potent thyromimetic activity in peripheral tissues and very short plasma half-life, triac was found to be an unsuitable substitute for T4 for this purpose. However, triac has been found to be useful in treating a rare form of thyroid hormone resistance.
Thus, it would be extremely desirable to develop novel pharmaceutical compositions capable of suppressing TSH secretion while reducing or avoiding the iatrogenic hyperthyroidism induced by comparable TSH-suppressive doses of T4 (L-thyroxine).
See also: Bracco, D., et al. J. Clin. Endocrinol. Metab., 77: 221-228 (1993); Burger, A. G. and Vallotton, M. B., xe2x80x9cThe metabolism of tetraiodothyroacetic acid and its conversion to triiodothryoacetic acid,xe2x80x9d Thyroid Hormone Metabolism, pages 223-239, W. A. Harland and J. S. Orr, editors, Academic Press, London, New York, San Francisco, (1975); Burger, A. G. et al. Acta Endocrinologica, 92: 455-467 (1979); Goolden, A. W. G., et al. The Lancet, 1: 890-891 (1956); Green, W. L. and Ingbar, S. H. J. Clin Endocr., 21: 1548-1565 (1961); Lerman, J. and Pitt-Rivers, R. J. Clin. Endocrinol. Metab., 16: 1470-1479 (1956); Lerman, J., J. Clin. Endocr., 21: 1044-1053 (1961); Liang, H., et al. Eur. J. Endocrinol., 137: 537-544 (1997); Menegay, C., et al. Acta Endocrinol. (Copenh), 121: 651-658 (1989); and Richardson-Hill, S., et al. J. Clin. Invest., 39: 523-533 (1960).
The present invention provides novel pharmaceutical compositions comprising tetrac which are capable of suppressing TSH secretion while reducing or avoiding the thyromimetic stimulation of peripheral tissues induced by a dose of L-thyroxine which produces an equivalent TSH-suppressive effect. The invention further provides pharmaceutical composites that comprise a combination of tetrac and L-thyroxine (T4).
Preferred pharmaceutical compositions are capable of suppressing TSH secretion while reducing or avoiding the thyromimetic stimulation of the tissues of the heart, liver, kidneys, muscle and bone as compared to the stimulation of said tissues induced by a dose of L-thyroxine which produces an equivalent TSH-suppressive effect.
The compositions of the present invention are capable of suppressing TSH secretion without suppressing the activity of the pituitary specific type II monodeiodinase.
The invention provides a method for suppressing TSH secretion while reducing or avoiding the thyromimetic stimulation of peripheral tissues induced by a dose of L-thyroxine which produces an equivalent TSH-suppressive effect comprising administration of a pharmaceutical composition comprising tetrac.
The method of the present invention may be used to treat patients suffering from malignancies or other abnormal growths of the thyroid gland. The method of the present invention is particularly useful for suppressing the growth of residual thyroid tissue in a thyroid cancer patient post thyroidectomy.
Tetrac is a natural metabolite of thyroxine (T4), the main secreted thyroid hormone. The thyromimetic potency of tetrac is less than triac because of its lower binding affinity for the thyroid hormone nuclear receptors. Additionally, tetrac is locally converted to triac, a potent inhibitor of TSH secretion, by the pituitary specific type II monodeiodinase. Due to its long half-life, tetrac assures a constant supply of triac and the small amounts of locally produced triac in the pituitary and its rapid metabolic half-life limits the thyromimetic activity of triac in other tissues of the body. Moreover, tetrac, unlike T4, does not suppress the activity of the pituitary specific monodeiodinase as its concentration in the plasma is increased. Therefore, following conversion to triac, tetrac is capable of suppressing TSH in an unrestrained fashion. In addition, tetrac is less thyromimetic in peripheral tissues as compared to T4 and is pharmaceutically more elegant than triac because of its longer plasma half-life.
Other aspects of the invention are disclosed infra.