Thyroxine

THYROXINE (Thyroxine), a hormone of the thyroid gland, isolated in 1919 by Kendall. Kendall mistakenly considered T. to be a derivative of indole, which explains its name (an abbreviation of Thyro-oxy-indol). In 1926, Harrington succeeded in significantly simplifying and improving the method of obtaining T. from the thyroid gland and increasing its yield 25 times. He proved that T. is the para-iodophenyl ester of diiodotyrosine and has the following structural formula (the position of the iodine atoms has not yet been precisely established): J

J

J

In 1927, Harrington, together with Barger, succeeded in obtaining T. synthetically. Synthetic T. has identical action on the organism to natural T. and is approximately 200-280 times cheaper than the latter. As a preparation, T. is official in the USA. It consists of colorless needle-shaped crystals, odorless and tasteless, unstable in sunlight, darkening at 220°, melting at 250° C with the elimination of iodine. Both natural and synthetic T. are optically inactive (racemic), and it is believed (Tiffeneau) that they racemize during the production process. Harrington succeeded in obtaining left- and right-rotating T. (with slight rotation), with the left-rotating isomer being approximately 3 times more active in experiments on tadpoles than the right-rotating one. T. contains 65% iodine. It is almost insoluble in water, in common organic solvents (alcohol, ether, acetone, gasoline, etc.) and in acids. It is soluble in dilute alkalis (less in concentrated ones), especially easily when heated, soluble in 50% alcohol in the presence of alkalis or mineral acids (but not acetic acid). When the alkaline solution of thyroxine is saturated with sodium chloride, the sodium salt of T. is precipitated. Under the influence of acids, T. is precipitated from the alkaline solution in an amorphous form. Physiologically, T. is a hormone of the thyroid gland. Recent data suggest that the natural hormone of the gland is probably not free T., but represents a complex peptide in which T. is contained (Dale). In addition to T., the thyroid gland contains other iodine-containing specifically acting substances, since even by Harrington's improved method, at best, only about 15% of the organic iodine in the thyroid gland can be obtained in the form of T. Furthermore, it has been experimentally and clinically proven that in equivalent iodine doses, T. is 1½-2 times less active than dried thyroid gland (see Thyreoidin). Based on thorough research on humans, it is believed (Plummer and Boothby) that the human body contains 14-15 mg of T., with the daily requirement being determined at 0.3-0.7 mg. Pharmacologically and therapeutically, T. has all the characteristic types of action of preparations from the thyroid gland (see Thyreoidin), having advantages over them in terms of definite chemical composition, accuracy of dosage, and the possibility of intravenous administration. The action of T. occurs after a certain latent period, which in humans when taken orally reaches several days, with the maximum effect from a single dose occurring approximately after 10 days and lasting 8-10 days, i.e., lasting a total of about 3 weeks. When administered intravenously, the effect occurs approximately after 9-10 hours (Plummer). In toxic doses (in animals), the latent period is shortened, decreasing with oral administration to 1-1½ days. In the body, T. is apparently destroyed slowly, which explains the continuation of the effect after its administration is stopped. In studies on myxedematous patients, data have been obtained allowing one to assume that a single dose of 14 mg of T. (i.e., equal to the total content of T. in the body) when administered intravenously is destroyed only after 1-2 months (Plummer and Boothby). T. has all the types of action of thyreoidin (see). Its action on metabolism is stronger than all chemical substances known to date; in strength of this action, it is closest to it the compounds of cresol and phenol, for example, dinitrophenol; it acts on metabolism 64 times stronger than adrenaline. Even with intravenous administration, T. does not have a direct effect on the cardiovascular system, changes in the activity of which are due to the increase in metabolism caused by T. (see Thyreoidin). In addition, T. increases the excitability of the endings of the autonomic nerves (probably especially the sympathetic ones). T. (synthetic) was introduced into therapy in 1926. The indications for the use of T. are the same as for thyreoidin. It is used mainly orally in small doses for prolonged periods, and due to more precise dosing, side effects are less frequently observed than with thyreoidin. Dosage should be individual, as it depends on individual sensitivity to T. and the degree of hypofunction of the thyroid gland. Usual oral doses are 0.25-0.5 mg per dose, rarely 1 mg. When administered intramuscularly or intravenously, a more rapid effect is achieved, but the possibility of side effects sharply increases. Therefore, parenteral treatment is used only in rare cases, at 0.5-1 mg of T. per day. T. (synthetic) is commercially available in tablets of ¼, ⅓, and 1 mg and in ampoules (0.1% solution) of ½-1 mg (factories Henning, Schering-Kahlbaum, Hoffmann-La Roche, etc.). At present, various derivatives of T. have been obtained (diiodide T., acetylthyroxine, etc.), but all of them are inferior to thyroxine in therapeutic effect.