Thyreoidin

THYREOIDIN (Thyreoidinum, Thyreoidinum siccum Ph. VII), the most common name for organ preparations obtained from the thyroid gland (syn.-Thyreocrin, Thyreo-glandol, etc.). Under this name, Ph. VII refers to the thyroid glands of animals, cleansed of connective tissue and fat, dried, and ground into a yellowish amorphous powder with a weak characteristic odor. The preparation must not contain mineral iodine compounds or other foreign impurities, organic or inorganic. Must contain from 0.17% to 0.23% iodine. Highest single dose-0.3, highest daily-1.0. Most commonly sold in the form of tablets, dragees, occasionally in liquid form (see below) for oral administration and (some preparations) for subcutaneous injection.

52S skin.-The name T. was first given by Baumann (1895) to the organic substance he isolated from the thyroid gland by boiling with 10% sulfuric acid (later called iodotyrosine, see Internal Secretion, Mod), which was of a non-protein nature and contained iodine (3-14%). This product was not of constant chemical structure, as it contained varying percentages of iodine, constituting about 4% of the weight of the dried gland, and was 3-4 times less active than equivalent amounts of the gland itself. Later, Oswald (A. Oswald, 1897) showed that iodotyrosine does not exist in the thyroid gland in a free state, but is bound to globulin in the form of iodotyroglobulin, which is found in the colloidal mass filling the follicles of the gland. Iodotyrosin is cleaved from the tyroglobulin when the latter is treated with acid. Iodotyroglobulin also did not prove to be a definite chemical compound, as the iodine content in it varies sharply (from traces to 1.75%); it constitutes from 14% to 60% of the weight of the dried thyroid gland. The active principle of T., iodotyrosine, and iodotyroglobulin is thyroxin (see), but it may not be the only one. T. has a specific, multifaceted, and powerful effect on the body. This effect is stronger the more pronounced the hypofunction of the patient's thyroid gland. With normal thyroid function, the effect is less, but symptoms of poisoning are more readily observed. Children's sensitivity to T. is relatively less than that of adults. The characteristic effect of T. with ordinary oral administration is fully manifested only after several (7-14) days with repeated administration; subcutaneous injections of liquid T. often do not give a specific effect at all due to the negligible content of hormone in such a preparation (iodine is often present in traces). Even a single very large dose of T. gives a significantly smaller effect than the same amount taken in the form of repeated small doses. The effect of T. continues for several days after administration is stopped. Experimental data show that the absorption of T. in the intestine is limited-the main part leaves the body without being absorbed in the first 2 hours (Palm, 1922). After absorption, T. can no longer be detected (by biological tests) in the blood very soon; it has been proven (B. Zavadovsky) that the active principle accumulates in the liver after 3-5 hours and possibly in other organs. The former assumption about the rapid inactivation of the active principle in the blood was not confirmed, since the latest research methods have shown that its destruction occurs very slowly, especially with repeated administration. The excretion of T. occurs mainly through urine and bile (and therefore feces) in a destroyed form (iodides); in an undestroyed form, the active principle is excreted in milk (Bang, specific action on the myxedematous child of the mother's milk who received T.). Excretion occurs very slowly-a single dose leaves the body on average after 6 weeks. These data explain the latent period of action, the peculiarities of the effect of repeated doses, and the gradual cessation of the effect. The most characteristic and well-studied is the effect of T. on metabolism: all types of metabolism are increased, and this is particularly sharply (by 60-150%) manifested in conditions of significant hypofunction of the thyroid gland, where metabolism is often reduced by as much as 40% from normal. Usually, on average, oxygen consumption and carbon dioxide excretion increase by 25-35%. The increase in metabolism is due to the intensification of oxidative processes. As a consequence of the latter, a characteristic increase in sensitivity to lack of oxygen is observed. The effect on metabolism is due to the active principle of T., not the iodine in it, since inorganic and organic (non-thyroidal) iodine compounds do not give a similar effect even in much larger doses. At the same time, the small iodine content in T. also characterizes its small effect on metabolism, since 4 atoms of iodine are included in the molecule of the active principle (thyroxin). The most accurate indicator of the effect of T. is the increase in basal metabolism. Along with this, nitrogen metabolism also increases: the excretion of nitrogenous products in urine (urea, ammonium, purines, uric acid, etc.) is enhanced, creatine appears in the urine. Nitrogen metabolism can increase so much that more nitrogen is excreted from the body than is introduced with food (negative nitrogen balance). In myxedematous patients, this can be explained in part by the resorption of the mucous edema, which is a protein colloidal fluid with a higher ratio of nitrogen to water than in blood serum. To a large extent, however, the negative nitrogen balance occurs due to the sharp involvement of the body's own tissues in nitrogen metabolism. At the same time, the specific-dynamic action of proteins and to a lesser extent of carbohydrates increases (2-5 times)-in other words, these substances introduced with food increase metabolism to a greater degree than usual. It is interesting to note that with small doses of T., nitrogen retention in the body can be observed; this seemingly paradoxical fact is explained by the extremely increased appetite, due to which much larger amounts of food are consumed and absorbed than are needed by metabolism. However, this fact has no therapeutic value (for increasing appetite) in view of the ease with which normal metabolism can be increased. The increase in carbohydrate metabolism is manifested by a significant increase in the respiratory coefficient, indicating increased combustion of carbohydrates; in addition, a sharp depletion of liver glycogen, increased sugar content in the blood, sometimes the appearance of glycosuria, and a significant decrease in carbohydrate tolerance are observed. The increase in fat metabolism first leads to a decrease and even disappearance of fat deposits in the body, and then to a decrease in fat content in the tissues themselves. In hypercholesterolemia, T. gives a significant and persistent decrease in blood cholesterol. Under the influence of T., water and salt metabolism also proceed much more intensively.-T. mobilizes water and NaCl from tissues, as a result of which the water content in muscles decreases by 1-2.5% (Parhon et al.); in urine, the content of NaCl, salts, sulfur, phosphorus, etc. increases. The amount of urine increases 1.5-2 times, and along with it, the feeling of thirst increases. The increase in diuresis is mainly of extrarenal origin, but a direct effect of T. on the kidneys is also possible, since with large doses of the preparation, the appearance of protein in urine is sometimes noted. Diuresis is favored by the direct dilating effect of T. on renal vessels (Creveld). As a result of the sharp increase in metabolism, a significant decrease in body weight is observed, which can reach several kg per week. The decrease in weight is due mainly to the increased loss of fluid in urine and insensible perspiration (Lohr). In addition, the destruction of proteins and fats of tissues contributes to weight loss. With very small doses of T., due to excessive (see above) food intake, an increase in weight can be observed, but not sharply expressed. The next characteristic effect of T. is its influence on morphogenesis. Depending on the size of the dose, T. has diametrically opposite effects on the growth of cells and tissues. In small doses, acceleration of division of the simplest organisms (e.g., Paramecium) and tissues in tissue cultures, acceleration of nerve regeneration in the triton, earlier calcification of long bones and accelerated healing of fractures are noted. The latter fact was noted by some physicians in patients with hypothyroidism. Experiments on tadpoles, axolotls, young rats, rabbits, and other animals showed that under the influence of T., an increase (2-3 times) in the weight of the heart, liver, kidneys, pancreas, adrenal glands, sex glands, a decrease in the size of the thyroid gland, pituitary gland and a delay in the development of the uterus can be obtained; after administration of T. is stopped, the mentioned organs gradually return to normal sizes. Amazing results in terms of growth were also obtained in humans-with long-term treatment of T. in cretins (see Cretinism), if treatment is started early, growth characteristic of normal people of the same age can be achieved. The greatest growth rate is observed in the first year of treatment, then it is relatively less as it approaches normal. On average, in the treatment of T. in cretins (41 cases) for 3-6 years, Jauregg obtained the following increase in growth in consecutive years of treatment: 9.5; 6.3; 5.5 and 5.7 cm. The ability to grow depends on whether the epiphyses are still open. It is usually difficult to achieve growth after the 20th year of life, although it has been observed at a later age: in 4 cretins from 20 to 23 years of age, body height increased by 6.5-22.5 cm (v. Eysselt), in a 25-year-old by 3 cm and in a 26-year-old by 7.5 cm (Kutschera von Aichbergen), in a 27-year-old by 4 cm (v. Jauregg) and even in a 45-year-old by 5 cm (Christoifersen). One should not strive for very rapid growth, as this makes the bones too pliable, deformations of the spine are possible. With large doses of T., a slowdown in the growth of young animals (tadpoles, chicks, guinea pigs, rats, rabbits) was obtained experimentally.

This is explained by such a sharp increase in metabolism that the introduced nutritional material becomes insufficient to cover the body's expenditures, and the animal's own tissues are drawn into metabolism. The growth of horny formations also changes under the influence of T.: in small doses it causes increased pigmentation and feathering in chickens, while in large doses early molting, feather loss, and accelerated growth of new feathers are observed. The characteristic brittleness and dryness of hair and nails in people with hypofunction of the thyroid gland disappear with T. treatment. Along with its effect on the growth of tissues and organs, T. also accelerates the metamorphosis of vertebrate larvae into adult form. This allowed Gudernatsch to propose as a test for the presence of the active principle of the thyroid gland its effect on tadpoles (dwarf frogs are obtained). Most invertebrates do not undergo accelerated metamorphosis. In adult cretins with childish appearance and mentality, T. undoubtedly accelerates their transformation into adult form, but improvement in brain development still far lags behind improvement in physical condition. Nevertheless, the mentality of cretins is significantly improved; they begin to show interest in their surroundings, become capable of self-care and certain crafts. Experimentally, under the influence of T., acceleration of mental processes is noted; according to experiments by B. Zavadovsky, the excitability of the cerebral cortex increases, reflex activity becomes more precise, and differentiation of inhibitory processes in the central nervous system improves. The effect of T. on the central nervous system manifests primarily as increased excitability; in severe cases this leads to the appearance of fear, neurasthenic conditions, muscle tremors, and insomnia. The central action of T. partly explains the increase in body temperature under its influence: besides increased metabolism, this occurs due to changes in the sensitivity of the temperature-regulating center to the temperature of the blood bathing it. As a result, increased heat production predominates over increased heat loss; at the same time, certain abnormalities in temperature regulation are usually observed—increased sensitivity to rising external temperature is noted. The excitability of the peripheral nervous system also increases, this especially applies to the autonomic nervous system, predominantly to its sympathetic division. This explains the increased sensitivity to adrenaline, decreased tolerance to carbohydrates, increased glycogenolysis, and the appearance of exophthalmos with large doses of T. The effect on metabolism is partly due to excitation of the sympathetic nervous system, since according to experiments by Abderhalden and Wertheimer, after paralysis of sympathetic endings with ergotamine, T. does not cause increased metabolism (however, the large doses of ergotamine used could have had a depressing effect on the protoplasm of tissue cells). The parasympathetic nervous system also responds to T. with increased excitability, as proven by direct experiments on the cardiac vagus and depressor (Asher, Cyon, Oswald) and the chorda tympani (Krontovsky). Conversely, with large doses of T., a decrease in the excitability of the endings of these nerves was noted (Albertoni). The definite effect of T. on the cardiovascular system was initially attempted to be explained by the direct action of the active principle of T. on it. However, the depression of the activity of an isolated heart and slowing of its rhythm when solutions of thyroid gland extracts are passed through, the dilation of blood vessels of isolated organs under the same conditions, and the rapid fall in blood pressure with intravenous administration of liquid T.—all this proved to be non-specific for the active principle of T., since the latter has a latent period of action (when thyroxin is injected into a vein, the effect occurs after 9-10 hours) and in chemically pure form (i.e., as thyroxin) does not exert a direct influence on the heart and blood vessels (see Thyroxin). Therefore, the above action should be attributed to the presence in T. of various tissue substances of non-specific action (see Organopreparats). When T. is administered orally, its effect develops gradually on the cardiovascular system in parallel with other types of action. Blood pressure slightly decreases, the pulse becomes softer and significantly more frequent (with large doses it can reach 150 per minute). Experimental analysis of T.-induced tachycardia showed that it occurs after complete denervation of the heart and after removal of the adrenal glands. Recently, Priestley showed that T.-induced tachycardia also occurs in the heart of a small dog transplanted into the back of a large dog and connected with the latter's body only by blood vessels, not by the nervous system. Therefore, tachycardia is considered of humoral origin, depending on increased cellular metabolism in the heart muscle (Thomas, Yater, etc.). Large doses of T. often caused degenerative changes in the heart muscle in animal experiments. Under the influence of T., an increase in the function of blood-forming organs is observed—in the bone marrow a picture of increased erythro-, leuco-, and thrombopoiesis is obtained, myelocytes and erythroblasts undergo rapid proliferation, disappearance of fat cells and increased blood filling of the organ are noted. In the peripheral blood, there is an increase in the amount of Hb, erythrocytes, reticulocytes, and thrombocytes; regarding leukocytes, the data are contradictory (more often lymphocytosis). Blood viscosity decreases, its protein content decreases, hydremia is noted; in myxedema, T. sometimes causes a significant increase in urea content in the blood (if water is removed from edemas more slowly than the nitrogen contained in them). The rate of erythrocyte sedimentation increases. As for the glands with internal secretion, the greatest interest is the effect of T. on the thyroid gland itself. Experimental data show that besides its replacement value for thyroid function, T. can also play the role of a stimulating agent. Although after partial removal of the thyroid gland Loeb did not obtain hypertrophy of the remainder when feeding animals T., with prolonged administration of large doses of T. to normal animals (guinea pigs, rats, dogs), initial hypertrophy of the gland was noted, which then transitioned into atrophy, and the hormonal activity of the gland sharply decreased (atrophy from inactivity, 'rest' of function). Bruns, removing segments of simple goiter (Struma simplex) in people before and during T. treatment, observed under the influence of the latter favorable histological changes; the size of the goiter decreased, which was associated with a decrease in its excessive colloid content. A long time ago, an increase in the adrenal glands under the influence of T. was noted, this especially applies to the cortical layer. With large doses of T., it was experimentally possible to establish an increase in the secretion of the adrenal medulla. The assumption of a depressing effect of T. on the islet apparatus of the pancreas is not yet sufficiently supported by factual material, since

Some authors (e.g., Glaser) describe histological changes similar to diabetic ones, while others deny this. Regarding the sex glands, some researchers (Abelin and Wiedmer, 1932) note the inhibitory effect of T.—prolongation of the resting state in the sexual cycle of females and even cessation of estrus, some reduction in testicle size, etc., but it is not yet clear to what extent this occurs with therapeutic doses of T. Regarding the exocrine glands, T. has a particularly pronounced stimulating effect on the sweat and sebaceous glands in myxedematous patients. When T. was administered to animals, a decrease in gastric secretion and increased secretion of saliva and intestinal juice were observed. With parenteral administration of liquid T., gastric secretion, on the contrary, slightly increased, which should be attributed to the non-specific action of the preparation. Interesting data have accumulated regarding changes in the body's reaction to certain poisons under the influence of T. Experimentally increased sensitivity to chloroform, morphine, strychnine, caffeine, veratrine, digitalis, and adrenaline has been established, and conversely, increased resistance to quinine. At the same time, it should be noted that Reid Hunt accidentally discovered (1911) that among all laboratory animals, only white mice develop increased resistance to methyl cyanide (acetonitrile) under the influence of T. Subsequently, this fact was investigated from a quantitative point of view and proposed (Haffner and Komiyarna) for the biological evaluation of T. preparations (see below). As early as Ewald pointed out the reduction of toxic symptoms when treating with T. if the patient simultaneously takes arsenic (e.g., in the form of Fowler's solution, 2-3 drops 2 times a day); this fact was attempted to be explained by the opposite effect of arsenic on metabolism, but this has not yet been experimentally confirmed. With an overdose of T., or when there is increased sensitivity to it, poisoning symptoms occur, which have been named thyreoidism. In many respects, they are similar to the symptoms of increased thyroid function (see Hyperthyreosis). Gradually increasing, they initially manifest with the following symptoms: rapid pulse (over 100 beats per minute), elevated body temperature (above 37°), palpitations, general weakness, insomnia, excited state of the nervous system, headache, sensation of trembling, shortness of breath, rushes of blood to the head, feeling of heat, profuse sweating, severe thirst, skin rashes (erythema, urticaria), loss of appetite, sharp weight loss, subsequently—diarrhea, vomiting, tremor, protein and cylinders in the urine, feeling of fear, attacks of angina pectoris, soporous state; individual cases of fatal outcome have been described in the era of the beginning of therapeutic use of T. Some of these phenomena have also been obtained in animals by prolonged administration of large doses of T.; on autopsy, myodegeneration of the heart and nephrosis were found. In humans, poisoning symptoms occur particularly easily with vigorous therapy of myxedema with T., which is explained by the flooding of the body with nitrogenous products from subcutaneous tissue. To prevent these phenomena, careful medical supervision during T. treatment, proper dosage of a preparation of specific activity for appropriate indications, is primarily required. When initial poisoning symptoms appear, administration of T. should be immediately stopped for 8-14 days (Pineles), and if necessary, the patient should be put to bed and symptomatic remedies applied. The specific activity of the dry T. preparation is guaranteed by the requirement that before the preparation is released for sale, its iodine content must be determined (it should be 0.17-0.23%), since the activity is more or less proportional to the iodine content in the preparation. However, in practice this requirement is not always observed, and since the thyroid gland of our cattle is often very rich in the active principle, T. with significantly higher iodine content (up to 0.4-0.5%) has been encountered; on the other hand, liquid T. preparations, on the contrary, are usually very poor in iodine (0.0003-0.008%). All this requires the physician to be cautious in dosing T. in each individual case. Since the iodine of the preparation is not always in the form of a specific (thyreoid) compound, international conferences on the standardization of medicinal substances propose determining activity also by the protective effect of the preparation against poisoning of white mice with acetonitrile (see above); the smallest amount of T. that, when administered once into the stomach of mice, doubles their resistance to acetonitrile after 24 hours is taken as the unit of activity. Other iodine compounds have almost no such effect. While this test has not yet become established here, abroad there are preparations indicating activity in biological units (5 and 10 units). T. has found extremely wide application due to physiological concepts of the multifunctional significance of the thyroid gland and due to the presence of a number of symptom complexes where hypofunction of the thyroid gland may be suspected to a greater or lesser extent. Usually T. is used for replacement therapy, less frequently as a homostimulating agent, and in individual cases symptomatically and for diagnostic purposes. The main indication for the use of T. is the state of hypofunction of the thyroid gland, namely myxedema, cretinism, cachexia strumipriva, myxoedeme fruste, goiter and obesity with symptoms of hypothyreosis. In addition, T. is often used in other conditions: chronic polyarthritis, delayed healing of fractures, chronic constipation, nephroses, various dermatitis, bronchial asthma, enurosis nocturna, some nervous and mental diseases, etc. In all these cases, T. therapy can be considered rational only in the presence of symptoms of hypothyreosis. T. is contraindicated in hyperthyreosis; extreme caution is required in far-advanced lesions of the heart and blood vessels, states of any kind of exhaustion (diabetes, especially tuberculosis, etc.) and with increased nervous and psychic excitability. For each case, an optimal dose of T. must be found, depending on the degree of insufficiency of the thyroid function of the patient, which is often difficult or even impossible to establish before treatment. Therefore, correct dosing is given only by testing T. on the patient, which requires caution and careful medical observation (at least during the first 53v months of treatment). As a general principle, treatment with T. is started with small doses and they are gradually increased. After eliminating the main manifestations of the disease in cases of replacement therapy, the dose is reduced by 5 and even by 10 times, leaving the patient on this dose for all subsequent years. Carnot proposed distinguishing 3 periods of T. treatment: 1) the period of preparation and testing (of the patient and the preparation) lasting 8-15 days, 2) the period of proper treatment—until obvious signs of recovery or improvement, and 3) the period of maintaining the effect—may continue for the rest of the patient's life. The average dosage by treatment periods for the main indications for T. therapy is given in the following table (all doses are indicated pro die). Indications Treatment periods Authors 1) Myxedema, cretinism, cachexia stru-mipriva 2) Hypothyreosis, myxoe-deme fruste 3) Struma simplex with hyperthyreosis 4) Adipositas with hypothyreosis ( 0.06 i 0.05 У 0.1 f 0.018-0.06 ( 0.01 -0.01 [ 0.001-0.1 0.06 -0.09 ( 0.01 -0.02 < 0.025-0.05 ( 0.15 -0.2 0.18-0.36 0.2 -0.4 0.2 -0.45 0.06-0.12 0.05 0.03 0.1-0.3 0.1-0.15 0.1 0.2-0.5 0.06-0.12 0.06-0.15 0.01-0.06 0.01-0.02 0.02-0.05 Halsey Laroche Pineles Halsey Laroche Janney Halsey Laroche Heckel Harvier Doses for children are approximately equal to ¹/₃- ¹1₂ of adult doses. The indicated scheme requires thoughtful application in cases of different severity, combination with diet, regimen, etc. (see details in Myxedema). In cases of using T. with an unclear pathogenesis of the disease (so-called therapia ex juvantibus), special caution is required due to the possible state of latent hyperthyreosis. The use of T. for diagnosing the functional state of the thyroid gland (Parisot and Richard's tests, Laroche and others) with conclusions about the results after several hours-days has not justified itself, as it reflects only the non-specific action of parenterally administered liquid T. The results of T. treatment with proper indication are remarkable (see Myxedema, Hyperthyreosis, Goiter, Obesity).-T. preparations in the USSR are produced in Moscow (factory of endocrine preparations, factory named after Semashko), Leningrad (Pharmakon factory), Kharkov (Organotherapeutic Institute) and Kiev (Organotherapeutic laboratory). They are mainly released in the form of tablets and dragees with T. content of 0.1, 0.2 and 0.3. According to Hunt's research, the stability of activity of dry T. is very long (over 12 years). Liquid T. is released for oral administration (30-40 drops 3-4 times a day) and for subcutaneous injections (1 cm³ daily or every other day).