Medicine stimulating thyrotrophic and thyroid hormones

FIELD: medicine.

SUBSTANCE: invention can be used for medical treatment of secondary hypothyroid state accompanied by low synthesis of thyrotrophic hormone by hypophysis and of iodine hormone by thyroid gland. Substance of invention implies application of peptide Lys-Glu-Asp-Gly as a medicine stimulating synthesis of thyrotrophic hormone by hypophysis and of thyroid hormone by thyroid gland.

EFFECT: high specific activity of introduced peptide and decrease of side effect risk.

4 tbl, 1 ex

 

The invention relates to medicine, namely to endocrinology, and can be used to stimulate the production of thyroid hormones by the thyroid gland.

Thyroid hormones: thyroxine (T4) and triiodothyronine (T3), are iodine-containing hormones that are synthesized And cells (thyrocytes) follicles of the thyroid gland. It is known that thyroid hormones are necessary for normal growth and development of the organism. They control the production of heat, the rate of absorption of oxygen are involved in maintaining normal function of the respiratory center, have inotropic and chronotropic effects on the heart, increase the number of b-adrenergic receptors in cardiac and skeletal muscle, adipose tissue and lymphocytes, increase the formation of erythropoietin and increase erythropoiesis, stimulate the motility of the gastrointestinal tract, stimulate the synthesis of many structural proteins in the body (1). When the change in the functional status of the thyroid gland are observed abnormalities in the cardiovascular, nervous systems, as well as violations of all types of metabolism, especially those related to energy production, changes in the immune system and hemostasis, reduced differentiation of growing tissues, which in total leads to a total change in all organs and systems (2). The function of the thyroid gland is under the control of Olam Central organs of the endocrine system - hypothalamus and adenogipofiza (3). Directly on the synthetic activity of the thyroid gland affects TSH. Thyroid-stimulating hormone (synonym: tireotropin, thyrotropin) is a glycoprotein with molecular weight of 28000, the molecule of which consists of a-subunit and b-subunit, which determines the species specificity of the hormone. TSH stimulates the growth and proliferation of follicular cells of the thyroid gland, increases blood circulation, metabolism, stimulates the formation of thyroid hormones thyroxine (T4) and triiodothyronine (T3). Deficiency of TSH (at loss of thyrotropic pituitary function) accompanied by a decrease in the secretion of thyroid hormones, the mass of the thyroid gland, albeit shrinking, but not dramatically; to increase the weight of the thyroid gland requires TSH level 100 times greater than its content, is necessary to stimulate its functional activity. The specificity of action of TSH is to accelerate the metabolism of iodine in the thyroid gland, its latency, and organification and the effect on the secretion of synthesized thyroid hormones, i.e. on their release from the complex with thyroglobulin. At the same time GTG increases the intensity of metabolism in the prostate. The action of TSH mediated through specific receptors on the membrane of the follicular cells of the thyroid gland, resulting in intense activity is : their adenylyl cyclase system (3).

Known means of thyrotropin-releasing hormone, taken as a prototype. It is a synthetic peptide analogue of thyroliberin hypothalamus can stimulate synthetic thyroid function through the stimulation of thyrotropin adenogipofiza. Under the influence of this drug is increased synthesis of TSH by the anterior lobe adenogipofiza that, in turn, leads to increased formation of thyroid hormones by the thyroid gland. The commercial name of the substance - Rivation (Rifathyroinum) - synonyms: thyrotropin-releasing Hormone, Liberal, Protirelin (Protirelin), Gartanin (Hirtonin), Relevant TRH (Relefact TRH), Tienen (Thypinone), Tirerack (Thyrefact), Tiregan (Tiregan) (4). All these drugs are chemically correspond Tripeptide with the formula: pyroglutamyl-histidyl-prolinamide.

According to some authors (5) introduction of the substance in the dose of 5 μg per kilogram of healthy people increases T3 1.6, T4 1.39, TSH in 3,35 (table 1).

Table 1

The influence of thyroliberin on the synthesis of thyroid hormones and TSH in healthy people (M±m)
The studied parametersHealthy people
The source dataAfter the introduction of thyroliberin
T446,7±of 7.9665,2±6,21
P<0,05
T30,72±0,261,2±0,45
P<0,01
TSH5,33±1,9617,86±to 4.52
P<0,05
With the introduction of tiroliberina patients secondary giratorios pituitary nature is an increase in T3 1.3, T4 1.06 a, TSH 1.07 (table 2).
Table 2

The influence of thyroliberin on the synthesis of thyroid hormones and TSH in people with secondary hypothyroidism pituitary nature (M±m)
The studied parametersPatients with secondary hypothyroidism pituitary nature
The source dataAfter the introduction of thyroliberin
T424,8±4,8226,4±6,32
P>0,5
T30,42±0,150,55±0,11
P>0,5
TSH5,62±2,026,02±1,82
P>0,5

The thyrotropin-releasing hormone involved in the regulation of a number of nervous and mental functions(wakefulness, sleep, emotions, learning, memory). A characteristic feature of thyroliberin is its ability to stimulate respiratory depression, and also to reduce neurological symptoms in traumatic brain injuries and concussions (6). The thyrotropin-releasing hormone interacts with various neurotransmitter systems, such as cholinergic/catecholaminergic, opioid, GABAergic, etc (7). Especially pronounced interaction tiroliberina with the cholinergic system (8). This interaction led to the use of thyroliberin for a number of diseases with failure of cholinergic structures (some types of dementia and myopathy) (9). The hormone has the Central stimulating effect, which combined with its neuroprotective activity and antidepressant action (10).

In connection with the foregoing, the main use of the drug in the clinic is the treatment of several diseases of the Central nervous system, mainly the brain and spinal cord, abstinence syndrome in alcoholism and depression of various etiology(10, 11, 12, 13). As a means of enhancing synthetic thyroid function, these drugs are not used, and used in medical practice only as a diagnostic tool in the differentiation of primary and secondary hypothyreosis (13). Their use as therapeutic agents is s difficult because of weak biological effect (5) and presence of large number of unwanted side effects. To these undesirable effects include hyperprolactinemia, fluctuations in blood pressure, headache, blindness, photophobia, anxiety, sweating, feeling of a lump in the throat, feeling of chest compression, pituitary apoplexy, abdominal pain, xerostomia, unpleasant taste in the mouth, allergic reactions; redness and soreness at the injection(4, 10, 11, 12, 13).

As a means of stimulating the production of thyroid hormones by the thyroid gland and TSH by the pituitary gland, using a synthetic peptide of structural formula Lys-Glu-Asp-Gly.

This peptide is a white crystalline powder, soluble in water. Based produce an aqueous solution containing 10 mg peptide in 1 ml of the Peptide with the structure of H - Lys-Glu-Asp-Gly-HE has a molecular mass of 447,45 (free peptide). The content of the basic substance for optical density (λ 230 nm)>95%, column; Delta Cancer, C - 18, 100A, 3,9×150 nm, 5μ; gradient (1-25)% MeCN in 0.1% TFA.

The synthesis of the peptide is carried out on solid phase using the Vos scheme, the structure of the obtained peptide confirm mass spectrometric analysis. Tetrapeptide the anterior pituitary is a combination of the amino acid sequence Lys-Glu-Asp-Gly (14).

In experimental study of the specific activity of the proposed drug revealed its ability article is to morovati the thyroid gland and thyreotropic adenogipofiza in the intact birds, and also identified the ability to increase the level of thyroid hormones and TSH in hypophysectomised birds. This is confirmed by the following examples.

Example 1. The influence of the peptide Lys-Glu-Asp-Gly in the synthesis of thyroid hormones in intact birds.

The study involved 100 birds breed CROSS Rhodonite-2" line PC at the age of 1 year. Intact birds were injected Lys-Glu-Asp-Gly taking into account circadian biorhythms from 10 to 11 am, 1 times a day, intramuscular injection of 0.1 mg/kg for 10 days. In accordance with the recommendations (15) the experiment was conducted on same-sex birds - cocks. For sampling required material all birds on the 40 day after hypophysectomy were subjected to deep ether anesthesia, and they have withdrawn the necessary amount of blood. The level of T3, T4 and TSH were determined at 40 days after starting the drug. Determination of hormone levels was performed using the reagents for immunoassay determination of thyroxine, triiodothyronine and TSH in serum. It is established that the use of Lys-Glu-Asp-Gly in the dose led to increased levels of T3 in the serum at 2.48 time T4 at 1.43 times, and TSH 1.24 times. The obtained data are given in table 3.

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Table 3

The influence of the peptide Lys-Glu-Asp-Gly synthesis of thyroid hormones and TSH in the intact birds (M±m)
The studied parameters12
Intact birdsBirds treated with Lys-Glu-Asp-Gly
n=50n=50
T323,1±2,7157,2±3,24
P<0,0001
T4128,8±3,1185,47±3,8
P<0,0001
TSHis 0.135±0,0120,167±0,015
P<0,1
Legend: P - significance of the differences between 1 and 2.

Example 2. The influence of the peptide Lys-Glu-Asp-Gly synthesis Cherednik of hormones in hypophysectomised birds. Experiments put on the birds breed CROSS Rhodonite-2" line PC (aged 1 year). Just work involved 150 birds, of which 8 was the natural decline. Each group contains from 45 to 50 birds. The objects of study were the serum of experimental animals. Study drug was administered with regard to circadian biorhythms - strictly from 10 to 11 am, 1 times a day, intramuscular injection of 0.1 mg/kg for 10 days, starting 5 days after surgery. The level of T3, T4 and TSH were determined for 40 days after the beginning of the introduction of the Reparata. Determination of hormone levels was performed using the reagents for immunoassay determination of thyroxine, triiodothyronine and TSH in serum. The control group of birds daily for 10 days was intramuscularly injected 1 ml of physiological solution.

It is established that the application of the peptide Lys-Glu-Asp-Gly resulted in increased levels of T3 in 2,38 times T4 1.5 times, the TSH level was not increased. The obtained data are given in table 4.

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Table 4

The influence of the peptide Lys-Glu-Asp-Gly synthesis of thyroid hormones, after hypophysectomy (M±m)
The studied parameters123
Intact birdsHypophysectomised birdsHypophysectomised birds treated with Lys-Glu-Asp-Gly
n=50n=45n=47
T332,1±2,7112,7±2,8130,2±0,21
P1<0,001
P2<0,001
T4128,8±3,172,3±2,7107,2±3,6
P1<0,001<0,001
P2<0,001
TSH0,914±0,016MX 0.317±0,0110,363±0,011
P1<0,001<0,001
P2
Legend: P1 - reliability of differences between 1, 2, 3; P2 - the significance of differences between 2 and 3.

Thus, in experimental study of the specific activity of the claimed funds established that the peptide Lys-Glu-Asp-Gly capable of stimulating the production of thyroid-stimulating hormone by the pituitary gland and thyroid hormones by the thyroid gland in a dose five times smaller than the prototype (thyrotropin-releasing hormone), and has a greater biological activity and does not lead to the development of side effects. The proposed tool can be used for the prevention and treatment of a wide spectrum of diseases of the thyroid gland, and pituitary gland accompanied hypothyroid States.

Sources of information

1. Balabolkin M.I. State and prospects of studying the problems of physiology and pathology of the thyroid gland. // Ter. archive. - 1997. No. 10. - P.5-11.

2. Ametov A.S., Granovskaya-Tsvetkova A.M. Hypothyroidism. // The wedge, Pharmacol., therapy. - 1997. No. 6 (1). - P.65-68.

3. Aleshin B. The., Gubsky VI Hypothalamus and the thyroid gland. // Medicine. M - 1983. - 184 S.

4. Mashkovsky M. D. Medicines. // M: Medicine - 1998 - Vol.2, GL, 463.

5. Korolyuk I.P., Nowicki A. Functional test thyrotropic releasing hormone in vitro. // Medical radiology - 1979 - No. 2, p 9.

6. Horita A. An update on the CNS action of TRH and its analogs. Life Sciences, 1998, v.62, pp.1443-1448.

7. Ashmarin I.P., Kalashev A.P., town Chepurnov S.A. unidirectional Cascade of regulatory processes carried out by short peptides (thyrotropin-releasing hormone). Physiological journal of the USSR, 1989, t, No. 5, 627-637.

8. Bunevicius R., Matutevicius V. Short-lasting behavioral effects of TRH in depressed woman: results of a placebo-controlled study. Psychoneuroendocrinology, 1993, v.18. No. 5-6, pp.445-449.

9. Iversen E. Thyrotropin releasing gormone. Danish Medical Bulletin, 1995, v.42, No.3, pp.257-268.

10. Prokhorov I.S., V.V. Kudryashov Psychotropic effect lysyl-vasopressin and tiroliberina. Psychiatric endocrinology, M., 1988 - 104-105.

11. Loosen R. T., Prange, A. J., Wilson, I.C. TRH (Protirelin) in depressed alcoholic men. Arch. Gen. Psychiatry, 1979, v.36, pp.540-547.

12. Marangell L. C., George, M. S., Callahen A. M. et al. Effects of intrathecal protirelin in refractory depressed patients. Arch. Gen. Psychiatry, 1997, v.54, no .3, pp.214-222.

13. The Ministry of health of the Russian Federation No. 292 dated 28.07.1999,

14. Khavinson V.H. Way to obtain peptides with tissue-specific activity, and farmakologicheski compositions on their basis / Wahawisal // Patent for the invention №2161501. - 2001.

15. Abzalov A.D. Hematological and immunological parameters is ur at different ages depending on the biologically active drugs / A.D. Abzalov // Vestnik OSU. - 2003. No. 6. - S-160.

The peptide of structural formula Lys-Glu-Asp-Gly, stimulating the production of thyroid-stimulating hormone by the pituitary gland and thyroid hormones by the thyroid gland.



 

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