WO1997011703A1

WO1997011703A1 - Preventive or remedy for hyperthyreosis

Info

Publication number: WO1997011703A1
Application number: PCT/JP1996/002616
Authority: WO
Inventors: Isao Makino; Hirotoshi Tanaka; Etsushi Fukawa; Takako Tani; Hiroshi Hashizume; Yoshinori Kasahara; Keiji Komoriya
Original assignee: Teijin Limited
Priority date: 1995-09-28
Filing date: 1996-09-13
Publication date: 1997-04-03
Also published as: AU6944796A

Abstract

A preventive or remedy for diseases caused by hyperthyroidism (for example, Basedow's disease, indolent thyroiditis, or subacute thyroiditis) which contains activated vitamin D as the active ingredient.

Description

Description Preventive or therapeutic agent for hyperthyroidism Technical field

The present invention relates to a novel agent for preventing or treating hyperthyroidism. More specifically, the present invention relates to a novel agent for preventing or treating diseases caused by hyperfunction of the thyroid gland, which contains active vitamin D as an active ingredient. Background art

The thyroid is an endocrine organ that produces thyroid hormones. Thyroid hormones act on the gastrointestinal tract, heart, bones, and the psychiatric nervous system. In other words, thyroid hormone exhibits a gastrointestinal motility, heart rate increase, osteolysis-enhancing action and the like. Thyroid hormone is mainly secreted by the thyroid gland by afflicted proxy emissions (T _4), some of which are Ridatsuyoichi de reduction by the enzyme in the liver or kidney, 3, 3 ', 5 - Application Benefits It is converted into yo one Dosai Ronin (T _3). Secreted Ding ₄ approximately 9 9 in the blood. 9 7% cyclic proxy emissions binding data Npaku, i.e. cyclic proxy emissions binding globulin emissions, serum albumin, and bind to Purearubumi down, about 0.0 to 3% exist in free form condition, Ding ₃ about 9 9. bound to 7% Gasa Lee proxy emission coupling capacitor Npaku serum albumin, about 0. 3% exists as the free. Thyroid hormone T ₃ and T ₄ are bonding force with force this receptor that acts by binding to the thyroid hormone receptor in the nucleus of the cell, towards the T ₃ is about 10 times more potent Ri good T _4. Then, T ₃ and cyclic Rokishin bound and unbound data Npaku its full rie body (fT3) is considered to be the active body of thyroid hormone. Thyroid hormone (T _4, T 3) of the blood concentration of the thyrotropin releasing hormone, which is secreted from the hypothalamus (TRH) and thyroid stimulating hormone is by Ri pituitary or et secretion stimulation of TRH (TS Η). When the concentration of thyroid hormone decreases, TRH, secreted TSH within the al, TSH is produced of T ₄ stimulates TSH receptors on the cell membrane of the thyroid and secretion. When the concentration of thyroid hormone increases, contrary to the TR Eta, reduces the secretion of TS Eta, the production of T _4, secretion decreases.

Diseases caused by hyperthyroidism, i.e., Graves' disease, a representative disease of hyperthyroidism, is an autoimmune disease caused by autoantibodies (TRAb) that stimulate TS Η receptors. . In addition, hyperthyroidism is also observed in the early stages of painless thyroiditis and subacute thyroiditis.

Treatment of Graves' disease is broadly divided into oral treatment with antithyroid drugs such as thiamazole, which inhibits thyroid hormone synthesis, medical treatment by subtotal removal of the thyroid gland, and radiation therapy to inhibit thyroid cells. You. Although antithyroid drugs are easy to treat, it is known that side effects such as skin itching, urticaria, rash, arthritis, and joint pain occur. Due to these side effects, a few percent of patients are unsuitable for antithyroid drugs, and either surgical treatment or radiation treatment is selected. At present, there are no effective oral treatments for hyperthyroidism other than antithyroid drugs.

— 1α — Hydroxitamin D ₃ (1α-OHD 3), 1 a, 24 (R)-Hydroxitamin D ₃ , 1, 2-Dihydroxyvitamine Activated vitamin D such as protein D ₃ (1α, 2δD 3) has an action of promoting calcium absorption in the small intestine and an action of regulating bone resorption and bone formation in bone. Based on various calcium metabolism disorders It is well known as a drug for treating diseases. Recently, it has been shown that activated vitamin D has a differentiation-inducing action and an immunoregulatory action in addition to the above-mentioned potency and bone metabolism regulating action (for example, “Biminmin D— New Trends, ”Tadao Suda et al., Published by Kodansha, 3rd edition, 1998, pages 85 to 103).

The relationship between such active Vita Mi emissions D and thyroid, conventionally, rats Bok culture thyroid follicles cells (FRTL - 5 Serurai down) to 1 alpha, and this the receptors 2 5 D ₃ is present (Molecular and Cellular Endocrinology, 81, 1991, 25-31), that metabolites of cholecalciferol may play a physiological role in regulating hormone secretion, thyroid cell growth and differentiation ( Molecular and Cel 1 u 1 ar Endocrono 1 ogy. 76, 1991, 201- 206, Jouna 1 of Cellular B i ochemi st ry, 49, 304 -309, 1992), 1, 2 5 D ₃ force FRTL — 5 cellulite iodine reduces the carrier number and by Ri called Toka et 1 to reduce the iodine accumulation under TSH stimulation to this, 2 5 D ₃ is also affects downstream Ri by cAMP production of c AMP sheet Gunaru pathway in emissions ^ B 1 ochem 1 ca 1 and Biophysical Research communicat ions. 182, 3, 1992, 1435- 1439), 1 Shed, 2 5 D ₃ is that there is likely to be inhibited in several steps of TSH / cAMP stimulation route (Thyroid, 3, 3. 1993, 245 - 251), is 1, 2 5 D ₃ Ade two exiled and this to reduce the click hydrolase AC activity (Endocr inology, 135, 2, 1994, 595 - 602), Vita Mi emissions D ₃ intensity of biological activity in thyroid cells derivatives bi evening Mi emissions D ₃ It is known that it may be due to affinity for the receptor (J. Steroid Biochem. Mole Biol., 50, 3/4, 145-150, 1994).

While with Kaka, none of these references FRTL - 5 in Lee emissions bi collected by filtration experiment using Serurai emissions, 1 shed, 2 5 D ₃ and the like TSH stimulation It only mentions the formation of MPs below and a significant reduction in iodine uptake and growth. That is, none of these documents describes or suggests the effect of activated vitamin D on hyperthyroidism, and furthermore, there is no description of the effect of activated vitamin D on hyperthyroidism. There is no mention or suggestion of its use as a therapeutic.

That is, an object of the present invention is to provide a novel agent for preventing or treating hyperthyroidism.

Furthermore, an object of the present invention is to provide a preventive or therapeutic agent for a disease caused by hyperthyroidism belonging to so-called hyperthyroidism, irrespective of its cause such as primary, pituitary, and autoantibodies. And there.

Another object of the present invention is to provide a preventive or therapeutic agent for Graves' disease, painless thyroiditis, subacute thyroiditis, and the like.

Still another object of the present invention is to provide a novel agent for preventing or treating such hyperthyroidism having few side effects.

The present inventors have conducted intensive studies on the effects of active vitamin D on hyperthyroidism and found that active vitamin D has a therapeutic effect on hyperthyroidism such as, for example, Basedow's disease. The present inventors have found that TSH receptor Yuichi acted on the thyroid gland in an excessively stimulated state to further reduce T ₃ and T ₄ . Disclosure of the invention

That is, the present invention is a preventive or therapeutic agent for a disease caused by hyperactivity of the thyroid gland, which comprises active vitamin D as an active ingredient. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the change over time of the free T ₃ (f τ 3) in Example 1. Show. In the figure, Hatashirushi represents a value of VD ₃ administration group, .smallcircle indicates the value of VD ₃ non-administration group.

FIG. 2 shows a time-dependent change of TSH in Example 1. In the figure, the hatched bar graph TSH values normal range (> 0. 3 4 IU Zm l) the VD ₃ administration group in, white bar graph is TSH value upper limit of normal (3. 6 0 IU Zm l ) or VD ₃ administration group, black open bars graph is the VD ₃ non-administration group in the normal range TSH values rather same as, bar charts Ding SH value is greater than or the same rather normal limit VD ₃ grid pattern The non-administration group is shown. FIG. 3 shows the time-dependent change of TRAb in Example 1. In the figure, Shoshirushi represents a value of VD ₃ administration group, .smallcircle indicates the value of VD ₃ non-administration group.

FIG. 4 shows the time-dependent change of Ca [A lb correction] in Example 1. In the figure, - mark indicates the value of VD ₃ administration group, .smallcircle indicates the value of VD ₃ non-administration group. BEST MODE FOR CARRYING OUT THE INVENTION

Active vitamin D in the present invention refers to vitamin D having physiological actions such as calcium and bone metabolism regulation, which is distinguished from vitamin D itself which has no physiological action. Katabiyu Mi emissions _D: to comprise a ,, active Vita Mi emissions 0 ₃ and its these derivatives is as an example of that, for example, 1 alpha - arsenide de proxy Vita Mi emissions D, 1 a, 24 — Dihydroxyvitamin D, 1, 25 — Dihydroxyvitamin D, 1 h, 24, 25 — Trihydroxyvitamin D, 24, 24 — Difluoro-1α, 25—Dihydroxyvititamin D, 26,26,26,27,27,27 —Hexafurile mouth 1α, 25—Dihydroxyvititamin D, 2 5 - arsenide de Rokishibita Mi down D ₃ - 2 6, 2 ₃ - Lac tons, 1 alpha, 2 5 - dihydric de proxy Vita Mi emissions D ₃ - 2 6, 2 ₃ — Lactone. Above all, 1 Evening D ₃ , 1 H, 24 (R) dihydroxyvitamin D ₃ , 1 a, 25 —Dihydroxyvitamin D ₃ is preferred.

The diseases caused by hyperthyroidism of the present invention include diseases belonging to so-called hyperthyroidism regardless of their causes such as primary, pituitary, and autoantibodies. Hyperthyroidism is classified into diffuse toxic goiter and toxic nodular goiter.Specific hyperthyroid disorders include, but are not limited to, those with Graves' disease, Examples include hyperthyroid state of Hashimoto's thyroiditis, chronic thyroiditis, indolent thyroiditis, subacute thyroiditis, toxic polynodular goiter, chronic purulent thyroiditis, and the like.

The diseases caused by hyperthyroidism of the present invention include, preferably, Graves 'disease, indolent thyroiditis, and subacute thyroiditis, among which, in particular, Graves' disease. It is mentioned that the disease is preferred.

The active ingredient of the present invention can be prepared as an oral preparation such as a soft capsule, a hard capsule, a tablet, a syrup, an injection or an external preparation by using a suitable excipient or the like by a known method. Can be used.

Such excipients include vegetable oils (eg, corn oil, cottonseed oil, coconut oil, armor oil, peanut oil, etc.), oily esters such as medium chain fatty acid glycerides, mineral oils, Vaseline, animal fats and oils, cellulosic derivatives (crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose), polyvinylpyrrolidone, dextrin, lactose, mannitol, sole Bitol, starch and the like. If necessary, additives such as an antioxidant, a wetting agent, a viscosity stabilizer, and a coloring agent can be added.

Specifically, oral preparations such as soft capsules, tablets, and dry syrup granules containing the active vitamin D of the present invention; ointments, creams, etc. The external preparations described in JP-B-57-45415, JP-B-63-44672, JP-B-63-6000, JP-A-61-8 It can be produced by the method described in JP-A-76-19.

The dose of active vitamin D required for the present invention is a prophylactically or therapeutically effective dose, and depends on the patient's age, body weight, type of combination therapy, frequency of treatment and type of desired effect. When used as a therapeutic agent, it is usually 100 g to 0.Olig Z days, more preferably 20 g to 0. lg Z days, and the number of administrations is usually 1 to 3 times Z days. For external preparations, more preferably 2 days from lig. When used as a prophylactic agent, the dose is usually 5 ^ g to 0.OS g Z days, more preferably 0.5 g to 0.5 lg / ⁷ days, and the number of doses is usually 1 to 3 times. Day. It is preferable to prepare the preparation so as to satisfy such conditions.

Thus, the present invention provides a novel preventive or therapeutic agent for a disease caused by hyperactivity of the thyroid gland, comprising active vitamin D as an active ingredient.

Further, according to the present invention, the use of activated vitamin D for the manufacture of a medicament for use in the prevention or treatment of diseases caused by hyperthyroid function, and the use of activated vitamin D in diseases caused by hyperthyroid function are also described. The present invention provides a method for preventing or treating diseases caused by hyperthyroidism, which comprises administering a prophylactically or therapeutically effective amount of active vitamin D to the accompanying human.

Such an agent for preventing or treating a disease caused by hyperactivity of the thyroid containing the active bimin D as an active ingredient of the present invention is, for example, an existing antithyroid such as methimazol and propylthioperacil. It can be used in combination with a pharmacotherapy or therapeutic agent, and the combination mode is not necessarily limited to simultaneous administration, and the administration route is not necessarily limited to the same route. Industrial applications

Active Vita Mi emissions D such as 1 a -〇 HD ₃ as an active ingredient of the present invention, conventional osteoporosis therapeutic agents to be used in adverse effects are observed Orazu, used as a conventional antithyroid agent There is no indication of liver damage, granulocytopenia, renal injury, etc. that have been identified with thiamazole, and it is expected to be indicated as a more safe therapeutic agent for hyperthyroidism.

In addition, the novel agent for preventing or treating hyperthyroidism of the present invention has an excellent effect in treating or preventing hyperthyroidism, and has an effect of having a low side effect.

In particular, the prophylactic or therapeutic agent of the present invention, alone or in combination with an existing antithyroid agent, can be used to treat Graves' disease, painless thyroiditis, subacute thyroiditis, etc. among diseases caused by hyperthyroidism. It has an excellent effect on the prevention or treatment of Graves 'disease, especially on the prevention or treatment of Graves' disease, and has the effect of reducing side effects.

Therefore, in consideration of the above-mentioned problems of the conventional therapeutic agent for the disease, in addition to providing a novel preventive or therapeutic agent, the significance of the prevention and treatment is extremely large. Example

The effects of the present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited thereto. Incidentally, in% represents the weight percent, 1 alpha - OHD ₃ is 1 alpha - shows the human de proxy Vita Mi emissions D _3. [Reference Example 1]

(1) Dissolve 3 lmg of 1-OHD in 1 ml of ethanol The solution was added to 100 ml of an ethanol solution in which 10 g of polyvinyl pyrrolidone (molecular weight: about 40,000) was dissolved, and the mixture was stirred and mixed for 10 minutes. Further, 30 g of crystalline cellulose was added to this solution, and the mixture was stirred and mixed for 10 minutes. Then, ethanol was distilled off under reduced pressure and dried to obtain 38.8 g of a reaction product. Content of 1 alpha ten HD ₃ of the reaction product was 0 0 2 5% 0.5.

(2) A powder having the following composition containing this composition was prepared and tableted using a single-shot tableting machine manufactured by Eljeka to obtain tablets having a diameter of 7 min and a thickness of about 2 mm. The tablets are those with about 1.5 wg including the 1 alpha _〇 HD ₃ agents in one tablet.

1.02 parts by weight of the composition of (1)

Lactose 50.0 parts by weight

Corn starch 27.5 parts by weight

Magnesium stearate 1.0 parts by weight

Talc 0.5 parts by weight

[Example 1]

3 0 Example Base dough patients untreated were randomly Ke divided into two groups of 1 alpha -〇 HD ₃ throw Azukagun (VD ₃ administered group) and non-administration group (VD ₃ non-administration group). The VD ₃ administration group, 1 Fei one OHD ₃ 1 - was administered 5 g Z Date 2 4 weeks. As shown in Table 1, there was no difference in the patient characteristics between the two groups. Treatment for Graves' disease was started with thiamazole 3 O mg / day and increased or decreased as appropriate according to symptoms. Propranolol was appropriately used as a β-blocker. Table 1 Patient background

Me2! I Sat SE

Various serum parameters shown in Table 2 were measured by the methods shown in Table 2 before treatment and at regular intervals after the start of treatment, and the results are shown in FIGS. 1 to 4.

Table 2 Inspection parameters and measurement methods

Off rie T _₃ (f T ₃₎ Figure 1 or found showing changes over time in (pg Zm l), f T 3 is significance in pairs before treatment value Ri by treatment after 2 weeks in both groups It can be seen that it has decreased. Incidentally, reduction of VD ₃ treated group (暴印), compared to VD ₃ non-administration group (.smallcircle), observed strongly Ri by 4 weeks was significant at 6-8 weeks. Moreover, the force that was not shown in the Figure;, unfavorable - T _₄ (f T ₄₎ also shows a low value for VD ₃ group administered non-administration group in the same treated starting 6-1 6 weeks, the difference Was significant at 12 weeks.

From Fig. 2 showing the time course of TSH (wIU ml), VD In the treatment group, cases in which the TSH value recovered within the normal range (> 0.34 IU / m 1) (hatched bar graph) were observed from the 4th week of treatment, and the upper limit of normality was observed at the 8th week (3.6). 0 IU / m 1) It can be seen that a case (open bar graph) showing the above was also observed. Number of cases that recovers above the upper limit of normal is significantly more as compared to the non-administration group with VD ₃ administration group of 8 to 1 6 weeks, the VD ₃ non-administration group 6 patients in the 1 week 6 (4 0%) In contrast, there were 13 cases (87%) in the administration group.

Figures 3 and 4 showing TRA b (%) and C a values (mg Z d 1) [A 1 b correction] significant difference was not observed in the group, and this action of one flight one 0 HD ₃ is not intended secondary to inhibition of these factors have been suggested.

Table 3, VD ₃ reduction start timing Thiamazole the non-administration group and administration group, the mean total dose and Puropura Roh low dosing period Le summarizes the mean total dose.

Table 3

ean ± SE

From Table 3, although any parameter also been made at low levels in VD ₃ dose groups compared to VD ₃ non-administration group, it is clear that there was not significant. [Example 2]

Effect of 1 a _〇 HD ₃ in methylthiophenyl © La sill administered rats Bok

(1) Method, measurement items, etc.

In rats that methylthiopyrimidine © La sill (MTU) and drinking-water, Ding _3, for the synthesis of T ₄ is suppressed, TSH by Fi over Doba' click causes enlargement of the thyroid gland becomes excessive secretion. Therefore, if active vitamin D has an effect on thyroid hormone secretion, etc. in such animals, it may be an active vitamin D in TSH hypersecretion state, ie, pituitary or TRAb hyperthyroidism. This is considered to be appropriate for a model for evaluating the action of MinD. Method>

8 weeks old SD rats, male, 5 animals / group, drinking water (0.01%) for 7 days, vehicle (0.2% triton X—100) administration or _{la _ OHD 3, (0 5} g Z kg.) Ni Let 's the administration group of the first group to the sixth group of under Symbol administration, vehicle and 1 α - OHD ₃ once a day 0. Oral administration was performed at 2 ml Z kg, and blood collection and dissection were performed 24 hours after the final administration.

Group 1: Vehicle administration

Group 2: MTU drinking water administration

Group 3: MTU drinking water administration + 1 α-0 HD ₃ administration

Group 4: la — OHD ₃ administration

Group 5: MTU drinking-water + subsequent MTU free in vehicle 3 daily doses Group 6: MTU drinking-water + then MTU No la - OHD ₃ 3 daily doses Measurement items>

Body weight, thyroid weight, serum T ₃ , T ₄ , TSH, Ca, IP (inorganic phosphorus), thyroid tissue cAMP level (2) The results obtained are expressed as the mean soil standard deviation for each group. The results are shown in Table 4. In the significance test, for groups 1 to 4, a Dunnett's multiple comparison test was performed for each measurement item using the second group as a control, and for the fifth and sixth groups, a Student's t test was performed. Was.

Ψstate) !!) ίί (Γ3 TSII c AM

(g)! (nig) (ng / ml) (ng / ml) (fmol / mg)

1 268.3 ± 3. Μ ± 3 0.88 ： ». 0.08" 4.8 ± Ο.Γ) 2 "7. | ± 0) 7 * 2I7 ± 79 I0.8 ± 0.19 7.7 ± 0 2 ι 2G2.3 ± 9.5G 25 ± 5 05Ί ± 009 Ι.6 ± 048 26.4 ± 5.12 472 ± <122 I0.9 ± 0.3I 7.7 ± 0.40

3 2ΒΊ.4 ± 9.90 29 ± 2 038 ± 008 '<! (Example) IG soil 102 I2.2 ± 0.29 "7.0 ± 0.G8

4 15 0.9Z ± 0.11 "5.5 Sat 0.72" 86 ± 2.G7 "227 ± GO 12.1 + 0.21" 7.5 ± 0.58

5 285.7 ± 8.53 24 ± 5 0.8G ± 0 II 4.8 ± 0.8Ι 9.9 ± l.39 32l ± 137 I0.7 ± 0.16 7.1 ± 0.40

6 27 5 Upper-120 20 ± 2 0.74 Sat 0.15 3.8 Sat 1.08 11 2 ± 4.12 407 ± 16l 12.1 ± 0.44 "80 ± 0.69

#: <0.05. Kit-0.01. Student's t-test for Fifth and ^ G ^.

u Table 4 shows that this animal model reflects the state in which TSH is excessively secreted due to feedback caused by the decrease in T ₃ and T.

In this model, 1 a — OHD ₃ acts on the thyroid gland in which TSH receptor Yuichi was overstimulated, further reducing T ₃ and T ₄ and concomitantly increasing TSH It is clear that he did.

The result is, serum C a concentration increases as dependent rather difficulty thinking of, the point of action of c A λί P numerical force et 1 Fei one OHD ₃ in signaling behind Ri good c A Micromax [rho It is presumed that there will be. The Conoco, 1 are traditional reported alpha 2 5 -. Contrary to the results that inhibits an increase in c AMP by TSH stimulation dihydric de proxy Vita Mi emissions D ₃ Guy emissions bi collected by filtration, Lee Nimbo suggests that there is no such effect. On the other hand, the increase of thyroid weight, 1 flight ten HD ₃ is cracked think that there is a high possibility that does not inhibit the signal transduction for cell proliferation.

From the above, 1 flight one OHD ₃ acts in a state similar to hyperthyroidism TSH receptions evening one is overstimulated, was considered to indicate a thyroid hormone synthesis inhibitory effect as a result.

In addition, the above results are considered to be in phenomenal agreement with Example 1.

[Example 3]

Thyroid hormone releasing hormone (TRH) Effect of 1 flight ten HD ₃ in administering rats

(1) Method, measurement items, etc. In drinking-water rat of TRH, secretion enhanced thyroid function enhanced state of TSH, i.e. T _3, is considered to be a state in which the synthesis is the promotion of T _4. Therefore, if active vitamin D has an effect on the secretion of thyroid hormone in such animals, it may be an active form in the hypersecretion state of SH, ie, pituitary or TRAb hyperthyroidism. This is considered to be appropriate for a model for evaluating the effects of vitamin D. Method>

TRH (0.4 mg / ml) in drinking water for 6 days, vehic le (0.2% triton X) was administered to 12-week-old SD rats, males, and three groups.

1 0 0) administration or 1 HD ₃ (0.0 2 0 1, 0

The 5 g / kg) administered as a treated group of the first group to the fifth group of the following, administered orally at veh ics le and 1 a -〇 HD ₃ once a day 0. 2 m 1 / kg Blood was collected and dissected 24 hours after the last administration.

Group 1: TRH non-administration + vehic le administration

Group 2: TRH drinking water administration + vehicle administration

Group 3: TRH drinking-water _{+ 1 α _ 0 HD 3 0} 0 2 g / Kg dose group 4:.. TRH drinking-water _{÷ ia _ OHD 3 0 1 g} / Kg administration

Group 5:. TRH administered in drinking water _{+ la _ OHD 3 0 5 g} / Kg administration

This is the same as in the second embodiment. (2) The obtained results are expressed as the average soil standard deviation for each group.

5 Shown in the table. Significance test uses the second group for each measurement item Dunnett's multiple comparison test was performed at 97/11703.

^ "

Thyroid ffi „¾ TSH c AMP

(g) (mg) ml) (Tmol / ing)

1 373.4 ± 89.2 17 ± 2.6 0.77 ± 0.12 "U ± 0.55 '8.2 Sat 1.8 10.1 ± 0.15 6.0 ± (U7

2 38G.1 ± 40.3 25.3 Sat 2.5 1.17 ± 0 '' l 7.2 ± 0.9G 8.8 ± 2.7 10.2 ± 0.05 6.0 ± 0.06

3 370.7 ± 58.4 25 ± I0.5 l.26 ± 0.09 6.8 Sat 1.7 / | 8.0 ± 3.7 ± 61 10.3 ± 0.24 6.5 ± 0.96

CO

4 390.5 ± 24 27 ± 8.2 16 ± 0.! ■ 7 ■ 8.0 ± 0.64 8.9 ± 3.0 42 ± 137 10.6 ± 0.34 6.9 ± 0.2I

5 3G5.1 ± 30.1 2Ί + Ι2 0.83 + 0.1! 1 '6.1 ± 0.35 5.7 ± 0.3 326 ± 84 11.9 ± 0.02' 7.6 ± 1.Ί7

*: <0.05, **: d 0.01. Dunnet's multiple comparison test using the second control.

00 ^ From Table 5, the animal model, hyperthyroid state by hypersecretion of TSH, i.e. T _3, is believed to reflect the conditions of the synthesis is the promotion of T _4.

And in this model, 1 Fei -. OHDO and S / zg Z kg significantly suppressed the increase of T 3 by TRH administered at a dose of, suppression tendency for T ₄ was observed. On the other hand, thyroid weight was not changed by the administration of 1 alpha -〇 HD _3, which is 1 alpha -〇 HD ₃ is in signal transduction for cell proliferation and supports the foregoing discussion that not to act.

That, 1 alpha - OHD ₃ alone acts on the hyperthyroid state, result to tau _3, believed to show a synthesis inhibitory effect of tau _4, hyperthyroidism therapeutic agents, such as Base dough disease Clinical application can be expected.

Claims

The scope of the claims

1. An agent for preventing or treating a disease caused by hyperactivity of the thyroid gland, which contains active vitamin D as an active ingredient.

2. Activated vitamin D force ^ 1 α-Hydroxitamin D, 1, 24-Dihydroxyvitamine D, 1, 25-Dihydroxy vitamine D, 1, 24, 2 5 — Trihydroxyvitamin D, 24, 24 — Difurylolo 1 h, 25 — Dihydroxyvitamin D, 26, 26, 26, 27, 27, 27, 27 —Hexafluoro 1-, 25-dihydroxyvitamin D, 25 —Hydroxyvitamin D ₃ —26,23—Lactone, 1α, 25—Dihydroxyvitamin D ₃ — 2 6,

23. The prophylactic or therapeutic agent according to claim 1, which is selected from the group consisting of lactones.

. 3 active Vita Mi emissions D force, 1 alpha - arsenide de Rokishibita Mi down _{D 3, 1 a, 2 4} (R) over di arsenide de proxy Vita Mi emissions D _3, 1, 2 5 - di arsenide de proxy Vita prophylactic or therapeutic agents ranging first claim of claim those selected Mi emissions D ₃ or Ranaru group or al.

4. The prevention or treatment according to any one of claims 1 to 3, wherein the disease caused by hyperthyroidism is Graves' disease, indolent thyroiditis, or subacute thyroiditis. Agent.