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WO1997011703A1 - Preventif ou remede contre l'hyperthyroidie - Google Patents

Preventif ou remede contre l'hyperthyroidie Download PDF

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Publication number
WO1997011703A1
WO1997011703A1 PCT/JP1996/002616 JP9602616W WO9711703A1 WO 1997011703 A1 WO1997011703 A1 WO 1997011703A1 JP 9602616 W JP9602616 W JP 9602616W WO 9711703 A1 WO9711703 A1 WO 9711703A1
Authority
WO
WIPO (PCT)
Prior art keywords
hyperthyroidism
emissions
group
thyroid
disease
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1996/002616
Other languages
English (en)
Japanese (ja)
Inventor
Isao Makino
Hirotoshi Tanaka
Etsushi Fukawa
Takako Tani
Hiroshi Hashizume
Yoshinori Kasahara
Keiji Komoriya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teijin Ltd
Original Assignee
Teijin Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Teijin Ltd filed Critical Teijin Ltd
Priority to AU69447/96A priority Critical patent/AU6944796A/en
Publication of WO1997011703A1 publication Critical patent/WO1997011703A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems

Definitions

  • 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.
  • 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.
  • 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 ⁇ ).
  • TRH hypothalamus
  • TSH thyroid stimulating hormone
  • TSH secreted TSH within the al
  • TSH is produced of T 4 stimulates TSH receptors on the cell membrane of the thyroid and secretion.
  • the concentration of thyroid hormone increases, contrary to the TR Eta, reduces the secretion of TS Eta, the production of T 4, secretion decreases.
  • Graves' disease a representative disease of hyperthyroidism, is an autoimmune disease caused by autoantibodies (TRAb) that stimulate TS ⁇ receptors. .
  • TRAb autoantibodies
  • 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.
  • 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.
  • radiation therapy to inhibit thyroid cells.
  • 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.
  • vitamin D such as protein D 3 (1 ⁇ , 2 ⁇ D 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.
  • 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).
  • an object of the present invention is to provide a novel agent for preventing or treating hyperthyroidism.
  • 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
  • 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.
  • FIG. 1 shows the change over time of the free T 3 (f ⁇ 3) in Example 1. Show.
  • 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.
  • 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.
  • 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.
  • - mark indicates the value of VD 3 administration group
  • .smallcircle indicates the value of VD 3 non-administration group.
  • 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-1 ⁇ , 25—Dihydroxyvititamin D, 26,26,26,27,27,27 —Hexafurile mouth 1 ⁇ , 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
  • 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.
  • 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.
  • 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, methyl
  • 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.
  • active vitamin D 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.
  • the dose For external preparations, more preferably 2 days from lig.
  • 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.
  • 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.
  • 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.
  • Active Vita Mi emissions D such as 1 a - ⁇ 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
  • Orazu used as a conventional antithyroid agent
  • 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.
  • 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.
  • the prophylactic or therapeutic agent of the present invention 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.
  • 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 _ ⁇ HD 3 agents in one tablet.
  • Example Base dough patients untreated were randomly Ke divided into two groups of 1 alpha - ⁇ 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.
  • 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 ⁇ -blocker.
  • Table 1 Patient background
  • Group 3 MTU drinking water administration + 1 ⁇ -0 HD 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.
  • 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.
  • Thyroid hormone releasing hormone Effect of 1 flight ten HD 3 in administering rats
  • 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.
  • Group 1 TRH non-administration + vehic le administration
  • Group 3 TRH drinking-water + 1 ⁇ _ 0 HD 3 0 0 2 g / Kg dose group 4:.. TRH drinking-water ⁇ ia _ OHD 3 0 1 g / Kg administration
  • T 3 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un préventif ou un remède contre des affections causées par l'hyperthyroïdie (par exemple, maladie de Basedow, la thyroïdite de type indolent ou la thyroïdite de type subaïgu), qui renferme de la vitamine D activée en tant que principe actif.
PCT/JP1996/002616 1995-09-28 1996-09-13 Preventif ou remede contre l'hyperthyroidie Ceased WO1997011703A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU69447/96A AU6944796A (en) 1995-09-28 1996-09-13 Preventive or remedy for hyperthyreosis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP25124995 1995-09-28
JP7/251249 1995-09-28

Publications (1)

Publication Number Publication Date
WO1997011703A1 true WO1997011703A1 (fr) 1997-04-03

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PCT/JP1996/002616 Ceased WO1997011703A1 (fr) 1995-09-28 1996-09-13 Preventif ou remede contre l'hyperthyroidie

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AU (1) AU6944796A (fr)
WO (1) WO1997011703A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501223B2 (en) 2003-06-20 2013-08-06 Hill's Pet Nutrition, Inc. Methods for dietary management of cats to avoid hyperthyroidism
US8993001B2 (en) 2006-01-26 2015-03-31 Hill's Pet Nutrition, Inc. Methods and compositions for treating feline hyperthyroidism

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5745415B2 (fr) * 1977-12-19 1982-09-28
JPS6187619A (ja) * 1984-10-08 1986-05-06 Teijin Ltd 活性型ビタミンｄ↓３類外用剤
JPS6346728B2 (fr) * 1982-05-27 1988-09-19 Teijin Ltd
JPS6360007B2 (fr) * 1983-02-22 1988-11-22
JPH0632740A (ja) * 1992-05-20 1994-02-08 F Hoffmann La Roche Ag 医薬製剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5745415B2 (fr) * 1977-12-19 1982-09-28
JPS6346728B2 (fr) * 1982-05-27 1988-09-19 Teijin Ltd
JPS6360007B2 (fr) * 1983-02-22 1988-11-22
JPS6187619A (ja) * 1984-10-08 1986-05-06 Teijin Ltd 活性型ビタミンｄ↓３類外用剤
JPH0632740A (ja) * 1992-05-20 1994-02-08 F Hoffmann La Roche Ag 医薬製剤

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Glossary of Medicine (17th Edition)", (1990), NANZANDO, p. 9, 624, 1558, 1880, 1913. *
VITAMINS, Vol. 61, No. 1, (January 1987) (Japan), YAMAMOTO I. et al., "Determination of Blood Vitamin Metabolites in Various Diseases", p. 1-12. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8501223B2 (en) 2003-06-20 2013-08-06 Hill's Pet Nutrition, Inc. Methods for dietary management of cats to avoid hyperthyroidism
US8993001B2 (en) 2006-01-26 2015-03-31 Hill's Pet Nutrition, Inc. Methods and compositions for treating feline hyperthyroidism

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Publication number Publication date
AU6944796A (en) 1997-04-17

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