CN107213149B - Application of artemisinin derivatives in preparation of drugs for treating or assisting in treating autoimmune thyroid diseases - Google Patents
Application of artemisinin derivatives in preparation of drugs for treating or assisting in treating autoimmune thyroid diseases Download PDFInfo
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- CN107213149B CN107213149B CN201710424537.4A CN201710424537A CN107213149B CN 107213149 B CN107213149 B CN 107213149B CN 201710424537 A CN201710424537 A CN 201710424537A CN 107213149 B CN107213149 B CN 107213149B
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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Abstract
The invention provides an application of artemisinin derivatives in preparation of a medicine for treating or assisting in treatment of autoimmune thyroid diseases, wherein the artemisinin derivatives and a medicine composition thereof can reduce the content of a thyroglobulin antibody (TGAb) and a thyroid peroxidase antibody (TPOAb), and have a good treatment effect on Graves diseases, chronic lymphocytic thyroiditis (hashimoto's thyroiditis, atrophic thyroiditis) or postpartum thyroiditis.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of artemisinin derivatives in preparation of medicines for treating or assisting in treating autoimmune thyroid diseases.
Background
The artemisinin derivative has obvious inhibition effect on animal humoral immunity and cellular immunity, and is clinically used for treating autoimmune diseases such as lupus erythematosus and the like, and a certain curative effect is obtained.
Clinically common autoimmune thyroid disorders include: graves 'disease, chronic lymphocytic thyroiditis (Hashimoto's thyroiditis, atrophic thyroiditis), postpartum thyroiditis, etc. Among them, Hashimoto's thyroiditis is the most common inflammatory disease of the thyroid gland. The clinical manifestations are diffuse lymphocyte infiltration, fibrosis, interstitial atrophy and eosinophilic change of acinar cells of thyroid gland. Multiple factors such as heredity, pregnancy, sex and environment act together to cause the immune function of a patient to be disordered and multiple lymphocytes in thyroid tissue to infiltrate, so that a series of autoantibodies aiming at the thyroid tissue, namely thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb), are generated, and the generation and development of autoimmune thyroiditis are caused beyond normal. The incidence rate of female is higher than that of male (1: 15-30), and is mostly in the age range of 30-50 years, and the incidence rate of female is in a growing trend in recent years, and the incidence rate is about 0.3-1.5/1000. Research shows that hashimoto thyroiditis is a risk factor of thyroid cancer.
At present, no specific medicine is available for autoimmune thyroid diseases, particularly hashimoto thyroiditis. Mainly adopts hormone therapy, replacement therapy or immunosuppressant therapy, although the drugs have certain clinical curative effect, the drugs still have problems in safety, such as side effects of drug hyperthyroidism and the like which still troubles the clinical treatment, and the drugs are easy to relapse once the drugs are stopped. Therefore, the development of safe and effective drugs for treating autoimmune thyroid diseases is urgent.
The artemisinin derivatives are clinically applied as antimalarial drugs for many years, and recent researches show that the artemisinin derivatives have the effects of immunoregulation and anti-inflammatory, and have certain curative effects on autoimmune lupus erythematosus through researches. The treatment effect of the artemisinin derivatives on the autoimmune thyroid diseases is not reported at present.
Disclosure of Invention
In view of the above, the present invention aims to provide an application of artemisinin derivatives in preparation of drugs for treatment or adjuvant therapy of autoimmune thyroid diseases.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
use of artemisinin derivatives in preparation of medicine for treating or adjunctively treating autoimmune thyroid diseases is provided.
Further, the artemisinin derivative is one or more of the compounds provided in the following (I) and/or (II):
(I) artemisinin, dihydroartemisinin, artemether, arteether, artesunate, artelinic acid, artesunone, arteolane, arteether maleate;
(II) the compounds of (I) are in pharmaceutically acceptable acid, alkali, salt, hydrate or ester.
Further, the molecular structural formula of the artemisinin, dihydroartemisinin, artemether, arteether, artesunate, artelinic acid, artesunone, arterolone and arteether maleate is as follows:
further, the autoimmune thyroid disease is one or more of Graves' disease, chronic lymphocytic thyroiditis or postpartum thyroiditis.
Further, the chronic lymphocytic thyroiditis is hashimoto's thyroiditis and/or atrophic thyroiditis.
Furthermore, the medicine for treating or assisting in treating the autoimmune thyroid diseases also comprises auxiliary materials.
Preferably, the medicine for treating autoimmune thyroid diseases is a pharmaceutically acceptable oral or external preparation and a dosage form thereof.
Preferably, the dosage form of the medicine for treating autoimmune thyroid diseases is tablets, capsules, emulsions, injections, pastes or patches.
Compared with the prior art, the application of the artemisinin derivative in preparing the medicine for treating or assisting in treating the autoimmune thyroid diseases has the following advantages:
the application of the artemisinin derivatives in treating autoimmune thyroid diseases is a new application, the artemisinin derivatives and the pharmaceutical composition thereof can reduce the content of a thyroglobulin antibody (TGAb) and a thyroid peroxidase antibody (TPOAb), and have a good treatment effect on Graves disease, chronic lymphocytic thyroid (inflammatory Hashimoto's thyroiditis, atrophic thyroiditis) or postpartum thyroiditis; in addition, the artemisinin derivatives have been clinically applied to treat malaria for years, so the artemisinin derivatives have incomparable advantages of other new drugs, definite side effects of the drugs, easy acceptance by patients, convenient understanding of the reaction of the patients to the drugs, definite administration routes, convenient synthesis of the artemisinin derivatives, mature production process, rapid production and high-efficiency preparation obtaining.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention will be described in detail with reference to examples.
Test materials and sources thereof in the normal group, model group, control group and administration group
1. Animal(s) production
Female SPF grade C57BL/6 mice, weighing 18-20g, were purchased from the center of laboratory animals at the military medical academy of sciences and housed in an SPF double corridor barrier environment. All animal experimental procedures were performed in sterile SPF animal houses.
2. Main experimental drugs and reagents
Porcine thyroglobulin (Sigma); freund's complete adjuvant (Sigma Co.); freund's incomplete adjuvant (Sigma Co.); sodium iodide, analytically pure; artemisinin (carbofuran technologies ltd); dihydroartemisinin (carbofuran technologies ltd); artemether (welfare technologies ltd); arteether (welfare science and technology limited); artesunate (welfare science ltd); artelinic acid (CarboMer, Inc); artemisone (largeway technologies ltd); arterolane (gold chemical Co., Ltd.) all other reagents were imported analytical grade reagents.
3. Main instrument
A full-automatic closed tissue dehydrator (Leica); paraffin embedding machines (Leica); semi-automatic rotary microtomes (Leica); fully automatic tissue staining machines (Leica); a water bath kettle (Leica) special for pathological section; full automatic sheet sealing machines (Leica); a full-wavelength microplate reader (Thermo fisher scientific).
Second, Experimental methods
1. Construction of autoimmune hashimoto thyroiditis model
Mice were divided into 2 groups, a normal group and a model group, the normal group drinking filtered tap water, the model group drinking high iodine water. Fully mixing pig thyroglobulin with equivalent volume of Freund's complete adjuvant to form a water-in-oil state, and injecting 100 mu g/mouse of a model group to serve as primary immunity; in the experiment of 2 weeks, after the porcine thyroglobulin is fully mixed with equivalent volume of Freund incomplete adjuvant to be in a water-in-oil state, 100 mu g of mice in a model group are injected with subcutaneous multiple points to strengthen immunity; after fully mixing porcine thyroglobulin with an equal volume of Freund's incomplete adjuvant to form a water-in-oil state, the experiment was boosted 1 time (100. mu.g/mouse) in the third and fourth weeks.
2. Therapeutic effect of artemisinin derivatives on autoimmune hashimoto thyroiditis
(1) Sign of success of modeling: starting from the 3 rd week of immunization, mice are killed every week, serum of the mice is taken to detect the content of thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb), and when the content of the thyroglobulin antibody (TGAb) and the thyroid peroxidase antibody (TPOAb) in the serum of the mice in the modeling group is more than 3 times of the content of corresponding antibodies in the serum of the mice in the normal group, successful modeling is marked.
(2) The administration method comprises the following steps: when the modeling is successful, the mice in the model group are averagely divided into ten groups, and the daily dosage of the control group and the 9 administration groups are respectively as follows: artemisinin group (150mg/kg), dihydroartemisinin group (20mg/kg), artemether group (50mg/kg), arteether group (130mg/kg), artesunate group (75mg/kg), artelinic acid group (40mg/kg), artemisone group (130mg/kg), arterane group (40mg/kg), arteether maleate group (5mg/kg), 6 mice per group, administration by gavage daily for 4 weeks, and weighing daily, the final body weights at the end of administration of mice are shown in table 1, the activity of mice was observed, and it was found that the activity of mice in the model group was decreased, the mice were listened, the hairs were erect, and the mental state of the mice in the administration group was improved to various degrees, and the skin and hair were smooth.
(3) Detection of specific antibodies: after the administration, blood was collected from the eyeball, and the supernatant was centrifuged to obtain serum, and the contents of thyroglobulin antibody (TGAb, IU/mL) and thyroid peroxidase antibody (TPOAb, IU/mL) in the serum of each group were measured (Table 1).
Third, experimental results
1. As shown in Table 1, the weight of the mice in the autoimmune hashimoto thyroiditis model group was low, and the weight of the group administered with artemisinin derivative was improved to a different extent compared to the control group.
2. As shown in Table 1, the test results show that the content of thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) in the serum of the mice is higher in the control group, and the content of the thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) in the serum of the mice administered with the artemisinin derivative is reduced to different degrees.
The results show that the artemisinin derivative has a certain inhibition effect on thyroglobulin antibodies (TGAb) and thyroid peroxidase antibodies (TPOAb), has a certain treatment effect on autoimmune hashimoto thyroiditis, and is expected to be developed into a medicament for treating autoimmune thyroid diseases.
TABLE 1 therapeutic Effect of artemisinin derivatives on Hashimoto's thyroiditis
Note: p <0.01 for normal group, # P <0.05 for model, and Δ P <0.01 for model.
The P value, i.e., the probability, reflects the magnitude of the likelihood of an event occurring. Statistics the P values obtained from the significance test method are generally significant with P <0.05 and very significant with P <0.01, meaning that the probability of sample-to-sample differences due to sampling errors is less than 0.05 or 0.01.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (6)
1. An application of artemisinin derivatives in preparing medicine for treating or adjunctively treating autoimmune thyroid diseases; the autoimmune thyroid disease is one or more of Graves disease, chronic lymphocytic thyroiditis or postpartum thyroiditis;
the artemisinin derivative is one or more of the compounds provided in the following (I) and/or (I I): (I) artemisinin, dihydroartemisinin, arteether, artelinic acid, artemisone, arteolane, arteether maleate; (I I) pharmaceutically acceptable salts of each of the compounds of (I).
2. Use according to claim 1, characterized in that: the molecular structural formula of the artemisinin, dihydroartemisinin, arteether forest acid, artemisone, arteolane and arteether maleate is as follows:
。
3. use according to claim 1, characterized in that: the chronic lymphocytic thyroiditis is hashimoto's thyroiditis and/or atrophic thyroiditis.
4. Use according to any one of claims 1 to 3, characterized in that: the medicine for treating or assisting in treating the autoimmune thyroid diseases also comprises auxiliary materials.
5. Use according to claim 4, characterized in that: the medicine for treating autoimmune thyroid diseases is a pharmaceutically acceptable oral or external preparation and a dosage form thereof.
6. Use according to claim 5, characterized in that: the medicament for treating the autoimmune thyroid disease is in the dosage form of tablets, capsules, emulsion, injection, paste or patches.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110548024A (en) * | 2018-05-30 | 2019-12-10 | 中国科学技术大学 | Therapeutic use of water-soluble artemisinin derivative-maleic acid aminoethyl artemisinin (SM934) |
| CN114340623B (en) * | 2019-08-29 | 2023-11-17 | 中国科学院上海药物研究所 | Pharmaceutical use of pyrimido [5,4-b ] pyrazine compound |
| CN111617074B (en) * | 2020-07-03 | 2021-08-24 | 中山大学附属第一医院 | Application of artemisinin or derivatives artesunate and dihydroartemisinin |
| WO2022000492A1 (en) * | 2020-07-03 | 2022-01-06 | 中山大学附属第一医院 | Use of artemisinin or derivatives artesunate and dihydroartemisinin |
| CN114668758A (en) * | 2021-05-17 | 2022-06-28 | 澳门大学 | Application of artemisinin and derivatives thereof in preparation of ChAT activity enhancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1561994A (en) * | 2004-04-02 | 2005-01-12 | 齐岩 | Medicinal compositon containing artemisine extract for treating rheumatoid arthritis and immunologic disease |
| WO2015084721A1 (en) * | 2013-12-02 | 2015-06-11 | Tabaczynski David A | Inhibition of isoprenoid biosynthetic pathways to treat autoimmune disorders |
| CN104906084A (en) * | 2014-03-11 | 2015-09-16 | 中山大学中山眼科中心 | Application of artemisinin and derivatives thereof in preparation of ophthalmic vascular disease prevention and treatment medicines, and medicinal composition |
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| CN103099902B (en) * | 2011-11-09 | 2015-02-18 | 上海中医药大学附属龙华医院 | Traditional Chinese medicine composition for treating subacute thyroiditis and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1561994A (en) * | 2004-04-02 | 2005-01-12 | 齐岩 | Medicinal compositon containing artemisine extract for treating rheumatoid arthritis and immunologic disease |
| WO2015084721A1 (en) * | 2013-12-02 | 2015-06-11 | Tabaczynski David A | Inhibition of isoprenoid biosynthetic pathways to treat autoimmune disorders |
| CN104906084A (en) * | 2014-03-11 | 2015-09-16 | 中山大学中山眼科中心 | Application of artemisinin and derivatives thereof in preparation of ophthalmic vascular disease prevention and treatment medicines, and medicinal composition |
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