CN116889558A - Application of agomelatine in preparing medicines for treating arthritis - Google Patents
Application of agomelatine in preparing medicines for treating arthritis Download PDFInfo
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- CN116889558A CN116889558A CN202311090605.XA CN202311090605A CN116889558A CN 116889558 A CN116889558 A CN 116889558A CN 202311090605 A CN202311090605 A CN 202311090605A CN 116889558 A CN116889558 A CN 116889558A
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- agomelatine
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- treating arthritis
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- 239000003814 drug Substances 0.000 title claims abstract description 24
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 206010003246 arthritis Diseases 0.000 title claims abstract description 23
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 22
- 229940079593 drug Drugs 0.000 title description 14
- 239000002552 dosage form Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 241000699670 Mus sp. Species 0.000 abstract description 18
- 208000024891 symptom Diseases 0.000 abstract description 5
- 230000002917 arthritic effect Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 7
- 102000000503 Collagen Type II Human genes 0.000 description 6
- 108010041390 Collagen Type II Proteins 0.000 description 6
- 238000002649 immunization Methods 0.000 description 6
- 230000003053 immunization Effects 0.000 description 6
- 230000008961 swelling Effects 0.000 description 6
- 241000287828 Gallus gallus Species 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 4
- 210000003423 ankle Anatomy 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 210000003371 toe Anatomy 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000009386 Experimental Arthritis Diseases 0.000 description 3
- 101000883515 Homo sapiens Chitinase-3-like protein 1 Proteins 0.000 description 3
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- 102000054350 human CHI3L1 Human genes 0.000 description 3
- 206010020718 hyperplasia Diseases 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 210000003414 extremity Anatomy 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 208000018937 joint inflammation Diseases 0.000 description 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 210000000707 wrist Anatomy 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010051728 Bone erosion Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 206010023230 Joint stiffness Diseases 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 210000001188 articular cartilage Anatomy 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013506 data mapping Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 210000005067 joint tissue Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008409 synovial inflammation Effects 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses an application of agomelatine in preparing a medicament for treating arthritis. Agomelatine is effective in ameliorating the arthritic symptoms in mice with arthritis models. Thus, agomelatine has a prospect of being developed into a medicament for treating arthritis. The prior art does not disclose the technical proposal of the invention, and the invention has outstanding substantive features and remarkable progress.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of agomelatine in preparing medicines for treating arthritis.
Background
Arthritis is a very high incidence worldwide and is of a wide variety, with Osteoarthritis (OA), rheumatoid arthritis (rheumatoid arthritis, RA), psoriatic arthritis (psoriatic arthritis, psA), gouty arthritis, juvenile idiopathic arthritis (juvenile idiopathic arthritis, JIA) and the like being the most common. All types of arthritis share common disease features including mononuclear cell infiltration, inflammation, synovial swelling, fascial formation, joint stiffness, and articular cartilage destruction. The exact cause of arthritis is not known nor is there any cure.
Agomelatine is a novel antidepressant drug and is mainly used for resisting depression, resisting anxiety, adjusting sleep rhythm and regulating biological clock clinically. As a novel action mechanism antidepressant, the safety condition of the antidepressant is different from SSRI/SNRAIs, the clinically relevant weight increase is not easy to occur, the incidence rate of sexual dysfunction is low, the gastrointestinal reaction risk is low, and no obvious withdrawal symptoms exist.
Currently, there is no report of agomelatine having anti-arthritic activity.
Disclosure of Invention
The invention aims to provide the use of agomelatine for the preparation of a medicament for the treatment of arthritis.
The above object of the present invention is achieved by the following technical scheme:
use of agomelatine for the preparation of a medicament for the treatment of arthritis.
Further, the medicine takes agomelatine as an active ingredient, also contains a pharmaceutically acceptable carrier or auxiliary material, and is prepared into a pharmaceutically acceptable dosage form.
Further, the carrier or adjuvant is solid, liquid or semi-solid.
Further, the dosage forms include tablets, capsules and injections.
The beneficial effects are that:
according to the invention, agomelatine can effectively improve the arthritis symptoms of an arthritis model mouse. Thus, agomelatine has a prospect of being developed into a medicament for treating arthritis.
Drawings
FIG. 1 is a graph showing clinical symptom scores for individual groups of CIA mice;
FIG. 2 shows ankle HE staining of individual groups of CIA mice;
FIG. 3 shows joint histopathological scores for individual groups of CIA mice.
Detailed Description
The following describes the essential aspects of the present invention in detail with reference to examples, but is not intended to limit the scope of the present invention.
1. Experimental materials
Methotrexate: m813626, microphone;
Agomelatine：HY-17038，MedChemExpress；
Immunization Grade Chick Type II collagen：20012，Chondrex；
Complete Freund's Adjuvant：7001，Chondrex；
Incomplete Freund's Adjuvant：7002，Chondrex；
sodium pentobarbital: p3761, SIGMA;
disposable syringe: 1ml of 0.45 x 16 (brown), xinjin shifeng.
2. Experimental method
1. A mouse
7 week old DBA/J1 mice were purchased from Beijing Wanfukang Biotechnology Co., ltd, fed in the front medical center animal house of the Kaschin Hospital of Sichuan university, 5 mice per cage, were freely drunk and fed, lighted for 12 hours/turned off for 12 hours, the temperature was maintained at 22-24℃and animal experiments were started after feeding for 1 week. The experimental method related to the subject has been approved by the biological ethics committee of the national institute of medicine, huaxi university.
2. Construction of an animal model for Experimental arthritis (CIA model)
An emulsifier comprising chicken type II collagen and complete Freund's adjuvant is provided. Taking out chicken type II collagen from refrigerator at-20deg.C, and thawing on ice in dark environment. A5 mL glass bottle is placed in an ice bath environment, a magnetic bead with proper size is placed in the glass bottle, a complete Freund adjuvant is added, an electromagnetic stirrer is started to enable the magnetic bead to rotate at 300rpm, and then chicken type II collagen is slowly dripped. After stirring for 30 minutes to 1 hour, the chicken type II collagen and complete adjuvant were checked for completion of emulsification. When the emulsion is good, the mixed liquid drops are not dispersed in water. CIA mouse model was constructed according to published protocols (ref: brand DD, latham KA, roslanier EF. Collagen-induced arthritis. Nature protocols 2007;Rosloniec EF,Whittington K,Proslovsky A,Brand DD.Collagen-Induced Arthritis Mouse model. Current protocols 2021):
for the first immunization, 100. Mu.L of 0.3% pentobarbital sodium was intraperitoneally injected into DBA mice at week 8, and 100. Mu.L of emulsifier was subcutaneously injected at 1.5-2cm of the root of the mice tail after the anesthesia was completed. After the injection is completed, the needle is quickly pulled out and pressed for 1 minute, and the mice are placed in the cage after no abnormality is observed.
Mice were boosted on day 21 after the first immunization. The emulsifying agent of chicken type II collagen and incomplete adjuvant is prepared according to the preparation method of the first emulsifying agent, after emulsification is successful, subcutaneous injection is carried out at the position, which is closer to the root of the tail, of the first immunization, 100 mu L of each injection is carried out, and the mice are placed in a cage after being fully pressed and observed to be free from abnormality.
3. Drug configuration
The medicines are weighed according to the daily dosage and the administration time of the mice, DMSO is added for dissolution, the dosage of every 6 mice for one day is divided into EP pipes of 1.5mL, and the EP pipes are stored at the temperature of minus 80 ℃ for no more than 3 months. The medicine diluent is prepared by ultrapure water: absolute ethyl alcohol: 2% acetic acid = 8:3:1 ratio. When mice are fed, a 1.5mL EP tube is taken, and a drug diluent is added, wherein the volume of the diluted drug is 600uL, and each mouse is administrated by stomach irrigation once a day, and 100uL each time. Note that the final DMSO concentration should be controlled to not exceed 5% when the drug is dissolved by DMSO. The model group was given drug dilutions containing the same DMSO concentration.
4. Experimental grouping and administration
On day 19 after the first immunization, mice were randomly grouped into 6 groups, each of which was divided into a normal mouse group (no modeling), a model control group (drug dilution administration), a positive control drug group, a drug group at high dose (10 mg/kg) and a low dose (1 mg/kg). From day 19 of primary immunization, each mouse was dosed daily by gavage with 100 μl of liquid until the end of the experiment. At day 49 after molding, mice were sacrificed at the end of the experiment and ankle joints were collected for fixation, decalcification, paraffin embedding, sectioning, HE staining.
5. Mouse joint inflammation score
Joint inflammation was scored every 2 days after boost. The scoring criteria were: for each limb, a score of 0 represents normal, a score of 1 represents a slight red swelling of 1 toe, a score of 2 represents a slight red swelling of 2 or more toes, a score of 3 represents a moderate red swelling of the whole wrist/ankle or a moderate red swelling of the whole toe, and a score of 4 represents a severe red swelling of the whole wrist/ankle or the whole toe. The maximum score for each limb was 4 and the maximum score for each mouse was 16.
6. Pathological scoring of arthritis
Three aspects of inflammation, bone erosion, synovial proliferation were scored on HE stained sections of each group of mice, with the scoring criteria as shown in table 1.
TABLE 1 pathological scoring criteria for arthritis
7. Data processing
Data mapping was performed using Prism6 software and data analysis was performed using SPSS software, and group-to-group differences and pairwise comparisons were performed by one-way ANOVA and Bonferroni methods. P <0.05 is statistically significant, P <0.05, P <0.01, P <0.001, P <0.0001.
3. Experimental results
We tested the therapeutic effect of the positive drugs MTX and Agomelatine (AOM) on CIA mouse models. The results showed that MTX (2 mg/kg) and AOM (10 mg/kg) groups reduced the mice arthritic symptoms score compared to the model group, the differences being statistically significant (p < 0.05) (FIG. 1).
As shown in the graph 2, compared with the normal mouse group, the CIA model control group has a large amount of local inflammatory cell infiltration, obvious synovial hyperplasia and joint bone destruction, which indicates that the model building of the arthritis model is successful; compared with the CIA model control group, the inflammatory cell infiltration, synovial hyperplasia and joint bone destruction conditions of all the administration groups are obviously relieved. As shown in the results of pathological scoring of the joint tissues of each group in FIG. 3, compared with a CIA model control group, MTX and AOM can reduce ankle synovial inflammation, synovial hyperplasia and bone destruction scores, and the difference is statistically significant (p is less than 0.05).
The experimental results show that agomelatine can effectively improve the arthritis symptoms of the arthritis model mice. Thus, agomelatine has a prospect of being developed into a medicament for treating arthritis.
The above-described embodiments serve to describe the substance of the present invention in detail, but those skilled in the art should understand that the scope of the present invention should not be limited to this specific embodiment.
Claims (4)
1. Use of agomelatine for the preparation of a medicament for the treatment of arthritis.
2. Use according to claim 1, characterized in that: the medicine takes agomelatine as an active ingredient, also contains a pharmaceutically acceptable carrier or auxiliary material, and is prepared into a pharmaceutically acceptable dosage form.
3. Use according to claim 2, characterized in that: the carrier or the auxiliary material is solid, liquid or semisolid.
4. Use according to claim 2, characterized in that: the dosage forms include tablets, capsules and injections.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311090605.XA CN116889558A (en) | 2023-08-28 | 2023-08-28 | Application of agomelatine in preparing medicines for treating arthritis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311090605.XA CN116889558A (en) | 2023-08-28 | 2023-08-28 | Application of agomelatine in preparing medicines for treating arthritis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116889558A true CN116889558A (en) | 2023-10-17 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311090605.XA Pending CN116889558A (en) | 2023-08-28 | 2023-08-28 | Application of agomelatine in preparing medicines for treating arthritis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116889558A (en) |
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2023
- 2023-08-28 CN CN202311090605.XA patent/CN116889558A/en active Pending
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