CN114949242B - Application of selenium-containing compound in preparation of osteoclast differentiation inhibitor - Google Patents
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
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- A—HUMAN NECESSITIES
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Abstract
The invention discloses application of a selenium-containing compound in preparation of an osteoclast differentiation inhibitor. The inventor discovers that the selenides such as the selenadiazole, the chitosan modified nano-selenium, the lentinan modified nano-selenium, the polyethylene glycol modified nano-selenium, the sodium selenite, the selenocysteine and the like have the characteristic of inhibiting the osteoclast generation, so that the selenides can be used as an osteoclast differentiation inhibitor medicine for treating diseases treated by the osteoclast differentiation inhibitor; in particular to selenocysteine, which has the advantages of low toxicity and remarkable pharmacological action.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of a selenium-containing compound in preparation of an osteoclast differentiation inhibitor.
Background
Stabilization of bone metabolism requires a dynamic balance and coupling between osteoclast-mediated bone resorption and osteoblast-mediated bone formation, both of which maintain functional balance in healthy individuals, and once the balance is broken, this may lead to the occurrence of skeletal diseases.
Osteoclasts are the only cells in the body responsible for bone resorption. It can differentiate into mature osteoclasts with functions after activation by osteoclast precursor cells. Since differentiated mature osteoclasts can absorb bone, excessive activation of the osteoclasts can cause bone loss and osteoporosis, fracture pain is caused, secondary reactive bone hyperplasia and even disability are caused. There are many diseases related to the overactivation of osteoclasts, and postmenopausal osteoporosis is typical, and it is important to treat tumor metastasis bone destruction, inflammation-related bone destruction (rheumatoid arthritis, septic arthritis, periodontitis, etc.), and the like. The number of bone destruction patients associated with osteoclast activation is enormous, and only primary osteoporosis (mainly including postmenopausal osteoporosis and the like) is hundreds of millions of patients worldwide.
Bone destruction diseases associated with the overactivation of osteoclasts are various in variety, the etiology is also very diverse, even one disease can have various pathogenesis-related factors, and some of the diseases belong to refractory diseases with ambiguous etiology or multiple etiology. But the medicine which directly aims at the osteoclast and inhibits the differentiation of the osteoclast can directly improve the bone destruction symptoms of related diseases across the causes of the diseases and effectively relieve the pains of the patients related to fracture, pain and the like. Therefore, the osteoclast differentiation inhibitor is a medicament for a plurality of bone destruction diseases related to the overactivation of osteoclasts such as postmenopausal osteoporosis and the like in recent years.
Although various drugs for treating the above diseases are capable of improving the diseases finally by improving hormone levels, anti-inflammatory and other different approaches, there are few osteoclast differentiation inhibitors which can be directed to osteoclasts clinically at present. In addition, while some drugs are capable of treating bone destruction diseases such as rheumatoid arthritis against etiologies such as anti-inflammatory diseases, theoretically with the possibility of directly or indirectly inhibiting osteoclastogenesis and inflammatory bone destruction, in fact many commonly used drugs have been reported to induce osteoclastogenesis or exacerbate osteoporosis. For example, two commonly used representative drugs for the treatment of rheumatoid arthritis: glucocorticoids (e.g., dexamethasone), methotrexate, both inhibit the production of inflammatory factors including tnfα in peripheral or diseased joints, but both agents cause bone destruction. Glucocorticoids (such as dexamethasone) promote the induction of osteoclast production in vitro, and osteoporosis is easily induced in vivo in animals and patients; methotrexate also promotes osteoclast formation and causes bone destruction after use.
Whereas currently common inhibitors of osteoclast differentiation are bisphosphates (such as zoledronic acid) and the inhibitor Denosumab of RANKL. Both osteoclast differentiation inhibitors were initially approved for the market as drugs for the treatment of postmenopausal osteoporosis, and have been approved in recent years for the addition of a new clinical indication, tumor metastasis bone destruction. However, bisphosphates are mostly required to be administered by injection and easily cause serious adverse reactions such as jawbone necrosis; the biological antibody preparation denomab aiming at the osteoclast activating factor RANKL needs subcutaneous injection, and has more expensive price. Therefore, more osteoclast differentiation inhibitor medicines which can be conveniently taken, economically and effectively are clinically needed.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of the prior art and provides application of a selenium-containing compound in preparation of an osteoclast differentiation inhibitor.
The aim of the invention is achieved by the following technical scheme:
application of selenium-containing compound in preparation of osteoclast differentiation inhibitor, wherein the selenium-containing compound is selenadiazole (SeD, C) 6 H 3 O 2 N 3 Se), chitosan-modified nano-selenium (CS-Se), lentinan-modified nano-selenium (Let-Se), polyethylene glycol-modified nano-selenium (Peg-Se), sodium selenite (Na) 2 SeO 3 ) And selenocysteine (SeCys) 2 Selenolysine, cysselcys); preferably selenocysteine SeCys 2 。
The osteoclast differentiation inhibitor is a medicine which can be used for treating the clinical indication of the bisphosphonate and the denomab.
The osteoclast differentiation inhibitor is an anti-postmenopausal osteoporosis drug, an anti-tumor metastasis bone destruction drug, an anti-bone destruction drug caused by rheumatoid arthritis and an anti-bone destruction disease drug related to excessive activation of various osteoclasts.
The osteoclast differentiation inhibitor comprises a selenium-containing compound and pharmaceutically acceptable pharmaceutical excipients.
The osteoclast differentiation inhibitor is in the form of oral administration, injection or external application.
Compared with the prior art, the invention has the following advantages and effects:
1. the inventor discovers that different selenides have direct and different inhibiting effect characteristics on osteoclast generation for the first time, so that the selenides can be used as osteoclast differentiation inhibitor medicines.
2. The invention provides application of different selenides in preparing osteoclast differentiation inhibitors. The osteoclast differentiation inhibitor can be used as a medicament for treating clinical indications approved to be treated by known osteoclast differentiation inhibitor medicaments such as biphosphate and denomab, for example, postmenopausal osteoporosis resisting medicaments, tumor metastasis bone destruction resisting medicaments, bone destruction resisting medicaments caused by rheumatoid arthritis, various bone destruction resisting medicaments related to overactivation of osteoclasts and the like. The osteoclast differentiation inhibitor comprises a selenium-containing compound and medical acceptable pharmaceutical excipients, and can be prepared into oral dosage forms, injection dosage forms or external dosage forms.
Drawings
FIG. 1 is a photograph of a graph showing the effect of various selenides on differentiation of mouse bone marrow macrophages into osteoclasts; wherein: RANKL is a ligand that activates the nuclear factor NF- κb receptor.
FIG. 2 is a graph of statistical results of the effect of different selenides on differentiation of mouse bone marrow macrophages into osteoclasts; wherein, compared with the blank control group, ### P<0.001; compared to RANKL group, P<0.05，**P<0.01，***P<0.001, ns indicates no significant difference.
FIG. 3 is a graph of cytotoxicity detection results for different selenides.
FIG. 4 is SeCys 2 Results of in vivo experiments in mice treated for arthritis.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art. The test methods for specific experimental conditions are not noted in the examples below, and are generally performed under conventional experimental conditions or under experimental conditions recommended by the manufacturer. The reagents and starting materials used in the present invention are commercially available unless otherwise specified.
The selenadiazole SeD (C) was tested in vitro 6 H 3 O 2 N 3 Se), three different modified nanoparticles (CS-Se, let-Se, PEG-Se), sodium selenite (Na 2 SeO 3 Sigma) and sodium selenate (Na 2 SeO 4 Sigma), selenocysteine (SeCys) 2 ，Selenocystine，CysSeSeCys，C 6 H 12 N 2 O 4 Se 2 Sigma), selenomethionine (SeM, C 5 H 11 NO 2 Se, sigma) was tested for its anti-osteoclast differentiation effect.
Example 1
Synthesis of three different nano-selenium:
the elemental nano-selenium (SeNPs) has the characteristics of low toxicity, high bioavailability and easy surface modification. However, unmodified SeNPs are poorly stable, are highly susceptible to aggregation, and their biological activity is greatly reduced by nanoscale changes. Studies have reported that the use of polymers in the synthesis of Senps can prevent aggregation of Senps, increasing stability and bioactivity. Therefore, polymers (CS, let, PEG) with different charges are selected to modify the Sepps, and three kinds of functionalized Sepps are synthesized, including chitosan nano-selenium CS-Se, lentinan nano-selenium Let-Se and polyethylene glycol nano-selenium PEG-Se.
1) The synthesis method of the Let-SeNPs and the CS-SeNPs comprises the following steps:
sodium selenite solution: 69mg of sodium selenite (molecular weight 172.94) was dissolved in 10mL of ultrapure water to obtain a sodium selenite solution having a concentration of 40 mM.
Ascorbic acid solution: 352.42mg of ascorbic acid (molecular weight 176.13) was dissolved in 20mL of ultrapure water to obtain an ascorbic acid solution having a concentration of 100 mM.
Let solution: 75mg of the Let lentinan powder (purity 80% of Shanxi French Natural products Co., ltd.) was dissolved in 15mL of ultrapure water to obtain a Let solution having a concentration of 4 mg/mL.
CS solution: 75mg of CS chitosan powder (Alatine, purity 80%) was dissolved in 15mL of ultrapure water, and then 150. Mu.L of glacial acetic acid was added to promote CS dissolution, to obtain a CS solution having a concentration of 4 mg/mL.
5mL of CS solution or 5mL of Let solution, then 2mL of sodium selenite solution, were added to the reaction flask, after stirring, 1mL of ultrapure water was added, stirring was continued, then 2mL of ascorbic acid solution was added, and then the reaction was stirred overnight. After the reaction is finished, dialyzing in distilled water by using a 6000-8000Da dialysis bag for overnight, and finally recovering CS-Sepps or Let-Sepps solution obtained after the dialysis.
2) Synthesis method of PEG-SeNPs
10mL of PEG 400 (polyethylene glycol 400) was added to a 50mL beaker, then 20mg of selenium powder (Aladin, s 105193) was weighed, sonicated for 10min and stirred for 5min to completely and uniformly disperse the selenium powder in the PEG 400. The transferring beaker is placed on a magnetic stirring heater, heated to the temperature of about 205 ℃, stirred while being heated, naturally cooled after reacting for 1 hour, transferred to a centrifuge tube, centrifuged at 2000rpm for 10min, taken out of the upper layer solution, and unreacted selenium powder is removed, and finally PEG-Sepps is obtained. (the stirring speeds were 300 rpm)
3) Synthetic methods for SeD are referred to in the references "Selenadiazole derivatives as theranostic agents for simultaneous cancer chemo-/radiotherapy by targeting thioredoxin reductase, journal of Materials Chemistry B,2015 Nov 14;3 (42): 8383-8393. Part "Synthesis and characterization of SeDs (1-3)" of the "section.
Example 2
Effect of different selenides on differentiation of mouse Bone Marrow Macrophages (BMMs) into osteoclasts:
taking femur and tibia of C57BL/6 mice (experimental animal center in Guangdong province) with health period of 6-8 weeks, peeling muscle, cutting off two ends, sucking ice precooled alpha-MEM culture medium with syringe, repeatedly flushing bone marrow cavity of femur and tibia, and flushing bone marrow cells until bone is reachedThe medullary cavity was whitened, the tissue mass was filtered with a 70 μm filter head, and the filtrate was transferred to a 60cm petri dish and cultured in an incubator with a medium of alpha-MEM containing 30ng/mL macrophage colony stimulating factor M-CSF. After 3 days of stationary culture, the supernatant was discarded, the bottom cells were digested with 0.25% pancreatin solution, and the cells were cultured at a ratio of 7X 10 3 The wells were inoculated in 96-well plates, M-CSF and RANKL were added to both the positive control group (RANKL group) and the drug group except the negative control group (Blank group) at a final concentration of 50ng/mL, and different selenium-containing compounds were added to the drug group simultaneously to a final concentration of 0.75. Mu.M, 1.5. Mu.M, 3. Mu.M, 6. Mu.M, 12. Mu.M, 24. Mu.M, 48. Mu.M (drug was prepared by dilution with a doubling ratio), 3 wells per group. The selenium-containing compound and the medium containing the stimulatory factors M-CSF and RANKL were changed 1 time every 2 days. TRAP staining was performed on days 4-5 of induction, osteoclastogenesis in 96-well plates was observed under a microscope and photographed, and counts were performed for osteoclasts positive for TRAP and greater than 3 nuclei (mauve, multiple cells fused together as osteoclasts). The results are shown in fig. 1 and 2.
Example 3
Effect of different selenides on cytotoxicity of mouse macrophage leukemia cells RAW264.7 (osteoclast precursor cells):
RAW264.7 cells (Shanghai Proc. Cell bank) were resuspended in DMEM medium containing phenol Red and were grown at 1X 10 3 The density of individual cells/wells was seeded in 96-well plates overnight and different selenium containing compounds were added at concentrations of 0.75. Mu.M, 1.5. Mu.M, 3. Mu.M, 6. Mu.M, 12. Mu.M, 24. Mu.M, 48. Mu.M, 96. Mu.M. Each group had 3 duplicate wells. After 48h incubation, the supernatant was removed, 0.5mg/mL MTT 100. Mu.L was added to each well, incubated in a 37℃incubator for 4h, the supernatant was discarded, 150. Mu.L DMSO was added, and after 10min shaking, absorbance was measured at 570nm using a Genios Pro Tecan microplate reader.
As can be seen from FIG. 3, except for SeD, na 2 SeO 3 Besides the greater toxicity of CS-Se and Let-Se, the other selenized in vitro concentration is less than or equal to 12 mu M has no obvious influence on the survival of RAW264.7 cells.
To sum up the above in vitro results, seCys is added to SeM 2 、SeD、CS-Se、Let-Se、Peg-Se、Na 2 SeO 3 、Na 2 SeO 4 The in vitro RANKL is inhibited to different degrees to induce the osteoclast precursor cells to form osteoclasts (shown in a figure 2 statistical chart of the number of the osteoclasts), so that the differentiation and the formation of the osteoclasts are directly inhibited, and the bone resorption function of the osteoclasts is inhibited.
Wherein, the biological activity and the toxic effect of the medicine are comprehensively considered, and SeCys 2 Most preferably.
Example 4
SeCys 2 Effects on type ii collagen-induced arthritis mice:
bovine type II collagen and complete Freund's adjuvant were mixed in a volume ratio of 1:1, placing the mortar in a mortar in proportion, keeping the mortar on ice at a low temperature to prevent inactivation, fully grinding for more than half an hour under the low temperature condition until the mortar becomes a milky solution (water-in-oil), uniformly grinding, taking a small drop of water, detecting whether the grinding is qualified or not, and if the emulsion drop in the water does not diffuse immediately, indicating that the grinding is fully used for injection molding. First, the hair at the root of the tail of a mouse (DBA mouse for 7-8 weeks, velocin) was shaved off with a shaver, and the ground collagen was slowly sucked up with a syringe and the syringe wall was forcibly flicked off to expel air. After the skin was sterilized with alcohol, the skin was injected with an intradermal needle (skin was gently lifted after needle insertion), collagen was slowly injected at a constant speed, a bump of a bag was formed at the injection site after injection, a carefully withdrawn needle was injected (rotated and withdrawn), and the injection was completed by gently wiping with an alcohol cotton ball, and the volume of collagen injected into each mouse was 100 μl, and the other mice except for the normal control group were subjected to a model immunization, and a second boost immunization was performed with an incomplete adjuvant in the same manner on day 21 after the initial immunization. The injection site during the secondary immunization should avoid the ulceration part formed after the primary immunization so as to avoid the injected collagen overflowing from the peeping part. On days 4 and 5 after the second immunization, the mice were started to be treated with the drug when the mice developed arthritic symptoms of joint redness. The drug was dissolved in 0.1mol/L hydrochloric acid to give 100X mother liquor (5 mg/mL and 20mg/mL, respectively), and stored in a refrigerator at-80 ℃. On the day of administration, the administration treatment was carried out after 100-fold dilution with physiological saline, and the drug was intraperitoneally injected into mice at a weight of 10. Mu.L/g.
The appearance of redness and swelling symptoms was observed in the toe and ankle areas of the mice approximately at the fourth to fifth days after the boost. We regularly observed the redness and swelling of the toes and ankle joint of each group of mice and recorded their foot swelling scores, once every 2 days for a period of five weeks. The criteria for foot swelling score are shown in the following table:
TABLE 1
| No red and swelling change | 0 point |
| Obvious swelling and reddening of the 1 toe | 1 minute |
| Slight swelling of the joints of the limbs or swelling of the 2 toes or more | 2 minutes |
| Obvious red and swelling of the joints of the limbs | 3 minutes |
| Swelling and reddening of sole and ankylosis | 4 minutes |
Note that: each mouse had a maximum score of 16 points
The observation results are shown in fig. 4: compared with the normal control group, the CIA model mice have swollen joints, show obvious arthritis and are given with SeCys 2 -0.5mg/kg and SeCys 2 After-2 mg/kg treatment, the swelling degree of arthritis can be obviously reduced, and the loss and the reduction of weight can be reducedLow arthritis score. The experimental result proves that SeCys 2 Has remarkable therapeutic effect on arthritis mice and can be a candidate drug for bone destruction diseases.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (3)
1. The application of selenium-containing compound as the only active ingredient in preparing the medicine for treating arthritis is characterized in that: the selenium-containing compound is selenocysteine.
2. Use of a selenium-containing compound according to claim 1 as sole active ingredient in the preparation of a medicament for the treatment of arthritis, characterized in that: the medicine comprises a selenium-containing compound and pharmaceutically acceptable pharmaceutic adjuvant.
3. Use of a selenium-containing compound according to claim 1 as sole active ingredient in the preparation of a medicament for the treatment of arthritis, characterized in that: the preparation of the medicine is oral dosage form, injection dosage form or external dosage form.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985000747A1 (en) * | 1983-08-10 | 1985-02-28 | Stockel Richard F | Use of selenium-containing compounds for negating the toxic effects of gold compounds used in the treatment of rheumatoid arthritis, and a novel selenium-containing gold compound and use thereof as an anti-rheumatoid arthritis medicine |
| EP2095829A1 (en) * | 2008-02-27 | 2009-09-02 | LEK Pharmaceuticals D.D. | Selenium containing modifying agents and conjugates |
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- 2022-01-27 CN CN202210098486.1A patent/CN114949242B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985000747A1 (en) * | 1983-08-10 | 1985-02-28 | Stockel Richard F | Use of selenium-containing compounds for negating the toxic effects of gold compounds used in the treatment of rheumatoid arthritis, and a novel selenium-containing gold compound and use thereof as an anti-rheumatoid arthritis medicine |
| EP2095829A1 (en) * | 2008-02-27 | 2009-09-02 | LEK Pharmaceuticals D.D. | Selenium containing modifying agents and conjugates |
Non-Patent Citations (3)
| Title |
|---|
| Meng Zhao, Ting Luo,et al.Food Chemistry of Selenium and Controversial Roles of Selenium in Affecting Blood Cholesterol Concentrations.《Journal of Agricultural and Food Chemistry 》.2021,第69卷全文. * |
| Moon H J, Ko W K, Han S W, et al.Antioxidants, like coenzyme Q10, selenite, and curcumin, inhibited osteoclast differentiation by suppressing reactive oxygen species generation.《Biochemical and biophysical research communications》.2012,第418卷摘要、结果部分、fig1-4. * |
| 硒对体外培养小鼠成骨细胞形态、增殖和活力的影响;冯丽芳;吴培福;孙立婷;韩博;;畜牧兽医学报(08);全文 * |
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