CN105326844A - Application of tofacitinib citrate and pharmaceutical composition thereof in preparation of medicine for treating sjogren syndrome - Google Patents
Application of tofacitinib citrate and pharmaceutical composition thereof in preparation of medicine for treating sjogren syndrome Download PDFInfo
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Abstract
The invention discloses tofacitinib citrate and application of a medicinal composition thereof in preparing a medicament for treating sjogren's syndrome, wherein the medicinal composition contains tofacitinib citrate and/or an optional pharmaceutically acceptable carrier or excipient. The medicinal composition obviously improves the dry mouth and eye symptoms.
Description
Technical Field
The invention relates to a medicinal composition, in particular to the application field of the medicinal composition in the preparation of a medicament for treating sjogren's syndrome, and specifically relates to tofacitinib citrate and the application of the composition in the preparation of the medicament for treating the sjogren's syndrome.
Background
Tofacitinib citrate (tofacitinib citrate), a novel drug developed by the japan wutian drug industry co-company with the american fevere drug for middle to severe active Rheumatoid Arthritis (RA) adult patients who do not respond sufficiently or are intolerant to methotrexate treatment, was approved by the FDA in the united states for marketing on day 11/6 of 2012, under the trade name XELJANZ.
The structure is as follows:
chemical name: 3- ((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2, 3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile citrate (1: 1).
Sjoumo Syndrome (SS) is a chronic autoimmune disease that attacks the exocrine glands, especially the salivary and lacrimal glands. It is manifested as dry mouth and eyes, and also as multiple organ and system damages. There is a large number of lymphocytes infiltrating the affected organs, and many autoantibodies are positive in serum.
The primary sicca syndrome belongs to global diseases, and the prevalence rate of the primary sicca syndrome in the population of China is 0.3% -0.7%, and the prevalence rate of the primary sicca syndrome in the population of the elderly is 3% -4%. The female is common in this disease, and the ratio of male to female is 1: 9 to 20. The onset age is usually 40 to 50 years old. Also found in children.
At present, the related research of tofacitinib citrate which is published is not used as a therapeutic drug for Sjogren syndrome.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel application of tofacitinib citrate and a composition thereof, namely an application of tofacitinib citrate and a medicinal composition thereof in preparing a medicament for treating sjogren's syndrome.
The technical scheme adopted by the invention for solving the technical problems is as follows: application of tofacitinib citrate and its pharmaceutical composition in preparing medicine for treating sjogren's syndrome is provided.
In one aspect, the application of the tofacitinib citrate and the pharmaceutical composition thereof in preparing the medicine for treating the sjogren's syndrome is as follows: the pharmaceutical composition is administered via the following route of administration: intravenous, intramuscular, oral, dermal, eye drop, or a combination thereof.
In a further aspect, the pharmaceutical composition is administered orally.
In a further aspect, the pharmaceutical composition is administered via eye drops.
According to a further technical scheme, the oral dosage of the medicinal composition is as follows: contains 1mg to 20mg of tofacitinib per day.
Preferably, the oral dosage of the pharmaceutical composition is: contains 3-10 mg of tofacitinib per day.
Preferably, the oral dosage of the pharmaceutical composition is: contains 3-5 mg of tofacitinib per day.
More preferably, the pharmaceutical composition is administered orally in a dosage of: contains 3mg of tofacitinib per day.
The pharmaceutical composition comprises tofacitinib citrate in an optional pharmaceutically acceptable form and/or an optional pharmaceutically acceptable carrier or excipient. The "optional pharmaceutically acceptable form of tofacitinib citrate" may be a pharmaceutically acceptable salt of tofacitinib, such as tofacitinib citrate.
In another aspect, the application of tofacitinib citrate and the pharmaceutical composition thereof in preparing the medicament for treating sjogren's syndrome is specifically as follows: the pharmaceutical composition contains 1 mg-20 mg (unit dose) of tofacitinib, and/or an optional pharmaceutically acceptable carrier or excipient.
Further, the application of the tofacitinib citrate and the medicinal composition thereof in preparing the medicament for treating the sjogren's syndrome is as follows: the pharmaceutical composition contains 3-10 mg (unit dose) of tofacitinib and/or an optional pharmaceutically acceptable carrier or excipient.
Further, the application of the tofacitinib citrate and the medicinal composition thereof in preparing the medicament for treating the sjogren's syndrome is as follows: the pharmaceutical composition contains 3-5 mg (unit dose) of tofacitinib and/or an optional pharmaceutically acceptable carrier or excipient.
Further, the application of the tofacitinib citrate and the medicinal composition thereof in preparing the medicament for treating the sjogren's syndrome is as follows: the pharmaceutical composition contains 3, 4, 5, 6, 7, 8, 9 or 10mg (unit dose) of tofacitinib, and/or optionally a pharmaceutically acceptable carrier or excipient.
Suitable pharmaceutically acceptable carriers or excipients can adopt carriers or excipients in the prior art, and preferably, the carriers or excipients can be hydroxypropyl cellulose, microcrystalline cellulose and lactose.
The application of the tofacitinib citrate and the medicinal composition thereof in preparing the medicaments for treating the sjogren's syndrome is used for treating at least one medicament selected from the following diseases: including hypolacrimation, dry eye syndrome, hyposalivation, and dry eye and mouth syndrome.
Compared with the prior art, the invention has the following advantages:
(1) the medicinal composition obviously improves the dry mouth and eye symptoms. Particularly, the invention can achieve the treatment effect by taking the oral dosage as low as 3-5 mg/day.
(2) The present invention finds a new and advantageous process for the preparation of pharmaceutical compositions of tofacitinib citrate for the treatment of sjogren's syndrome. The method comprises formulating tofacitinib citrate active agent and carrier/excipient in a specific ratio and formulating into tablets in an effective and economical manner to a desired unit dosage.
(3) The invention finds that the tofacitinib citrate with specific dosage is particularly beneficial to the treatment of sjogren's syndrome. In the application method of the tofacitinib citrate pharmaceutical composition in preparing the medicine for treating the sjogren syndrome, the pharmaceutical composition is prepared to contain 3-5 mg (unit dose) of tofacitinib.
(4) The pharmaceutical composition of the invention is used for preparing a medicament for treating diseases related to exocrine dysfunction.
(5) The pharmaceutical composition of the invention is useful for the treatment of at least one drug selected from the following conditions: including hypolacrimation, dry eye syndrome, hyposalivation, and dry mouth syndrome.
Detailed Description
Example 1: preparation of tablets (5 mg/tablet)
The formula is as follows:
tofacitinib citrate 8g (equivalent to tofacitinib 5g)
25g of hydroxypropyl cellulose, 25g,
30g of microcrystalline cellulose and 30g of cellulose,
30g of lactose is added into the milk powder,
1000 pieces were prepared.
The preparation method comprises the following steps: weighing the raw materials and the auxiliary materials in the formula, adding the raw materials and the auxiliary materials into a three-dimensional mixer, mixing for 15 minutes, then adding 10g of magnesium stearate, and mixing for 5 minutes by using the three-dimensional mixer to obtain the total mixed granules. Tabletting the total mixed granules according to 8mg of tofacitinib citrate (equivalent to 5mg of tofacitinib) contained in each tablet, wherein the weight of the tablet is about 103mg, and the hardness is controlled to be 8-10 kg.
Example 2: administration to SS mouse model (tofacitinib citrate)
1. And (3) dose conversion: 1-20 mg of tofacitinib is administrated daily by referring to an equivalent dose ratio table converted from body surface area between human and animals, and the dosage is converted into 0.15-3 mg/kg of mice; prednisone acetate 20mg for adult per day, converted into mouse dosage of 3.0 mg/kg-1Generally, it is calculated on the basis of the adult body mass of 60 kg.
2. Experimental animals: 40 BALB/C inbred line mice with the age of 8 weeks are selected, the SPF grade is achieved, the male and female are not limited, and the body mass is about 20 g. Strictly following the principle of '3R', the temperature of natural light in an experimental animal feeding room is controlled to be 18-19 ℃, the humidity is controlled to be 40-70%, and animals can eat and drink water freely. The experiment was terminated by cervical draining.
3. Main drugs and reagents:
tofacitinib citrate high dose group: 3mg of
The dosage group in tofacitinib citrate is as follows: 1.5mg
Tofacitinib citrate low dose group: 0.15mg
Prednisone acetate group
Blank group
Freund's complete adjuvant; PBS buffer solution; CD4, CD8 agents
4. Grouping, namely randomly dividing 40 mice into 4 groups, namely a blank control group, a tofacitinib citrate high-dose group, a tofacitinib citrate medium-dose group and a tofacitinib citrate low-dose group, wherein each group comprises 10 mice.
5. Establishing an animal model, namely respectively modeling a model control group, a high-dose group, a medium-dose group and a low-dose group of tofacitinib citrate and mice: taking 10 mice of the same species respectively, taking submaxillary gland under aseptic condition, homogenizing, adding PBS to dilute to 1000 mug. multidot.mL-1Adding Freund's complete adjuvant, adjusting the concentration to 500 mug. multidot.mL-1The mice were injected with a total amount of 1mL each at multiple points in the tail root, and at the same time, the mice were injected with 0.5mL of tetanus vaccine in the back.2 mice in the model control group are sacrificed at 5 weeks after model building, and by observation of pathological morphology, SS typical pathological changes such as characteristic lymphocyte infiltration, gland atrophy and the like are found in submaxillary glands of the model mice, which indicates that the model building is successful.
6. The administration method comprises feeding the blank control group normally without any drug; the model control group is perfused with normal saline; the tofacitinib citrate high-dose group is 3 mg.d of tofacitinib citrate-1Performing intragastric administration; the dosage group in tofacitinib citrate is 1.5 mg.d-1Performing intragastric administration; the tofacitinib citrate low-dose group is 0.15 mg.d of tofacitinib citrate-1Performing intragastric administration; prednisone acetate group is given to prednisone acetate of 0.08 mg. d-1And (5) performing intragastric administration.
7. Observation index
7.1 measurement of Water intake in mice: adding 150mL of water every 3 days, weighing the water after 3 days, and subtracting the residual water from the added water to obtain the water drinking amount of each cage of mice every 3 days.
7.2 salivary flow determination: after 2 weeks of gavage, the sterilized absorbent cotton balls were prepared into 5mg dry weight cotton balls, which were placed in the mouse's back cheek, and after 5min, the cotton balls were taken out and weighed on an electronic balance. Saliva secretion (mg) is the wet weight of cotton balls-dry weight of cotton balls.
7.3 mouse salivary gland T cell subpopulation content: 2mL of anticoagulated blood is taken from mouse orbit, 20 mu of LCD4/CD8FITC/PE labeled antibody is added to the bottom of a flow tube, 100 mu of LEDTA anticoagulated mouse peripheral blood is added to the bottom of 5mL of flow tube and is gently shaken to be fully and uniformly mixed with the antibody, the mixture is incubated for 20-30 min at room temperature in a dark place, 2mL of erythrocyte lysate is added, the mixture is placed for 10min in a dark place after being uniformly mixed, and the erythrocyte is dissolved until the liquid is transparent. Sample tube at 1000 r.min-1Centrifuging for 5min, pouring out supernatant, adding 2ml LPBS washing solution to resuspend cells, 1000r min-1Centrifuging for 5min, and removing supernatant; adding a proper amount of labeled secondary antibody, and incubating for 20min at room temperature in a dark place; add 2mLPBS wash to resuspend cells at 1000r min-1Centrifuging for 5min, and removing supernatant; add 0.5mLPBS wash to resuspend the cells and flow cytometer detect.
8. The statistical method comprises the following steps: statistical analysis was performed using SPSS15.0 software. The measurement data are expressed in x + -s, the t test is adopted, the variance is checked by the sum of ranks, the comparison between the grade data is checked by the sum of ranks, the counting data is checked by the x 2 test, and the difference is statistically significant when P < 0.05.
9. Results
9.1 comparing the water intake of the mice in each group: the water intake of each group of mice is not different at the initial molding stage, the water intake of 12d mice is obviously increased after antigen injection, the water intake of the mice of a model control group gradually rises until the end of an experiment, and the water intake of the mice of each dosage group of tofacitinib citrate and the mice of a prednisone acetate group is reduced to a certain extent and is maintained at a certain level. See table 1.
9.2 comparison of salivary flow changes in groups of mice: after 2 weeks of molding, the salivary flow of the mice in the model control group is obviously reduced compared with that in the blank control group (P < 0.01). The saliva flow of the mice can be increased to different degrees (P <0.01 or P <0.05) in each administration group compared with the model control group; the action of the prednisone acetate group is obvious in the medium and high dose group of tofacitinib citrate, and the action of the low dose group of tofacitinib citrate is weaker. See table 2.
TABLE 1 Water intake for each group of mice vs. mL
Table 2 saliva flow changes of the groups of mice are compared in mg,
note: compared with a blank control group, 1) P is less than 0.01; compared with a model control group, 2) P is less than 0.01, and 3) P is less than 0.05.
Example 3 case
56 patients with sjogren's syndrome were selected. Of these, 50 women, 6 men, and an average (35. + -. 12) year of age. The course of the disease is 6 months to 45 months. The diagnostic criteria were in accordance with the International Classification of Sjogren's syndrome (diagnostic) criteria (ARA, 1993).
3.1 methods of taking medicine
Open tests were used, with no control group. Tofacitinib citrate 5mg is administered orally 1 time a day for 36 weeks.
3.2 Observation index
Blood sedimentation (ESR), blood routine, urine routine, rheumatoid factor, liver function, kidney function, immunoglobulin (IgG, IgM, IgA), salivary gland ECT, Schirmer test, serum protein electrophoresis, and 10cm visual simulation scale were measured before administration, at 12, 24, and 36 weeks after administration, to evaluate the degree of illness of the doctor and the patient, respectively. During the test period, second-line antirheumatic drugs, glucocorticoid, tripterygium glycosides and other drugs are forbidden.
3.3 evaluation of therapeutic Effect
The medicine is divided into 3 grades of significant effect, effective and ineffective, 50 percent of the patients who progress in each item of blood sedimentation, salivary gland ECT, Schirmer test, immunoglobulin and gamma globulin are determined to be effective, and 4 of 5 patients who progress in each item of immunoglobulin and gamma globulin are determined to be significant effect. The 3 of the 5 effective ones are effective in treatment. If less than 3 of 5 items are effective, the therapeutic effect is determined to be ineffective.
3.4 adverse reaction and tolerance evaluation: adverse reactions occurred in each subject during the course of the test were recorded, 0 is no adverse reaction: 1 is mild adverse reaction, and does not affect daily life and work; 2, the medicine is moderate adverse reaction, which affects daily life and work; 3, severe adverse reaction, which should be stopped.
3.5 statistical methods
All data are provided withData analysis calculations were performed using the SPSS10.0 statistical analysis software, and the significance of differences between the two groups was tested using the t-test for two independent samples. Significance was found to be P < 0.05.
3.6 results
3.6.1 Observation of efficacy of tofacitinib citrate in treating sjogren's syndrome
TABLE 1 Tofacitinib citrate curative Observation of Sjogren's syndrome (%)
| Number of weeks | High efficiency | Display efficiency | Total effective rate |
| For 12 weeks | 25.0(14/56) | 5.3(3/56) | 30.4(17/56) |
| 24 weeks | 62.5(35/56) | 16.1(9/56) | 78.6(44/56) |
| For 36 weeks | 64.2(36/56) | 26.8(15/56) | 91.0(51/56) |
3.6.2 Effect of tofacitinib on immune indices of Sjogren syndrome patients
Note: + significant difference compared with the pretreatment, P is less than 0.05
3.6.3 Effect of tofacitinib citrate on the salivary gland ECT, Schirmer test in Sjogren's syndrome patients
Results are based on isotope report results, and Schirmer test is abnormal in the range of less than 10 mm. As a result, the difference of the salivary gland ECT between 5.3 percent (3/56) at 12 weeks of treatment, 14.3 percent (8/56) at 24 weeks and 17.9 percent (10/56) at 36 weeks of treatment compared with that before treatment (0/56) is not significant, and P & gt 0.05; the Schirmer test showed no significant difference between 1.8% (1/56) at 12 weeks, 5.3% (3/56) at 24 weeks, 8.9% (5/56) at 36 weeks compared to pre-treatment (0/56), P > 0.05; however, as the administration time is prolonged, the number of patients having improved salivary secretion and lacrimal secretion tends to increase.
3.6.4 evaluation of adverse reactions and tolerance
In the experimental process, adverse reactions occur within 12 weeks of treatment, the degree is mild, the incidence rate of the adverse reactions is 12.5% (7/56), the adverse reactions mainly include abdominal discomfort, abdominal pain and increased stool frequency, and the adverse reactions are not treated and continue to take the medicine for a while. In the experiment, the tofacitinib citrate is not found to have obvious influence on leucocyte, platelet, hemoglobin, liver function and kidney function.
Therefore, the clinical curative effect of the tofacitinib citrate on 56 patients with sjogren's syndrome is observed through open clinical experimental research, and the clinical symptoms, physical signs and immune indexes of the patients, particularly the blood sedimentation and gamma globulin values, are obviously improved after the tofacitinib citrate is taken for 12 weeks, which is possibly related to the anti-inflammatory effect of the tofacitinib citrate.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and all simple modifications and equivalent variations of the above embodiments according to the technical spirit of the present invention are included in the scope of the present invention.
Claims (10)
1. Application of tofacitinib citrate and its pharmaceutical composition in preparing medicine for treating sjogren's syndrome is provided.
2. The use of tofacitinib citrate and pharmaceutical composition thereof according to claim 1 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein said pharmaceutical composition is administered via the following route of administration: intravenous, intramuscular, oral, dermal, eye drop, or a combination thereof.
3. The use of tofacitinib citrate and its pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein the oral dosage of the pharmaceutical composition is: contains 1mg to 20mg of tofacitinib per day.
4. The use of tofacitinib citrate and its pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein the oral dosage of the pharmaceutical composition is: contains 3-10 mg of tofacitinib per day.
5. The use of tofacitinib citrate and its pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein the oral dosage of the pharmaceutical composition is: contains 3-5 mg of tofacitinib per day.
6. The use of tofacitinib citrate and its pharmaceutical composition according to claim 2 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein the oral dosage of the pharmaceutical composition is: contains 3mg of tofacitinib per day.
7. Use of tofacitinib citrate and pharmaceutical compositions thereof as claimed in any of claims 1 to 6 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein the pharmaceutical composition comprises tofacitinib, optionally in a pharmaceutically acceptable form, and/or optionally a pharmaceutically acceptable carrier or excipient.
8. The use of tofacitinib citrate and its pharmaceutical composition according to any of claims 1 to 6 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein the pharmaceutical composition comprises 1mg to 20mg of tofacitinib, and/or optionally a pharmaceutically acceptable carrier or excipient.
9. Use of tofacitinib citrate and pharmaceutical compositions thereof according to any one of claims 1 to 6 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein said pharmaceutical compositions are used for the preparation of a medicament for the treatment of disorders associated with exocrine dysfunction.
10. Use of tofacitinib citrate and pharmaceutical composition thereof according to any of claims 1 to 6 for the preparation of a medicament for the treatment of sjogren's syndrome, wherein said pharmaceutical composition is used for the treatment of at least one of the following disorders: including hypolacrimation, dry eye syndrome, hyposalivation, and dry eye and mouth syndrome.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106370757A (en) * | 2016-11-16 | 2017-02-01 | 杭州朱养心药业有限公司 | Tofacitinib citrate tablet pharmaceutical composition and quality control method |
| CN114129515A (en) * | 2021-11-29 | 2022-03-04 | 郑州大学第一附属医院 | Tofacitinib nanocrystal eye drop and preparation method thereof |
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| CN104530055A (en) * | 2014-12-23 | 2015-04-22 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of tofacitinib citrate |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104530055A (en) * | 2014-12-23 | 2015-04-22 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of tofacitinib citrate |
Non-Patent Citations (2)
| Title |
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| JING-FENG HUANG ET AL: "Immunomodulatory Effect of the Topical Ophthalmic Janus Kinase Inhibitor Tofacitinib (CP-690,550) in Patients with Dry Eye Disease", 《OPHTHALMONOGY》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106370757A (en) * | 2016-11-16 | 2017-02-01 | 杭州朱养心药业有限公司 | Tofacitinib citrate tablet pharmaceutical composition and quality control method |
| CN114129515A (en) * | 2021-11-29 | 2022-03-04 | 郑州大学第一附属医院 | Tofacitinib nanocrystal eye drop and preparation method thereof |
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Application publication date: 20160217 |