CN102793693A - Applications of vorinostat in aspect of drugs for treating autoimmune diseases and inflammatory diseases - Google Patents
Applications of vorinostat in aspect of drugs for treating autoimmune diseases and inflammatory diseases Download PDFInfo
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Abstract
The invention discloses applications of vorinostat in aspect of drugs for treating autoimmune diseases. The experiment result disclosed by the invention shows that due to the vorinostat, the morbidity of the experimental autoimmune encephalomyelitis of mice is reudced, and also the average score, the highest score and the total score of clinical marks are reduced; spinal cord inflammatory cell infiltration and spinal cord demyelination can be alleviated; the weight percent of a cell Th1 related to IFN (Interferon)-gamma secretion and a cell Th17 cell related to IL-17A secretion accounting for positive T cells CD4 in the spleen can be reduced. Therefore the invention relates to the preparation of the drug for inhibiting the experimental autoimmune encephalomyelitis of an animal model, and the drug is expected to treat the diseases related to multiple sclerosis, ophthalmoneuromyelitis, acute disseminated encephalomyelitis and the like.
Description
Technical field
The invention belongs to the pharmaceutical chemistry applied technical field, relate to the application of medicine Vorinostat (Vorinostat) aspect preparation conduct treatment multiple sclerosis and animal model experiment systemic autoimmune encephalomyelitis medicine thereof.
Background technology
Multiple sclerosis (Multiple Sclerosis; MS) be to become characteristics with central nervous system's white matter demyelinating disease; Good sending out in person between twenty and fifty, age of onset is many at 20～40 years old, can cause various symptoms; Comprise sensation change, visual disorder, muscle weakness, melancholy, coordination and difficulty speaking, serious fatigue, cognitive disorder, disequilibrium, body heat and pain etc., serious can cause activeness obstacle and deformity.The cause of disease of multiple sclerosis is unclear, is considered to autoimmune disease more.Still there is not effective healing way certainly so far.
EAE (Experimental Autoimmune Encephalomyelitis, EAE) cause encephalitis antigen by isotype, allotype, xenogenesis abnormal shape such as myelin albumen (PLP), MBP (MBP), myelin oligodendrocyte glycoprotein (MOG) and myelin associated glucoprotein (MAG) are inductive, the responsive animal of experiment produces, by the cell immune response mediation, be the reactive autoimmune disease of tardy paraphilia of characteristic with central nervous system's white matter demyelination.Different according to the genetic background of the method for the composition of sensitinogen, sensitization and animal can be induced the EAE of acute, acute, the chronic clinical and pathological characteristic of excess of export.Wherein the course of disease of chronic recurrent EAE is the delay recidivist, and its pathological characters is similar with MS, and all show as inflammatory cell infiltration and central nervous system's white matter demyelination and change, with the MS fairly similar, be the ideal model of MS.Can induce the animal model of chronic recurrent EAE as multiple sclerosis.Though its pathology takes place also to be understood fully, generally believe that the LADA encephalomyelitis is the inflammation of the central nervous system disease that is caused by the autoimmune inflammation that auxiliary type T cell (TH1 and TH17) mediates.Increasing research shows, TH17 cell effect unusual relevant with multiple sclerosis and experimental autoimmune encephalomyelitis, and in autoimmune disease and infectious disease, bring into play important regulatory role.Therefore, Vorinostat is regulated in the EAE generating process the protective effect and the action target spot thereof of body, will help provides new approaches for the treatment of human multiple sclerosis.
Vorinostat Chinese another name N-hydroxy-n '-the phenyl suberamide, be a kind of Antibiotic FR 901228 (HDACIs).The acetylation of histone level of nucleosome can influence the gene order of some transcription factor near its position, place, influences transcribing of specific gene.The acetylation level of histone is regulated by the acetylation of histone enzyme (HATs) and the histon deacetylase (HDAC) (HDACs) of mutual antagonism.Antibiotic FR 901228 (HDACIs) then changes chromatin Structure through suppressing HADs, carries out gene expression regulation at transcriptional level.(suberoylanilide hydroxamic acid SAHA) has been approved for the clinical treatment cutaneous T cell lymphoma to Antibiotic FR 901228, has multiple HDACIs to be in clinical experimental stage.Except clear and definite anti-tumor activity, HDACIs also demonstrates immunoregulatory activity.Experiment in vitro of the present invention shows that HDACIs can suppress the lymphocytic activation of T, propagation and secrete cytokines; The research that utilizes the autoimmune disease animal model to carry out has also confirmed its immunosuppressive activity.But Vorinostat does not still have report to the regulating action of the EAE of the helper T lymphocyte TH1 of inflammatory reaction and the mediation of TH17 subgroup and to the therapeutical effect of multiple sclerosis.
Summary of the invention
The objective of the invention is to disclose the application of Vorinostat aspect preparation treatment LADA and nervous system inflammation property disease medicament.Wherein self property exempted from disease refers to: multiple sclerosis (Fig. 1-11); LADA retinitis (Fig. 8-11); Optic neuromyelitis (Fig. 8-11); Struma lymphomatosa (Fig. 8-11); Autoimmune hemolytic anemia (Fig. 8-11); AT (Fig. 8-11); Myasthenia gravis (Fig. 8-11); Primary biliary cirrhosis (Fig. 8-11); Aggressive chronic hepatitis (Fig. 8-11); Chronic glomerulus scorching (Fig. 8-11); Myositis (Fig. 8-11); Can (which figure or experiment representative be treated these diseases to systemic sclerosis (Fig. 8-11)?).Nervous system inflammation property disease refers to multiple sclerosis (Fig. 1-11), optic neuromyelitis (Fig. 8-11) and acute disseminated encephalomyelitis (Fig. 6-11).
The typical therapeutic effect of the present invention is: the application of Vorinostat aspect preparation treatment autoimmune encephalomyelitis medicine; Wherein Vorinostat is preferably 100 mg/Kg body weight/day in the effective dose of the animal model experiment systemic autoimmune encephalomyelitis of treatment multiple sclerosis.The conversion adult is 5-6g/ days according to the using dosage of 50-60Kg body weight.
The present invention uses the animal model experiment systemic autoimmune encephalomyelitis of treatment multiple sclerosis to carry out a large amount of pharmacological evaluation, and experimental result shows: Vorinostat can reduce sickness rate, clinical score average mark, clinical score best result and the clinical score total points of mouse experiment systemic autoimmune encephalomyelitis; Can alleviate spinal cord inflammatory cell infiltration and spinal cord demyelination; And can alleviate the relevant Th1 cell of the secretion of IFN-γ in the spleen and secrete the percent that relevant Th17 cell accounts for the CD4 positive T cell with IL-17A.Experimental autoimmune encephalomyelitis is the closely-related experimental animal model of multiple sclerosis, optic neuromyelitis and acute disseminated encephalomyelitis; Therefore, the present invention is expected to become clinically the medicine of diseases such as treatment multiple sclerosis, optic neuromyelitis and acute disseminated encephalomyelitis.
The application of Vorinostat disclosed by the invention (Vorinostat) aspect preparation conduct treatment multiple sclerosis and animal model experiment systemic autoimmune encephalomyelitis medicine thereof; Normally take with the form of pharmaceutical composition; Orally-ingestible or non-oral administration are perhaps with the oral or non-oral administration of chemical compound (like tablet, slow releasing preparation, capsule, injection, the solution) safety that forms with pharmaceutically acceptable carrier, excipient and other additive.When oral administration, compositions can be mixed with tablet, sugar-coat agent or capsule.For the preparation combination of oral medication can adopt lactose or starch to do carrier, gelatin, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone etc. are suitable bonding agent or become an agent.Can select starch or microcrystalline Cellulose for use as disintegrating agent, often with Pulvis Talci, santocedl, tristerin, calcium stearate or magnesium etc. are as suitable antiadhesives and lubricant.For example, can prepare tablet through the compacting wet granular.Active component and carrier and optionally with a disintegrate additive composition mixture; The aqueous solution of this mixture and binding agent; Alcohol property or aqueous alcohol property solution carry out granulating in suitable device; Dried particles adds other disintegrating agent subsequently, and lubricant and antiplastering aid are with this mixture tabletting.Series compound of the present invention can the injection form administration, though dosage changes according to treatment target, administering mode, symptom and other factor.The dosage of the actual Vorinostat of taking (Vorinostat) chemical compound should be decided according to relevant situation by the doctor; These situation comprise by the condition of therapist; The person's of choosing route of administration, age, body weight, patient are to the individual reaction of medicine, order of severity of patient's symptom or the like.
Description of drawings:
Fig. 1 is Vorinostat (vorinostat) chemical structural formula figure;
Fig. 2 is oral Vorinostat (vorinostat, 100mg/kg) the sickness rate figure of reduction mouse experiment systemic autoimmune encephalomyelitis; Explain that Vorinostat can reduce the sickness rate of multiple sclerosis, optic neuromyelitis and acute disseminated encephalomyelitis;
Fig. 3 is oral Vorinostat (vorinostat, 100mg/kg) the average component of clinical score of reduction mouse experiment systemic autoimmune encephalomyelitis; Explain that Vorinostat can treat multiple sclerosis, optic neuromyelitis and acute disseminated encephalomyelitis;
Fig. 4 is oral Vorinostat (vorinostat, 100mg/kg) the clinical score best result figure of reduction mouse experiment systemic autoimmune encephalomyelitis; Explain that Vorinostat can alleviate the occurring degree of multiple sclerosis, optic neuromyelitis and acute disseminated encephalomyelitis;
Fig. 5 is oral Vorinostat (vorinostat, 100mg/kg) the total component of clinical score of reduction mouse experiment systemic autoimmune encephalomyelitis; Explain that Vorinostat can treat multiple sclerosis, optic neuromyelitis and acute disseminated encephalomyelitis;
Fig. 6 is that (vorinostat 100mg/kg) alleviates the spinal cord inflammatory cell infiltration figure (H&E dyeing) of mouse experiment systemic autoimmune encephalomyelitis to oral Vorinostat; Explain that Vorinostat suppresses the infiltration of central nervous system's inflammatory cell, can treat central nervous system's autoimmune diseases associated with inflammation multiple sclerosis, refreshing neuromyelities and acute disseminated encephalomyelitis;
Fig. 7 is that (vorinostat 100mg/kg) alleviates the spinal cord demyelination (Luxol fast blue dyeing) of mouse experiment systemic autoimmune encephalomyelitis to oral Vorinostat; Explain that Vorinostat can treat disease multiple sclerosis, optic neuromyelitis and the acute disseminated encephalomyelitis of the characteristics that become with central nervous system's white matter demyelinating disease;
Fig. 8 is that (vorinostat 100mg/kg) reduces the percent (flow cytometer data typical case representative graph) that the relevant Th1 cell of IFN-γ secretion in the spleen of mouse experiment systemic autoimmune encephalomyelitis accounts for the CD4+T cell to oral Vorinostat; Explain that it is the disease of characteristics that Vorinostat can be treated with helper T lymphocyte TH1 and the mediation of TH17 subgroup;
Fig. 9 is that (vorinostat 100mg/kg) reduces the percent (flow cytometer data block diagram) that the relevant Th1 cell of IFN-γ secretion in the spleen of mouse experiment systemic autoimmune encephalomyelitis accounts for the CD4+T cell to oral Vorinostat; Explain that it is the disease of characteristics that Vorinostat can be treated with helper T lymphocyte TH1 and the mediation of TH17 subgroup;
Figure 10 is that (vorinostat 100mg/kg) reduces the percent (flow cytometer data typical case representative graph) that the relevant Th17 cell of IL-17A secretion in the spleen of mouse experiment systemic autoimmune encephalomyelitis accounts for the CD4+T cell to oral Vorinostat; Explain that it is the disease of characteristics that Vorinostat can be treated with helper T lymphocyte TH1 and the mediation of TH17 subgroup;
Figure 11 is that (vorinostat 100mg/kg) reduces the percent (block diagrams of flow cytometer data) that the relevant Th17 cell of IL-17A secretion in the spleen of mouse experiment systemic autoimmune encephalomyelitis accounts for the CD4+T cell to oral Vorinostat; Explain that it is the disease of characteristics that Vorinostat can be treated with helper T lymphocyte TH1 and the mediation of TH17 subgroup;
(n=8, figure is expressed as mean+SD, * p 0.05, * * p 0.01, * * * p 0.001, the t check).
The specific embodiment:
Below in conjunction with embodiment the present invention is described, the scheme of embodiment described here does not limit the present invention; One of skill in the art can make improvements and change according to spirit of the present invention; Described these improvement and variation all should be regarded as within the scope of the invention, and scope of the present invention and essence are limited claim, and wherein Vorinostat (vorinostat) has commercially available; The reagent that other is used all has commercially available except that special mark.
Embodiment 1
1.1 the structure principle of experimental autoimmune encephalomyelitis (EAE) mouse model
Myelin oligodendrocyte glycoprotein (MOG is selected in this experiment for use
35-55) MEVGWYRSPFSRVVHLYRNGK is as antigen immune C57BL/6 mice, sets up MOG
35-55-EAE (experimental autoimmune encephalomyelitis) mouse model.Mostly laboratory sensitinogen commonly used is brain or myeloid tissue's homogenate, MBP composition or its polypeptide fragment etc.; Mostly the immunity object is that rodent makes up the EAE model; Different sensitinogens can produce the different EAE model of disease symptom; Can be according to the different sensitinogen of type selecting of its EAE model that will set up, and the immune object of different quilts.Though content is seldom in myelin protein for the myelin oligodendrocyte glycoprotein of using in this experiment; Only account for the 0.01%-0.05% of myelin protein composition; But because MOG is present in the outermost layer of myelin film and oligodendrocyte; Have hyperimmunization originality, and in making up the EAE process, find that MOG can cause that the demyelination antibody response can cause central nervous system's myelin protein composition of t cell responses again.Therefore, go immune mouse can set up pathogeny and clinical symptoms with myelin oligodendrocyte glycoprotein with the extremely similar EAE model of multiple sclerosis (MS).Now, many evidence proof MOG and anti-MOG antibody play a part very important in the pathogenic process of MS, and the domestic and international in recent years correlation technique of this laboratory reference is set up the inductive stable chronic EAE ideal model of MOG.When utilizing the MOG immune mouse, should prepare the antigen adjuvant emulsion, domestic emulsifying agent is generally all selected freund adjuvant; Antigen adjuvant is a nonspecific immunity strengthening agent, adds adjuvant and can change antigenic physical behavior, and prolong the time that antigen stops in vivo; But also stimulator antigen presenting cells and lymphocyte, thereby the effect that enhance immunity is replied, it can also cause that the delayed blood-brain barrier permeability increases and autoimmune response; CFA (freund adjuvant) is the strongest adjuvant of current effect; It improves the concentration of tubercule bacillus by Bacillus tuberculosis's preparation, can improve incidence rate and the relapse rate of EAE; But also cause injection site necrosis easily, now domestic also have utilize bacillus calmette-guerin vaccine to replace the Bacillus tuberculosis to prepare freund adjuvant.This experiment adopts the Bacillus tuberculosis to prepare freund adjuvant.The injectable daytime is coughed toxin to immune animal two days later; Inject purpose that the daytime coughs toxin and be becoming for the permeability that increases blood vessel wall and blood vessel surface adhesion molecule; The T cell that helps sensitization sees through blood brain barrier, attacks neural myelin, causes the immunologic injury of marrowbrain tissue.After immune animal; Add again cough toxin with the daytime after; Shorten the incubation period of mice, and clinical manifestation is more serious, and the most serious time-frequency is died on one's deathbed or be dead; Add and do not add incubation period and the clinical symptoms of EAE that the daytime coughs the mice of toxin and differ greatly, added the acute EAE model of inducing that pertussis toxin, PT can success.
1.2 the construction method of EAE mouse model
1.21 laboratory animal and source
30 of female wild type C57BL/6 pathogen-free domestic (SPF level) mices, age in 6-8 week, body weight 18-20g; Available from Beijing Vital River Experimental Animals Technology Co., Ltd.; Raise the Experimental Animal Center in Medical University Of Tianjin, the feeding environment of mice is room temperature 20-25 ℃, and relative humidity is 40%-60%.
1.22 the preparation of antigen adjuvant emulsion
Mycobacterium (the Mycobacterium tuberculosis of 100 μ gMOG35-55 polypeptide and 500 μ g deactivations; Tubercule bacillus; Available from Difco company) mix emulsifying fully with 100 μ l normal saline and 100 μ l Freund ' s adjuvants (available from SIGMA company).
1.23 experiment is divided into groups
Be the drug effect of research Vorinostat in the EAE in mice animal model, mice is divided four groups at random, and every group of 8 mices are respectively two normal saline matched groups and two 100 mg/kg/ days Vorinostat administration groups.A matched group and a Vorinostat administration group inspection record every day EAE in mice incidence and clinical function of nervous system are classified to behind the immune induction 30 days; Spinal cord and spleen are got in another matched group and Vorinostat administration group execution in the 15th day after the EAE in mice onset peak period is immune induction.
1.23 experimental technique and step
1.231 2 some injections of the subcutaneous branch of mice back emulsifying agent (100 μ l/ point).
1.232 the while is at the pertussis toxin, PT of tail vein injection 200ng on the same day.
1.233 immunity is every mice tail vein injection 200ng pertussis toxin, PT (pertussis toxin is available from List Biological Laboratories) once more after 48 hours.
1.234 it is 100 mg/kg/ days that every day is used Vorinostat gastric infusion, dosage in the beginning in the 7th day behind the immune induction of Vorinostat administration group.
1.235 mice begins to take place EAE after 7-14 days.Every day inspection record EAE in mice incidence and the classification of clinical function of nervous system.
1.24 EAE mouse model clinical score standard
Mice after the MOG immunity, the next day adopt blind method by two observers, adopt 5 fens international marking systems that mice is carried out clinical score, the clinical function of nervous system classification of every day inspection and record disease was until back 30 days of MOG immunity.The EAE in mice animal model function of nervous system concrete standard of marking is following: 0 minute, Non Apparent Abnormality did not have tangible clinical symptoms; 0.5 divide, the part tail is unable lax; 1 minute, the tail paralysis was visible slight clumsy fully; 2 minutes, back myasthenia of limbs was slow in action, mild ataxia; 2.5 divide acroparalysis after one; 3 minutes, acroparalysis behind the bilateral can not be recovered after passive the standing up, but can move after stimulating; 3.5 divide acroparalysis behind the bilateral, preceding myasthenia of limbs; 4 minutes, acroparalysis before the acroparalysis companion behind the bilateral; 5 minutes, moribund condition or death.
1.3 EAE mouse model onset peak period is handled
Make paraffin section 1.31 get myeloid tissue
1.311 spinal cord is fixed
Behind immune induction, got myeloid tissue in the 15 day, tissue is placed embedded box, 4% neutral paraformaldehyde is fixed, and 30 min are above or spend the night.
1.312 tissue dewatering
In the flowing water flushing myeloid tissue formaldehyde 30min → 75% ethanol 30min → 85% ethanol 30min → 95% ethanol I 1h → 95% ethanol II 2h → 95% ethanol III is spent the night or 2h → anhydrous alcohol I 30min → anhydrous alcohol II 30min → anhydrous alcohol III 30min
1.313 transparency of organization (low temperature): xylene I 15 min → xylene II 10 min → xylene III 10 min
1.314 organize waxdip (60 ℃): stone (melting) wax I 90 min → stone (melting) wax II 60 min → open embedded box; Take out tissue; Put into the mould (comprising molten wax) of preheating, embedded box is put top → continuation and is added stone (melting) wax, until the embedded box lower submerged in stone (melting) wax.
1.315 cooling: take out mould, place 4 ℃ of refrigerator overnight, fully after the cooling, room temperature storage is subsequent use
1.316 paraffin section
Spinal cord slice thickness is 10um, and wax disk(-sc) is put into 45 ℃ of warm water, and it is launched naturally.Hold the anticreep slide and fish for wax disk(-sc), then 60 ℃ of baking sheet >=4h.
1.32 myeloid tissue's paraffin section dyeing
1.321 paraffin section de-waxing: paraffin section → xylene I 10 min → xylene II 10 min → xylene III 10 min
1.322 paraffin section aquation: 100% ethanol 2min → 95% ethanol 2min → 85% ethanol 2min → 75% ethanol 2min → distilled water flushing 1min
1.323 paraffin section HE dyeing: hematoxylin 10 min → tap water rinsing 1～3s → hydrochloride alcohol breaks up rapidly; (1 concentrated hydrochloric acid adds among the 70% ethanol 100ml) 1～3s → 0.1% ammonia/PBS; (7.4～8.0) are returned blue 30s～1min → tap water flushing 2-5min → distilled water rinsing 1～3s → 0.5% Yihong dyeing 1min → distilled water rinsing 1～3s → 75% ethanol, 10～30s → 85% ethanol, 10～30s → 95% ethanol 30s～1min → anhydrous alcohol 2～3min → transparent envelope and are hidden: xylene I 3-5min → xylene II 3-5 min →; (xylene is moistening) dripped natural gum → add coverslip.
1.324 paraffin section Luxol fast blue dyeing: paraffin section de-waxing → dehydration to 95% ethanol → place Luxol to consolidate blue solution; Under 60 ℃ of temperature; Incubated overnight (16-24 h) → taking-up section is embathed in 95% alcoholic solution, the too much dye liquor of flush away → taking-up section; In deionized water, embathe → cut into slices and in 0.05% lithium carbonate solution, embathe 3-10s → taking-up section immediately fast; Place 70% alcoholic solution to break up, can clearly distinguish → take out section, in deionized water, wash → cut into slices and in 0.05% lithium carbonate solution, embathe gently for several times up to grey matter and white matter; Place 70% alcoholic solution to embathe for several times then; Become aeruginous up to the white matter color transition, during several no color of grey matter, stop in the differentiation → section deionized water flushing complete 95% ethanol 30s～1min → anhydrous alcohol 2～3min → transparent envelope and hide: xylene I 3-5min → xylene II 3-5 min → (xylene is moistening) dripped natural gum → add coverslip.
Do cell inner dyeing 1.33 get spleen
1.331 cell is prepared
1.3311 anesthetized mice, aseptic separating spleen.
1.3312 it is broken fully to grind spleen gently with the syringe plug, adds the aseptic ultra-pure water of 1.8ml, adds the aseptic rapid mixing of 10xPBS of 200 μ l behind the mixing rapidly.
1.3313 cell suspension is with 40 μ m screen filtrations.
1.3314 and add twice of 2-3ml serum-free RPMI1640 culture medium flushing screen cloth.
1.3315 the 1500rpm/minx5min centrifugal collecting cell is abandoned supernatant, re-suspended cell.
1.3316 with 6mlRPMI1640 complete medium re-suspended cell.
1.3317 the adjustment cell density is 5x10
6/ ml
1.332 stimulating cytokine secretion
1.3321 it is Brefeldin A (BFA) 1 μ l/ml that every hole adds concentration, 100ng/ml phorbol ester (PMA) and final concentration 1 μ g/ml calcium ion mycin (Ionomycin), 37 ℃, 5% CO
2Stimulated 5 hours.
1.333 collecting cell carries out cytokine dyeing
1.3331 the 1500rpm/min centrifugal collecting cell is abandoned supernatant.
1.3332 fully add fluorescent labeling surface antibody CD4 behind the re-suspended cell, 4 ℃ of lucifuges were reacted 30 minutes.
1.3333 every pipe adds staining buffer (SB) 1ml, 1500rpm/min washes twice, abandons supernatant.
1.3334 every pipe adds BD cytofix/prem reagent 250 μ l, 4 ℃ of lucifuges were reacted 30 minutes
1.3335 every pipe adds BD cytoprem/wash reagent, 1800rpm/min washes once, abandons supernatant.
1.3336 every pipe adds confining liquid 25 μ l (comprising 20 μ l 10%BSA and 5 μ l rat blood serums), 4 ℃ of lucifuges were reacted 30 minutes.
1.3337 add fluorescently-labeled cytokine antibodies IFN-γ and IL-17A (and homotype contrast), 4 ℃ of lucifuges were reacted 30 minutes.
1.3338 every pipe adds BD cytoprem/wash reagent, 1800rpm/min washes once, abandons supernatant.
1.3339 every pipe adds SB 1ml, 1800rpm/min washes once, abandons supernatant, and cell is resuspended with 2%PFA 200 μ l.
1.334 the up flow type cell instrument detects
1.4 experimental result:
Experimental autoimmune encephalomyelitis is the typical animal model of people's multiple sclerosis; The Vorinostat of per kilogram of body weight filling every day stomach 100mg of the present invention can significantly reduce the sickness rate (Fig. 2) of mouse experiment systemic autoimmune encephalomyelitis, suppresses clinical score average mark (Fig. 3), clinical score best result (Fig. 4) and the clinical score total points (Fig. 5) of mouse experiment systemic autoimmune encephalomyelitis morbidity; Alleviate spinal cord inflammatory cell infiltration (Fig. 6) and spinal cord demyelination (Fig. 7); And can alleviate the relevant Th1 cell (Fig. 8, Fig. 9) of the secretion of IFN-γ in the mouse spleen and secrete the percent (Figure 10, Figure 11) that relevant Th17 cell accounts for the CD4+T cell with IL-17A.
Vorinostat has the obvious treatment effect to mouse experiment systemic autoimmune encephalomyelitis.Comprehensive The above results explains that Vorinostat can suppress the infiltration of inflammatory cell among the central nervous system, can treat autoimmune inflammation property disease multiple sclerosis.
Vorinostat raw material 50g and 280g starch mix homogeneously with starch slurry (get starch 220g water and process starch slurry) system granule, sieve, and drying is encapsulated.
Embodiment 3
Vorinostat raw material 80g and starch 340g mix homogeneously with starch slurry (get starch 210g water and process starch slurry) system granule, sieve, and drying adds 6 ‰ magnesium stearate, mixing, and compacting is wrapped film-coat and is promptly got in flakes.
Embodiment 4
Vorinostat raw material 100g, starch 400g and cellulose sieve in right amount; And fully mix, an amount of polyvinylpyrrolidonesolution solution is mixed with above-mentioned powder, sieve; Make wet granular in 60 ℃ of dryings; With the carboxymethyl starch sodium salt, 6 ‰ magnesium stearate and Pulvis Talci sieve in advance, join tabletting in the above-mentioned granule then.
Claims (5)
1. the application of Vorinostat aspect preparation treatment LADA and nervous system inflammation property disease medicament.
2. the described application of claim 1, wherein autoimmune disease refers to: multiple sclerosis, LADA retinitis, optic neuromyelitis, struma lymphomatosa, autoimmune hemolytic anemia, AT, myasthenia gravis, primary biliary cirrhosis, aggressive chronic hepatitis, chronic glomerulus inflammation, myositis, systemic sclerosis.
3. the described application of claim 1, wherein nervous system inflammation property disease refers to multiple sclerosis, optic neuromyelitis and acute disseminated encephalomyelitis.
4. the described application of claim 3, wherein said multiple sclerosis refers to: central nervous system's white matter demyelinating disease becomes the disease of characteristics.
5. the application of Vorinostat aspect preparation treatment autoimmune encephalomyelitis medicine; Its consumption is 5-6g.
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| CN105055386A (en) * | 2015-08-12 | 2015-11-18 | 天津医科大学总医院 | Application of vorinostat for preparation of immunomodulatory drugs |
| CN107362148A (en) * | 2017-07-27 | 2017-11-21 | 东曜药业有限公司 | A kind of pharmaceutical composition for treating tumour and its preparation method and application |
| CN107362148B (en) * | 2017-07-27 | 2020-04-21 | 东曜药业有限公司 | Pharmaceutical composition for treating tumors and preparation method and application thereof |
| US10953011B2 (en) | 2019-05-31 | 2021-03-23 | Viracta Therapeutics Inc. | Methods of treating virally associated cancers with histone deacetylase inhibitors |
| CN110327332A (en) * | 2019-07-06 | 2019-10-15 | 河北医科大学第二医院 | Amlexanox is alleviating application and its experimental method in EAE morbidity |
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