CN105770874A - Use of ulinastatin in preparation of drugs for treating multiple sclerosis - Google Patents
Use of ulinastatin in preparation of drugs for treating multiple sclerosis Download PDFInfo
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- CN105770874A CN105770874A CN201610153866.5A CN201610153866A CN105770874A CN 105770874 A CN105770874 A CN 105770874A CN 201610153866 A CN201610153866 A CN 201610153866A CN 105770874 A CN105770874 A CN 105770874A
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- rat
- eae
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
The invention belongs to the technical field of medicine and particularly discloses use of ulinastatin in the preparation of drugs for treating multiple sclerosis. It is proved herein that by treating a multiple sclerosis rat (EAE model) with ulinastatin, weight reduction can be significantly reduced for the EAE rat, death rate of the EAE rat can be significantly reduced, onset latency can be significantly delayed, and neural protection can be achieved; in addition, ulinastatin can also increase TGF-beta and IL-10 expression, restore the balance of Th1/Th2 cell factors and relieve EAE process by reducing IL-2, IFN-gamma and TNF-alpha expression and can accelerate EAE recovery b adjusting apoptosis-promoting Bax and Fas proteins and inhibiting Bcl protein expression. The ulinastatin of the invention has low toxic and side effect, is high in safety, can protect heart, liver, kidney and lung, is low in cost and has a promising development prospect as a drug for treating multiple sclerosis.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically disclose UTI purposes in preparation treatment multiple sclerosis medicine.
Background technology
UTI is the protease inhibitors of a kind of wide spectrum, belongs to mankind's endogenous suppression anti-inflammatory agent.It is mainly in liver
Synthesis, is discharged with urine by renal metabolism, and its low molecular weight compositions being decomposed to form also has the work of the strongest suppression hydrolase
With.There is stronger anti-inflammatory, immunological regulation, improve microcirculation, Hemorrhagic shock, anti-tissue ischemia and neuroprotection.Additionally,
Research shows, UTI is respectively provided with protective effect to important organs such as the heart of human body, liver, kidney, lungs.
Chinese patent application 201010299506.9 discloses UTI for preparing treatment Autoimmune Encephalomyelitis medicine
Purposes and pharmaceutical composition, this patent show use UTI treatment Autoimmune Encephalomyelitis disease curative effect with swash
Element is suitable, and steady quality is reliable, and bad reaction is little.
Multiple sclerosis (multiple sclerosis, MS) is the LADA of a kind of long-term central nervous system, struvite
Disease.Although the multiple sclerosis cause of disease is the brightest, but numerous research is thought, multiple sclerosis is to take off marrow with central nervous system white matter
The autoimmune disease of sheath lesion characteristic, is the individual self-immunprocess occurred with environmental factor effect of inheritance susceptible,
Morbidity may be infected with virus, immunomodulatory disorders, inherent cause, environmental factor are relevant, ultimately results in central nervous system marrow
Sheath depigmentation, oligodendroglia damages, and part can have aixs cylinder and damaged nerve cell.Fall ill more than 20～40 years old, be to cause
One of principal disease of between twenty and fifty non-traumatic disability.Its incidence of disease is higher, can cause various symptom, including limb adynamia, limb
Body numbness, vision disorder, incoordination, spirit disturbance in cognition, dizziness vomiting, headache, disturbance of sphincter, epilepsy etc., sternly
Can causing or activity obstacle and deformity of weight.
The medicine having the treatment multiple sclerosis that evidence-based medicine EBM argument supports at present is fairly limited and expensive.MS at present
Drug therapy is mainly for anti-inflammatory and immunological regulation, and the treatment of acute stage standard classical is heavy dose of pulse treatment with methylprednisolone, and it is usually
With serious side effect such as infection, sexual gland suppression and tumour etc., and suppress endogenous brain to protect path, increase neuron
Lose.Additionally, the overwhelming majority still uses Adrenal Glucocorticoid, immunodepressant etc. to treat, effect is limited and secondary work
With greatly, especially there is obvious hepatotoxicity wind agitation, renal toxicity and teratogenesis, it is therefore desirable to find safer more effective medicine.
Summary of the invention
It is an object of the invention to provide a kind of new application of UTI, specially UTI in preparation treatment multiple sclerosis
Purposes in medicine.Present invention demonstrates that use UTI treatment multiple sclerosis rat, losing weight of rat can be significantly inhibited,
Significantly reduce rats death rate and extend latent time of falling ill, and there is neuroprotection；Additionally, UTI is also by extensive
The balance of multiple Th1/Th2 cell factor, regulates immune response, and by suppression apoptosis, is finally reached treatment multiple sclerosis
Purpose.
To achieve these goals, the present invention adopts the following technical scheme that
UTI purposes in preparation treatment multiple sclerosis medicine.
Further, the formulation of described medicine is injection.
Further, described injection, with UTI as active ingredient, adds pharmaceutically acceptable auxiliary material or complementary composition
It is prepared from.
Further, described injection is parenteral solution or freeze drying powder injection.
Correspondingly, the acceptable auxiliary material of described parenteral solution or complementary composition are selected from water for injection, mannitol, sodium chloride and grape
At least one in sugar.
Correspondingly, the acceptable auxiliary material of described freeze drying powder injection or complementary composition are selected from mannitol, lactose, gelatin hydrolysate, chlorine
Change at least one in sodium and glucose.
The present invention passes through rat experimental autoimmune encephalomyelitis (Experimental autoimmune
Encephalomyelitis, EAE) model, study the UTI result for the treatment of to multiple sclerosis.Result shows, Wu Sita
The result for the treatment of of the more commercially available prednisone acetate parenteral solution of effect of fourth treatment multiple sclerosis more preferably, demonstrate superior anti-inflammatory,
Suppression apoptosis and nervous system protective effect, alleviate losing weight of EAE rat, delay disease time, alleviate EAE rat
The state of an illness, as treatment multiple sclerosis medicine there is good DEVELOPMENT PROSPECT.
Compared with prior art, present invention have an advantage that
(1) UTI derives from human body, and toxic and side effect is low, and security is high, with the interference treating multiple sclerosis in the market
The medicines such as element β, Adrenal Glucocorticoid and immunodepressant compare, and will not cause hepatotoxicity wind agitation, renal toxicity and teratogenesis, instead
And the heart, liver, kidney, lung organ are respectively provided with protective effect, and there is no immunogenicity, allergic reaction incidence is low, does not exists
Teratogenesis.
(2) UTI that the present invention provides compares the medicine of commercially available treatment multiple sclerosis, and cost substantially reduces, and alleviates patient's
Financial burden, and preparation technology is simple, stable in properties, is suitable for industrialized production.
(3) the invention demonstrates that, use UTI treatment multiple sclerosis rat (EAE model), EAE rat can be significantly inhibited
Lose weight, significantly reduce EAE rats death rate and extend latent time of falling ill, and there is neuroprotection；Additionally, it is black
Si Tading, also by reducing IL-2, IFN-γ, the expression of TNF-α, increases TGF-β and the expression of IL-10, recovers Th1/Th2
The balance of cell factor, regulates immune response, alleviates the EAE course of disease, and is withered by regulation rush apoptosis Bax, Fas albumen and suppression
Die the expression of Bcl albumen, promote the clinical recovery of EAE.
Detailed description of the invention
The present invention is further detailed explanation by the following examples.
Embodiment 1, Ulinastatin injection
Preparation method: take the UTI aqueous solution 100,000,000 unit of filtration sterilization, adds 20 grams of mannitol and dissolves, add citron
Acid buffer regulation pH, to neutral, injects water to 1000 milliliters, adds sodium chloride regulation isotonic, aseptic filtration, packing
In 500 cillin bottles, to obtain final product.
Embodiment 2, Ulinastatin injection
Preparation method: take the UTI aqueous solution 100,000,000 unit of filtration sterilization, adds 20 grams of mannitol and dissolves, add citron
Acid buffer regulation pH, to neutral, injects water to 2000 milliliters, adds sodium chloride regulation isotonic, aseptic filtration, packing
In 1000 cillin bottles, to obtain final product.
Embodiment 3, Ulinastatin injection
Preparation method: take the UTI aqueous solution 100,000,000 unit of filtration sterilization, adds 20 grams of mannitol and dissolves, add citron
Acid buffer regulation pH, to neutral, injects water to 4000 milliliters, adds sodium chloride regulation isotonic, aseptic filtration, packing
In 2000 cillin bottles, to obtain final product.
Embodiment 4, UTI freeze drying powder injection
Preparation method: take the UTI aqueous solution 100,000,000 unit after filtration sterilization, adds 20 grams of mannitol and dissolves, add Chinese holly
Rafter acid buffer regulation pH, to neutral, injects water to 1000 milliliters, adds sodium chloride regulation isotonic, aseptic filtration, packing
In 500 cillin bottles, aseptically freeze-drying, to obtain final product.
Test example one, the UTI Effect study to EAE rat
1. experimental animal
SPF level SD rat 60, at 3～4 monthly ages, body weight 220～240g, male and female half and half, by Guangdong Medical College's zoopery
Center provides；Rat freely absorbs conventional feed and running water, and raising room temperature is 18 DEG C-25 DEG C.
2. test method
Rat is randomly divided into 6 groups, often organizes each 10, respectively Normal group, model group, prednisone acetate treatment group,
UTI high, medium and low dosage group.In addition to Normal group, all prepare EAE model for remaining each group, the preparation method of model
As follows: after rat anesthesia, (contained knot in the lower abdomen multiple spot hypodermic injection of rat both sides by MOG35-55 and complete Freund's adjuvant
Close rhzomorph H37RA) the emulsification antigen (every give 0.3mg MOG35-55 and 0.6mg H37RA) that is mixed to prepare with 1: 2, immunity is worked as
Only, induced rat produces EAE, and normal group is in bodies such as same injection location for it and lumbar injection pertussis toxin 500ng/ next day
Long-pending physiological saline.3rd day beginning intraperitoneal injection of immunity, prednisone acetate treatment group injection prednisone acetate parenteral solution
(Central China pharmaceutcal corporation, Ltd, traditional Chinese medicines quasi-word H42021216,25mg/ml) 1.0ml；UTI high, medium and low dosage group
The injection Ulinastatin injection for preparing of the embodiment of the present invention 1 respectively, administration concentration be respectively 100,000 U/ml, 50,000 U/ml,
2.5 ten thousand U/ml, dosage is 1.0ml；Normal group and model group inject the physiological saline of 1.0ml respectively, and each group is administered every day
1 time, Continuous Observation 25 days, self administration of medication same day, weigh every day and observe the changes of weight of rat, statistics rat morbidity latent
Nervous function is also marked by Fu Qi, M & M, after off-test, puts to death rat, takes rat cerebral tissue and measures
Inflammatory factor TNF-α, TGF-β, IL-2, IL-10, IFN-γ and the expression of antiapoptotic factors Bcl-2, Bax, Fas, wherein
Use the content of enzyme linked immunosorbent assay (ELISA) (ELISA) kit method detection inflammatory factor, use ImmunohistochemistryMethods Methods to measure
The protein expression of antiapoptotic factors.And rat corpses is carried out comprehensive postmortem, visually observe the rat heart, liver, kidney, lung, spleen, chest
The change of the major organs such as gland, enteron aisle.
Neuroscore standard: use the every aggregate value method of weighting point-score of Weaver 15 points, it may be assumed that tail: 0 is without exception, 1
For tail semi-paralysis, 2 is tail pamplegia；Four limbs: 0 is without exception, 1 changes for gait, and 2 is paresis, and 3 is pamplegia (each limb
Body separately scoring, if four limbs pamplegia meter 12 points)；Death is 15 points.
3. result of the test
Table 1 respectively organize rat before body weight and the modeling of different time weight ratio compared with changing value
Note: data are different groups on the same day and compare, and compare with Normal group,###P ＜ 0.001；Compare with model group,*P ＜ 0.05,**P ＜ 0.01,***P ＜ 0.001；With prednisone acetate treatment group,ΔP ＜ 0.05,ΔΔP ＜ 0.01,ΔΔΔP ＜ 0.001.
Rat modeling starts disease symptoms occur on the 7th day, and appetite reduces, and body weight begins to decline, and as shown in Table 1, rat is carried out
After EAE modeling, body weight all significantly reduces, and wherein the rat of model group and prednisone acetate treatment group is reopened at the 7th day body and begins
Decline, within the 14th day, decline the most notable, within the 21st day, occur.The rat of prednisone acetate treatment group was at the 7th day and
Within 25 days, body weight fall is more notable than model group, shows that prednisone acetate treatment does not improve the appetite of rat, enters on the contrary
One step reduces.UTI high, medium and low dosage group all can reduce the reduction of rat model body weight, and dosage group high, middle
Effect is preferable.
Table 2 respectively organizes the rat incidence of disease, the death rate and results contrast in incubation period
| Group | The incidence of disease (%) | The death rate (%) | Incubation period (d) |
| Model group | 100 | 12.86 | 8.16±1.02 |
| Prednisone acetate group | 100 | 2.45 | 10.22±0.86* |
| High dose group | 100 | 0.00 | 11.16±1.05* |
| Middle dosage group | 100 | 0.00 | 10.86±0.92* |
| Low dose group | 100 | 0.00 | 9.96±0.78* |
Note: compare with model group,*P ＜ 0.05.
As shown in Table 2, the treatment of prednisone acetate and UTI does not reduce the EAE incidence of disease of rat, but can be notable
Extend EAE to fall ill latent time, and significantly reduce the death rate of EAE rat, UTI the most of the present invention is high, in,
The most there is not rats death in low dose therapy group, and the longest for latent time with high dose group prolongation EAE morbidity, shows crow
The result for the treatment of of Si Tading high dose group is preferable.
Table 3 is respectively organized the Neuroscore of rat different time and is compared
Note: compare with model group,*P ＜ 0.05,**P ＜ 0.01.
As shown in Table 3, started to occur One's spirits are drooping after each group rat immunity at the 7th day, tail limp, drag vertical, hind limb weakness,
And peaking at the 14th day neurologic score, there is paralysis in hind leg, tends to be steady the 21st day state of an illness.Prednisone acetate and
The treatment of UTI makes the rat EAE state of an illness relatively model group significantly alleviate, wherein with prednisone acetate and UTI high dose
The result for the treatment of of group is preferable, and UTI high dose group was the neurologic score relatively prednisone acetate of the 7th, 14,21 and 25 days
Treatment group is low.
Inflammatory Factors Contents change (ng/ml) of table 4 Ge Zu rat cerebral tissue
Note: compare with normal group,#P ＜ 0.05,##P ＜ 0.01；Compare with model group,*P ＜ 0.05,**P ＜ 0.01.
As shown in Table 4, after the rat immunity of model group, the content of its brain tissue TNF-α, IL-2 and IFN-γ dramatically increases,
And the content of TGF-β and IL-10 significantly reduces, show rat myelin protein reactivity CD4 of model group+Th1 activity increases,
Promote Th1 emiocytosis IL-2, IFN-γ, TNF-α thus promote immune response, induce EAE；And by Th2 emiocytosis
The TGF-β with immune suppression function and IL-10 secretion reduce, result above shows, the rat Th1/Th2 after immunity is thin
Intracellular cytokine is unbalance, promotes EAE disease progression, uses prednisone acetate and UTI high-dose therapy all can recover Th1/Th2
The balance of cell factor, alleviates the course of disease.
Antiapoptotic factors SABC positive cell number (individual) of table 5 Ge Zu rat cerebral tissue
Note: compare with normal group,##P ＜ 0.01；Compare with model group,*P ＜ 0.05,**P ＜ 0.01；With prednisone acetate
Treatment group compares,ΔP ＜ 0.05,ΔΔP ＜ 0.01.
As shown in Table 5, after the rat immunity of model group, its brain tissue Bcl protein expression positive cell number significantly reduces, Bax
Dramatically increase with Fas protein expression positive cell number, show that the protein expression promoting apoptosis in EAE rat cerebral tissue increases,
Anti-apoptotic proteins is expressed and is reduced.And after giving prednisone acetate treatment, its brain tissue Bcl, Bax and Fas protein expression does not has
Significant change, shows that prednisone acetate does not has inhibitory action to the apoptosis phenomenon of EAE central nervous system in rat；Give crow department
His fourth treatment pole significantly increases brain tissue Bcl protein expression positive cell number and reduces Bax albumen, the Fas protein expression positive
Cell number, its result for the treatment of is notable compared with the result for the treatment of of prednisone acetate, and result above shows, UTI is withered by regulation rush
Die the expressing thus promote the clinical recovery of EAE of Bax, Fas albumen and suppression apoptosis Bcl albumen.
Additionally, rat is carried out comprehensive postmortem, it was found that the heart of UTI treatment group rat, liver, kidney, lung, spleen,
The most there is not exception in thymus gland, enteron aisle, stomach, and the heart of prednisone acetate treatment group rat, liver, kidney, lung, spleen, thymus gland,
The most there is not exception in stomach, but has the duodenum of 3 rats ulcerative phenomena occur, shows the security that UTI is treated
Relatively prednisone acetate is high.
The clinical observation on the therapeutic effect of test example two, UTI treatment acute stage multiple sclerosis
1. test method
Screen 120 example multiple sclerosis volunteer patients, the maleest 63 examples, female 57 example, age 25-55 year, mean age
35 years old, the course of disease 6 months-4 years, the diagnostic criteria of multiple sclerosis met McDonald (2005) diagnostic criteria, gets rid of tuberculosis
Disease and other patients to hormone therapy taboo, be randomly divided into treatment group and control group, often organize each 60 examples, and wherein treatment group is given
Giving UTI to treat, control group gives prednisone acetate and treats, and two groups of patients are at age, sex, incidence
Etc. the no significant difference of aspect, there is comparativity.
Treatment group medication is: the UTI taking 100,000 U is dissolved in 500ml 5% glucose injection, drip-feed,
The most quiet 1h, every day 2 times, uses 5d continuously, adjusts dosage according to the ordinary circumstance of patient, and maintaining treatment is to gradually
Drug withdrawal.
Control group medication is: dosage is 40mg/d, takes prednisone acetate and is dissolved in 5% glucose injection, vein
Instil, use 5d continuously, adjust dosage according to the ordinary circumstance of patient, and maintaining treatment is to gradually drug withdrawal.
Therapeutic evaluation: patients with multiple sclerosis is carried out Neurological evaluation according to Kurtzke nervous function scale (EDSS),
Before observing two groups of drug therapy and treatment terminate after the vision of patient, brain stem, brain, 4 nervous functions of cerebellum are marked.
Effective: EDSS scoring reduces >=2 points, effectively: EDSS scoring reduce 0.5-1.5/, invalid: EDSS marks
Do not reduce even that sb.'s illness took a turn for the worse.
2. result of the test
Before and after the group volunteer patients's treatment of 6 liang of table, Neuroscore compares
Note: compare with before treatment,*P ＜ 0.05,**P ＜ 0.01；Compare with control group,#P ＜ 0.05.
After multiple sclerosis volunteer patients uses prednisone acetate and UTI to treat, its vision, brain stem, brain and little
Brain EDSS scoring all significantly reduce, scoring reduce 0.5-1.5/, show that prednisone acetate and UTI are to urgency
Property phase multiple sclerosis volunteer patients all demonstrates preferable curative effect.In addition, after using UTI to treat, volunteer patients is big
It is notable that brain EDSS scoring reduces relatively prednisone acetate group, and result above shows, UTI is big protection multiple sclerosis patient
The effect of brain function is good compared with prednisone acetate.
Although the present invention is open as above with preferred embodiment, but they are not for limiting the present invention, the protection model of the present invention
Enclose and should be as the criterion with the content that claims hereof protection domain is defined.Any be familiar with the art person, without departing from
In the spirit and scope of the present invention, the various changes made or equivalent, all should belong to protection scope of the present invention.
Claims (6)
1. UTI purposes in preparation treatment multiple sclerosis medicine.
Purposes the most according to claim 1, it is characterised in that the formulation of described medicine is injection.
Purposes the most according to claim 2, it is characterised in that described injection, with UTI as active ingredient, adds
Pharmaceutically acceptable auxiliary material or complementary composition are prepared from.
4. according to the purposes described in Claims 2 or 3, it is characterised in that described injection is parenteral solution or freeze drying powder injection.
Purposes the most according to claim 4, it is characterised in that the acceptable auxiliary material of described parenteral solution or the sorting of complementary one-tenth
At least one in water for injection, mannitol, sodium chloride and glucose.
Purposes the most according to claim 4, it is characterised in that the acceptable auxiliary material of described freeze drying powder injection or complementary one-tenth
It is selected from least one in mannitol, lactose, gelatin hydrolysate, sodium chloride and glucose.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610153866.5A CN105770874A (en) | 2016-03-17 | 2016-03-17 | Use of ulinastatin in preparation of drugs for treating multiple sclerosis |
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| CN201610153866.5A CN105770874A (en) | 2016-03-17 | 2016-03-17 | Use of ulinastatin in preparation of drugs for treating multiple sclerosis |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002059308A2 (en) * | 2000-12-08 | 2002-08-01 | Genentech, Inc. | Method of diagnosing and treating cartilage disorders |
| CN101972471A (en) * | 2010-10-08 | 2011-02-16 | 广东天普生化医药股份有限公司 | Application of Ulinastatin in preparing drug for curing autoimmune encephalomyelitis and pharmaceutical composition thereof |
-
2016
- 2016-03-17 CN CN201610153866.5A patent/CN105770874A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002059308A2 (en) * | 2000-12-08 | 2002-08-01 | Genentech, Inc. | Method of diagnosing and treating cartilage disorders |
| CN101972471A (en) * | 2010-10-08 | 2011-02-16 | 广东天普生化医药股份有限公司 | Application of Ulinastatin in preparing drug for curing autoimmune encephalomyelitis and pharmaceutical composition thereof |
Non-Patent Citations (1)
| Title |
|---|
| 兰亚明等: "乌司他丁对小鼠脑脊髓炎神经再生作用研究", 《中国生化药物杂志》 * |
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Application publication date: 20160720 |