CN104940179B - Application of the bagodryl hydrochloride in Experiment on therapy Autoimmune Encephalomyelitis medicine is prepared - Google Patents
Application of the bagodryl hydrochloride in Experiment on therapy Autoimmune Encephalomyelitis medicine is prepared Download PDFInfo
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Abstract
The present invention relates to pharmaceutical technology field, the present invention has carried out high flux screening using the small-molecule drug of more than 600 kind FDA approvals, it is found that wherein bagodryl hydrochloride is most obvious to the inhibitory action of CD4+T cells.The present invention further constructs experimental autoimmune encephalomyelitis animal model (EAE models), and the effect using EAE scale-model investigations bagodryl hydrochloride to inflammatory demyelinate damage in vivo, experiment, which finds that bagodryl hydrochloride has, can adjust TH17 cell differentiations and the in vivo effect such as inflammatory demyelinate damage.Prevention or Experiment on therapy Autoimmune Encephalomyelitis medicine, and the application in prevention or treatment multiple sclerosis medicine is prepared are being prepared the invention provides bagodryl hydrochloride.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of new medical usage of bagodryl hydrochloride, i.e. hydrochloric acid
Application of the diphenhydramine in prevention or Experiment on therapy Autoimmune Encephalomyelitis, multiple sclerosis medicine is prepared.
Background technology
Bagodryl hydrochloride (Diphenhydramine Hydrochloride) is antiallergy class non-prescribed medicine medicine, its
Shown in chemical structural formula such as formula (I), molecular formula:C17H22NOCl molecular weight:291.82,168-172 DEG C of fusing point.
No. CAS：147-24-0
No. MDL：MFCD00012479
No. EINECS：205-687-2
No. RTECS：KR7000000
No. PubChem：24277771
Bagodryl hydrochloride is clinically used for skin allergy, such as nettle rash, eczema, dermatitis, drug rash, itch, nerve at present
Property dermatitis, insect bite disease, solar dermatitis, allergic rhinitis.And food, drug allergy etc..
Bagodryl hydrochloride is the derivative of monoethanolamine, can with the histamine competitive effect cell that is discharged in tissue
H1 acceptors, so as to prevent anaphylactoid breaking-out, release the effect such as cause convulsion and hyperemia of histamine.In addition, bagodryl hydrochloride
There is the effect of telling of stronger town.
Experimental autoimmune encephalomyelitis (experimental autoimmune encephalomyelitis,
EAE it is) based on a kind of CD4+T with specific sensitization cell-mediated, to occur list around thin vessels in central nervous system
The autoimmune disease that individual nucleus infiltration and myelinoclasis are characterized.
Experimental autoimmune encephalomyelitis animal model be human multiple sclerosis (multiple sclerosis,
MS ideal animals model).It is significant in the research of clinical neuroimmunology.Multiple sclerosis is with nervous centralis
System white matter Demyelmating disease is changed into the autoimmunity disease of main feature.The position that MS most often involves be periventricular white matter,
Optic nerve, spinal cord, brain stem and cerebellum, major clinical feature are that central nervous system white matter is dispersed in many focuses of distribution and the course of disease
The alleviation recurrence of presentation, the space of sings and symptoms is multiple and the course of disease time is multiple.
Multiple sclerosis disease prognosis mala, FDA medicine such as mitoxantrone, dimethyl fumarate etc. of certification can only
Postpone and alleviate the seriousness of morbidity but can not thoroughly cure MS, therefore new medicine is urgently developed come more preferably by new approach
Alleviate the disease puzzlement of MS patient in ground.
The content of the invention
It is an object of the invention to provide the new medical usage of bagodryl hydrochloride, specifically bagodryl hydrochloride is in system
Application in standby prevention or Experiment on therapy Autoimmune Encephalomyelitis, multiple sclerosis medicine.
The present inventor is directed to finding a kind of medicine for having and alleviating EAE morbidities always, and then preferably alleviates MS patient
Symptom.Present invention in-depth study by long-term, high flux has been carried out using the small-molecule drug of more than 600 kind FDA approvals
Screening, it is found that wherein bagodryl hydrochloride is most obvious to the inhibitory action of CD4+T cells.The present invention further constructs experimental
Autoimmune Encephalomyelitis animal model (EAE models), and using EAE scale-model investigations bagodryl hydrochloride to inflammatory in vivo
The effect of demyelinate damage, experiment, which finds that bagodryl hydrochloride has, can adjust TH17 cell differentiations and internal inflammatory de- marrow
The effects such as sheath damage.
The present invention constructs EAE models.The construction method of EAE models, also refers to document：Xu Quangang, Wang Xiaohui, Huang De
Sunshine, Wu Weiping, MOG_ (35-55) induction experimental autoimmune encephalomyelitis mouse models, China's practicality medical magazine,
《Chinese Journal of Neuromedicine》02 phase in 2006.
Medicine used in the present invention -- bagodryl hydrochloride, can in the daily tail vein injection EAE models of 10mg/kg
Substantially suppress inflammation incidence.
The invention provides one kind played by suppressing internal inflammatory cell TH17 cells alleviation inflammation disease (such as EAE,
MS etc.) medicine bagodryl hydrochloride.
Prevention or Experiment on therapy Autoimmune Encephalomyelitis medicine are being prepared the invention provides bagodryl hydrochloride
In application.
Further, the answering in prevention or treatment multiple sclerosis medicine is prepared the invention provides bagodryl hydrochloride
With.
Medicine of the present invention, be using bagodryl hydrochloride as sole active composition, or include hydrochloric acid benzene sea draw
Bright pharmaceutical composition.
In described medicine, the content of bagodryl hydrochloride is 0.1-99wt%, is preferably 0.5-50wt%.
Described pharmaceutical composition, can be made pharmaceutical preparation with the conventional pharmaceutical adjuvants in pharmacy.
Described pharmaceutical preparation, can be tablet, granule, capsule, dripping pill, injection, powder-injection, or aerosol
Deng.
Beneficial effects of the present invention are as follows：
The present invention has excavated the medical application of bagodryl hydrochloride, has opened up a new application field.
Result of the present invention shows, can be relieved after the bagodryl hydrochloride intervention of EAE 10mg/kg concentration is given
The clinical score of EAE morbidities, and the time of morbidity can be delayed.It has also been found that giving bagodryl hydrochloride in terms of histology
Inflammatory cell infiltration is significantly reduced in EAE mouse spinal cord white matters, and demyelinate phenomenon is also substantially eased.Bagodryl hydrochloride salt
Sour diphenhydramine can be used for preparing prevention or Experiment on therapy Autoimmune Encephalomyelitis medicine, further, hydrochloric acid benzene sea
Lamine can also be used to prepare prevention or treatment multiple sclerosis medicine.
The present invention provides new treatment means for clinic EAE, MS treatment.
Brief description of the drawings
Fig. 1 is clinical with 10mg/kg concentration intraperitoneal injection EAE mouse models for bagodryl hydrochloride in the embodiment of the present invention 1
The effect of scoring；Wherein, abscissa is morbidity number of days (D), and ordinate is Disease Clinical Score (score).* P ＜ are represented
0.05, * * represents P ＜ 0.01, and * * * represent P ＜ 0.001.
Fig. 2 takes after EAE mouse models are injected intraperitoneally with 10mg/kg concentration for bagodryl hydrochloride in the embodiment of the present invention 1
Its spinal cord carries out effect after HE dyeing；Wherein, arrow meaning is inflammatory cell aggregate site.
Fig. 3 takes after EAE mouse models are injected intraperitoneally with 10mg/kg concentration for bagodryl hydrochloride in the embodiment of the present invention 1
Its spinal cord carries out infiltrating inflammatory cells statistical result after HE dyeing；Abscissa is medicine and control, and ordinate is infiltrating cells number
Measure (per mm2)；* P ＜ 0.05 are represented, * * represent P ＜ 0.01, and * * * represent P ＜ 0.001.
Fig. 4 takes after EAE mouse models are injected intraperitoneally with 10mg/kg concentration for bagodryl hydrochloride in the embodiment of the present invention 1
Its spinal cord carries out effect after luxol＆Fast blue dyeing；Wherein, arrow meaning is demyelinated sites.Fig. 5 is implemented for the present invention
Bagodryl hydrochloride is injected intraperitoneally after EAE mouse models with 10mg/kg concentration in example 1 takes its spinal cord to carry out luxol＆Fast
Demyelinating area statistical result after blue dyeing；Abscissa is medicine and control, and ordinate is demyelinating area ratio (%).*
P ＜ 0.05 are represented, * * represent P ＜ 0.01, and * * * represent P ＜ 0.001.
Embodiment
In conjunction with embodiment and accompanying drawing, the present invention is described in detail, but the implementation of the present invention is not limited only to this.
The experimental method of unreceipted actual conditions in the following example, generally according to normal condition, or according to manufacturer
Proposed condition.Unless otherwise indicated, otherwise percentage and number are calculated by weight.
Embodiment 1：Effect of the bagodryl hydrochloride in experimental autoimmune encephalomyelitis (EAE)
Material and method
1. experimental animal
C57BL/6J mouse (female, 8-12 weeks) have purchased from Nanjing biological medicine research institute and Shanghai Si Laike experimental animals
Limit company.All zooperies obtain the accreditation of the animal ethics committee of The 2nd Army Medical College.
2.EAE modelings and internal bagodryl hydrochloride intervention
1) not formula adjuvant completely is prepared：Tuberculin Mtb (being purchased from Difco companies of the U.S.) is dissolved in incomplete Fu Shizuo
In agent CFA (being purchased from sigma companies), add CFA in grinding with ceramic mortar, last concentration of ordinary dissolution is 4mg/ml；
2)MOG35-55Powder (myelin oligodendroglia glycoprotein35-55, purchased from gill biochemical corp) be dissolved into it is sterile
In PBS, last concentration of ordinary dissolution is 2mg/ml；
3) by resulting solution in above-mentioned 1 and 2, by 1：1 is mixed, and glass syringe is beaten to mixing white breast completely to push back
Shape, first drips in water, if not disperse is opened, and represents completely mixed；
4) according to 300ul/ only, mouse back subcutaneously divides 3 points of injections；(close to any 3 points of caudal posterior)
5) intraperitoneal injection pertussis toxin PTX (being purchased from Calbiochem-EMD Chemicals companies), every 200ul；
6) after 48 hours, pertussis toxin PTX, every 200ul are injected intraperitoneally again；
7) 10-14 days mouse start morbidity, mouse invasion are carried out as follows scoring：
Experimental animal is divided into following two groups, every group 8：
Bagodryl hydrochloride group, i.e. above step 1) start to give the sea drawing of intraperitoneal injection hydrochloric acid benzene to Day 0 after 7) modeling
Bright, 10mg/kg is daily；Injection is scored daily during 24 days.
Control group, i.e. above step 1) to Day 0 after 7) modeling to start to give intraperitoneal injection DMSO, 200ul daily；Injection
Scored daily during 24 days.
3. sample preparation
Experimental animal, from aorta perfusion, first using 1 × PBS solution, uses 4% afterwards after 4% chloral hydrate anesthesia
PFA, the careful spinal cord for taking out mouse, rear fixation is stayed overnight in 4%PFA, and 20% sucrose dehydration (1-2 days) treats that it sinks to the bottom, then put
To the dehydration of 30% sucrose, treat that it sinks to the bottom.Then tissue is freezed rapidly, coronal section is made by 20um thickness, be affixed on scribble it is bright
On the slide of glue or it is stored in standby in 50% glycerine.
4.Luxol＆Fast blue are dyed
5.HE is dyed
6 statistical analyses
All experiments are at least in triplicate；At least 8 animals of every group of experiments in vivo, data value mean standard error table
Show, the significant difference between each group is analyzed using one-way analysis of variance (ANOVA) and Student ' the t methods of inspection, p
＜ 0.05 is considered to have statistical significant difference.
7 experimental results
(1) EAE modelings and internal bagodryl hydrochloride intervene clinical score result as shown in Fig. 1, table 1.
Table 1：EAE modelings and internal bagodryl hydrochloride intervene clinical score result
Bagodryl hydrochloride drug-treated EAE mouse can be relieved progression of disease compared to control group, significantly reduce
Disease incidence time and the order of severity, have protective effect in EAE morbidities.
(2) LFB-PAS coloration results
As a result as shown in Figure 4, Figure 5, after bagodryl hydrochloride was with 10mg/kg concentration intraperitoneal injection EAE mouse models 16 days
Its spinal cord is taken to carry out after luxol＆Fast blue dyeing；Obvious demyelinate portion is not found compared with control group, around substantia alba medullae spinalis
Position.Demyelinating area is counted after luxol＆Fast blue dyeing, is as a result shown compared with control group, bagodryl hydrochloride group ridge
Marrow demyelinating area ratio compared with overall substantia alba medullae spinalis area is significantly lower than control group, with statistical significance.
(3) HE coloration results
As a result as shown in Figure 2 and Figure 3, after bagodryl hydrochloride was with 10mg/kg concentration intraperitoneal injection EAE mouse models 16 days
Its spinal cord is taken to carry out after HE dyeing；It was found that inflammatory cell is considerably less than control group in substantia alba medullae spinalis aggregate site.Soaked after HE dyeing
Moisten inflammatory cell statistics, as a result show per mm2Substantia alba medullae spinalis inflammation cellular infiltration quantity is significantly lower than control group, as a result with system
Meter learns meaning.
8 conclusions：
The clinic that EAE morbidities can be relieved after the bagodryl hydrochloride intervention of EAE 10mg/kg concentration is given is commented
Point, and the time of morbidity can be delayed.It has also been found that giving the EAE mouse spinal cord white matters of bagodryl hydrochloride in terms of histology
Middle inflammatory cell infiltration is significantly reduced, and demyelinate phenomenon is also substantially eased.Bagodryl hydrochloride can be used for preventing or treating
EAE、MS。
The preferred embodiment to the invention is illustrated above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make a variety of equivalent on the premise of without prejudice to the invention spirit
Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.
Claims (7)
1. application of the bagodryl hydrochloride in prevention or Experiment on therapy Autoimmune Encephalomyelitis medicine is prepared.
2. application of the bagodryl hydrochloride in prevention or treatment multiple sclerosis medicine is prepared.
3. application according to claim 1 or 2, it is characterised in that described medicine, is using bagodryl hydrochloride as only
One active ingredient, or the pharmaceutical composition comprising bagodryl hydrochloride.
4. application according to claim 3, it is characterised in that in described medicine, the content of bagodryl hydrochloride is
0.1-99wt%.
5. application according to claim 3, it is characterised in that in described medicine, the content of bagodryl hydrochloride is
0.5-50wt%.
6. application according to claim 3, it is characterised in that the routine in described pharmaceutical composition and pharmacy is medicinal
Pharmaceutical preparation is made in auxiliary material.
7. application according to claim 6, it is characterised in that described pharmaceutical preparation be tablet, granule, capsule,
Dripping pill, injection, powder-injection, or aerosol.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1077891A (en) * | 1993-03-05 | 1993-11-03 | 中国人民解放军空军南京医院 | " Naixianjing " and preparation method thereof |
| CN1535685A (en) * | 2003-04-03 | 2004-10-13 | 王刚生 | Adhesive plaster for curing neurodermatitis |
| CN101102760A (en) * | 2003-09-15 | 2008-01-09 | 康宾纳特克斯公司 | Methods and reagents for the treatment of immunoinflammatory disorders |
-
2015
- 2015-05-29 CN CN201510284220.6A patent/CN104940179B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1077891A (en) * | 1993-03-05 | 1993-11-03 | 中国人民解放军空军南京医院 | " Naixianjing " and preparation method thereof |
| CN1535685A (en) * | 2003-04-03 | 2004-10-13 | 王刚生 | Adhesive plaster for curing neurodermatitis |
| CN101102760A (en) * | 2003-09-15 | 2008-01-09 | 康宾纳特克斯公司 | Methods and reagents for the treatment of immunoinflammatory disorders |
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