CN107998116A - Application of the acetamide in anti-inflammatory drug, immunomodulator, antipsoriatic thing - Google Patents

Abstract

The invention discloses application of the acetamide in anti-inflammatory drug, immunomodulator, antipsoriatic thing.Using the present invention, acetamide has anti-inflammatory an obvious effect, and the horizontal conspicuousnesses of IL 17F and the TNF ɑ in serum decline, and the expression rises of IL 22, show that acetamide has anti-inflammatory and immunosuppressive effect.Acetamide has nospecific immunity and specific immunity adjustment effect, and acetamide can make serum antibody generation is horizontal to raise, and 1 β, IL 6 of IL is horizontal in up-regulation serum, lowers TNF alpha levels in serum, and can dramatically increase thymus gland coefficient.Acetamide confrontation psoriasis has obvious effect, can lower IL 17F and IL 23 in serum, significant cell factors of the IL 17F and IL 23 as psoriasis, and, acetamide has improvement result to the cell of epidermis, spinous layer and skin corium.

Description

Application of the acetamide in anti-inflammatory drug, immunomodulator, antipsoriatic thing

Technical field

The present invention relates to immunological regulation practical technique field, more particularly to acetamide is in anti-inflammatory drug, immunomodulator, anti- Application in psoriasis.

Background technology

Immune to generally fall into two kinds of inherent immunity and adaptive immunity, inherent immunity has specificity extensively, identification mechanism Conservative PAMP (pathogen associated molecular pattern), acceptor PRR；Adaptive immunity then has very precisely specific, reaction The characteristics of personality of pathogen, antigen recognition receptor are TCR and BCR.Innate immune response is that host resists the of pathogenic microorganism One of defence line, and start and participate in adaptive immune response；Adaptive immunity is acquired body, antigentic specificity, disease-resistant original The efficient defence mechanism of microorganism infection.Basic immunology is studied by recent year immunological investigation team to be prevented with clinical disease Close connection is controlled, influences the related to amynologic mechanism of human health in infectious diseases, autoimmune disease and tumour etc. Major disease on, not only there is novel academic viewpoint also to have breakthrough progress.

Antibody is primarily present a kind of glycoprotein in blood and tissue fluid, and be otherwise known as immunoglobulin, antibody master If being produced by the thick liquid cell of the B cell proliferation differentiation generation of antigenic stimulus, it can be combined with antigentic specificity, be humoral immunity The important effector substance in the inside.Early in 1890, Emil von Behring learned in Germany and his colleague studies antitetanic Found when plain the clostridium tetani put out a fire of animal be immunized after serum in containing the material to neutralize a toxin, will it is immune after animal Serum transfers to can make with other animals these animals also produce can specificity be directed to the immunity of clostridium tetani, therefore, The generation of antibody and the mechanism of action are slowly clear.With aging, human body reduces the immune function of exotic antigen, Whittingham has found that its slow potency of speed for the IgG antibody that the elderly's antibacterial body infiltration first immunisation produces is low, secondary to exempt from IgG antibody potency after epidemic disease is to be substantially less than young man.1975, Makinodan by the mouse to 0~45 monthly age (people's The corresponding age is 0~105 years old) hemolysin experiment confirmation 0~7.5 monthly age of mouse of sheep red blood cell stimulation has been carried out respectively (quite 0~17.5 years old of month people) stage is the constantly elevated process of antibody level, and 7.5~45 monthly ages (equivalent to people 17.5~ 105 years old) stage antibody level is gradually reduced.Therefore, the antibody level in the elderly's body is increased, so as to improve the immune of the elderly Power is necessary.

The discovery of cell factor further deepens people to immune response and immunoregulatory understanding.Cell factor is internal Glycoprotein of the number molecular weight in 80kd once, internal content is very low but it but be able to can just work in pg levels.Cell The factor can generally be produced in the case where cell is upset, but also have can spontaneous generation such as IL-1.Its target cell is typically thin Born of the same parents itself or neighbouring cell, there is various active or different cell factors to have an identical activity, usual various kinds of cell because Network can be mutually formed between son mutually adjust and play a role.It can be played to target in addition, cell factor is only combined with acceptor The effect of cell.With the increase at age, internal many cytokine levels are increasing or are subtracting relative to normal person Few is unbalance so that hypoimmunity, the increase of diseased possibility.

Opposite, with advancing age, the immune organ of old man is gradually degenerated, and clinically has confirmed that people's thymus gland is going out About 11g when raw, (10~12 years old) puberty is maximum, there are about 35g, drastically shrinks back after sexal maturity, only possible to weight at 60 years old There is 15g.The degeneration of immune organ is also further confirmed the reason for immunocyte based intracellular cvtokine is horizontal unbalance.

For this reason, the present invention is necessary to propose a kind of immunomodulator, the immunity degradation caused by aging is resisted.

On the other hand, psoriasis (psoriasis) is a kind of by cell and numerator mediated with innate immune system and adaptability The proliferative skin disease of the relevant chronic inflammation of immune system.

The histopathology of clinical psoriasis is mainly shown as keratinocyte hyperplasia, and acanthosis, inflammation are thin Born of the same parents increase, blood vessel hyperplasia is expanded.In addition, another feature of psoriasis is the cytokine profiles expression of cutaneous lesion.It is existing There is treatment psoriasis generally to use dexamethasone, dexamethasone is a kind of artificial synthesized corticosteroid, is that glucocorticosteroid swashs Element.But extensive application glucocorticoid can cause metabolism for a long time and water and salt metabolic disturbance, class adrenal cortex work(occur Can hyperfunction syndrome, such as edema, Diagnostic value, hypertension, glycosuria, thinning of skin, moon shaped face, buffalo hump, central obesity, more The symptoms such as hair, acne, myasthenia and amyotrophia.For children, can because suppress the secretion of growth hormone and caused by negative nitrogen balance, make Growth and development is affected.

Therefore, the present invention be also necessary to propose it is a kind of it is new can substitute dexamethasone, for treating the medicine of psoriasis.

However, on application of the acetamide to immunological regulation, psoriasis, there is not been reported.

The content of the invention

The technical problems to be solved by the invention are, there is provided acetamide is in anti-inflammatory drug, immunomodulator, anti-psoriasis Application in medicine.

In order to solve the above technical problem, the present invention provides application of the acetamide in anti-inflammatory drug is prepared, the second The structural formula of acid amides is：

As the improvement of such scheme, the dosage of the acetamide is 0.2-2g/kg.

Correspondingly, the present invention provides application of the acetamide in immunomodulator is prepared, the structural formula of the acetamide is：

As the improvement of such scheme, the dosage of the acetamide is 0.7-6g/kg.The concentration of the acetamide is 0.035-0.3g/ml。

As the improvement of such scheme, the immunomodulator is non-specific immunomodulator；Alternatively, the immune tune Section agent is specific immunity conditioning agent；Or the immunomodulator is to have nospecific immunity and specific immune function concurrently Immunomodulator.

Correspondingly, the present invention discloses application of the acetamide in antipsoriatic thing is prepared, the structural formula of the acetamide For：

As the improvement of such scheme, the dosage of the acetamide is 0.7-2g/kg.

Implement the present invention, have the advantages that：

The present invention utilizes acetamide small molecule, its molecular weight is only 59.07, and anti-inflammatory, immune bidirectional modulation and anti-silver are considered to be worth doing Disease is respectively provided with obvious effect, specifically：

First, acetamide has anti-inflammatory an obvious effect, and the horizontal conspicuousnesses of the IL-17F and TNF- ɑ in serum decline, IL-22 Expression rise, IL-22 belongs to the member of IL-10 families, be in people's body inherent immunity and adaptive immunity can produce it is thin Intracellular cytokine, the IL-17F expressions that the Tumor necrosis factor TNF-ɑ and inherent immunity produced with reference to inherent immunity is produced decline, It may infer that acetamide has anti-inflammatory and immunosuppressive effect, while being acted as in acquired immunity and adaptive immunity With.

2nd, acetamide has adjustment effect to nospecific immunity and specific immunity.Acetamide can make immunocompromised The horizontal rise of the serum antibody of model mice and normal mouse generation, raises IL-1 β, IL-6 level in serum, lowers in serum TNF-α is horizontal, and can dramatically increase thymus gland coefficient.Therefore, the immunity degradation that acetamide is caused for aging is possible to play Certain effect, there is immunological enhancement.

3rd, acetamide confrontation psoriasis has obvious effect, can lower in serum IL-17F and IL-23, IL-17F and Significant cell factors of the IL-23 as psoriasis, the decline of its expression imply that acetamide works in T lymphocytic immunities And the skin of Pigs with Psoriasis is better.And acetamide has improvement to the cell of epidermis, spinous layer and skin corium Effect.

Brief description of the drawings

Fig. 1 is animal skin PASI scoring change curves；

Fig. 2A is animal skin situation map (A. blank control groups；B. imiquimod model group；C. dexamethasone positive group)；

Fig. 2 B are animal skin situation map (D. acetamide high dose groups；E. acetamide middle dose group；F. acetamide low dosage Group)；

Fig. 3 A treat 12 days dermal pathology HE stained slices result (A. blank control groups for each group mouse；B. imiquimod Model group；C. dexamethasone positive group)；

Fig. 3 B treat 12 days dermal pathology HE stained slices result (D. acetamide high dose groups for each group mouse；E. acetyl Amine middle dose group；F. acetamide low dose group).

Embodiment

To make the object, technical solutions and advantages of the present invention clearer, the present invention is made into one below in conjunction with attached drawing It is described in detail on step ground.

Clinically the medicine of strengthen immunity and health products have very much, including levamisol, astragalus polyose, Newborn Bovine Liver are lived Property peptide etc., also have the compound of this group of numerous acetamide derivatives or acetamide-containing, but small-molecule substance it is few again It is few.

For this reason, the present invention provides application of the acetamide in immunomodulator is prepared, the structural formula of the acetamide is：

Acetamide alias acetamide, molecular formula are CH₃CONH₂, molecular weight is only 59.07.Hydroxyl in acetic acid is taken by amino Generation and generate compound.

The dosage of the acetamide is 0.7-6g/kg, and the concentration of the acetamide is 0.035-0.3g/ml.Specifically, institute 0.7g/kg, 2g/kg, 6g/kg can be selected by stating the dosage of acetamide, but not limited to this.The concentration of the acetamide can be selected 0.035g/ml, 0.1g/ml, 0.3g/ml, but not limited to this.

Acetamide has adjustment effect to nospecific immunity and specific immunity.Therefore the immunomodulator is non-specific Property immunomodulator；Alternatively, the immunomodulator is specific immunity conditioning agent；Or the immunomodulator is non-to have concurrently The immunomodulator of specific immunity and specific immune function.

Effect of the acetamide in terms of immunological regulation is discussed further with reference to experiment

1st, animal packet

It is another to take male KM mouse 90, adaptability by weight to be randomly divided into blank control group, endoxan after feeding three days Model control group, the non-model group of spleen aminopeptide, spleen aminopeptide-endoxan model group, the non-model group of acetamide high dose, acetamide (i.e. positive controls and acetamide high dose, middle dose group set up one to totally 8 groups of high, medium and low dosage-endoxan model group more A non-model group), every group 10.Each group animal gastric infusion, blank control group, endoxan model control group are given and are distilled Water, the non-model group of spleen aminopeptide, spleen aminopeptide-endoxan model group give spleen Antide, and dosage is set to 0.8mg/kg, given the test agent The high, medium and low dosage of acetamide is 6g/kg, 2g/kg, 0.7g/kg respectively, and acetamide sample is dissolved with distilled water, and acetamide is high Middle low dosage concentration is 0.3g/ml, 0.1g/ml, 0.035g/ml respectively, and all animal successive administrations 30 days, capacity, which is administered, is 20ml/kg, while weight is measured weekly 1 time.

2nd, antibody tormation level detection-serolysin test

The 25th day intraperitoneal injection 2% hematocrit sheep red blood cell (SRBC) of 0.2ml of each group animal successive administration is immunized.After 5 days, For 300~400ul of all animal eye socket venous blood collections in centrifuge tube, room temperature places about 1h, and solidification blood and tube wall are peeled off, make blood Clear fully to separate out, 3500rpm centrifugation 10min, collect serum.With physiological saline by serum doubling dilution, by different dilution factors (1: 2,1:4,1:8,1:16,1:32,1:64,1:128,1:256,1:512) serum is respectively placed in 96 hole round bottom cell plates, per hole 100 μ l, add the SRBC suspensions of 100 μ l 0.5% (v/v), mix, and load in the square position of moistening and are capped, are incubated in 37 DEG C of incubators 3h is educated, observes hemagglutination degree, serum agglutination degree is generally divided into 5 grades (0- IV) record.

Antibody level=(S1+2S2+3S3 ... nSn)

1,2,3 ... n represent the index of two-fold dilution in formula, and S represents the rank of aggegation degree, and antibody product is bigger, Represent that serum antibody is higher.

0 grade of red blood cell all sinks, and concentrates on the round point shape that bottom hole portion forms densification, and surrounding liquid is fair-skinned clearly.

Largely for heavy collection in bottom hole into round spot shape, surrounding has the red blood cell of a small amount of aggegation to I grade of red blood cell.

The red blood cell of II grade of aggegation forms thin layer in bottom hole, and center can substantially see a loose red point.

The uniform shakedown of red blood cell of III grade of aggegation is dispersed in bottom hole into a thin layer, and may be seen indistinctly a small red dot at center.

The uniform shakedown of red blood cell of IV grade of aggegation is dispersed in bottom hole into a thin layer, and grumeleuse is sometimes into convolution shape.

3rd, the foundation of immunosuppression mouse model

In addition to negative control group, one of high dose group and positive controls not modeling group, remaining 5 groups of mouse are the 27th It starts to be injected intraperitoneally High-Dose Cyclophosphamide 80mg/Kg weight/only respectively, is administered 3 days altogether.

4th, zootomy and index determining

4.1 index determining

Enzyme-linked immunosorbent assay method (ELISA) detection mouse peripheral blood middle clearly TNF-α, IL-1 β, IL-6 and IFN- The content of γ, each group mouse last dose next day pluck eyeball and take blood, and each cell in serum is detected using double antibody sandwich ELISA The content of the factor and interferon, the operation of stringent by specification, according to standard curve calculate each group TNF-α, IL-1 β, IL-6 and The content of IFN-γ.(to detect in serum exemplified by IL-1 β contents)

4.2 organ indexs measure

Cervical dislocation is put to death after each group mouse takes blood, and the Main Immune Organs thymus gland and spleen for winning mouse weigh weight simultaneously Calculate organ coefficient.

Example：Spleen coefficient=spleen weight (mg)/weight (g) × 100%

5th, experimental result

5.1 antibody tormations are horizontal

Compared with blank group, model group antibody suppresses (P by conspicuousness<0.01), the non-model group of spleen aminopeptide, the high agent of acetamide The antibody level for measuring non-model group and the non-model group of acetamide middle dosage significantly or even extremely significantly raises (P<0.05, P<0.01)； Compared with model group, the antibody level group of the high, medium and low dose modal group of spleen aminopeptide model group, acetamide has extremely notable rise (P<0.01), the horizontal change of Serum Antibody generation refers to table 2-1 under different condition.

Under table 2-1 different conditions Serum Antibody generation it is horizontal relatively (N=10)

Table 2-1 The level of antibody production in serum under different conditions(N=10)

Note：Compared with model group^*P<0.05,^**P<0.01；Compared with blank group^#P<0.05,^##P<0.01。

5.2 Cytokine of Serum are horizontal

IL- β are compared with blank group conspicuousness liter in the non-model group of spleen aminopeptide, acetamide high dose and the non-model group serum of middle dosage Height, TNF-α then show as conspicuousness and decline (P<0.05)；After model foundation, IL- β levels are shown compared with blank group in model group serum Write rise (P<0.05), remaining index has no conspicuousness change (P<0.05), removed in medicine group in acetamide high dose group serum IL-6 levels have conspicuousness to raise (P compared with model group<0.05) outside, other indexs of remaining medicine group have no significant change (P> 0.05).Cytokine of Serum and Interferon level change are as shown in table 2-2.

The horizontal comparison of table 2-2 Cytokine of Serum (N=10)

Table 2-3 Comparison of cytokine levels in serum(N=10)

Note：Compared with model group^*P<0.05,^**P<0.01；Compared with blank group^#P<0.05,^##P<0.01。

5.3 immune organ spleens, thymus gland organ coefficient

As shown in table 2-3, after caused by cyclophosphamide immunosuppression mouse model is established, thymus gland, the Spleen coefficient of model group The obvious atrophy compared with blank group, conspicuousness decline (P<0.01), but the thymus gland of each medicine group, Spleen coefficient are compared with model group And indifference (P>0.05)；Acetamide is high, the thymus gland coefficient of the non-model group group of middle dosage is significantly raised compared with blank group, Spleen coefficient It is then that pole conspicuousness reduces (P<0.05), thymus gland, the Spleen coefficient of the non-model group of spleen aminopeptide have no conspicuousness change (P>0.05).

Table 2-3 thymus gland, spleen organ coefficient (N=10)

Table 2-4 Organ coefficients of thymus and spleen(N=10)

Note：Compared with model group^*P<0.05,^**P<0.01；Compared with blank group^#P<0.05,^##P<0.01。

6th, experiment conclusion

Acetamide has adjustment effect to nospecific immunity and specific immunity.Acetamide can make immunodeficiency models The horizontal rise of the serum antibody of mouse and normal mouse generation, raises IL-1 β, IL-6 level in Normal animal serum, lowers blood TNF-α is horizontal in clear, after the mice model of acetamide therapeutic intervention endoxan processing, can dramatically increase thymus gland system Number.

The principle of serum hemolysin is the animal blood serum that sheep red blood cell (SRBC) (SRBC) was immunized, and is tied with a certain amount of SRBC Close, immunocompetent lymphocytes discharges hemolysin under the conditions of 37 DEG C, and in the presence of complement, the sheep that can dissolve surrounding is red Cell, so as to form a macroscopic hemolysis plaque around each antibody forming cell.Body antibody tormation and B lymphs Cell is related.Serolysin test result of study is prompted, and acetamide is equal to normal physiological and immunocompromised two states mouse Tool can significantly raise the antibody level in serum, play the immune effect of enhancing and it acts on normal mouse and becoming apparent. Clinically the medicine of strengthen immunity and health products much include levamisol, astragalus polyose, Newborn Bovine Liver Active Peptide etc., also have The compound of this group of numerous acetamide derivatives or acetamide-containing, but small-molecule substance is fewer and fewer.

Cell factor IL-1 β and TNF-α are internal proinflammatory inflammation factor, they are interrelated, interaction and meeting Form an inflammatory network.Experimental result shows the horizontal significantly rises of the IL-1 β in the Normal Mouse Serum after acetamide intervention, And TNF-α level is then remarkably decreased, the IL-6 in acetamide high dose model group is then significantly raised.Wherein possible cause is, In normal mouse, under the stimulation of external sheep red blood cell (SRBC), inflammatory factor IL- β and TNF- ɑ rise to certain level, Acetamide is small-molecule substance, and acetamide can solve Tetramine and fluoroacetamide poisoning, improve neural cell injury, it may be it Can pass through blood-brain barrier, stimulate neuroendocrine cascade reaction, cause the release of steroid substances, so lower IL-1 β with TNF- ɑ are horizontal, but IL-1 can be produced constantly in physiological conditions, therefore level still shows rise.

Endoxan is broad-spectrum anti-tumor medicine, is widely used in treatment leukaemia and other tumours, is extremely strong immunosupress Agent.Using High-Dose Cyclophosphamide as immunodeficiency models modeling agent in this experiment, modeling significant effect, is mainly reflected in immune The notable atrophy of organ thymus gland and spleen.The bioactivity of IL-6 includes antiviral and anti-infectious function, causes in endoxan Pathology body in, mononuclear macrophage, endothelial cell and the fibroblast under the long term administration of acetamide effect are in body IL-6 is secreted during infection to increase, and among blood, mobilizes the systemic immune system of body to participate in anti-infective reaction.

In conclusion Binding experiment result, which can be seen that acetamide can strengthen, is immunized and may play certain anti-inflammatory work With.

Correspondingly, the application the present invention provides acetamide in anti-inflammatory drug is prepared, the structural formula of the acetamide are：

The dosage of the acetamide is 0.2-2g/kg.Specifically, the dosage of the acetamide can select 0.2g/kg, 0.7g/kg, 2g/kg, but not limited to this.

Effect of the acetamide in terms of anti-inflammatory is discussed further with reference to experiment

1 experimental method

1.1 therapeutic administratp

60 KM mouse according to weight be randomly divided into blank control group, model control group, dexamethasone positive controls and Totally 6 groups of the high, medium and low dosage group of acetamide, every group 10, half male and half female.Blank control group and model control group gavage distilled water, Dexamethasone Injection, dosage 10mg/kg is injected intraperitoneally in dexamethasone positive controls, and acetamide is dissolved with distilled water, high, In, low dosage be respectively 2g/kg, 0.7g/kg, 0.2g/kg, gastric infusion.Each group animal is according to drug dose successive administration 7 My god, two times a day, when dosing interval 3 is small twice.

1.2 intraperitoneal injection LPS establish inflammation mouse model

For all animals when fasting for solids but not liquids 12 is small after the last administration, in addition to blank control group, remaining each group animal is disposable The LPS that dosage is 15mg/kg is injected intraperitoneally, establishes inflammatory model mouse.

1.3 ELISA detection Cytokine of Serum TNF-α, IL-17F, IL-22 and IL-23

After all animal intraperitoneal injection LPS 3h, etherization and orbital venous plexus blood sampling, blood room temperature standing 30min, 10min is centrifuged with 3000rpm after serum precipitation, takes -80 DEG C of refrigerators of upper serum to save backup.

All animal blood serums are swapped out using each cytokine content in ELISA kit measure serum according to standard curve Calculate each group TNF-α, the content of IL-17F, IL-22 and IL-23.

1.4 dissection materials

Animal cervical dislocation is put to death after blood sampling and solution takes immune organ thymus gland and spleen, is weighed and is calculated organ coefficient.

1.5 statistics and analysis

Using SPSS 19.0 carry out statistical analysis, data withRepresent, with P<0.05 expression statistics has conspicuousness Difference, P<0.01 expression statistics has pole significant difference.

2 experimental results

2.1 Cytokine of Serum horizontal expressions

Compared with blank group, IL-17F, IL-23, IL-22 and TNF-α level have extremely aobvious in LPS inflammatory model group serum Write rise；Compared with LPS inflammatory model groups, the positive group of dexamethasone and acetamide medicine group energy conspicuousness lower LPS inflammation moulds IL-17F and TNF-α in type mice serum is horizontal, up-regulation IL-22 levels (P<0.01, P<0.05), IL-23 in each medicine group And there was no significant difference (P>0.05) it is, specific as shown in table 3-1.

The horizontal comparison of table 3-1 Cytokine of Serum (N=10)

Table 3-1 Comparison of cytokine levels in serum(N=10)

Compared with model group,^**P<0.01,^*P<0.05。

2.2 immune organ organ coefficients change

As shown in table 3-2, LPS inflammatory model groups are compared with blank control group, the high, medium and low dosage group of acetamide and model Control group compares, immune organ thymus gland coefficient, Spleen coefficient there are no significant difference (P>0.05)；And the positive group of dexamethasone with Model group compares, and the organ coefficient of thymus gland and spleen shows that conspicuousness declines (P<0.01).

Table 3-2 spleens, thymus gland organ coefficient compare (N=10)

Table3-2 Comparison of organ coefficients in spleen and thymus(n =10)

Compared with model group,^**P<0.01,^*P<0.05。

3rd, experiment conclusion

TNF-α, the horizontal of IL-17F, IL-22 and IL-23 significantly raise in serum after mouse peritoneal injection LPS, prompt Inflammation mouse model is set up.After test medicine therapeutic intervention, proinflammatory inflammation factor TNF-α, IL-17F are significantly reduced, anti-inflammatory cells because Sub- IL-22 rises, acetamide can adjust specificity and non-specific immune function, prompt acetamide to have anti-inflammatory and immunological regulation Effect, while work in acquired immunity and adaptive immunity, it can be adapted for systemic loupus erythematosus (SLE), class wind The treatment of the autoimmune diseases such as wet arthritis (RA), psoriasis, leucoderma.

LPS is the cell wall constituent of gram-negative bacteria, and the endotoxin of gram-negative bacteria, is its important causative agent Matter.LPS is made of lipid A, core polysaccharide and specific polysaccharide, and wherein lipid A is the master of endotoxin toxicity and biological activity Want component and without species specificity, therefore different strain is similar by the toxic action that endotoxin produces.On the one hand, LPS can cause to send out Thermal response, leukocytosis reaction, or even shock death.On the other hand, can be by the mould on cell membrane during LPS stimulating expression of macrophage Formula identification receptor, such as：Toll-like receptor, scavenger receptor etc. identify and combine, and activate downstream signaling pathway, induce autophagy and The protective mechanisms such as inflammatory reaction, play the role of anti-infectious.

This experiment prepares mouse inflammatory model with low dose of LPS intraperitoneal injections, excites the immune system in Mice Body, LPS is the strong activator of tumor necrosis factor, and the TNF- ɑ conspicuousnesses rise in this experimental model animal body confirms inflammation mould Type is created as.Under the induction of LPS, except TNF- ɑ, there is IL-17F, it belongs to proinflammatory inflammation factor as the former, and small Under the action of acetamide administration, the horizontal conspicuousnesses of IL-17F and TNF- ɑ in serum decline mouse.IL-22 belongs to IL-10 house The member of race, is the cell factor that inherent immunity and adaptive immunity can produce in people's body, it ranges our anti-inflammatory Cell factor, participate in resistance microorganism, play defence, protective effect, it either helper T lymphocyte 17 secrete, Can there is T lymphocytes 22 or natural killer cells 22 to produce.Clinical and experiment confirms that IL-22 can be in psoriasis, dystopy Property dermatitis and ulcerative colitis in high expression.In experiment, after acetamide is to LPS inflammatory model mouse therapeutic interventions, IL-22 expression The IL-17F expressions that rise, the tumor necrosis factor produced with reference to inherent immunity and inherent immunity produce decline, and can push away Disconnected acetamide has anti-inflammatory and immunosuppressive effect, while working in acquired immunity and adaptive immunity.

Correspondingly, the present invention discloses application of the acetamide in antipsoriatic thing is prepared, the structural formula of the acetamide For：

The dosage of the acetamide is 0.7-2g/kg.

Effect of the acetamide in terms of anti-psoriasis is discussed further with reference to experiment, specifically acetamide is exempted from The curing psoriasis effect of epidemiology relevant disease imiquimod induction.

First, the skin being grievously injured degree situation of change and skin PASI scorings

1st, Normal group mouse skin is smooth, thickness is consistent, at any time administration time increase, and skin simultaneously without exception changes Become.And there is the scales of skin that peel off and thickens in the psoriasis model mouse of imiquimod induction skin after imiquimod intervention, but this experiment Middle animal skin, which has no, there is obvious erythema, therefore animal PASI scorings=scales of skin that peel off scores+thicken scoring, and imiquimod is applied to 5th day, PASI scorings reached peak, and concrete outcome is shown in Fig. 1, Fig. 2A and Fig. 2 B and table 4-1.

Table 4-1 skins with time change PASI scoring (N=10)

Table 4-1 The PASI score of skin over time(N=10)

Compared with model group,^*P ＜ 0.01.^*P ＜ 0.05.

2nd, Cytokine of Serum expression

Compared with blank control group, the horizontal conspicuousness up-regulation of IL-17F, IL-23 and TNF-α of model group, IL-22 levels Conspicuousness lowers (P ＜ 0.01, P ＜ 0.05)；The psoriasis that dexamethasone and acetamide height, middle dosage induce imiquimod is small After mouse therapeutic intervention, IL-17F is horizontal to be relatively remarkably decreased (P ＜ 0.05) with imiquimod model group；With imiquimod model group Compare, TNF-α is horizontal in the positive group serum of dexamethasone, and IL-23, TNF-α level have significantly in acetamide middle dosage serum Decline (P ＜ 0.01, P ＜ 0.05).

Table 4-2 Cytokine of Serum expressions

Table4-2 Expression level of cytokines in serum

Compared with model group,^**P ＜ 0.01,^*P ＜ 0.05.

3rd, mouse back skin lesion pathological change

HE coloring pathological sections observe 200 times and 400 times the results show that control group mice skin has no different under the microscope Often.Compared with the control group, the mouse skin layer of imiquimod modeling group thickens substantially, cuticula hyperkeratosis and parakeratosis, With the appearance of Munro microabscesses, acanthosis, inside there is inflammatory cell and epidermal cell fragment, telangiectasis and distortion Substantially, but red blood cell is excessive and unobvious (as shown in Figure 3A).The psoriasis that dexamethasone and acetamide induce imiquimod After sample model mice therapeutic intervention, the positive group skin epidermis thickness of dexamethasone is significantly lower than model group, and hyperkeratinization mitigates, spine Layer is thinning, without obvious blood vessel dilatation and Munro microabscesses, has significant difference with model group.The high, medium and low dosage group of acetamide Mouse skin layer is thinning, and spinous layer is still thicker, but without significant Munro microabscesses, telangiectasis and inflammatory cell infiltration, Concrete outcome refers to figure below 3B.

It should be noted that Fig. 3 A treat dermal pathology HE stained slices result (A. blank controls in 12 days for each group mouse Group；B. imiquimod model group；C. dexamethasone positive group)；Fig. 3 B treat dermal pathology HE dyeing in 12 days for each group mouse and cut Piece result (D. acetamide high dose groups；E. acetamide middle dose group；F. acetamide low dose group).In each group picture, upper figure is 200 times of amplification as a result, figure below is 400 times of result of amplification.

4th, experiment conclusion

The psoriasis mouse model for being similar to the mankind, the dermal pathology of animal pattern can be successfully established by imiquimod There is typical parapsoriasis sample and changes in the results show of cutting into slices.The psoriasis model mouse that acetamide induces imiquimod carries out After therapeutic intervention, Cytokine of Serum IL-17F levels can be significantly lowered, skin improves, and prompts acetamide to consider silver to be worth doing Disease model mouse has therapeutic effect, and is realized by suppressing the immune function of T cell mediateds.

Change is tended to we can see that acetamide is to imiquimod induction by skin lesion performance and PASI scorings in experiment The skin of psoriasis model mouse play obvious therapeutic effect, it is increasingly severe in model group animal skin psoriasiform In the case of, acetamide but inhibits the model skin lesion, and it is smooth and without the obvious scales of skin that peel off to visually observe skin epidermis.For psoriasis Diagnosis, except visually substantially observing, pathological section is opposite goldstandard, the skin of each acetamide medicine group mouse in this experiment Damage pathological section figure shows that acetamide has improvement result to the cell of the epidermis of model mice, spinous layer and skin corium, treats Effect is notable, and epidermis is thinning, without significant Munro microabscesses, telangiectasis and inflammatory cell infiltration.

The generation of psoriasis, development and recover related to cytokine profiles, the existing relevant factor of humoral immunity with carefully Born of the same parents are immune-related, these cell factors can be body itself directly secretion or preceding cell factor is stimulated and produced.Silver The key link of immune response is mainly the side such as signal path and antigen presentation of NF- κ B, IFN-γ and IL-23 aspect in bits disease Face.The water of proinflammatory cytokine IL-17F and TNF- ɑ after psoriasis model mouse is administered in acetamide in this experiment in serum Flat expression is remarkably decreased, and psoriasis is the disease of an inflammatory cell infiltration, and experimental result confirms that the antiphlogistic effects of acetamide are bright It is aobvious, confrontation Th17T cell secretion IL-17F significant effects.In addition, acetamide middle dosage also can induce the table of the IL-23 in serum Up to decline, IL-23 results from bone marrow cell, it can promote the Proliferation, Differentiation of Th17 lymphocytes, then further induces IL-17 Generation.Significant cell factors of the IL-17F and IL-23 as psoriasis, the decline of its expression imply that acetamide exists T lymphocytic immunities work and so that the skin of Pigs with Psoriasis are better.

In conclusion acetamide small molecule of the present invention is respectively provided with significantly anti-inflammatory, immune bidirectional modulation and anti-psoriasis Effect.

Further, the acetamide can form the medicine of various formulations with medically acceptable auxiliary material, such as tablet, cream Agent, spray, capsule or pill.The method that specifically medicine is made in explaination acetamide by taking tablet as an example below.

Tablet, the acetamide for taking purity to be higher than 99.9%, adds ethanol stirring and is allowed to dissolve, the ethanol that extract is made is molten Liquid.Suitable beta-cyclodextrin is taken again, suitable quantity of water is added and stirs evenly, and the ethanol solution of extract is added under stirring, it is high Fast shear agitation makes precipitation to suspension, standing is formed, and adds appropriate amount of starch, co-grinding, sieving, granulation, dry, coating Sugar-coat, to obtain the final product.

It should be noted that when other preparations are made in acetamide, with reference to the prior art.

The above disclosed power for being only a kind of preferred embodiment of the present invention, the present invention cannot being limited with this certainly Sharp scope, therefore equivalent variations made according to the claims of the present invention, are still within the scope of the present invention.

Claims (9)

1. application of the acetamide in anti-inflammatory drug is prepared, it is characterised in that the structural formula of the acetamide is：

2. application as claimed in claim 1, it is characterised in that the dosage of the acetamide is 0.2-2g/kg.

3. application of the acetamide in immunomodulator is prepared, it is characterised in that the structural formula of the acetamide is：

4. application as claimed in claim 3, it is characterised in that the dosage of the acetamide is 0.7-6g/kg, the acetamide Concentration be 0.035-0.3g/ml.

5. application as claimed in claim 3, it is characterised in that the immunomodulator is non-specific immunomodulator.

6. application as claimed in claim 3, it is characterised in that the immunomodulator is specific immunity conditioning agent.

7. application as claimed in claim 3, it is characterised in that the immunomodulator is has nospecific immunity and special concurrently The immunomodulator of property immune function.

8. application of the acetamide in antipsoriatic thing is prepared, it is characterised in that the structural formula of the acetamide is：

9. application as claimed in claim 8, it is characterised in that the dosage of the acetamide is 0.7-2g/kg.