CN103040874A - Application of physically modified cobra venom in preparation of medicines for treating systemic lupus erythematosus - Google Patents
Application of physically modified cobra venom in preparation of medicines for treating systemic lupus erythematosus Download PDFInfo
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Abstract
The invention relates to an application of physically modified cobra venom in preparation of medicines for treating systemic lupus erythematosus. According to the invention, animal experiments show that total venom of physically modified Chinese cobra in the range of (10-3000microgrammes/kg) can remarkably treat or improve clinical manifestations of systemic lupus erythematosus such as tissue damages and functional abnormalities of various organs, rise of urine protein and abnormal activities, alleviate tissue damages of organs such as kidney, spleen, lymph gland and thymus as well as skin damage, reduce the content of urine protein, correct abnormal daily performances and spontaneous activities, improve abnormal blood routine and biochemical functions of blood due to diseases, and even remove the tolerance state of splenic lymphocyte to foreign antigens to a certain extent and adjust the abnormal cell factor level. The venom has the advantages of small use level, safety, oral administration, injection, delivery through oral mucous membrane and nasal mucosa and skins and the like.
Description
Technical field
New medicine use technical field of the present invention is specifically related to the purposes of cobra-venom in the preparation medicament for treating systemic lupus erythematosus behind a kind of physical modification.
Background technology
Snake venom is the complex mixture that is made of the various ingredients that the poison gland of Serpentis is secreted.Fresh venom is Ovum Gallus domesticus album sample thick liquid, has special fishy smell.Different Serpentis kind venom color and lusters are different, and it is faint yellow that Chinese cobra venom is.Being protein more than 90% in the dry of snake venom, is the main component of its toxicity and its biologic activity.The Chinese cobra venom composition mainly contains other proteinoid such as cobra venom factor (1%-2%), cardiotoxin (having another name called cytotoxin 40%-50%), neurotoxin (10%).But motherland's traditional medicine is thought Naja and toxic component the meridian dredging thereof, wind-damp dispelling, and have the effect of building body.As far back as earlier 1900s, people just begin to use snake venom and alleviate malignant, tumor pain, neuralgia and arthralgia, a series of reports that similar morphine sample analgesic activity is arranged about snake venom occur subsequently.Along with deepening continuously of research, now, snake venom and goods thereof have been applied to clinical, and except analgesic activity, research is found at rheumatism, antitumor and good curative effect is being arranged aspect the nervous system disease.Successively found that many proof snake venom can affect experiment and the research of the immunologic function of laboratory animal again in recent years, opened up a brand-new road for the application clinically of following snake venom, had very great suggestion.With solving a lot of relevant seriousness diseases of multiple and immunologic dysfunction that still past medical help at present, have great practical value and application prospect.
Summary of the invention
The object of the invention is to provide the application of the cobra-venom behind a kind of physical modification in the preparation medicament for treating systemic lupus erythematosus, and a kind of New methods in working of systemic lupus erythematosus is provided.
In order to solve these problems of the prior art, technical scheme provided by the invention is:
The application of cobra-venom behind a kind of physical modification in the preparation medicament for treating systemic lupus erythematosus.
Preferably, the cobra-venom behind the described physical modification is that heating-up temperature is 100 ± 5 ℃ with cobra-venom deionized water dissolving post-heating degeneration, and be 5min～10min heat time heating time.
Preferably, the cobra-venom behind the described physical modification is selected from Chinese cobra venom behind the physical modification or the Thailand's cobra-venom behind the physical modification.
Preferably, the form of administration of the cobra-venom behind the described physical modification is selected from oral instant medicine film, oral liquid, capsule, varnish, cataplasma, spray and injection.
Preferably, cobra-venom and the pharmaceutic adjuvant behind the cobra-venom behind the described physical modification and other drug active component composition compound preparation or the physical modification forms single preparations of ephedrine.
The invention provides Chinese cobra venom behind the physical modification or Thailand's cobra-venom in the multiple organ-tissue damage of preparation treatment and dysfunction, urine protein raises, the purposes in the unusual medicine of behavioral activity.Preferably, described systemic lupus erythematosus (sle) comprises having multiple organ-tissue damage and dysfunction, and urine protein raises, the disease that behavioral activity is unusual.Cobra-venom is always poison of Naja among the present invention, comprises having multiple organ-tissue damage and dysfunction with can be used for preparing systemic lupus erythematosus behind its physical modification, and urine protein raises, the medicine of the disease that behavioral activity is unusual.
The present invention relates to the purposes of Chinese cobra venom in the preparation medicament for treating systemic lupus erythematosus.The Chinese cobra total poison of the present invention after zoopery confirms physical modification be effective dose (mice 10-3000 μ g/kg pharmaceutically, people 1～1000 μ g/kg) kidney of the internal energy mitigation system lupus erythematosus appearance of scope, spleen, lymph node, the damage of the organ-tissues such as thymus and skin lesion, reduce urine protein content, correct unusual daily behavior and spontaneous activity, improve unusual routine blood test and blood biochemical function due to the disease, even removed to a certain extent the tolerance status of splenocyte to exotic antigen, the cytokine levels of dysregulation, it is little to have a consumption, safety, can be oral, injectable, can see through the advantages such as mouth and nose mucosa and percutaneous drug delivery.
The present invention processes by the total poisons physical method of Chinese cobra and reaches the attenuation synergistic purpose, the kidney that cobra venom energy mitigation system lupus erythematosus after the physical treatment occurs, spleen, lymph node, the damage of the organ-tissues such as thymus and skin lesion, reduce urine protein content, correct unusual daily behavior and spontaneous activity, improve unusual routine blood test and blood biochemical function due to the disease, even removed to a certain extent the tolerance status of splenocyte to exotic antigen, the cytokine levels of dysregulation, therefore have the effect of systemic lupus erythematosus, its curative effect surpasses the neurotoxin (Cobratoxin) of undressed cobra venom or purification.Described medicine comprises oral liquid, oral instant medicine film, capsule, varnish, cataplasma, spray and injection etc., and described medicine also comprises various folk prescriptions and compound preparation.
Chinese cobra venom has been used for the treatment of clinically rheumatism and has alleviated malignant, tumor pain, neuralgia and arthralgia etc., but all uses the mix preparation of the neurotoxin of purification, multiple snake venom or the compound preparation of cobra venom and other Chinese medicine.In view of naja naja atra venom toxicity is larger, the medicinal ingredient in the snake venom mainly is protein, and its structure and biological activity can be changed by chemical factors.Snake venom is after with hydrogen peroxide treatment, and disulfide bond is opened, and its toxicity reduces greatly, but analgesic activity also almost disappears, and the prompting biologic activity is destroyed.And the reversibility degeneration can occur after the protein heating, change has occured in degeneration rear space structure, or the part macro-molecular protein is decomposed into small molecular weight protein because of heating part.Mouse test proves that the snake venom toxicity after this heat denatured obviously reduces, and drug effect increases.The inventor find the Chinese cobra venom of heat denatured can mitigation system organ-tissue damage and the skin lesions such as the kidney that occurs of lupus erythematosus, spleen, lymph node, thymus, reduce urine protein content, correct unusual daily behavior and spontaneous activity, improve unusual routine blood test and blood biochemical function due to the disease, even removed to a certain extent the tolerance status of splenocyte to exotic antigen, the cytokine levels of dysregulation, prompting has good therapeutical effect to systemic lupus erythematosus (sle).This discovery will be to treating multiple organ-tissue damage and dysfunction, and urine protein raises, and the research that behavioral activity is unusual and drug development produce great impact, and value for clinical application is arranged, for Chinese cobra venom is opened up clinical new purposes.
The total poison of described Naja is to use in the situation of deionized water dissolving, and heating-up temperature is that the time obtains behind 5min～10min about 100 ℃.
With respect to scheme of the prior art, advantage of the present invention is:
1. adopt through the total poison of the Chinese cobra of physical modification, toxicity is low and drug effect is high.
2. Chinese cobra venom can not only improve the unusual daily behavior of systemic lupus erythematosus (sle) disease and can also improve its unusual spontaneous activity.
3. the kidney damage that can not only the mitigation system lupus erythematosus occurs of Chinese cobra venom can also alleviate the urine protein that causes because of the kidney damage symptom that seriously raises.
4. immune organ and tissue (being mainly spleen, lymph node, the thymus) damage that can not only the mitigation system lupus erythematosus occurs of Chinese cobra venom, the skin lesion that can also palliate a disease and occur.
5. Chinese cobra venom can not only improve the unusual routine blood test that systemic lupus erythematosus (sle) occurs, and can also improve the unusual blood biochemical function that disease occurs.
6. Chinese cobra venom has been removed the splenocyte of systemic lupus erythematosus (sle) appearance to a certain extent to the tolerance status of exotic antigen, makes its recovery can produce corresponding state of immune response to the exotic antigen foreign body normally.
7. Chinese cobra venom can not only reduce IgG anti-double-chain DNA autoantibody in the serum, can also reduce the level that produces interleukin-6 in the closely-related serum with autoantibody.
8. Chinese cobra venom can not only reduce inflammatory factor Tumor Necrosis Factor Alpha Levels in the serum, can also improve the level of the serum endocomplement C3 of serious reduction.
9. the Chinese cobra venom consumption is few, and effective range is large, and the effect of good systemic lupus erythematosus is arranged from 10～3000 μ g/kg.Human dosage is about 1～1000 μ g/kg.
The invention discloses the purposes of Chinese cobra venom in the medicine of preparation systemic lupus erythematosus.The present invention finds that the total poison of modification Chinese cobra is in (10-3000 μ g/kg) scope internal energy clinical manifestation such as the damage of multiple organ-tissue and dysfunction to systemic lupus erythematosus (sle), urine protein raises, Deviant Behavior activity etc. has obvious treatment or improvement effect, it can alleviate kidney, spleen, lymph node, the damage of the organ-tissues such as thymus and skin lesion, reduce urine protein content, correct unusual daily behavior and spontaneous activity, improve unusual routine blood test and blood biochemical function that disease occurs, even removed to a certain extent the tolerance status of splenocyte to exotic antigen, the cytokine levels of dysregulation, it is little to have a consumption, safety, can be oral, injectable, can see through the advantages such as mouth and nose mucosa and percutaneous drug delivery.
Description of drawings
The invention will be further described below in conjunction with drawings and Examples:
Fig. 1 is that Chinese cobra venom is on the impact of urine protein content in the model of systemic lupus erythematosus Mus body;
Fig. 2 is that Chinese cobra venom is on the impact of model of systemic lupus erythematosus Mus spontaneous activity;
Fig. 3 is that Chinese cobra venom is on the impact of model of systemic lupus erythematosus Mus routine blood test;
Fig. 4 is that Chinese cobra venom is on the impact of model of systemic lupus erythematosus Mus blood biochemistry;
Fig. 5 is that Chinese cobra venom is on the impact of the model of systemic lupus erythematosus Mus cells in vivo factor;
Fig. 6 is that Chinese cobra venom is on the impact of spleen lymphocyte proliferation ability in the model of systemic lupus erythematosus Mus body;
Fig. 7 is that Chinese cobra venom is on the impact of the relevant organ coefficient of model of systemic lupus erythematosus Mus;
Fig. 8 is that Chinese cobra venom is on the impact of the relevant internal organs pathology of model of systemic lupus erythematosus Mus.
The specific embodiment
Below in conjunction with specific embodiment such scheme is described further.Should be understood that these embodiment are not limited to limit the scope of the invention for explanation the present invention.The implementation condition that adopts among the embodiment can be done further adjustment according to the condition of concrete experiment, and not marked implementation condition is generally the condition in the normal experiment.
The animal pharmacodynamic experiment of the Chinese cobra venom systemic lupus erythematosus after the embodiment physical treatment
In the zoopery of Chinese cobra venom systemic lupus erythematosus, administering mode adopts gastric infusion in the EXAMPLE Example, and dosage is at 10-3000 μ g/kg, once a day.Chinese cobra venom is that purchase in 2011 economizes the foster She Chang of Yingtan Yujiang County rainbow from Jiangxi, China.Natural cobra-venom is obtained with the degeneration of deionized water dissolving post-heating, and the control heating-up temperature is at 100 ± 5 ℃ during heat denatured, and be the Chinese cobra venom after 5min～10min obtains physical modification heat time heating time.
The MRL/lpr mice is divided into 5 groups at random, (n=10) female, 12w age, body weight 32-38g: model group (giving distilled water), Chinese cobra venom heating small dose group (20 μ g/kg), middle dosage group (40 μ g/kg), heavy dose of group (80 μ g/kg), Radix Tripterygii Wilfordii positive controls (10mg/kg).
From administration, detect weekly the urine protein content of once respectively organizing mice.Adopt the range estimation albustix that urine protein is detected in the experiment.The result divides negative, trace ,+(30mg/dl), ++ (100mg/dl), +++(300mg/dl), ++ ++ (2000mg/dl) six ranks, be designated as respectively 0,1,2 during statistics, marked in 3,4,5 minutes, at last by the rank test statistical analysis, the urine protein content that can find model group in whole long-term experiment process continued to increase (0-12w) before this, was stabilized in afterwards +++-++ ++ (13-18w), serious urine protein phenomenon is arranged namely.The urine protein content of each snake venom administration group and positive group has in various degree reduction with respect to model group, wherein the albumen effect of falling of each dosage of snake venom all obviously is better than positive Radix Tripterygii Wilfordii, and has dosage correlation, heavy dose of effect is best, the urine protein content that records reduces the most remarkable, middle dosage takes second place, and low dose is relatively the most weak.The results are shown in Figure 1 for Chinese cobra venom on the impact of urine protein content in the model of systemic lupus erythematosus Mus body (
N=10); Compare * P＜0.05 with matched group, * * P＜0.01, * * * P＜0.001.
In snake venom successive administration process, lupus model mice skin lesion occurred in 16w during age.Main manifestations is red speckle not of uniform size to occur at Head And Face and ears exterior feature, and at whole piece Mus tail punctation has appearred, speckle becomes large age with increasing, speckle also increases with increasing age, and this kind state punctations or speckle after model mouse continued for two weeks begin incrustation, come off, yet this place's skin is also simultaneously thereupon rotten to the corn or come off, show as the Head And Face decortication, auricle fracture, the rotten to the corn phenomenon of afterbody.By contrast, the skin lesion of each snake venom administration group is lighter.The overwhelming majority only exists ears and Head And Face the little speckle of a small amount of redness to occur, and afterbody there is no that punctation produces.The skin lesion of positive group and model control group are without larger difference, and skin lesion is also more serious.In the time of the lupus model mice skin lesion, find that also model mouse has similar manic symptoms when daily routines.Major embodiment is liveness superelevation in mouse cage, is in the excitatory state of the lower jumping of leaping up in the non-stimulated situation, and is few quiet; Irritability, the crawl difficulty is large, and the speed of running away is fast, and jumping characteristic is good, and is vigilant high, and fierce and brutal, aggressivity is high, and the object of food operator and excitation is stung in happiness.Same positive then relatively quiet with the contrast of administration relative model, easily crawl is safe during experimental implementation, rarely attacks injury.
Between each experimental group, really there are differences because observing this Mus daily behavior, in order to make this species diversity more specific, datumization and it can be added up and finally obtain favourable digital proof.This Mus has been carried out the detection of spontaneous activity.Carry out the mensuration of spontaneous activity in this experiment with video frequency following system, adopt total distance, the activity time, peripheral distance, the periphery time etc. is index.Get wherein certain section interior spontaneous activity index of time.Concrete experiment is per two all once spontaneous activity situations of this Mus that detect after administration.Adopt the universal spontaneous activity viewing system of large mice (JLBehv-LAG-4, Jiliang Software Sci-Tech Co., Ltd., Shanghai) to detect.Determine detecting duration according to the preliminary experiment result is 30 minutes, according to the parallel test principle, each treated animal point detection time is consistent, and avoids because of also different errors that cause of the locomotor activation of time point different animals own.At last each data unification biweekly is added up again, be found that lupus erythematosus model mouse activity in the spontaneous activity inspection box increases unusually, it is many and relatively have significant difference with each administration group to show as the total activity distance.What particularly point out is, it is movable that the lupus Mus mainly concentrates on periphery, lessly be present in the middle section activity, the total activity amount that the administration group then is dose dependent reduces, the activity distance shortens, and within the activity time, relatively large ratio movable at middle section, the periphery activity time reduces relatively, and has significant difference between model mouse and the administration Mus.According to the pertinent literature report, animal total activity amount increases when it is generally acknowledged central nervous excitation, and the total activity amount reduces during central nerve inhibition; And it has been generally acknowledged that middle section is relatively unsafe zone for animal, and less entering, Exploratory behavior mainly concentrates on the surrounding zone.Central authorities' distance ratio increases, and central authorities' time of staying increases or shortens incubation period of entering middle section and shows that all anxiety alleviates.May be overexcited because of the disease reason so this experimental result has illustrated the nervus centralis of lupus model mice to a certain extent, and the anxiety tendency is arranged; In this simultaneously, positive group and the nervus centralis of the mice of each snake venom administration group the situation of being overexcited has then had improvement in various degree because of administration, the therapeutic effect of each administration group of snake venom is better than positive group and is obvious dosage correlation, increases with dosage the overwrought inhibitory action of nervus centralis is strengthened.See Fig. 2 be Chinese cobra venom on the impact of model of systemic lupus erythematosus Mus spontaneous activity (
N=10); Compare * P＜0.05 with model control group, * * P＜0.01, * * * P＜0.001.
Mice is put to death in experiment when proceeding to four months, plucks eyeball and gets blood, and the gained whole blood gets as required packing of serum in 4 degree centrifugal (3000-4000 rev/min), after carry out the detection of the following index.
Get about 200ul serum and make routine blood test and detect with relevant blood parameters, find the ill rear leukocyte of obvious model group, neutrophilic granulocyte, mononuclear cell and blood platelet disorders increase.All index values of administration group mice all have and reduce that the prompting tissue inflammation infects even the phenomenon such as downright bad or hemorrhage has in various degree improvement.Except heavy dose of snake venom group therapeutic effect was not obvious, it is the most remarkable that each index of middle dosage snake venom group reduces, and namely therapeutic effect is best, and low dose is taken second place.The curative effect of positive drug is then relatively unstable, especially fails to improve the mononuclear cell unusual condition, and low when high when to the improvement degree of other three Indexes Abnormalities also being.The results are shown in Figure 3 for Chinese cobra venom on the impact of model of systemic lupus erythematosus Mus routine blood test (
N=10); Blood biochemical aspect, total protein raises unusually in the lupus erythematosus model mouse body, and main manifestations is that globulin raises, A/G reduces.The abnormal protein situation then is significantly improved in the Mice Body after the administration.Except the curative effect of low dose of snake venom administration group significantly, it is best that the abnormal protein of heavy dose of snake venom administration group improves situation, middle dosage takes second place.There is unstability equally in positive Radix Tripterygii Wilfordii curative effect when unusual as the treatment routine blood test.Model mouse exists liver and cardiomyopathy, detecting its glutamate pyruvate transaminase and creatine kinase in the serum increases unusually, but the serum content of these two kinds of materials all decrease (namely recovering to normal level) after treatment, respectively organize data, the therapeutic effect that can find out heavy dose of snake venom administration group is best, these two kinds of index values were reduced to substantially near normal range, and the therapeutic effect of other each group is then relatively not remarkable or unstable.Fig. 4 be Chinese cobra venom on the impact of model of systemic lupus erythematosus Mus blood biochemistry (
N=10) compare * P＜0.05 with model control group, * * P＜0.01, * * * P＜0.001.
Detect the difference of Cytokine of Serum in each group Mice Body with elisa (ELISA) test kit.Detected respectively interleukin-6 (relevant with the generation of autoantibody), IgG anti-double-chain DNA autoantibody, serum complement C3 (because serious autoimmune response has occured, consume in a large number complement C3 and cause serum complement C3 and sharply reduce during systemic lupus erythematosus (sle)), inflammatory factor-α (TNF-α).We find that lupus model mice is intraserous and really have multiple a large amount of autoantibody after the statistics, and main here what detect is IgG anti-double-chain DNA autoantibody.IgG anti-double-chain DNA autoantibody value also raises unusually after testing.Pointed out that to exist IL-6 in the model mouse body unusual.Simultaneously because the inflammatory reaction of multiple internal organs has occured in the model mouse body, it is extraordinary that present embodiment detects the level of inflammatory factor-α in the serum (TNF-α) as scheduled, and the autoimmune response of extraordinary generation to occur to consume complement and cause complement to be exhausted be that numerical exception is on the low side.Also detecting the various dose snake venom gives rear intraserous cytokine numerical value recovering to normal level is in various degree arranged substantially.Wherein the curative effect of low dose of snake venom is the most remarkable, and middle dosage takes second place.Heavy dose of group fails to detect good therapeutic effect temporarily with positive the group on part index number.The results are shown in Figure 5 for Chinese cobra venom on the impact of the model of systemic lupus erythematosus Mus cells in vivo factor (
N=10) compare * P＜0.05 with model control group, * * P＜0.01, * * * P＜0.001.
Each group is selected the part mice and is used for the spleen lymphocyte proliferation experiment, detects splenocyte and is subjected to the post-stimulatory multiplication capacity situation of exotic antigen.With shredding on its splenocyte sieve, repeatedly wash filtration with PBS first, mix rear centrifugal (1500 rev/mins with erythrocyte cracked liquid with the 1:1 volume ratio, 5min), discard upper strata liquid, add behind the equivalent PBS repeatedly pressure-vaccum, break up this liquid, make precipitation (cell) and solution mix homogeneously.After so repeatedly carrying out two times centrifugal, add equivalent 1640 culture medium solutions, the same centrifugal after, add at last the 1640 culture medium solution suspendibles that contain 10% hyclone, counting.The final concentration that final splenocyte is cultivated at 96 orifice plates is 2 * 10
6Cell/ml.Cultured cells is divided into culture medium (acellular) group, culture medium+groups of cells, and culture medium+cell+conA group, the conA final concentration is 5 μ g/ml, each group is all established 6 secondary holes.Cultivate two days later, 4 hours in advance at each hole adding 20ul MTT (5mg/ml), after four hours, each hole adds about 150ul DMSO liquid, make resolution of precipitate become colored solutions, survey immediately each hole absorbance (OD) behind the 10min in 490nm wavelength place. final result display model group and positive administration group embody basic state of anergy for the stimulation of ConA, this and its only autoantigen reaction sensitivity is closely related, also be the feature performance that SLE occurs.Low dose of snake venom group can be improved splenocyte preferably to the tolerance status of exotic antigen; be that the immunologic function of splenocyte is to some extent to normal recovery; breed in a large number behind the irriate; with the model group significant difference; relatively each group can find that low dose of snake venom group curative effect is best simultaneously; middle dosage takes second place, and heavy dose is the most weak.Fig. 6 be Chinese cobra venom on the impact of spleen lymphocyte proliferation ability in the model of systemic lupus erythematosus Mus body (
N=6), compare * P＜0.05 with model control group, * * P＜0.01, * * * P＜0.001.
Put to death the relevant internal organs that obtain behind the mice and weigh, the data obtained is in order to calculate organ coefficient, and statistical analysis finds that the spleen of lupus model mice increases unusually, and it is extraordinary to show as index and spleen index.Its thymus index is less than normal than normally.The while cardiomyopathy, cardiomyocyte cell death can make cardiac weight unusually on the low side.The spleen hypertrophy situation of administration group suppresses to some extent, and showing as index and spleen index has in various degree decline, wherein the inhibition situation performance of positive group and the spleen hypertrophy of heavy dose of snake venom group better, relatively there were significant differences with model group.The thymus index of each administration group and cardiac weight also have the normal level that rises in various degree after treatment, wherein each group of snake venom has the dosage positive correlation, and rising value and the model group comparing difference of the cardiac weight of especially middle dosage and heavy dose of snake venom group are remarkable.Minimum because of thymic weight, significant difference appears in a small amount of sample difficulty, and each administration group only shows as numerically on the rise, and snake venom administration group still has the dosage positive correlation.Positive drug wouldn't be remarkable to the unusual improvement effect of thymus and cardiac weight.The results are shown in shown in Figure 7, Fig. 7 be Chinese cobra venom on the impact of the relevant organ coefficient of model of systemic lupus erythematosus Mus (
N=10), compare * P＜0.05 with model control group, * * P＜0.01, * * * P＜0.001.
In addition part internal organs such as kidney, spleen, lymph, thymus are further made the pathological change that HE dyeing paraffin section is observed organs and tissues, the relevant internal organs pathology difference between each group relatively, and the result please refer to Fig. 8.Fig. 8 is that Chinese cobra venom is on the impact (* 400) of the relevant internal organs pathology of model of systemic lupus erythematosus Mus.The Splenic structure of lupus erythematosus model mouse among Fig. 8 A (model contrast) is unusual, the white pulp area change, and the red pulp area reduces, and extraordinary the increasing of spleen endolymph cell quantity, can be observed a dark intensive lamellar under the mirror; Still unusually but slightly better than model, lymphocyte quantity descends the Splenic structure of Radix Tripterygii Wilfordii group (positive control) to some extent among Fig. 8 B, and the red pulp area also has increase; Among Fig. 8 C the Splenic structure of snake venom heating small dose group than front two groups good, normal spleen trabeculae structure appears, red pulp area and lymphocyte quantity trend towards normally; Snake venom adds the Splenic structure of pining for the dosage group and trends towards normally red pulp white pulp clear in structure among Fig. 8 D; The Splenic structure normal of the heavy dose of group of snake venom heating among Fig. 8 E, red pulp white pulp structure is normal; The lymph node structure of lupus erythematosus model mouse among Fig. 8 F (model contrast) is unusual, and lymphocyte quantity is too much, and lymphatic nodule and paracortical area area increase unusually; The lymph node structure of Radix Tripterygii Wilfordii group (positive control) begins to recover normal among Fig. 8 G, can observe the lymphatic sinusoid structure; The lymph structure of snake venom heating small dose group trends towards normally among Fig. 8 H, tunicle, and it is good that the subcapsular sinus structure normally reaches trabecularism; Snake venom adds the lymph node structure of pining for the dosage group and trends towards normally can having observed blood vessel around under the part visual field among Fig. 8 I; The lymph node structure normal of the heavy dose of group of snake venom heating among Fig. 8 J, tunicle and girder all exist, and structure is good than other groups; The thymus structure of lupus erythematosus model mouse among Fig. 8 K (model contrast) is unusual, corticohyperplassia, and the medullary substance atrophy is when low multiple even do not observe medullary substance; The thymus structure of Radix Tripterygii Wilfordii group (positive control) trends towards normally among Fig. 8 L, and just volume is less than normal; The thymus structure of snake venom heating small dose group trends towards normally among Fig. 8 M, cortex, and the medullary substance boundary is clearly demarcated; Snake venom adds the thymus structure normal of pining for the dosage group among Fig. 8 N; The thymus structure normal of the heavy dose of group of snake venom heating among Fig. 8 O, cortex and medullary substance boundary are clearly demarcated; The Renal Structure of lupus erythematosus model mouse among Fig. 8 P (model contrast) is unusual, and numbers of glomeruli reduces unusually, glomerule swelling, and volume increases, massive inflammatory cells infiltrated; The Renal Structure of Radix Tripterygii Wilfordii group (positive control) is still unusual among Fig. 8 Q, all have inflammatory cell infiltration in glomerule and the renal tubules, but the structural deterioration degree is lighter than model group; The Renal Structure of snake venom heating small dose group slightly is better than model group and positive group among Fig. 8 R, without or only have lighter inflammatory cell infiltration; Snake venom adds the Renal Structure normal of pining for the dosage group among Fig. 8 S.Glomerule and renal tubules structure normal; The Renal Structure normal of the heavy dose of group of snake venom heating among Fig. 8 T.
In sum, as can be known:
Naja naja atra venom oral administration behind the physical modification can not only improve the unusual spontaneous activity that unusual daily behavior that the systemic lupus erythematosus (sle) disease occurs can also improve appearance.The kidney damage that Chinese cobra venom oral administration behind the physical modification can not only the mitigation system lupus erythematosus occurs can also alleviate the urine protein that causes because of the kidney damage symptom that seriously raises.
Immune organ and tissue (being mainly spleen, lymph node, the thymus) damage that Chinese cobra venom behind the physical modification can not only the mitigation system lupus erythematosus occurs, the skin lesion that can also palliate a disease and occur.Chinese cobra venom oral administration behind the physical modification can not only improve the unusual routine blood test that systemic lupus erythematosus (sle) occurs, and can also improve the unusual blood biochemical function that disease occurs.
Chinese cobra venom oral administration behind the physical modification has been removed the splenocyte of systemic lupus erythematosus (sle) appearance to a certain extent to the tolerance status of exotic antigen, makes its recovery can produce corresponding state of immune response to the exotic antigen foreign body normally.Chinese cobra venom oral administration behind the physical modification can not only reduce IgG anti-double-chain DNA autoantibody in the serum, can also reduce the level that produces interleukin-6 in the closely-related serum with autoantibody.Chinese cobra venom oral administration behind the physical modification can not only reduce inflammatory factor Tumor Necrosis Factor Alpha Levels in the serum, can also improve the level of the serum endocomplement C3 of serious reduction.
Above-mentioned example only is explanation technical conceive of the present invention and characteristics, and its purpose is to allow the people who is familiar with technique can understand content of the present invention and according to this enforcement, can not limit protection scope of the present invention with this.All equivalent transformations that spirit is done according to the present invention or modification all should be encompassed within protection scope of the present invention.
Claims (5)
1. the application of the cobra-venom behind the physical modification in the preparation medicament for treating systemic lupus erythematosus.
2. application according to claim 1 is characterized in that the cobra-venom behind the described physical modification is that heating-up temperature is at 100 ± 5 ℃ with cobra-venom deionized water dissolving post-heating degeneration, and be 5min～10min heat time heating time.
3. application according to claim 1 is characterized in that cobra-venom behind the described physical modification is selected from Chinese cobra venom behind the physical modification or the Thailand's cobra-venom behind the physical modification.
4. application according to claim 1 is characterized in that the form of administration of the cobra-venom behind the described physical modification is selected from oral instant medicine film, oral liquid, capsule, varnish, cataplasma, spray and injection.
5. application according to claim 1 is characterized in that cobra-venom and pharmaceutic adjuvant formation single preparations of ephedrine after cobra-venom behind the described physical modification and other drug active component form compound preparation or physical modification.
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| CN103690566A (en) * | 2013-12-19 | 2014-04-02 | 苏州人本药业有限公司 | Application of cobra venom in preparation of immunomodulator |
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| CN102133232A (en) * | 2011-03-18 | 2011-07-27 | 苏州大学 | Cobra venom physical modification method and application in preparation of analgesia or immunosuppressive drugs |
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| CN102133232A (en) * | 2011-03-18 | 2011-07-27 | 苏州大学 | Cobra venom physical modification method and application in preparation of analgesia or immunosuppressive drugs |
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| 孙升华: "神奇虎斑蛇毒征服红斑狼疮", 《世纪行》, no. 11, 30 November 1998 (1998-11-30), pages 40 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103690566A (en) * | 2013-12-19 | 2014-04-02 | 苏州人本药业有限公司 | Application of cobra venom in preparation of immunomodulator |
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