CN103040873B - Use of physically modified cobra venom in preparation of medicines for treating immunosenescence and related diseases - Google Patents
Use of physically modified cobra venom in preparation of medicines for treating immunosenescence and related diseases Download PDFInfo
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Abstract
The invention discloses use of physically modified cobra venom in preparation of medicines for treating immunosenescence and related diseases. According to the invention, animal experiments show that total venom of physically modified Chinese cobra in the range of (10-3000microgrammes/kg) can effectively various pathological changes of tissues of the body caused by immunosenescence. The total venom of physically modified Chinese cobra has the specific effect of alleviating inflammatory lesion and structural damage of myocardium, liver, lungs, spleen, lymph, thymus, kidney and skins. Under a light microscope, structural abnormalities in immune organs and other tissues as well pathological manifestations such as cellular damage and degeneration and even death of normally aged mice can be seen. Degeneration of immune organs treated by venom is remarkably reduced, and structures of main organs are improved to different extent. Venom treatment does not affect normal biochemical functions of the aged body, but also converts abnormal biochemical functions to normal functions. The venom can improve decrease of learning and memory ability caused by aging, exercise tolerance decrease and the like. 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
The invention belongs to technical field of new application of medicine, be specifically related to the purposes of the cobra-venom after a kind of physical modification in preparation treatment immunosenescence and relevant disease medicine.
Background technology
Snake venom is the complex mixture that the various ingredients of being secreted by the poison gland of Serpentis is formed.Fresh venom is Ovum Gallus domesticus album sample thick liquid, has special fishy smell.Different Serpentis kind venom color and luster is different, and Chinese cobra venom is faint yellow.In the dry of snake venom, more than 90% is protein, is the main component of its toxicity and its biologic activity.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%).Motherland's traditional medicine thinks that Naja and toxic component thereof can the meridian dredging, wind-damp dispelling, and the effect with building body.As far back as earlier 1900s, people just start to apply snake venom to alleviate malignant, tumor pain, neuralgia and arthralgia, occur a series of report having similar morphine sample analgesic activity about snake venom subsequently.Along with deepening continuously of research, now, snake venom and goods thereof have been applied to clinical, and except analgesic activity, research finds at rheumatism, antitumor and in nervous system disease, has good curative effect.Successively find that snake venom can affect the immunologic function of laboratory animal again in recent years.
Summary of the invention
The object of the invention is to provide the application of a kind of cobra-venom in preparation treatment immunosenescence and relevant disease medicine, provides a kind of New methods in working for the treatment of because the multiple organ histologic lesion sexually transmitted disease (STD) caused by immunosenescence becomes.
In order to solve these problems of the prior art, technical scheme provided by the invention is:
The application of a kind of cobra-venom in preparation treatment immunosenescence and immunosenescence relevant disease medicine.Preferably, the degeneration of natural cobra-venom deionized water dissolving post-heating obtains by the cobra-venom after described physical modification, and control heating-up temperature during heat denatured at 100 ± 5 DEG C, heat time heating time is 5min ~ 10min.
Preferably, described natural cobra-venom is selected from Chinese cobra venom or Thailand's cobra-venom.Preferably, described immunosenescence and relevant disease comprise the disease with inflammatory lesion or organ-tissue structural damage.Preferably, the form of administration of the cobra-venom after described physical modification is selected from oral instant medicine film, oral liquid, capsule, varnish, cataplasma, spray and injection.
Preferably, described medicine is the single preparations of ephedrine that cobra-venom after the compound preparation that forms of cobra-venom after physical modification and other drug active component or physical modification and pharmaceutic adjuvant are formed.Preferably, described compound preparation is cobra-venom after physical modification, the natural cobra venom of non-modified and pharmaceutic adjuvant be mixed to form.
The present invention seeks to: provide modification Chinese cobra venom to cause or purposes in the relevant disease medicament being major lesions feature with multiple organ tissue inflammatory pathological changes and structural damage in preparation treatment immunosenescence.In technical solution of the present invention, natural glasses calmy poison physical modification method is by the degeneration of cobra-venom deionized water dissolving post-heating, and heating-up temperature is at about 100 DEG C, and heat time heating time is obtain after 5min ~ 10min.
In the present invention, natural cobra-venom is that Naja is always malicious, will can be used for preparation treatment medicine with take multiple organ tissue inflammatory pathological changes and structural damage as main symptom disease relevant to immunosenescence after its physical modification.Preferably, described cobra-venom is the total snake venom of Chinese cobra.According to the homogeny of composition and drug effect, described natural cobra-venom can be Thailand's cobra-venom and other cobra-venom.
Through zoopery, the present invention confirms that the total poison of Chinese cobra after physical modification pharmaceutically can effectively alleviate because of the multiple organ-tissue pathological changes of whole body in immunosenescence and relevant disease in effective dose (as mice 10-3000 μ g/kg) scope, concrete effect comprises and alleviates immune organ spleen, lymph, the decline of thymus, cell injury and textural anomaly, cardiac muscle can also be alleviated, liver, lungs, kidney and dermal inflammatory pathological changes and structural damage, under light microscopic, there is textural anomaly the organ-tissue inside of visible usual aging object, cell damage, the morbid state performances such as degeneration is even dead, and above-mentioned performance is all improved in varying degrees after the total poison treatment of Chinese cobra after physical modification.From the above, the total poison treatment of Chinese cobra after physical modification does not only affect the normal biochemical function of senile organism but also abnormal biochemical function can be made to turn to normal development, and old and feeble relevant ability of learning and memory decline can be improved, the phenomenons such as endurance reduction, have consumption little, safe, can oral, injectable, can pass through the advantage such as nasal mucosa and percutaneous drug delivery.
The present invention reaches attenuation synergistic object by the process of Chinese cobra total poisons physical method, cobra venom after physical treatment can treat the relevant cardiac muscle of immunosenescence and liver, lungs, spleen, lymph, thymus, kidney and dermal inflammatory pathological changes and damage, its curative effect exceedes 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 prescription and compound preparation.
Chinese cobra venom has been used for the treatment of rheumatism clinically 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 ratio is comparatively large, the mainly protein of the medicinal ingredient in snake venom, its structure and biological activity can be changed by chemical factors.Snake venom is after by hydrogen peroxide treatment, and disulfide bond is opened, and its toxicity reduces greatly, but analgesic activity also almost disappears, and prompting biologic activity is destroyed.And reversibility degeneration can be there is after protein heating, degeneration rear space structure there occurs change, or 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.
Through studying for a long period of time, the present inventor finds that the Chinese cobra venom of heat denatured effectively can alleviate the multiple organ-tissue pathological changes of whole body because immunosenescence causes, concrete effect comprises and alleviates cardiac muscle and liver, lungs, spleen, lymph, thymus, kidney and dermal inflammatory pathological changes and structural damage, under light microscopic, there is textural anomaly the organ-tissue inside of visible usual aging object, the morbid state performances such as cell damage, degeneration are even dead, and above-mentioned performance is all improved in varying degrees after snake venom treatment.Point out infectious disease that immunosenescence is correlated with and institute with organ-tissue damage and have good therapeutical effect.This discovery, produces great impact by the research of immunosenescence and relevant disease and drug development, and has value for clinical application, for Chinese cobra venom opens up clinical new purposes.The total poison of described Naja is when using deionized water dissolving, and heating-up temperature is about 100 DEG C (100 ± 5 DEG C), and the time obtains after 5min ~ 10min.
Relative to scheme of the prior art, advantage of the present invention is:
Adopt always malicious through the Chinese cobra of physical modification, toxicity is low and drug effect is high.Chinese cobra venom can alleviate multiple organ tissue inflammatory lesion degree in immunosenescence and relevant disease, and finally makes it turn to normal level to develop.Inflammatory lesion is multiple at liver, lungs, kidney, and naja naja atra venom can alleviate the inflammatory lesion degree of liver, lungs, kidney obviously, and makes it to recover to normal configuration.Chinese cobra venom can not only alleviate multiple organ organizational structure damage in immunosenescence and relevant disease and can recover its normal configuration and function gradually.Concrete effect comprises and alleviates spleen, lymph, thymus, cardiac muscle, liver, the structural damage of lungs, kidney and skin and recover the normal structure and fuction of above organ-tissue.
Chinese cobra venom can slow down the abnormal internal organs body weight change of multiple organ tissue in immunosenescence and relevant disease.Indirect reaction alleviates organ-tissue degree of injury even may make it restore to normal configuration.Chinese cobra venom not only on immunosenescence and relevant disease original still normal physiological biochemical function without impact, immunosenescence even can be made to cause multiple organ tissue abnormalities biochemical functions and to recover to normal level development.
The learning and memory function of the decline that Chinese cobra venom can make immunosenescence be correlated with presents ascendant trend in various degree.The anti-fatigue ability weakened that Chinese cobra venom can make immunosenescence be correlated with both endurance presents and strengthens trend in various degree.Chinese cobra venom can not only make skin and hair abnormal restoring in immunosenescence and relevant disease to normal level, even can be superior to normal level.Namely the degree such as dense shiny black of hair growth is all significantly better than normal hair level.Chinese cobra venom consumption is few, from the effect that 10 ~ 3000 μ g/kg have well treatment immunosenescence and relevant disease, is about 1 ~ 1000 μ g/kg through conversion people with dosage.
The invention discloses the purposes of Chinese cobra venom in preparation treatment immunosenescence and relevant disease medicine.The present invention finds that the total poison of modification Chinese cobra effectively can alleviate the multiple organ-tissue pathological changes of the whole body relevant to immunosenescence in (10-3000 μ g/kg) scope, concrete effect comprises and alleviates cardiac muscle and liver, lungs, spleen, lymph, thymus, kidney and dermal inflammatory pathological changes and structural damage, under light microscopic, there is textural anomaly the organ-tissue inside of visible usual aging object, the morbid state performances such as cell damage, degeneration are even dead, and above-mentioned performance is all improved in varying degrees after snake venom treatment.Snake venom treatment does not only affect the normal biochemical function of senile organism but also abnormal biochemical function can be made to turn to normal development.Improve the relevant ability of learning and memory of immunosenescence to decline, the phenomenons such as endurance reduction.Have consumption little, safe, can oral, injectable, can pass through the advantage such as nasal mucosa and percutaneous drug delivery.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the invention will be further described:
Fig. 1 be Chinese cobra venom to the kidney in immunosenescence and relevant disease, the impact (pathology) of lung and hepatitis;
Fig. 2 is the impact (pathology) of Chinese cobra venom on multiple organ organizational structure damage in immunosenescence and relevant disease;
Fig. 3 is the impact of Chinese cobra venom on the abnormal organ coefficient of multiple organ in immunosenescence and relevant disease;
Fig. 4 is the impact that Chinese cobra venom detects immunosenescence and relevant disease Biochemical Indexes;
Fig. 5 is that Chinese cobra venom is on routine blood test impact in immunosenescence and relevant disease;
Fig. 6 be Chinese cobra venom on the decline that immunosenescence is correlated with ability of learning and memory impact (Y labyrinth);
The impact (the rotary-type tired instrument of mice) of Fig. 7 to be Chinese cobra venom on immunosenescence be correlated with endurance declined.
Detailed description of the invention
Below in conjunction with specific embodiment, such scheme is described further.Should be understood that these embodiments are not limited to for illustration of the present invention limit the scope of the invention.The implementation condition adopted in embodiment can do further adjustment according to the condition of specific experiment, and not marked implementation condition is generally the condition in normal experiment.
The animal pharmacodynamic experiment of the naja naja atra venom after embodiment physical treatment
By C57BL/6 mice (n=45), female, body weight 16-18g, is divided into 3 groups (often organizing 15): saline control group at random, Chinese cobra venom heating (30 μ g/kg), Chinese cobra venom heating (100 μ g/kg).Gastric infusion 1 year by a definite date, dosage at 10-3000 μ g/kg, once a day.Chinese cobra venom is within 2011, buy to support She Chang from Jiangxi, China province Yingtan Yujiang County rainbow.The degeneration of natural cobra-venom deionized water dissolving post-heating obtained, control heating-up temperature during heat denatured at 100 ± 5 DEG C, heat time heating time is the Chinese cobra venom after 5min ~ 10min obtains physical modification.
In normal C57BL/6 Mice Body, I gG slowly increases before 20 monthly ages, and IgG2b is high level, and IgG1 is low value.Along with the growth of C57BL/6 Mouse Age, body is aging with increasing age, and organ dysfunction fails, and immunologic dysfunction, the chance of occurrence of disease increases.
Experimental result is as follows:
Fig. 1 is the kidney of Chinese cobra venom to this Mus, the impact (× 400) of lung and hepatitis.The kidney of first visible usual aging Mus, lungs and liver all there occurs more serious inflammation, and identical point is that a large amount of lymphocytic infiltration is mainly around the blood vessel of three internal organs, there is part usual aging Mus can also see swollen blood vessels in its kidney, distortion, surrounding cell injury in a organized way, downright bad.Lung regulating liver-QI is also all there occurs blood vessel inflammatory infiltration and be diffusivity extremely around, and cell injury in a organized way near enclosing around blood vessel one, downright bad, karyon disappears, and has cell debris.And three kinds of internal organs after administration only have the even NIP generation of slight local inflammation.
Concrete, in Figure 1A there is blood vessel and surrounding inflammation thereof in serious kidney in usual aging C57BL/6 mice (contrast), and numbers of glomeruli seriously reduces; With the then basic NIP reaction of snake venom (30 μ g/kg) gavage mice in Figure 1B, but numbers of glomeruli is on the low side; With the same basic NIP reaction of snake venom (100 μ g/kg) gavage mice in Fig. 1 C, numbers of glomeruli is normal; The lungs inflammation that in Fig. 1 D, usual aging C57BL/6 mice (contrast) is not only serious as seen, also have blood vessel and alveolar structure to destroy, alveolar wall and alveolar septum thicken; With inflammatory reaction in snake venom (30 μ g/kg) gavage mice then basic apneumia in Fig. 1 E; With the same basic NIP reaction of snake venom (100 μ g/kg) gavage mice in Fig. 1 F, occasionally there is slight alveolar septum congested; The blood vessel that in Fig. 1 G, usual aging C57BL/6 mice (contrast) is serious is as seen inflammation extremely around, hepatic portal vein what blood, and hepatocyte structural failure is even dead; Use snake venom (30 μ g/kg) gavage mice substantially without inflammatory reaction in liver in Fig. 1 H, mild hepatocellular degeneration or damage; Substantially react without inflammation equally with snake venom (100 μ g/kg) gavage mice in Fig. 1 I.
Fig. 2 is eight kinds of internal organs pathology figure (× 400).First heart pathological examination figure is seen, the cardiac muscle fiber of normal control is due to fracture, disappear, occurred a large amount of cardiac muscle fiber crack and crack be significantly greater than arbitrary administration group (without or only there is a small amount of cardiac muscle fiber crack), even snake venom group (100 μ g/kg) returns to normal myocardium substantially.In the cardiac muscle fiber of matched group there is light gray foreign body tissue in large area, and what have even appears at visceral pericardium gap, and visceral pericardium is thickened.See lungs pathological examination again, these lungs, except blood vessel wall inflammatory infiltration extremely around, outside surrounding tissue cells necrosis, are also shown in alveolar wall and lung septal thickening, have influence on alveolar function, show as body respiratory dysfunction.The heart of same snake venom administration group and the performance of lungs pathomorphism are better than matched group all greatly, and larger dose group is wherein better, close to normal structure.In Fig. 2 A there is larger crack in the visible cardiac muscle fiber of usual aging C57BL/6 mice (contrast); Reduce with snake venom (30 μ g/kg) gavage mouse cardiac muscle fiber crack in Fig. 2 B, tend to be essentially normal; Less with snake venom (100 μ g/kg) gavage mouse cardiac muscle fiber crack in Fig. 2 C, structure is normal; In Fig. 2 D there is serious lungs inflammatory reaction in usual aging C57BL/6 mice (contrast), and alveolar wall and alveolar septum thicken, and have interval congestion and edema; In Fig. 2 E, with snake venom (30 μ g/kg), extremely surrounding structure is normal for gavage mice alveolar, occasionally has the slight pulmonary venous pleonaemia in local; Normal with snake venom (100g/kg) gavage mice lung structure in Fig. 2 F.
Hepatic pathology result display in Fig. 2 G ~ L, the liver of contrast has more serious ill pathological manifestations (× 400).The hepatocyte majority degeneration of visible liver except inflammation around hepatic portal vein in figure, damage is even dead, and the even disappearance under light microscopic there being visible cell karyopycnosis, kytoplasm swelling, without normal configuration.Spleen and lymph and thymus pathological examination also show, the immune organ of normal control Mus all there occurs serious pathological changes, first be that spleen Red marrow and white pulp boundary are unclear, and the lymphocyte overwhelming majority that spleen tunicle makes a circle in white pulp next week there occurs degeneration, downright bad, karyon diminishes and even disappears, and has a lot of cell debris to exist, and obviously occurs a large amount of macrophage.In Fig. 2 G, usual aging C57BL/6 mice (contrast) liver vessel inflammation and have hepatocyte cavity shape steatosis extremely around, damages even dead; Make moderate progress by snake venom (30 μ g/kg) gavage mouse liver cellular swelling phenomenon in Fig. 2 H, present more hepatocyte, the structures such as karyon has increase than contrast, hepatic sinusoid are also normal; Normal by snake venom (100 μ g/kg) gavage mouse liver structure in Fig. 2 I; Usual aging C57BL/6 mice (contrast) tunicle structural failure in Fig. 2 J, the mortality of white pulp endolymph cell, macrophage exists in a large number engulfs dead cell ， Red marrow white pulp unclear boundaries, and spleen normal configuration disappears; Normal by snake venom (30 μ g/kg) gavage mouse spleen structure in Fig. 2 K, there is periarterial lymphatic sheath; Normal by snake venom (100 μ g/kg) gavage mouse spleen structure in Fig. 2 L, there is germinal center ， Red marrow white pulp distinct.
Simultaneously the lymph node of Fig. 2 M ~ R and thymus pathological examination (× 400) show, cortex of lymph node and the medullary substance boundary of usual aging Mus are unclear, the thinning even structural deterioration of tunicle, girder, the structures such as lymphatic sinusoid are close to and disappear, the most degeneration of a circle lymphocyte near even under tunicle, damage is even downright bad, cell volume increases, and karyon diminishes and even disappears, and has cell debris to exist in a large number and the macrophage quantity of phagocyte fragment is abnormal increases.In this experiment, the thymus inner cortex of usual aging mice increases, and medullary substance atrophy, almost without medullary substance.Usual aging C57BL/6 mice (contrast) capsule of lymph node structural deterioration in Fig. 2 M, girder and lymphatic sinusoid structure disappear, and cortex medullary substance boundary is unclear, and a large amount of cell death in cortex, structural deterioration, a large amount of macrophage occurs engulfing dead cell; Normal with snake venom (30 μ g/kg) gavage mouse lymph junction structure in Fig. 2 N, cortex medullary substance distinct, girder, lymphatic sinusoid structure occurs; With snake venom (100 μ g/kg) gavage mouse lymph nodes cortex medullary substance distinct in Fig. 2 O, there is girder, the structures such as lymphatic sinusoid; Usual aging C57BL/6 mice (contrast) thymic cortex endolymph cell hyperplasia in Fig. 2 P; Make moderate progress by snake venom (30 μ g/kg) gavage Mouse Thymic Cortex endolymph cell hyperplasia phenomenon in Fig. 2 Q, medullary substance area starts to expand; In Fig. 2 R with the thymic cortex of snake venom (100 μ g/kg) gavage mice and medullary substance structure normal.
Finally observe kidney and dermal pathology result (× 400) in Fig. 2 S ~ Z.The Renal Structure heavy damage of usual aging Mus can be found out from Pathological.Numbers of glomeruli sharply reduces, and only has minority glomerule in the visual field, and glomerular volume is abnormal, structural deterioration, and prompting has a large amount of glomerule to damage early stage in execution, and degeneration even disappears.Renal tubules textural anomaly, tube wall thickening, luminal stenosis, the pyknosis of tube wall cell nuclear, cell space color is light, has the degeneration even phenomena of mortality (cell debris appearance), administration group then in dose dependent show good Renal Structure.The numbers of glomeruli and the size that mainly can be observed kidney recover even have most structure normal to normal level gradually; Renal tubules, blood vessel etc. extremely around also NIP to occur and structure is normal.Emphasis is dermal pathology result, and in the skin finding usual aging object in experiment, the structure such as hair follicle and sebaceous gland is all abnormal.The intra-acinous cell body of perifollicolar contrasting Corium Mus skin in figure is very big, and nuclear pyknosis, what have does not even have karyon, is all kytoplasm (a large amount of little fat drips).Under normal circumstances, glandular cell volume is little, and quantity is many, and only have minority to belong to the period of maturation (the large final cracking release sebum of gradual change), the hair follicle structure of administration group is comparatively normal, attached sebaceous gland, and acinus is few, becomes large ripe glandular cell also few, even do not have in it.And the attached acinus of control mice hair follicle not only quantity is many and have a large amount of ripe glandular cells; Simultaneously sebum secretion is excessively prosperous, and in it, some composition toxic action to skin is crossed strong etc., cause final poisoning, wither, come off.Specifically compared to contrast Mus, the few cortex of administration Mus dermal tissue component is thin, and this belongs to the normal pathological manifestations of aging.The a large amount of acinus of contrast skin endogenous cause of ill, the existence of glandular cell becomes agent structure, so that is full of sebaceous gland in the visual field, and adipose cell then because occupied area seldom and is not easily observed in the same visual field, is even left in the basket because being difficult to observe by contrast.In Fig. 2 S, usual aging C57BL/6 mice (contrast) numbers of glomeruli seriously reduces, renal tubules textural anomaly, tube wall thickening, luminal stenosis, and tube wall cell has the degeneration phenomena of mortality; In Fig. 2 T there is serious inflammatory reaction in usual aging C57BL/6 mice (contrast), glomerule and the heavy damage of renal tubules structure, and renal interstitial is congested; In Fig. 2 U, with snake venom (30 μ g/kg), gavage murine glomerular slightly increases but structure is normal, and renal tubules tube wall slightly thickens, and exhausted most urinary cast parietal cell is in good condition; In Fig. 2 V with the glomerule of snake venom (100 μ g/kg) gavage mice and renal tubules structure normal; Usual aging C57BL/6 mice (contrast) perifollicolar sebaceous gland hyperplasia in Fig. 2 W; Usual aging C57BL/6 mice (contrast) perifollicolar sebaceous gland hyperplasia compressing hair follicle in Fig. 2 X, hair follicle structure is abnormal; Normal by snake venom (30 μ g/kg) gavage mouse hair follicles structure in Fig. 2 Y, just overall cortex is thinner; Normal by snake venom (100 μ g/kg) gavage mouse hair follicles structure in Fig. 2 Z, cortex is thinner equally.
Fig. 3 is the impact of Chinese cobra venom on the organ organ index that immunosenescence is correlated with.Because of thymic cortex adaptability hypertrophy so thymic factor D injection is increase in usual aging mice, but through its cardiac muscle of mice of snake venom treatment, liver, spleen, lymph node, lungs, kidney, the damage of the organs such as brain all alleviates or returns to normal level, do not have the necrosis of cell or the damage of structure with or disappear so the body weight of these internal organs is relatively greater than usual aging contrast Mus, only has thymus because of adaptability hypertrophy, normal structure is returned to after treatment, i.e. cortex medullary substance clear-cut, tunicle, the structures such as thymus corpuscle all occur, cortex is paraplasm no longer, therefore thymus organ index declines.In Fig. 3 in A, B, C, D, E, F, G figure,
*represent and compare, p<0.05 with matched group (usual aging C57BL/6 group),
*represent and compare with matched group, p<0.01,
* *represent and compare with matched group, p<0.001.
When giving Chinese cobra venom and being about 11w, between each group mice, skin and hair starts to occur notable difference.Matched group hair is thinning, and between Head And Face, omoplate, back finds that there is depilation phenomenon, cutis laxa, and muscle is more unable, increases the weight of with increasing age; By contrast, still in good condition to the black hair of two groups of snake venom treatment, even original than this Mus black is more glossy, and skin elasticity is also obviously be better than usual aging matched group.Then when administration 19w, its depilation phenomenon of usual aging object is further serious, and depilation site area significantly increases, but each loses hair or feathers, position independently exists all the time and do not have connection phenomenon, still has normal skin hair both; Also occurred difference between two groups of snake venom administration groups, snake venom (30 μ g/kg) has minority animal to start to occur depilation phenomenon although group skin and hair net assessment is still better than matched group simultaneously; Snake venom (100 μ g/kg) group is then extraordinary remains its shiny black dense hair health growth, and having no an example has the morbid state performances arbitrarily such as depilation.Along with snake venom continue give, when administration 34 weeks, between two treatment groups of snake venom there is reversion in situation once more.First, the position of originally losing hair or feathers of usual aging object in contrast no longer includes expansion, both no longer depilation also there is no hair regeneration phenomenon certainly, the feature performance at this moment of this Mus is that hair color starts change, there is a large amount of canescence pityrosporum shape squama-similar dandruff, whole skin is dispersed in existence, the especially more concentrated existence in epilating area, trichoxerosis.Mouse Weight is significantly less than normal compared with administration group simultaneously, and thin and weak, activity is few, muscle weakness etc.And two groups of administration groups have a clear superiority in than contrast in these areas, totally seem young active.Emphasis is that reversion has appearred in depilation phenomenon between two groups at this moment.Low dose of snake venom administration group recovers original normal hair conditions substantially in this stage, and hair color is shiny black, and range estimation seems than denser before, and activity is also good; Only have and do not recover completely individually, but its depilation position scope is obviously reducing, surface is point-like (new piliation original state) darkly, and namely the depilation state of this group mice has obtained good improvement, substantially get well skin and hair and the mental status after snake venom treatment.And heavy dose group minority starts to occur depilation phenomenon, but there is not white squama in hair, more find that there is significantly depilation position inflammatory reaction in the future.This group state smaller dose group is poor, but still is better than usual aging contrast, and at least its hair color is shiny black, movable normal.
Mice is put to death after 12 months in administration, pluck eyeball and get blood, room temperature leaves standstill a few hours, after seeing that face, EP area within a jurisdiction has obvious layering namely to have a small amount of serum naturally to separate out, by serum at 4 DEG C, centrifugal 10 minutes of 4000r/mi n, sent to hospital by separating obtained serum and do blood biochemical and blood routine examination, acquired results is shown in Fig. 4 and Fig. 5.In each multiple figure of Fig. 4 and Fig. 5, * represents and to compare, p<0.05 with matched group (usual aging C57BL/6 group), * represents and to compare with matched group, p<0.01, * * * represents and to compare with matched group, p<0.001.
Fig. 4 is the impact that Chinese cobra venom detects immunosenescence and relevant disease Biochemical Indexes, the normal biochemical function that Chinese cobra venom is not only relevant to immunosenescence does not as can be seen from Figure make significant difference and (mainly comprises ALT, AST, serum sodium etc.), multiple organ tissue abnormalities biochemical function caused by immunosenescence (mainly albumin, globulin, A/G, serum creatinine, blood urea nitrogen, blood potassium etc.) even can be made to recover to normal level development.Because this usual aging mice easily produces immunologic tolerance, serum immune globulin yields poorly, namely globulin total amount is low, through snake venom treatment after globulin total amount can be made to increase, albumin decline, this also pointed out snake venom really can by increase immunoglobulin amount to reach therapeutical effect, both this immunity of organism tolerance effect had been removed, recover normal immunological response gradually, thus the chemical result having globulin to increase, infer with front and back and echo mutually.Fig. 5 is the impact of Chinese cobra venom on the routine blood test in immunosenescence and relevant disease.In experiment, usual aging object numeration of leukocyte is on the low side; wherein especially on the low side for main cause with lymphocyte count; this and immunosenescence cause immunodeficiency to be closely related; after snake venom treatment; these two indexs are gradually to normal recovery; treat with low dose of snake venom the effect obtained more remarkable, see A and B in Fig. 5.
The agility of the daily routines of each group of mice, liveness etc. and physical condition also have obvious difference.Administration group frequent activity and matched group relative silence in mouse cage; Contrast Mus is easy to get when climate change (particularly moist sombre weather) flu, and administration group body constitution is relatively better.Test have employed Y maze experiment to study the space identity memory ability difference between each group of mice.The difference of resisting fatigue and endurance level between each group of mice is studied with the rotary-type tired instrument of mice.
Fig. 6 is the impact of Chinese cobra venom on the ability of learning and memory of the decline that immunosenescence is correlated with.What adopt in this experiment is the electricity irritation test of Y labyrinth.Concrete grammar: every mice first adapts to 3-5min in labyrinth, then starts formal experiment.Each electric shock time delay is 3-5s, general 5s, until continuous 9 correct responses are association in the training process of mice.Three days on pretreatment, train every mice every day 20 times, namely fix frequency of training method, record the correct number of times of mice every day, correct number of times is more, illustrates that learning capacity is stronger.Within about 3-4 days, most mice can reach association's standard, can eliminate indivedual overacfivity or excessively blunt type.Early stage, learning process can carry out preliminary assessment according to each group of mice study natural law or every day after correct response rate statistics, the results are shown in Figure 6(A and B). then carry out the detection of memory retention, account for total percentage ratio detecting number of times with correct response number of times and represent the memory retention number of times of the correct response (/ always detect number of times × 100%), the higher explanation memory of this value is better.Detection time, point was after learning phase continuous three days respectively, first week, the 3rd week, the 9th week.The results are shown in Figure 6(C and D).By Fig. 6, we can obtain as drawn a conclusion: be all significantly better than usual aging contrast Mus with the ability of learning and memory of two groups of mices of snake venom treatment, errors number every day being embodied in first three day of snake venom treatment group study is less, correct response rate higher (compared to usual aging object), and significant difference.Three groups of mices reach association's standard in unification on the 4th of study, so, from then on start day to have carried out memory retention test experience.The memory retention that the result obtained is still snake venom treatment group will be significantly higher than usual aging matched group, can from figure every day errors number and correct response rate obtain this conclusion.Fig. 6 is at A, B, C, D tetra-in figure, * represent and compare with matched group (usual aging C57BL/6 group), p<0.05, * * represents and to compare with matched group, p<0.01, * * * represents and to compare with matched group, p<0.001.
Fig. 7 is the impact that Chinese cobra venom declines on exercise tolerance.The instrument adopted in experiment is the rotary-type tired instrument of YLS-10B mice.Test as follows: by constant for experimental period in the more unified time period: in 1 o'clock to 3 o'clock afternoon, front and back all can not be tested.Within one day, twice experiment can be carried out.Run at each group of random selecting 5 mice stand in channels, three groups of totally 15 mices, meanwhile, the passage that each mice is run also is Stochastic choice, some interference effects that may produce to avoid channel difference at every turn.The first round terminates rear scouring instrument, can test after the clean drying of instrument to totally 15 mices of each group of remainder.As experiment need be repeated after terminating, after being then set in the 3rd day of the last experiment end, by Fig. 7, we obtain conclusion: after giving snake venom treatment, the anti-fatigue ability of this mice and endurance are significantly higher than usual aging matched group, no matter be that to have carried out total testing time be 35.5 minutes or 60 minutes, the time of on average running of two treatment group mices of snake venom and distance of running are all more than matched group, and significant difference.Fig. 7 A, in B, * represents and compares p<0.05 with matched group (usual aging C57BL/6 group), and * * represents and to compare with matched group, and p<0.01, * * * represents and to compare with matched group, p<0.001.When each group of C57BL/6 Mus carries out Y labyrinth and mice rotary-type tired instrument experiment, there occurs seborrheica depilation in various degree.
This tests comprehensive multiple organ pathological study result and organ weight, biochemical indicator, and ability of learning and memory and exercise tolerance test, draw the following conclusions: cobra-venom effectively can alleviate the multiple organ-tissue pathological changes of whole body because of immunosenescence and relevant disease, concrete effect comprises the Aging structural change alleviating spleen, lymph and these immune organs of thymus, cardiac muscle, liver can also be improved, lungs, kidney and dermal inflammatory pathological changes and structural damage.Snake venom treatment energy leukocyte increasing and lymphocyte count, reduce Archon ratio.Improve learning and memory and improve exercise tolerance ability.Snake venom can be thought thus to pass through to alleviate immunity of organism aging degree and finally serve certain antiinflammatory and the effect slowing down body aging.
In sum, confirm through test, the naja naja atra venom oral administration after physical modification can alleviate multiple organ tissue inflammatory lesion degree in immunosenescence and relevant disease, and finally makes it recover to normal level.Chinese cobra venom oral administration after physical modification can alleviate the multiple organ organizational structure damage in immunosenescence and relevant disease and recover its normal configuration and function gradually.Concrete effect comprises and alleviates spleen, lymph, thymus, and cardiac muscle, liver, the structural damage of lungs, kidney and skin and recover the normal structure and fuction of above organ-tissue.Because inflammatory lesion is multiple at liver, lungs, kidney, so be significantly the inflammatory lesion degree that naja naja atra venom can alleviate liver, lungs, kidney.
Chinese cobra venom oral administration after physical modification can slow down the abnormal organ coefficient change of multiple organ tissue in immunosenescence and relevant disease.Indirect reaction alleviates organ-tissue degree of injury.Chinese cobra venom oral administration after physical modification not only on the normal blood biochemical function in immunosenescence and relevant disease without impact, even can make organ-tissue abnormal blood biochemical function to normal level development recover.
Chinese cobra venom oral administration after physical modification can make the learning and memory function of old and feeble relevant decline return to normal level to some extent.Chinese cobra venom oral administration after physical modification can make the endurance level of old and feeble relevant reduction return to normal level to some extent.Chinese cobra venom oral administration after physical modification can not only make abnormal skin hair in diseases associated with senescence return to normal level, even can be superior to normal level.Namely the degree such as dense shiny black of hair growth is all significantly better than normal hair level.
Above-mentioned example, only for technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalent transformations of doing according to spirit of 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 after a physical modification in the disease medicament that preparation treatment immunosenescence is relevant with immunosenescence; The degeneration of natural cobra-venom deionized water dissolving post-heating obtains by the cobra-venom after described physical modification, and control heating-up temperature during heat denatured at 100 ± 5 DEG C, heat time heating time is 5min ~ 10min,
The disease of the organ-tissue structural damage of disease caused by immunosenescence that described immunosenescence is correlated with, concrete effect comprises and alleviates immune organ spleen, lymph, the decline of thymus, cell injury and textural anomaly, cardiac muscle, liver can also be alleviated, lungs, kidney and dermal inflammatory pathological changes and structural damage.
2. application according to claim 1, is characterized in that described natural cobra-venom is selected from Chinese cobra venom or Thailand's cobra-venom.
3. application according to claim 1, is characterized in that the form of administration of the cobra-venom after described physical modification is selected from oral instant medicine film, oral liquid, capsule, varnish, cataplasma, spray and injection.
4. application according to claim 1, is characterized in that described medicine is the single preparations of ephedrine that cobra-venom after the compound preparation that forms of cobra-venom after physical modification and other drug active component or physical modification and pharmaceutic adjuvant are formed.
5. application according to claim 4, is characterized in that described compound preparation is cobra-venom after physical modification, the natural cobra venom of non-modified and pharmaceutic adjuvant is mixed to form.
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