CN109793894A - Application of the dog immunoglobulin in preparation dog hemolytic anemia drug - Google Patents
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Abstract
The present invention relates to application of the dog immunoglobulin in preparation dog hemolytic anemia drug; pass through the test of dog Garden Onion Poisoning, dog poisoning by paracetamol test model; it confirms that dog immunoglobulin has the protective effect after being oxidized to dog due to red blood cell, and then plays the role of preventing haemolysis.Compared with model group or control group; red blood cell can be obviously protected using dog immunoglobulin, oxidation red blood cell can be prevented by the phagocytosis of macrophage, so that it is slow to reduce red blood cell value, hematocrit value; therefore it can extend the time-to-live of dog, provide valuable time for treatment.Therefore dog immunoglobulin can be used for the new drug development of dog hemolytic anemia drug, and confirm important in inhibiting to drug targets.
Description
Technical field
The invention belongs to field of medicaments, are related to application of the dog immunoglobulin in preparation dog hemolytic anemia drug, tool
Body is related to dog immunoglobulin red blood cell caused by preparation treatment dog allium poisoning, drug poisoning etc. and is oxidized, and generates
Heinz body, so as to cause the application in dog hemolytic anemia drug.
Background technique
Hemolytic anemia caused by the poisoning of dog allium, drug poisoning etc. belongs to Immune-mediated hemolytic anemia
It (IMHA), is that chronic reticuloendothelial system haemolysis and (or) acute intravascular hemolysis are caused due to the erythrocyte antibody (EA) of itself
A kind of immunity disease, belongs to type Ⅱ allergy, is the common of the most common immunity disease of dog and dog hemolytic anemia
The cause of disease.It is dead due to excessive blood loss to will lead to dog if treatment is not in time.The drug for the treatment of Immune-mediated hemolytic anemia at present
There are glucocorticoid, imuran, cyclosporin, cyclophosphamide and danazol, these drugs can generate certain in application
Side effect, such as inhibit activity, the hepatotoxicity of lymphocyte.
Immunoglobulin is that (Ig) refers to globulin similar with antibody in antibody activity or chemical structure.Ig is blood
A kind of glycoprotein in liquid and tissue fluid, receiving Proliferation, Differentiation after antigen (such as pathogen) stimulation as B cell is produced by thick liquid cell,
Its main function is to play immune response with antigen, generates antigen-antibody complex, so that harm of the pathogen to body is blocked,
So that pathogen is lost pathogenic effects, is the important effect molecule of humoral immunity.At present have no dog immunoglobulin for treat by
Allium poisoning, drug poisoning cause the report of dog hemolytic anemia.
Summary of the invention
The present invention in view of the above technical problems, passes through the test of dog Garden Onion Poisoning, dog poisoning by paracetamol test model
Confirm the protective effect after dog immunoglobulin is oxidized dog due to red blood cell, it was found that dog immunoglobulin to dog onion and
Hemolytic anemia caused by poisoning by paracetamol has preferable therapeutic effect.
Application of the dog immunoglobulin in preparation dog hemolytic anemia drug is provided simultaneously, specifically, ball is immunized in dog
Albumen preparation dog allium poisoning or drug poisoning caused by red blood cell be oxidized, generate heinz body, so as to cause
Dog hemolytic anemia drug in application.
Wherein, allium includes the plants such as verdant (shallot), garlic, onion, fragrant-flowered garlic.
Drug of the present invention is limited to Canidae or felid uses.
Drug of the present invention is pharmaceutically acceptable any dosage form.It specifically can by dog immunoglobulin and pharmaceutically
Acceptable auxiliary material is prepared into various dosage forms.The auxiliary material can be starch, sucrose, dextrin, microcrystalline cellulose, pregelatinated and form sediment
The conventional medicines such as powder, sodium carboxymethylcellulose, crospovidone, ethyl alcohol, polyvinylpyrrolidone, magnesium stearate, magnesia are auxiliary
One of material is a variety of.The dosage form can be oral preparation or injection.The oral preparation be tablet, capsule or
Pellet.The injection is injection or injection freeze-dried powder.
Dog immunoglobulin is preferably prepared into injection by the present invention.Preferably, the injection be intravenous injection or
Intramuscular dose.
When dog immunoglobulin is as intravenous injection, the present invention also carries out the dosage of dog immunoglobulin
Screening, it is determined that optimal use dosage.Specifically, the application method of the drug are as follows: the agent of dog intravenous immunoglobulin
Amount is that 5-10ml/kg weight is used in conjunction 3-7 days one time a day.The final present invention confirms dog immunoglobulin to food by research
Have the function of slowing down disease progression with dog hemolytic anemia caused after onion and paracetamol, delay progression of the disease.
Compared with prior art, the invention has the benefit that
Dog immunoglobulin, structure contain complete Fab and Fc segment, can be with mononuclear macrophage into after in vivo
On Fc receptor combine, and play sealing process, and then red blood cell is prevented to be destroyed, play the role of preventing haemolysis.This hair
It is bright to confirm that dog immunoglobulin has to dog due to red by the test of dog Garden Onion Poisoning, dog poisoning by paracetamol test model
Cell be oxidized after protective effect, and then play the role of prevent haemolysis.Compared with model group or control group, exempted from using dog
Epidemic disease globulin can obviously protect red blood cell, can prevent oxidation red blood cell by the phagocytosis of macrophage, thus make red blood cell value,
Hematocrit value reduces slowly, therefore can extend the time-to-live of dog, provides valuable time for treatment.Therefore dog is immune
Globulin can be used for the new drug development of dog hemolytic anemia drug, and confirm important in inhibiting to drug targets, with hormone
Equal drugs are small compared to toxic side effect, and safety is good, more preferable with other drugs combination therapeutic effect.
Detailed description of the invention
In order to illustrate the technical solutions in the embodiments of the present application or in the prior art more clearly, below will be to institute in embodiment
Attached drawing to be used is needed to be briefly described, it should be apparent that, the accompanying drawings in the following description is only one recorded in the present invention
A little embodiments are also possible to obtain other drawings based on these drawings for those of ordinary skill in the art.
Fig. 1 is animal gum photo figure before the embodiment of the present invention 1 is treated, and gum is in pale asphyxia；
Fig. 2 is animals tongue photo figure before the embodiment of the present invention 1 is treated, and tongue is in pale asphyxia；
Fig. 3 is animal gum photo figure after the treatment of 1 middle dose group of the embodiment of the present invention, and gingiva color restores normal, in light
It is red；
Fig. 4 is animals tongue photo figure after the treatment of 1 middle dose group of the embodiment of the present invention, and tongue color restores normal, in light
It is red；
Fig. 5 is that the embodiment of the present invention 1 treats proerythrocyte state diagram, a large amount of heinz bodies occurs；
Fig. 6 is red blood cell state diagram after the treatment of 1 middle dose group of the embodiment of the present invention, and heinz body disappears, and is occurred a large amount of
Granulophilocyte.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, below in conjunction with embodiment to this
Invention is further detailed.Implement below for illustrating the present invention, but is not intended to limit the scope of the invention.If not special
It does not indicate, the conventional means that technological means used in implementation is well known to those skilled in the art, raw materials used is commercially available
Commodity.It is to use cold ethanol method from dog serum by Xinuo Biological Science & Technology Co., Ltd., Changchun the present invention relates to dog immunoglobulin
Purifying is prepared, and purity reaches 95.0% or more.Test is Chinese rural area dog with dog, is purchased from Changchun Economic Technological Development Zone brightness
Military fierce dog Breeding base.
1 dog immunoglobulin of embodiment causes the treatment effectiveness evaluation of hemolytic anemia to dog Garden Onion Poisoning
1, the foundation of hemolytic anemia model caused by dog Garden Onion Poisoning
Onion mixes can feeding dog after crushing, establish dog Garden Onion Poisoning model.Evaluation index is the color of tongue, gum,
Red blood cell number, hematocrit, total bilirubin, Hai Enci (Heize) corpusculum and reticulocyte counts.As a result dog after feeding onion
Tongue and gum variation sickly (such as Fig. 1 and Fig. 2), 95% or more red blood cell contains Heize corpusculum (such as Fig. 5).Dog
Red blood cell number, hematocrit reduce obvious, total bilirubin is significantly raised.
2, test grouping
Will feeding onion after second day will spirit it is depressed, tongue, gum pale asphyxia dog pick out, be randomly divided into 4 groups,
Every group 10, it is respectively set as control group (IV group), intravenous dog immunoglobulin high dose group (10ml/kg weight) (I group), quiet
Infuse dog immunoglobulin middle dose group (5ml/kg weight) (II group), intravenous dog immunoglobulin low dose group (2.5ml/kg body
Weight) (III group).
3, the usage and dosage of drug
Control animals (IV group) refuse any processing；Intravenous dog immunoglobulin components are not according to the drug dose of setting
It is injected intravenously, continuous use 3 days (because heinz body probably needs 3 days from generating sharply reducing in animal model
Time).The usage and dosage of specific grouping and drug is shown in Table 1.
The usage and dosage of 1 animal packet of table and drug
4, treatment effectiveness evaluation index
The spirit, appetite of close observation experimental animal after medication, and the change of the tongue and gum of observation experiment animal daily
Change.
Respectively before feeding onion, administration 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 16 days, 23 days, 30
It is put in blood routine measurement pipe from forelimb or/and hind leg vein blood sampling 2mL, the survey for red blood cell number and hematocrit
It is fixed.
Respectively before feeding onion, administration 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 11 days, 13 days, 15
It is drawn 2 liquid of bleeding from above-mentioned blood routine measurement pipe and is put into 1.5mL centrifuge tube, and granulophilocyte dye is added by the amount of 1:1
Color liquid mixes, and stands 20 minutes.It takes 1 drop on glass slide, observes result with oil mirror after drying.1000 red blood cells are counted, are remembered
Reticulocyte counts and Heize corpusculum number are recorded, precentagewise reports result.
Respectively before feeding onion, administration 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 11 days, 13 days from
Forelimb or/and hind leg vein blood sampling 2mL are put in biochemical tube, measure total bilirubin.
5, dog Garden Onion Poisoning causes the therapeutic effect of hemolytic anemia
1st~2 day appearance spirit depressed, anorexia symptom of 42 test dogs after feeding onion.1 after feeding onion~
2 days, the gum of dog was pale, tongue grey black.By blood film as it can be seen that heinz body occurs in 95% or more red blood cell.From
Random selection 40 is served only for testing in 42.
Height, middle dose group the 3rd day after the treatment test the spirit of dog, appetite returns to normal, high, middle dose group examination
It tests dog tongue and gingiva color and restores fast than low dose group and control group, wherein middle dose group is seen figures 3 and 4.Low dose group and
5 days after edible onion, spirit, appetite return to normal control group.
The variation of each group red blood cell number and hematocrit is as shown in table 2.From the test result of table 2 it is found that with feeding ocean
Compare before green onion, all downward trend is presented after feeding onion in medicine group and control group red blood cell number, hematocrit, and red blood cell number exists
It minimizes within 5th day, hematocrit was minimized at the 6th day.When red blood cell number and hematocrit minimize value,
High, middle dose group value is apparently higher than low dose group and control group, and is in significant difference.Start slowly to increase later, high,
Middle dose group was restored at the 16th day in normal range (NR), and low dose group was restored at the 23rd day to normal range (NR), and control group is the
Restore to normal range (NR) within 30 days.
The variation of table 2 each group red blood cell number and hematocrit
The variation of heinz body sum and granulophilocyte sum is shown in Table 3 in blood after dog feeding onion.Medicine group and
Control group tests dog the 1st day after edible onion, and 95.0% or more red blood cell occurs heinz body (see Fig. 5), and with feeding
It is extremely significant (P < 0.01) compared to difference before hello onion；Beginning heinz body quantity is begun to decline within 3rd day, high dose group sea grace
Thatch corpusculum decrease speed is lower than other groups, and high dose group can not detect heinz body at the 13rd day, and middle dose group was at the 11st day
Heinz body can not be detected, low dose group and control group can not detect heinz body at the 9th day.
Each group granulophilocyte sum gradually increases after feeding onion, increases at the 6th day at most, with feeding onion
It is preceding extremely significant (P < 0.01) compared to difference, and high, middle dose group granulophilocyte sum is considerably less than low dose group and control
Group, and be in significant difference (P < 0.05), wherein the red blood cell state of middle dose group is as shown in Figure 6；Each networking later is knitted red thin
Born of the same parents' number is gradually reduced in normal range (NR).
The variation of table 3 each group heinz body and granulophilocyte
Note: * * indicates extremely significant (P < 0.01) with difference before feeding onion, and # is indicated compared with low dose group and control group
Significant difference (P < 0.05)
The variation of each group test total bilirubin is shown in Table 4.From the test result of table 4 it is found that after feeding onion, medicine group and right
Gradually risen according to a group total bilirubin for test dog, until the 3rd day, the content of total bilirubin reaches maximum value, although medicine group and
Control group total bilirubin maximum value still in the normal range, but with feeding onion before comparing difference it is extremely significant (P < 0.01), say
There is haemolysis in bright dog.Medicine group total bilirubin value significant difference (P < 0.05) compared with the control group at this time, illustrates intravenous
Dog immunoglobulin can inhibit total bilirubin to increase, and red blood cell is prevented to be destroyed.Although intravenous dog immunoglobulin low dosage
Difference is not significant compared with the control group for the indices of group, but numerically, which can press down to a certain extent
The generation of hematoclasis, prevention haemolysis processed, but its effect is not so good as high dose group and middle dose group.From the otherness of indices
Compare it is found that high, middle dose group equal significant difference or extremely significant, but comparing difference between high, middle dose group compared with the control group
Not significant, therefore, it is recommended that clinical use dosage is 5ml/kg weight, injection 1 time daily is used continuously 3 days.
The variation of 4 each group of table test total bilirubin
Note: * indicates that significant difference (P < 0.05) compared with the control group, * * indicate the extremely significant (P of difference compared with the control group
< 0.01), ## indicates extremely significant (P < 0.01) with comparing difference before feeding onion
2 dog drug poisoning of embodiment causes the therapeutic effect of hemolytic anemia to be evaluated
1, the foundation of hemolytic anemia model caused by dog paracetamol
15 dogs are pressed into bodyweight p paracetamol, 200mg/kg weight is disposably given, establishes acetparaminosalol
Carbdism model.
2, test grouping
Test dog is randomly divided into 3 groups, every group 5.I group is set as dog immunoglobulin group (medicine group), and II group is set as sun
Property control group, III group is set as negative control group (model group), begins to be controlled with drug when testing dog and clinical symptoms occur
It treats.
3, the usage and dosage of drug
The usage and dosage of drug is shown in Table 5.
The usage and dosage of 5 drug of table
4, treatment effectiveness evaluation index
Clinical indexes include the state of mind, drink/appetite, vomiting, the variation of syneresis, visual mucous membrane.
It takes a blood sample for 24 hours from forelimb or/and hind leg vein in feeding paracetamol, 2 liquid of bleeding is drawn from heparin tube and are put
Enter in 1.5mL centrifuge tube, granulophilocyte dyeing liquor is added by the amount of 1:1, mixes, stands 20 minutes.Take 1 drop in glass slide
On, result is observed with oil mirror after drying.
Before feeding paracetamol, treatment before, treatment the 2nd day, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days
It is put in blood routine measurement pipe from forelimb or/and hind leg vein blood sampling 2ml, the measurement for red blood cell number and hematocrit.
The clinical symptoms of close observation test dog during test, until counting each group dead animal quantity when off-test.
5, dog drug poisoning causes the therapeutic effect of hemolytic anemia
There is spiritual depressed, appetite stimulator in 15 test dogs, 8~12h after oral paracetamol, and part dog goes out
Phenomena such as now vomiting, diarrhea, body temperature increase, tongue, the gum etc. of all dogs only become pale afterwards for 24 hours for experimental animal medication
Color.Thus illustrate that model is successfully established.
Influence of the dog immunoglobulin to sick dog clinical symptoms: medicine group gives dog immunoglobulin+injection reduced form
+ 0.9% sodium chloride injection of glutathione, positive controls give+0.9% chloride injection of glutathione for injection
Liquid, negative control give 0.9% sodium chloride injection.
Negative control group and positive controls test dog tongue, gum become pale asphyxia, dog immunoglobulin group after administration
Test the tongue of dog, gingiva color is baby pink.From clinical symptoms it is found that can protect dog blood after giving dog immunoglobulin
Red blood cell in liquid, to mitigate the symptom of anaemia, the therapeutic effect after dog immunoglobulin is added is better than injection reduced form
Glutathione group.
Medicine group, positive controls, negative control group test dog for 24 hours, go out after oral paracetamol in blood
Existing heinz body.The retention time of heinz body in vivo can be extended after dog immunoglobulin therapy is added.Dog is immune
Globulin can prevent phagocytosis of the macrophage to oxidation red blood cell.
The red blood cell value of three groups of test dogs and the comparing result of cell pack value are shown in Table 6.From 6 test result of table it is found that medicine
Object group, positive controls, the red blood cell value of negative control group test dog and hematocrit value gradually decrease, treatment the 3rd~4
Its value of minimizing.From test result it is found that medicine group red blood cell value and the amplitude of hematocrit value reduction are minimum, with feminine gender
Control group, which tests dog red blood cell value and hematocrit value, reduces amplitude maximum.Test result illustrates that dog immunoglobulin can be protected
Red blood cell is protected, is better than with glutathione for injection combination effect and glutathione for injection group is used alone.
The comparing result of table 6 red blood cell value and cell pack value
Animal survival quantity statistics: medicine group dead 3, positive controls dead 4, negative control group is all dead.
Each group experimental animal death time and The dead quantity are shown in Table 7.
7 each group of table tests dog death condition table
To sum up, the core mechanism of dog cat poisoning by paracetamol is that cellular glutathione is exhausted, has lacked glutathione
In conjunction with the accumulation of N- acetyl benzoquinone imine causes concentration to increase.Due to its electrophilic sub-feature, N- acetyl benzoquinone imine covalent bond is thin
Born of the same parents' albumen (for example, enzyme, structural proteins and regulatory protein) destroys protein function and cell membrane by lipid peroxidation.In addition,
Glutathione depletion makes cell vulnerable to oxidative damage.Glutathione, which is replenished in time, to poisoning dog cat to prevent cell by oxygen
Change, alleviates poisoning symptom.And immunoglobulin, structure contain complete Fab and Fc segment, it, can be with monokaryon into after in vivo
Fc receptor on macrophage combines, and plays sealing process, and then prevent the destruction for being oxidized red blood cell, and it is molten to play prevention
The effect of blood.Duplicate protection can be played the role of by being used in combination with glutathione.
It is above that certain exemplary embodiments of the invention are only described by way of explanation, undoubtedly, for ability
The those of ordinary skill in domain without departing from the spirit and scope of the present invention can be with a variety of different modes to institute
The embodiment of description is modified.Therefore, foregoing description is regarded as illustrative in nature, and should not be construed as wanting right of the present invention
Ask the limitation of protection scope.These modifications or improvements without departing from theon the basis of the spirit of the present invention belong to the present invention
Claimed range.
Claims (8)
1. application of the dog immunoglobulin in preparation dog hemolytic anemia drug.
2. application of the dog immunoglobulin according to claim 1 in preparation dog hemolytic anemia drug, feature exist
In, the hemolytic anemia be poisoned as dog allium or drug poisoning caused by red blood cell is oxidized, to generate Hai Enci small
Body, so as to cause dog hemolytic anemia.
3. application of the dog immunoglobulin according to claim 1 or 2 in preparation dog hemolytic anemia drug, feature
It is, the drug is limited to Canidae or felid uses.
4. application of the dog immunoglobulin according to claim 3 in preparation dog hemolytic anemia drug, feature exist
In the drug is pharmaceutically acceptable any dosage form.
5. application of the dog immunoglobulin according to claim 4 in preparation dog hemolytic anemia drug, feature exist
In the dosage form is injection.
6. application of the dog immunoglobulin according to claim 5 in preparation dog hemolytic anemia drug, feature exist
In the injection is injection or injection freeze-dried powder.
7. application of the dog immunoglobulin according to claim 5 in preparation dog hemolytic anemia drug, feature exist
In the injection is intravenous injection or intramuscular dose.
8. special according to application of the dog immunoglobulin described in claim 5,6 or 7 in preparation dog hemolytic anemia drug
Sign is, the application method of the drug are as follows: the dosage of dog intravenous immunoglobulin is 5-10ml/kg weight, daily 1
It is secondary, it is used in conjunction 3-7 days.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1654072A (en) * | 2004-02-10 | 2005-08-17 | 中国人民解放军军事医学科学院野战输血研究所 | Immunoglobulin for dog intravenous injection, its preparing method and the formulation thereof |
| CN109312000A (en) * | 2016-03-30 | 2019-02-05 | Ab生物科学有限公司 | Recombinate Intravenous immunoglobuin (rIVIG) composition and its production and application method |
-
2019
- 2019-04-03 CN CN201910264115.4A patent/CN109793894A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1654072A (en) * | 2004-02-10 | 2005-08-17 | 中国人民解放军军事医学科学院野战输血研究所 | Immunoglobulin for dog intravenous injection, its preparing method and the formulation thereof |
| CN109312000A (en) * | 2016-03-30 | 2019-02-05 | Ab生物科学有限公司 | Recombinate Intravenous immunoglobuin (rIVIG) composition and its production and application method |
Non-Patent Citations (1)
| Title |
|---|
| 苏壁伶: "犬免疫溶血性貧血之致病機轉與靜脈注射人類免疫球蛋白治療評估之研究(1/2)", 《台北市：台湾大学兽医学系暨研究所》 * |
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