CN102614296B - Traditional Chinese medicine composition for preventing and curing respiratory diseases of livestock and application of traditional Chinese medicine composition - Google Patents
Traditional Chinese medicine composition for preventing and curing respiratory diseases of livestock and application of traditional Chinese medicine composition Download PDFInfo
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Abstract
The invention discloses a traditional Chinese medicine composition for preventing and curing respiratory diseases of livestock. The traditional Chinese medicine composition includes, by weight, from 10 to 45 parts of calculus bovis artifactus, from 5 to 15 parts of toad, from 90 to 125 parts of fructus forsythiae, from 85 to 110 parts of radix isatidis, from 30 to 65 parts of dangshen, from 200 to 255 parts of cordate houttuynia, from 70 to 120 parts of fructus momordicae, from 95 to 120 parts of dandelion, from 50 to 85 parts of radix sophorae flavescentis, from 5 to 25 parts of almond, from 25 to 75 parts of divaricate saposhnikovia roots and from 130 to 165 parts of liquorice. The traditional Chinese medicine composition can increase immunity of the livestock, prevents diseases, promotes growth of the livestock, is fine in effect, is safe and non-toxic, and can effectively prevent drug resistance. Oral solution prepared by the traditional Chinese medicine composition is low in dosage and pharmacy cost, and is conveniently taken with water.
Description
Technical field
The invention belongs to the field of Chinese medicines, relate to a kind of Chinese medicine composition and application thereof that prevents and treats livestock and birds respiratory disease.Chinese medicine composition of the present invention is pure Chinese medicinal preparation, has the effect of logical nourish throat, relieving cough and resolving phlegm, heat-clearing and toxic substances removing, cures mainly the poultry, the domestic animal respiratory tract disease that are caused by various viruses, mycoplasma and escherichia coli etc.The Chinese medicine oral liquid of being made by this Chinese medicine composition is named and is exhaled the poison drink for gold.
Background technology
The development of aquaculture in the respiratory tract disease serious threat of poultry, and some zoonosis is also threatening human health.Livestock and birds respiratory disease is caused by the mutual synergism such as one or more antibacterials, virus, parasite, chlamydia, environmental factors, is the current principal disease that affects China's aquaculture development, often causes huge economic loss to aquaculture.Wherein porcine respiratory disease is day by day serious, becomes the main epidemic disease of the global pig industry economy of impact.There is the stages of growth of animals or poultry in this disease, and obvious symptom is arranged clinically, shows as that fervescence, appetite descend or useless food, dyspnea, and ill poultry growth promoter is obstructed, becomes thin, mortality rate is high.The tool report, the sickness rate of large-scale pig farm is 30%～60%, and mortality rate reaches 5%～30%.Chicken house infectious bronchitis or infectious laryngotracheitis mortality rate are 10%～20%, and reach 50%～70% with the mortality rate of the mixed infections such as newcastle.Antibacterial can prevent and treat with antibiotics, but easily produces drug resistance and drug residue; Vaccine immunity is used in the secondary infection of viral respiratory disease microbe satellite disease, often causes immuning failure.Therefore, exploitation has resisting respiratory tract disease, the little medicine of side effect has great importance.
Diaphoretic medicine in Chinese herbal medicine, antipyretic can reach by antiviral, antipyretic-antalgic, enhancing human body immunity function the purpose for the treatment of Animal diseases.The Chinese herbal medicine ultimate principle is strengthening vital QI to eliminate pathogenic factors or the righting of getting rid of evils, and improves the immunologic function of body, improves specificity and the non-specific immunity of body, therefore has the characteristics such as application safety, drug residue free.
Therefore developed a kind of Chinese medicine that can be used to prevent and treat livestock and birds respiratory disease, to reduce the sickness rate of poultry, increased economic efficiency.
Summary of the invention
The object of the invention is to the characteristics of preventing and treating for the livestock and birds respiratory disease of background technology proposition, a kind of Chinese medicine composition of preventing and treating livestock and birds respiratory disease is provided.This Chinese medicine composition can anti-bacteria and the propagation of virus, improves the immunity of animal.
Another object of the present invention is to provide a kind of medicine of preventing and treating livestock and birds respiratory disease.
Another purpose of the present invention is to provide the preparation method of above-mentioned control livestock and birds respiratory disease medicine.
Another purpose of the present invention is to provide the application of above-mentioned Chinese medicine composition in the medicine of preparation control livestock and birds respiratory disease.
Purpose of the present invention can be achieved through the following technical solutions:
A kind of Chinese medicine composition of preventing and treating livestock and birds respiratory disease comprises the Chinese medicine of following weight parts: 130～165 parts, 10～45 parts of artificial Calculus Boviss, 5～15 parts of Bufo siccuss, 90～125 parts of Fructus Forsythiaes, 85～110 parts of Radix Isatidis, 30～65 parts of Radix Codonopsis, 200～255 parts of Herba Houttuyniae, 70～120 parts of Fructus Momordicaes, 95～120 parts of Herba Taraxacis, 50～85 parts of Radix Sophorae Flavescentiss, 5～25 parts, Semen Armeniacae Amarum, 25～75 parts of Radix Saposhnikoviaes and Radix Glycyrrhizae.
This Chinese medicine composition has logical nourish throat, relieving cough and resolving phlegm, heat-clearing toxin-expelling functions, can be used for preventing and treating livestock and birds respiratory disease.
In a preferred embodiment of the invention, the Chinese medicine of above-mentioned Chinese medicine composition (crude drug) composition and ratio is preferably: 140～160 parts, 20～40 parts of artificial Calculus Boviss, 8～12 parts of Bufo siccuss, 100～120 parts of Fructus Forsythiaes, 85～100 parts of Radix Isatidis, 35～50 parts of Radix Codonopsis, 205～240 parts of Herba Houttuyniae, 90～105 parts of Fructus Momordicaes, 97～110 parts of Herba Taraxacis, 60～80 parts of Radix Sophorae Flavescentiss, 10～25 parts, Semen Armeniacae Amarum, 50～70 parts of Radix Saposhnikoviaes and Radix Glycyrrhizae.
Further be preferably: 150 parts, 30 parts of artificial Calculus Boviss, 10 parts of Bufo siccuss, 110 parts of Fructus Forsythiaes, 90 parts of Radix Isatidis, 40 parts of Radix Codonopsis, 210 parts of Herba Houttuyniae, 110 parts of Fructus Momordicaes, 100 parts of Herba Taraxacis, 70 parts of Radix Sophorae Flavescentiss, 20 parts, Semen Armeniacae Amarum, 60 parts of Radix Saposhnikoviaes and Radix Glycyrrhizae.
A kind of medicine of preventing and treating livestock and birds respiratory disease, to be made by above-mentioned Chinese medicine composition and the acceptable adjuvant of pharmacy, difference according to pharmaceutical dosage form, selected adjuvant is also different, in this medicine, can be any dosage form, be preferably peroral dosage form, it is that all on the pharmacy meaning can supply oral dosage form, for example tablet, powder, granule or oral liquid.Further be preferably oral liquid, this oral liquid is named and is exhaled poison drink for gold.
The medicine of above-mentioned control livestock and birds respiratory disease, preparation by the following method: after described 12 flavor Chinese medicine components are mixed, decoct with water 2～3 times, the centrifuging and taking supernatant mixes supernatant and concentrates, and presses 0.06gL
-1～0.1gL
-1Consumption add sodium benzoate, mixing, sterile filling.
The application of above-mentioned Chinese medicine composition in the medicine of preparation control livestock and birds respiratory disease.
Radix Saposhnikoviae, Semen Armeniacae Amarum, Fructus Forsythiae, Radix Isatidis, Herba Houttuyniae, Radix Sophorae Flavescentis etc. can suppress Bacillus typhi, Salmonella paratyphi, escherichia coli, hemophilus influenza, micrococcus catarrhalis, streptococcus pneumoniae, and dysentery bacterium, Bacillus proteus, diphtheria corynebacterium and vibrio cholera, staphylococcus aureus, eight connect coccus, streptococcus etc.Therefore these medicines bacterial infection that can prevent and treat animal.
There is inhibiting Chinese herbal medicine to mainly contain Fructus Forsythiae, Flos Lonicerae, Radix Isatidis, Folium Isatidis, Radix Bupleuri, the Radix Astragali, Radix Glycyrrhizae, Ganoderma, Bulbus Allii, Herba Houttuyniae, Rhizoma Polygoni Cuspidati and Herba Andrographis, Radix Isatidis etc. to common Respirovirus.
Rare Chinese medicine artificial Calculus Bovis and Bufo siccus can clear away heart-fire heat, relieving cough and reducing sputum, the antiinflammatory of relievining asthma.
Beneficial effect of the present invention:
At first the present invention take the abundant Chinese medicine of China's species as the basis, filters out tens flavor Chinese medicines and filters out the good prescription of immunoenhancement result as the component medicine from the Chinese medicine with immunological enhancement; Result shows, the Chinese medicine composition action effect that the present invention screens is better.
Chinese medicine has the characteristics of safety non-toxic, can effectively prevent drug-fast generation.By the oral administration solution of present composition preparation, dosage is little, and drug cost is low, by the drinking-water convenient drug administration.
The present composition can improve the immunity of poultry body, and prevent disease promotes growth.
The specific embodiment
Embodiment 1
Take the Chinese crude drug of following weight: artificial Calculus Bovis 30g, Bufo siccus 10g, Fructus Forsythiae 110g, Radix Isatidis 90g, Radix Codonopsis 40g, Herba Houttuyniae 210g, Fructus Momordicae 110g, Herba Taraxaci 100g, Radix Sophorae Flavescentis 70g, Semen Armeniacae Amarum 20g, Radix Saposhnikoviae 60g and Radix Glycyrrhizae 150g.Decoct with water 3 times, decoct 1h at every turn, the centrifuging and taking supernatant mixes supernatant and is concentrated into 1L (crude drug concentration 1gml
-1), press 0.1gL
-1Consumption add sodium benzoate, mixing, sterile filling make oral liquid, are called gold and exhale poison drink.
One. toxicity test
1.1. laboratory animal: mice ICR is 20g approximately, male and female half and half, and totally 40, the quality certification number is credit number: scxk (Soviet Union) 2007-0001, Yangzhou University's comparative medicine center provides.Sub-cage rearing after mice is bought is freely drunk water, and environmental adaptation is used for test after raising 3～5d.30 of healthy SD rats, male and female half and half are provided by Nanjing University of Traditional Chinese Medicine's experimental animal center, the quality certification number: SCXK2002 (Soviet Union)-0018.
1.2. tested medicine
The gold of embodiment 1 preparation is exhaled poison drink oral liquid, crude drug concentration 1gml
-1
2. method
2.1. acute toxicity test
White mice ICR is divided into test group and blank group at random, and 20 every group, water is can't help in fasting (12h) before test.Test group is by body weight 0.04mlg
-1(gold of mice administration 0.04ml embodiment 1 preparation of every 1g is exhaled poison drink oral liquid, and crude drug concentration is 1gml
-1) disposable gastric infusion; The blank group gives the equivalent normal saline.Continuous Observation 14d records the situations such as behavior, activity, food ration, body weight, feces, death of Kunming white mice, and dead white mice is not put to death after 14d, cuts open inspection.
2.2. repetitively administered toxicity test
Get 28 of healthy SD rats, water is can't help in fasting (12h) before test.28 rats are divided into 4 groups, 3 medicine matched groups (be divided into height, in, low), and 1 blank group, wherein male and female are half-and-half in every group.The high dose group dosage is 10gkg
-1(every 1kg rat administration 10g crude drug, tested medicine are that the gold of embodiment 1 preparation is exhaled poison drink oral liquid, and its crude drug concentration is 1gml
-1), middle dosage group dosage is 5gkg
-1(every 1kg rat administration 5g crude drug, tested medicine are that the gold of embodiment 1 preparation is exhaled poison drink oral liquid, and its crude drug concentration is 1gml
-1), the low dose group dosage is that (every 1kg rat administration 2g crude drug, tested medicine are that the gold of embodiment 1 preparation is exhaled poison drink oral liquid to 2g.kg-1, and its crude drug concentration is 1gml
-1), not administration of matched group, 5 weeks of successive administration.The single cage of animal is raised, ad lib drinking-water.
2.2.1. test grouping and dosage see Table 1.
Table 1. test grouping and dosage
2.2.2. main inspection item
(1) body weight and food-intake: weigh weekly 1 time, and adjust dosage according to body weight change.Every day entry food-intake and amount of drinking water are added up weekly 1 food-intake and amount of drinking water, and food-intake, the water yield represent with grams and the milliliter number that every 100g body weight needs every day respectively
(2) normal blood index inspection: the indexs such as blood sampling detection leukocyte (WBC) counting and classification, platelet (PLT) counting.
(3) blood parameters: blood sampling detects the indexs such as serum albumin/globulin (A/G), albumin (ALB).
3. result
3.1. the acute toxicity tests
Administration white mice on same day hair color is smooth, and feces is that brown, quality are rarer soft, ingests, movable less; White mice activity in the 2nd day, ingest, body weight gain, feces etc. recover normal, compare no significant difference with the blank group; Nothing death and other abnormal generations in 14d; Put to death simultaneously two groups of white mice and cut open inspection, each main organs of perusal (heart, liver, spleen, lungs, kidney) no abnormality seen changes.
3.2. repetitively administered toxicity test result
3.2.1. activities in rats, diet, two just and by hair color pool etc. show no obvious abnormalities change within experimental period, have no the symptoms such as vomiting, sialorrhea, dyspnea.
3.2.2. it is good respectively to organize rat growthing development after administration, body weight gain is compared with matched group and is shown no obvious abnormalities, and Epidemiological Analysis is compared there was no significant difference with matched group by statistics, sees Table 2.
The gold of table 2. embodiment 1 preparation exhales poison drink oral liquid on the impact of rat body weight
3.2.3. the impact on normal blood index
In, low dose group can obviously improve PLT content, but through consulting the correlational study data, all in range of normal value, the index that each dosage group has statistical significance has no obvious regularity to its numerical value under the different dosing amount, and and dosage between have no significant correlation, see Table 3.
The gold of table 3. embodiment 1 preparation exhales poison drink oral liquid on the impact of rat blood conventional index
Each dosage group has between the index of statistical significance and dosage and has no significant correlation, sees Table 4.
The gold of table 4. embodiment 1 preparation exhales poison drink oral liquid on the impact of rat blood biochemical indicator
4. discuss
(1) gold of embodiment 1 preparation exhales poison drink oral liquid maximum dosage-feeding result of the test to show, is showed no obvious toxic reaction after the white mice administration, in 14d also without death.Therefore, maximum dosage-feeding is 40g.Kg
-1
(2) under this experimental condition, after 5 weeks of SD rat oral gavage administration, blood coagulation system index, blood parameters and organs and tissues check and are showed no obvious abnormalities, the index that each dosage group has statistical significance does not have no evident regularity simultaneously at dosage, and and dosage between have no significant correlation, infer without obvious toxicology meaning.
Two. clinical trial
1.1. test material
1.1.1. trial drug:
Control drug is that the gold of embodiment 1 preparation is exhaled poison drink oral liquid (crude drug content is 1g.ml
-1); Tylosin tartrate (content 80%, lot number 2010100510) is provided by Ningxia Tairui Pharmaceutical Co., Ltd.; Levofloxacin hydrochloride (content 98%, lot number 2010061501) and doxycycline hydrochloride (content 98%, lot number 2010051601) are provided by Shandong XinHua Pharmacy stock Co., Ltd.
1.1.2. experimental animal: 500 27 age in days broiler chicken (infected chicken septico-mycoplasma disease), Nan Jingquan cultivates livestock corporation and provides.
1.2. test method
1.2.1. test grouping:
Test chicken is 500 of the 27 age in days broiler chicken of natural infection morbidity chicken, cuts open inspection according to the clinical symptoms binding of pathological and changes and be diagnosed as chronic respiratory disease, is divided at random 5 groups, every group of 100 plumages.The conventional raising fed the complete feed that does not contain antibacterials, free choice feeding and drinking-water, and carry out clinical observation.Test chicken grouping and disposition see Table 5.
Administration grouping and the processing of table 5 test chicken
1.2.2. medicine for treatment:
Testing program by table 1 is carried out medicine for treatment.Observe the clinical symptoms change of chicken after medication, dead chicken is carried out pathology cut open inspection, to determine the cause of the death and log.(gold of embodiment 1 preparation exhales poison drink oral liquid 0.002% to exhale poison drink oral liquid for the gold that adds 20ml in 1000L water, tartaric acid Taylor rhzomorph 0.05% adds the 0.05g medicine in 100ml water, levofloxacin hydrochloride 0.01% is for adding the medicine of 0.01g in 100ml water, doxycycline hydrochloride 0.02% is for adding 0.02g in 100ml water)
1.3. index of assessment of curative effect
1.3.1. mortality rate: during therapeutic test, have typical chronic respiratory disease and dead, necropsy has typical characteristic pathological changes, is judged to the death of failing to respond to any medical treatment, and calculates the mortality rate of each group.
1.3.2. cure rate: during therapeutic test, the mental status, respiratory symptom, appetite, feces recover normal after the treatment administration, and the clinical symptoms that no longer occurs obviously infecting all belongs to healing.Calculate cure rate according to curing the chicken number.
1.3.3. effective percentage: after medicine for treatment, healing or clinical symptoms show as disease chicken spirit state, respiratory symptom improvement etc. and all are considered as effectively.Cure or chicken number that clinical symptoms takes a turn for the better calculates effective percentage, i.e. total effective rate for every group during according to off-test.
1.3.4. invalid: after medicine for treatment, the clinical symptoms performance is without taking a turn for the better or increasing the weight of as invalid.
2. result and discussion
Result after the various drug effects of table 6.
2.1. therapeutic test the results are shown in Table 6, can find out that the gold of embodiment 1 preparation exhales poison drink oral liquid to have therapeutic effect preferably to mycoplasma galliseplicum disease, cure rate difference 96%, and effective percentage is respectively 98%.The gold of embodiment 1 preparation exhales poison drink oral liquid group cure rate and effective percentage obviously to be better than the levofloxacin hydrochloride treatment group, doxycycline hydrochloride treatment group and tylosin tartrate treatment group.
2.2. in the aviculture production practices, chronic respiratory disease is more and more general, general chicken house all has generation, and sickness rate is higher, is difficult to stop, and brings very big harm to poultry husbandry.Primary disease adopts Drug therapy more, yet along with antibiotic continuous application, particularly antibiotic abuse, makes pathogen more and more stronger to Antibiotic resistance, causes some antibiotic to face to examine effect very poor.So, need at present the existing antibacterials of utilizing of reasonable standard and the new medicine with obvious antibacterial effect of research and development when this disease for the treatment of.
Embodiment 2
Take the Chinese crude drug of following weight: artificial Calculus Bovis 20g, Bufo siccus 8g, Fructus Forsythiae 100g, Radix Isatidis 85g, Radix Codonopsis 35g, Herba Houttuyniae 205g, Fructus Momordicae 90g, Herba Taraxaci 97g, Radix Sophorae Flavescentis 60g, Semen Armeniacae Amarum 10g, Radix Saposhnikoviae 50g and Radix Glycyrrhizae 140g.Decoct with water 3 times, decoct 1h at every turn, the centrifuging and taking supernatant mixes supernatant and is concentrated into 900ml (crude drug concentration 1gml
-1), press 0.1gL
-1Consumption add sodium benzoate, mixing, sterile filling make oral liquid.
Embodiment 3
Take the Chinese crude drug of following weight: artificial Calculus Bovis 40g, Bufo siccus 12g, Fructus Forsythiae 120g, Radix Isatidis 100g, Radix Codonopsis 50g, Herba Houttuyniae 240g, Fructus Momordicae 103g, Herba Taraxaci 110g, Radix Sophorae Flavescentis 80g, Semen Armeniacae Amarum 25g, Radix Saposhnikoviae 70g and Radix Glycyrrhizae 150g.Decoct with water 3 times, decoct 1h at every turn, the centrifuging and taking supernatant mixes supernatant and is concentrated into 11L (crude drug concentration 1gml
-1), press 0.1gL
-1Consumption add sodium benzoate, mixing, sterile filling make oral liquid.
Embodiment 4
Take the Chinese crude drug of following weight: artificial Calculus Bovis 15g, Bufo siccus 12g, Fructus Forsythiae 98g, Radix Isatidis 95g, Radix Codonopsis 40g, Herba Houttuyniae 250g, Fructus Momordicae 115g, Herba Taraxaci 115g, Radix Sophorae Flavescentis 80g, Semen Armeniacae Amarum 10g, Radix Saposhnikoviae 35g and Radix Glycyrrhizae 135g.Decoct with water 3 times, decoct 1h at every turn, the centrifuging and taking supernatant mixes supernatant and is concentrated into 1L (crude drug concentration 1gml
-1), press 0.1gL
-1Consumption add sodium benzoate, mixing, sterile filling make oral liquid.
Claims (8)
1. Chinese medicine composition of preventing and treating livestock and birds respiratory disease is characterized in that being comprised of the Chinese medicine of following weight parts: 130 ~ 165 parts, 10 ~ 45 parts of artificial Calculus Boviss, 5 ~ 15 parts of Bufo siccuss, 90 ~ 125 parts of Fructus Forsythiaes, 85 ~ 110 parts of Radix Isatidis, 30 ~ 65 parts of Radix Codonopsis, 200 ~ 255 parts of Herba Houttuyniae, 70 ~ 120 parts of Fructus Momordicaes, 95 ~ 120 parts of Herba Taraxacis, 50 ~ 85 parts of Radix Sophorae Flavescentiss, 5 ~ 25 parts, Semen Armeniacae Amarum, 25 ~ 75 parts of Radix Saposhnikoviaes and Radix Glycyrrhizae.
2. the Chinese medicine composition of control livestock and birds respiratory disease according to claim 1 is characterized in that described Chinese medicine is: 140 ~ 160 parts, 20 ~ 40 parts of artificial Calculus Boviss, 8 ~ 12 parts of Bufo siccuss, 100 ~ 120 parts of Fructus Forsythiaes, 85 ~ 100 parts of Radix Isatidis, 35 ~ 50 parts of Radix Codonopsis, 205 ~ 240 parts of Herba Houttuyniae, 90 ~ 105 parts of Fructus Momordicaes, 97 ~ 110 parts of Herba Taraxacis, 60 ~ 80 parts of Radix Sophorae Flavescentiss, 10 ~ 25 parts, Semen Armeniacae Amarum, 50 ~ 70 parts of Radix Saposhnikoviaes and Radix Glycyrrhizae.
3. the Chinese medicine composition of control livestock and birds respiratory disease according to claim 1 is characterized in that described Chinese medicine is: 150 parts, 30 parts of artificial Calculus Boviss, 10 parts of Bufo siccuss, 110 parts of Fructus Forsythiaes, 90 parts of Radix Isatidis, 40 parts of Radix Codonopsis, 210 parts of Herba Houttuyniae, 110 parts of Fructus Momordicaes, 100 parts of Herba Taraxacis, 70 parts of Radix Sophorae Flavescentiss, 20 parts, Semen Armeniacae Amarum, 60 parts of Radix Saposhnikoviaes and Radix Glycyrrhizae.
4. a medicine of preventing and treating livestock and birds respiratory disease, is characterized in that being made by the described Chinese medicine composition of any one in claim 1 ~ 3 and the acceptable adjuvant of pharmacy.
5. the medicine of control livestock and birds respiratory disease according to claim 4, is characterized in that described medicine is peroral dosage form, and it is tablet, powder, granule or oral liquid.
6. the medicine of control livestock and birds respiratory disease according to claim 5, is characterized in that described medicine is oral liquid.
7. the medicine of control livestock and birds respiratory disease according to claim 4, is characterized in that described medicine prepares by the following method: after described 12 flavor Chinese medicine components are mixed, decoct with water 2 ~ 3 times, each 1h, the centrifuging and taking supernatant mixes supernatant and concentrates, by 0.06 gL
-1～0.1gL
-1Consumption add sodium benzoate, mixing, sterile filling.
8. the application of Chinese medicine composition claimed in claim 1 in the medicine of preparation control livestock and birds respiratory disease.
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| JP5578646B2 (en) * | 2009-06-19 | 2014-08-27 | 株式会社和漢生薬研究所 | Orally administered composition for pharyngitis and influenza prevention / treatment |
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| CN1562151A (en) * | 2004-03-30 | 2005-01-12 | 沈惠明 | Medicinal formulation for treating upper respiratory track infection and its design method |
| CN101897800A (en) * | 2010-07-14 | 2010-12-01 | 河北农业大学 | Traditional Chinese medicine oral liquid for treating mycoplasma gallisepticum infection |
| CN101966285A (en) * | 2010-10-13 | 2011-02-09 | 郑州后羿制药有限公司 | Traditional Chinese medicine and traditional Chinese medicine aerosol for preventing and curing chicken respiratory diseases and preparation method thereof |
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