WO2001028584A1 - Traitement de maladies et d'infections respiratoires - Google Patents

Traitement de maladies et d'infections respiratoires Download PDF

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Publication number
WO2001028584A1
WO2001028584A1 PCT/AU2000/001254 AU0001254W WO0128584A1 WO 2001028584 A1 WO2001028584 A1 WO 2001028584A1 AU 0001254 W AU0001254 W AU 0001254W WO 0128584 A1 WO0128584 A1 WO 0128584A1
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WIPO (PCT)
Prior art keywords
virus
ion channels
parainfluenza virus
protein
human parainfluenza
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PCT/AU2000/001254
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English (en)
Inventor
David Ian Cook
Karl Kunzelmann
Alex Howard Beesley
John Atherton Young
Nicholas King
Guna Karupiah
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The University Of Sydney
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Priority to AU10074/01A priority Critical patent/AU1007401A/en
Publication of WO2001028584A1 publication Critical patent/WO2001028584A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus

Definitions

  • the present invention relates to the treatment of respiratory diseases and infections, particularly cystic fibrosis (CF) and influenza.
  • CF cystic fibrosis
  • Cystic fibrosis a common inherited respiratory disease, for example, is characterised by excessive sodium absorption and deficient chloride secretion by respiratory epithelium (1, 2). These abnormalities lead to increased water absorption from the airways resulting in the formation of thick mucous which can cause severe obstruction of bronchi.
  • many respiratory infections particularly those produced by viruses such as influenza viruses, parainfluenza viruses and rhinoviruses, cause abnormal production of fluid in airways which can lead to rhinorrhea (3), accumulation of fluid in the eustachian tubes and middle ear with subsequent development of otitis media (3, 4, 5), and pulmonary oedema (6, 7).
  • viruses, or components derived therefrom, which inhibit Na + ion channels in respiratory epithelium may be used in novel alternative therapies of other diseases which are characterised by overactivity of epithelial Na + ion channels, for example, the autosomal dominant form of hypertension, Liddle's syndrome (12).
  • the present invention provides a method of treating or preventing the symptoms of a viral or bacterial infection, said symptoms being those caused by abnormal production of fluid by epithelia, wherein said method comprises administering to a subject a composition comprising an agent which inhibits a protein involved in a signal transduction mechanism regulating epithelial Na + ion channels, especially amiloride-sensitive Na + ion channels, and wherein said signal transduction mechanism is one which is activated by haemagglutinin.
  • the method of the first aspect may be used for the treatment or prevention of symptoms of a viral infection caused by abnormal production of fluid by respiratory epithelia or epthelium of the eustachian tubes and middle ear. Accordingly, the method of the first aspect is preferably used for the treatment or prevention of rhinorrhea, otitis media and/or pulmonary oedema. As indicated above, such conditions are typical symptoms of infection by orthomyxoviridae (e.g. influenza viruses A, B and C), and paramyxoviridae (e.g. parainfluenza viruses such as human parainfluenza virus 1, human parainfluenza virus 3, bovine parainfluenza virus 3, and murine parainfluenza virus 1 (i.e.
  • orthomyxoviridae e.g. influenza viruses A, B and C
  • paramyxoviridae e.g. parainfluenza viruses such as human parainfluenza virus 1, human parainfluenza virus 3, bovine parainfluenza virus 3, and
  • the method of the first aspect is primarily intended for human therapeutic use but may also be useful in veterinary applications, particularly in dogs, cats, horses, cattle and birds (e.g. chickens and turkeys).
  • composition used in the method of the first aspect preferably comprises an agent for inhibiting either or both of the intracellular signal transduction proteins, phospholipase C and protein kinase C (which the applicant has found become activated during inhibition of Na + ion channels by influenza haemagglutinin) .
  • an agent for inhibiting phospholipase C is U-73122 (Calbiochem).
  • An example of a suitable agent which inhibits protein kinase C is bisindolylmaleimide I (Calbiochem).
  • a suitable agent is an antibody or fragment thereof (or other suitable binding partner of haemagglutinin) that binds to haemagglutinin such that interaction of the haemagglutinin with the epithelial cell surface receptor is prevented.
  • the agent may be present in the composition in admixture with a suitable pharmacologically-acceptable carrier.
  • the composition may be administered by any suitable route but, preferably, orally, nasally, topically, intramuscularly or intravenuously.
  • the preferred route of administration is nasally or orally by way of an aerosolised composition.
  • composition used in the method of the first aspect will be preferably administered to provide a dosage of the agent in the range of 0.01 to 2.0 mg/kg/day for a topical agent administered by inhalation and of 0.1 to 20.0 mg/kg/day for an agent that is administered systemically.
  • the present invention provides a method of treating or preventing mucous obstruction of airways in a subject, said method comprising administering to said subject a composition comprising a viral or bacterial preparation which inhibits Na + ion channels in respiratory epithelium, in an amount effective to cause hydration of lung mucous.
  • the method of the second aspect is primarily intended for human therapeutic use but the method may also be useful in veterinary applications, particularly in the treatment of airway mucous obstructions in dogs, cats, horses, cattle and birds.
  • the airway mucous obstructions may be associated with cystic fibrosis, asthma, bronchitis or bronchiectasis.
  • composition used in the method of the second aspect may comprise a viral preparation such as a virus or a component derived therefrom which inhibits Na + ion channels, especially amiloride-sensitive Na + ion channels, in respiratory epithelium.
  • a composition comprising a viral preparation may further comprise a pharmacologically-acceptable carrier, particularly of the kind suitable for aerosolisation (e.g. saline-based compositions (13, 14)).
  • Preferred viruses are selected from orthomyxoviridae (e.g. influenza viruses A, B and C), paramyxoviridae (e.g parainfluenza viruses, newcastle disease virus, viruses causitive of mumps, etc.) and other viruses which include a haemagglutinating protein (e.g. rhinoviruses). They are preferably rendered non-infectious (e.g. cold-adapted viruses (15) and "split virus" preparations) .
  • orthomyxoviridae e.g. influenza viruses A, B and C
  • paramyxoviridae e.g parainfluenza viruses, newcastle disease virus, viruses causitive of mumps, etc.
  • viruses which include a haemagglutinating protein e.g. rhinoviruses
  • They are preferably rendered non-infectious (e.g. cold-adapted viruses (15) and "split virus" preparations) .
  • Preferred virally-derived components are derived from viruses selected from those mentioned in the preceding paragraph.
  • the virally-derived components may be in the form of a crude fraction from disrupted virus preparations or, alternatively, may be in the form of a pure preparation of an isolated viral protein or proteins. They may also take the form of a peptide or polypeptide fragment of a viral protein.
  • Most preferred virally-derived components consist of or comprise a haemagglutinating protein, especially haemagglutinin, or a fragment or analog thereof which is capable of inhibiting Na + ion channels, especially amiloride-sensitive Na + ion channels, in respiratory epithelium.
  • composition used in the method of the second aspect may comprise a bacterial preparation such as a bacteria or a component derived therefrom which inhibits Na + ion channels, especially amiloride-sensitive Na + ion channels, in respiratory epithelium.
  • a composition comprising a bacterial preparation may further comprise a pharmacologically-acceptable carrier.
  • Preferred bacteria are selected from bacteria including a haemagglutinating protein (e.g. Bordatella pertussis) .
  • the bacteria are preferably rendered non-infectious by, for example, treating the bacteria with solubilizing agents such as detergents and, optionally, treatment by chromatography or other method of purification to remove interfering pharmacological activities.
  • Preferred bacterially-derived components are derived from bacteria selected from those mentioned in the preceding paragraph.
  • the bacterially- derived components may be in the form of cell membrane fractions, whole cell lysates or, alternatively, may be in the form of a pure preparation of an isolated bacterial protein or proteins. They may also take the form of a peptide or polypeptide fragment of a bacterial protein.
  • Most preferred bacterially-derived components consist of or comprise a haemagglutinating protein or a fragment or analog thereof which is capable of inhibiting Na + ion channels, especially amiloride-sensitive Na + ion channels, in respiratory epithelium.
  • the applicant has found that the inhibition of Na + ion channels by influenza haemagglutinin involves activation of intracellular signal transduction proteins, phospholipase C and protein kinase C. Accordingly, it is further proposed that agents which stimulate these enzymes may also be used in novel alternative therapies of respiratory diseases such as cystic fibrosis.
  • the present invention provides a method of treating or preventing mucous obstruction of airways in a subject, said method comprising administering to said subject a composition comprising an agent which stimulates a protein involved in a signal transduction mechanism regulating Na + ion channels, especially amiloride-sensitive Na + ion channels, in respiratory epithelium, in an amount effective to cause hydration of lung mucous, wherein said signal transduction mechanism is one which is activated by haemagglutinin.
  • the method of the third aspect is primarily intended for human therapeutic use but may also be useful in veterinary applications.
  • the method of the third aspect is preferably used for treatment or prevention of airway mucous obstructions associated with cystic fibrosis, asthma, bronchitis or bronchiectasis.
  • the composition used in the method of the third aspect preferably comprises an agent for stimulating phospholipase C (e.g. G-protein stimulators which, in turn, stimulate phospholipase C) or an agent which stimulates protein kinase C such as 1,2-dioctanoyl-sn-glycerol and phorbol esters.
  • the composition may further comprise a pharmacologically- acceptable carrier, particularly of the kind suitable for aerosolisation.
  • the composition may be administered orally, topically, intramuscularly or intravenously, but is preferably administered nasally.
  • viruses and bacteria, or components derived from those viruses or bacteria, which inhibit Na + ion channels in respiratory epithelium may be useful in the treatment of diseases which are characterised by overactivity of Na + ion channels in other types of epithelia (e.g. renal epithelia).
  • the present invention provides a method of treating a disease characterised by overactivity of epithelial Na + ion channels, said method comprising administering to said subject an effective amount of a composition comprising a viral or bacterial preparation which causes inhibition of epithelial Na + ion channels, especially amiloride-sensitive Na + ion channels.
  • the viral or bacterial preparation may be replaced with a compound which binds and stimulates the epithelial cell receptor recognised by influenza haemagglutinin.
  • Such compounds may mimic the receptor-binding region of influenza haemagglutinin or may otherwise bind to the receptor to bring about the stimulation of phospholipase C and/or protein kinase C activity.
  • the present invention extends to methods involving the administration of compositions comprising such compounds.
  • the present invention provides a method of treating a disease characterised by overactivity of epithelial Na + ion channels, said method comprising administering to said subject an effective amount of a composition comprising an agent which stimulates a protein involved in a signal transduction mechanism regulating epithelial Na + ion channels, especially amiloride-sensitive Na + ion channels, wherein said signal transduction mechanism is one which is activated by haemagglutinin.
  • haemagglutinating protein refers to a protein capable of agglutination of the red blood cells of an appropriate species.
  • Haemagglutinating activity may be measured by any of the known methods in the art, for example by adding a 0.5% v/v chicken red blood cell suspension to a diluted stock of the virus, bacteria or component thereof being tested as contained in a 96-well U-bottom cluster plate (26, 27). The results are measured in haemagglutinating units (HAU), wherein one HAU corresponds to the highest dilution of influenza virus stock at which complete agglutination of a 0.5% v/v chicken red blood cell suspension occurs.
  • HAU haemagglutinating units
  • Figure 1 Panel A. Original recordings showing the response of the tracheal epithelium to 10 mmol/1 amiloride under (i) control conditions, (ii) following 1 h exposure of the apical membrane to UV-inactivated PR8 (10 6 pfu/ml prior to inactivation) and (iii) following 1 h apical exposure to active PR8 virus (10 6 pfu/ml).
  • Panel B Concentration-response curve for amiloride.
  • Panel C Panel C.
  • Panel A Original recordings showing the effects of 10 ⁇ mol/1 forskolin plus 100 ⁇ mol/1 IBMX on tracheal epithelium, before and after 1 h apical exposure to 10 ⁇ pfu/ml PR8.
  • Panel B Original recordings showing the effects of 100 ⁇ mol/1 carbachol on tracheal epithelium, before and after 1 h apical exposure to 10 6 pfu/ml PR8.
  • Panel C The effects of 1 h apical exposure to 10 6 pfu/ml PR8 virus on the current activated by 10 ⁇ mol/1 forskolin plus 100 ⁇ mol/1 IBMX and by 100 ⁇ mol/1 carbachol.
  • Figure 3. Panel A.
  • DOG (10 ⁇ mol/1; DOG) and BIM (0.1 ⁇ mol/1; BIM) on the amiloride-sensitive short circuit current.
  • Example 1 Inhibition of Na + ion channels by influenza virus and parainfluenza virus
  • M-l mouse cortical collecting duct cells were provided by Dr C. Korbmacher (Oxford University, UK). The cells were grown for three days on permeable supports (Transwell - Coll, Costar, Cambridge MA) in DMEM/F12 media containing: 10% fetal calf serum, glutamine (2 mmol/1), penicillin (100,000 U/l), streptomycin (100,000 U/l) and dexamethasone (0.1 ⁇ rnol/1).
  • IBMX 3-isobutyl-l-methylxanthine
  • DOG 1,2- dioctanoyl-sn-glycerol
  • BIM bisindolylmaleimide I
  • staurosporine pertussis toxin
  • cytochalasin D carbachol and chloroquine
  • U-73122 and Go-6983 were from Calbiochem
  • the apical membrane of the epithelium was exposed to UV-inactivated PR8 influenza virus for 1 hour. This had no effect on the electrical properties of the epithelium (Figs lA(ii) and lC). Similarly, exposure to virus-free allantoic fluid was without effect (Fig. IC).
  • the inhibition was not therefore a non-specific consequence of endocytosis of the virus (see also Fig. 4A).
  • Studies on the time-course of the inhibition revealed a linear decline in the amiloride- sensitive short circuit current which was 50% complete after approximately 60 minutes (Fig. ID).
  • the dependence of the inhibition on virus concentration is shown in Fig. IE.
  • the Sendai virus (2.5 x 10 7 pfu/ml) was also found to be inhibitory; reducing the amiloride-sensitive current from 31.7 ⁇
  • These early steps include: (i) the binding of haemagglutinin in the viral coat to sialic acid residues on a receptor protein in the apical membrane, which can be inhibited by pre-treatment with neuraminidase (17); (ii) the endocytosis of the virus-receptor complex, which can be blocked by cvtochalasin D (18); and (iii) uncoating of the virus due to the movement of H + through the M2 protein in the viral coat, which can blocked by amantidine (19, 20) or by chloroquine, which dissipates the endosomal pH gradient (21).
  • Staurosporine a non-selective inhibitor of serine and threonine kinases, partially prevented the inhibitory effect of the virus, but also itself significantly reduced the amiloride-sensitive current (Fig. 4C). Since Na + ion channels in respiratory epithelium have not previously been shown to be regulated by protein kinase C, it was shown that the activator of protein kinase C, 1,2-dioctanoyl-sn-glycerol (DOG), inhibits the amiloride-sensitive current (Fig. 4D), whereas inhibition of protein kinase C with BIM stimulates it (Fig. 4D). Pertussis toxin (300 ng/ml for 3 hours) did not prevent the inhibitory effect of the virus, although, like staurosporine, it reduced the base-line amiloride-sensitive current (data not shown).
  • DOG 1,2-dioctanoyl-sn-glycerol
  • HN protein which exhibits minimal amino acid sequence homology to influenza haemagglutinin (25), indicates that similar results may be achieved with any viral or bacterial pathogen having haemagglutinating activity. This is further supported by the results achieved with Concanavalin A and pertussis toxin.

Abstract

Il s'est avéré que le virus de la grippe, notamment sa protéine d'hémagglutinine, provoquait l'inhibition des canaux ion Na+ dans l'épithélium des voies respiratoires. Cette observation a permis la mise au point de nouvelles méthodes permettant, (i), de traiter et/ou de prévenir des symptômes associés à une infection virale ou bactérienne (par exemple la rhinorrhée, l'otite moyenne et/ou l'oedème pulmonaire), (ii), de traiter et/ou de prévenir des obstructions des muqueuses des voies aériennes (celles qui sont, par exemple, associées à la mucoviscidose, à l'asthme, à la bronchite ou à la bronchectasie) et, (iii), de traiter des états pathologiques caractérisés par une suractivité des canaux ion Na+ épithéliaux (l'hypertension, par exemple).
PCT/AU2000/001254 1999-10-15 2000-10-16 Traitement de maladies et d'infections respiratoires WO2001028584A1 (fr)

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AUPQ3447 1999-10-15

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Cited By (12)

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Publication number Priority date Publication date Assignee Title
EP1435969A2 (fr) * 2001-09-20 2004-07-14 Inologic, Inc. Procede de modulation de l'absorption des ions sodium dans les cellules epitheliales
EP1480648A1 (fr) * 2002-01-31 2004-12-01 Picoral Pty Ltd Composes antiviraux
WO2005018560A3 (fr) * 2003-08-20 2005-06-30 Parion Sciences Inc Methodes permettant de reduire les risques d'infection a des pathogenes
DE102008034265A1 (de) * 2008-07-22 2010-01-28 Beiersdorf Ag Wirkstoffkombination aus Anisfruchtextrakt und Hyaluronsäure
US7682619B2 (en) 2006-04-06 2010-03-23 Cornell Research Foundation, Inc. Canine influenza virus
US7745442B2 (en) 2003-08-20 2010-06-29 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens
US9586910B2 (en) 2011-06-27 2017-03-07 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US9586911B2 (en) 2013-12-13 2017-03-07 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epthelial sodium channel blocking compounds
US9593084B2 (en) 2012-12-17 2017-03-14 Parion Sciences, Inc. Chloro-pyrazine carboxamide derivatives with epithelial sodium channel blocking activity
US9695134B2 (en) 2012-12-17 2017-07-04 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(n-(4-phenylbutyl)carbamimidoyl)pyrazine-2-carboxamide compounds
CN106924337A (zh) * 2017-04-12 2017-07-07 江苏农牧科技职业学院 黄秦艽在制备治疗畜禽病毒性传染病的药物中的应用
US10167266B2 (en) 2002-02-19 2019-01-01 Parion Sciences, Inc. Sodium channel blockers

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1435969A4 (fr) * 2001-09-20 2006-08-16 Inologic Inc Procede de modulation de l'absorption des ions sodium dans les cellules epitheliales
EP1435969A2 (fr) * 2001-09-20 2004-07-14 Inologic, Inc. Procede de modulation de l'absorption des ions sodium dans les cellules epitheliales
EP1480648A1 (fr) * 2002-01-31 2004-12-01 Picoral Pty Ltd Composes antiviraux
EP1480648A4 (fr) * 2002-01-31 2007-10-31 Picoral Pty Ltd Composes antiviraux
US10167266B2 (en) 2002-02-19 2019-01-01 Parion Sciences, Inc. Sodium channel blockers
US8314105B2 (en) 2003-08-20 2012-11-20 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens
WO2005018560A3 (fr) * 2003-08-20 2005-06-30 Parion Sciences Inc Methodes permettant de reduire les risques d'infection a des pathogenes
US7745442B2 (en) 2003-08-20 2010-06-29 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens
US7682619B2 (en) 2006-04-06 2010-03-23 Cornell Research Foundation, Inc. Canine influenza virus
DE102008034265A1 (de) * 2008-07-22 2010-01-28 Beiersdorf Ag Wirkstoffkombination aus Anisfruchtextrakt und Hyaluronsäure
US9586910B2 (en) 2011-06-27 2017-03-07 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US11578042B2 (en) 2011-06-27 2023-02-14 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US10752597B2 (en) 2011-06-27 2020-08-25 Parion Sciences, Inc. 3,5-diamino-6-chloro-N—(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US10071970B2 (en) 2012-12-17 2018-09-11 Parion Sciences, Inc. Chloro-pyrazine carboxamide derivatives with epithelial sodium channel blocking activity
US9695134B2 (en) 2012-12-17 2017-07-04 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(n-(4-phenylbutyl)carbamimidoyl)pyrazine-2-carboxamide compounds
US10246425B2 (en) 2012-12-17 2019-04-02 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-phenylbutyl)carbamimidoyl) pyrazine-2-carboxamide compounds
US9593084B2 (en) 2012-12-17 2017-03-14 Parion Sciences, Inc. Chloro-pyrazine carboxamide derivatives with epithelial sodium channel blocking activity
US9957238B2 (en) 2013-12-13 2018-05-01 Parion Sciences, Inc. Arylalkyl-and aryloxyalkyl-substituted epithelial sodium channel blocking compounds
US10233158B2 (en) 2013-12-13 2019-03-19 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epithelial sodium channel blocking compounds
US9586911B2 (en) 2013-12-13 2017-03-07 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epthelial sodium channel blocking compounds
CN106924337A (zh) * 2017-04-12 2017-07-07 江苏农牧科技职业学院 黄秦艽在制备治疗畜禽病毒性传染病的药物中的应用

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