EP0837695A1 - Vaccins d'actinomyces pyogenes et d'actinomyces pyogenes/fusobacterium necrophorum utiles pour immuniser le betail bovin et ovin - Google Patents

Vaccins d'actinomyces pyogenes et d'actinomyces pyogenes/fusobacterium necrophorum utiles pour immuniser le betail bovin et ovin

Info

Publication number
EP0837695A1
EP0837695A1 EP96921496A EP96921496A EP0837695A1 EP 0837695 A1 EP0837695 A1 EP 0837695A1 EP 96921496 A EP96921496 A EP 96921496A EP 96921496 A EP96921496 A EP 96921496A EP 0837695 A1 EP0837695 A1 EP 0837695A1
Authority
EP
European Patent Office
Prior art keywords
pyogenes
cell culture
inoculum
cattle
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96921496A
Other languages
German (de)
English (en)
Other versions
EP0837695A4 (fr
Inventor
T. G. Nagaraja
M. M. Chengappa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kansas State University
Original Assignee
Kansas State University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/483,382 external-priority patent/US5861162A/en
Application filed by Kansas State University filed Critical Kansas State University
Priority to EP05000534A priority Critical patent/EP1535626B1/fr
Publication of EP0837695A1 publication Critical patent/EP0837695A1/fr
Publication of EP0837695A4 publication Critical patent/EP0837695A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/05—Actinobacteria, e.g. Actinomyces, Streptomyces, Nocardia, Bifidobacterium, Gardnerella, Corynebacterium; Propionibacterium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/114—Fusobacterium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
    • A61K2039/521—Bacterial cells; Fungal cells; Protozoal cells inactivated (killed)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A61K2039/552—Veterinary vaccine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine

Definitions

  • the present invention is broadly concerned with novel inocula for administration to cattle or sheep in order to lessen or prevent the incidence of liver abscesses and/or foot rot. More particularly, the invention pertains to such inocula, methods of preparing the same and methods of lessening the incidence of liver abscesses and/or foot rot in cattle or sheep via administration of the inocula.
  • the invention relates to an A. pyogre/ies-derived inoculum, and in another aspect to a multivalent inoculum comprising a first bacterial component in the form of an inactivated cell culture product of A. pyogenes and a second bacterial component in t e form of an inactivated cell culture product of F. necrophorum.
  • Liver abscesses in feed lot cattle are a serious economic problem, causing condemnation of over 3 million livers and an estimated loss of $15 million annually in the United States. This estimate is based primarily on condemnation of liver and other organs, and does not include economic losses stemming from reduced feed efficiencies and lowered weight gains.
  • a number of studies have confirmed that cattle with abscessed livers gain less (average 4-5%) and have reduced feed efficiencies (average 7%) compared with cattle having healthy livers. The average incidence of abscessed liver in grain-fed cattle approximates 25-30%.
  • Liver abscesses in cattle are part of a disease complex where the abscessation is secondary to primary foci of infection in the rumen epithelium.
  • the pathogenesis can be summarized as follows: (1) ruminal lesions are induced by acidosis that follows rapid change in diet from high-roughage to high grain, prolonged feeding of high grain diet (sometimes referred to as an all-concentrate diet), or occasionally by foreign body penetration of the rumen epithelium; (2) bacteria present in the rumen invade the epithelium and form focal abscesses in the rumen wall; and (3) bacteria enter the portal circulation, and are carried to the liver where they localize in the parenchyma with subsequent abscess formation.
  • F. necrophor ⁇ m is the primary etiologic agent of liver abscesses in ruminant animals.
  • the organism has been recognized as an animal and human pathogen since the late 1800s, and is associated with numerous necrotic disease conditions in domestic and wild animals.
  • the organism is also the primary etiologic agent of foot rot, foot abscesses, calf diphtheria, and is frequently isolated from cases of mastitis, metritis, and necrotic lesions of the oral cavity.
  • the ability of F. necrophorum to establish in the liver is attributed to the production of a toxin called leukotoxin (or leucocidin).
  • the toxin is soluble, proteinaceous and has specificity for bovine leukocytes.
  • the leukotoxin is believed to aid in the establishment of F. necrophorum in the liver by directly impairing the normal defense mechanism and indirectly by the damage caused by cytolytic products released from neutrophils and macro- phages to the hepatic cells. Therefore, the leukotoxin elaborated from F. necrophorum plays a critical role in F necrophorum infection of the liver.
  • F. necrophorum is a gram-negative, nonsporeforming, nonmotile, strictly anaerobic and pleomorphic organism. Morphologically, the organism varies from short rods to filamentous with pointed and rounded ends. Cell lengths range from coracoid bodies of 0.5-0.7 ⁇ m in diameter to filaments over 100 ⁇ m. Surface colonies are 1-2 mm in diameter, circular, transparent to opaque, and with some strains producing ⁇ or ⁇ hemolysis. The organism ferments glucose, fructose and maltose only weakly with final pH around 5.0- 6.3. It ferments lactate to acetate, propionate, and butyrate. Butyrate is the major product from lactate fermentation. Indole is produced from peptone. F.
  • necrophorum has been isolated from the normal flora in the oral cavity, gastrointestinal cavity, and genitourinary tract of humans and animals. The organism is also known to survive in the soil.
  • biotypes A, B, AB and C
  • Biotype A most frequently isolated from liver abscesses, is more pathogenic than biotype B, which predominates in ruminal wall abscesses.
  • Biotype AB is rarely isolated, and has pathogenicity intermediate that of biotypes A and B.
  • Biotype C is non-pathogenic. It has been suggested in the past to utilize F. necrophorum bacterin as an agent for immunizing cattle and sheep against liver necrosis, EPO Application No.
  • Emery et al. (Vet. Microbiol.. 12:255-268, 1986) prepared material by gel filtration of 18-hour culture supernate of F. necrophorum. This elicited significant immunity against challenged from viable F.
  • Actinomyces pyogenes is a gram-positive, cocco-bacillary shaped, facultative organism that is associated with a number of pyogenic conditions (termed "Pyobacillosis") in animals and humans. It is frequently isolated in mixed culture with other bacteria including F necrophorum. In liver abscesses and foot rot in cattle, A. pyogenes is the second most frequent pathogen isolated. In addition to liver abscesses and foot rot, the organism is also a frequent isolated from pyogenic infections of a number of organs such as lungs, mammary glands, joints and the uterus, the pathogenic mechanism of A. pyogenes is not well understood.
  • exotoxins hemolysin or leukotoxin
  • enzymes such as proteinase, DNases, and neuraminidase.
  • no A pyogenes-derived vaccines or inocula for immunizing cattle and sheep against liver abscesses and/or foot rot have been prepared in the past.
  • the present invention relates to inocula for cattle and sheep in order to immunize such ruminants and lessen the incidence therein of liver abscesses and/or foot rot.
  • the invention pertains to methods of preparing such inocula and of lessening the incidence of the aforementioned pathogenic conditions in cattle and sheep.
  • an inoculum for administration to cattle or sheep which comprises a bacterial component and a compatible carrier mixed with the latter.
  • the bacterial component consists essentially of an inactivated cell culture product of A. pyogenes; e.g., the component is selected from the group consisting of separated A. pyogenes cells, A pyogenes cellular subunits or fragments, the supernatant elaborated by A pyogenes cells in cell culture, and mixtures thereof.
  • the carrier may be one of a number of suitable adjuvants such as alumina hydroxide or the oil- based or metallic salt adjuvants.
  • the A pyogenes inoculum is prepared by forming a cell culture of a strain of A pyogenes in a growth media such as Brain Heart Infusion broth or RPM1 1640 media using an overnight culture with incubation at 35-39 °C for 12-48 hours. At the end of the incubation period (most preferably after about 36 hours), a cell culture product is inactivated using formalin, ⁇ -propiolactone, heat, radiation or any other known method of inactivat ⁇ on. In particularly preferred forms, the entire cell culture is inactivated and chilled for two days. Thereafter, the inactivated cell culture is centrifuged and the supernatant antigenic material is recovered. As indicated previously, in alternate proce- dures, the entire cell culture, separate cells or cellular subunits may be used as the antigenic material. In any case, after inactivation and separation as desired, the antigenic material is mixed with a suitable adjuvant carrier.
  • a suitable adjuvant carrier such as Brain Heart Infusion broth or RPM1
  • the invention also comprehends a multi-valent inoculum for administration to cattle or sheep which includes first and second bacterial components in a compatible carrier.
  • the first bacterial component comprises an inactivated cell culture product of A pyogenes and the second component comprises an inactivated cell culture product of F. necrophorum.
  • the first A pyogrenes-derived bacterial component is prepared as set forth above, i.e., use is made of an A pyogenes inoculum in accordance with the invention.
  • the second F. necrophorum-de ⁇ ved bacterial component is prepared in the manner described in PCT Publication No. WO 94/00556 which is incorporated by reference herein.
  • the F necrophorum second bacterial component for the multi-valent vaccine is in the form of inactivated leukotoxin-containing supernatant elaborated by F, necrophorum cells in cell culture.
  • Culturing of F. necrophorum preferably involves culturing a biotype A strain in a suitable growth medium such as Brain Heart Infusion broth at a temperature of from about 35-41 °C and a pH of from about 6.5-8 for a period of from about 4-9 hours.
  • the preferred strain of F. necrophorum has ATCC Accession No. 55329.
  • leukotoxin supernatant is separated and inactivated by any known means, preferably through the use of formalin.
  • the final multivalent inoculum in accordance with the invention is prepared by mixing the first and second bacterial components derived from the respective first and second cell cultures.
  • the bacterial components are present in the final multivalent inoculum at about a 1 :1 (v/v) ratio. It has been determined that the inocula of the present invention will have particular utility in those cases where A pyogenes becomes a significant etiological agent.
  • cattle fed a high concentrate diet including at least about 90% by weight grain characteristically have a high incidence of liver abscesses (greater than 50%). It has now been discovered that a high percentage of abscessed livers from cattle fed concentrate diets exhibit A. pyogenes upon bacteriological examination. Therefore, cattle fed concentrate diets can also materially benefit from treatment with the inocula of the invention.
  • Example 1 the bacterial flora of liver abscesses from feedlot cattle fed with or without the antibiotic tylosin were examined. A total of 36 liver abscesses from tylosin-fed cattle were examined, along with 41 liver abscesses from cattle not fed tylosin. This study revealed that there was a higher incidence of A. pyogenes in the liver abscesses of tylosin-fed animals. Accordingly, it was deduced that in tylosin-fed animals, the role of F. necro- phorum is lessened and A. pyogenes assumes a greater role than in animals not fed tylosin. The results of this study are set forth in the following table.
  • a pyogenes is aerobic, it is not a normal inhabitant of the rumen; however, the bacterium may be a component of the epimural flora of the rumen (bacteria attached to the rumen wall). Facultative or aerobic bacteria have a better chance of surviving in anaerobic conditions by adhering to the rumen wall where extensive blood supply provides oxygen. The close proximity of the rumen wall enhances the opportunity of the bacterium to get into portal circulation and thereby enter the liver. The bacteria could remain dormant and multiply if conditions (such as entry into the liver) become conducive. The higher incidence of A pyogenes in tylosin-fed cattle is surprising because the organism is quite sensitive to tylosin.
  • Example 2 the liver abscesses of cattle fed an all-concen ⁇ trate diet (100% grain) were bacteriologically examined. It is known that feedlots making use of all-concentrate diets have a high incidence of liver abscesses (greater than 50%). In this study, the livers of 24 animals were examined and it was found that 19 were abscessed. Eighteen of these abscesses were cultured and F. necrophorum was found in 12 abscesses whereas A pyogenes was found in 17 abscesses. This data is summarized in the following Table 2.
  • Anaerobic Facultative A. pyogenes utilizes 0 2 to create anaerobic condition for F. necrophorum growth
  • lactate Produces lac ⁇ A. pyogenes provides sub ⁇ endproducts tate strate for F. necrophorum growth
  • Example 3 Hemolysis Weakly positive Strongly Hemolytic activity of A. positive pyogenes provides iron required for F. necrophorum growth
  • Example 3 the preparation of a monovalent A pyogenes vaccine is described, as well as the preparation of a multivalent A. pyogenes/F. necrophorum vaccine.
  • a suitable strain of A pyogenes is grown in a Brain Heart Infusion broth (DIFCO Laboratories, Detroit, Ml) or RPMI 1640 medium (GIBCO Laboratories, Grand Island, NY). The growth medium is inoculated with an overnight culture (1-5% inoculum size) of A pyogenes and is incubated at 35-
  • the culture is inactivated by adding formalin (0.3-0.4%) on a vol./vol. basis.
  • formalin 0.3-0.4% on a vol./vol. basis.
  • the inactivated whole culture is chilled in an ice bath and refrigerated for one or two days. Thereafter, the inactivated cell culture is centrifuged (13,500 g for 15-30 minutes) and the supernatant antigenic material is recovered.
  • the whole cell culture (bacterin) or cellular subunits can be used as the antigenic material.
  • the antigenic material is then mixed with a suitable adjuvant (e.g., aluminum hydroxide or other commercially available oil-based or metallic salt adjuvant) to complete the vaccine.
  • a suitable adjuvant e.g., aluminum hydroxide or other commercially available oil-based or metallic salt adjuvant
  • the vaccine may then be conventionally administered to sheep or cattle (one or more vaccinations) to elicit antibodies in the animals and will prevent the establishment of A pyogenes in the animal's liver or feet, or any other organs.
  • the F. necrophorum leukotoxoid vaccine component is prepared by growing a F. necrophorum biotype A strain (e.g., strain 25, ATCC Accession No. 55329) in a pre-reduced (0.05% cysteine HCI) anaerobically sterilized Brain-Heart Infusion broth (DIFCO Laboratories, Detroit, Ml) at 39 °C for 7 hours (absorbance 0.8 at 600 nm). The culture supernatant is obtained by centrifugation at 13,500 g for 30 minutes at 4°C, filtered through a 0.45 ⁇ m membrane filter (Micron Separations, Inc., Westborough, MA) and inactivated with 0.3% formalin. F. necrophorum leukotoxin and protein concentrations in the cell culture supernatant are assayed before and after inactivation with formalin.
  • a F. necrophorum biotype A strain e.g., strain 25, ATCC Accession No. 55
  • the inactivated supernatant is mixed with Ribi adjuvant
  • the A pyogenes vaccine and the F. necrophorum vaccine component are mixed on a 1 :1 v/v basis.
  • the multivalent vaccine can then be conventionally administered (typically via one or more injections) to cattle or sheep.
  • the monovalent or multivalent vaccines of the invention may be conventionally administrated via parenteral injection or other known techniques in order to elicit the production of appropriate antibodies in the ruminant animals. Such administrations may be at one time or multiple administrations spaced over a period of time.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne de nouveaux agents d'inoculation de ruminants, tels que vaches ou moutons, utiles pour les immuniser et pour réduire l'incidence d'abcès du foie et/ou de piétin. Dans un mode de réalisation, l'invention concerne un vaccin dérivé d'A. pyogenes qui comprend un produit inactivé d'une culture de cellules (par exemple un surnageant élaboré par des cellules) d'A. pyogenes dans un récipient approprié. Dans un autre mode de réalisation, l'invention concerne un vaccin multivalent qui contient au moins un premier et un deuxième composant bactériens dans un excipient. Le premier composant est un produit inactivé d'une culture de cellules d'A. pyogenes et le deuxième composant est un produit inactivé de culture de cellules de F. necrophorum. Les agents d'inoculation décrits sont particulièrement utiles pour les animaux ruminants particulièrement exposés aux infections par A. pyogenes qui entraînent des abcès du foie et/ou le piétin, c'est-à-dire lorsque les animaux sont traités régulièrement aux antibiotiques ou lorsqu'ils ont un régime concentré riche en céréales.
EP96921496A 1995-06-07 1996-06-07 Vaccins d'actinomyces pyogenes et d'actinomyces pyogenes/fusobacterium necrophorum utiles pour immuniser le betail bovin et ovin Withdrawn EP0837695A4 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05000534A EP1535626B1 (fr) 1995-06-07 1996-06-07 Vaccins d'actinomyces pyogènes et d'actinomyces pyogènes/fusobactérium nécrophorum utiles pour immuniser le bétail bovin et ovin

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US47761995A 1995-06-07 1995-06-07
US08/483,382 US5861162A (en) 1995-06-07 1995-06-07 Multivalent inocula for lessening incidence of liver abscesses in cattle
US477619 1995-06-07
US483382 1995-06-07
PCT/US1996/009972 WO1996040237A1 (fr) 1995-06-07 1996-06-07 Vaccins d'actinomyces pyogenes et d'actinomyces pyogenes/fusobacterium necrophorum utiles pour immuniser le betail bovin et ovin

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP05000534A Division EP1535626B1 (fr) 1995-06-07 1996-06-07 Vaccins d'actinomyces pyogènes et d'actinomyces pyogènes/fusobactérium nécrophorum utiles pour immuniser le bétail bovin et ovin

Publications (2)

Publication Number Publication Date
EP0837695A1 true EP0837695A1 (fr) 1998-04-29
EP0837695A4 EP0837695A4 (fr) 2001-03-21

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ID=27045613

Family Applications (2)

Application Number Title Priority Date Filing Date
EP96921496A Withdrawn EP0837695A4 (fr) 1995-06-07 1996-06-07 Vaccins d'actinomyces pyogenes et d'actinomyces pyogenes/fusobacterium necrophorum utiles pour immuniser le betail bovin et ovin
EP05000534A Expired - Lifetime EP1535626B1 (fr) 1995-06-07 1996-06-07 Vaccins d'actinomyces pyogènes et d'actinomyces pyogènes/fusobactérium nécrophorum utiles pour immuniser le bétail bovin et ovin

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP05000534A Expired - Lifetime EP1535626B1 (fr) 1995-06-07 1996-06-07 Vaccins d'actinomyces pyogènes et d'actinomyces pyogènes/fusobactérium nécrophorum utiles pour immuniser le bétail bovin et ovin

Country Status (11)

Country Link
EP (2) EP0837695A4 (fr)
JP (1) JPH11507377A (fr)
KR (1) KR19990022534A (fr)
AR (1) AR003432A1 (fr)
AT (1) ATE506074T1 (fr)
AU (1) AU713257B2 (fr)
BR (1) BR9610775A (fr)
CA (1) CA2223754C (fr)
DE (1) DE69638358D1 (fr)
MX (1) MX9709785A (fr)
WO (1) WO1996040237A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112015012288B1 (pt) 2012-11-29 2022-07-26 Cornell University Uso de uma composição veterinária
AU2016228514B2 (en) * 2015-03-12 2021-06-17 Zoetis Services Llc Pyolysin methods and compositions

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3853990A (en) * 1973-01-22 1974-12-10 E Madigan Infectious kerating bacterin and antiserum and method of preparing same
DE69133172T2 (de) * 1990-06-07 2003-04-30 Bayer Ag Bacterin zur Behandlung von Lebernekrose verursacht durch F. Necrophorum
ATE196654T1 (de) * 1992-06-26 2000-10-15 Univ Kansas State Fusobacterium necrophorum leukotoxoid vakzin

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9640237A1 *

Also Published As

Publication number Publication date
CA2223754C (fr) 2011-02-22
BR9610775A (pt) 1999-07-13
KR19990022534A (ko) 1999-03-25
AR003432A1 (es) 1998-08-05
EP0837695A4 (fr) 2001-03-21
AU713257B2 (en) 1999-11-25
CA2223754A1 (fr) 1996-12-19
EP1535626A2 (fr) 2005-06-01
WO1996040237A1 (fr) 1996-12-19
MX9709785A (es) 1998-10-31
DE69638358D1 (de) 2011-06-01
EP1535626B1 (fr) 2011-04-20
AU6270996A (en) 1996-12-30
EP1535626A3 (fr) 2005-06-08
JPH11507377A (ja) 1999-06-29
ATE506074T1 (de) 2011-05-15

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