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WO1999058145A3 - Immunomodulators for vaccines - Google Patents

Immunomodulators for vaccines Download PDF

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Publication number
WO1999058145A3
WO1999058145A3 PCT/GB1999/001461 GB9901461W WO9958145A3 WO 1999058145 A3 WO1999058145 A3 WO 1999058145A3 GB 9901461 W GB9901461 W GB 9901461W WO 9958145 A3 WO9958145 A3 WO 9958145A3
Authority
WO
WIPO (PCT)
Prior art keywords
agent
binding
etxb
ctxb
immunomodulators
Prior art date
Application number
PCT/GB1999/001461
Other languages
French (fr)
Other versions
WO1999058145A2 (en
Inventor
Timothy Raymond Hirst
Neil Andrew Williams
Original Assignee
Univ Bristol
Timothy Raymond Hirst
Neil Andrew Williams
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 GBGB9809958.3A external-priority patent/GB9809958D0/en
Priority claimed from GBGB9812316.9A external-priority patent/GB9812316D0/en
Priority to US09/674,935 priority Critical patent/US7914791B1/en
Priority to NZ507911A priority patent/NZ507911A/en
Priority to CA 2331832 priority patent/CA2331832A1/en
Priority to GB0027072A priority patent/GB2353472A/en
Priority to EP19990922284 priority patent/EP1075274A2/en
Priority to MXPA00010934A priority patent/MXPA00010934A/en
Priority to HU0104842A priority patent/HUP0104842A3/en
Priority to EA200001134A priority patent/EA004794B1/en
Application filed by Univ Bristol, Timothy Raymond Hirst, Neil Andrew Williams filed Critical Univ Bristol
Priority to PL34451999A priority patent/PL344519A1/en
Priority to BR9910305A priority patent/BR9910305A/en
Priority to JP2000547996A priority patent/JP4666761B2/en
Priority to KR1020007012486A priority patent/KR20010043441A/en
Priority to AU39394/99A priority patent/AU3939499A/en
Publication of WO1999058145A2 publication Critical patent/WO1999058145A2/en
Publication of WO1999058145A3 publication Critical patent/WO1999058145A3/en
Priority to IS5694A priority patent/IS5694A/en
Priority to IL139467A priority patent/IL139467A/en
Priority to NO20005599A priority patent/NO20005599L/en
Priority to AU2003261492A priority patent/AU2003261492B2/en
Priority to US13/038,021 priority patent/US20110223194A1/en

Links

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
    • A61K39/12—Viral antigens
    • A61K39/245—Herpetoviridae, e.g. herpes simplex virus
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • 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
    • A61K39/12—Viral 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
    • A61K39/385—Haptens or antigens, bound to carriers
    • 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
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/543—Mucosal route intranasal
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55544—Bacterial toxins
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
    • 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
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16611—Simplexvirus, e.g. human herpesvirus 1, 2
    • C12N2710/16634—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • AIDS & HIV (AREA)
  • Biotechnology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

There is disclosed the use of: (i) EtxB, CtxB or VtxB free from whole toxin; (ii) an agent other than EtxB or CtxB, having GM1-binding activity, or an agent other than VtxB having Gb3-binding activity; or (iii) an agent having an effect on intracellular signalling events mediated by GM1-binding or Gb3 binding; as an immunomodulator for a vaccine against infectious diseases.
PCT/GB1999/001461 1998-05-08 1999-05-10 Immunomodulators for vaccines WO1999058145A2 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
KR1020007012486A KR20010043441A (en) 1998-05-08 1999-05-10 Immunomodulators for vaccines
AU39394/99A AU3939499A (en) 1998-05-08 1999-05-10 Vaccine
JP2000547996A JP4666761B2 (en) 1998-05-08 1999-05-10 Immunomodulators for vaccines
CA 2331832 CA2331832A1 (en) 1998-05-08 1999-05-10 E.coli heat-labile enterotoxin subunit b (etxb) as an immunomodulator
GB0027072A GB2353472A (en) 1998-05-08 1999-05-10 Vaccine
EP19990922284 EP1075274A2 (en) 1998-05-08 1999-05-10 Immunomodulators for vaccines
MXPA00010934A MXPA00010934A (en) 1998-05-08 1999-05-10 Vaccine.
HU0104842A HUP0104842A3 (en) 1998-05-08 1999-05-10 Vaccine
EA200001134A EA004794B1 (en) 1998-05-08 1999-05-10 Vaccine
US09/674,935 US7914791B1 (en) 1998-05-08 1999-05-10 Vaccine
PL34451999A PL344519A1 (en) 1998-05-08 1999-05-10 Vaccine
BR9910305A BR9910305A (en) 1998-05-08 1999-05-10 Vaccine
NZ507911A NZ507911A (en) 1998-05-08 1999-05-10 Immunomodulators for vaccines
IS5694A IS5694A (en) 1998-05-08 2000-10-31 vaccine
IL139467A IL139467A (en) 1998-05-08 2000-11-05 USE OF EtxB, CtxB OR VtxB IN THE MANUFACTURE OF A VACCINE AGAINST INFECTIOUS DISEASES
NO20005599A NO20005599L (en) 1998-05-08 2000-11-06 Vaccine
AU2003261492A AU2003261492B2 (en) 1998-05-08 2003-11-07 Vaccine
US13/038,021 US20110223194A1 (en) 1998-05-08 2011-03-01 Vaccine

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB9809958.3 1998-05-08
GBGB9809958.3A GB9809958D0 (en) 1998-05-08 1998-05-08 Vaccine
GBGB9811954.8A GB9811954D0 (en) 1998-05-08 1998-06-03 Vaccine
GB9811954.8 1998-06-03
GB9812316.9 1998-06-08
GBGB9812316.9A GB9812316D0 (en) 1998-06-08 1998-06-08 Cancer vaccines

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/038,021 Division US20110223194A1 (en) 1998-05-08 2011-03-01 Vaccine

Publications (2)

Publication Number Publication Date
WO1999058145A2 WO1999058145A2 (en) 1999-11-18
WO1999058145A3 true WO1999058145A3 (en) 2000-02-03

Family

ID=27269307

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/001461 WO1999058145A2 (en) 1998-05-08 1999-05-10 Immunomodulators for vaccines

Country Status (18)

Country Link
EP (1) EP1075274A2 (en)
JP (1) JP4666761B2 (en)
KR (1) KR20070067719A (en)
CN (1) CN100335130C (en)
AU (1) AU3939499A (en)
BR (1) BR9910305A (en)
CA (1) CA2331832A1 (en)
CZ (1) CZ302333B6 (en)
EA (1) EA004794B1 (en)
GB (1) GB2353472A (en)
HU (1) HUP0104842A3 (en)
IL (1) IL139467A (en)
IS (1) IS5694A (en)
MX (1) MXPA00010934A (en)
NO (1) NO20005599L (en)
NZ (1) NZ507911A (en)
PL (1) PL344519A1 (en)
WO (1) WO1999058145A2 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7914791B1 (en) 1998-05-08 2011-03-29 Trident Pharmaceuticals, Inc. Vaccine

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9513371D0 (en) 1995-06-30 1995-09-06 Biocine Spa Immunogenic detoxified mutant toxins
GB9326174D0 (en) * 1993-12-22 1994-02-23 Biocine Sclavo Mucosal adjuvant
US20010036917A1 (en) 1995-07-05 2001-11-01 Williams Neil Andrew Therapeutic agents
GB9622660D0 (en) 1996-10-31 1997-01-08 Biocine Spa Immunogenic detoxified mutant toxin
US6818222B1 (en) 1997-03-21 2004-11-16 Chiron Corporation Detoxified mutants of bacterial ADP-ribosylating toxins as parenteral adjuvants
US7115730B1 (en) 1999-04-27 2006-10-03 Chiron Srl Immunogenic detoxified mutant E. coli LT-A-toxin
GB0030067D0 (en) * 2000-12-11 2001-01-24 Univ Bristol Therapeutic agent
GB0115382D0 (en) 2001-06-22 2001-08-15 Univ Bristol Mutant
CN111100824B (en) * 2020-01-21 2021-11-05 暨南大学 A strain of Bacillus and its application in denitrification and sulfur removal in aquaculture water

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372928A2 (en) * 1988-12-07 1990-06-13 University Of Leicester Heat-labile toxin B subunit fusion proteins
US5241053A (en) * 1990-09-05 1993-08-31 Takeda Chemical Industries, Ltd. Fused proteins comprising glycoprotein gD of HSV-1 and LTB
WO1997002045A1 (en) * 1995-07-05 1997-01-23 Oratol Limited Therapeutic agents and autoimmune diseases
EP0919243A1 (en) * 1997-11-25 1999-06-02 Duphar International Research B.V Vaccine containing B subunits of heat-labile enterotoxin (LTB) of Escherichia coli as an adjuvant
WO1999036088A1 (en) * 1998-01-16 1999-07-22 Maxim Pharmaceuticals, Inc. RECOMBINANT CtB-BASED VACCINES

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0372928A2 (en) * 1988-12-07 1990-06-13 University Of Leicester Heat-labile toxin B subunit fusion proteins
US5241053A (en) * 1990-09-05 1993-08-31 Takeda Chemical Industries, Ltd. Fused proteins comprising glycoprotein gD of HSV-1 and LTB
WO1997002045A1 (en) * 1995-07-05 1997-01-23 Oratol Limited Therapeutic agents and autoimmune diseases
EP0919243A1 (en) * 1997-11-25 1999-06-02 Duphar International Research B.V Vaccine containing B subunits of heat-labile enterotoxin (LTB) of Escherichia coli as an adjuvant
WO1999036088A1 (en) * 1998-01-16 1999-07-22 Maxim Pharmaceuticals, Inc. RECOMBINANT CtB-BASED VACCINES

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
HIRST T R ET AL: "Cholera toxin and related enterotoxins as potent immune modulators.", SOCIETY FOR APPLIED BACTERIOLOGY SYMPOSIUM SERIES, (1998) 27 26S-34S, XP000856429 *
NASHAR T O ET AL: "Importance of receptor binding in the immunogenicity, adjuvanticity and therapeutic properties of cholera toxin and Escherichia coli heat-labile enterotoxin.", MEDICAL MICROBIOLOGY AND IMMUNOLOGY, (1998 JUN) 187 (1) 3-10, XP000857029 *
NASHAR T O ET AL: "Modulation of B-cell activation by the B subunit of Escherichia coli enterotoxin: receptor interaction up-regulates MHC class II, B7, CD40, CD25 and ICAM-1.", IMMUNOLOGY, (1997 AUG) 91 (4) 572-8., XP002123821 *
RICHARDS C M ET AL: "Induction of mucosal immunity against herpes simplex virus type 1 in the mouse protects against ocular infection and establishment of latency.", JOURNAL OF INFECTIOUS DISEASES, (1998 JUN) 177 (6) 1451-7., XP002123823 *
WILLIAMS N A ET AL: "Immune modulation by the cholera-like enterotoxins: from adjuvant to therapeutic.", IMMUNOLOGY TODAY, (1999 FEB) 20 (2) 95-101, XP002123822 *
ZHANG T ET AL: "ORAL IMMUNIZATION WITH THE DODECAPEPTIDE REPEAT OF THE SERINE-RICH ENTAMOEBA HISTOLYTICA PROTEIN (SREHP) FUSED TO THE CHOLERA TOXIN B SUBUNIT INDUCES A MUCOSAL AND SYSTEMIC ANTI-SREHP ANTIBODY RESPONSE", INFECTION AND IMMUNITY,US,AMERICAN SOCIETY FOR MICROBIOLOGY. WASHINGTON, vol. 63, no. 4, pages 1349-1355, XP000645273, ISSN: 0019-9567 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7914791B1 (en) 1998-05-08 2011-03-29 Trident Pharmaceuticals, Inc. Vaccine

Also Published As

Publication number Publication date
WO1999058145A2 (en) 1999-11-18
EA004794B1 (en) 2004-08-26
EP1075274A2 (en) 2001-02-14
HUP0104842A2 (en) 2002-04-29
CN100335130C (en) 2007-09-05
NO20005599D0 (en) 2000-11-06
EA200001134A1 (en) 2001-08-27
CZ302333B6 (en) 2011-03-16
GB2353472A (en) 2001-02-28
KR20070067719A (en) 2007-06-28
JP2002514607A (en) 2002-05-21
CA2331832A1 (en) 1999-11-18
CZ20004147A3 (en) 2001-05-16
BR9910305A (en) 2001-01-09
NO20005599L (en) 2001-01-08
PL344519A1 (en) 2001-11-05
HUP0104842A3 (en) 2002-12-28
GB0027072D0 (en) 2000-12-20
IL139467A0 (en) 2001-11-25
IS5694A (en) 2000-10-31
IL139467A (en) 2011-11-30
NZ507911A (en) 2004-04-30
JP4666761B2 (en) 2011-04-06
CN1308546A (en) 2001-08-15
AU3939499A (en) 1999-11-29
MXPA00010934A (en) 2003-07-14

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