WO2003101477A1 - Use of uk114 in the treatment of leishmaniasis - Google Patents

Use of uk114 in the treatment of leishmaniasis Download PDF

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Publication number
WO2003101477A1
WO2003101477A1 PCT/EP2003/005551 EP0305551W WO03101477A1 WO 2003101477 A1 WO2003101477 A1 WO 2003101477A1 EP 0305551 W EP0305551 W EP 0305551W WO 03101477 A1 WO03101477 A1 WO 03101477A1
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Prior art keywords
leishmaniasis
treatment
macrophages
ubiquitin
animals
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PCT/EP2003/005551
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French (fr)
Inventor
Antonio Salvaggio
Ferdinando Nicoletti
Battesimo Macri'
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PHARMAPRODUCTS UK Ltd
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PHARMAPRODUCTS UK Ltd
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Priority to DE60301886T priority Critical patent/DE60301886D1/en
Priority to AU2003238407A priority patent/AU2003238407A1/en
Priority to JP2004508832A priority patent/JP2005529932A/en
Priority to BR0311596-8A priority patent/BR0311596A/en
Priority to US10/516,465 priority patent/US20060100142A1/en
Priority to EP03732475A priority patent/EP1511510B1/en
Priority to AT03732475T priority patent/ATE306279T1/en
Priority to MXPA04012050A priority patent/MXPA04012050A/en
Publication of WO2003101477A1 publication Critical patent/WO2003101477A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • 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

Definitions

  • This invention relates to the use of the protein UK114, possibly associated with ubiquitin, to treat leishmaniasis in humans and animals.
  • the protozoa of the Leishmania genus are intracellular parasites of the macrophages and dendritic cells of the dog, man and numerous wild animals.
  • leishmaniasis presents in three clinical forms: visceral (known in man as
  • the vector is a sand-fly of the Phlebotomus genus in the Old World and the Lutzomyia genus in the New World.
  • the protozoa multiply in the sand-fly and are transformed into infectious organisms.
  • Parasites of the Leishmania genus appear as rounded or oval organisms in the macrophage, with the rod-like kinetoplast adjacent to the nucleus.
  • the organism which measures 2 to 5 ⁇ m in diameter, possesses a rudimentary flagellum that does not extend beyond the edge of the cell. This amastigote form of the parasite is ingested by the sand-fly during the blood meal.
  • the protozoon is transformed in the intestine of the intermediate host into the promastigote form, characterised by a long free flagellum that protrudes from the anterior extremity of the parasite.
  • the organism has an elongated shape and can grow to a length of 15 ⁇ m, excluding the flagellum, which usually has the same dimensions as the body.
  • the amastigotes ingested reach the intestine of the sand- fly, where they are transformed into promastigotes.
  • the promastigotes divide repeatedly by binary fission, and subsequently migrate in the anterior direction. In the pharynx, the parasites turn into highly mobile metacyclic promastigotes, which migrate towards the proboscis.
  • the promastigotes are transmitted to the new vertebrate host by means of the sand-fly's bite.
  • the promastigotes are ingested by the monocytes/macrophages. After being ingested, the promastigote turns into an amastigote.
  • the amastigotes divide by binary fission in the parasitophorous vacuole until their number is sufficient to rupture the macrophage. The amastigotes thus released are ingested by other macrophages.
  • the ability of the amastigotes to survive in the macrophages and spread throughout the body depends on factors intrinsic to the parasite and on factors associated with the type of cell-mediated immune response developed by the host.
  • Th lymphocytes If parasitic macrophages are sufficiently stimulated by T-helper (Th) lymphocytes, they produce numerous lysosome enzymes and other factors including oxygen metabolites, hydrogen superoxide and peroxide and nitrous oxide (NO), which are toxic to the parasite.
  • Th lymphocytes T-helper lymphocytes
  • IL interleukin
  • Thl response In laboratory animals, resistance to Leishmania infection is characterised by the Thl response, with production of IL-12 and interferon gamma (IFN ⁇ ) and activation of the macrophages which eliminate the parasite.
  • IFN ⁇ interferon gamma
  • Th2 In animals sensitive to infection, the response is type Th2, characterised by production of IL-4 and IL-10 with consequent suppression of the parasiticidal activity of the macrophages and stimulation of the B lymphocytes with an increase in the production of immunoglobulins.
  • the humoral immune response in leishmaniasis is impressive, but not protective.
  • the specific antibodies produced against Leishmania have no neutralising action against the parasite.
  • the protozoon spreads throughout the body, in the macrophages.
  • the parasite has been observed in all the organs and tissues of the body except the central nervous system.
  • the pathogenesis of the skin lesions present in most sufferers is not yet clear.
  • the persistence of the parasite in the macrophage continually stimulates infiltration by inflammatory cells, especially plasma cells, macrophages and lymphocytes, into the dermis.
  • the deposit of immunocomplexes is the main cause of dermatitis which, on histological examination, often presents lesions similar to those caused by other diseases induced by immunocomplexes, such as systemic Lupus erythematosus.
  • the skin alterations may be the result of vasculitis.
  • canine leishmaniasis The symptoms of canine leishmaniasis are highly variable, and may include peripheral lymphadenopathy (over 90% of infected subjects), skin lesions (>80%), chronic conjunctivitis (50%), onychogryphosis (40%), anorexia (>35%), increased appetite (30%), weight loss (30%), fever (20%), kidney failure (20%), epistaxis (10%), uveitis (8%) and gait disorders (6%).
  • the skin signs are among the most important in the disease.
  • Various types of macroscopic and microscopic lesions have been described in canine leishmaniasis: dry exfoliative dermatitis, ulcerative dermatitis, nodular dermatitis, sterile pustular dermatitis, paronychia, and nasal and/or digital hyperkeratosis.
  • the skin lesions are generally chronic, symmetrical and not itchy.
  • the current elective treatment based on antimony gluconate administered by infiltration (in cutaneous 1.) or injection (in the other forms) can cause toxic effects (nausea and vomiting) sufficiently serious to require discontinuance of the treatment, which is replaced by treatment with aromatic diamines such as pentamidine, whose tolerability is generally poor.
  • protein UK114 of extractive or recombinant origin will therefore be opportunely administered to subjects suffering from leishmaniasis by the parenteral route, in particular subcutaneously or intramuscularly, at doses ranging between approx. 0.5 and 10 mg a day, until the disappearance or substantial reduction of the symptoms.
  • the compositions according to the invention in the form of solutions or suspensions in preferably aqueous sterile solvents, may also contain ubiquitin in a quantity corresponding to 0.1-5 mg per unit dose.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

This invention relates to the use of the protein UK114, possibly associated with ubiquitin, for the treatment of leishmaniasis in humans and animals.

Description

USE OF UK114 IN THE TREATMENT OF LEISHMANIASIS
This invention relates to the use of the protein UK114, possibly associated with ubiquitin, to treat leishmaniasis in humans and animals.
The protozoa of the Leishmania genus are intracellular parasites of the macrophages and dendritic cells of the dog, man and numerous wild animals. On the basis of the classification criteria used in human medicine, leishmaniasis presents in three clinical forms: visceral (known in man as
"kala-azar"), cutaneous and mucocutaneous.
In the case of the dog, a cutaneous and a visceral form were separately classified in the past because of the characteristic clinical picture, but they are now both regarded as progressive forms of the same disease, known as "generalised canine leishmaniasis".
The vector is a sand-fly of the Phlebotomus genus in the Old World and the Lutzomyia genus in the New World. The protozoa multiply in the sand-fly and are transformed into infectious organisms. Parasites of the Leishmania genus appear as rounded or oval organisms in the macrophage, with the rod-like kinetoplast adjacent to the nucleus. The organism, which measures 2 to 5 μm in diameter, possesses a rudimentary flagellum that does not extend beyond the edge of the cell. This amastigote form of the parasite is ingested by the sand-fly during the blood meal. The protozoon is transformed in the intestine of the intermediate host into the promastigote form, characterised by a long free flagellum that protrudes from the anterior extremity of the parasite. The organism has an elongated shape and can grow to a length of 15 μm, excluding the flagellum, which usually has the same dimensions as the body. The amastigotes ingested reach the intestine of the sand- fly, where they are transformed into promastigotes. The promastigotes divide repeatedly by binary fission, and subsequently migrate in the anterior direction. In the pharynx, the parasites turn into highly mobile metacyclic promastigotes, which migrate towards the proboscis. The promastigotes are transmitted to the new vertebrate host by means of the sand-fly's bite. In the vertebrate host, the promastigotes are ingested by the monocytes/macrophages. After being ingested, the promastigote turns into an amastigote. The amastigotes divide by binary fission in the parasitophorous vacuole until their number is sufficient to rupture the macrophage. The amastigotes thus released are ingested by other macrophages. The ability of the amastigotes to survive in the macrophages and spread throughout the body depends on factors intrinsic to the parasite and on factors associated with the type of cell-mediated immune response developed by the host. If parasitic macrophages are sufficiently stimulated by T-helper (Th) lymphocytes, they produce numerous lysosome enzymes and other factors including oxygen metabolites, hydrogen superoxide and peroxide and nitrous oxide (NO), which are toxic to the parasite.
The type of cell-mediated immune response and interleukin (IL) profile produced determine resistance or sensitivity to Leishmania infection. In laboratory animals, resistance to Leishmania infection is characterised by the Thl response, with production of IL-12 and interferon gamma (IFNγ) and activation of the macrophages which eliminate the parasite. Conversely, in animals sensitive to infection, the response is type Th2, characterised by production of IL-4 and IL-10 with consequent suppression of the parasiticidal activity of the macrophages and stimulation of the B lymphocytes with an increase in the production of immunoglobulins.
The humoral immune response in leishmaniasis is impressive, but not protective. The specific antibodies produced against Leishmania have no neutralising action against the parasite. In animals sensitive to the disease the protozoon spreads throughout the body, in the macrophages. The parasite has been observed in all the organs and tissues of the body except the central nervous system. Slow, continuous contact between the parasitic antigen and the immunocompetent cells forms the basis for the pathogenetic development of the disease, which is characterised by: hyperglobulinaemia, generally polyclonal, associated with continual stimulation of the B lymphocytes, which causes an increase in total proteins and inversion of the albumin/globulin ratio; production of auto-antibodies, probably due to a cross-reaction between parasitic antigens and self-antigens, causing thrombocytopenia and anaemia; production and deposit of immunocomplexes responsible for the vasculitis, glomerulonephritis and polyarthritis syndromes.
The pathogenesis of the skin lesions present in most sufferers is not yet clear. According to some authors, the persistence of the parasite in the macrophage continually stimulates infiltration by inflammatory cells, especially plasma cells, macrophages and lymphocytes, into the dermis. According to other authors, the deposit of immunocomplexes is the main cause of dermatitis which, on histological examination, often presents lesions similar to those caused by other diseases induced by immunocomplexes, such as systemic Lupus erythematosus. Finally, the skin alterations may be the result of vasculitis.
The symptoms of canine leishmaniasis are highly variable, and may include peripheral lymphadenopathy (over 90% of infected subjects), skin lesions (>80%), chronic conjunctivitis (50%), onychogryphosis (40%), anorexia (>35%), increased appetite (30%), weight loss (30%), fever (20%), kidney failure (20%), epistaxis (10%), uveitis (8%) and gait disorders (6%).
The skin signs are among the most important in the disease. Various types of macroscopic and microscopic lesions have been described in canine leishmaniasis: dry exfoliative dermatitis, ulcerative dermatitis, nodular dermatitis, sterile pustular dermatitis, paronychia, and nasal and/or digital hyperkeratosis. The skin lesions are generally chronic, symmetrical and not itchy.
Recent studies clearly demonstrate the existence of a TNF-independent compensation mechanism able to activate the macrophages in the anti- leishmania response. As the Thl response mediated by interleukin-12 (IL-12) and interferon gamma (IFNγ) is paradoxically responsible not only for activation of the macrophages, but also for nearly all the symptoms of leishmaniasis, it may be advantageous to boost this compensation mechanism by inhibiting the Thl response.
The current elective treatment, based on antimony gluconate administered by infiltration (in cutaneous 1.) or injection (in the other forms) can cause toxic effects (nausea and vomiting) sufficiently serious to require discontinuance of the treatment, which is replaced by treatment with aromatic diamines such as pentamidine, whose tolerability is generally poor.
It has now been found that the protein with molecular weight 14 kDa in SDS-PAGE, obtainable by extraction from mammal liver with perchloric acid, called UK114 and disclosed in EP 574394 and US 5792744, is useful in the treatment of leishmaniasis, possibly associated with ubiquitin (UK110). Recombinant protein UK114 is known from WO 00/63368. Subcutaneous administration of UK114 and ubiquitin to a group of 10 dogs with manifest clinical symptoms of leishmaniasis (peripheral lymphadenopathy and skin lesions of a high degree, mainly represented by sores and bleeding ulcers with loss of substance, anorexia and weight loss), at the doses and times indicated in the table, led to complete healing of all the lesions during the treatment period. No adverse effects were observed during the treatment.
These findings demonstrate that the administration of UK114 and ubiquitin cures the clinical symptoms of leishmaniasis in a totally safe manner. This is very interesting in view of the high toxicity of the drugs currently used in treatment, and the possibility of a response that is sometimes unsatisfactory from the clinical standpoint.
TABLE
Figure imgf000006_0001
According to the invention, protein UK114 of extractive or recombinant origin will therefore be opportunely administered to subjects suffering from leishmaniasis by the parenteral route, in particular subcutaneously or intramuscularly, at doses ranging between approx. 0.5 and 10 mg a day, until the disappearance or substantial reduction of the symptoms. The compositions according to the invention, in the form of solutions or suspensions in preferably aqueous sterile solvents, may also contain ubiquitin in a quantity corresponding to 0.1-5 mg per unit dose.
b
BIBLIOGRAPHY
1. Urquhart G.M., Armour J., Duncan J.L., Dunn A.M, Jennings F.W.
Veterinary Parasitology 2nd ed., Italian edition edited by C. Genchi, UTET 1998.
2. Murray H.W., Jungbluth A., Ritter E., Montelibano C, Marino
M.W. Visceral Leishmaniasis in Mice Devoid of Tumor Necrosis Factor and Response to Treatment, Infection and Immunity, November 2000, p. 6289- 6293, Vol. 68, No. 11. 3. Katzung B.G. Basic & Clinical Pharmacology, 1995 by Appleton & Lange, E.N., Connecticut.

Claims

1. Use of the protein UK 114, possibly in combination with ubiquitin, for the preparation of pharmaceutical or veterinary compositions for the treatment of leishmaniasis in humans and animals.
2. Pharmaceutical or veterinary compositions containing the extractive or recombinant protein UK 114, possibly associated with ubiquitin, together with a suitable vehicle, for the treatment of leishmaniasis in humans and animals.
PCT/EP2003/005551 2002-06-04 2003-05-27 Use of uk114 in the treatment of leishmaniasis Ceased WO2003101477A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DE60301886T DE60301886D1 (en) 2002-06-04 2003-05-27 USE OF UK114 FOR THE TREATMENT OF LEISHMANIASIS
AU2003238407A AU2003238407A1 (en) 2002-06-04 2003-05-27 Use of uk114 in the treatment of leishmaniasis
JP2004508832A JP2005529932A (en) 2002-06-04 2003-05-27 Use of UK114 in the treatment of leishmaniasis
BR0311596-8A BR0311596A (en) 2002-06-04 2003-05-27 Use of uk114 in the treatment of leishmaniasis
US10/516,465 US20060100142A1 (en) 2002-06-04 2003-05-27 Use of uk114 in the treatment of leishmaniasis
EP03732475A EP1511510B1 (en) 2002-06-04 2003-05-27 Use of uk114 in the treatment of leishmaniasis
AT03732475T ATE306279T1 (en) 2002-06-04 2003-05-27 USE OF UK114 FOR THE TREATMENT OF LEISHMANIASIS
MXPA04012050A MXPA04012050A (en) 2002-06-04 2003-05-27 Use of uk114 in the treatment of leishmaniasis.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2002MI001205A ITMI20021205A1 (en) 2002-06-04 2002-06-04 USE OF PROTEINS FOR THE TREATMENT OF LEISHMANIOSIS
ITMI2002A001205 2002-06-04

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EP (1) EP1511510B1 (en)
JP (1) JP2005529932A (en)
AT (1) ATE306279T1 (en)
AU (1) AU2003238407A1 (en)
BR (1) BR0311596A (en)
DE (1) DE60301886D1 (en)
IT (1) ITMI20021205A1 (en)
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WO (1) WO2003101477A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024074870A1 (en) * 2022-10-06 2024-04-11 Instituto Politecnico Nacional Peptide veterinary composition for immunotherapy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042366A1 (en) * 1997-03-25 1998-10-01 Zetesis S.P.A. The use of proteins extractable from animal organs for the preparation of medicaments for the treatment of pathological conditions characterized by hyperproduction of tumor necrosis factor (tnf)
WO1999043340A1 (en) * 1998-02-24 1999-09-02 Zetesis S.P.A. Oral compositions at low dosage of cytotoxic proteins
WO2000078329A2 (en) * 1999-06-22 2000-12-28 Zetesis S.P.A. The use of the protein uk 114 for inhibiting organ transplant rejection

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042366A1 (en) * 1997-03-25 1998-10-01 Zetesis S.P.A. The use of proteins extractable from animal organs for the preparation of medicaments for the treatment of pathological conditions characterized by hyperproduction of tumor necrosis factor (tnf)
WO1999043340A1 (en) * 1998-02-24 1999-09-02 Zetesis S.P.A. Oral compositions at low dosage of cytotoxic proteins
WO2000078329A2 (en) * 1999-06-22 2000-12-28 Zetesis S.P.A. The use of the protein uk 114 for inhibiting organ transplant rejection

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; July 2001 (2001-07-01), KHASKHELY NOOR MOHAMMAD ET AL: "Pre-exposure with low-dose UVA suppresses lesion development and enhances Th1 response in BALB/c mice infected with Leishmania (Leishmania) amazonensis.", XP002253827, Database accession no. PREV200100345475 *
JOURNAL OF DERMATOLOGICAL SCIENCE, vol. 26, no. 3, July 2001 (2001-07-01), pages 217 - 232, ISSN: 0923-1811 *
NICOLETTI FERDINANDO ET AL: "Prevention and treatment of lethal murine endotoxemia by the novel immunomodulatory agent MFP-14.", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 45, no. 5, May 2001 (2001-05-01), pages 1591 - 1594, XP002253826, ISSN: 0066-4804 *
PANERAL A E ET AL: "CHRONIC ADMINISTRATION OF UK-114, A MULTIFUNCTIONAL EMERGING PROTEIN, MODULATES THE TH1/TH2 CYTOKINE PATTERN AND EXPERIMENTAL AUTOIMMUNE DISEASES", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, NEW YORK ACADEMY OF SCIENCES, NEW YORK, NY, US, vol. 876, 1999, pages 229 - 235, XP000971426, ISSN: 0077-8923 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024074870A1 (en) * 2022-10-06 2024-04-11 Instituto Politecnico Nacional Peptide veterinary composition for immunotherapy

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BR0311596A (en) 2005-04-26
MXPA04012050A (en) 2005-09-08
DE60301886D1 (en) 2006-02-23
ATE306279T1 (en) 2005-10-15
US20060100142A1 (en) 2006-05-11
JP2005529932A (en) 2005-10-06
AU2003238407A1 (en) 2003-12-19
ITMI20021205A1 (en) 2003-12-04
ITMI20021205A0 (en) 2002-06-04
EP1511510A1 (en) 2005-03-09
EP1511510B1 (en) 2005-10-12

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