EP2001454A2 - Utilisation d'au moins un inhibiteur de la phospholipase a2 cytosolique comme médicament pour le traitement symptomatique de la mucoviscidose - Google Patents
Utilisation d'au moins un inhibiteur de la phospholipase a2 cytosolique comme médicament pour le traitement symptomatique de la mucoviscidoseInfo
- Publication number
- EP2001454A2 EP2001454A2 EP07731257A EP07731257A EP2001454A2 EP 2001454 A2 EP2001454 A2 EP 2001454A2 EP 07731257 A EP07731257 A EP 07731257A EP 07731257 A EP07731257 A EP 07731257A EP 2001454 A2 EP2001454 A2 EP 2001454A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- cpla2
- inhibitor
- use according
- mucus
- cystic fibrosis
- 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- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/121—Ketones acyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- 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
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention is in the field of symptomatic treatment of cystic fibrosis.
- Cystic fibrosis (Cystic Fibrosis, CF) is an autosomal recessive genetic disorder caused by a mutation in the CFTR gene, a 250 kb gene that encodes a protein of 1480 amino acids called CFTR protein (Cystic Fibrosis, CF)
- This protein belongs to the family of chloride channels. To date more than 1000 mutations responsible for the disease have been described, but the most common, (discovered in 1989), called ⁇ F508, is present in about 70% of patients. This mutation consists of the deletion of an amino acid, a phenylalanine at position 508,
- Influenzae which can lead to an exacerbated inflammatory response in the airways, characterized by a massive influx of neutrophils. These pathogens are responsible for most episodes of bronchial infections. The lack of control of this inflammatory process, often associated with bronchial obstruction, causes destruction of lung tissue resulting in a gradual loss of respiratory function until death.
- This disease is also characterized by digestive disorders mainly due to exocrine pancreatic insufficiency present in 90% of patients. These respiratory and digestive manifestations dominate the clinical picture, but the respiratory compromise conditions the vital prognosis of the patients.
- mucoid character is virtually specific to the infection.
- the incidence of mucoid strains increases with age and the progression of respiratory disease. Bronchopulmonary involvement evolves by relapses which lead in a few months or several decades to chronic respiratory insufficiency. Complications such as recurrent pneumothorax or haemoptysis can make life worse.
- cystic fibrosis can only be treated symptomatically. Management is mainly based on respiratory physiotherapy and anti-infectious treatment with antibiotics. In addition to its heaviness, this treatment must be followed for life.
- Antibiotic therapy must comply with a certain number of binding general principles: appropriate choice of antibiotics, prevention of resistance due to the chronicity of bronchial infection, high doses over long periods of time (at least two weeks), only parenteral administration for antipyocyanic antibiotics.
- Molecules make it possible to thin the mucus and in particular rhDNase, catalytic enzyme of hydrolysis of the extracellular DNA which makes it possible to reduce the viscosity of the mucus then easier to evacuate by the physiotherapy.
- rhDNase catalytic enzyme of hydrolysis of the extracellular DNA which makes it possible to reduce the viscosity of the mucus then easier to evacuate by the physiotherapy.
- nocturnal oxygen therapy becomes necessary. But, lung transplantation is the last resort.
- cPLA2 cytosolic phospholipase A2
- AA is then metabolized by two distinct enzymatic pathways involved in inflammation: the cyclooxygenase (COX) pathway that results in the production of prostaglandins, particularly prostaglandin E2 (PGE2); and the lipooxygenase pathway that results in the production of leukotrienes, particularly leukotriene B4 (LTB4).
- COX cyclooxygenase
- PGE2 prostaglandin E2
- LTB4 leukotriene B4
- LTB4 leukotriene B4
- PGE2 prostaglandin E2
- CFTR mice '' ' stimulated by instillation with lipopolysaccharide (LPS) of Pseudomonas aeruginosa that causes inflammation of the airways secrete more mucus than wild mice.
- LPS lipopolysaccharide
- instillation is meant an administration by air, more specifically intratracheally.
- the inventors have also shown that this secretion of mucus is inhibited by aspirin, a COX inhibitor.
- Mucus is essentially mucins (glycoproteins) and MUC5AC is one of the most abundant mucins in the lungs of cystic fibrosis patients.
- the subject of the invention is the use of at least one inhibitor of cytosolic phospholipase A2 (cPLA2) in the preparation of a medicament for the symptomatic preventive and / or curative treatment of cystic fibrosis, particularly increased secretion of cystic fibrosis. mucus secretory epithelia of the respiratory and digestive mucous membranes.
- cPLA2 cytosolic phospholipase A2
- cPLA2 inhibitor any chemical or biological molecule, natural or synthetic, any composition which, whatever its mechanism, induces after administration a decrease, or even a complete inhibition, of the activity of the cPLA2 or the expression of the cPLA2 gene.
- cakA2 inhibitor ATK (Arachidonyl) may be mentioned as an inhibitor of cPLA2.
- the cPLA2 inhibitor is a siRNA that interferes with the expression of the cPLA2 gene.
- the inhibitor of cPLA2 used according to the invention is ATK.
- a combination of cPLA2 inhibitors (2 or more) in the preparation of a medicament for the treatment of diseases of the respiratory tract leading to a increased secretion of mucus, including the symptomatic treatment of cystic fibrosis.
- the cPLA2 inhibitor is used in the preparation a drug for the treatment of cystic fibrosis. It can also be envisaged that the cPLA2 inhibitor is used in the preparation of a medicament for the symptomatic treatment of increased mucus secretion in asthma, chronic obstructive pulmonary disease (COPD) such as laryngitis and pharyngitis, pneumonia, influenza, pneumoconiosis, chronic bronchitis and emphysema or aspergillary asthma.
- COPD chronic obstructive pulmonary disease
- the cPLA2 inhibitor may be used in the medicament in an amount of between 0.01 mg to 2 g, preferably from 1 mg to 1 g, very preferably from 10 mg to 500 mg.
- the inhibitor of cPLA2 such as, for example PATK
- the term "symptomatic treatment” refers to the preventive and / or curative treatment of symptoms related to the disease. This treatment also improves the management of patients (reduction of suffering, improvement of the lifespan, slowing of the progression of the disease etc.). The treatment may also be carried out in combination with other ingredients or treatments, such as in particular other active compounds for treating the pathologies or traumas specified in the present application.
- the subject of the invention is the use of at least one inhibitor of cytosolic phospholipase A2 (cPLA2) in the preparation of a medicament for the symptomatic treatment of the increased mucus secretion of cystic fibrosis said medicament to be administered in addition to gene therapy of cystic fibrosis.
- cPLA2 cytosolic phospholipase A2
- the drug according to the invention can take any conceivable form for its administration.
- it may be liquid as a syrup or solution for intramuscular injection or intravenous or solid such as a powder or a tablet.
- the administration can be carried out by any method known to those skilled in the art, preferably orally, aerosolized, or by injection, typically intraperitoneal, intra-cerebral, intrathecal, intravenous, intravenous. -arterial or intramuscular. Oral administration is preferred. As a long-term treatment, the preferred route of administration will be sublingual, oral or transcutaneous.
- the daily dose of cPLA2 inhibitor used according to the invention will be the minimum dose to obtain the desired therapeutic effect. This dose will depend on various factors such as the weight of the subject to be treated. If necessary, the daily dose may be administered in two, three, four, five, six or more doses taken daily or in multiple sub-doses administered at appropriate intervals during the day.
- the amount selected will depend on multiple factors, in particular the route of administration, the duration of administration, the timing of administration, the rate of elimination of the compound, the or various products used in combination with the compound, age, weight and physical condition of the patient, as well as his medical history, and other information known in medicine.
- the medicaments according to the invention may also comprise at least one other therapeutically active ingredient for simultaneous, separate or spread use over time, in particular during treatment in a subject suffering from a pathology as defined above.
- the medicaments according to the invention advantageously comprise one or more excipients or inert carriers, that is to say pharmaceutically inactive and non-toxic vehicles.
- the drugs may contain one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc.
- Agents or vehicles that can be used in formulations include methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, cyclodextrins, polysorbate 80, mannitol, gelatin, lactose, vegetable oils or animal, acacia, etc.
- compositions may be formulated as injectable suspension, gels, oils, tablets, suppositories, powders, capsules, capsules, etc., optionally using dosage forms or devices providing sustained and / or delayed release.
- an agent such as cellulose, carbonates or starches is advantageously used.
- mice were tested for at least 5 mice per treatment category, 5-7 weeks old.
- mice and their wild homologs cPLA2 + / + , of the same genetic background were obtained from the "Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo” (Uozomi et al., Nature, 1997). These mice were 6-8 weeks old at the time of the experiment.
- P. aeruginosa LPS serotype 10 (Sigma, St. Louis, MO) EDTA, phenylmethylsulphoxide and dithiothreitol (Sigma, St. Louis, MO)
- Anti-MUC5AC antibody (clone 45 M1, Neomarkers, Fermont, CA, USA)
- Antibodies mouse IgG (Dako Cytomation Envision System). Amino Ethyl Carbazol (Sigma, St. Louis, MO).
- the products used were dissolved in saline solution (or physiological saline) and injected intratracheally (i.t.) or intraperitoneally (i.p.).
- the usage protocol was as follows:
- ATK (20 mg / kg, i.p.), 30 min before LPS and 24 h after.
- mice were anesthetized with 2% Xylazine (8 mg / kg) and Ketamine 1000 (40 mg / kg) prior to instillation of LPS (330 ⁇ g / kg, i.t.).
- mice were anesthetized with Pentobarbital (i.p.) at 200 mg / kg and their incised and cannulated tracheas.
- the LBAs were performed with successive washings with 1 ml of saline solution containing 5 mM EDTA and protease inhibitors (5 mM phenylmethylsulphoxide, 5 mM dithiothreitol).
- the counting of the cells was carried out by an automatic counter Counter ZM (Coultronic, Margency, France). This allows to highlight the state of inflammation of the lungs.
- Sections 5 ⁇ m thick were stained with Hemotoxylin / Eosin, periodic acid-Schiff (PAS) and Alcian blue (Alcian blue: AB, pH 2.4) according to standard methodologies (Normal and Pathological Histology).
- MLJ5AC (clone 45 M 1) for 2 h at room temperature, at a concentration of 8 ⁇ g / ml in 1X PBS.
- Mouse lungs were homogenized with lysis buffer (Quiagen RLT buffer). The homogenates were centrifuged, and equivalent amounts of proteins (10-50 ⁇ g) were deposited on the 7.5% electrophoresis gel (Tris / Glycine / SDS-polyacrylamide).
- the proteins were then transferred to a nitrocellulose membrane (Millipore) previously treated with PBS at 5% milk / Tween 1% o.
- the membrane was then incubated for 1 hour at room temperature in the presence of the primary antibody, then washed 3 times with PBS / Tween 1% o.
- the membrane was then incubated for 1 hour at room temperature in the presence of the secondary antibody, then washed with PBS / Tween 1% o.
- Actin control makes it possible to normalize the level of expression of the MU5AC protein.
- the intensity of the bands is measured with an image analyzer.
- Lung homogenates were prepared according to Filgueiras et al. (Lipids 22: 731-735, (1987)).
- the lipids were extracted by the method of Bligh and Dyer (Can.
- the spots corresponding to phosphatidylcholine (PC) were then recovered and their radioactivity measured using standard scintillation fluid.
- the cPLA2 activity was expressed in counts per minute (cpm).
- CF mice secrete more MUC5AC in LBAs both in baseline conditions than after LPS treatment compared with WT mice.
- mice received a dose of saline and a dose of aspirin.
- mice received a dose of saline and a dose of ATK.
- Table 4 The "control” mice received a dose of saline and a dose of ATK.
- mice received a dose of saline.
- the secondary antibody used is an anti-mouse IgG antibody (Dako Cytomation Envision System).
- the measurement of the quantity is related to the measurement of the amount of actin mRNA measured in the same sample for normalization (MUC5AC mRNA / Actin mRNA).
- the primary antibody used is an anti-cPLA2 monoclonal antibody (CeII Signaling or Santa Cruz).
- the secondary antibody used is an anti-mouse antibody (Dako Cytomation Envision System).
- the measurement of the quantity is related to the measurement of the amount of actin messenger RNA measured in the same sample for normalization (cPLA2 mRNA / Actin mRNA). Table 7
- Histological or immunohistochemical analyzes performed on sections of the lungs of mice, confirm the results obtained in the measurements of the mucus production by the cells of the bronchial epithelium.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0603059A FR2899471A1 (fr) | 2006-04-06 | 2006-04-06 | Utilisation d'au moins un inhibiteur de la phospholipase a2 cytosolique comme medicament pour le traitement des maladies respiratoires |
PCT/FR2007/000582 WO2007118996A2 (fr) | 2006-04-06 | 2007-04-05 | Utilisation d'au moins un inhibiteur de la phospholipase a2 cytosolique comme médicament pour le traitement symptomatique de la mucoviscidose |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2001454A2 true EP2001454A2 (fr) | 2008-12-17 |
Family
ID=37441809
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP07731257A Withdrawn EP2001454A2 (fr) | 2006-04-06 | 2007-04-05 | Utilisation d'au moins un inhibiteur de la phospholipase a2 cytosolique comme médicament pour le traitement symptomatique de la mucoviscidose |
Country Status (6)
Country | Link |
---|---|
US (1) | US20100093985A1 (fr) |
EP (1) | EP2001454A2 (fr) |
JP (1) | JP2009532445A (fr) |
CA (1) | CA2648239A1 (fr) |
FR (1) | FR2899471A1 (fr) |
WO (1) | WO2007118996A2 (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130209403A1 (en) | 2010-09-08 | 2013-08-15 | Ruprecht-Karls-Universitaet | Use of inhibitors of phospholipase a2 for the treatment or prevention of flavivirus infection |
GB201806663D0 (en) * | 2018-04-24 | 2018-06-06 | Avexxin As | 2-Oxothiazole compositions for treatment of fibrotic disease |
CN114767859A (zh) * | 2022-04-11 | 2022-07-22 | 山东大学齐鲁医院 | 靶向cPLA2在放射诱导的肺损伤防治中的应用 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6630496B1 (en) * | 1996-08-26 | 2003-10-07 | Genetics Institute Llc | Inhibitors of phospholipase enzymes |
US6350892B1 (en) * | 1997-09-23 | 2002-02-26 | Bristol-Myers Squibb Company | Trifluoromethyl ketone analogs as selective cPLA2 inhibitors |
US20020165119A1 (en) * | 2001-01-31 | 2002-11-07 | Alan Leff | Method of treating inflammatory conditions by inhibiting cytosolic phospholipase A2 |
DK1451154T3 (da) * | 2001-12-03 | 2008-05-19 | Wyeth Corp | Inhibitorer af cytosolisk phospholipase A2 |
EP1849011A2 (fr) * | 2005-02-14 | 2007-10-31 | University of Pittsburgh of the Commonwealth System of Higher Education | Utilisation de l'il-17f dans le diagnostic et la therapie des inflammations des voies aeriennes |
-
2006
- 2006-04-06 FR FR0603059A patent/FR2899471A1/fr not_active Withdrawn
-
2007
- 2007-04-05 EP EP07731257A patent/EP2001454A2/fr not_active Withdrawn
- 2007-04-05 US US12/295,965 patent/US20100093985A1/en not_active Abandoned
- 2007-04-05 CA CA002648239A patent/CA2648239A1/fr not_active Abandoned
- 2007-04-05 JP JP2009503616A patent/JP2009532445A/ja active Pending
- 2007-04-05 WO PCT/FR2007/000582 patent/WO2007118996A2/fr active Application Filing
Non-Patent Citations (1)
Title |
---|
See references of WO2007118996A2 * |
Also Published As
Publication number | Publication date |
---|---|
CA2648239A1 (fr) | 2007-10-25 |
WO2007118996A2 (fr) | 2007-10-25 |
FR2899471A1 (fr) | 2007-10-12 |
US20100093985A1 (en) | 2010-04-15 |
JP2009532445A (ja) | 2009-09-10 |
WO2007118996A3 (fr) | 2008-04-10 |
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