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WO2009122181A1 - Nouvelle combinaison destinée au traitement de troubles inflammatoires - Google Patents

Nouvelle combinaison destinée au traitement de troubles inflammatoires Download PDF

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Publication number
WO2009122181A1
WO2009122181A1 PCT/GB2009/000879 GB2009000879W WO2009122181A1 WO 2009122181 A1 WO2009122181 A1 WO 2009122181A1 GB 2009000879 W GB2009000879 W GB 2009000879W WO 2009122181 A1 WO2009122181 A1 WO 2009122181A1
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WO
WIPO (PCT)
Prior art keywords
kit
statin
parts
disease
seratrodast
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.)
Ceased
Application number
PCT/GB2009/000879
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English (en)
Inventor
Johan Raud
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.)
Cardoz AB
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Cardoz AB
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Filing date
Publication date
Application filed by Cardoz AB filed Critical Cardoz AB
Publication of WO2009122181A1 publication Critical patent/WO2009122181A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Atherosclerotic lesions develop over many years. Pathological processes, such as cholesterol accumulation in the artery wall, foam cell formation, inflammation and cell proliferation are typically involved.
  • HDLs high-density lipoproteins
  • LDLs low-density lipoproteins
  • triglycerides are all indicators in determining the risk of developing atherosclerosis and associated cardiovascular disorders, such as coronary artery diseases (e.g. angina pectoris, myocardial infarction, etc.), stroke (including cerebro-vascular accident and transient ischaemic attack) and peripheral arterial occlusive disease.
  • HMG-CoA reductase inhibitors hydroxymethylglutaryl-CoA reductase inhibitors
  • statins cholesterol lowering drugs
  • statins have significantly reduced mortality from coronary heart disease and stroke.
  • these drugs suffer from the disadvantage that they are not equally effective in ail patients and are known to have certain side effects (e.g. changes in liver function, myopathy and rhabdomyolysis), and atherosclerosis remains a major cause of death and disability.
  • side effects e.g. changes in liver function, myopathy and rhabdomyolysis
  • atherosclerosis remains a major cause of death and disability.
  • a recent review article suggests that statins do not reduce serious cardiovascular events during the first four months of treatment in patients with acute coronary syndromes.
  • a combination product comprising:
  • statins include Acitemate, benfluorex, Clestin, colestolone, dihydromevinolin, meglutol, rawsonol, as well as the compounds with the following code names: ATM 6000, BAY-10-2987, BAY-x-2678, BB-476, BIO- 002, BIO-003, BIO-2, BMS-180431 , CP-83101, DMP-565, FR-901512, GR- 95030, HBS-107, KS-01-019, L-659699, L-669262, NR-300, P-882222, PTX- 023595, RP 61969, S-2468, SC-32561 , sc-45355, SDZ-265859, SQ-33600, U- 20685, and NO-enhancing/releasing statins, such as NCX-6550 (nitropravastatin) and NCX-6560 (nitroatorvastatin).
  • NCX-6550 nitrogenpravastatin
  • Combination products according to the invention provide for the administration of seratrodast as hereinbefore defined in conjunction with a statin as hereinbefore defined, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises seratrodast, and at least one comprises a statin, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including seratrodast and a statin).
  • Combination products according to the invention may comprise pitavastatin lactone, mevastatin lactone, fluvastatin lactone, rosuvastatin lactone, pravastatin lactone and atorvastatin lactone, and particularly lovastatin lactone and simvastatin lactone.
  • Inflammatory conditions include arteritis, diabetes mellitus, metabolic syndrome, endometriosis, acne, skin burns, rosacea, seborrheic dermatitis, skin ulcers, Marfan syndrome and, more preferably, allergy (including allergic conjunctivitis and allergic rhinitis), ankylosing spondylitis, asthma, atopic dermatitis, chronic obstructive pulmonary disease, contact dermatitis, cystitis, gouty arthritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, osteoarthritis, pancreatitis, prostatitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, tendinitis, bursitis, Sjogren's syndrome, systemic lupus erythematosus, uveitis, urticaria, vasculitis, diabetic vascular complications, migraine, atherosclerosis and associated cardiovascular
  • Conditions that may be mentioned include endometriosis, atopic dermatitis, Marfan syndrome and, more preferably, migraine, asthma, chronic obstructive pulmonary disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis and, more particularly, atherosclerosis and associated cardiovascular disorders.
  • Patient groups that may be mentioned include those with acute coronary syndromes.
  • acute coronary syndrome(s) will be understood by the skilled person to include any abnormal ischaemic myocardial state, often but not exclusively associated with chest pain and/or an abnormal electrocardiogram (ECG). Such syndromes are the most common presentation of myocardial infarction (heart attack).
  • ECG electrocardiogram
  • trie term is largely synonymous with the term “unstable angina”, as opposed to “stable angina” (i.e. angina that develops during exertion and resolves at rest). Exertional angina that occurs at worsening rate (“crescendo angina”) will similarly be regarded by the skilled person as within the definition "unstable”.
  • the term "administration in conjunction with” includes that the two components of the combination product (seratrodast and statin) are administered (optionally repeatedly), either together, or sufficiently closely in time, to enable a beneficial effect for the patient, that is greater, over the course of the treatment of the relevant condition, than if either a formulation comprising seratrodast, or a formulation comprising statin, are administered (optionally repeatedly) alone, in the absence of the other component, over the same course of treatment. Determination of whether a combination provides a greater beneficial effect in respect of, and over the course of treatment of, a particular condition will depend upon the condition to be treated or prevented, but may be achieved routinely by the skilled person.
  • Patients include mammalian (including human) patients.
  • Preferred modes of delivery include oral (particularly), intravenous, cutaneous or subcutaneous, nasal, intramuscular, or intraperitoneal delivery.
  • Seratrodast and statins will generally be administered together or separately in the form of one or more pharmaceutical formulations in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutically acceptable adjuvant, diluent or carrier may be selected with due regard to the intended route of administration and standard pharmaceutical practice.
  • Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.
  • Such pharmaceutically acceptable carriers may also impart an immediate, or a modified, release of either active ingredient, whether administered together in a combined preparation or in the form of a kit of parts.
  • the amount of active ingredients in the formulation(s) will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe.
  • the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease, as well as genetic differences between patients.
  • the medical practitioner or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient.
  • the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the combination products/methods described herein may have the advantage that, in the treatment of the conditions mentioned hereinbefore, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it/they may have other useful pharmacological properties over, similar methods (treatments) known in the prior art for use in the treatment of inflammatory disorders (such as atherosclerosis and associated cardiovascular conditions) or otherwise.
  • differentiated or undifferentiated MM6 cells (at 1-15*10 6 /mL; 0.5-1 ml_) are incubated for 5-30 minutes (at 37 0 C in PBS with calcium) with 25-50 ⁇ M arachidonic acid and 2-10 ⁇ M calcium ionophore A23187 (A23187 may also be used without arachidonic acid).
  • the MM6 cells may also be stimulated with documented biologically active concentrations of adenosine diphosphate (ADP), and/or the thromboxane analogue U-46619, with or without A23187 and/or arachidonic acid as above.
  • ADP adenosine diphosphate
  • thromboxane analogue U-46619 adenosine diphosphate
  • the MM6 incubations/stimulations above may also be performed in the presence of human platelets (from healthy donor blood) with an MM6:platelet ratio of 1 :10 to 1:10000.
  • the incubations/stimulations are stopped with two volumes of cold methanol and prostaglandin B 2 (PGB 2 ) added as internal standard.
  • the samples are centrifuged and the supematants are diluted with water to reach a final methanol concentration of 30% and pH is adjusted to 3-4.
  • Arachidonic acid metabolites in the supernatant are extracted on preconditioned (1 ml_ methanol followed by 1 mL H 2 O) C18 solid phase columns (Sorbent Technology, U.K.).
  • Metabolites are eluted with methanol, whereafter one volume of water is added to the eluate.
  • 76 ⁇ L of each sample is mixed with 39 ⁇ L H 2 O (other volume ratios may also be used).
  • a Waters RCM 8*10 column is eluted with methanol/acetonitrile/H 2 O/acetic acid (30:35:35:0.01 v/v) at 1.2 mL/min.
  • the absorbance of the eluate is monitored at 270 nm for detection and quantitation of PGB 2 and LTB 4 .
  • Commercially available enzyme immuno-assay kits (EIA/ELISA kits) for measuring LTB 4 may also be used according to instructions from the kit manufacturer(s).
  • EIA/ELISA kits enzyme immuno-assay kits
  • PGE 2 prostaglandin E 2
  • TXB 2 thromboxane B 2
  • test drug(s) serum-derived neuropeptides
  • statin serum-derived neuropeptides
  • statin serum-derived neuropeptides
  • PBMC or PMN are incubated for 5-30 minutes (at 37 0 C in PBS with calcium) with 25-50 ⁇ M arachidonic acid and 2-10 ⁇ M calcium ionophore A23187 (A23187 may also be used without arachidonic acid).
  • the PBMC/PMN may also be stimulated with documented biologically active concentrations of adenosine diphosphate (ADP), and/or the thromboxane analogue U-46619, with or without A23187 and/or arachidonic acid as above.
  • ADP adenosine diphosphate
  • U-46619 adenosine diphosphate
  • test drug(s) serum-derived neurotrophic factor(s)
  • mice Male CBA or NMRI mice weighing approximately 15-30 g, or male Wistar or Sprague-Dawley rats weighing approximately 150-450 g, are used (other strains of mice and rats may also be used). Acute tissue injury and acute inflammation is achieved in the distal part of the tail or one of the ears using a scalpel under aseptic conditions. One, two or three parallel, approximately 5-15 mm long, longitudinal cuts are made through all layers of the skin.
  • Gene expression may also be analyzed using quantitative or semi-quantitative PCR. Analysis of gene expression at the protein level may be analyzed using commercially available enzyme immuno-assay kits (EIA/ELISA kits) (according to instructions from the manufacturer(s)), or conventional Western blot and/or immunohistochemical approaches.
  • EIA/ELISA kits enzyme immuno-assay kits
  • zymosan or one or more of the other pro-inflammatory stimuli
  • the animals are sacrificed.
  • the peritoneal cavity is then flushed with 1-3 mL of a lavage buffer (ice-cold PBS with or without 3-5 mM EDTA or 5-10 units/mL heparin).
  • a lavage buffer ice-cold PBS with or without 3-5 mM EDTA or 5-10 units/mL heparin.
  • Total and differential leukocyte counts in the lavage fluid are done with a hemocytometer following staining with Turk's solution and/or in cytospin preparations stained with May-Grunwald Giemsa or a modified Wright's (Diff-Quik) stain, respectively, by light microscopy using standard morphological criteria. Other established methods for determining total and differential leukocyte counts may also be used.
  • the cell pellets of the lavage fluid are resuspended in 0.1-1.0 mL 0.05 IvI KHPO 4 pH 6.0 with 0.5% HTAB and stored frozen (-2O 0 C to -80°) until analysis of myeloperoxidase (MPO) content as described by Rao ef a/ (J. Pharmacol. Exp. Then 269, 917-25 (1994)).
  • Identical cell pellets from separate animals are stored frozen (-80 0 C) in RLT buffer (QIAGEN, Valencia, CA) until further processing for microarray experiments (see Example 12).
  • Test drug(s) may also be administered simultaneously with intraperitoneal injection of zymosan or the other proinflammatory stimuli). 2-24 hours after injection of zymosan (or one or more of the other stimuli), the animals are sacrificed. The peritoneal cavity is then flushed with 10-20 ml of a lavage buffer (e.g. ice-cold PBS with or without 3-5 mM EDTA or 5-10 units/mL heparin).
  • a lavage buffer e.g. ice-cold PBS with or without 3-5 mM EDTA or 5-10 units/mL heparin.
  • differentiated or undifferentiated NB4 or HL-60 cells are incubated for 5-30 minutes (at 37°C in PBS with calcium) with 10-40 ⁇ M arachidonic acid and/or 2-10 ⁇ M calcium ionophore A23187.
  • the NB4 and HL-60 cells may also be stimulated with documented biologically active concentrations of adenosine diphosphate (ADP), fMLP, and/or the thromboxane analogue U- 46619, with or without A23187 and/or arachidonic acid as above.
  • ADP adenosine diphosphate
  • fMLP adenosine diphosphate
  • thromboxane analogue U- 46619 with or without A23187 and/or arachidonic acid as above.
  • Metabolites are eluted with methanol, whereafter one volume of water is added to the eluate.
  • 76 ⁇ L of each sample is mixed with 39 ⁇ l_ H 2 O (other volume ratios may also be used).
  • a Waters RCM 8> ⁇ 10 column is eluted with methanol/acetonitrile/H 2 O/acetic acid (30:35:35:0.01 v/v) at 1.2 mL/min.
  • the absorbance of the eluate is monitored at 270 nm for detection and quantitation of PGB 2 and LTB 4 .
  • Commercially available enzyme immuno-assay kits (EIA/ELISA kits) for measuring LTB 4 may also be used according to instructions from the kit manufacturer(s).
  • EIA/ELISA kits enzyme immuno-assay kits
  • PGE 2 prostaglandin E 2
  • TXB 2 thromboxane B 2
  • chemokines and mediators such as IL-1 ⁇ , IL-6, TNF, IL-8, IL-10, IL-12p70, MCP-1 , PAF, C5a, differentiated or undifferentiated NB4 or HL-60 cells (at 1-10 ⁇ 10 6 /mL) are incubated (37 0 C, 5% CO2) for 4-24 hours (in RPMI-1640 with 1-10% fetal bovine serum, with or without supplements) with lipopolysaccharide (LPS 1-100 ng/mL), phorbol-12-myristate-13-acetate (PMA 1-100 ng/mL) or calcium ionophore A23187 (1-10 ⁇ M), or combinations of these stimuli.
  • LPS lipopolysaccharide
  • PMA 1-100 ng/mL phorbol-12-myristate-13-acetate
  • calcium ionophore A23187 1-10 ⁇ M
  • effects of the drugs on spontaneous or stimulated adhesion and/or migration of these cells may also be analyzed (freshly isolated human blood polymorphonuclear cells (PMN) isolated according to standard protocols may also be used).
  • PMN human blood polymorphonuclear cells isolated according to standard protocols may also be used.
  • Spontaneous or stimulated (with fMLP, IL-8, PAF, LTB 4 or other relevant PMN activating factors) adhesion of the PMN or neutrophil-like cells to e.g. cultured endothelial cells or protein-coated artificial surfaces are studied using well established and documented experimental approaches and assays.
  • Venous blood is collected by venepuncture without stasis, using siliconized vacutainer tubes containing 1/10 volume of 129 mM trisodium citrate (Becton Dickinson, Meylan, France).
  • Whole blood platelet P-selectin expression reflecting platelet activity
  • leukocyte CD11 b expression reflecting leukocyte activity
  • single platelet and platelet-platelet microaggregate counting and platelet-leukocyte aggregates (PLAs) are measured using flow cytometric assays, essentially as described previously (see e.g. Li et al. Circulation 100, 1374 (1999) for reference).
  • Platelets are identified with FITC conjugated anti-CD42a (GPIX) MAb Beb 1 (Becton Dickinson), and leukocytes are identified with RPE conjugated anti-CD45 MAb J33 (Immunotech).
  • Samples drug-treated or untreated blood + antibodies with or without the stimuli, as above are incubated at room temperature in the dark for 20 min. Afterwards, the samples are diluted and mildly fixed with 0.5% (v/v) formaldehyde saline, and analysed for the various platelet and leukocyte parameters with a Beckman-Coulter EPICS XL-MCL flow cytometer (Beckman- Coulter Corp., Hialeah, FL).
  • Platelet P-selectin expression data are reported as the percentages of P-selectin positive cells in the platelet population and as absolute counts of P-selectin positive platelets.
  • Leukocyte CD11b expression is reported as mean fluorescence intensity (MFI) of the total leukocyte population and of leukocyte subpopulations.
  • Platelet-leukocyte aggregates are presented as both absolute counts and percentages of platelet-conjugated leukocytes in the total leukocyte population and among lymphocytes, monocytes, and neutrophils.
  • Other relevant reagents, experimental conditions/approaches, equipment and modes of analysis to measure corresponding platelet and leukocyte activation in human whole blood may also be used.
  • inflammatory mediators e.g. histamine, tryptase, cytokines, chemokines
  • gene expression and protease e.g. MMPs such as MMP2, MMP3, MMP9
  • MMPs such as MMP2, MMP3, MMP9

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur des produits de combinaison comprenant: (a) du sératrodast ou un sel ou solvate pharmaceutiquement acceptable de ce dernier; et (b) une statine ou un sel ou solvate pharmaceutiquement acceptable de celle-ci. Les produits de combinaison selon l'invention trouvent une utilité particulière dans le traitement de l'athérosclérose et des états associés.
PCT/GB2009/000879 2008-04-04 2009-04-03 Nouvelle combinaison destinée au traitement de troubles inflammatoires Ceased WO2009122181A1 (fr)

Applications Claiming Priority (2)

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US6495308P 2008-04-04 2008-04-04
US61/064,953 2008-04-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013136070A1 (fr) 2012-03-13 2013-09-19 University Court Of The University Of Dundee Inhibiteur de sik pour l'utilisation dans une méthode de traitement d'un trouble inflammatoire et/ou immunitaire

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007674A2 (fr) * 2007-07-11 2009-01-15 Cardoz Ab Nouvelle association pour une utilisation dans le traitement de troubles inflammatoires

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009007674A2 (fr) * 2007-07-11 2009-01-15 Cardoz Ab Nouvelle association pour une utilisation dans le traitement de troubles inflammatoires

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BALK E M ET AL: "Effects of statins on vascular structure and function: A systematic review", AMERICAN JOURNAL OF MEDICINE, XX, XX, vol. 117, no. 10, 15 November 2004 (2004-11-15), pages 775 - 790, XP004641139, ISSN: 0002-9343 *
HORIGUCHI T ET AL: "Study on the usefulness of seratrodast in the treatment of chronic pulmonary emphysema", ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH, ECV EDITIO CANTOR VERLAG, AULENDORF, DE, vol. 52, no. 10, 1 January 2002 (2002-01-01), pages 764 - 768, XP002998194, ISSN: 0004-4172 *
ISHIZUKA T: "THROMBOXANE A2 RECEPTOR BLOCKADE PREVENTS ATHEROSCLEROTIC PROCESS BY ITS ANTI-INFLAMMATORY EFFECT", VASCULAR DISEASE PREVENTION, BENTHAM SCIENCE PUBLISHERS, GB, vol. 3, no. 2, 1 May 2006 (2006-05-01), pages 143 - 148, XP008078040, ISSN: 1567-2700 *
SHIOKOSHI TAKAHIRO ET AL: "Downregulation of nitric oxide accumulation by cyclooxygenase-2 induction and thromboxane A2 production in interleukin-1beta-stimula ted rat aortic smooth muscle cells.", JOURNAL OF HYPERTENSION MAR 2002, vol. 20, no. 3, March 2002 (2002-03-01), pages 455 - 461, XP009120606, ISSN: 0263-6352 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013136070A1 (fr) 2012-03-13 2013-09-19 University Court Of The University Of Dundee Inhibiteur de sik pour l'utilisation dans une méthode de traitement d'un trouble inflammatoire et/ou immunitaire

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