EP1223983A2 - Procedes et compositions pour prevoir, diagnostiquer et traiter la lipodystrophie - Google Patents

Procedes et compositions pour prevoir, diagnostiquer et traiter la lipodystrophie

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Publication number
EP1223983A2
EP1223983A2 EP00969122A EP00969122A EP1223983A2 EP 1223983 A2 EP1223983 A2 EP 1223983A2 EP 00969122 A EP00969122 A EP 00969122A EP 00969122 A EP00969122 A EP 00969122A EP 1223983 A2 EP1223983 A2 EP 1223983A2
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European Patent Office
Prior art keywords
group
members
composition
upodystrophy
levels
Prior art date
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EP00969122A
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German (de)
English (en)
Inventor
Kevin C. Kain
Lena Serghides
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Individual
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Individual
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Priority claimed from CA002289365A external-priority patent/CA2289365A1/fr
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Publication of EP1223983A2 publication Critical patent/EP1223983A2/fr
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2026—IL-4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G01N33/56988—HIV or HTLV
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value

Definitions

  • this invention relates to a method of predicting those individuals at risk of developing Upodystrophy associated with antiretroviral therapy, by measuring a decrease in CD36 levels, as well as compositions and methods for up- regulating CD36 for the treatment of Upodystrophy associated with protease inhibitor therapy for HTV infection.
  • Combination antiretroviral therapy that includes protease inhibitors, represents a significant advance in the therapy of HTV-1 infection, conferring virologic, morbidity and survival benefits to users (1-4).
  • Protease inhibitors (Pis) interfere with post-translational processing of viral proteins by binding to the active site of the HTV aspartyl protease (4-7).
  • Pis in combination with HTV reverse transcription inhibitors, are now in widespread usage as the standard for antiretroviral therapy (8,9).
  • all currently used HTV-1 ARV has been associated with side effects that include peripheral fat wasting, central adiposity, hyperlipidemia, and insulin resistance as part of a syndrome known as Upodystrophy (7, 10-12).
  • Pis may mediate these effects by binding to two proteins, cytoplasmic retinoic-acid binding protein 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP), that are involved in lipid metabolism (7). If Pis bind to CRABP-1, as speculated, they might inhibit the synthesis of cis-9-retinoic acid, which is the sole ligand for the retinoid X receptor (RXR).
  • CRABP-1 cytoplasmic retinoic-acid binding protein 1
  • LRP low density lipoprotein-receptor-related protein
  • RXR functions as a heterodimer with the peroxisome-proliferator- activated receptor type gamma (PPAR- ⁇ ), a nuclear receptor which regulates adipocyte differentiation, function and apoptosis (16-19).
  • PPAR- ⁇ has also been demonstrated to promote monocyte/macrophage (m ⁇ ) maturation and uptake of oxidized low density lipoprotein (OxLDL) (20).
  • RXR and PPAR- ⁇ agonists have been shown to improve hyperlipidemia and insulin response in rodent animal models of diabetes and obesity (21,22) but there has been no reported use of these compounds as treatment for HTV -associated Upodystrophy.
  • PPAR- ⁇ has been demonstrated to promote the uptake of OxLDL by transcriptional induction of the scavenger receptor CD36 (20).
  • CD36 has also been demonstrated to function as a free fatty acid receptor and transporter in adipose tissue (18,19).
  • a method of predicting which patients receiving antiretroviral or protease inhibitor therapy are at risk of developing Upodystrophy is provided.
  • the method comprises the steps of:
  • compositions for the treatment of HTV infection are provided.
  • the composition comprises, as an active ingredient, a product which up-regulates CD36 in combination with a pharmaceutically effective amount of a protease inhibitor, or other anti-retroviral agent in admixture with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the product comprises a PPAR ⁇ -RXR agonist, a PPAR ⁇ agonist, a RXR agonist, or natural or synthetic ligands thereof.
  • the invention also includes a method of determining whether a test compound causes Upodystrophy in a mammal comprising:
  • test compound (a) administering the test compound to (i) a mammal, or (ii) a cell expressing CD36 or a mimetic thereof or (iii) an in vitro cell free system capable of expressing CD36 or a mimetic thereof;
  • the level of CD36 is measured in a blood sample or a fraction thereof.
  • the cells can include, but are not limited to, mammalian or human monocyte/macrophage cell lines (for example, THP-1, U937 cell lines etc.), mammalian or human adipocyte cell lines (for example 3T3L1 cell line etc.), other mammalian or human cell lines expressing CD36 (for example C32 melanoma cells etc.), or COS, Chinese Hamster Ovary (CHO) cell lines or other mammalian, insect or yeast cells transfected with or expressing CD36.
  • the decrease in CD36 levels can be in the range of
  • the tested compound optionally comprises a HTV protease inhibitor or other antiretroviral agent.
  • Another embodiment of the invention includes a method of (i) identifying an individual at risk of antiretroviral or protease inhibitor-associated Upodystrophy or (ii) diagnosing an individual having antiretroviral or protease inhibitor-induced Upodystrophy comprising the steps of:
  • Monocytes were fixed in 3% paraformaldehyde and were then stained for CD36 expression by incubation with a 1:100 dilution of the monoclonal anti-CD36 antibody FA6-152 (Immunotech) in RPMI-0 with 1% BSA, on ice for 30 minutes, followed by a 1: 100 dilution of FTTC linked anti-mouse IgG secondary antibody (Serotec). A secondary antibody only and an unstained control were also performed.
  • CD36 expression was quantitated by flow cytometry using the Epics Elite flow cytometer (Beckman-Coulter) on at least 10,000 monocytes when possible. Data was analyzed using Elite software (Beckman-Coulter).
  • CD36 expression was again determined on the isolated monocytes as above. CD36 expression was expressed as fluorescence intensity over secondary only stained controls.
  • THP-1 and C32 cells were treated with THP-1 and C32 cells.
  • monocyte CD36 from the two healthy controls at baseline and after 1 and 2
  • THP-1 cells, a human pre-monocytic cell line, treated with ritonavir expressed -20% less CD36 than control treated cells (P ⁇ 0.05, paired Student's t, N 4).
  • Antiretroviral therapy that included the protease inhibitors, nelfinavir, ABT-378, and ritonavir, induced a marked decrease in CD36 expression in a proportion of healthy and HTV-infected individuals (-70%) taking these drugs.
  • ARVs and Pis may induce CD36 deficiency by inhibiting retinoic acid metabolism by their action on cytochrome P450 3 A and/or CRABP-1 (7), leading to lowered 9-cis-retinoic acid levels, reduced activation of the RXR-PPAR ⁇ heterodimer and decreased CD36 expression (20).
  • Ritonavir has been shown to be the most potent inhibitor of 9-cis-retinoic acid levels and was the most likely to induce Upodystrophy as well (7,10).
  • the present invention also provides a composition and method of up-regulating CD36 for preventing or treating Upodystrophy associated with protease inhibitor or antiretroviral therapy.
  • PPAR ⁇ is a member of the nuclear hormone receptor superfamily, and as a heterodimer with the retinoid X receptor (RXR) activates transcription of target genes by binding to DR-1 (direct repeat with 1 nucleotide spacer) type hormone response elements (27).
  • RXR retinoid X receptor
  • PPAR ⁇ is primarily expressed in adipose tissue, mammary and colonic epithelium and in myelomonocytic cells (28).
  • the CD36 promoter contains a PPAT ⁇ -RXR binding site, and the PPAR ⁇ -RXR complex can modulate CD36 gene expression through direct promoter interaction (28).
  • PPAR ⁇ and RXR ligands are now known including but not limited to prostaglandins A, D, and especially prostanoid 15-deoxy- ⁇ I2 14 -prostaglandin J2 (15d-PGJ2), thiazolidinedione (TZD) class of antidiabetic drugs (including ciglitazone, troglitazone, pioglitazone, rosiglitazone, englitazone etc.), non- steroidal-anti-inflammatory drugs (NSAIDs including indomethacin, flufenamic acid, fenoprofen, ibuprofen), L-tyrosine-based agonists (including GW1929), cytokines (including TL-4, GM-CSF, M-CSF
  • Upodystrophy associated with PI therapy can be reversed by treating individuals with PPAR ⁇ agonists, RXR agonists, PPAR ⁇ -RXR agonists and natural or synthetic ligands thereof.
  • Upodystrophy in susceptable patients can be prevented by combining ARV therapy with with PPAR ⁇ agonists, RXR agonists, PPAR ⁇ -RXR agonists and natural or synthetic ligands thereof .
  • Toward these objectives we have initiated a number of pilot studies. In one prospective cohort study we examine whether different PI regimens and ARV drugs differ in their ability to induce CD36 deficiency and subsequent Upodystrophy.
  • Participants are randomly assigned to different ARV treatment arms and CD36 levels, blood lipids and other metabolic parameters are assessed prior to and after initiating PI treatment. Patients are followed for 24 months to determine the proportion in each treatment arm developing Upodystrophy.
  • individuals identified as at increased risk of developing Pi-induced Upodystrophy as determined by CD36 levels are randomized to a PPAR ⁇ -RXR agonist or placebo and followed for 1 year to determine if PI therapy combined with a PPAR ⁇ -RXR agonist prevents Upodystrophy.
  • a sample of consecutive patients with Pi-induced Upodystrophy are randomized to receive a PPAR-RXR agonist or placebo, to demonstrate that the active agents can reverse CD36 deficiency in vivo.
  • products which upregulate CD36 can be selected and designed in the manufacture of pharmaceutical compositions for the treatment of Upodystrophy.
  • the pharmaceutical compositions can be administered to patients by methods known to those skilled in the art, such as orally, aerosol administration, direct lavage and parenteral injection. Dosages to be administered depend on patient needs, on the desired effect and on the chosen route of administration.
  • the products may be introduced using in vivo delivery vehicles such as liposomes. They may also be introduced into cells using physical techniques such as microinjection and electroporation or chemical methods such as coprecipitation and incorporation of DNA into liposomes.
  • the pharmaceutical compositions could include an active ingredient, in association with one or more pharmaceutically acceptable vehicles, such as carriers, excipients or diluents, and contained in buffered solutions with a suitable pH and isoosmotic with the physiological fluids.
  • suitable products such as carriers, excipients or diluents
  • the methods of combining suitable products with the vehicles is well known to those skilled in the art.
  • the composition could include a targeting agent for the transport of the active compound to specified sites within tissue.
  • oral formulations of the composition according to the present invention are preferred.
  • the oral formulations contain a pharmaceutically inert carrier, including conventional solid carriers, which are conveniently presented in tablet or capsule form.
  • compositions of the present invention may be formulated in a variety of ways.
  • Aqueous solutions of composition of the present invention may be encapsulated in polymeric beads, liposomes, nanoparticles or other injectable depot formulations known to those of skill in the art. (Examples thereof may be found, for example, in Remington's Pharmaceutical Sciences, 18th Edition, 1990.) Doses are selected to provide effective upregulation of CD36.
  • compositions including a liquid pharmaceutically inert carrier such as water may also be considered for both parenteral and oral administration.
  • a liquid pharmaceutically inert carrier such as water
  • Other pharmaceutically compatible liquids may also be used.
  • the use of such liquids is well known to those of skill in the art. (Examples thereof may be found, for example, in Remington's
  • the dose level and schedule of administration may vary depending on the particular product used, the method of administration, and such factors as the age and condition of the patient.
  • formulations may also be considered for other means of administration such as parenterally, per rectum, and transdermally.
  • the usefulness of these formulations may depend on the particular compound used and the particular patient receiving the compound.
  • Suitable formulations are known to those of skill in the art. (Examples thereof may be found, for example, in Remington's Pharmaceutical Sciences, 18th Edition, 1990.)
  • the invention also includes methods of determining whether a test compound causes Upodystrophy in a mammal, preferably a human.
  • the method may include (a) administering the test compound to (i) a mammal, or (ii) a cell expressing CD36 or a mimetic thereof or (iii) an in vitro cell free system capable of expressing CD36 or a mimetic thereof; (b) determining whether the test compound changes the level of CD36 in the mammal, the cell or the system.
  • a change in the level of CD36 is predictive that the mammal will develop Upodystrophy.
  • Any suitable cell may be used, such as a mammalian, insect or yeast cell.
  • Any suitable cell free system may also be used, such as a system capable of expressing CD36 or a mimetic thereof.

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  • Urology & Nephrology (AREA)
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  • Obesity (AREA)
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Abstract

Cette invention porte sur un procédé destiné à prévoir, chez des individus à risques, le développement de la lipodystrophie en associant une thérapie antirétrovirale. Ce procédé consiste à : (a) mesurer les niveaux de CD36 chez le patient avant d'utiliser un inhibiteur de protéase ou une thérapie antirétrovirale ; (b) mesurer les niveaux de CD36 chez le patient après introduction d'un inhibiteur de protéase ou après une thérapie antirétrovirale ; (c) déterminer si les niveaux de CD36 après introduction de l'inhibiteur de protéase ou après la thérapie antirétrovirale sont modifiés, ce changement laissant entrevoir le développement ultérieur de la lipodystrophie. Cette invention porte également sur une composition utilisée pour traiter ou prévoir la lipodystrophie en association avec un inhibiteur de protéase ou une thérapie antirétrovirale. La composition comprend un agoniste de PPARη-RXR qui régule de manière positive CD36 en le mélangeant à un véhicule, excipient ou diluant, acceptable d'un point de vue pharmaceutique. La composition peut être utilisée dans un procédé visant à prévenir ou traiter la lipodystrophie. L'invention porte en outre sur un procédé visant à déterminer si un composé de test provoque la lipodystrophie chez un mammifère.
EP00969122A 1999-10-19 2000-10-18 Procedes et compositions pour prevoir, diagnostiquer et traiter la lipodystrophie Withdrawn EP1223983A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US16034699P 1999-10-19 1999-10-19
US160346P 1999-10-19
CA2289365 1999-11-12
CA002289365A CA2289365A1 (fr) 1999-10-19 1999-11-12 Methodes et compositions pour prevoir, diagnostiquer et traiter la lipodystrophie
PCT/CA2000/001208 WO2001028532A2 (fr) 1999-10-19 2000-10-18 Procedes et compositions pour prevoir, diagnostiquer et traiter la lipodystrophie

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EP1223983A2 true EP1223983A2 (fr) 2002-07-24

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WO (1) WO2001028532A2 (fr)

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Publication number Priority date Publication date Assignee Title
FR2824332A1 (fr) * 2001-05-04 2002-11-08 Inst Nat Sante Rech Med Acide nucleique codant le polypeptide cgl1 et application de cet acide nucleique et du polypeptide cgl1 au diagnostic et en therapeutique
FR2854078B1 (fr) * 2003-04-28 2008-01-11 Univ Toulouse Procede de fabrication d'une composition therapeutique immuno-stimulante.
WO2005037189A2 (fr) * 2003-08-13 2005-04-28 The Burnham Institute Activite cytoplasmique du recepteur retinoide x et sa regulation par des ligands et sa dimerisation
US20050239889A1 (en) * 2004-04-26 2005-10-27 Jean Gosselin In vivo release of endogenous anti-microbial mediators by leukotriene B4 (LTB4) administration
EP1656934A1 (fr) * 2004-11-12 2006-05-17 Cognis IP Management GmbH Utilisation d'acides gras physiologiquement actifs pour le traitement de la lipodystrophie

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Publication number Priority date Publication date Assignee Title
US6509313B1 (en) * 1996-02-28 2003-01-21 Cornell Research Foundation, Inc. Stimulation of immune response with low doses of cytokines
WO2000000194A1 (fr) * 1998-06-27 2000-01-06 Photogenesis, Inc. UTILISATION OPHTHALMOLOGIQUE D'AGONISTES DE PPARη ET D'ANTAGONISTES DE PPAR$g(g)
JP2000191549A (ja) * 1998-12-28 2000-07-11 Applied Res Syst Ars Holding Nv Ｈｉｖに関連した異形症／代謝不全症候群の治療
AU2730100A (en) * 1999-01-19 2000-08-01 Glaxo Group Limited Methods of screening protease inhibitors, of inducing mice susceptible to hiv protease inhibitor-induced dyslipidemia, and genes associated therewith

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See references of WO0128532A2 *

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AU7894900A (en) 2001-04-30
WO2001028532A3 (fr) 2002-01-03
WO2001028532A2 (fr) 2001-04-26

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