Classifications

• • 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
  • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
  • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
  • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
  • G01N33/5058—Neurological cells
• • 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
  • 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
  • A61K38/22—Hormones
  • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• • 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
  • A61K38/22—Hormones
  • A61K38/27—Growth hormone [GH], i.e. somatotropin
• • 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
  • A61K49/00—Preparations for testing in vivo
  • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
• • 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
  • A61P3/04—Anorexiants; Antiobesity agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
• • 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
  • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
  • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• • 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
  • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
  • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
  • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
  • A01K2267/00—Animals characterised by purpose
  • A01K2267/03—Animal model, e.g. for test or diseases
  • A01K2267/035—Animal model for multifactorial diseases
  • A01K2267/0362—Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• the present invention is in the field of human medicine, particularly in the treatment of obesity and disorders associated with obesity such as diabetes mellitus. More specifically the invention relates to a method for treating obesity by administering a compound which blocks ghrelin action.
• the present invention provides a method of selectively inhibiting ghrelin activity in a mammal comprising administering to a mammal in need thereof a therapeutically-effective amount of a compound selected from the group consisting of a growth hormone secretagogue receptor antagonist (GHS-RA) and a ghrelin neutralizing agent (GNA) .
• the invention further provides a method for treating obesity and related disorders in a mammal comprising administering to a mammal in need thereof a therapeutically-effective amount of a compound selected from the group consisting of a growth hormone secretagogue receptor antagonist (GHS-RA) and a ghrelin neutralizing agent (GNA) .
• Other embodiments include in vi tro and in vivo screening and assay methods .
• GHRH growth hormone-releasing peptides
• GHS-R GHS receptor
• Obesity also called diverence or fatness
• body fat usually caused by the consumption of more calories than the body uses. The excess calories are then stored as fat, or adipose tissue.
• Overweight if moderate, is not necessarily obesity, particularly in muscular or large-boned individuals . In general, however, a body weight 20 percent or more over the optimum tends to be associated with obesity.
• treating or treatment describes the management and care of a patient for the purpose of combating the disease, condition, or disorder.
• Treating includes the administration of a compound of present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
• Treating obesity therefore includes the inhibition of food intake, the inhibition of weight gain, and inducing weight loss in patients in need thereof.
• the term 'related disorders' includes but is not limited to type II diabetes, cardiovascular disease, cancer, and other disease states whose etiology stems from obesity.
• the term 'administering' or 'administration' as used herein includes any means for introducing a GHS-RA or GNA into the body such that the substance is able to interact with the GHS-R or secreted ghrelin.
• Preferred routes of administration will introduce the substance into the systemic circulation. Examples include but are not limited to oral; transdermal; subcutaneous, intravenous, and intramuscular injection.
• the active agents of the present invention are administered to a mammal, preferably a human, in accord with known methods, such as intravenous administration as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebral, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, intraocular, intralesional, oral, topical, inhalation or through sustained release.
• a therapeutically-effective amount is at least the minimal dose, but less than a toxic dose, of an active agent which is necessary to impart therapeutic benefit to a mammal. Stated another way, a therapeutically-effective amount is an amount which induces, ameliorates or otherwise causes an improvement in the obese state of the mammal.
• Carriers' as used herein include pharmaceutically- acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically-acceptable carrier is an aqueous pH buffered solution.
• physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecule weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt- forming counterions such as sodium; and/or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG) , and PLURONICS®.
• buffers such as phosphate, citrate, and other organic acids
• antioxidants including ascorbic acid
• low molecule weight (less than about 10 residues) polypeptides proteins, such as serum
• 'mammal' refers to any animal classified as a mammal, including humans, domestic, farm and zoo animals, and sports or companion animals, etc. In a preferred embodiment of the invention, the mammal is a human.
• 'antibody' is used in the broadest sense and specifically includes monoclonal antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies .
• 'monoclonal antibody' refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally-occurring mutations that may be present in minor amounts .
• Antibody fragments means a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody.
• antibody fragments include Fab, Fab', F(ab')l and Fv fragments; diabodies; linear antibodies (Zapata et al . , Protein Engin . S(10): 1057-1 062 (1991)); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
• the term 'Fv' is the minimum antibody fragment, which contains a complete antigen-recognition and binding site. This region consists of a dimer of one heavy- and one light chain variable domain in tight, non-covalent association.
• variable domain the three complementarity-determining regions (CDRs) of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer.
• CDRs complementarity-determining regions
• the Fab fragment also contains the constant domain of the light chain and the 'first constant domain (CHI) of the heavy chain.
• Fab fragments differ from Fv fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region.
• Fab'-SH is the designation herein for Fab' in which the cysteine residue (s) of the constant domains bear a free thiol group.
• F(ab') z antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
• Papain digestion of antibodies produces two identical antigen-binding fragments, called Fab fragments, each with a single antigen-binding site, and a residual Fc fragment, a designation reflecting the ability to crystallize readily.
• Pepsin treatment yields an F(ab') 2 fragment that has two antigen-combining sites and is still capable of cross- linking antigen.
• immunoglobulins The 'light chains' of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains .
• immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes) , e.g., IgGl, IgG2, IgG3, IgG4, IgA and IgA2.
• Fv'Single-chain Fv' antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain.
• the Fv polypeptide further comprises a polypeptide linker between the VH and VL domain, which enables the sFv to form the desired structure for antigen binding.
• the term ' immunoadhesion' designates antibodylike molecules that combine the binding specificity of a heterologous protein (an 'adhesion') with the effector functions of immunoglobulin constant domains.
• the immunoadhesions comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is heterologous), and an immunoglobulin constant domain sequence.
• the adhesion part of an immunoadhesion molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand.
• the immunoglobulin constant domain sequence in the immunoadhesion may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3 or IgG-4 subtypes, IgA (including IgG-1 and IgA-2) , IgE, IgD or IgM.
• 'diabodies' refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy-chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL) .
• VH heavy-chain variable domain
• VL light chain variable domain
• Diabodies are described more fully in, for example, EP 404.097, WO 93/1 1161; and Hollinger et al . , Proc. Natl. Acad. Sci . USA 90: 6444-6448 (1993) .
• a GHS-RA is any compound that partially or fully antagonizes, blocks, or otherwise inhibits the biological action of ghrelin by binding to the GHS-R without stimulating the release of growth hormone. Therefore GHS (compounds that bind the GHS-R and stimulate the release of GH) are not consistent with the claimed method.
• GHS-RA are compounds useful in the presently claimed method and include but are not limited to natural products, synthetic organic compounds, peptides, proteins, antibodies, antibody fragments, single chain antibodies, and antibody based constructs. The current level of skill in the art of receptor binding and growth hormone assays places GHS-RAs well within the grasp of the ordinarily skilled artisan. There are several routine approaches for identifying a GHS-R.
• GHS-RA test compound is first checked to determine if it binds GHS-R. This is accomplished using routine radiometric binding methods .
• a second messenger reporter such as calcium can be used to determine binding.
• Assay is described in Kojima et al . , Nature 402: 656-60 (1999). Compounds that bind GHS-R are then exposed to primary pituitary cells, for example, and release of growth hormone is determined using standard commercially available assays.
• Compounds that bind but do not stimulate the release of GH should then be assayed for ghrelin antagonism by exposing pituitary cells to the GHS-RA in the presence of ghrelin and then assaying for GH release.
• Antibody-based GHS-RAs are also consistent with the claimed method.
• Anti-GHS-R antibodies may be generated by a variety of well-known methods that include traditional antisera production and monoclonal antibody techniques.
• Ghrelin neutralizing agents represent another aspect of the invention.
• ghrelin is neutralized or otherwise rendered biologically inactive apart from the receptor.
• Agents suitable for this application are those which specifically bind ghrelin, preferably with a higher affinity constant than the GHS-R.
• Antibody or antibody-based agents are preferred because they can be purposefully generated using well established techniques.
• Kojima et al . Nature 402: 656-60 (1999) .
• Immunoadhesions Fc fusion constructs, similar to Enbrel®, where the soluble ligand-binding domain of the GHS- R is fused to a human Fc
• Dosages and desired drug concentration of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary artisan. Animal experiments provide reliable guidance for the determination of effective doses for human therapy.
• an article of manufacture containing materials useful in the presently claimed methods comprises a container and a label.
• Suitable containers include, for example, bottles, vials, syringes, and test tubes .
• the containers may be formed from a variety of materials such as glass or plastic.
• the container holds a composition which is effective for specifically inhibiting ghrelin action and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle) .
• the active agent in the composition is a GHS-RA and/or a GNA.
• the label on, or associated with, the container indicates that the composition is used for treating obesity and/or related disorders.
• the article of manufacture may further comprise a second container comprising a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial end user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
• Five-minute fractions were collected while monitoring the U.V. at 214 nm (2.0A).
• the appropriate fractions were combined, frozen and lyophilized.
• MALDI- ass spectral analysis indicated a mass of 3313.85 g for the purified ghrelin, which was consistent with the theoretical molecular weight.
• Example 2 Animals Wild-type mice (129SV strain) and NPY-knockout mice were obtained from Taconic Farms ® . Eight-week old dwarf rats were purchased at Harlan UK. Animals were housed individually in a temperature controlled environment (25 C°) with a 12-hour light and 12-hour dark (18.00 - 06.00) photoperiod. All mice had ad libi tum access to pelleted mouse food (5008 PMI ® Nutrition International) and tap water . Mice were between 9 and 13 weeks of age and were injected daily between 17.00 and 18.00 with 0.1 ml of phosphate buffered saline (PBS) containing 0 or 8 mg/kg/d ghrelin over 13 days . Food intake and body weights were measured daily at O ⁇ .OOh. All animal experiments were conducted in accordance with the principles and procedures outlined in the National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals.
• NASH National Institute of Health
• RQ is the ratio of VC0 2 to V0 2 .
• CV calorific value of oxygen
• Total calories expended were calculated to determine daily fuel utilization.
• proportion of protein, fat and carbohydrate that is utilized during that 24-hour period we used Flatt's proposal and assumed that protein utilization was equivalent to protein intake for adult stable animals (Flatt, J.P., J. Nutr Biochem 2, 193-202 (1991)).
• DXA dual-energy X-ray absorptiometry
• Body composition was measured on day 14 of the treatment period by DXA using a Norland p-DEXA ® (Norland,
• the system provides a non-invasive method for quantification of whole body composition and is based on the differential attenuation of high and low energy x-rays by the tissues in the scan area.
• Soft tissues attenuate the energy beam less than bone; of the soft tissue mass, fat tissue attenuates the beam less than lean tissue.
• Fat mass consists primarily of adipose tissue, but lean mass includes organs, tendons, cartilage, blood and body water in addition to skeletal muscle. In the present study, fat mass, lean mass and bone mineral content (bone mass) were measured and reported. Mice were anesthetized with inhalation of isoflorane and placed on the instrument platform in ventral position. Measurements were performed at a speed of 10 mm/ in and a resolution of 0.5 x 0.5 mm. Quality controls using phantom ID2232 and Calibration Standard 82315 (Norland) were performed before starting measurements .
• Example 5 Example 5
• mice were treated with GHRP-2 for 18 days.
• Hypothalamic RNA levels (measured by RT-PCR) of neuropeptide Y (NPY) , agouti-related-protein (AGRP) , pro- opio-melanocortin (POMC) and melanocyte-concentrating hormone (MCH) were not changed.
• GHRP-6 increases c- fos expression in NPY-neurons (Vernon, R. G.; J Endocrinol 150, 129-40 (1996)) and because these neurons also release AGRP, a natural melanocyte stimulating hormone antagonist
• Recombinant CHO cells expressing the human growth hormone secretagogue receptor cDNA described by Howard et al . , Science 273: 974-977 (1996) are grown and harvested in nutrient medium.
• Membrane preparations are then obtained by first washing the cells with PBS buffer, then twice washing with cold buffer (25 mM HEPES, 2 M MgCl 2 , 1 mM EDTA, 20 ⁇ g/ml Leupeptin, 1 mM PMSF, 2 ⁇ g/ml Aprotinin, 50 ⁇ g/ml Trypsin Inhibitor, pH 8.0) and resuspending in buffer.
• the cell suspension is lysed in a glass Teflon® homogenizer, and the resulting sample is then centrifuged at 35,300 X g for 30 minutes at 4°C.
• the supernatant is removed, and the pellet is resuspended in cold buffer and homogenized. Aliquots may then be prepared and stored at -80°C.
• a sample of the membrane preparation is pre- incubated with a test compound or a control compound with and without added grhelin in buffer (25 mM HEPES, 0.2%
• BSA 2.6 mM Mg, 0.8 mM ATP, 0.1 mM GTP, 5 mM creatine phosphate, creatine kinase 50 U/ml, 0.2 mM IBMX, pH 7.6) is added and incubated for an additional 30 minutes. Incubations are stopped by adding 10 mM EDTA.
• cAMP-b phycoerythrin conjugate is added followed by the addition of affinity purified anti-cAMP rabbit antiserum.
• anti-rabbit IgG coated assay beads are added and incubated for an additional 15 minutes. Plates are then evacuated and read on a Pandex® PFCIA reader.
• ghrelin binding shows decreasing fluorescent intensity due to increased cAMP concentration. Fluorescent intensity values are correlated to rate of cAMP production (pmol/min/mg) . Conversely, inhibition of ghrelin binding by either receptor blockade or ghrelin neutralizations shows no decrease in fluorescent intensity.
• ghrelin is mainly generated by the stomach and secreted into circulation
• total energy 1795 ⁇ 105 kcal
• plasma ghrelin decreased by 30% 2 hours after the meal (p ⁇ 0.01), and over the 24h sampling period (p ⁇ 0.05).
• plasma ghrelin levels did not decrease after meals.
• ghrelin release is a normal response to fasting.
• Such elevated ghrelin stimulates appetite and the utilization of carbohydrate (determined in above examples using rodents) and thus corrects hypoglycemia resulting from fasting.
• Ingestion of glucose rescues hypogylcemia and thus inhibits ghrelin secretion from the stomach to prevent hyperglycemia .
• ghrelin plays an important role in the regulation of blood glucose. Agents that block ghrelin action may be useful for the treatment of diabetes .

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