US20050143467A1 - Stimulation of cpt-1 as a means to reduce weight - Google Patents

Stimulation of cpt-1 as a means to reduce weight Download PDF

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US20050143467A1
US20050143467A1 US10/503,605 US50360505A US2005143467A1 US 20050143467 A1 US20050143467 A1 US 20050143467A1 US 50360505 A US50360505 A US 50360505A US 2005143467 A1 US2005143467 A1 US 2005143467A1
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cpt
activity
fatty acid
agent
malonyl
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Jagan Thupari
Leslie Landreee
Gabrielle Ronnett
Francis Kuhajda
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School of Medicine of Johns Hopkins University
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Assigned to JOHNS HOPKINS UNIVERSITY OF MEDICINE LICENSING AND TECHNOLOGY DEVELOPMENT, THE reassignment JOHNS HOPKINS UNIVERSITY OF MEDICINE LICENSING AND TECHNOLOGY DEVELOPMENT, THE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KUHAJDA, FRANCIS P., RONNETT, GABRIELE, THUPARI, JAGAN N., LANDREE, LESLIE E.
Publication of US20050143467A1 publication Critical patent/US20050143467A1/en
Priority to US11/537,968 priority patent/US7459481B2/en
Priority to US12/266,425 priority patent/US20090124684A1/en
Assigned to NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR reassignment NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: THE JOHNS HOPKINS UNIVERSITY
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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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • 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
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • This invention is directed to a method for development of therapeutics that selectively enhance fatty acid oxidation, increase energy production, and reduce adiposity while preserving lean mass, through the pharmacological stimulation of CPT-1 activity.
  • C75 Cerulenin treatment of MCF-7 human breast cancer cells in vitro significantly inhibits fatty acid oxidation, probably through increased levels of malonyl-CoA (Loftus, et al. (2000) Science, 288: 2379-2381).
  • C75 is a member of a family of ⁇ -methylene- ⁇ -butyrolactones which are known inhibitors of fatty acid synthase (FAS) (Kuhajda, et al. (2000) Proc. Natl. Acad Sci USA, 97: 3450-3454).
  • FAS fatty acid synthase
  • C75 reduces the expression of hypothalamic neuropeptide-Y (NPY) leading to reversible inanition (Loftus, et al, 2000).
  • NPY hypothalamic neuropeptide-Y
  • NPY hypothalamic neuropeptide-Y
  • ob/ob mice there was profound loss of fat in the liver and peripheral tissues despite the increased levels of hepatic malonyl-CoA (Loftus, et al., 2000).
  • Malonyl-CoA is a potent inhibitor of fatty acid oxidation through its action as an inhibitor of carnitine-palmitoyl-transferase-1 (CPT-1) (Witters, et al. (1992) J. Biol. Chem., 267: 2864-2867).
  • CPT-1 enables the entry of long-chain acyl-CoA's into the mitochondria for fatty acid oxidation.
  • FAS inhibitors genetically and diet-induced obese mice undergo a selective and significant loss of adipose tissue despite the high levels of malonyl-CoA induced by FAS inhibition.
  • malonyl-CoA is a potent inhibitor of fatty acid oxidation through its inhibition of carnitine palmitoyltransferase-1 (CPT-1, E.C. 2.3.1.21), the rapid and selective loss of adipose tissue was surprising. High systemic levels of malonyl-CoA would be expected to inhibit fatty acid oxidation leading instead to a selective loss of lean mass during C75 induced inanition.
  • this invention provides a method of inducing weight loss comprising administering an agent that stimulates carnitine palmitoyl transferase-1 (CPT-1) activity to the patient in need, including human patients.
  • CPT-1 carnitine palmitoyl transferase-1
  • the agent is administered in an amount sufficient to increase fatty acid oxidation.
  • the agent is administered in an amount sufficient to antagonize malonyl CoA inhibition of CPT-1.
  • the agent is administered in an amount sufficient to increase malonyl CoA level.
  • malonyl CoA level is not substantially increased.
  • Substantial increase in malonyl CoA level as contemplated herein is equivalent to about one-half the K i for malonyl CoA inhibition of CPT-1.
  • the agent which stimulates CPT-1 activity also inhibits fatty acid synthase (FAS).
  • FAS fatty acid synthase
  • FAS is not significantly inhibited. Insignificant inhibition as contemplated herein is less that 15%, preferably less than 10%, and more preferably less than 5% inhibition.
  • Methods for assay of FAS activity are disclosed in U.S. Pat. No. 5,981,575, incorporated herein by reference.
  • the agent which stimulates CPT-1 activity is not a compound of formula: wherein R is a substitute selected from the group consisting of:
  • this invention provides a method for stabilizing weight comprising chronic administration of an agent that stimulates CPT-1 activity in an amount that does not significantly inhibit FAS.
  • the agent is administered in an amount sufficient to increase fatty acid oxidation.
  • the agent is administered in an amount sufficient to antagonize malonyl CoA inhibition of CPT-1.
  • the agent is administered in an amount sufficient to increase malonyl CoA level.
  • upon administration of the agent malonyl CoA level is not substantially increased. Substantial increase in malonyl CoA level as contemplated herein is equivalent to about one-half the K i for malonyl CoA inhibition of CPT-1.
  • this invention provides a method of screening for agents that induce weight loss, comprising determining whether a candidate weight loss agent stimulates CPT-1 activity; and selecting an agent that stimulates CPT-1 activity.
  • this method further comprises determining whether the candidate weight loss agent is an antagonist of malonyl CoA inhibition of CPT-1, and candidate weight loss agents are selected that obviate malonyl CoA inhibition of CPT-1.
  • this invention provides a therapeutic composition comprising an agent that stimulates CPT-1 activity and L-carnitine.
  • the therapeutic composition comprises an antagonist of malonyl CoA inhibition of CPT-1.
  • this invention provides a nutritional composition comprising nutritionally sufficient amounts of fats, carbohydrates and amino acids, said composition further comprising an antagonist of malonyl CoA inhibition of CPT-1 and L-carnitine.
  • the nutritional composition is adapted for parenteral administration.
  • FIG. 1 shows the effect of C75 on fatty acid oxidation in MCF-7 cells, compared to the effect of Etomoxir.
  • FIG. 2 shows concentration dependent stimulation of CPT-1 activity by C75 and inhibition by malonyl CoA.
  • FIG. 3 shows reversible stimulation of CPT-1 by C75.
  • FIG. 4 shows stimulation of CPT-1 by various C75 analogs.
  • FIG. 5 shows concentration dependent enhancement of cellular ATP levels by C75 in MCF-7 cells.
  • FIG. 6 shows concentration dependent stimulation of fatty acid oxidation by C75 in mouse adipocytes.
  • FIG. 7 shows concentration dependent enhancement of cellular ATP levels by C75 in mouse adipocytes.
  • FIG. 8 shows respiratory exchange ratio (RER) measured by indirect calorimetry for mice in the absence (A) and presence (B, C) of C75.
  • CPT-1 carnitine palmitoyltransferase-1
  • the peripheral (non-CNS) weight loss effect of C-75 is at least in part due to CPT-1 stimulation and increased fatty acid oxidation with concomitant fatty acid synthesis inhibition.
  • C75 is the prototype agent for stimulation of CPT-1; reference to C75 hereinafter includes other suitable agents which stimulate CPT-1 activity, except where indicated otherwise by context.
  • C-75 abolishes the inhibitory effect of malonyl-CoA on CPT-1 activity.
  • C75 exhibits kinetic features of a slow-binding inhibitor with purified FAS (1), its interaction with CPT-1 appears rapid and competitive.
  • the stimulatory effect of C75 upon fatty acid oxidation may be due to either its direct stimulation of CPT-1 activity, its interference of malonyl-CoA inhibition of CPT-1, or both.
  • the effects of C75 are not restricted to murine CPT-1, as human CPT-1 was similarly affected.
  • C75 also increased ATP levels in both the human and murine cells.
  • C75 The effect of C75 on fatty acid metabolism in vivo mirrored the alterations seen on a cellular level.
  • C75 and its family of ⁇ -methylene- ⁇ -butyrolactones appear to act as competitive agonists of CPT-1.
  • This agonist activity of C75 appears to overcome inhibitory effects of malonyl CoA on the same enzyme.
  • the increased fatty acid oxidation induced by C75 is an important mechanism accounting for marked reduction in adiposity seen during C75 treatment of mice.
  • this invention describes a method to develop therapeutics that selectively enhance fatty acid oxidation, increase energy production, and reduce adiposity while preserving lean mass, through the pharmacological stimulation of CPT-1 activity.
  • compositions containing C75 and/or other agents that stimulate CPT-1, and methods of administering such agents are within the skill of the art, particularly in view of the description in U.S. Pat. No. 5,981,575, the text of which is incorporated herein by reference.
  • CPT-1 stimulating agents to increase energy production by administering the agents contemporaneously with fatty acids or compounds containing fatty acid residues is also within the skill of the art, particularly in view of the nutritional compositions disclosed in U.S. Pat. No. 4,434,160, the text of which is incorporated herein by reference.
  • Cerulenin an FAS inhibitor, increases malonyl-CoA amount in MCF-7 cells (3).
  • cerulenin causes inhibition of fatty acid oxidation through the malonyl-CoA inhibition of CPT-1 (Thupari, et al. (2001) Biochem. Biophys. Res. Comm., 285: 217-223).
  • CPT-1 fatty acid synthase
  • Human breast cancer cell line MCF-7 was obtained from the American Type Culture Collection. 1 ⁇ 10 6 MCF-7 cells were plated in T-25 flasks in triplicate and incubated overnight at 37° C. Drugs were then added as indicated diluted from 5 mg/ml stock in DMSO. After 2 hours, medium with drugs was removed and cells were preincubated for 30 min. with 1.5 ml of the following buffer: 114 mM NaCl, 4.7 mM KCl, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , glucose 11 mM.
  • assay buffer containing: 114 mM NaCl, 4.7 mM KCl, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , glucose 11 mM, 2.5 mM palmitate (containing with 10 ⁇ Ci of [1- 14 C]palmitate) bound to albumin, 0.8 mM L-carnitine, and cells were incubated at 37° C. for 2 h. Following the incubation, 400 ⁇ l of benzethonium hydrochloride was added to the center well to collect released 14 CO 2 . Immediately, the reaction was stopped by adding 500 ⁇ l of 7% perchloric acid to the cells.
  • C75 treatment increased rather than decreased fatty acid oxidation in MCF-7 cells. This implies a direct effect of C75 upon carnitine palmitoyltransferase-1 (CPT-1).
  • CPT-1 activity was assayed in MCF-7 cells by the following published procedure: MCF-7 cells were plated in DMEM with 10% fetal bovine serum at 10 6 cells in 24-well plates in triplicate. Following overnight incubation at 37° C., the medium was removed and replaced with 700 ⁇ l of assay medium consisting of: 50 mM imidazole, 70 mM KCl, 80 mM sucrose, 1 mM EGTA, 2 mM MgCl 2 , 1 mM DTT, 1 mM KCN, 1 mM ATP, 0.1% fatty acid free bovine serum albumin, 70 ⁇ M palmitoyl-CoA, 0.25 ⁇ Ci [methyl- 14 C]carnitine, 40 ⁇ g digitonin with or without 20 ⁇ M malonyl-CoA.
  • MCF-7 cells were treated with C75 at 10 or 20 ⁇ g/mL for 1 hr before CPT-1 activity was assayed.
  • the assay was performed with the C75 and malonyl-CoA concentrations indicated (“M” indicates malonyl-CoA at 20 ⁇ M).
  • the level of malonyl-CoA inhibition of the CPT-1 activity is consistent with the activity of the liver isoform of CPT-1 in MCF-7 cells.
  • the K i of malonyl-CoA for the liver isoform of CPT-1 is ⁇ 7 ⁇ M while the K i for the muscle isoform of CPT-1 is 0.07 ⁇ M.
  • MCF-7 cells express predominantly the liver isoform of CPT-1 (consistent with the immunoblot analysis).
  • MCF-7 cells were untreated (left bar) or treated with C75 at 20 ⁇ g/ml for one hour before CPT-1 activity was measured (middle and right bars).
  • C75 was removed from the assay buffer and replaced with buffer (middle bar) or malonyl-CoA 20 ⁇ M was added (left & right bars).
  • the optimum carbon chain length for CPT-1 activation is between 6 and 16 carbons.
  • 3T3-L1 adipocytes were used in assays similar to those performed with the MCF-7 cells.
  • 3T3-L1 cells were obtained from the American Type Culture Collection, and cells were cultured in DMEM with high glucose (4.5 g/l) (Gibco 12100-046) with 10% fetal calf serum and Biotin (Sigma B-4639) 0.008 g/L. Differentiation was initiated three days after the cells were confluent, when the standard culture medium was replaced with differentiation medium.
  • the differentiation medium contained standard culture medium to which the following were added to achieve the final concentrations: methylisobutylxanthine (MIX) 0.5 mM, dexamethasone (DEX) 1 ⁇ M, and insulin 10 ⁇ g/ml. After 48 hrs, the differentiation medium was replaced with post-differentiation medium which contained insulin at the above concentration, without MIX and DEX. The differentiated cells were ready to be used for experiments in 7-10 days.
  • MIX methylisobutylxanthine
  • DEX dexamethasone
  • C75 increased CPT-1 activity and fatty acid metabolism in the NIH 3T3-L1 cells differentiated into adipocytes.
  • CPT-1 activity, fatty acid oxidation, and total cellular ATP were measured as described in Examples 2, 1, and 4.
  • C75 at doses of 20 ⁇ g/ml or greater significantly increased fatty acid oxidation (see FIG.
  • C75 induces a profound and rapid stimulation of fatty acid oxidation in vivo.
  • Mice were maintained in the Oxymax calorimeter (Oxymax Equal Flow System®, Columbus Instruments, Columbus, Ohio). Oxygen consumption and CO 2 production was measured in up to four mice simultaneously using the indirect calorimeter. Measurements were recorded every 15 minutes over the entire course of the experiments.
  • the respiratory exchange ratio (RER) was calculated by the Oxymax® software version 5.9. RER is defined as the ratio of CO 2 to O 2 at any given time irrespective if equilibrium was reached. Mice were maintained on water and mouse chow ad libitum. In the control mice ( FIG.
  • C75 treatment led to a rapid, profound increase in fatty acid oxidation as measured by RER.
  • C75 treated animals are able to significantly reduce adipose mass and reverse fatty liver, by allowing fatty acid oxidation to occur despite the high levels of malonyl-CoA generated during FAS inhibition in vivo.

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US11/537,968 US7459481B2 (en) 2002-02-08 2006-10-02 Stimulation of CPT-1 as a means to reduce weight
US12/266,425 US20090124684A1 (en) 2002-02-08 2008-11-06 Stimulation Of CPT-1 As A Means To Reduce Weight

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JP2005523270A (ja) * 2002-02-08 2005-08-04 ジョーンズ・ホプキンス・ユニバーシティ・スクール・オブ・メディシン 体重を減少させる方法としてのｃｐｔ−１の促進
WO2004005277A1 (fr) * 2002-07-09 2004-01-15 Fasgen, Inc. Nouveaux composés, compositions pharmaceutiques les contenant et méthodes d'utilisation desdits composés
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ZA200700024B (en) * 2004-05-26 2008-06-25 Fasgen Llc Novel compounds, pharmaceutical compositions containing same, and methods of use for same
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MXPA04007556A (es) 2005-12-05
US20070087037A1 (en) 2007-04-19
US20090124684A1 (en) 2009-05-14
KR20040082417A (ko) 2004-09-24
WO2003066043A1 (fr) 2003-08-14
AU2003215111A1 (en) 2003-09-02
EP1471906A1 (fr) 2004-11-03
EA200401052A1 (ru) 2005-02-24
CN1313089C (zh) 2007-05-02
IL163312A (en) 2011-12-29
JP2010047594A (ja) 2010-03-04
EA007029B1 (ru) 2006-06-30
CA2474884A1 (fr) 2003-08-14
US20050106217A1 (en) 2005-05-19
EP1471906A4 (fr) 2006-02-01
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