WO2002067958A1 - Method for determining efficacy of reverse cholesterol transport enhancing agents - Google Patents
Method for determining efficacy of reverse cholesterol transport enhancing agents Download PDFInfo
- Publication number
- WO2002067958A1 WO2002067958A1 PCT/US2002/005722 US0205722W WO02067958A1 WO 2002067958 A1 WO2002067958 A1 WO 2002067958A1 US 0205722 W US0205722 W US 0205722W WO 02067958 A1 WO02067958 A1 WO 02067958A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- test agent
- protein
- rct
- agent
- mammal
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- Reverse cholesterol transport is the means by which excess tissue cholesterol is returned to the liver for disposal. It is believed that defects in RCT result in accumulation of cholesterol in tissues in the form of xanthomas and atherosclerotic lesions. It is thus desirable to enhance reverse cholesterol transport in patients with atherosclerosis or xanthomas.
- ABCAl A key gene that promotes RCT is ABCAl (ABCAl is also referred to in the published literature as ABCl) (see Mott et al, Atherosclerosis, 152:457-468 (2000)). This gene is believed to function as a "pump” which removes cholesterol from cells to high density lipoprotein (HDL). In keeping with this function in RCT, it has been reported that expression of the ABCAl gene is increased by cholesterol loading of cells (Langmann et al, Biochem. Biophys. Res. Comm., 257, 29-33 (1999)). Mutations in the ABCAl gene result in Tangier disease. Cultured cells from patients with Tangier disease are defective in cholesterol efflux (Francis et al. (1995) J. Clin. Invest. 96:78-87), and the patients' condition is marked by massive accumulation of cholesterol in peripheral tissues and very low HDL cholesterol levels.
- LXR liver X-receptor
- LXR is believed to upregulate genes including ABCA8, an additional "pump" protein, and CETP, a protein that moves cholesterol from HDL to other lipoproteins. Therefore, it has been found that ligands of LXR, including ligands of both LXR and LXR ⁇ , can be useful as drugs to increase the expression of ABCAl, increase levels of HDL and thereby decrease the risk of atherosclerosis, myocardial infarction and related conditions such as peripheral vascular disease and ischemic stroke. Other factors that act to upregulate the proteins needed for RCT are also the subject of ongoing research.
- CD 14 is a 55 kDa protein expressed as both a soluble protein in plasma (sCD14) and as a membrane protein on the surface of monocytes and macrophages (mCD14) (Wright, S. D. (1999), Innate recognition of microbial lipids, Inflammation: Basic Principles and Clinical Correlates, 3rd ed., J. I. Gallin, and R. Snyderman eds. Raven Press, New York, NY).
- sCD14 binds a broad range of phospholipids and can shuttle these lipids into and out of membranes (Yu, B., Hailman, E., and Wright, S. D. (1997) J. Clin. Invest. 99, 315-324; Vasselon, T., Pironkova, R., and Detmers, P. A. (1997) J. Immunol. 159, 4498-4505; Vasselon, T., Hailman, E., Thieringer, R., and Detmers, P. A. (1999) J. Exp. Med. 190, 509-521; Wurfel, M.
- the shuttle function of CD 14 is illustrated by the finding that the rate of transport of insoluble LPS into HDL particles (Wurfel, et al, ibid.) or cells (Hailman, E., Vasselon, T., Kelley, M., Busse, L. A., Hu, M. C, Lichenstein, H. S., Detmers, P. A., and Wright, S. D. (1996) J. Immunol. 156, 4384-4390) is dramatically enhanced by the addition of sCD14. Kinetic analysis of this facilitated transport shows that the LPS is first bound to sCD14, and the bound lipid is then surrendered to the HDL particle (Wurfel, et al, ibid.).
- the plasma membrane contains phospholipid and cholesterol in approximate molar equivalence, and cells are known to export these two lipids together (Oram, J. F., and Yokoyama, S. (1996) J. Lipid Res. 37, 2473-2491). However, it was previously unknown if CD14 was involved in facilitating export of cholesterol from cells.
- CD14 participates in RCT, and that the CD14 gene is upregulated by agents that increase RCT.
- One object of the present invention is to provide a method for determining the efficacy of a known or potential reverse cholesterol transport- enhancing agent in mammals, particularly humans, that avoids the need for measuring cellular protein or mRNA levels and instead employs blood level measurements of CD 14 levels.
- this invention provides a method for evaluating the efficacy of a reverse cholesterol transport-enhancing test agent in a mammal comprising: measuring the level of CD14 protein present in a standard sample of the mammal's blood to obtain one CD 14 protein measurement; measuring the level of CD 14 protein present in a sample of the mammal's blood after administration of the test agent to obtain a second CD14 protein measurement; and comparing the two CD14 protein measurements to determine if the measurement obtained after test agent administration is greater than the measurement obtained from the standard blood sample; and wherein the CD14 protein is selected from sCD14 and mCD14 and is the same for both measurements.
- FIGS la, lb and lc are graphs showing the effect of sCD14 concentration on cholesterol efflux.
- [ H] cholesterol-labeled THP-1 cells were incubated with the indicated concentration of sCD14 (closed circles), apo A-I (open circles) or HSA (inverted triangles) in RPMI for 30 min (a and b) or for 20h (c). Each point represents the mean of three measurements ⁇ SD (a) or the average of duplicate samples ⁇ range (b and c). Data are representative of five independent experiments with similar results.
- Figures 2 is a graph showing the kinetics of cholesterol efflux by sCD14 and/or apo A-I.
- [ 3 H] cholesterol-labeled THP-1 cells were incubated with or without 5 ⁇ g/ml of sCD14 and/or 100 ⁇ g/ml of apo A-I in RPMI. Background efflux without proteins at each time was measured and subtracted from other data point.
- Figures 3 is a graph showing the dose dependent additive effect of sCD14 for cholesterol efflux to apo A-I but not to HDL.
- THP-1 cells were incubated in buffer containing 50 ⁇ g/ml of apo A-I, HDL3 or HDL with or without the indicated concentration of sCD14 for lh.
- Open bar without sCD14; hatched bar, 10 ⁇ g/ml sCD14; black bar, 25 ⁇ g/ml sCD14. Background efflux without proteins at each time was measured and subtracted from other data point.
- FIGS. 4a and 4b are graphs showing inhibition for apo A-I-dependent cholesterol efflux by various anti-CD 14 antibodies.
- [ 3 H] cholesterol- (a) or [ 3 H]choline- (b) labeled THP-1 cells were incubated with or without apo A-I and/or various anti-CD 14 antibodies for 20h. Antibodies are indicated at the bottom of the bars.
- Antibody concentrations were 10 ⁇ g/ml for mAb and 100 ⁇ g/ml for polyclonal antibody (a and b).
- Asterisks show statistical significance (p ⁇ 0.01) compared to the data without anti-CD 14. Data are representative of three independent experiments with similar results.
- Figures 5a and 5b are graphs showing that activation of LXR increases mRNA expression of ABCAl and CD14.
- THP-1 or HepG2 cells (5 x 105 cells/well) were plated in 6-well plates, and mixed with buffer (open bar) or 22(R)-OH cholesterol (10 ⁇ M, closed bar). After overnight incubation ( ⁇ 16 hr) at 37oC, RNA samples were prepared from the cultured cells, and mRNAs for ABCAl (a) and CD 14 (b) were measured as described in Example 4, below. Results are presented as fold of control (untreated cells), and data are shown as the means ⁇ range of duplicate determinations.
- CD14 participates in RCT.
- CD14 is expressed both as a soluble protein in plasma (sCD14) and as a membrane protein on the surface of monocytes (mCD14).
- sCD14 soluble protein in plasma
- mCD14 monocytes
- Addition of sCD14 to cells enhances cellular efflux of cholesterol to apolipoprotein A-I (apoAI), and blockade of mCD14 with antibodies blocks cellular efflux of cholesterol.
- apoAI apolipoprotein A-I
- mCD14 apolipoprotein A-I
- addition of 22 hydroxycholesterol, a ligand for LXR and a compound known to enhance cholesterol efflux from cells causes coordinate upregulation of not only ABCAl but also CD 14 mRNA.
- measurements of blood levels of CD 14 can be used to provide a measure of efficacy of RCT- enhancing agents.
- CD14 is readily assayed in plasma and it is stable.
- sCD14 can be measured by ELISA (enzyme-linked immunosorbent assay) on plasma
- mCD14 can be measured by FACS (fluorescent activated cell sorting) on blood monocytes.
- Assays for measuring blood levels of sCD14 and mCD14 are described in the published literature.
- an ELISA assay for measuring sCD14 is described in Detmers PA, Zhou D, Powell D, Lichenstein H, Kelley M, Pironkova R. Endotoxin receptors (CD 14) are found with CD 16 (Fc gamma Rm) in an intracellular compartment of neutrophils that contains alkaline phosphatase, J Immunol.
- This invention provides a method for evaluating the efficacy of a known or potential reverse cholesterol transport-enhancing agent, herein referred to as a test agent, in a mammal comprising measuring the level of CD14 protein present in a standard sample of the mammal's blood to obtain one CD 14 protein measurement; measuring the level of CD 14 protein present in a sample of the mammal's blood after administration of the test agent to obtain a second CD 14 protein measurement; and comparing the two CD 14 protein measurements to determine if the measurement obtained after test agent administration is greater than the measurement obtained from the standard blood sample; and wherein the CD 14 protein is selected from sCD14 and mCD14 and is the same for both measurements.
- Measurement of blood levels of CD 14 is required to practice the instant invention. Either sCD14 or mCD14 may be measured, but comparisons are intended to be made between or among measurements of the same form of CD14, that is measurements of sCD14 are to be compared against other measurements of sCD14, and measurements of mCD14 are to be compared against other measurements of mCD14.
- test agent The agent which is being evaluated for its efficacy at enhancing RCT will be referred to herein as the test agent.
- the test agent can be any agent, chemical or non-chemical, desired to be and capable of being tested with a mammal.
- the term "test agent” encompasses both known RCT-enhancing agents, such as LXR ligands, and potential RCT-enhancing agents whose activity for enhancing RCT is not yet known or confirmed.
- the term 'test agent' is intended to include not only compounds, mixtures of compounds and pharmaceuticals, but also vitamins and consumable dietary items such as foods and food supplements.
- test agent further includes known and potential physical and behavioral inducers of RCT enhancement such as physical exercise and/or weight-loss dieting.
- the tested physical and behavioral inducers of RCT enhancement may also be administered in combination with a drug therapy, for example weight-loss dieting along with administration of a weight-loss drug. Therefore, the instant method invention can be used, for example, to screen agents such as compounds, foods, vitamins and/or different types of physical and behavioral activities for their RCT-enhancing activity, as well as to evaluate the relative activity of known RCT-enhancing agents.
- the instant invention is not limited by any particular type of agent that is or can be tested; rather, the invention encompasses the use of CD 14 measurements as a biological marker for indicating whether or not enhancement of RCT has occurred.
- the blood sample may be taken at any time of choice after the start of test agent administration. Persons skilled in the art are capable of determining a desired length of time for administration of the test agent before the mammal's blood sample is taken, which may vary depending on the chosen test agent or combination of agents and the objective of the experiment. For example, since HMG-CoA reductase inhibitors take about 2 weeks to exert their LDL lowering effect, a blood sample could be taken 2-4 weeks after the start of a daily HMG-CoA reductase inhibitor drug therapy; or the blood sample could be taken immediately following a physical exercise workout or a meal, or after a period of weeks or months of following an exercise or weight-loss dietary regimen. Blood samples could be taken at a variety of times during the administration of a test agent to determine when, if at all, an RCT- enhancement occurs.
- the results from the CD 14 blood measurement must be compared to the results of a standard blood sample from the mammal.
- the "standard" blood sample includes both a sample obtained absent administration of the test agent to the mammal, as well as a sample obtained after administration to the mammal of a known RCT-enhancing agent which is different from the test agent.
- the standard blood sample may be obtained absent the physical or behavioral inducer (for example, a blood sample from a rested state or before the start of a weight-loss diet) or it could be obtained after a different type of physical or behavioral activity for comparison of results, such as a standard blood sample obtained after physical exercise or a weight-loss diet that is different from the tested agent.
- the physical or behavioral inducer for example, a blood sample from a rested state or before the start of a weight-loss diet
- a different type of physical or behavioral activity for comparison of results such as a standard blood sample obtained after physical exercise or a weight-loss diet that is different from the tested agent.
- the known RCT-enhancing agent also referred to herein as a standard RCT-enhancing agent
- the test agent must be a different agent than the standard RCT-enhancing agent that is administered to obtain the standard blood sample.
- test blood sample and the standard blood sample are obtained and measured is a matter of choice and is not intended to be limited to any particular order.
- one embodiment of this invention is a method for evaluating the efficacy of a reverse cholesterol transport-enhancing test agent in a mammal comprising: measuring the level of CD 14 protein present in a sample of the mammal's blood absent administration of the test agent to obtain one CD 14 protein measurement; measuring the level of CD 14 protein present in a sample of the mammal's blood after administration of the test agent to obtain a second CD14 protein measurement; and comparing the two CD 14 protein measurements to determine if the measurement obtained after test agent administration is greater than the measurement obtained absent test agent administration; and wherein the CD14 protein is selected from sCD14 and mCD14 and is the same for both measurements.
- Another embodiment of this invention is a method for determining relative efficacy for a reverse cholesterol transport-enhancing test agent in a mammal comprising: measuring the level of CD14 protein present in a sample of the mammal's blood after administration of a standard RCT-enhancing agent to obtain one CD14 protein measurement; measuring the level of CD 14 protein present in a sample of the mammal's blood after administration of the test agent to obtain a second CD 14 protein measurement; and comparing the two CD14 protein measurements to determine the relative efficacy of the test agent as compared to that of the standard RCT-enhancing agent; and wherein the CD14 protein is selected from sCD14 and mCD14 and is the same for both measurements.
- the methods of this invention are useful for evaluating efficacy of any agents having reverse cholesterol transport-enhancing activity and those agents which are desired to be screened for such activity.
- classes of agents that could be screened include but are not limited to compounds such as LXR ligands, human peroxisome proliferator activated receptor (PPAR) agonists, including agonists of PPAR ⁇ , PPAR ⁇ and PPAR ⁇ as well as agonists having activity for one or more of the PPAR subtypes, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors including ACAT-1 (sometimes referred to as ACAT I), described in U.S.
- PPAR human peroxisome proliferator activated receptor
- HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
- ACAT acyl-coenzyme A:cholesterol acyl
- Patent No. 5,834,283, and ACAT-2 (sometimes referred to as ACAT U), described in WO 97/45439, fish oils, vitamins such as nicotinic acid (vitamin B3), niacinamide and analogs thereof, and alcohols such as ethanol.
- LXR includes all subtypes of this receptor and corresponding genes which encode such subtypes. Specifically LXR includes LXR ⁇ and LXR ⁇ , and ligands of LXR include agonists and antagonists of LXR ⁇ and/or LXR ⁇ .
- LXR ⁇ has been referred to under a variety of names and for purposes of this application LXR ⁇ should be understood to mean any gene referred to as LXR ⁇ , LXRa, LXRalpha, RLD- 1, NR1H3 or a gene with homology to accession number U22662 or a protein with homology to a protein encoded by such a polynucleotide.
- LXR ⁇ should be understood to include any gene referred to as LXRb, LXR ⁇ , LXRbeta, NER, NER1, UR, OR-1, R1P15, NR1H2 or a gene with homology to accession number U07132 or a protein with homology to a protein encoded by such a polynucleotide.
- LXR ligands can be identified by published procedures such as described in Zhou et al (1998), Molecular Endo, 12: 1594-1604, herein incorporated by reference. LXR ligands include compounds such as 22(R)-hydroxycholesterol, 20(S)-hydroxycholesterol and 25-hydroxycholesterol, all well known for their LXR activity.
- PPAR agonists are well known in the art and can be identified by known assays.
- Examples of PPAR ⁇ agonists include compounds commonly referred to as glitazones, for example troghtazone, pioglitazone and rosightazone, as well as those compounds included within the structural class known as thiazolidinediones, in addition to those PPAR ⁇ agonists outside the thiazolidinedione structural class.
- PPAR ⁇ agonists include, for example the fibrate class of compounds such as clofibrate, fenofibrate and gemfibrozil.
- PPAR ⁇ and PPAR ⁇ agonists can be identified, for example, by the assay described in.
- PPAR ⁇ agonists can be identified, for example, by the assays described in WO97/28149 published August 7, 1997, herein incorporated by reference, which also provides examples of PPAR ⁇ agonists.
- Compounds that have inhibitory activity for HMG-CoA reductase can be readily identified using assays well known in the art. For example, see the assays described or cited in U.S. Patent 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33, herein incorporated by reference.
- HMG-CoA reductase inhibitors include but are not limited to compounds known as "statins" which are part of a structural class of compounds that contain a moiety which can exist as either a 3-hydroxy lactone ring or as the corresponding 3,5-dihydroxy open-acid.
- HMG-CoA reductase inhibitors encompass statins in their lactonized and their dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof.
- Examples of HMG-CoA reductase inhibitors of the statin class include but are not limited to lovastatin (see US Patent No. 4,342,767); simvastatin and dihydroxy open-acid simvastatin (see US Patent No. 4,444,784); pravastatin (see US Patent No.
- Compounds which have inhibitory activity for ACAT can be readily identified using assays well-known in the art, for example as described in Chang C.C., Lee C.Y., Chang, E.T., Cruz, J.C., Levesque, M.C., Chang, T.Y.: J. Biol. Chem. 273:35132-35141 (1998), Recomhinant acyl-CoA: cholesterol acyltransf erase- 1 (ACAT-1) purified to essential homogeneity utilizes cholesterol in mixed micelles or in vesicles in a highly cooperative manner, herein incorporated by reference.
- ACAT inhibitors include but are not limited to compounds described in U.S. Patent No.'s 5,120,738; 5,340,807; 5,475,130; 5,668,136; 5,760, 087; and additionally described in published patent applications WO96/26925; WO97/16184; EP 0 635 501 Al (European Application No. 94305305.8)Sliskovic, D.R., CI-1011 : An atypical ACAT inhibitor with antiatherosclerotic activity, Proceedings, XTVth International Symposium on Medicinal Chemistry, F. Awouters (editor) Elsevier Science B.V., 433-441 (1997); and Tanaka, A.
- [ 3 H] cholesterol-labeled THP-1 cells were incubated with increasing concentrations of sCD14, apo A-I or the control protein, HSA, and radioactivity in the supernatant was determined.
- the initial rate of cholesterol efflux was explored in studies of short duration (30 min, Fig. la and with extended dose response in Fig. lb).
- sCD14 strongly potentiated cholesterol efflux with a potency similar to that of apo A-I in 30 min assays.
- the efflux of cholesterol to apo A-I is saturable at 10-20 ⁇ g / ml (Fig. la and lb)
- CD14-mediated cholesterol efflux in 30 min assays did not show saturation even up to 100 ⁇ g/ml (Fig. lb). Because of the linear dose-dependence of sCD14-mediated efflux and because no other cholesterol acceptor was present in the incubation, these observations appear most consistent with a direct, low affinity binding of cholesterol to sCD14.
- sCD14 per se is unlikely to be a significant reservoir or destination for the cholesterol in plasma.
- sCD14 employed a macrophage-like cell line (THP-1) which expresses mCD14.
- THP-1 macrophage-like cell line
- mCD14 also contributes to lipid export to apo A-I
- monoclonal and polyclonal anti-CD14 antibodies were incubated with THP-1 cells, and apo A-I-dependent lipid efflux was measured.
- Fig. 4a two anti-CD14 mAb, MY4 and UCH-M1, and polyclonal anti- CD14 each inhibited cholesterol efflux from THP-1 cells to apo A-I by 34-39 %.
- Parallel studies showed similar but somewhat weaker inhibition of phospholipid efflux by these antibodies (Fig. 4b).
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02725010A EP1401456A4 (en) | 2001-02-21 | 2002-02-19 | Method fron determining the efficacy of reverse cholesterol transport enhancing agents |
CA002438899A CA2438899A1 (en) | 2001-02-21 | 2002-02-19 | Method for determining efficacy of reverse cholesterol transport enhancing agents |
US10/467,760 US20040071633A1 (en) | 2002-02-19 | 2002-02-19 | Method for determining efficacy of reverse cholesterol transport enhancing agents |
JP2002567324A JP2004527737A (en) | 2001-02-21 | 2002-02-19 | Methods for determining the efficacy of reverse cholesterol transport enhancers |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27035601P | 2001-02-21 | 2001-02-21 | |
US60/270,356 | 2001-02-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002067958A1 true WO2002067958A1 (en) | 2002-09-06 |
Family
ID=23030997
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2002/005722 WO2002067958A1 (en) | 2001-02-21 | 2002-02-19 | Method for determining efficacy of reverse cholesterol transport enhancing agents |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1401456A4 (en) |
JP (1) | JP2004527737A (en) |
CA (1) | CA2438899A1 (en) |
WO (1) | WO2002067958A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756067A (en) * | 1993-11-08 | 1998-05-26 | Peptide Delivery Systems Pty Ltd | Labelled diagnostic compositions and method of their use |
US6040147A (en) * | 1997-04-02 | 2000-03-21 | The Brigham And Women's Hospital, Inc. | Systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases and as tools to aid in the selection of agents to be used for the prevention and treatment of atherosclerotic disease |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6120994A (en) * | 1997-05-23 | 2000-09-19 | Queen's University At Kingston | Antioxidant responsive element |
-
2002
- 2002-02-19 WO PCT/US2002/005722 patent/WO2002067958A1/en not_active Application Discontinuation
- 2002-02-19 EP EP02725010A patent/EP1401456A4/en not_active Withdrawn
- 2002-02-19 CA CA002438899A patent/CA2438899A1/en not_active Abandoned
- 2002-02-19 JP JP2002567324A patent/JP2004527737A/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5756067A (en) * | 1993-11-08 | 1998-05-26 | Peptide Delivery Systems Pty Ltd | Labelled diagnostic compositions and method of their use |
US6040147A (en) * | 1997-04-02 | 2000-03-21 | The Brigham And Women's Hospital, Inc. | Systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases and as tools to aid in the selection of agents to be used for the prevention and treatment of atherosclerotic disease |
Non-Patent Citations (1)
Title |
---|
See also references of EP1401456A4 * |
Also Published As
Publication number | Publication date |
---|---|
EP1401456A4 (en) | 2005-04-20 |
EP1401456A1 (en) | 2004-03-31 |
JP2004527737A (en) | 2004-09-09 |
CA2438899A1 (en) | 2002-09-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Thieringer et al. | Activation of peroxisome proliferator-activated receptor γ does not inhibit IL-6 or TNF-α responses of macrophages to lipopolysaccharide in vitro or in vivo | |
Kurtz et al. | Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin–angiotensin system | |
Ali et al. | Rosiglitazone causes bone loss in mice by suppressing osteoblast differentiation and bone formation | |
Berger et al. | Distinct properties and advantages of a novel peroxisome proliferator-activated protein γ selective modulator | |
Chapman | Fibrates in 2003: therapeutic action in atherogenic dyslipidaemia and future perspectives | |
Majai et al. | PPARγ‐dependent regulation of human macrophages in phagocytosis of apoptotic cells | |
Lewiecki et al. | Two‐year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD | |
Van Wijk et al. | Rosiglitazone improves postprandial triglyceride and free fatty acid metabolism in type 2 diabetes | |
Fiorucci et al. | Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor γ contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis | |
Mudaliar et al. | New oral therapies for type 2 diabetes mellitus: the glitazones or insulin sensitizers | |
Westhuyzen et al. | Biology and relevance of C-reactive protein in cardiovascular and renal disease | |
Toomey et al. | Profound resolution of early atherosclerosis with conjugated linoleic acid | |
Walcher et al. | C-Peptide induces Chemotaxis of Human CD4-Positive cells: involvement of Pertussis toxin–sensitive G-Proteins and phosphoinositide 3-Kinase | |
Broom et al. | Characterization of N-(adamantan-1-ylmethyl)-5-[(3R-aminopyrrolidin-1-yl) methyl]-2-chloro-benzamide, a P2X7 antagonist in animal models of pain and inflammation | |
Uluçkan et al. | CD47 regulates bone mass and tumor metastasis to bone | |
Harrity et al. | Muraglitazar, a novel dual (α/γ) peroxisome proliferator–activated receptor activator, improves diabetes and other metabolic abnormalities and preserves β-cell function in db/db mice | |
Candido et al. | Human full-length osteoprotegerin induces the proliferation of rodent vascular smooth muscle cells both in vitro and in vivo | |
Davies et al. | Unique ability of troglitazone to up-regulate peroxisome proliferator-activated receptor-γ expression in hepatocytes | |
Dalbeth et al. | The non-thiol angiotensin-converting enzyme inhibitor quinapril suppresses inflammatory arthritis | |
Sherratt et al. | Role of omega-3 fatty acids in cardiovascular disease: the debate continues | |
Zhu et al. | CETP inhibition improves HDL function but leads to fatty liver and insulin resistance in CETP-expressing transgenic mice on a high-fat diet | |
Cui et al. | Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo | |
Han et al. | Lysophosphatidylcholine up-regulates CXCR4 chemokine receptor expression in human CD4 T cells | |
Kones et al. | Current treatment of dyslipidemia: evolving roles of non-statin and newer drugs | |
Kolovou et al. | Postprandial hypertriglyceridaemia revisited in the era of non-fasting lipid profile testing: a 2019 expert panel statement, narrative review |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002725010 Country of ref document: EP Ref document number: 10467760 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2438899 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002567324 Country of ref document: JP |
|
WWP | Wipo information: published in national office |
Ref document number: 2002725010 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2002725010 Country of ref document: EP |