EP1499357A1 - Traitement du syndrome metabolique - Google Patents

Traitement du syndrome metabolique

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Publication number
EP1499357A1
EP1499357A1 EP03725104A EP03725104A EP1499357A1 EP 1499357 A1 EP1499357 A1 EP 1499357A1 EP 03725104 A EP03725104 A EP 03725104A EP 03725104 A EP03725104 A EP 03725104A EP 1499357 A1 EP1499357 A1 EP 1499357A1
Authority
EP
European Patent Office
Prior art keywords
insulin
growth hormone
treatment
patients
sensitising agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03725104A
Other languages
German (de)
English (en)
Inventor
Bernhard Saller
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Health AB
Original Assignee
Pfizer Health AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0209642A external-priority patent/GB0209642D0/en
Priority claimed from GB0218912A external-priority patent/GB0218912D0/en
Application filed by Pfizer Health AB filed Critical Pfizer Health AB
Publication of EP1499357A1 publication Critical patent/EP1499357A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the invention relates to the treatment of metabolic syndrome.
  • Metabolic syndrome is a cluster of health problems rather than a single disease. Multiple interrelated abnormalities in glucose and lipid metabolism result in insulin-resistant hyperglycemia, hyperinsulinemia, a high triglyceride (TG) level, a low high-density lipoprotien cholesterol (HDL-C) level and abdominal or visceral obesity.
  • the abnormalities seem to be connected by insulin resistance, that is a reduced sensitivity of the tissues of the body to the action of insulin, caused by visceral obesity.
  • the body compensates for this state by secreting more insulin from the pancreas, hence causing hyperinsulinemia.
  • Type II diabetes can develop when the pancreas is unable to sustain this level of insulin secretion.
  • the high insulin levels in the blood also contribute to abnormalities in blood lipids, that is triglycerides and cholesterol.
  • the consequences of metabolic syndrome are perhaps more important than its causes.
  • the syndrome is characterised by glucose intolerance; abnormal cholesterol and triglyceride levels, in particular there is usually a reduction in HDL-C; and upper body obesity. All of these features are independent high risk factors for cardiac disease. Individually each substantially increases the risk of cardiac disease, but in combination the effect is dramatic. The result is a great increase in the risk of hypertension, atherosclerotic changes and myocardial infarction.
  • other resulting conditions include, as mentioned, Type II diabetes which can have such resultant problems as microangiopathy, neuropathy, retinopathy and nephropathy; and Polycystic Ovaryian Syndrome (PCOS) in women.
  • PCOS is characterised by ovarian cysts, high androgen levels, hirsuitism and infertility. Women with PCOS have an increased risk of endometrial cancer.
  • rhGH used in patients with central obesity, however, may be limited by an increase in insulin resistance which is known to occur during the early course of rhGH therapy. This may be of particular importance in metabolic syndrome patients who are characterized by a highly increased risk to develop type 2 diabetes.
  • Metformin is a biguanide, which improves glycaemic control by enhancing insulin sensitivity in the liver and in muscles. It does not stimulate insulin secretion.
  • metabolic syndrome is an important disorder which can result in serious cardiovarcular disease. Whilst metabolic syndrome may be improved by lifestyle changes, for example to diet and exercise levels, what is required is a pharmacological treatment which can be used to help combat this dangerous syndrome.
  • the inventors have surprisingly found that the combination of growth hormone (GH) and an insulin sensitising agent, for example, metformin provides a beneficial treatment for patients suffering from metabolic syndrome.
  • GH growth hormone
  • an insulin sensitising agent for example, metformin
  • the invention provides a pharmaceutical composition comprising growth hormone and an insulin sensitising agent, for use in the treatment of metabolic syndrome.
  • the composition may be in combination with one or more pharmaceutically acceptable carriers.
  • the GH is recombinant human GH.
  • analogue we mean a substance having the same biological activity as described here and having at least 65%, preferably 75%, most preferably 85% homology with naturally occurring growth hormone.
  • the insulin sensitising agent is preferably a biguanide, most preferably metformin.
  • Alternative insulin sensitising agents include PPAR gamma insulin sensitising agents and thiazolodeniones, for example the troglitazone and rosiglitazone families. However, this list is not exclusive.
  • Insulin sensitising agents that are known, or are under development include:
  • V411 (DIABH®, Glaucanin) Pioglitazone (ACTOS, AD 4833, U 72107, U 72107A, U 72107E, ZACTOS®)
  • Rosiglitazone (Avandia®, BRL 49653, BRL 49653C) Chemical Name: 2,4
  • HQL 975 Chemical Name: 3-[4-[2-(5-Methyl-2-phenyloxazol-4-yl) ethoxy]phenyl]-2(S)-(propylamino) propionic acid; YM 268, Chemical Name: 5,5'-Methylene-bis(l,4- ⁇ henylene)bismethylenebis (thiazolidine-2,4-dione) .
  • PPAR agonists under development include:
  • KRP 297 Chemical Name: 5-(2,4-Dioxothiazolidin-5-ylmethyl)-2-methoxy-N-[4-(trifluoromethyl) benzyl]benzamide;
  • a further aspect of the invention provides the use of a growth hormone or analogue thereof and an insulin sensitising agent in the preparation of a pharmaceutical composition to reduce waist circumference.
  • the invention also provides the use of growth hormone or analogue and an insulin sensitising agent in the preparation of pharmaceutical compositions for the treatment of metabolic syndrome.
  • the insulin sensitising agent reduces the insulin antagonist action of the growth hormone.
  • the invention further provides a method of treatment of metabolic syndrome comprising the step of administering an insulin sensitising agent and growth hormone or analogue thereof to a patient suffering from metabolic syndrome.
  • the insulin sensitising agent and growth hormone may be administered simultaneously, or may be administered separately.
  • an insulin sensitising agent in the treatment of metabolic syndrome, in combination with treatment with growth hormone.
  • growth hormone in the treatment of metabolic syndrome, in combination with treatment with an insulin sensitising agent.
  • metformin is administered orally in the form of metformin hydrochlori.de tablets.
  • the preferred daily dose is in the range of 1000-2000 mg.
  • the tablets may be given in two doses daily or in extended-release form in one dose.
  • the growth hormone is preferably administered in a subcutaneous injection, the dose being individually regulated according to body weight and IGF-levels.
  • Figure 1 shows the baseline characteristics of 25 men with metabolic syndrome.
  • Figure 2 shows the lipid metabolism characteristics of the same 25 men with metabolic syndrome.
  • RM ANONA repeated measure analysis of variance
  • FIG. 4 Shows the changes over 18 months in BMI, total body fat, and waist circumference in the two groups of patients treated either with Metformin+GH or with Metformin+Placebo.
  • the Figure gives the results from the 14 patients who completed the study (mean ⁇ SEM).
  • Figure 5 Shows the change over 18 months in fasting plasma glucose and area under the curve (AUC) of glucose during oGTT in the two groups of patients treated either with Metformin+GH or with Metformin+Placebo.
  • FIG. 6 Shows the percentage change in glucose disposal rate (GDR) in the two groups of patients treated either with Metformin+GH or with Metformin+Placebo.
  • rhGH recombinant human Growth Hormone
  • 25 non-smoking men with metabolic syndrome were selected to complete the study.
  • the patients had a body mass index (BMI) between 30-40 kg/m2, fasting plasma glucose levels without antidiabetic medication of between 110 mg/dl (6.1 mmol/1) and 145 mg/dl (8.0 mmol/1), and HbAlc ⁇ 7.5%.
  • Hypertension if present, was treated by angiotensin converting enzyme inhibitors or angiotensin LI receptor antagonists.
  • Antihypertensive drug therapy was kept stable during the study period. Lipid-lowering medication, the use of drugs to reduce body weight such as orlistat or sibutramine, and the use of glucocorticoids was not allowed during the study period. The same was true for any medication influencing growth hormone levels.
  • COPD Chronic obstructive pulmonary disease
  • Cardiovascular or cerebrovascular events Suspicion of malignant disease; - Development of severe diabetes mellitus requiring insulin therapy;
  • RhGH was supplied in vials, each containing I.E. of rhGH by Pharmacia & Upjohn, hi accordance with the randomisation list, indistinguishable placebo vials were given to patients from the placebo group as a single subcutaneous injection before bedtime.
  • RhGH and placebo were stored in a secure refrigerator at 2-8°C.
  • ECG 12-lead electrocardiogram
  • Laboratory assessment see below
  • GHRH/arginine-test
  • ECG 12-leas electrocardiogram
  • Laboratory assessments see below
  • Oral glucose tolerance test
  • the test was carried out according to the following protocol: 1 ⁇ g/kg. i.v. Somatorelin (GHRH Ferring® at 0 min);
  • Euglycemic-hyperinsulinemic clamp test was performed based on the protocol of De Fronzo, et al. Prior to insulin clamp study, all subjects consumed a diet containing at least 200 g. of carbohydrate per day for 3 days. The studies were performed at 8 a.m. after a 12-h overnight fast. A polyethylene catheter was inserted into an antecubital vein for infusion of insulin and 20% dextrose. A second catheter was inserted into a hand vein and the hand was heated during the study to ensure arterialization of venous blood. All blood samples for glucose and hormone analyses were drawn from the heated hand catheter, h sulin-mediated glucose disposal was determined by the euglycemic insulin clamp technique.
  • Human insulin was administered as a continuous infusion (40 mU/m 2, min) for 180 min. Plasma glucose concentration was measured every 5 min. Infusion of 20% dextrose was not begun until 5 min. after the initiation of insulin infusion and was periodically adjusted to maintain the arterialized plasma glucose concentrations at 95 mg/dl. Blood samples for determination of serum insulin concentrations were collected before insulin infusion was started and after 120 and 180 min.
  • peripheral glucose utilisation is equal to the rate of glucose infusion to maintain euglycemia.
  • the final 60 min. of the infusion period (between 120 and 180 min.) was used for determination of peripheral glucose utilisation. Data are expressed in milligrams per kilogram fat free mass per minute.
  • Serum GH levels were determined by a chemiluminescence immunometric assays (Nichols Institute Diagnostics GmbH , Bad Nauheim, Germany). The assay was calibrated against the WHO 1 st international standard (80/505) for human GH. ftitra- and interassay coefficients of variation (Cvs) for a low point of the standard curve were 5.4% and 7.9%, respectively. Plasma IGF-I concentrations were measured by an immunoradiometric assay (Nichols Institute Diagnostics GmbH, Bad Nauheim, Germany). The assay was calibrated against the WHO 1 st International Reference Reagent 87/518.
  • ⁇ ntra- and interassay Cvs for low IGF-I concentrations were 2.4% and 5.2%, respectively, hi our laboratory the normal IGF-I ranges were 114-492 ⁇ g/L for adults aged 25-39 yr, 90-360 ⁇ g/L for adults aged 40-54 yr, and 71-290 ⁇ g/L for adults aged > 55 yr.
  • Plasma glucose was determined by the glucose oxidase method (glucose autoanalyzer, EBIO 6666, Eppendorf, Germany). Plasma insulin levels were assessed by radioimmunoassay (Biochem Immunosystems, Freiburg, Germany). HbAlc was determined by DCA 2000 (Bayer, Leverkusen, Germany, upper limit 6.3%). Total testosterone was measured by an automated chemiluminescence immunoassay (ACS 180, Bayer diagnostics, Fernwald, Germany).
  • Red blood cell counts, white blood cell counts, serum levels of sodium, potassium, creatinine, liver enzymes, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, lipoprotein (a) (Lp(a)), apolipoprotein Al, apolipoprotein B, fibrrnogen, and prostate specific antigen were determined by routine methods.
  • the data if not marked otherwise, represent the mean ⁇ standard deviation (SD). Comparisons between baseline values of the two groups were performed using the unpaired Wilcoxon/Mann/Whitney test (WMW). Absolute differences between time points were analyzed per group using the paired Wilcoxon signed rank test (WSR). The areas under the curve of glucose and insulin were determined per times. For those AUC measures as for BMI and total body fat time courses were compared by repeated measure analysis of variance (RM ANON A). Occurrence of side effects were compared by chi-square test (CHI). All p-values were given unadjusted and therefore interpreted explorative. All tests were conducted at a two-sided significance level at 5%.
  • Met+GH group 12.5 mg/d hydrochlothiazide (12.5 mg/die) and 60 mg/d metoprolol
  • Met+Placebo group amlodipine 10 gm/d; quinalapril 10 mg plus hydrochlorthiazide 12.5 mg/d and benazepril 10 mg/d).
  • Max 34,6 33,8 34,3 35,1 35,0 34,7 mean 32,2 31,0 31,1 31,1 31,1 30,9
  • Max 41,2 41,2 39,0 38,2 39,7 38,3 mean 33,7 33,5 32,9 32,3 32,7 32,5 t° 3,8 3,9 3,3 3,0 3,6 3,0
  • Max 1,08 1,42 mean 0,89 1,15 kD 0,12 0,19
  • V7b are data collected 4 weeks after withdrawal of GH / placebo
  • Max 190 262 234 244 202 223 222 mean 144 149 151 172 159 160 173
  • Max 251 485 490 501 500 563 244 mean 173 379 412 434 400 425 172 r* 58 60 83 61 95 138 41
  • N7b are data collected 4 weeks after withdrawal of GH / placebo Table 10
  • Glucose tolerance test Glucose 0 min (mmol 1)
  • Max 6,77 6,77 6,66 7,16 6,77 6,11 mean 5,92 6,14 6,25 6,68 6,20 5,84 D 0,66 0,37 0,28 0,38 0,45 0,20
  • Glucose tolerance test Glucose 60 min (mmol/1)
  • Max 15,71 17,37 16,54 16,38 16,04 15,10 mean 11 ,12 12,17 11 ,78 12,09 11 ,17 10,94
  • Glucose tolerance test Glucose 120 min (mmol/1)
  • Glucose tolerance test Glucose AUC (mmol/1 120 min)
  • Max 1417 1515 1366 1505 1419 1226 mean 1005 1116 1150 1186 1061 1028 D 257 241 154 203 180 202
  • Max 115,5 230,3 514,4 200,2 370,9 246,1 mean 79,8 117,3 154,2 104,4 129,9 140,3
  • Max 295,6 495,1 278,4 238,9 414,7 478,6 mean 186,3 226,7 189,8 172,4 188,9 247,0 r D 85,9 134,1 82,2 58,1 120,8 135,4
  • Max 2903,7 2874,3 1908,6 2128,1 2340,5 2337,6 mean 1941 ,5 1803,8 1375,7 1281,3 1513,4 1647,1 f D 843,6 779,5 476,2 507,0 700,6 577,4
  • Max 1018,1 1435,0 1972,4 2031 ,2 1380,5 1881 ,3 mean 504,1 701 ,0 771 ,7 701 ,6 516,4 778,2
  • Max 4734,8 5237,8 3935,5 2019,0 2888,7 3511 ,4 mean 1681,8 1963,7 1905,2 1266,4 1358,0 1706,8 r° 1770,7 1944,7 1537,2 725,0 1238,4 1153,9
  • Max 117527 147016 247602 164537 139999 183070 mean 79092 81337 107204 88240 80316 98028
  • Glucose disposal (mg/kg/min) (euglycemic hyperinsulinemic clamp)
  • Max 50,09 42,49 35,58 36,60 mean 34,06 30,55 29,91 29,60
  • GDR the slight increase in GDR seen in patients treated with metformin and rhGH is most probably due to changes of body composition with a preferential reduction in visceral adipose depots associated with the reduction in visceral adipose depots associated with the reduction of waist circumference, hi addition, GDR might have been influenced by the slight increase of skeletal muscle mass seen in the rhGH treated group.
  • Dyslipoproteinemia is one of the major characteristics of the metabolic syndrome and a central finding in patients with growth hormone deficiency.
  • the increase of HDL-cholesterol may be influenced by the additional administration of rhGH.
  • the increase of lipoproteins were also similar in both groups. This observation might indicate an rhGH independent effect, even though rhGH may increase Lp(a).
  • the increase of lipoproteins in the group treated with metformin alone remains speculative, even though some previous trials could not demonstrate an effect of metformin on lipoprotein levels.
  • the dropout rate was similar in the two treatment groups and most of the dropouts were due to non-compliance. Since most of the dropouts due to non-compliance occurred after the first 12 months of treatment, the high dropout rate is partly due to the study design including double blind sc injections over a period of 18 months.
  • the present study demonstrates that in patients with metabolic syndrome and impaired FPG levels, and 18-month treatment with metformin in combination with rhGH was not associated with sustaining negative effects on glucose metabolism and was even more effective in reducing waist circumference than treatment with metformin alone.
  • an insulin sensitising agent for example metformin
  • metformin might be an effective therapeutic approach in high risk patients with central obesity and that treatment with metformin might be effective in reducing the insulin antagonistic effects of rhGH.
  • Rotondi M Pietrosante M, Lombardi G, Bellastella A, Carella C, Colao A

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'une hormone de croissance ou d'un analogue de celle-ci avec un sensibilisateur à l'insuline (par exemple la metformine) dans le traitement du syndrome métabolique.
EP03725104A 2002-04-26 2003-04-24 Traitement du syndrome metabolique Withdrawn EP1499357A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB0209642 2002-04-26
GB0209642A GB0209642D0 (en) 2002-04-26 2002-04-26 Metabolic syndrome
GB0218912 2002-08-14
GB0218912A GB0218912D0 (en) 2002-08-14 2002-08-14 Metabolic syndrome
PCT/EP2003/004357 WO2003090784A1 (fr) 2002-04-26 2003-04-24 Traitement du syndrome metabolique

Publications (1)

Publication Number Publication Date
EP1499357A1 true EP1499357A1 (fr) 2005-01-26

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP03725104A Withdrawn EP1499357A1 (fr) 2002-04-26 2003-04-24 Traitement du syndrome metabolique

Country Status (11)

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EP (1) EP1499357A1 (fr)
JP (1) JP2005523915A (fr)
KR (1) KR20040101545A (fr)
CN (1) CN1646167A (fr)
AU (1) AU2003227683A1 (fr)
BR (1) BR0309375A (fr)
CA (1) CA2483005A1 (fr)
IL (1) IL164670A0 (fr)
MX (1) MXPA04010544A (fr)
PL (1) PL372900A1 (fr)
WO (1) WO2003090784A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10231976B2 (en) * 2010-02-08 2019-03-19 Prairie Pharmaceuticals LLC Methods for the use of progestogen as a glucocorticoid sensitizer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03090784A1 *

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Publication number Publication date
BR0309375A (pt) 2005-03-29
AU2003227683A1 (en) 2003-11-10
PL372900A1 (en) 2005-08-08
MXPA04010544A (es) 2005-08-16
CN1646167A (zh) 2005-07-27
IL164670A0 (en) 2005-12-18
WO2003090784A1 (fr) 2003-11-06
JP2005523915A (ja) 2005-08-11
KR20040101545A (ko) 2004-12-02
CA2483005A1 (fr) 2003-11-06

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