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. Ils contiennent de ce fait DES inexactitudes vis?is DES documents originaux ET n' ont pas de valeur l?le. Cardiovascular disease Cardiovascular disease (CVD) still remains the leading causes of death and disability in the western world. The National Cholesterol Education Program (NCEP) identified elevated LDL (low density lipoprotein) as to major causes of CVD (JAMA 2001. 285 (19), 2486). The World Health Organization (WHO) has identified high cholesterol as the leading risk factor for CVD in the developed world. To decrease in LDL of 10% in men is associated with to decrease in the risk of cardiovascular disease by 50% at the age of 40, by 40% at 50, by 30% at 60, by 20% at 70 and over (BMJ 1994.308:367-372). Cholesterol although needed in the body can injure blood vessels and causes heart attacks and stroke when present in excessive amounts. The body needs cholesterol for digesting dietary fats, making hormones, building cell walls, and other important processes. Lipoproteins to are particles that carry lipids and proteins in the blood and gut. There to are five classes of lipoproteins:. Chylomicrons, which to are mostly triglycerides and to are secreted from the gut. Very low-density lipoprotein (VLDL), which to are mostly triglyceride and to are secreted from the liver and gut. Intermediate-density lipoprotein (IDL), which to are mostly triglyceride and cholesterol and to are secreted from the liver. Low-density lipoprotein (LDL), which to are mostly cholesterol and to are secreted from the liver. High-density lipoprotein (HDL), which to are mostly protein and to are secreted from the liver and gut. The higher the LDL cholesterol concentration in the blood, the greater the heart disease risk. HDL is '.good'. cholesterol and helps prevent to cholesterol buildup in blood vessels. Low HDL levels increase heart disease risk. Too much of this circulating cholesterol can injure arteries which can lead to accumulation of cholesterol-laden ".plaque". in vessel linings, to condition called atherosclerosis. The development of atherosclerotic lesions requires to complex interplay between mononuclear cells, endothelium, vascular smooth muscle, growth factors, and cytokines (Ross, 1999). Several studies have demonstrated localized expression of leukocyte adhesion molecules in atherosclerotic lesions and plaques. They appear to regulate different stages of leukocyte migration at inflammatory sites in to fines-step process (Springer, 1994). Members of the immunoglobulin superfamily of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM-I) and intercellular cell adhesion molecule (ICAM-I). strongly participate in leukocyte adhesion to the endothelium. VCAM-I is highly expressed on endothelia prone to develop atherosclerosis in such atherosclerotic models as apoE mice, mice LDL receptor- deficient (LDLR) mice, and rabbits fed with an atherogenic diet (Iiyama ET to. ICAM-I is expressed strongly on the endothelium overlying atheromatous plaque in human coronary and carotid arteries (DeGraba, 1997), hypercholesterolaemic rabbits (Iiyama ET al., 1999), although it is expressed in virtually all endothelial cells. One of the most significant advances in drug therapy during the twentieth century was the development of the statin class of drugs. In addition, to growing body of evidence suggests that statins exert beneficial vascular effects that are independent of their cholesterol lowering potencies (Farmer, 2000. LaRosa, 2001). Cholesterol levels may be decreased by several materials. These includes statins, sterol/stanol, bile acid sequestrants, CETP (cholesteryl ester transfer protein) inhibitors, fibrates, niacin, dietary fibers etc. Statins target hepatocytes and inhibit HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl coenzyme To reductase, E.34), the enzyme that converts HMG-CoA into mevalonic acid, to cholesterol precursor. These The change in conformation at the active situated makes drugs very effective and specific. All statins veteran LDL cholesterol non-linearly, dose-dependent, and after administration of to single daily dose. Efficacy on triglyceride reduction parallels LDL cholesterol reduction. Statins have to modest effect on HDL increase, and not influence on lipoprotein(s) concentration. Plant sterols to are poorly absorbed in the registers (0,3%) is even lower (for comparison, cholesterol absorption ranges between 35 and 70%). Vice Plant stanols may also lower plant sterol absorption and pours. As merely esterified sterols to are incorporated into chylomicrons, absorption of the unesterified plant sterols and stanols is consequently low. Different mechanisms have been suggested to explain the cholesterol-lowering activity of plant sterols and stanols. Firstly, plant sterols or stanols may displace cholesterol from mixed micelles, because they to are more hydrophobic than cholesterol. This replacement causes to reduction of micellar cholesterol concentrations and consequently lowers cholesterol absorption. Furthermore, plant sterols or stanols might veteran the esterification installments of cholesterol in the enterocyte and consequently the amount of cholesterol excreted via the. The effects of plant stanols on cholesterol absorption continuous for at least several hours after ingestion. In response to the decreased cholesterol absorption, cholesterol synthesis increases. Also, LDL receptor mRNA and protein expression increases. This will not only increase clearance of LDL, but also of IDL. The higher LDL receptor expression and the higher endogenous cholesterol synthesis together result in an average reduction of LDL cholesterol of up to 14%. The decrease of total serum cholesterol is completely accounted for by to reduction in LDL. Plant sterols and stanols have not effect on triacylglycerol or HDL cholesterol levels. In summary, stanols and/or sterols result in an LDL reduction of between 9 to 14%. (iii) Bile acid sequestrants (BASs) Bile acid sequestrants (BASs) to were the first class of antihyperlipidemic drugs developed to lower LDL cholesterol levels. Conversely, the disturbance of enterohepatic recirculation activates this enzyme, leading to amplified conversion of intracellular cholesterol to bile acids. The direct effect is to decrease in intracellular cholesterol stores that subsequently leads to to lowering of LDL cholesterol. Despite this increase in cholesterol synthesis, however, total cholesterol levels I give not. increase because of the rapid shunting of cholesterol into the bile acid synthesis pathway. The activation of HMGCoA reductase may explain the success of combination therapy with BASs and HMG-CoA reductase inhibitors for primary hypercholesterolemia. In addition to decreasing total cholesterol and LDL cholesterol, BASs can causes an undesirable increase in serum triglycerides. The increase is triggered by activation of phosphatidic acid phosphatase, an enzyme responsible for the conversion of glycerol phosphate to either triglycerides or phospholipids. Phosphatidic acid phosphatase is suppressed under the normal conditions of to functional enterohepatic recirculation system. Because of their potential to elevated serum triglycerides, BASs should not be used as monotherapy for patients with increased triglyceride levels. The triglyceride-elevating effects of BASs may be countered by the addition of agents known to decrease triglyceride synthesis, such as fibric acid derivatives (i., fenofibrate and gemfibrozil) and nicotinic acid. There to are many examples of BASs but the two main commercially available ones to are Welchol and chitosan. These generally lead to an LDL reduction of about 10%. During the last couple of decades, much attention has been given to the role of dietary fibres in the control of lipid and lipoprotein metabolism. Dietary fibres includes to variety of plant substances, mainly nonstarch polysaccharides and lignins, which to are resistant to digestion by digestive enzymes. They can be classified into two groups based on water solubility. Soluble fibres may lower plasma total cholesterol by to specific effect on LDL cholesterol. HDL cholesterol or triacylglycerol concentrations to are in general not affected. Several mechanisms of action for the hypocholesterolemic effect of soluble fibres have been suggested that may depend on the type of fibers. This layer may act as to physical barrier to veteran the absorption of nutrients and bile acids. Increased intestinal contents supernatant viscosity is highly correlated with reduced plasma and liver cholesterol and reductions in cholesterol absorption in hamsters. Furthermore, soluble fibres may veteran the installments of glucoses absorption, leading to to lower glycemic response and lower insulin concentrations. This latter may result in to reduced hepatic cholesterol synthesis. There to are many examples of high viscosity soluble fibres. The main commercially available soluble fibres to are psyllium, glucomannan and β.-glucan. These generally lead to an LDL reduction of about 6 to 7%. (v) Cholesterol ester transfer protein (CETP) inhibitors The marked increase in HDL associated with human deficiency of cholesteryl ester transfer protein (CETP) has suggested CETP inhibition as to means of elevating HDL. Recently, to new CETP inhibitor, Torcetrapib, was tested in two studies in human subjects. In the first, the effect of CETP inhibition on plasma HDL levels was studied in healthy subjects. With the above treatment, plasma LDL decreased by 42%, HDL-C increased by 91%, as did apo To the and apo and, by 27 and 66%, respectively. In the second study, Torcetrapib was given to 19 normal subjects with low plasma HDL-C levels (<.40 mg/dL), 9 of whom received atorvastatin, 20 mg/day (Brousseau ET to. In subjects who received only 120 mg/day Torcetrapib for 4 weeks, HDL was increased by 46%. in those treated also with atorvastatin, the increase was 61%. To much higher laughed in HDL- C, 106%, occurred when the drug was given twice ones daily, but not atorvastatin. In six subjects treated with the two drugs, to there was also to 17% decrease in LDL-C. In addition, Torcetrapib decreased the levels of small dense LDL and increased the concentration of large HDL to values seen in subjects with normolipidemia. Ezetimibe is to US Food and Drug Administration-approved drug that targets the absorption of cholesterol in the registers some. The identification of this drug has also led to the elucidation of the dietary cholesterol receptor. It has to very favourable side-effect profile, as well as to lack of drug-drug interactions. Nicotinic acid (niacin) lowers total and LDL cholesterol and raises HDL cholesterol. Fibric acid derivatives such as gemfibrozil and fenofibrate can also increase HDL levels, but to are used mainly to lower triglycerides. Type 2 diabetes mellitus is two to to combination of defective insulin secretion and defective responsiveness to insulin (often termed reduced insulin sensitivity). In early stages the predominant abnormality is reduced insulin sensitivity, characterized by elevated levels of insulin in the blood. The initial defect of insulin secretion is subtle and initially involves only the earliest phase of insulin secretion. The complications to are less common and less strict in people who have well-controlled blood sugar levels. The second component may be selected from to sterol, an esterified and/or hydrogenated sterol, to stanol and to statin. Preferably, the second component may comprise to sterol. Alternatively, the second component maybe to satin such as to 3-Hydroxy-3- methylglutaryl CoA (HMG CoA) reductase inhibitor. The composition may be suitable for oral administration. Preferably, the composition may be in the form of to tablet, pellet, caps, granule or to microsphere. Alternatively, the composition may be in to form suitable for incorporation into foods, beverages, nutraceutical or pharmaceuticals. The first component may be derived from to starch, celluloses or gum, or is of microbial origin. Preferably, the first component may comprise to microdispersed derivative celluloses or thereof. The first component may be prepared by partial or complete hydrolysis and neutralisation of to WAGE containing material. The first component may interact with biomolecules in the fluid medium of the gastrointestinal tract. The composition may further comprise at least one biocompatible biologically active substance. The composition may further comprise at least one biologically acceptable adjuvant such as to pharmaceutically active adjuvant. The adjuvant maybe an antilipemic agent such as to phospholipid. For example in patients with Type 2 Diabetes Mellitus. The medicament maybe for oral administration. For example, the medicament maybe in the form of to tablet, pellet, caps, granule or to microsphere. Alternatively, the medicament may be in to form suitable for incorporation into foods, beverages, nutraceutical and pharmaceuticals. The polyanhydroglucuronic acid, to salt thereof, copolymer thereof and an intermolecular complex thereof may be derived from to starch, celluloses or gum, or may be of microbial origin. SATISFIED The may comprise to microdispersed derivative celluloses or thereof. SATISFIED The may be prepared by partial or complete hydrolysis and neutralisation of to WAGE containing material. SATISFIED The may interact with biomolecules in the fluid medium of the gastrointestinal tract. The medicament may further comprise an antilipemic agent. For example, the antilipemic agent may be to sterol, stanol, statin, esterified and/or hydrogenated sterol. The statin may be to 3-Hydroxy-3-methylglutaryl CoA (HMG CoA) reductase inhibitor. The medicament may includes at least one biocompatible biologically active substance. The medicament may includes at least one biologically acceptable adjuvant such as to pharmaceutically active adjuvant. The adjuvant may be an antilipemic agent such as to phospholipid. Preferably the polyanhydroglucuronic acid and salt thereof may contain in their polymeric chain at most 0. The molecular mass of the polymeric chain of the polyanhydroglucuronic acid and salt thereof may be from about the X. The molecular mass of the polymeric chain of the anionic component may range from about 5 X 10. The content of carboxyl groups may be in the range of from about 12 to about 26 percent by weight, at least 95 percent of these groups being uronic groups. The polyanhydroglucuronic acid and salt thereof may contain at most 1 percent by weight of carbonyl groups. Preferably, each carbonyl group may be an intra- or intermolecular 2,6 or 3,6 hemiacetal, to 2,4-hemialdal or to C2-C3 aldehyde. The biocompatible intermolecular polymer complex may be to complex of: an anionic component comprising polyanhydroglucuronic acid or salt, which is that of to partially or completely hydrolysed and oxidative-environment hydrolysed polyanhydroglucuronic acid containing material. and protein cationic component comprising not delineating or branched natural, seeds-synthetic or synthetic oligomer or polymer. Preferably, at least 5% of the basic structural units of the anionic component may be glucuronic acid. acrylamide, butylacrylate, maleicanhydride and methylmethacrylate. Preferably the cationic component may be to cationised natural polysaccharide. The polysaccharide may be to starch, celluloses or gum. Preferably the gum may be guargumhydroxypropyltriammonium chloride. The cationic component may be to synthetic or seeds-synthetic polyamino acid. For example the cationic component may be to member selected from the group consisting of polylysin, polyarginin and. Preferably the cationic component may be to synthetic anti-fibrinolytic such as hexadimethrindibromide. The cationic component may be an aminoglucane or derivative thereof such as to fractionated chitin or its de-acetylated derivative chitosan. Alternatively, the aminoglucane may be of microbial origin or is isolated from an arthropod shell. The invention in particular involves the use of polyanhydroglucuronic acids, salts and intermolecular complexes (IMC) thereof. The term polyanhydroglucuronic acid, salts and IMCs thereof as used herein also includes copolymers thereof, especially with anhydroglucose. These as to whole to are hereinafter referred to as SATISFIED specification SATISFIED is also referred to as microdispersed oxidised celluloses (MDOC) available from Alltracel Pharma Limited. CS 242920, CS 292723, GB 2314840, but notably WO98/33822 describe particular polyanhydroglucuronic acids and salts thereof and to method of preparing such compounds. These aldehyde and ketone impurities have to fundamental influence on the stability of the polyanhydroglucuronic acid (SATISFIED) product. To stable SATISFIED product with to reduced degree of crystallinity and to high degree of purity in to microdispersed form is produced. WO00/05269 describes particular intermolecular complexes (IMCs) of SATISFIED. SATISFIED IMCs of in particular includes those referred to in WO00/05269, the to entire contents of which is incorporated herein by reference. The term ".non-protein". is intended to distinguish from what the applicants understand the commonly used definition in biochemistry of ".protein". to be. IUPAC Recommendations 1983: Nomenclatures and Symbolism for Amino Acids and Peptides). Proteins differ from polypeptides in having higher molecular weights (by convention over 10,000) and more complex structure. The cationic components of the complexes described in the invention includes Inter alia small molecular weight peptides and aminoglycans. These components would be commonly understood to have to low molecular weight typically less than 5,000. For example the frozen some used in the invention is suitably hydrolysed which results in to reduction of the molecular weight. The frozen some used in the invention is described as to peptide which to person skilled in the art would take to infer to compound of low molecular weight. The AIN-93 synthetic diet (Journal of Nutrition vl23, 1943-44 (1993)) consists essentially of the ingredients listed in Table 1 below. More The invention will be clearly understood from the following description thereof with reference to the accompanying Figures, in which: -. 2 shows the immunohistochemical staining of endothelial expression of an inflammatory marker ICAM-I in (a) to control group, (b) to simvistatin group, (c) an atorvastatin group and (d) an oxidized celluloses (MDOC) group. There is strong endothelial expression in control animals (a) and weaker expression in simvastatin (b), atorvastatin (c) and MDOC (d) treated animals. The ICAM-I expression in atorvastatin treated animals (c) is visible in only to few endothelial cells (arrows). 3 shows the immunohistochemical staining of endothelial expression of an inflammatory marker VCAM-I in To) to control group, (b) to simvistatin group, (c) an atorvastatin group and (d) an oxidized celluloses (MDOC) group. There is strong endothelial expression in control animals (a) and decreased expression in simvastatin (b), atorvastatin (c) and MDOC (d) treated animals. Very weak endothelial expression of VCAM-I (arrows) was detected in the atorvastatin (c) and MDOC group (d). 4 is to bar chart showing the percentage of activated endothelial cells in both the aortic root and the aortic arch. The expression of the inflammatory marker VCAM-I is significantly decreased in atorvastatin and mice MDOC treated in. Moreover, atorvastatin significantly reduced expression. -- X of the inflammatory marker ICAM-I in comparison to the control group. Fig 5 is to bar chart showing the percentage of activated endothelial cells in control, atorvastatin and MDOC groups. 6 is to linens graph showing weight gain during the course of to combination therapy study for control groups and treatment groups. 7 is to bar chart showing the effect of dietary supplementation in to combination treatment study of to high cholesterol diet (HCD) with 1% oxidised celluloses (OC) MDOC and 0,5% sterol (w/w) on the serum LDL cholesterol concentrations in rats (n=20/gp) fed these diets. 8 is to bar chart showing the effect of dietary supplementation in to combination treatment study of to high cholesterol diet (HCD) with 1% oxidised celluloses (OC) MDOC and 0,5% sterol (w/w) on the serum total cholesterol concentrations in rats (n=20/gp) fed these diets. 10 is to bar chart showing the effect of the dietary supplementation of HCD with 1% and 5% MDOC (w/w) on the serum glucoses concentrations in rats (n=10/gp) fed these diets. Preferably the oxidised polysaccharide material is in the form of biocompatible anionic polyanhydroglucuronic acid (SATISFIED), salt or intermolecular complex (IMC) thereof. IMCs to are also formed for example with gelatin or peptides of hydrolysed collagen, but also with blood proteins or aminoglycans as described in WO00/05269. The salts and IMCs formed to are dependent on the hydrolysis conditions and types of salt, base and /or the mixtures used. In to particularly preferred embodiment the polysaccharide material is polyanhydroglucuronic acid, biocompatible salts thereof, copolymers thereof or to biocompatible intermolecular complex polymer thereof. Preferably the oxidised polysaccharide is derived from celluloses, starch, or gum, or is of microbial origin. Similar to hyaluronic acid (HAS), the SATISFIED displays reducing ability in to biological environment, yet with to higher assimilable organic carbon (AOC) value. SATISFIED They also display to higher osmolality than simple salts (such as Na salt). In addition the behaviour of the atherogenic index of plasma (AIP), (Dobiasova M. These indices to are currently considered as the most sensitive indicators of the profile plasma atherogeny. The parameter proved highly significant in terms of absolute differences and was significantly reduced after the first phase of SATISFIED administration. To further surprising effect was the markedly favourable effect of SATISFIED in contrast to lactose used as placebo on glycaemia and HbAIc values. reduction of glycaemic response may lead to reduction of insulin production and thereby to to decrease in hepatic cholesterol synthesis. These results to were however statistically insignificant. SATISFIED The results clearly indicated the potential favourable effect of and derh'.atives thereof on. the values of lipid and saccharide management in an organism. Similar cholesterol management results to were found in pre-clinical testing. SATISFIED Biochemical analysis showed treatment resulted in to very mild and insignificant lowering of total serum cholesterol in mice in comparison to the control group. Endothelial expression of VCAM-I in the aorta significantly decreased in WAGE (MDOC) treated mice when compared to non-treated mice. SATISFIED This potential anti-inflammatory effect may be related to the mild hypolipidemic effect of. This reduces the potential risks to the subject compared with other types of antilipemic remedies. The composition of the present invention may be used as an effective agent to lower serum cholesterol in animals, particularly humans. 1) Dairy Products—. such as cheeses, butter, milk and other dairy beverages, spreads and dairy mixes, ice cream and yoghurt. 2) Fat-Based Products—.such as margarines, spreads, mayonnaise, shortenings and dressings. 3) Cereal-Based Products—. comprising grains (for example, bread and pastas) however processed. 4) Confectionaries—. such as chocolate, candies, chewing gum, desserts, non-dairy toppings, sorbets, icings and other fillings. 6) Miscellaneous Products—.including eggs, processed foods such as soups, pre-prepared paste sauces, pre-formed meals and the like. Alternatively, the composition may be applied directly onto to food or into to beverage by the consumer prior to ingestion. Example To - Preparation of Polymer Complexes Materials: long-fibers cotton—.medicinal cotton wool oxidised by NxOy (proprietary). C6OOH 18. Neratovice) N-HANCE 3000 guargumhydroxypropyltriammoniumchloride (Aqualon—. Hercules). Procedures: 30 g of N-HANCE 3000 to were placed into to 5 1 beaker and 3 1 of demineralised water 2. Contents of the beaker to were intensely stirred for 30 minutes. The pH value was adjusted to less than 4,5 by addition of an acetic acid solution leading to to viscosity laughed grade to were added and the contents heated up to to temperatures of 50. On dissolution of the calcium chloride the stirring was interrupted and 2,7 kg of the raw oxidised cotton wool to were introduced. The mixer was closed and the contents to were agitated for 120 seconds. Then the pH value of the contents was adjusted by addition of to 20% solution of Na2CO3 to 6-6. The fibers suspension was slowly agitated for 10 minutes. Then the pH value was readjusted to 4,0 and the prepared viscous solution of N-HANCE 3000 was introduced. The contents of the mixer to were stirred intensely for 30 seconds. Subsequently 60 1 of synthetic rectified ethanol cone. 98% to were introduced into the mixer. After another 15 seconds from adding the ethanol the contents of the mixer to were transferred onto to vibrating screen, and the supernatant. The filtration cake was redispersed in the mixer in 60 1 of to 18 mixture of 1 of synthetic rectified ethanol cone. The fibers suspension was filtered again on the vibrating screen. The isolated material thus prepared may further servants to preseems final products of the nonwoven type via to wet or dry process. Example B - Preparation of Polymer Complexes (IMC-MDOC) Materials: oxidised short-fibers cotton (Linters - Temming) (proprietary) C6OOH 16. Neratovice). redistilled water (PhBs 1997). ethanol, synthetic rectified cone. Equipment: turbostirrer: ULTRA TURAX (Janke-Kunkel) sulphonation flask 1 1 heater 1,5 kW laboratory centrifuges: 4000 rpm thermostated water bath pH meter SMALL glass thermometer rotary vacuum dryer or hot-air dryer. Into to 1 1 sulphonation flask equipped with to turbostirrer and to heater, 400 mililiter of redistilled H2O to were placed, and 8 g of NaOH to were added. On dissolution, 50 g of oxidised Linters to were added, the contents to were heated up to 70°.C and the stirring intensity set to to maximum. After 20 minutes, 40 g of 30% H2O2 to were added into the flask, temperatures was increased to 85°.C, and maintained for another 10 minutes. The contents to were then cooled down to 50°.C on to water bath and frosted of solution (10 g of frozen some in 70 g of redistilled H20) warmed up to 50°.C was added to the hydrolysate. The temperatures was decreased to 25-30°.C and the pH of the system was checked and adjusted to to value of 6. Subsequently, 626 mililiter of synthetic rectified ethanol cone. 98% to were added gradually under intense stirring. The suspension of IMC thus formed was isolated using to laboratory centrifuges. The supernatant liquid was filtered away and the cake was redispersed into 250 mililiter of 50% ethanol. 98% and let to stay for 4 hours. It was then centrifuged again, redispersed into 99,9% isopropanol, and let to stay for to minimum of 10 hours at. The gel formed was centrifuged again and the product was dried in to rotary vacuum dryer or to hot-air dryer. The product can be used, for instance, for microembolisation, for preparation of haemostatic dusting powders, for manufacture of polymer drugs, and based on cytostatics, or for preparation of spheric particles for macroembolisation. Example C - Preparation of Tablets and Pellets from MDOC (Microdispersed Oxidised Celluloses) Materials: MDOC (SATISFIED CaTNa salt of), particle size 0.m, specific surface area 86 m2/g, COOH group content 22. Equipment: tabletting machine (KORSCH EK 0, Berlin) 100 g of MDOC to were introduced into the tabletting machine. The tabletting force was set at to value of 5 kN. The tablets prepared to were smooth and cohesive and had to weight of 0. Disintegration installments of the tablets in to you go up of it Fl/1 was 15 minutes at 20°.C, and 8 minutes at 37°.C. To patient aged 55, displaying an increased cholesterol content in blood was treated by MDOC tablets administered orally for 50 days, at to dose of 6 tablets daily. After the treatment both LDL content and total cholesterol content to were significantly reduced. Blood analysis: before treatment after treatment. Example and - Preparation of Tablets and Pellets from IMC-MDOC Complex Material: oxidised short-fibers cotton (Linters - Temming) (proprietary). Neratovice) redistilled water (PhBs 1997) ethanol, synthetic rectified cone. Neratovice) frosted of (PhBs 1997) Equipment: turbostirrer: ULTRA TURAX (Janke-Kunkel) sulphonation flask 1 litre heater 1,5 kW laboratory centrifuges: 4000 rpm thermostated water bath pH meter SMALL glass thermometer rotary vacuum dryer or hot-air dryer Procedures: Into to 1 litre sulphonation flask equipped with to turbostirrer and to heater, 400 mililiter of redistilled H2O to were placed, 15,0 g of 20% Na2CO3 solution to were introduced under stirring. Subsequently, 50 g of oxidised Linters to were added to the white emulsion formed and the contents to were heated up to 95°.C with the stirring intensity set to to maximum. After 10 minutes, 30 g of 30% H2O2 to were added into the flask and the hydrolysis continued for another 10 minutes. The contents to were then cooled down to 60°.C on to water bath and the pH of the system was adjusted to to value of 4. To ice creams some solution (1O g of frosted of in 70 g of redistilled H2O) warmed to 50°.C was added and left to react for another 20 minutes. The flask contents to were then cooled to 30°.C in to water bath and 626 mililiter of synthetic rectified ethanol cone. 98% to were added gradually under intense stirring. The suspension of IMC thus formed was isolated using to laboratory centrifuges. The supernatant liquid was filtered away and the cake was redispersed into 250 mililiter of 50% ethanol. 98% and alllowed stand for 4 hours. It was then centrifuged again, redispersed into 99,9 % isopropanol, and left to stand for to minimum of 10 hours at 20°.C. The gel formed was centrifuged and the product was dried in to rotary vacuum dryer or to hot-air dryer. The product can be used, for instance, for microembolisation, for preparation of haemostatic dusting powders, for manufacture of polymer drugs, and based on cytostatics, or for preparation of spheric particles for macroembolisation. Preparation of Tablets and Pellets from IMC-MDOC Complex magnesium stearate (SIGMA) ascorbic acid (MERCK) α.-tocoferol acetate (Slovakofarma Hlohovec). ethanol synthetic rectified (Chemopetrol Litvinov, to Equipment: tabletting machine (KORSCH EK 0, Berlin) blender (Nautamix 300) counter-flow drier (BINDER) 10 kg of IMC-MDOC complex of composition according to Example 2 to were placed into the blender. 660 g of micronised ascorbic acid, 1660 g of α.-tocoferol acetate emulgated in 2500 mililiter of ethanol and 1000 g of magnesium stearate to were added. The mixture was homogenised for 3 hours and dried in to counter-flow drier at to temperatures of 50°.C until the ethanol was removed. 100 g of the resulting dry powder to were introduced into the tabletting machine. The tabletting force was set at to value of 7 kN. The tablets prepared to were smooth and cohesive and had to weight of 0. Disintegration installments of the tablets in to you go up of it Fl/1 was 17 minutes at 20°.C, and 8 minutes at 37°.C. To patient aged 57, displaying an increased cholesterol content in blood was treated by IMC-MDOC tablets administered orally for 50 days, at to dose of 6 tablets daily. After the treatment both LDL content and total cholesterol content to were significantly reduced. Before Blood analysis treatment after treatment. Example G - Preparation of Granules from MDOC in to Fluid Bed Materials:.m, specific surface area 86 m2/g, COOH group content 22. Set of vibrating screens with mesh size 100, 150, 200, 250, 350, 500.m mixer, bottom agitated, vessel size 1000 mililiter, 8000 rpm, equipped with to nozzle for inlet of the granulation medium counter-flow drier (BINDER) Procedures: 100 g of MDOC to were placed into the mixer, the mixer was closed and the agitation begun. To water mist was gradually injected into the mixer at to installments of 10 g/45 seconds. The granulated formed was transferred to the counter-flow drier and dried at to 45 temperatures of C until the humidity content was reduced to below 6% b/w. The dried granules to were sieve-screened using the set of vibrating screens. The individual fractions to were packaged into glass vials in amounts of 0. The preparation was sterilised by y irradiation with to dose of 25 kGy. The product may be used as to) an embolisation agent, or b) an antilipemicum. Example H - Preparation of Granules from IMC-MDOC Complex Materials: IMC-MDOC complex as prepared in Example 2 Set of vibrating screens with mesh size 100, 150, 200, 250, 350, 500.m mixer, bottom agitated, vessel size 1000 mililiter, 8000 rpm, equipped with to nozzle for inlet of the granulation medium counter-flow drier BINDER. 100 g of MDOC to were placed into the mixer, the mixer was closed and the agitation. Saturated water vapour was gradually injected into the mixer at to installments of 10 g/45 seconds. The granulated formed was transferred to the counter-flow drier and dried at to temperatures of 45°.C until the humidity content was reduced to below 6% b/w. The dried granules to were sieve-screened using the set of vibrating screens. The individual fractions to were packaged into glass vials in amounts of 0. The preparation was sterilised by range irradiation with to dose of 25 kGy. The product may be used as to) an embolisation agent, or b) an antilipemicum. More The invention will be clearly understood from the following Examples thereof given by way of illustration only. The Ethical Committee of the Faculty of Pharmacy, Charles University, approved the protocols of the animal experiments. The protocol of experiments was pursued in accordance with the directive of the Ministry of Education of the Czech Republic (Not mice, generated by gene targeting, have been shown to develop pronounced hypercholesterolemia and atherosclerotic lesions (Reddick ET al., 1994) with certain features resembling those seen in humans (mice Nakashima ET al. on to C57BL/ 6J background (n = 32) weighing 10-15 g to were kindly provided by Prof. Poledne (IKEM, Prague, Czech Republic) and housed in the SEMED, (Prague, Czech Republic). mice to were weaned at 5 weeks of age and randomly subdivided into four groups. The control group of animals (n = 8) was fed with the standards laboratory diet (chow diet) for another 4 weeks after the weaning. In both simvastatin (n = 8) and atorvastatin (n = 8) group, statins to were added to the chow diet at the dosage of 10 mg/kg for day. In MDOC group (n = 8) MDOC was added to the chow diet at the dosage 50 mg/kg for day. Mice All treated were fed with the experimental diet for another 4 weeks after weaning with water to libitum throughout the study. Each mouse, in both statins and MDOC group, lived in to separated cage obtaining 6 g of food (in specially prepared pellets) daily. The food consumption was monitored every day. Not differences in the food consumption were visible, either among animals of one experimental group nor between experimental groups. The dose of simvastatin and atorvastatin used in the present study was based on the doses used in previous studies with hyperlipidemic mice (Laufs ET to. The dose of MDOC was based on the results of to small pilot study. At the end of the treatment period, all animals to were fasted overnight and euthanized. Blood samples to were collected via cardiac puncture at the Time of death. Serum lipoprotein fractions to were prepared using NaCl density gradient ultracentrifugation (Beckman TL 100, High Pole, CA). The lipoprotein fractions to were distinguished in the following density ranges: very low density lipoprotein (VLDL)<.1. Total concentration and lipoprotein fraction concentration of. Sequential tissue sectioning started in the mouse heart until the aortic root containing semilunar valves together with the aorta appeared. From this point on, serial cross- sections (7 Am) to were cut on to cryostat and placed on gelatin-coated slides. Sections to were air-dried and then slides to were fixed for 20 min in acetone at -20, Endogenous peroxidase activity was blocked with 0,3% hydrogen peroxide in phosphate buffered you go up of it (PBS) for 15 min. After blocking of nonspecific binding sites with 10% normal horse serum (Sigma-Aldrich Chemie, Steinheim, Germany) in PBS solution (pH 7,4) for 30 min, slides to were incubated with primary antibodies for 1 h at room temperatures. Antibody reactivity was detected using HRPconjugated biotin- avidin complexes (Vector Laboratories, USA) and developed with substrate diaminobenzidine tetrahydrochloride as. Nonimmune Specificity of the immunostaining was assessed by staining with isotype-matched immunoglobulins. Stereological methods for the estimation of immunohistochemical staining of VCAM-I, ICAM-I, and Von Willebrand factor to were used as previously described (Nachtigal ET to. In brief, the systematic uniform random sampling and the principle of the point-counting method to were used for the estimation (Weibel, 1979). consecutive serial cross-sections to were cut into 7 i'.m thick slices, which gave us 0,350 milimeter lengths of the vessel called the reference volume. To systematic uniform random sampling was used in the reference volume where the parameter: to characterizes the test grid. and P is the number of positive tests points hitting either the atherosclerotic lesion or immunostaining. The area of Von Willebrand factor expression was considered as to total area of intact endothelium. Thus, the area of VCAM-I, and ICAM-I expression indicates the percentage of activated endothelial cells calculated as Where: area (x) is the area of VCAM-I or ICAM-I in the endothelium and area (Von Will) is the area of Von Willebrand factor expression in the endothelium. Ottawa, Canada) and with image analysis software LUCIA version 4,82 (Laboratory Imaging, Prague, Czech Republic). Stereological analysis was performed with to PointGrid module of the ELLIPSE software (ViDiTo, Kosice, Slovakia). All values in the graphs are presented as to meanTSEM of n = 8 animals.05 or less to were considered statistically significant. (g) Atherosclerosis Animals to are to be killed by pentobarbital injection. Thoracic aortas to are rapidly removed, immersion fixed in 10% neutral buffered formalin, and stained with oil red Or (0.) interfaced to to color room (Toshiba 3 CCD) mounted on to dissecting microscope. Tissue cholesterol will be measured enzymatically as described, after extraction with to chloroform/methanol mixture (2:1) according to the method of Folch ET to. The abdominal aortas to are rapidly excised, after injection of sodium pentobarbital, and placed in oxygenated Krebs-bicarbonate buffer. Force changes in response to angiotensin II added to the bath will be recorded on to chart recorder. Total cholesterol, VLDL, LDL, HDL and TAG to were measured. CHOL, HDL-CHOL, TGl and VLDL+LDL) Total serum cholesterol (SER.CHOL) to are to be measured enzymatically using to commercial kit from Wako Fine Chemicals (Richmond, Sigma Chemical Co Total Goes HDL cholesterol (HDL-CHOL) will be assayed using this same kit after precipitation of VLDL and LDL with serum triglycerides (blanked) (TGI) will be assayed enzymatically with Sigma Chemical Co VLDL and LDL (VLDL+LDL) cholesterol concentrations will be calculated as the difference between total and HDL cholesterol. Biochemical analysis showed that statins treatment did not decrease levels of total cholesterol and VLDL (Fig. By contrast, atorvastatin treatment increased levels of the total serum cholesterol in comparison to the control group (23, However, MDOC treatment decreased total serum cholesterol in comparison to the control group (17, Example 2 - Endothelial expression of VCAM-I in apoE. Members of the immunoglobulin superfamily of endothelial adhesion molecules, vascular cell adhesion molecule (VCAM-I) and intercellular cell adhesion molecule (ICAM-I) strongly participate in leukocyte adhesion to the endothelium and play an important role in all stages of atherogenesis. Immunohistochemical staining of VCAM-I and ICAM-I. Not atherosclerotic lesion or other morphological abnormalities in the aortic arch were visible in any mice in the experiment. The expression of VCAM-I and ICAM-I was observed in vessel endothelium in all groups of animals (Fig. Furthermore, ICAM-I expression was stronger then VCAM-I in each experimental group. Moreover, ICAM-I expression decreased in both statins (Fig. 2d) treated mice compared to the control group (Fig. The same results to were observed even for VCAM-I staining (Fig. However, the strongest diminution of mice ICAM-I and VCAM-I expression was visible in the atorvastatin treated (Fig 2c, 3c). Mice Results of the stereological analysis confirmed that ICAM-I staining was much stronger in all compared to the VCAM-I staining (Fig. percentage of activated endothelial cells ICAM-I /von Willebrand slightly decreased in simvastatin (22,12 %) treated animals in comparison to the control mice. However, significant diminution of both ICAM-1/von Willebrand (2,001) staining was observed in atorvastatin treated animals in comparison to the control group (Fig. In addition, VCAM- 1/von Willebrand staining significantly decreased even in MDOC treated animals (3, Example 3 —. Mice VCAM expression in activated endothelial cells on to C57BL/6J background (n=24) were weaned at 5 weeks of age and randomly divided into 3 groups. Control group (n=8) - mice consumed to standard diet for 4 weeks (6 g of diet for day). MDOC group (n=8) - mice consumed to standard diet supplemented with MDOC (50 mg/kg for day) for 4 weeks (6 g of diet for day). Atorvastatin group (n-8) - mice consumed to standard diet supplemented with atorvastatin (10 mg/kg for day) for 4 weeks (6 g of diet for day). Not differences in the average weekly food consumption and body weight were detected during the study. At the end of the treatment all animals to were fasted overnight, and euthanized. Blood samples to were collected at the Time of death via cardiac puncture. Sequential 20 μ.m sections of the aortic lumen to were cut, dried and fixed. Estimation of immunohistochemical staining of VCAM-I and ICAM-I was carried out. systematic uniform random sampling and the principle of point cutting to were used for this determination. Fifty consecutive serial cross sections to were cut in to 7 μ.m thick slices. Each tenth section was used, thus five sections for each staining to were used for the stereological estimation. The area of von Willebrand factor expression was considered as to total area as the total area of intact endothelium. Thus, the area of VCAM and ICAM expression is defined as the percentage of the von Willebrand factor expression (the This method is described in more detail in Nachtigal ET to (2004). The percentage of VCAM expressing activated endothelial cells was calculated as described in the study design section. The results for the control, atorvastatin and MDOC groups to were compared and the means to were plotted in Figures 5. Table 2 —. Statistical results for VCAM expression in the control, atorvastatin and MDOC groups. The results presented in Figures 5 demonstrate that atorvastatin treatment greatly reduced the expression of VCAM (pO. The MDOC group also had to significantly reduced VCAM expression (pO. These pre-clinical studies have demonstrated that MDOC is able to significantly decrease (77%) the expression of VCAM-I in the aorta. Therefore VCAM is intimately linked to the development of atherosclerotic plaques and its reduction by MDOC may decrease the chance of atherosclerosis. This conclusion adds further valuable evidence for to significant role in cardiovascular disease reduction by MDOC. The mechanism by which this effect occurs is most likely two to the dietary reduction of LDL by MDOC. Atherosclerotic arteries produces excess reactive oxygen species such as super oxide anion Or Oxidised LDL (oxLDL) accumulates in the atheroma and promotes macrophage survival and growth and monocyte proliferation and hence foam cell development. The lowering of LDL by MDOC may therefore veteran the amount of oxLDL produced. Hence, the reduced accumulation of oxLDL might contribute to decreased numbers of macrophages in atheroma during lipid lowering and hence the atherosclerotic risk. This shows the potential of the hypolipidemic substance MDOC to decrease endothelial expression of VCAM-I in very early stages of atherogenesis. This potential anti inflammatory effect may be related to the mild hypolipidemic effect of MDOC. Rats with to body weight of approximately 175g were obtained from Charles River Laboratories, Ballina, Ireland. After 1 wk of acclimation, 80 rats to were allocated to 4 similar groups (n = 20 for group) on the basis of their body weight. The rats to were housed in groups of two and three in dust-free standards cages with autoclaved processed sawdust as bedding material. The rats to were housed in an environmentally controlled room (temperatures 22 ±. 3°.C) with to 12-h lightrdark cycle. Throughout the study, the rats had free access to food and drinking water. Clinical observation and body weight measurement to were conducted weekly. -- During the adaptation period, rats to were fed the AIN-93 synthetic diet for one week. Subsequently, all rats to were fed the AIN-93 diet supplemented with 3% cholesterol for another week (High cholesterol diet. HCD). During the experimental period the rats to were divided into 4 groups and to were fed different diets for 4 weeks according to Table 3. The diets to were prepared in pellet form by Special Diet Services, Essex, England.The High Cholesterol Diet (HCD) fed to the rats was supplemented for each group as described below. Oxidised celluloses (OC) MDOC was prepared as described above. Generic sterols (Gen) to were purchased from commercially available products. One-way ANOVA to are used to determine treatment differences (SigmaStat version 1. Differences among means will be inspected using appropriated multiple comparisons test and to were considered significant at P<.0. Not difference across treatments in final body weights was observed (p >. 0. Weight gain during the course of the study for the control group and for the three treatment groups. Example 5 - combination therapy changes in LDL cholesterol. Blood was allowed to clot and then transferred to to refrigerated 10 centrifuges and centrifuged at 2,500 rpm for minutes at 2-8°.C. The collected serum was frozen at —.20. Serum LDL and HDL-cholesterol to were measured enzymatically by using commercial available kits (EZ LDL™., EZ HDL™.: Cholesterol kits, Trinity Biotech). Total cholesterol was measured using the commercially available kits from Human, Germany. Serum glucoses was determined by colorimetric glucoses oxidase assay (Sigma-Aldrich). Triglycerides to were measured with to commercially available kit from Sigma-Aldrich. -- One-way ANOVA to are used to determine treatment differences (SigmaStat version 1. Differences among means will be inspected using appropriated multiple comparisons test and to were considered significant at P<.0. Table 5 The effect of the dietary supplementation of to High Cholesterol Diet (HCD) with 1% oxidized celluloses (OC) MDOC and 0,5% sterol (w/w) on the serum LDL cholesterol concentrations in rats (n-20/gp) fed these diets. The differences in the mean values among the treatment groups are greater than would be expected by chance. to there is to statistically significant difference (p<.0. All Pairwise Multiple Comparison Procedures (Student-Newman-Keuls Method):. Table 5 illustrates an example of to combination therapy of the present invention. The example comprises four groups of subjects and the effectes on LAL (bad) cholesterol reduction. The four groups to are: to control group that received not agent. to group that receive 1% (w/w) oxidised celluloses (OC) MDOC. to group that received 0,5% (w/w) sterol. and to final group that received both the 1% (w/w) OC MDOC and the 0. As can be seen from Figures 7, the combination of 0,5% sterol (w/w) caused to greater decrease in the level of LDL (bad) cholesterol than either 0. Therefore the combination of OC (MDOC) and sterol is more effective as an anti-atherosclerosis or an anti-hyperlipidemic. Example 6 - combination therapy, changes in total cholesterol. Blood was allowed to clot and then transferred to to refrigerated 10 centrifuges and centrifuged at 2,500 rpm for minutes at 2-8°.C. The collected serum was frozen at —.20. Serum LDL and HDL-cholesterol to were measured enzymatically by using commercial available kits (EZ LDL™., EZ HDL™.: Cholesterol kits, Trinity Biotech). Total cholesterol was measured using the commercially available kits from Human, Germany. Serum glucoses will be determined by colorimetric glucoses oxidase assay (Sigma -. Triglycerides to were measured with to commercially available kit from Sigma -. One-way ANOVA to are used to determine treatment differences (SigmaStat version 1. Differences among means will be inspected using appropriated multiple comparisons test and to were considered significant at P<.0. Table 6 The effect of the dietary supplementation of to High Cholesterol Diet (HCD) with 1% oxidized celluloses (OC) MDOC and 0,5% sterol (w/w) on the serum Total cholesterol concentrations in rats (n=20/gp) fed these diets. The differences in the mean values among the treatment groups are greater than would be expected by chance. to there is to statistically significant difference (p=0. All Pairwise Multiple Comparison Procedures (Student-Newman-Keuls Method):. All other comparisons to are not significant. Table 6 illustrates an example of to combination therapy of the present invention. The example comprises four groups of subjects and the effectes on LAL (bad) cholesterol reduction. The four groups to are: to control group that received not agent. to group that receive 1% (w/w) oxidised celluloses (OC) MDOC. to group that received 0,5% (w/w) sterol. and to final group that received both the 1% (w/w) OC (MDOC) and the 0. As can be seen from Figures 8, the combination of 0,5% sterol (w/w) caused to greater decrease in the level of total cholesterol than either 0. (MDOC) and sterol is more effective as an anti-atherosclerosis or an anti-hyperlipidemic. Rats with to body weight of approximately 175g were obtained from Charles River Laboratories, Ballina, Ireland. After 1 wk of acclimation, 30 rats to were allocated to 3 similar groups (n = 10 for group) on the basis of their body weight. The rats to were housed in groups of two and three in dust-free standards cages with autoclaved processed sawdust as bedding material. The rats to were housed in an environmentally controlled room. Throughout the study, the rats had free access to food and drinking water. Clinical observation and body weight measurement to were conducted ounces to week. During the adaptation period, rats to were fed the AIN-93 synthetic diet for one week. Subsequently, all rats to were fed the AIN-93 diet supplemented with 1% cholesterol for another week (High cholesterol diet. HCD). During the experimental period the rats to were divided into three groups and to were fed different diets for 25 days. The first group was fed the AIN-93 diet supplemented with 1% cholesterol. The second and third groups. to were also fed the AIN-93 diet supplemented with 1% cholesterol and 1% or 5% oxidized celluloses respectively. The diets to were prepared in pellet form by Special Diet Services, Essex, England. OC (MDOC) was prepared as described above. One-way ANOVA was used to determine treatment differences (SigmaStat version 1. Differences among means to were inspected using Tukey multiple comparisons test and to were considered significant at P<.0. If normality test failed non-parametric tests to were used. The Kruskal-Wallis non-parametric ANOVA test was performed with multiple Dunn'.s post ANOVA comparisons test. The three treatment groups started with similar mean body weights that to were not statistically different from each other. These mean body weights ranged from 256. To summary of the body weights is provided in Figures 9 and the weight gain over the course of the study is also presented. Table 7 Weight gain during the course of the study for the control group and for the two treatment groups. All rats gained weight during the study period with not differences across treatments in final body weights (p >. 0. Blood was allowed to clot and was then transferred to to refrigerated 10 centrifuges and centrifuged at 2,500 rpm for minutes at 2-8°.C. The collected serum was then frozen at —.20. One-way ANOVA was used to determine treatment differences (SigmaStat version 1. Differences among means to were inspected using Tukey multiple comparisons test and to were considered significant at P<.0. If normality test failed non-parametric tests to were used. The Kruskal—. Wallis non-parametric ANOVA test was performed with multiple Dunn'.s post ANOVA comparisons test. The results of the fasting serum glucoses levels to are presented in Figures 10. These results indicated to reduction in the serum glucoses in the rats fed to HCD supplemented with MDOC. The group of rats fed the HCD supplemented with 5% MDOC (w/w) significantly reduced the glucoses concentration in the serum to 90. Fasting blood glucoses concentrations in the rats fed the HCD supplemented with 5% MDOC was significantly decreased (~9%) compared to the control group. This result may have very interesting possibilities for management of diabetes mellitus. CHD is to long-term complication of diabetes mellitus. The American Diabetes Association recognized the relationship of diabetes and CHD. It has documented goals of which optimal serum lipid levels, as well as maintenance of near-normal blood glucoses levels to are of primary importance (ADA, 2000). The potential of MDOC to manage both the glucoses and serum lipid levels may be of great significance to diabetes mellitus sufferers. The examples herein can be performed by substituting the generically or specifically described therapeutic compounds or inert ingredients for those used in the preceding examples. Hereinbefore The invention is not limited to the embodiments described which may be varied in detail. Morphology of the endothelium over atherosclerotic plaques in human coronary arteries. Expression of inflammatory mediators and adhesion molecules in human atherosclerotic plaque. The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Pleiotropic effects of statins and their clinical significance. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. The application of stereological methods for the quantitative analysis of the atherosclerotic lesions in rabbits. Application of stereological methods for the quantification of VCAM-I and ICAM-I expression in early stages of rabbit atherogenesis. Mice ApoE-deficient develop lesions of all phases of atherosclerosis throughout the arterial tree. Upregulation of VCAM-I and ICAM-I at atherosclerosis-prone sites on the endothelium in the ApoEdeficient mouse. Arteriosclerosis Thrombosis and Vascular Biology 18, 842 —. 851. Evaluation of lesional development and progression. Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arteriosclerosis Thrombosis and Vascular Biology 21, 115 - 121.Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Statins I give more than just lower cholesterol. Practical Methods for Biology Morphometry, vol. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein And Recevoir DES mises à. jour par courrier é.lectronique concernant les activité.s de OMPI sur les brevets ET the PCT