• 专利附录
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    • 专利摘要:

    公开号:NL1006774A1
    申请号:NL1006774
    申请日:1997-08-14
    公开日:1998-02-20
    发明作者:Hester Hendrina Vorster；Frederick Johannes Veldman
    申请人:Univ Potchefstroom；Kisch Octrooibureau；
    IPC主号:
    专利说明:

    Anti-atherosclerosis and anti-thrombotic agent and its uses.
    This invention relates to a pharmaceutical for the prevention or treatment of any of the following conditions in mammals: atherosclerosis, thrombosis, undesirably high free radical levels, undesirably long fibrin clot lysis times, undesirable fibrin clot characteristics, undesirably high levels of free fatty acids and obesity and its use.
    It is well known that atherosclerosis is primarily caused by elevated cholesterol levels in humans and thrombosis is caused by the polymerization of fibrin to form fibrin clots.
    Low-density lipoprotein cholesterol (LDL-C), which occurs in relatively high concentrations, is particularly responsible for an increase in cardiovascular diseases, especially when the LDL-C is oxidized by free radicals, such as lipid peroxides. Although dietary dietary fibers have been reported to modify lipid metabolism in humans, no effects of fiber, fiber constituents or metabolites thereof on lipid peroxidation have been described.
    It is further known that fermentable non-starch polysaccharides, such as pectin, are fermented in the colon of a mammal to short chain fatty acids or derivatives thereof, such as acetate, propionate and butyrate. The butyrate is absorbed by the colon cells, while the propionate and acetate continue to the liver. The propionate is retained in the liver while the acetate is distributed to the mammal's cells and plasma.
    It is an object of the present invention to provide a novel pharmaceutical agent for the prevention or treatment of any of the following mammalian conditions: atherosclerosis, thrombosis, undesirably high free radical levels, undesirably long fibrin clot lysis times, undesirable fibrin clot characteristics, undesirably high levels of free fatty acids and obesity and their use.
    According to the invention, there is provided a pharmaceutical agent for the prevention or treatment of any of the following conditions in mammals: atherosclerosis, thrombosis, undesirably high free radical levels, undesirably long fibrin clot lysis times, undesirable fibrin clot characteristics, undesirably high levels of free fatty acids and obesity comprising a short chain fatty acid, or a pharmaceutically acceptable salt, derivative or precursor thereof, in a pharmaceutically acceptable protective coating which is resistant to digestion and dissolution in the stomach and small intestine of a mammal, but is digestible or soluble in the colon of a mammal.
    Preferably, the pharmaceutically acceptable salt of the short chain fatty acid is its calcium salt.
    Preferably the short chain fatty acid comprises acetic acid.
    The protective coating can include a natural or synthetic resin such as shellac.
    The pharmaceutical agent preferably comprises calcium acetate in the form of a capsule, tablet or pill coated with such a resin.
    Preferably, the agent comprises between 0.1 grams and 100.0 grams of the acetate.
    In accordance with another aspect of the invention, a method of treating or preventing one or more of these conditions in a mammal comprises the step of administering to the mammalian colon an agent containing a short-chain fatty acid or a pharmaceutically acceptable salt , derivative or precursor thereof.
    Preferably, the agent is administered to the colon through the mammal's alimentary tract.
    According to another aspect of the invention, there is provided the use of an agent comprising a short chain fatty acid or a pharmaceutically acceptable salt, derivative or precursor thereof in a method of treating or preventing one or more of these conditions in mammals.
    According to another aspect of the invention, there is provided the use of an agent comprising a short chain fatty acid or a pharmaceutically acceptable salt, derivative or precursor thereof in the manufacture of a medicament for use in a method of treating or preventing one or more of these disorders in mammals.
    Furthermore, the aforementioned method of the invention comprises the step of orally administering the agent in the form of a capsule, pill or tablet coated with a protective coating which is resistant to digestion and dissolution in the stomach and small intestine of a mammal, but is soluble or digestible in the colon of this mammal.
    Furthermore, according to the invention, the pharmaceutically acceptable salt is preferably the calcium salt of the short chain fatty acid.
    Still further, according to the invention, the short chain fatty acid is preferably acetic acid.
    Finally, according to the invention, the protective coating preferably comprises a natural or synthetic resin such as shellac.
    Applicant has found that the aforementioned clinical effects can be achieved by administering the agent to a human at least once a day in an amount between 0.1 gram and 100.0 gram.
    The invention will now be further described by the following non-limiting examples.
    The abbreviations used in the examples indicate the following:
    ApoA - Apoprotein A
    ApoB - Apoprotein B
    BMI - Quetelet index = weight / (height) 2 DBP - Diastolic blood pressure FFA - Free fatty acids FFA / ALB - Free fatty acid to albumin ratio
    Heamatocrit -% packed cells in blood HDL-C - High-density lipoprotein cholesterol IR - Insulin resistance LDL-C - Low-density lipoprotein cholesterol LP (a) - Lipoprotein (a) MPC - Macromolecular protein complex SBC - Systolic blood pressure TBARM - With thiobarbituric acid reactants malondialdehyde TC - Total cholesterol TG - Triglycerides TP - Total protein μΤ - Mass / length ratio from turbidity EXAMPLE 1
    The respective effects of pectin and an acetate when administered to a mammalian colon were determined in a first experiment. The experiment was conducted in the two phases shown in Figure 1.
    Twenty adult men took part in the experiment and these individuals did not receive any medication for any chronic disease at the time, nor had any history of cardiovascular disease. At the time, all individuals followed a diet high in fiber and low in fat. During the first phase, ten individuals consumed a total of 15 grams of pectin per day in four servings, while the other ten consumed a total of 15 grams of placebo (starch) per day in four servings.
    During the second phase, the first group consumed a total of 7.5 grams of calcium acetate per day in four servings and the second group consumed a total of 15 grams of pectin per day in four servings. The calcium acetate was administered in capsules coated with a protective coating comprising a resin commercially known as shellac. This protective coating is resistant to digestion and dissolution in the stomach and small intestine, but not resistant to the enzymes of the organisms commonly found in the colon, so that the calcium acetate was released into the colon. Details about the individuals are shown in Table 1.
    TABLE 1: PERSONAL DATA OF INDIVIDUALS PARTICIPATING IN THE EXPERIMENT
    After each phase, blood samples were taken from the individuals and a large number of variables were tested. The results of these tests are shown in Tables 2 to 5.
    Table 2 Averages and standard devlatles of body weight and BMI changes
    Table 3 Averages and standard deviations of haemheological and haemostatic variables from baseline and at the end of supplementation
    Table 4 Averages and Standard Deviations of Baseline and End of Supplement Lipid Variables
    Table 5 Averages and standard deviations of metabolism variables from the baseline and at the end of supplementation
    The results of the above experiments will now be briefly discussed.
    BODY WEIGHT AND OUETELET INDEX (BMI) CHANGES
    As is clear from Table 2, no significant changes in body weight or BMI were observed in any of the groups during phase 1. The acetate supplementation (phase 2), however, caused a decrease in body weight (from 88.16 + 12.35 kg to 83.09 + 10.80 kg). While this decrease may not be statistically significant, it may be clinically significant for those individuals who lost weight.
    HAEMORHEOLOGICAL AND HAEMOSTATIC VARIABLES
    As shown in Table 3, pectin supplementation in both groups during both phases caused a significant decrease in clot lysis time, Macromolecular Protein Complex (MPC), clot fibrin content, Hemoglobin (Hb), plasma viscosity, and a significant increase in fibrin clot compressibility, mass / length ratio from turbidity (μΤ) and clot permeability.
    Apart from a significant decrease in plasma viscosity in the placebo group during phase 1 (from 1.80 ± 0.09 to 1.70 + 0.07 cP), no other changes were observed in this group.
    Furthermore, Table 3 clearly shows that acetate supplementation caused a significant decrease in hematocrit (Ht), Hb, plasma viscosity, MPC, clot fibrin content and clot lysis time, while significant increases were measured in clot compressibility and permeability. Although the change in fibrinogen was not significant, it is worth noting that acetate supplementation caused an 11.2% decrease in the group's total piasmafibrinogen concentration.
    LIPIDE CHANGES
    As shown in Table 4, pectin supplementation caused significant decreases in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and Apo protein A (ApoA), Apoprotein B (ApoB), lipoprotein (a) (Lp (a)), tribarbituric reactants of malondialdehyde (TBARM) and hydrogen peroxide (H202) during phase 1. During phase 2, HDL-C was significantly increased.
    It is also clear that ApoA decreased significantly in the placebo group. A significant decrease in ApoB was also observed. There were no other significant changes.
    Therefore, it appears that acetate supplementation caused a substantial decrease in TC, ApoA, ApoB, TG and H 2 O 2, while a significant increase in the percentage of HDL-C was also evident.
    METABOLIC VARIABLES
    As shown in Table 5, which reflects the mean (SD) changes in some metabolic variables of both groups during both phases, pectin supplementation caused a significant increase in acetate levels and a significant decrease in free fatty acid (FFA) levels and ratio of FFA / albumin.
    Apart from a significant increase in the FFA / albumin ratio, no other significant changes were observed in the placebo group.
    It is also clear that acetate supplementation caused a substantial increase in acetate levels and a significant decrease in FFA and the ratio of FFA / albumin.
    EXAMPLE 2
    The effect of the acetate on the fibrin clot structure was further determined by in vitro studies and the results and results and a discussion of them are presented below.
    ACETATE AND FIBRINE CLOTS STRUCTURE
    The effect of different concentrations of acetate on fibrin clot structure properties (n = 5 for each variable tested) is reflected in Table 6.
    TABLE 6: The Effect of Different Concentrations on Fibrous Nestoteric Structure Properties (n = 5 (for each variable tested)
    * differ significantly from 0 μπιοΐ / ΐ acetate (p <0.05; Student's t test).
    It is clear from Table 6 that as the acetate concentration gradually increased from 0 μιηοΐ / ΐ to 75, 100 and 150 μπιοΐ / ΐ, the permeability increased accordingly. The fiber thickness from turbidity (μΤ) increased significantly. The clot selly sis time decreased significantly, indicating enhanced fibrinolysis at gradual acetate concentrations. These changes in network characteristics are not due to altered fibrinogen conversion because the fibrin content in the tested acetate concentration range did not change significantly. These findings probably indicate that the fibrin in the presence of acetate shows increased lateral polymerization. Therefore, a larger amount of fibrin is incorporated into the main network and the cross-linking in the network differs from that of the control network.
    The effect of different concentrations of acetate on clot fibrin content and sample viscosity (n = 5 for each variable tested) is reflected in Table 7 and the relationship between fibrin network lysis and acetate concentrations is shown in Figure 2.
    TABLE 7: Effect of Different Acetate Concentrations on Clot Fibrin Content and Sample Viscosity (n = 5 for each variable tested)
    * differ significantly from 0 μπιοΐ / ΐ acetate (p <0.05; Student's t test).
    Referring to Table 7 and Figure 2, the lysis rate of radiolabeled fibrin clots in the presence of different concentrations of acetate was quantitated by measuring I12S released in the medium over a period of time. Thus, it appears that increasing acetate concentrations enhanced fibrinolysis.
    Referring to Figure 3, the kinetics of network growth were then examined by continuously recording changes in turbidity at 608 nm, during network development under identical experimental conditions. As shown in Figure 3, a gradual increase in acetate enhanced the entire kinetics. The lag phase became shorter, the increase in turbidity was greater, and the turbidity at equilibrium was increased proportionately.
    ACETATE AND LIPID PEROXYDATION
    The effect of acetate on peroxidation of blood lipids in vitro (n = 5 for each measurement) is shown in Table 8 and the relationship between inhibition of peroxidation and the acetate concentration is shown in Figure 4.
    TABLE 8: The effect of acetate on peroxidation of blood lipids in vitro (n = 5 for each measurement)
    * Signiferous differences of 0 μιηοΐ / ΐ acetate (p <0.05; Student's t-test).
    Table 8 and Figure 4 show that there is a linear analogy between the degree of free-radical inhibition and the acetate concentration. An inhibition of free-radical formation with 46.97, 56.01, 67.11 and 73.12% was caused by 50 μΜ, 100 μΜ, 200 μΜ and 300 μΜ acetate, respectively. All of these changes were significant (p <0.05). However, the graph of Figure 4 suggests that acetate does not completely inhibit peroxidation. It appears from linear regression analysis that minimal inhibition may cause a 56.12% decrease in peroxidation in vitro (r = 0.98; m = -0.836). The results showed that pectin supplementation caused a 49% decrease in free radical content, which corresponds to an acetate concentration of 70 μπι when related to this in vitro study. This value is within the physiological range. However, it is important to realize that the Cu2 + concentration used to induce oxidation is a drastic measure, causing unusually high oxidation rates.
    NEW EFFECTS
    Pectin supplementation did not cause material changes in piasmafibrinogen levels. However, significant differences were found in the properties of networks that developed in plasma from the pectin group. Networks were more permeable and had lower tensile strength. Its fibrin content had decreased markedly.
    A decrease in fibrin content partly explains some of the altered network characteristics due to altered fibrin (fibrinogen) conversion. These findings indicate that lateral polymerization was enhanced and therefore a greater amount of fibrin was included in the main fiber network. The enlarged main network fiber diameter is reflected in the turbidimetric measurement shown in Figure 3. The fibrin fiber thickness appears to be determined by its growth kinetics, and the differences in fiber diameter have been attributed to the kinetics of fibrin (fibrinogen) breakdown and subsequent fibrin fiber build-up. It is known that the mass-to-length ratio of fibrin fiber is determined by the rates at which the fibrin monomer is generated and from its build-up to fibrin fiber. When thrombin is added to fibrinogen, the fibrin monomer is generated depending on the relative amounts of enzyme and substrate.
    Turbidimetric changes represented by the lag phase, the increasing turbidity phase and the equilibrium phase together represent the degradation of fibrinogen to fibrin monomer; the initial aggregation of monomer to protofibrils; and the growth of protofibrils into an opaque network for. The lag phase corresponds to the time required for the overall action of thrombin on fibrinogen until the appearance of turbidimetrically detectable fibrin and includes the enzymatic degradation of fibrinogen and the initial aggregation to protofibrils. The fibrinogen solution forms a gel during the early part of the second phase in which the turbidity increases rapidly. The resulting thickness of the fibers shortens the total circumferential length of the fibers and thus increases permeability. Networks with fibers of increased thickness and permeability are less resistant to lysis. Increased clot compressibility also indicates a decrease in the tensile strength of fibrin. Increases in permeability and decreases in tensile strength indicate less fiber cross-linking within the network.
    The changes in fibrin network characteristics (μΤ and clot lysis time) were directly related to changes in plasma acetate levels.
    Acetate supplementation did not significantly alter piasmafibrinogen levels, but a decrease of 11.2% was observed in this group. Significant differences were also found for the properties of fibrin networks developed in plasma. These results were also observed in the results of the pectin group. Changes in clot structure properties were also related to changes in acetate levels. These results strongly suggest that acetate plays a role in the effect of pectin on clot structure properties.
    Gradually increasing amounts of acetate were used in vitro to investigate the possibility that acetate may be directly responsible for changes in in vivo fibrin clot structure characteristics, excluding the effect of other possible changes occurring in the plasma medium. The results indicated that acetate directly influences fibrin clot structure properties in the same manner as during pectin and acetate supplementation. Increasing amounts of acetate caused significant changes in the clot characteristics.
    Although it is known that dietary dietary fiber may modify lipid metabolism in humans, no effects of fiber or fiber constituents or metabolites on lipid peroxidation have been described so far. During the experiments, pectin supplementation caused a significant 49% decrease in the hydrogen peroxide content of blood lipids. This effect was accompanied by a decrease in total cholesterol. The change in lipid peroxides was directly related to the change in TC and acetate levels.
    Acetate supplementation caused a significant decrease in the free radical content of blood lipids. The effect was accompanied by a decrease in total cholesterol. The change in free radical concentration was directly related to the change in TC and acetate levels.
    The outright effect of acetate on lipid peroxidation was accomplished in vitro to rule out the effect of significant decreases in TC, as described for the results through acetate and pectin intervention.
    The results showed that increasing amounts of acetate in vitro decreased the sensitivity of lipoproteins to free radical attacks.
    In the acetate supplementation group, a clinically significant but statistically insignificant decrease in body weight of 5.0 kg was observed. Acetate has previously been shown to inhibit food intake in sheep. The acetate effect can therefore possibly be attributed to direct mechanisms and a decrease in food intake. No weight reduction was measured in the pectin supplementation group. The weight loss from acetate supplementation may have contributed to lowering TC and TG.
    POSSIBLE MECHANISMS
    The results showed that both acetate and pectin induce changes in network properties in vivo. However, pectin and acetate also showed significant effects on other metabolic variables in vivo. Plasma is an aqueous mixture of proteins, lipids, carbohydrates, amino acids, salts and other substances. A change in any of these components of plasma would be directly reflected in the properties of fibrin networks. Therefore, it could be expected that acetate and pectin can modify network characteristics by a combination of their effect on metabolism (modulating mechanism), possible direct effects (steric exclusion, etc.) and altered fibrin conversion (kinetic mechanism).
    The mechanism underlying these differences is currently unclear, but when tested with artificially added acetate, the reagents were added only a few minutes before the network developed. The induced changes are therefore due to a direct effect of acetate on fibrin. Therefore, it appears that in the presence of acetate added in this way, the developed networks simulated changes observed in network characteristics of both acetate and pectin supplemented plasma. This indicates that acetate may be directly responsible for partial changes in fibrin network characteristics.
    The physiochemical nature of acetate defines the behavior of this acid in living organisms. Molecules (such as acetate) of compounds containing O-H groups attract by an intermolecular force caused by the difference in electronegativity of oxygen and hydrogen atoms. This gives acetate the ability to form hydrogen bonds between 0-H, H-F, Η-Cl and H-N. Hydrogen bridges are the determining factor determining the properties of acetate in solution. There are two types of hydrogen bonds, intramolecular and intermolecular. Intermolecular bridges may link to the effects of acetate on the in vitro and in vivo fibrin clot structure. Fibrinogen is a very large molecule with a variety of different bonds. It is not impossible for acetate to form hydrogen bonds with the fibrin molecule, which has both 0-H and H-N groups. This can have steric effects on the fibrinogen molecule, causing a change in fibrinogen-thrombin interaction, which subsequently leads to an altered clotting process. This would lead to changes in the fibrin clot structure.
    Both pectin and acetate reduce peroxidation of blood lipids in vivo. Apart from acetate, no other measured variable could explain this antioxidant effect of pectin and acetate in vivo. The underlying mechanism is not clear. From the in vitro results, it appears that acetate directly inhibits lipid peroxidation. This indicates that pectin fermentation produces substances (acetate) with anti-oxidant properties. This can be direct evidence that acetate protects against lipid peroxidation by inhibiting free radical release, rather than protecting the blood lipids against it.
    It will be understood that short chain fatty acids, such as acetic acid, or its pharmaceutically acceptable salts, derivatives or precursors, in a pharmaceutically acceptable protective coating that is resistant to digestion and dissolution in a mammal's stomach and small intestine, but is soluble and digestible in the colon of such a mammal, could be used as a pharmaceutical for preventing or treating any of the following mammalian disorders: atherosclerosis, thrombosis, undesirably high free radical levels, undesirably long fibrin clot lysis times, undesirable fibrin clot character statistics, undesirably high levels of free fatty acids and obesity and their use. It will further be appreciated that such short chain fatty acids can be further used in methods of treating or preventing one or more of these conditions in mammals.
    It will furthermore be clear that a large number of detailed variations on the invention as described above are without doubt possible, without going beyond the scope and / or spirit of the appended claims.
    权利要求:
    Claims (24)
    [1]
    Pharmaceutical agent for the prevention or treatment of any of the following mammalian disorders: atherosclerosis, thrombosis, undesirably high free radical levels, undesirably long fibrin clot lysis times, undesirable fibrin clot characteristics, undesirably high levels of free fatty acids and obesity, which is a fatty acid with short chain, or a pharmaceutically acceptable salt, derivative or precursor thereof, in a pharmaceutically acceptable protective coating that is resistant to digestion and dissolution in the stomach and small intestine of a mammal, but is digestible or soluble in the colon of a mammal.
    [2]
    The pharmaceutical agent according to claim 1, wherein the pharmaceutically acceptable salt of the short chain fatty acid is its calcium salt.
    [3]
    Pharmaceutical agent according to claim 1 or 2, wherein the short chain fatty acid comprises acetic acid.
    [4]
    Pharmaceutical agent according to any of the preceding claims, wherein the protective coating comprises a natural or synthetic resin such as shellac.
    [5]
    Pharmaceutical agent according to claim 4, which contains calcium acetate in the form of a capsule, tablet or pill coated with such a resin.
    [6]
    Pharmaceutical agent according to claim 5, containing between 0.1 gram and 100.0 gram of the acetate.
    [7]
    7. Pharmaceutical agent essentially as described herein and given for illustration.
    [8]
    8. Method for treating or preventing one or more of the following mammalian disorders: atherosclerosis, thrombosis, undesirably high free radical levels, undesirably long fibrin clot lysis times, undesirable fibrin clot characteristics, undesirably high levels of free fatty acids and obesity step of administering to the mammalian colon an agent comprising a short chain fatty acid, or a pharmaceutically acceptable salt, derivative or precursor thereof.
    [9]
    The method of claim 8, wherein the agent is administered via the mammal's digestive tract.
    [10]
    The method of claim 8 or 9, wherein the pharmaceutically acceptable salt is the calcium salt of the short chain fatty acid.
    [11]
    The method of any one of claims 8 to 10, wherein the short chain fatty acid is acetic acid.
    [12]
    The method of any of claims 8 to 11, wherein the agent is administered in a pharmaceutically acceptable protective coating which is resistant to digestion and dissolution in the stomach and small intestine of a mammal, but is digestible or soluble in the colon of a mammal.
    [13]
    The method of any one of claims 8 to 12, wherein the agent is administered to a human at least once a day in an amount between 0.1 grams and 100.0 grams per day.
    [14]
    A method of treating or preventing mammalian disorders substantially as described and illustrated herein.
    [15]
    Use of an agent comprising a short chain fatty acid or a pharmaceutically acceptable salt, derivative or precursor thereof, in a pharmaceutically acceptable protective coating that is resistant to digestion and dissolution in the stomach and small intestine of a mammal, but is digestible or is soluble in a mammalian colon, in a method of treating or preventing one or more of the following mammalian disorders: athero sclerosis, thrombosis, undesirably high free radical levels, undesirably long fibrin clot lysis times, undesirable fibrin clot characteristics, undesirably high levels of free fatty acids and obesity.
    [16]
    The use according to claim 15 of an agent, wherein the pharmaceutically acceptable salt is the calcium salt of the short chain fatty acid.
    [17]
    Use of an agent according to claim 15 or 16, wherein the short chain fatty acid is acetic acid.
    [18]
    Use according to any of claims 15 to 17 of an agent, wherein the protective coating comprises a natural or synthetic resin such as shellac.
    [19]
    Use according to any of claims 15 to 18 of an agent, wherein the agent that can be administered to a human at least once a day is present in an amount between 0.1 gram and 100.0 gram per day.
    [20]
    Use of an agent comprising a short chain fatty acid or a pharmaceutically acceptable salt, derivative or precursor thereof, in the manufacture of a medicament for use in a method of treating or preventing one or more of the following conditions in mammals: atherosclerosis, thrombosis, undesirably high levels of free radicals, undesirably long fibrin clot lysis times, undesirable fibrin clot characteristics, undesirably high levels of free fatty acids and obesity, the drug having a pharmaceutically acceptable protective coating resistant to digestion and dissolution in the stomach and a small intestine of a mammal, but is digestible or soluble in the colon of a mammal.
    [21]
    The use of an agent according to claim 20, wherein the pharmaceutically acceptable salt is the calcium salt of the short chain fatty acid.
    [22]
    The use of an agent according to claim 20 or 21, wherein the short chain fatty acid is acetic acid.
    [23]
    The use of an agent according to any one of claims 20 to 22, wherein the protective coating comprises a natural or synthetic resin, such as shellac.
    [24]
    Use of an agent comprising a short chain fatty acid or a pharmaceutically acceptable salt, derivative or precursor thereof, substantially as described and illustrated herein.
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    同族专利:
    公开号 | 公开日
    US6528095B1|2003-03-04|
    WO1999011254A1|1999-03-11|
    NL1006774C2|1998-09-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO1999011254A1|1996-08-14|1999-03-11|Potchefstroom University For Christian Higher Education|Anti-atherosclerotic and anti-thrombotic agent and the use thereof|JPS6136222A|1984-07-26|1986-02-20|Chugai Pharmaceut Co Ltd|Remedy for hyperphosphatemia|
    US4721716A|1984-08-06|1988-01-26|Neesby Torben E|Method for desensitizing the gastrointestinal tract from food allergies|
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    CN1520284A|2001-05-29|2004-08-11|波切夫斯特鲁姆基督教高等教育大学|Anorexic compsn. comprising calcium acetate|
    US7790670B2|2002-03-01|2010-09-07|Glanbia NutritionalsLtd.|Compositions and methods for treatment of body weight conditions|
    US20030203004A1|2002-04-24|2003-10-30|Kelm Gary Robert|Compositions comprising short and long chain fatty acids and methods of their use for the management of body weight|
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    法律状态:
    1998-05-06| AD1A| A request for search or an international type search has been filed|
    1998-09-01| RD2N| Patents in respect of which a decision has been taken or a report has been made (novelty report)|Effective date: 19980721 |
    1998-12-01| PD2B| A search report has been drawn up|
    2004-02-02| SD| Assignments of patents|Owner name: POTCHEFSTROOM UNIVERSITY FOR CHRISTIAN HIGHER EDUC |
    2006-04-03| SD| Assignments of patents|Owner name: NORTH WEST UNIVERSITY Effective date: 20060123 |
    2006-04-03| TD| Modifications of names of proprietors of patents|Owner name: NORTH-WEST UNIVERSITY Effective date: 20060123 |
    2013-03-13| V1| Lapsed because of non-payment of the annual fee|Effective date: 20130301 |
    优先权:
    申请号 | 申请日 | 专利标题
    ZA9601173|1996-08-14|
    ZA961173|1996-08-14|
    EP9704875|1997-08-29|
    PCT/EP1997/004875|WO1999011254A1|1996-08-14|1997-08-29|Anti-atherosclerotic and anti-thrombotic agent and the use thereof|
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