CN88101370A - Act on pharmaceutical composition of cardiovascular system and preparation method thereof - Google Patents

Act on pharmaceutical composition of cardiovascular system and preparation method thereof Download PDF

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Publication number
CN88101370A
CN88101370A CN198888101370A CN88101370A CN88101370A CN 88101370 A CN88101370 A CN 88101370A CN 198888101370 A CN198888101370 A CN 198888101370A CN 88101370 A CN88101370 A CN 88101370A CN 88101370 A CN88101370 A CN 88101370A
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China
Prior art keywords
quality
fatty acid
contain
algae
selenium
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Pending
Application number
CN198888101370A
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Chinese (zh)
Inventor
盖尔格·巴克太
彼得·利特瑞特·那格
拉热丝·盖尔格·那格
盖尔格·布拉克
米克劳丝·哥瑞斯
雅诺斯·派里那克
玛瑞雅·包瑞斯
米克劳丝·法毕安
埃塞比特·巴克
拉斯劳·巴哥那牙
加保·奶米特
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Caola Kozmetikaies Haztartasvegyipari Vallalat (hu) 90 Bocskaiut Budapest Han
Original Assignee
Caola Kozmetikaies Haztartasvegyipari Vallalat (hu) 90 Bocskaiut Budapest Han
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.)
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Application filed by Caola Kozmetikaies Haztartasvegyipari Vallalat (hu) 90 Bocskaiut Budapest Han filed Critical Caola Kozmetikaies Haztartasvegyipari Vallalat (hu) 90 Bocskaiut Budapest Han
Publication of CN88101370A publication Critical patent/CN88101370A/en
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/02—Algae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to the medicament composition that acts on cardiovascular system, what wherein contain 0.5-50% (quality) contains selenium algae and the 99.5-50% (C that contains at least 2 two keys of quality 18-22Fatty acid or derivatives thereof and with mutually blended carrier and/or additive and the antioxidant that is usually used in pharmaceuticals industry of any amount.
The present invention also provides the method for preparing this medicament composition.

Description

The present invention relates to the medicament composition that acts on cardiovascular system.
The present invention also provides these preparation of compositions methods.
Known C 18-22ω-3 insatiable hunger is closed fatty acid and is had good biological activity.Eicosapentaenoic acid in these chemical compounds (EPA) and docosahexenoic acid (DHA) are more outstanding, and Dyerberg etc. (lancet 15,117(1978)) point out that above-mentioned two kinds of acid have important and multiple biological agent.
Goodnight etc. have summed up poly-insatiable hunger and have closed the material impact (see " arteriosclerosis " 2,87(1982)) of fatty acid (particularly EPA and DHA) in the too high and thrombosis disease of blood fat.
Contain EPA and DHA and early had introduction as the medicament composition of active ingredient, as at Deutsche Bundespatent № 3,438, be used for reducing blood cholesterol level in 630, and then in the Japanese patent application № 58.08077 and 64.49097 of issue, be used for anti-sclerencephaly and prevent that the cardiac from forming thrombosis.
Several pieces of articles have reported that specially EPA and DHA can suppress platelet aggregation, thereby thrombosis is had inhibitory action.(Spencer and Caraega:, Prostagl, Leacotrienes and Med.23,129(1986); Knopp etc.; New Engl, Journ of Med.314,937(1986)).
The antivirus action of EPA and DHA has been described in United States Patent (USP) № 4,513,008.
The active ingredient of fish oil (as: EPA and DHA) is the biosynthetic precursor of PG-3 series, and they can suppress the deleterious metabolite (as: TXA that produced by so-called " arachidonic acid chain type catabolic process " (chain of the complex biochemical process that begins from arachidonic acid) 2And TXB 2) formation.
Poly-insatiable hunger is closed fatty acid and also have unhelpful pathology characteristic except that above-mentioned beneficial effect is arranged: self can be in the human organism oxidation Decomposition, form the deleterious active aldehyde material of body (as: the third two acetaldehyde).These aldehyde materials mainly react with deleterious mode and connective tissue on a kind of physiology, produce so-called " wax sample lipofuscin pigmentation ".
Known also further that since time immemorial the mankind are promptly for nutrition and edible purpose and use algae.The people that mainly are the Far East consume algae; Recently, the people of developing country use exsiccant algae or algae tablet widely.
Algae is the material with high nutritive value, because contain the necessary material of health of high concentration in the algae that does, for example: vitamin, protein has the protein complexes of trace element, saccharide, fatty acid and analog thereof are closed in poly-insatiable hunger.
Zajic has described the general and detailed condition of relevant algae in " character of algae and product " (Edition Planum, New York, 1970).
Begun the research aspect trace element and trace element biological effect over past ten years.Therefore, known selenium is one of material most important and necessary in the life.Selenic benefit mainly is the effect of its direct activation glutathion-peroxidase, because selenium is a requisite element of glutathion-peroxidase prothetic group.And this enzyme is the most important interior inhibitor of giving birth in the deleterious peroxidization process.
Selenium itself has the dead effect of the blood of reduction, can improve the ischemia of heart, and oxygen supply is not enough and the infraction situation, and can suppress central nervous system " wax sample lipofuscin pigmentation ".Selenium has benefit for periodontitis.Selenium also has effective active anticancer and confirms to have the probability of attenuating cancer development.In addition, selenium also is counted as the inhibitor of genetic gene mutation.
Selenium can not accumulated in organism, therefore should be replenished continuously.Up to now, selenium all is that form (as: selenium dioxide, sodium selenite) with inorganic compound offers human body.Many bodies change or disease (as: hepatic necrosis, myonecrosis, the destruction of erythrocyte membrane, between the matter infringement, the ST section is raised in the electrocardiogram, mulberry heart syndrome, Kwashiorkor syndrome (protein malnutrition, and multiple sclerosis), all be proved to be because shortage selenium is caused.
(" Nutrition Review " 35 such as Thressa, 7(1977)) Shamberger (" J.of Env.Path.and Tox " 4,305(1980)) and Masukawa etc. (" Experientia 39,405(1983)) all reported selenic biological agent widely.
The purpose of this invention is to provide a kind of novel medicament composition that mainly acts on cardiovascular system, this medicament composition can be with DHA, EPA, and algae and selenic superiority gather together, and remove poly-insatiable hunger simultaneously and close the worn-out sick of fatty acid.
The present invention is based on a kind of like this understanding, is about to contain selenic algae and closes fatty acid with poly-insatiable hunger and use and can achieve the above object fully.
Therefore, the present invention relates to a kind of medicament composition that acts on cardiovascular system, it contains the 0.5-50%(quality) contain selenium algae and 99.5-50%(quality) contain the C that two keys are closed at least 2 insatiable hungers 18-22The fatty acid or derivatives thereof mixes mutually with any amount and the carrier that is generally used for medicament industry and/or additive and/or antioxidant.
The present invention also further relates to the method for preparing above-mentioned composition, comprises the quality with 0.5-50%() contain selenium algae and 99.5-50%(quality) 2 insatiable hungers that have at least close the C of two keys 18-22The carrier that is generally used for pharmaceuticals industry of fatty acid or derivatives thereof and any amount and/or additive and/or antioxidant mix.
Compositions of the present invention contains suitable eicosapentaenoic acid (EPA) and docosahexenoic acid (DHA) and contains the selenium algae.
In our pending application application (Hungarian patent application number: described the method that preparation contains the selenium algae 575/88).
The C of one of compositions composition 18-22The raw material that fatty acid is closed in ω-3 insatiable hunger is a fish oil, can from various sea water and fresh-water fishes, obtain, and mainly from mackerel, morrhua, Mylopharyngodon piceus, sardine, (as: cod liver oil and shark liver oil) obtains in the liver of sepiellae seu sepiae and these fishes.
Except EPA and DHA, fatty acid and other unhydrolyzed composition are closed in the insatiable hunger that also contains a large amount of saturated fat acid and low degree in the fish oil.It is crucial removing these compositions, because can increase the amount calories of absorption and the level that improves triglyceride the blood sensitively from the dosage of the therapeutic composition of Preparation fish.In addition, may contain steroid in the unhydrolyzed composition as cholesterol, vitamin D (and provitamin) and/or vitamin A.Vitamin D and A accumulate in the human organism,, can not carry out to reaching the necessary long-term treatment of required effect with the pharmaceutical composition that contains these vitamin for this reason.Therefore from fish oil, remove these above-mentioned compositions, as: full fatty acid that insatiable hunger is closed with part and the non-hydrolysis composition (as: cholesterol, vitamin A and vitamin D) that closes.Like this, EPA and the DHA total amount in fish oil is concentrated to and surpasses 50%.
As algae, chlorella or scenedesmus use just very appropriate, and they can supply the human consumption, and owing to its very good biological effect as a kind of requisite raw material of modern nutrition.
In order to suppress the oxidation of the compositions among the present invention, be suitable for and use alpha-tocopherol (vitamin E), glutathion or traditional antioxidant as: butylated hydroxytoluene as effective antiseptic.Can use in the pharmaceuticals industry normally used material as excipient or carrier, as: lactose, starch or magnesium stearate.
Pharmaceutical research confirms: the compositions healthy effect of paying that is safe from harm, because when 100 times of the common dosage of use compositions, there is any variation in the microsomal enzyme system that does not observe rat liver.Behind combination treatment, obviously reduced in the intravital cumulant of machine with matched group comparison brown pigment.In development test, compositions of the present invention is used for the female rat of Wistar, the time was six weeks, can observe a kind of phenomenon of indubitable inhibition platelet aggregation.
Optimum effective dose every day (is that 75 kilograms people calculates by average weight) that contains the compositions of fish oil and algae powder is 2 grams, wherein contains the selenium of 240 μ g.Average fish oil composition constitute 22% EPA and 43% DHA.
The major advantage of the present composition is summarized as follows:
A) superiority with EPA and DHA and selenium and algae combines.
B) can remove by the full caused illeffects of lipoid composition and vitamin A and D that closes in the known compositions that contains fish oil.
C) can remove because the probability that fatty acid produces " wax sample lipofuscin pigmentation " is closed in the poly-insatiable hunger of application.
D) contain selenium in the compositions and in algae, concentrated as a kind of natural materials, when selenium after algae is taken, selenium can heavily absorb better and can more effectively bring into play its effect.
E) compositions has therapeutical effect preferably for atopy pathological changes patient, can be used for eczema, asthma, allergic conditions, allergic rhinitis and/or atopy pathological changes, as: migraine, segmental enteritis, ulcerative colitis, otitis media, the prophylactic treatment of the nephrotic syndrome and diabetes.
Compositions of the present invention is particularly useful for the treatment of cardiovascular system diseases, is used for apoplexy, thromboembolism, and as apoplexy, infraction and young patient's Keshan ' s syndrome and the prevention that is used for improper situation.
Following nonrestrictive experimental example can describe the application of invention in detail.
Can prepare the poly-insatiable hunger of the ω-3 that is used for the present composition according to experimental example 1 and 2 and close fatty acid, be rich in selenic algae and can prepare according to experimental example 3.Experimental example 4-6 has described medicament composition of the present invention.
Experimental example 1
The NaOH of 2Kg is dissolved in 70 liters 95% ethanol, again under 50-60 ℃ of temperature to the cod liver oil that wherein adds 10Kg.Mixture in refluxed under nitrogen 2 hours, is stirred and is cooled to 10 ℃, be settled out the sodium salt that fatty acid is closed in insatiable hunger.Leach crystallization and use a little washing with alcohol.Ethanol evaporation filtrate is boiled boiled-out water with 20 liters again and is added in the residue, and 5 liters of hexane extractions of reuse to be removing non-hydrolization compound fully, as: cholesterol.The pH value that makes water that adds sulfuric acid acidation is 2,15 liters of hexane extractions of reuse.Wash organic facies with water, dry on anhydrous sodium sulfate, evaporate, obtain the enriched oil of 3.2Kg, wherein DHA content is 36.8%, EPA content is 31.8%.Oil is for brown and have fish and smell flavor.Again it is mixed with the bleaching soil phase, under nitrogen, heated 10 minutes and filtered while hot in 105 ℃.The tasteless nothing of glassy yellow that obtains 1.6Kg was smelt oil to the distillation of 170 ℃/1 millimetres of mercury with deodorization in 3 hours under vacuum, and component content is constant.
Experimental example 2
Be added drop-wise under 50-60 ℃ in the cod liver oil of 24Kg in the 40%NaOH solution that stirs down 8Kg, this oil is to be dissolved under 60 ℃ in 16 liters the methanol.Again mixture was stirred 45 minutes down in 60 ℃.Under about 60 ℃, 15% hydrochloric acid of 20Kg is joined in the solution again.After the separation, use the 15% salt pickling organic facies of 10Kg, and then wash until neutrality with 180 liters of hot tap-waters.After the phase-splitting, 100 liters of acetone are joined in the oil phase again, be heated to about 45 ℃ then, the solution that again the 3.8Kg lithium hydroxide monohydrate is dissolved in 30 premium on currency adds wherein.Stir after 30 minutes, mixture is placed spent the night, filter, evaporation acetone filtrate.The 15% hcl acidifying residue that adds about 8Kg is with hexane extraction 3 times and evaporation.Whole purification process process should be carried out under nitrogen.Get the pure fish oil of 6.4Kg, wherein the counting of iodine is 258, and the counting of acid is 160.
Above-mentioned 1Kg purification cod liver oil is added drop-wise under 60 ℃ in 9 liters of methanol solutions of the carbamide that contains 3kg.Under same temperature, stirred the mixture 2 hours, then cooling.Under-10 ℃, place and spend the night, filter, filtrate is evaporated.2.5 liters 1: 1 hydrochloric acid is joined in the residue, mixture was stirred 15 minutes.Behind hexane extraction, wash hexane with water until neutrality, dry and evaporation on anhydrous sodium sulfate, fatty acid is closed in ω-3 insatiable hunger that obtains 0.34kg, and the counting of iodine is 315, wherein contains 24% EPA and 42% DHA.
Experimental example 3
The culture medium of 8 liters of Knop-Pringsheim is packed in the vial of cultivation algae of 10 liters of capacity, add the sodium selenite of 40mg again.The cultivation that so obtains was sterilized 30 minutes for following 121 ℃ based on the high pressure of 1 crust.Then, cool off this antiseptic solution, with pure Scenedesmus obtisiusculus(scenedesmus) cultivate and to be inoculated in this solution, therefore planting algae is easy to take in selenium.To contain the 5%(volume) CO 2Filtrated air feed down culture medium in 25 ℃, whole system is thrown light on a discharge tube, wavelength 440-700 μ m, 4000 luxs.Cultivate after 14 days, algae is separated from culture medium, the algae piece with the ultrasonic treatment gained carefully is dried under the temperature below 65 ℃.Get the algae powder of 6g, wherein selenic content is 1200 μ g/g.
Experimental example 4
100g is contained selenium algae powder (Se content: 260 μ g/g) join 65% of 150 grams and concentrate in the cod liver oil (containing 22%EPA and 43%DHA), behind the mixing, add 0.1% vitamin E again.Pack into the active ingredient that so obtains in the soft capsule and enclose in the porous paillon foil.
Experimental example 5
The method of reference example 4 is operated, and only uses following raw material: 65% cod liver oil (EPA content is 22%, DHA content 43%) of 400 grams; 70.6 gram contain selenium algae powder (1200 μ g/g); 0.4 the vitamin E of gram.Pack into behind the mixing and can hold in the capsule of 500mg active ingredient.
Experimental example 6
Use known medicament apparatus and method preparation to contain the tablet of following compositions:
Contain concentrated EPA and DHA(EPA content 22%,
DHA content 43%) and contain 0.1% vitamin E
Cod liver oil 200mg
Contain selenium algae powder (Se content: 86mg 1500 μ g/g)
Lactose 140mg
Starch 60mg
Polyvinylpyrrolidone 3.5mg
Magnesium stearate 3.5mg
If desired, can in pelleter, give the tablet sugar coating.

Claims (10)

1, a kind of medicament composition that acts on cardiovascular system wherein comprises the C that two keys are closed in two insatiable hungers that has that contains selenium algae and 99.5-50% (quality) of 0.5-50% (quality) 18-22The fatty acid or derivatives thereof and with blended carrier and/or additive and the antioxidant that is generally used for pharmaceuticals industry of any amount.
2, the compositions in the claim 1 wherein comprises the 5-35%(quality) contain the selenium algae.
3, the compositions in the claim 1 wherein comprises the 15-25%(quality) contain the selenium algae.
4, the compositions in the claim 1, wherein comprise 95-65% (quality) contain the C that two keys are closed in 2 insatiable hungers at least 18-22The fatty acid or derivatives thereof.
5, the compositions in the claim 1 wherein comprises the 85-75%(quality) the C that contains 2 unsaturated double-bonds at least 18-22The fatty acid or derivatives thereof.
6, the medicament composition of any one among the claim 1-5 wherein comprises the fatty acid that is extracted and closes fatty acid as insatiable hunger from sea water fish oil.
7, the medicament composition of any one among the claim 1-6 wherein comprises 5,8,11,14,17-eicosapentaenoic acid and 4,7,10,13,16, and the 19-docosahexenoic acid closes fatty acid as insatiable hunger.
8, a kind of preparation acts on the method for the medicament composition of cardiovascular system, comprising with the 0.5-50%(quality) contain selenium algae and 99.5-50%(quality) contain the C that two keys are closed in 2 insatiable hungers at least 18-22Be generally used for the carrier in the pharmaceuticals industry and/or additive and antioxidant of fatty acid or derivatives thereof and any amount mix.
9, a preparation method in the claim 8 wherein is with the 5-35%(quality) contain selenium algae and 95-65%(quality) contain the C that two keys are closed in 2 insatiable hungers at least 18-22Fatty acid mixes mutually.
10, a preparation method in the claim 8 wherein is with the 15-25%(quality) contain selenium algae and 85-75%(quality) contain the C that two keys are closed in 2 insatiable hungers at least 18-22Fatty acid mixes mutually.
CN198888101370A 1987-03-18 1988-03-18 Act on pharmaceutical composition of cardiovascular system and preparation method thereof Pending CN88101370A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU871173A HU204199B (en) 1987-03-18 1987-03-18 Process for producing pharmaceutical compositions containing unsaturated fatty acids and selenium as active components
HU1173/87 1987-03-18

Publications (1)

Publication Number Publication Date
CN88101370A true CN88101370A (en) 1988-11-09

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CN (1) CN88101370A (en)
AT (1) AT395818B (en)
AU (1) AU610141B2 (en)
BE (1) BE1002428A3 (en)
CH (1) CH675075A5 (en)
DD (1) DD280904A5 (en)
DE (1) DE3809225A1 (en)
DK (1) DK148788A (en)
ES (1) ES2009569A6 (en)
FI (1) FI881307A (en)
FR (1) FR2612399B1 (en)
GB (1) GB2203042B (en)
GR (1) GR1000447B (en)
HU (1) HU204199B (en)
IL (1) IL85776A (en)
IT (1) IT1216142B (en)
LU (1) LU87169A1 (en)
NL (1) NL8800693A (en)
NO (1) NO881214L (en)
PT (1) PT87017B (en)
SE (1) SE8800988L (en)
YU (1) YU55388A (en)
ZA (1) ZA881957B (en)

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Publication number Priority date Publication date Assignee Title
HU210122B (en) * 1988-03-23 1995-02-28 Biorex Kutato Fejlesztoe Kft Process for production of composition against thromboembolytic conditions of circulating system and heart
DE3901048A1 (en) * 1989-01-14 1990-07-19 Chimicasa Gmbh ANTIKACHECTIKUM
GB9001121D0 (en) * 1990-01-18 1990-03-21 Efamol Holdings Efa compositions and therapy
GB2363331B (en) * 2000-06-17 2003-02-05 Raymond Clifford Noble Supplement to enhance fertility
FR2816211B1 (en) * 2000-11-08 2005-04-01 Brif NEW DIETETIC AND / OR COSMETIC COMPOSITIONS FOR IMPROVING MUCOUS DROUGHT
US20040076695A1 (en) 2002-07-08 2004-04-22 Advanced Vision Research EPA and DHA enriched omega-3 supplement for the treatment of dry eye, meibomianitis and xerostomia
AU2003214316A1 (en) * 2003-01-14 2004-09-06 Francois Bruneau Photosynthetic micro-organisms enriched with biologically-active molecules, preparation method thereof and uses of same
CN107998227A (en) * 2016-10-28 2018-05-08 新时代健康产业（集团）有限公司 A kind of health products of cardioprotection and preparation method thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4513008A (en) * 1982-07-30 1985-04-23 The Vinoxen Company, Inc. Virucidal compositions and therapy
CA1239587A (en) * 1983-10-24 1988-07-26 David Rubin Combined fatty acid composition for lowering blood cholestrol and triglyceride levels

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JPS6427A (en) 1989-01-05
GR1000447B (en) 1992-07-30
DD280904A5 (en) 1990-07-25
GR880100170A (en) 1989-01-31
IL85776A (en) 1992-09-06
FI881307A0 (en) 1988-03-18
GB2203042B (en) 1990-10-03
AU610141B2 (en) 1991-05-16
AT395818B (en) 1993-03-25
SE8800988L (en) 1988-09-19
IT8819838A0 (en) 1988-03-18
FI881307A (en) 1988-09-19
IL85776A0 (en) 1988-09-30
FR2612399B1 (en) 1991-03-29
GB8806530D0 (en) 1988-04-20
CH675075A5 (en) 1990-08-31
NL8800693A (en) 1988-10-17
ZA881957B (en) 1989-01-25
NO881214L (en) 1988-09-19
HUT52388A (en) 1990-07-28
BE1002428A3 (en) 1991-02-05
DK148788D0 (en) 1988-03-18
FR2612399A1 (en) 1988-09-23
ES2009569A6 (en) 1989-10-01
DK148788A (en) 1988-09-19
PT87017A (en) 1988-04-01
PT87017B (en) 1992-06-30
HU204199B (en) 1991-12-30
IT1216142B (en) 1990-02-22
AU1326188A (en) 1988-09-22
YU55388A (en) 1989-10-31
GB2203042A (en) 1988-10-12
SE8800988D0 (en) 1988-03-18
ATA73788A (en) 1992-08-15
NO881214D0 (en) 1988-03-18
LU87169A1 (en) 1989-10-26
DE3809225A1 (en) 1988-11-03

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