EP0203118A1 - Verfahren zur herstellung von fettsäuren, insbesonderem gamma-linolensäure ab tetrahymena, erhaltene produkte und pharmazeutische präparate oder nahrungsmittel enthaltend gamma-linolensäure oder derivate davon als antiagglutinationsmittel für blutplättchen - Google Patents

Verfahren zur herstellung von fettsäuren, insbesonderem gamma-linolensäure ab tetrahymena, erhaltene produkte und pharmazeutische präparate oder nahrungsmittel enthaltend gamma-linolensäure oder derivate davon als antiagglutinationsmittel für blutplättchen

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Publication number
EP0203118A1
EP0203118A1 EP85905749A EP85905749A EP0203118A1 EP 0203118 A1 EP0203118 A1 EP 0203118A1 EP 85905749 A EP85905749 A EP 85905749A EP 85905749 A EP85905749 A EP 85905749A EP 0203118 A1 EP0203118 A1 EP 0203118A1
Authority
EP
European Patent Office
Prior art keywords
linolenic acid
acid
tetrahymena
fatty acids
aggregation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP85905749A
Other languages
English (en)
French (fr)
Inventor
Raymond Devis
Rachad Saliba
Philippe Thonart
Claude Artois
Daniel Dive
Jean Guillaume
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
FACULTE DES SCIENCES AGRONOMIQUES DE L'ETAT
Universite Catholique de Louvain UCL
Institut National de la Sante et de la Recherche Medicale INSERM
Original Assignee
FACULTE DES SCIENCES AGRONOMIQUES DE L'ETAT
Universite Catholique de Louvain UCL
Institut National de la Sante et de la Recherche Medicale INSERM
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by FACULTE DES SCIENCES AGRONOMIQUES DE L'ETAT, Universite Catholique de Louvain UCL, Institut National de la Sante et de la Recherche Medicale INSERM filed Critical FACULTE DES SCIENCES AGRONOMIQUES DE L'ETAT
Publication of EP0203118A1 publication Critical patent/EP0203118A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/64—Fats; Fatty oils; Ester-type waxes; Higher fatty acids, i.e. having at least seven carbon atoms in an unbroken chain bound to a carboxyl group; Oxidised oils or fats
    • C12P7/6409—Fatty acids
    • C12P7/6427—Polyunsaturated fatty acids [PUFA], i.e. having two or more double bonds in their backbone
    • C12P7/6431—Linoleic acids [18:2[n-6]]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/64—Fats; Fatty oils; Ester-type waxes; Higher fatty acids, i.e. having at least seven carbon atoms in an unbroken chain bound to a carboxyl group; Oxidised oils or fats
    • C12P7/6436—Fatty acid esters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/64—Fats; Fatty oils; Ester-type waxes; Higher fatty acids, i.e. having at least seven carbon atoms in an unbroken chain bound to a carboxyl group; Oxidised oils or fats
    • C12P7/6436—Fatty acid esters
    • C12P7/6445—Glycerides
    • C12P7/6472—Glycerides containing polyunsaturated fatty acid [PUFA] residues, i.e. having two or more double bonds in their backbone

Definitions

  • the present invention is based on an in-depth study of the biochemistry and metabolism of postaglanins in superior vertebrates - including humans - which has led to admitting the possibility of the nonphysiological nature of prostaglandins. These seem to have no specific role; they act mainly by an unnecessary mimicry of the protein hormones and some of them are even dangerous for the body, especially most of those from arachidonic acid, including especially the endoperoxides PGG2 and PGH2 and thromboxane Tx 2 One of their metabolites, responsible for irreversible platelet aggregation.
  • prostaglandins have predominantly dietary precursors and therefore fortuitous.
  • the aim of the present invention is to find a way to neutralize the dangerous effects of 1 'aci' arachidonic whose excess can be responsible for irreversible platelet aggregation and therefore tromboses vascular and stroke.
  • the object of the invention can be achieved by a process characterized in that it comprises at least the stages of production of the Tetrahymena ciliated protozoa in an adequate medium and the extraction of total fatty acids of said Tetrahymena. These fatty acids do not contain any toxic individuals and can be easily identified and measured.
  • Tetrahymena fatty acids are characterized by their richness in 7-linolenic or cis-6,9,12- octadecatrienoic acid which constitutes, depending on the strains and the culture conditions, 20 to 45% by weight of the total fatty acids and by the presence , among others, oleic and cilienic acids which constitute, respectively and according to the strains and the culture conditions, 1 to 15% and 1 to 10% by weight of the total fatty acids.
  • Tetrahymena oil whose anti-platelet aggregation properties were tested and quantified on a series of human plasmas from young subjects (25 to 35 years old) of the male sex.
  • linolenic acid alone, has a relatively less anti-platelet aggregation effect
  • Tetrahymena oil is harmless: this oil can constitute a food or a food additive whose anti-aggregating action is thus opposed to that, always dangerous in the long run, of "medicated" anti-aggregating agents. , such as aspirin and corticosteroids.
  • Tetrahymena of which that of T. rostrata is available, was preferred because it exhibits the fastest growth in the skimmed milk-yeast medium or yeast extract medium used.
  • Tetrahymena is carried out in a fermenter.
  • the preferred culture medium consists of skimmed milk and yeast or yeast extract.
  • the invention therefore also relates to the products resulting from the aforementioned process and to medicamentous or food preparations, in particular for dietetic use, containing at least 7 -linolenic acid in the form of free acid or in the form of a derivative in particular in the form of an ester, preferably in the form of a methyl ester.
  • Said medicinal or food preparations may contain either directly the product, qualified as extraction of Tetrahymena oil, or one or more of : s constituents of this oil, namely at least 7 -linolenic acid or a derivative of '' and possibly other constituents exerting an anti-platelet aggregation effect or other effects.
  • 7-linolenic acid derivative is also understood to mean dihomo-7-linolenic acid and its esters.
  • fatty acids can be used in the form of derivatives, such as fatty acid esters, in particular methyl esters.
  • fatty acid derivatives are carried out by the conventional methods of organic synthesis and, in the particular case of the formation of an ester by the conventional techniques of esterification.
  • Medicinal or food preparations can of course contain other constituents, in particular adjuvants useful for the desired activity such as vitamin E (-tocopherol acetate).
  • additives for convenient administration.
  • additives can be solid or liquid, organic or inorganic pharmaceutical carriers or auxiliaries, suitable such as water, organic solvents of paraffinic type, gelatin, lactose, starch, magné ⁇ stearate. sium, talc, adequate vegetable and animal fats and oils, gum, polyalkylene glycols or binders and other usual agents.
  • compositions according to the invention generally contain at least 30% by weight of 7-linolenic acid or the equivalent of its derivatives and possibly of adjuvant substances.
  • compositions according to the invention can be administered in human medicine orally in dosage units containing more than 20% by weight of -linolenic acid or the equivalent of its derivatives, with a non-toxic support acceptable in pharmacies.
  • dosage unit is meant a unit dose which can be administered to a patient and can easily be handled and conditioned, remaining in the form of a physically stable unit dose, comprising the active ingredient. either alone or as a mixture with solid or liquid pharmaceutical diluents or carriers.
  • the pharmaceutical compositions according to the invention can be administered one to several times a day, at appropriate intervals, but always according to the condition of the patient and according to the prescriptions of the doctor.
  • the appropriate daily dose of the compositions according to the invention generally ranges from 20 mg to 150 mg per kg of bodyweight.
  • Example 1 Production of fatty acids from Tetrahymena.
  • the active part of the air filters is a sintered stainless steel cartridge with a thickness of 2 mm.
  • the sterile air is introduced at the base of the fermen ⁇ tors via a rotary sparger secured to the shaker shaft ( Figure 32).
  • Fermenters are equipped with automatic regulation, recording and digital display systems for pH, temperature and stirring speed (depending on the concentration of dissolved O2).
  • a computer Hewlett-Packard 9826; printer: Hewlett-Packard 2671G; Interface; Hewlett-Packard 6942A Multiprogram
  • the pH is measured by a pH meter (Tacussel) connected to a sterilizable probe (Ingold) pres ⁇ sure with compressed air. Buffers, at pH 4 and 7, are used for calibration.
  • solutions of H2SO42N connected to the fermenters via variable speed peristaltic pumps.
  • the dissolved O2 is measured by "a sterilizable galvanic probe (Biolafitte, model
  • Dissolved LO2 is expressed in percent: the 100% corresponds to a medium saturated with O2 in the absence of Tetrahymena.
  • the temperature is measured by a platinum probe (Biolafitte).
  • the temperature regulation is ensured by a circulation of water ther o- stated in an exchanger formed by a flattened stainless steel tube immersed in the culture medium.
  • a liquid container of anti-foam (Antifoam Emulsion, Sigma No. A.5758) is connected to fermenter 100 liters via a peristaltic pump which starts to operate as soon as the foam comes into contact with an electrode adjustable in height.
  • the anti-foaming liquid is added mechanically.
  • a device (Funda) fixed on the upper stage of the 20 liter fermenter, ensures the pumping and breaking of the foams thanks to its rotating discs. _,
  • Sterilization of the .fermen ⁇ tor containing the culture media is carried out at 110-115 ° C for 30 minutes with stirring. Sterilization is carried out with steam, indirectly up to 100 ° C, then beyond, with a slight admission of steam by the air diffuser to compensate for evaporation and sterilize the stirring shaft sealing device and the sterile air intake circuit. All the connection pipes are sterilized by allowing the steam to escape through the traps. Steam is introduced directly against the current into the air filters;
  • the media are sterilized by autoclaving at 110-115 ° C for 30 minutes.
  • the aqueous H2S042n solution (see below) contained in an Erlenmeyer flask is sterilized by autoclaving. age at 120-125 ° C for 20 minutes.
  • methyl esters are analyzed by gas chromatography with, as internal standard, methyl nonadecanoate and standard mixtures and with a column of polyethylene glycol succinate.
  • the peripheral speed of the turbines has, for each fermenter, a minimum value which amounts to 0.94 meters / second for the fermenter of 20 liters and to 1.69 meters / secone for the 100 liter fermenter.
  • the speed is adjusted so that it keeps its minimum value until the concentration of dissolved O2 becomes less than 40%. In this case, it increases in proportion to the difference.
  • skim milk powder of 1% (w / v) each.
  • the starting pH is fixed at around 5.5 by H2SO4, it initially decreases slightly probably as a result of the increase in the CO2 concentration at the start of growth, then increases rapidly to reach the value 7 where it will be fixed by automatic pumping of H2S042N.
  • the yield compared to lactose considering that the milk powder contains 50% lac ⁇ tose is 40.1%.
  • Example 2 Action of Tetrahymena fatty acids on platelet aggregation in vitro. The principle of the measurement method The exploration of platelet aggregation was carried out killed by a photometric method. ' It consists of
  • an aggregation inducer to plasma enriched in platelets, an aggregation inducer, the most common of which are ADP, adrena ⁇ line (or epinephrine) and collagen.
  • ADP adrena ⁇ line
  • epinephrine adrena ⁇ line
  • collagen adrena ⁇ line
  • optical transmission increases with the formation of platelet aggregates and decreases when disaggregation occurs.
  • This photometric method allows qualitative and quantitative observation of the aggregation phenomenon and makes it possible to detect certain plasma or platelet anomalies which result in an absence of aggregation (thrombopathies) or in hyperaggregation (thrombophilia).
  • the two aggregation waves (the reversible) and the irreversible) can be followed with a photometric device, the aggregometer.
  • the aggregometer Depending on the aggregating agent added to the platelet-rich plasma, one of the two phases may be missing.
  • the first phase or reversible phase is absent and the response is characterized by a lag time followed directly by the irreversible aggregation phase.
  • ADP the two phases are generally present and the response to the aggregometer is therefore biphasic.
  • the concentration of ADP or the blood donor the first phase of aggregation may not be followed by the second.
  • the two phases may not be separated over time and are therefore not distinguished using the aggregometer.
  • the incubation of a plasma enriched in platelets, with an inhibitor of one and / or the other of the two aggregation phases, modifies the platelet response to the aggregating agent: the fact is detected at 1 aggregometer.
  • An anti-aggregant inhibiting the second phase of aggregation for example, attenuates or decreases, during an in vitro test, the response to collagen and the second curve of the response to ADP.
  • the platelet aggregation is monitored, at 25 ⁇ 2 ° C, with a Born Aggregometer MK.III device (from the Pharmacological-Research, Department of Pharmacology, Royal College of Surgeons, London - England) to which is connected a Perkin-Elmer Recor ⁇ der 56 recorder.
  • a monochromatic light ray of 640 nm passes through a silicone glass bowl (10 x 75 mm) containing 1 ml of blood plasma enriched in platelets (PRP).
  • PRP blood plasma enriched in platelets
  • a small magnetic bar covered with poly- ethylene and performing 1150 revolutions / minute, ensures the agi ⁇ tation of the plasma in the bowl.
  • PRP represents 0% optical transmission and a plasma low in platelets (PPP) represents 100% transmission.
  • the addition of an aggregating agent (ADP or collagen) to PRP is followed by a variation in optical transmission. This variation is recorded for 6 minutes, in accordance with the conventional operating mode.
  • Blood donors Seven male blood donors, under the age of 35, fasting for at least 9 hours and without any medical treatment.
  • PRP and PPP all the utensils used are made of silicone glass or plastic.
  • the blood is taken from citrate: 1 volume of 3.8% citrate (weight / volume) in distilled water for 9 volumes of blood.
  • the PRP is obtained by centrifuging the blood at 300 g for 9 minutes.
  • the platelets of the supernatant are counted using a coulter counter (model ZF, orifice of the electrode 70 microns) and if the number is greater than 300,000 platelets / mm ⁇ , it is adjusted to this value by dilution with PPP.
  • the PPP is obtained by centrifuging the blood at 2000 g for 10 minutes.
  • the PRP and PPP are kept at laboratory temperature during the analysis.
  • Collagen (Stago) is diluted with Micha ' ⁇ lis buffer to a concentration of 400 ⁇ g / ml. Incubate in a water bath at 37 ° C for 10 minutes to polymerize the collagen.
  • the ADP and collagen solutions are stored in the melting ice during the analysis.
  • this test is repeated at regular intervals (2 to 4 times) during the analysis.
  • the results of the collagen aggregation are expressed by the aggregation at 6 minutes from the single aggregation wave B obtained;
  • the results will be expressed by the maximum aggregation of the first wave A and by the 6-minute aggregation of the second wave B.
  • the two waves are not separated in time and the results have been expressed by the intensity of the aggregation at 6 minutes.
  • the aggregation in first or second phase represents the difference in optical transmission between the PRP (0%) and respectively the highest point of wave A and the point reached at the 6th minute for wave B.
  • normal responses means the results recorded in the presence of an aggregator, but in the absence of the substance to be tested.
  • the "blank” tests carried out at regular intervals during the analysis, allow us to calculate the "normal” response of each blood donor.
  • the aggregation obtained with the same aggregating agent, but in the presence of one of the products tested, is compared to that of the normal response.
  • the following example illustrates our calculation method: for the first blood donor, two "blank" tests with 40 ⁇ g of collagen / ml of PRP provided aggregations at 6 minutes, respectively 81.7%
  • This value is greater than E and is therefore significant.
  • Table 2 provides, for each blood donor, the platelet concentration in PRP and the "normal responses" (with E values) to collagen (40 ⁇ g / ml) and ADP (0.25 ⁇ g / ml).
  • methyl y-linolenate is an inhibitor of platelet aggregation and preferentially inhibits the second wave of aggregation at ADP or the unique B collagen aggregation wave.
  • inhibition of the second wave of ADP aggregation is present in four PRPs (out of the five tested) and the average is around 55%.
  • Inhibition of the first wave of aggregation is present, but weakly, in two PRPs, and is not significant in the other two. It could not be measured in the fifth (donor 2).
  • the average (in four PRPs) is very insignificant and is around 10%.
  • the ADP aggregation tests show that the second wave of aggregation is inhibited, on average (for the two PRPs tested) by about 65% and the first wave is inhibited about 29%.
  • dihomo- ⁇ -linolenic (from 7 -linolenic) is faster than its transformation into arachidonic and an equilibrium (dynamic), characterized by an increase in the ratio of dihomo-7-linolenic / arachidonic concentrations , installs in .the ⁇ - plates.
  • the concentration of 7 -linolenic acid and the time required to reach this balance vary from subject to subject. It is possible that this concentration may be less than 1 mg / ml, which would explain the similar responses observed with the concentrations of 1 and 6 mg / ml. Likewise, the equilibrium in question, which supposes a significant reduction in the amount of arachidonic acid present in the plates, does not however completely eliminate this acid. This would prevent total inhibition of the aggregation.
  • Vitamin E By mixing a rich source of 7-linolenic acid (or 7-linolenic acid itself) with vitamin E in food, the antiagregant power of this source is increased. Vitamin E also has another role in the mixture: to prevent, as an antioxidant, the degradation of unsaturated acids including, above all, 7-linolenic.
  • the inhibition reached an average of 54%, - but for two PRPs (donors 5 and 6), it was greater than 80% (see figures) at concentrations greater than 575 ⁇ g / ml, the inhibition is, on average, greater than 70%.
  • the inhibition of the first wave of aggregation is, on average, only significant from concentrations above 230 ⁇ g / ml where it reaches around 15% .
  • Inhibition of the second wave of ADP aggregation reaches approximately 30% at 57.5 ⁇ g / ml, approximately 50% at 115 ⁇ g / ml and becomes greater than 70% from 575 ⁇ g / ml .
  • the inhibition mainly affects wave B (irreversible) and that a fatty acid concentration greater than 230 ⁇ g / ml must be exceeded to detect significant inhibition of the first aggregation wave.
  • the mixture of fatty acids of T. rostrata contains (by weight) about 30% 7 -linolenic acid and about 10% oleic acid. These two acids, taken separately, have only very weak inhibitions compared to the mixture of fatty acids of Tetrahymena and the simple summation of these three inhibitions in pairs (taking into account, * for example, the respective contents and results tables 2 and 3) cannot, in any case, explain the powerful anti-aggregating power of the mixture ge. To try to explain this power, several hypo-
  • oleic acid is a cyclooxygenase inhibitor: it binds to the enzyme without being a substrate of it.
  • Dihomo-7-linolenic and arachidonic acids are, by contrast, substrates.
  • concentration of each of them as well as the respective affinities of the enzyme determine the acid which will preferably be fixed. It can be assumed that the affinity of the cyclooxygenase for the dihomo- ⁇ -linolenic is the most , important and that the competition, in the presence of the three acids, is mainly between arachidonic and oleic.
  • the antiagregant effect due to the increase in dihomo-7-linolenic acid would be augmented by another antiagregant effect: that due to the inhibition by oleic acid of the binding of arachidonic acid to cyclooxygenase.
  • the possible intervention of cilienic acid would have an identical or analogous explanation.
  • Tetra ⁇ hymena fatty acids constitutes in itself a powerful antiagre- glove. Its power far exceeds those of ' acids
  • N.S. non-significant values based on the values of E in Table 1.
  • M average of the values (non-significant values are considered to be zero). M is not significant if it is less than or equal to the average of E.

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EP85905749A 1984-12-03 1985-11-25 Verfahren zur herstellung von fettsäuren, insbesonderem gamma-linolensäure ab tetrahymena, erhaltene produkte und pharmazeutische präparate oder nahrungsmittel enthaltend gamma-linolensäure oder derivate davon als antiagglutinationsmittel für blutplättchen Withdrawn EP0203118A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8418393 1984-12-03
FR8418393A FR2574089B1 (fr) 1984-12-03 1984-12-03 Procede de production d'acides gras, en particulier d'acide g-linoleique a partir de tetrahymena, produits obtenus et preparation medicamenteuse ou alimentaire contenant de l'acide g-linolenique ou ses derives en tant qu'agent anti-agregation plaquettaire

Publications (1)

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EP0203118A1 true EP0203118A1 (de) 1986-12-03

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EP85905749A Withdrawn EP0203118A1 (de) 1984-12-03 1985-11-25 Verfahren zur herstellung von fettsäuren, insbesonderem gamma-linolensäure ab tetrahymena, erhaltene produkte und pharmazeutische präparate oder nahrungsmittel enthaltend gamma-linolensäure oder derivate davon als antiagglutinationsmittel für blutplättchen

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EP (1) EP0203118A1 (de)
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WO (1) WO1986003518A1 (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0252716B1 (de) * 1986-07-08 1993-01-07 Suntory Limited Verfahren zur Herstellung von Bishomo-Gamma-Linolensäure und Eicosapentaensäure
JP2746371B2 (ja) * 1987-12-21 1998-05-06 サントリー株式会社 ビスホモ−γ−リノレン酸及びこれを含有する脂質の製造方法
JP3070611B2 (ja) * 1989-03-07 2000-07-31 サントリー株式会社 △▲上５▼―不飽和化酵素阻害剤
WO1993020717A2 (en) * 1992-04-13 1993-10-28 Research Corporation Technologies, Inc. Reducing gastrointestinal irritation in infant nutrition
EP0708176B1 (de) * 1994-10-21 2004-10-06 Nutrinova Nutrition Specialties & Food Ingredients GmbH Verfahren zur Kultivierung lipidabhängiger Tetrahymeniden und ein Verfahren zur Herstellung von biogenen Wertstoffen aus lipidabhängigen Tetrahymeniden
DE19903095C2 (de) * 1999-01-27 2003-05-22 Nutrinova Gmbh Gewinnung von gamma-Linolensäure aus Protozoen der Gattung Colpidium
WO2001019201A1 (en) * 1999-09-13 2001-03-22 Florin Christensen Jorge Methods for treating cholesterol-containing foodstuffs using live ciliates
US6534100B1 (en) 1999-09-13 2003-03-18 German A. Valcarce Methods for treating cholesterol-containing foodstuffs using live ciliates
DE10106660A1 (de) * 2001-02-12 2002-08-29 Celanese Ventures Gmbh Verfahren zur Herstellung von gamma-Linolensäure aus einer Ciliaten-Kultur durch Zusatz geeigneter Vorläufermoleküle zu dem Kulturmedium
DE102005058369A1 (de) * 2005-12-06 2007-06-14 Lts Lohmann Therapie-Systeme Ag Ungesättigte Fettsäuren als Thrombin-Inhibitoren

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Publication number Priority date Publication date Assignee Title
GB1580444A (en) * 1976-11-04 1980-12-03 Bio Oil Res Pharmaceutical compositions
FR2490631A1 (fr) * 1980-09-24 1982-03-26 Roussel Uclaf Nouvelle composition lipidique utilisable en dietetique, reanimation et therapeutique
US4386072A (en) * 1981-06-26 1983-05-31 Horrobin David F Treatment of disorders of inflammation and immunity and disorders associated with smooth muscle spasm and compositions therefor

Non-Patent Citations (1)

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Title
See references of WO8603518A1 *

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WO1986003518A1 (fr) 1986-06-19
FR2574089B1 (fr) 1987-04-10
FR2574089A1 (fr) 1986-06-06

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