NO324534B1 - Material prepared from a combination of non-β-oxidizable fatty acid analogues and a plant oil or fish oil and uses thereof - Google Patents
Material prepared from a combination of non-β-oxidizable fatty acid analogues and a plant oil or fish oil and uses thereof Download PDFInfo
- Publication number
- NO324534B1 NO324534B1 NO20043093A NO20043093A NO324534B1 NO 324534 B1 NO324534 B1 NO 324534B1 NO 20043093 A NO20043093 A NO 20043093A NO 20043093 A NO20043093 A NO 20043093A NO 324534 B1 NO324534 B1 NO 324534B1
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- Prior art keywords
- accordance
- fatty acid
- oil
- alkyl
- carbon
- Prior art date
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Description
OMRÅDET FOR OPPFINNELSEN FIELD OF THE INVENTION
Den foreliggende oppfinnelsen vedrører et materiale omfattende en planteolje og/eller fiskeolje og en ikke-3-oksiderbarfettsyreanalog, samt anvendelser derav. The present invention relates to a material comprising a plant oil and/or fish oil and a non-3-oxidizable fatty acid analogue, as well as applications thereof.
Anvendelse av en kombinasjon av ikke-P-oksiderbare fettsyreanaloger og en planteolje eller fiskeolje har vist overraskende synergistiske effekter. Den foreliggende oppfinnelse vedrører en sammenblanding fremstil fra en kombinasjon av ikke-P-oksiderbare fettsyreanaloger og en planteolje eller fiskeolje, og anvendelse av nevnte materialet for fremstilling av et farmasøytisk eller ernæringsmessig materiale for prevensjon og/ eller behandling av insulin resistens, obesitet, diabetes, fettlever, hyperkolesterolemi, dyslepidemi, aterosklerose, koronar hjertesykdom, trombose, stenose, sekundær stenose, myokardisk infarkt, slag, forhøyet blodtrykk, endotelisk dysfunksjon, prokoagulent tilstand, polysistisk eggstokksyndrom, metabolsk syndrom, cancer, inflammatoriske forstyrrelser og prolifererende hudforstyrrelser. The use of a combination of non-P-oxidizable fatty acid analogues and a vegetable oil or fish oil has shown surprising synergistic effects. The present invention relates to a mixture prepared from a combination of non-P-oxidizable fatty acid analogues and a plant oil or fish oil, and the use of said material for the production of a pharmaceutical or nutritional material for contraception and/or treatment of insulin resistance, obesity, diabetes, fatty liver, hypercholesterolemia, dyslipidemia, atherosclerosis, coronary heart disease, thrombosis, stenosis, secondary stenosis, myocardial infarction, stroke, elevated blood pressure, endothelial dysfunction, procoagulant state, polycystic ovary syndrome, metabolic syndrome, cancer, inflammatory disorders and proliferative skin disorders.
BAKGRUNN FOR OPPFINNELSEN BACKGROUND OF THE INVENTION
I tidligere patentsøknader har oppfinner beskrevet nyttige applikasjoner av ikke-P-oksiderbare fettsyreanaloger ifølge foreliggende oppfinnelse i behandling og hindring av obesitet (NO 2000 5461), diabetes (NO 2000 5462), primær og sekundær stenose (NO 2000 5463), cancer (NO 2002 5930), prolifererende hudforstyrrelser (NO 2003 1080), inflammatoriske og autoimmune forstyrrelser (NO 2003 2054). Det er tidligere kjent at oljer kan ha fordelaktige effekter (Dallongeville et al, J. Biol. Chem. Vol 276, No. 7, pp. 4634-4639. 2001 og Demoz et al, Biochemica et Biophysica Acta 1199, pp 238-244. 1994). In previous patent applications, the inventor has described useful applications of non-P-oxidizable fatty acid analogues according to the present invention in the treatment and prevention of obesity (NO 2000 5461), diabetes (NO 2000 5462), primary and secondary stenosis (NO 2000 5463), cancer (NO 2002 5930), proliferative skin disorders (NO 2003 1080), inflammatory and autoimmune disorders (NO 2003 2054). It is previously known that oils can have beneficial effects (Dallongeville et al, J. Biol. Chem. Vol 276, No. 7, pp. 4634-4639. 2001 and Demoz et al, Biochemica et Biophysica Acta 1199, pp 238-244 . 1994).
Overraskende har oppfinnerne funnet at anvendelse av en konvensjon av ikke-oksiderbare fettsyreanaloger med en planteolje eller fiskeolje har synergistiske nyttige biologiske effekter. Oppfinnerne har vist at kombinasjonen av ikke-oksiderbare fettsyreanaloger med en planteolje eller fiskeolje senker konsentrasjonen av plasmakolesterol, triglyserider og fosfolipider, og øker fettacyl CoA oksidase aktivitet. Basert på disse uventede funn forventes det at kombinasjonen av ikke-P-oksiderbare fettsyreanaloger og en planteolje eller fiskeolje vil ha en øket preventiv og/ eller terapeutisk effekt på alle sykdommer som de ikke-P-oksiderbare fettsyreanaloger er effektive mot, sammenlignet med effekten av fettsyreanaloger alene. Surprisingly, the inventors have found that using a convention of non-oxidizable fatty acid analogs with a vegetable oil or fish oil has synergistic beneficial biological effects. The inventors have shown that the combination of non-oxidizable fatty acid analogues with a plant oil or fish oil lowers the concentration of plasma cholesterol, triglycerides and phospholipids, and increases fatty acyl CoA oxidase activity. Based on these unexpected findings, it is expected that the combination of non-P-oxidizable fatty acid analogs and a plant oil or fish oil will have an increased preventive and/or therapeutic effect on all diseases that the non-P-oxidizable fatty acid analogs are effective against, compared to the effect of fatty acid analogues alone.
DETALJERT BESKRIVELSE AV OPPFINNELSEN DETAILED DESCRIPTION OF THE INVENTION
Den foreliggende oppfinnelse vedrører et materiale og anvendelse av et preparat omfattende en kombinasjon av: The present invention relates to a material and the use of a preparation comprising a combination of:
i) en planteolje eller fiskeolje, og i) a vegetable oil or fish oil, and
ii) en ikke-P-oksiderbarfettsyreanalog, hvor nevnte ikke-P-oksiderbare fettsyreanalog har følgende generelle formel (I) ii) a non-P-oxidizable fatty acid analog, wherein said non-P-oxidizable fatty acid analog has the following general formula (I)
Ri-[x;-CH2]n-COOR2Ri-[x;-CH2]n-COOR2
- hvor Ri er et C1-C24 alkyl, alkenyl eller alkynyl, og - where R 1 is a C1-C24 alkyl, alkenyl or alkynyl, and
- hvor R2 representerer hydrogen eller C1-C4 alkyl, og - where R2 represents hydrogen or C1-C4 alkyl, and
- hvor n er et heltall fra 1 til 12, og - where n is an integer from 1 to 12, and
- hvor /' er et oddetall og indikerer posisjonen i forhold til COOR2, og - where /' is an odd number and indicates the position in relation to COOR2, and
- hvor X, uavhengig av hverandre er valgt fra gruppen omfattende O, S, SO, S02, Se og CH2, og - where X is independently selected from the group comprising O, S, SO, SO 2 , Se and CH 2 , and
- med den forutsetning at minst en av X, ikke er CH2, - with the proviso that at least one of X, is not CH2,
- eller et salt, prodrug eller kompleks derav. - or a salt, prodrug or complex thereof.
De ikke-P-oksiderbare fettsyreanaloger ifølge formel (I) er langkjedete fettsyreanaloger som er analoge til de som naturlig forekommer in vivo. De gjenkjennes således av de samme enzymer som B- og i noen tilfeller io-oksiderbare naturlige langkjedete fettsyrer, men de kan ikke oksideres på denne måte. The non-P-oxidizable fatty acid analogues according to formula (I) are long-chain fatty acid analogues which are analogous to those naturally occurring in vivo. They are thus recognized by the same enzymes as B- and in some cases io-oxidizable natural long-chain fatty acids, but they cannot be oxidized in this way.
Under B-oksidasjonen blir en fettsyre enzymatisk oksiderende spaltet mellom karbon 2 og 3 (idet man teller fra karboksylsyreenden av fettsyren), noe som resulterer i fjerning av to karbonatomer på den ene side av oksideringssetet som eddiksyre. Trinnet repeteres deretter på den nå to karboner kortere fettsyre, og repeteres igjen inntil fettsyren er fullstendig oksidert. P-oksidasjon er den vanligste vei hvor hovedandelen av fettsyrene kataboliseres in vivo. P-oksidering som blokkeres av forbindelsene av (I) oppnås ved innsetting av en ikke-oksidbar gruppe i x-posisjonen i formelen ifølge foreliggende oppfinnelse. During the B-oxidation, a fatty acid is enzymatically oxidatively cleaved between carbons 2 and 3 (counting from the carboxylic acid end of the fatty acid), resulting in the removal of two carbon atoms on one side of the oxidation site as acetic acid. The step is then repeated on the now two carbon shorter fatty acid, and repeated again until the fatty acid is completely oxidized. P-oxidation is the most common pathway by which the majority of fatty acids are catabolized in vivo. P-oxidation which is blocked by the compounds of (I) is achieved by inserting a non-oxidizable group in the x-position in the formula according to the present invention.
co-oksidering er et alternativ til P-oksidering. Det er en mindre vanlig måte og langsommere biologisk prosess, som oksiderer fettsyren, ikke fra karboksylenden, men i stedet fra metyl/ hydrofobisk hodegruppeende av molekylet, her benevnt R-i. I fettsyreanalogene ifølge (I), kan co-oksidering blokkeres ved innsetting av en dobbel-eller trippelbinding i metyl/ hydrofobisk hodegruppe nær metylenden, eller at Ri er C6- C24 alkylgrupper subsidiert med forskjellige blokkerende forbindelser. Denne blokkering av uj-oksidasjon potensierer effektene av de P-oksiderbare fettsyreanaloger ved at deres nedbrytelse ytterligere reduseres. co-oxidation is an alternative to P-oxidation. There is a less common way and slower biological process, which oxidizes the fatty acid, not from the carboxyl end, but instead from the methyl/hydrophobic head group end of the molecule, here referred to as R-i. In the fatty acid analogues according to (I), co-oxidation can be blocked by inserting a double or triple bond in the methyl/hydrophobic head group near the methylene end, or that Ri are C6-C24 alkyl groups subsidized with various blocking compounds. This blocking of uj-oxidation potentiates the effects of the P-oxidizable fatty acid analogues by further reducing their breakdown.
Selv om der kan være store strukturelle forskjeller mellom forskjellige ikke- P-oksiderbare fettsyreanaloger i formel (I), så forventes de biologiske funksjoner av alle forbindelser av formelen til å være tilsvarende på grunn av at de alle blokkerer P-oksidasjon på samme måte. Denne manglende evne av fettsyreanalogene til å kunne P-oksideres (og i noen tilfeller u)-oksideres), fører til at analogene bygges opp i mitokondria, som dermed utløser p-oksidering av in vivo naturlig forekommende fettsyrer, som deretter leder til mange av de biologiske effekter av fettsyreanalogene ifølge oppfinnelsen. (Berge RK et al. (2002) Curr Opin Lipidol 13(3):295-304). Although there may be large structural differences between different non-P-oxidizable fatty acid analogues of formula (I), the biological functions of all compounds of the formula are expected to be similar due to the fact that they all block P-oxidation in the same way. This inability of the fatty acid analogs to be P-oxidized (and in some cases u)-oxidized) leads to the analogs building up in the mitochondria, which thus triggers the p-oxidation of naturally occurring fatty acids in vivo, which then leads to many of the biological effects of the fatty acid analogues according to the invention. (Berge RK et al. (2002) Curr Opin Lipidol 13(3):295-304).
Fettsyre P-oksidasjonsreaksjonsveien er hoved reaksjonsvei for metabolisme av fett. Den innledende og hastighetsbegrensende reaksjon utføres i peroksisomer i lever ved acyl-CoA oksidase. Acyl-CoA oksidase katalyserer dehydrogeneringen av acyl-CoA tioestere til de korresponderende trans-2-enoyl CoA. En fettsyreanalog i samsvar med formel (I); tetradesyltioeddiksyre (TTA), har blitt anvendt tidligere av oppfinnerne av oppfinnelsen for å teste de forskjellige biologiske effekter av fettsyren. Med foreliggende oppfinnelse ble dets effekt på acyl-CoA oksidase testet, og likeledes effekten av forskjellige planteoljer og fiskeoljer, alene eller i kombinasjon. TTA alene effektuerte en stor økning i dette enzymets aktivitet sammenlignet med negativ kontroll. Plante- og fiskeoljene alene utviste en svært liten økning i acyl- CoA oksidase aktivitet sammenlignet med negativ kontroll. Solsikkeoljen økte ikke aktiviteten av TTA idet den administreres samtidig. Dette er hva en kunne forvente, det vil si at acyl- CoA oksidase aktiviteten av TTA med oljer vil være den samme som for uten tilsetning av oljer. Fiskeolje og olivenolje viste en liten potensiering av økningen av acyl- CoA oksidase aktivitet med TTA. Soyaolje uten TTA hadde neglisjerbare effekter på acyl- CoA oksidase aktivitet, men kombinert med TTA utviste den en 60 % økning sammenlignet med effekten av TTA alene. Denne potensiering av TTA som en acyl- CoA oksidase aktivator med soyaolje er ganske uventet. The fatty acid P-oxidation reaction pathway is the main reaction pathway for fat metabolism. The initial and rate-limiting reaction is carried out in peroxisomes in the liver by acyl-CoA oxidase. Acyl-CoA oxidase catalyzes the dehydrogenation of acyl-CoA thioesters to the corresponding trans-2-enoyl CoAs. A fatty acid analog according to formula (I); tetradecylthioacetic acid (TTA), has been used previously by the inventors of the invention to test the various biological effects of the fatty acid. With the present invention, its effect on acyl-CoA oxidase was tested, and likewise the effect of different plant oils and fish oils, alone or in combination. TTA alone effected a large increase in this enzyme's activity compared to the negative control. The plant and fish oils alone showed a very small increase in acyl-CoA oxidase activity compared to the negative control. The sunflower oil did not increase the activity of TTA when administered at the same time. This is what one would expect, that is to say that the acyl-CoA oxidase activity of TTA with oils will be the same as for without the addition of oils. Fish oil and olive oil showed a small potentiation of the increase of acyl-CoA oxidase activity with TTA. Soybean oil without TTA had negligible effects on acyl-CoA oxidase activity, but combined with TTA it showed a 60% increase compared to the effect of TTA alone. This potentiation of TTA as an acyl-CoA oxidase activator by soybean oil is quite unexpected.
I foreliggende oppfinnelse ble effekten av ikke-B-oksiderbare fettsyreanaloger på fosfolipidnivåer også testet, og likeledes effekten av forskjellige planteoljer og fiskeoljer, alene eller sammen med TTA. Solsikkeolje og fiskeolje reduserte fosfolipidnivåene, og potensierte TTAers evne til å gjøre dette utover de fosfolipidsenkende evner til enten TTA eller oljene alene. Soyaolje og olivenolje økte faktisk fosfolipidnivåene, men, uventet, disse oljer potensierte vesentlig TTAs evne til å redusere fosfolipidnivåene. Effekten av soyaolje er spesielt bemerkelsesverdig, idet den selv økte fosfolipidnivåene med 10 % sammenlignet med kontroll, men idet den ble gitt med TTA senket fosfolipidnivået med ytterligere 40 % sammenlignet med TTA alene. In the present invention, the effect of non-B-oxidizable fatty acid analogues on phospholipid levels was also tested, and likewise the effect of various plant oils and fish oils, alone or together with TTA. Sunflower oil and fish oil reduced phospholipid levels, potentiating the ability of TTAs to do this beyond the phospholipid-lowering abilities of either TTA or the oils alone. Soybean oil and olive oil actually increased phospholipid levels, but, unexpectedly, these oils significantly potentiated TTA's ability to reduce phospholipid levels. The effect of soybean oil is particularly remarkable, as it alone increased phospholipid levels by 10% compared to control, but when given with TTA lowered phospholipid levels by an additional 40% compared to TTA alone.
I foreliggende oppfinnelse ble effekten av ikke-B-oksiderbare fettsyreanaloger på kolesterolnivået også testet, og likeledes effekten av forskjellige planteoljer og fiskeoljer, alene eller sammen med TTA. TTA senket kolesterolnivået mer enn noen av plante- eller fiskeoljene alene. Solsikkeolje eller fiskeolje uten TTA senket kolesterolnivået noe, og med TTA var kolesterolnivået lavere enn for TTA alene. Olivenolje og soyaolje øker faktisk kolesterolnivåene i seg selv, men, ganske uventet, idet de tilsettes til TTA så forbedrer disse TTAs evne til å senke kolesterolet. Denne TTA- potensierende effekt var større med soyaolje, som reduserte kolesterolnivået med 60 % sammenlignet med TTA alene. In the present invention, the effect of non-B-oxidizable fatty acid analogues on the cholesterol level was also tested, and likewise the effect of various plant oils and fish oils, alone or together with TTA. TTA lowered cholesterol levels more than either vegetable or fish oil alone. Sunflower oil or fish oil without TTA lowered the cholesterol level somewhat, and with TTA the cholesterol level was lower than for TTA alone. Olive oil and soybean oil actually increase cholesterol levels by themselves, but, rather unexpectedly, when added to TTA, they enhance TTA's ability to lower cholesterol. This TTA-potentiating effect was greater with soybean oil, which reduced cholesterol levels by 60% compared to TTA alone.
TTA har blitt vist å redusere plasma triacylglyserolnivået ved å øke antallet mitokondrier og stimulere mitokondrien B-oksidasjon av normalt mettede og umettede fettsyrer til ketonlegemer (Froyland L et al. (1997) J Lipid Res 38: 1851-1858). I foreliggende oppfinnelse blir det funnet at denne effekt var ytterligere uventet potensiert ved tilsetning av planteoljer og fiskeoljer. Olivenolje, solsikkeolje og fiskeolje senket alle triacylglyserolnivåene på egen hånd, og solsikkeolje og fiskeolje enda mer enn TTA alene, og ytterligere potensierte den kolesterolsenkende effekt av TTA over det som fremgår for enten oljene eller TTA alene. Soyaolje viste de mest spektakulære resultater, på egen hånd så økte faktisk kolesterolnivået med 15 % sammenlignet med kontroll, men ganske uventet så potensierte den TTAs kolesterolsenkende evne med 130 %. TTA has been shown to reduce plasma triacylglycerol levels by increasing the number of mitochondria and stimulating mitochondrial B-oxidation of normally saturated and unsaturated fatty acids to ketone bodies (Froyland L et al. (1997) J Lipid Res 38: 1851-1858). In the present invention, it is found that this effect was further unexpectedly potentiated by the addition of plant oils and fish oils. Olive oil, sunflower oil, and fish oil all lowered triacylglycerol levels on their own, and sunflower oil and fish oil even more than TTA alone, further potentiating the cholesterol-lowering effect of TTA over that seen with either the oils or TTA alone. Soybean oil showed the most spectacular results, on its own it actually increased cholesterol levels by 15% compared to control, but quite unexpectedly it potentiated TTA's cholesterol-lowering ability by 130%.
Nivået av fettsyrer i blodet er normalt bestemt av de relative rater av lipolyse og esterifisering i adipost vev, og opptaket av fettsyrer i muskel. I musklene inhiberer fettsyrer glukoseopptak og oksidering. Økte nivåer av fettsyrer og triacylglyserol i blodet og muskler korrelerer derfor med obesitet og insulin resistens, og likeledes med en redusert evne til å metabolisere glukose (Olefsky JM (2000) J Clin Invest 106: 467-472; Guerre-Millo M et al (2000) J Biol Chem 275: 16638-16642). Stimulering av fettsyreoksidering og redusert plasma fettsyrekonsentrasjon med ikke-B-oksiderbare fettsyreanaloger og planteolje og/ eller fiskeoljer kan derfor hindre og behandle insulin resistens og sykdommer forårsaket derav (Shulman Gl (2000) J Clin Invest 106 (2): 171-176). TTA har blitt funnet å fullstendig hindre høyfett dietts-indusert insulin resistens og adipositet, og redusere adipositet, hyperglysemi og insulin sensitivitet i obese rotter (Madsen M et al. (2000) J Lipid Res 43(5): 742-50). På grunn av de uventede synergistiske resultater funnet av oppfinnerne ved anvendelse av både TTA og planteoljer og/ eller fiskeoljer, uten å være bundet av en spesifikk teori for hva resultatene viser, kan vi nå forvente at denne kombinasjon vil være enda mer effektiv i behandling av disse tilstander. Vi forventer også at TTA potensieres av fiskeoljer og planteoljer i behandling av beslektede sykdommer og forstyrrelser inkluderende høyt blodtrykk, økte lipid- og kolesterolnivåer, endotelisk dysfunksjon, prokoagulent tilstand, polysistisk eggstokksyndrom og metabolsk syndrom. The level of fatty acids in the blood is normally determined by the relative rates of lipolysis and esterification in adipose tissue, and the uptake of fatty acids in muscle. In the muscles, fatty acids inhibit glucose uptake and oxidation. Increased levels of fatty acids and triacylglycerol in the blood and muscles therefore correlate with obesity and insulin resistance, and likewise with a reduced ability to metabolize glucose (Olefsky JM (2000) J Clin Invest 106: 467-472; Guerre-Millo M et al ( 2000) J Biol Chem 275: 16638-16642). Stimulation of fatty acid oxidation and reduced plasma fatty acid concentration with non-B-oxidizable fatty acid analogues and plant oil and/or fish oils can therefore prevent and treat insulin resistance and diseases caused therefrom (Shulman Gl (2000) J Clin Invest 106 (2): 171-176). TTA has been found to completely prevent high-fat diet-induced insulin resistance and adiposity, and reduce adiposity, hyperglycemia and insulin sensitivity in obese rats (Madsen M et al. (2000) J Lipid Res 43(5): 742-50). Due to the unexpected synergistic results found by the inventors using both TTA and plant oils and/or fish oils, without being bound by a specific theory for what the results show, we can now expect that this combination will be even more effective in the treatment of these conditions. We also expect TTA to be potentiated by fish oils and plant oils in the treatment of related diseases and disorders including high blood pressure, increased lipid and cholesterol levels, endothelial dysfunction, procoagulant condition, polycystic ovary syndrome and metabolic syndrome.
Familien peroksisom proliferator aktivert reseptor (PPAR) er pleiotrofe regulatorer av cellulære funksjoner så som cellulær proliferasjon, differensiering og lipid homeostase (Ye JM et al., (2001) Diabetes 50: 411-417). PPAR- familien omfatter tre subtyper; PPARa, PPARB og PPARy. TTA er en potent ligand for PPARa (Forman BM, Chen J, Evans RM (1997) Proe Nati Acad Sei 94: 4312-4317; Gottlicher M et al. (1993) Biochem Pharmacol 46: 2177-2184; Berge RK et al (1999) Biochem J 343(1): 191-197) og aktiverer også PPARB og PPARy (Raspe E et al. The peroxisome proliferator activated receptor (PPAR) family are pleiotrophic regulators of cellular functions such as cellular proliferation, differentiation and lipid homeostasis (Ye JM et al., (2001) Diabetes 50: 411-417). The PPAR family comprises three subtypes; PPARα, PPARB and PPARγ. TTA is a potent ligand for PPARα (Forman BM, Chen J, Evans RM (1997) Proe Nati Acad Sei 94: 4312-4317; Gottlicher M et al. (1993) Biochem Pharmacol 46: 2177-2184; Berge RK et al ( 1999) Biochem J 343(1): 191-197) and also activates PPARB and PPARy (Raspe E et al.
(1999) J Lipid Res 40: 2099-2110). Som en PPARa- aktivator stimulerer TTA katabolismen av fettsyrer med å øke deres cellulære opptak. Senking av plasma triglyseridnivåer med TTA forårsaket et skift i lever cellulær metabolisme, mot PPARa regulert fettsyremetabolisme i mitokondrier. (Grav HJ et al. (2003) J Biol Chem 278(33): 30525-33) Idet effekten av TTA på plasma triacylglyserol er rettet mot PPARa- aktivering, som er demonstrert med fravær av denne effekt i PPARa knockout mus, så reduserer fiskeolje plasma triacylglyserolnivået selv i knockout mus (Dallongeville J et al. (2001) J Biol Chem 276: 4634-4639). (1999) J Lipid Res 40: 2099-2110). As a PPARα activator, TTA stimulates the catabolism of fatty acids by increasing their cellular uptake. Lowering plasma triglyceride levels with TTA caused a shift in liver cellular metabolism, towards PPARα regulated fatty acid metabolism in mitochondria. (Grav HJ et al. (2003) J Biol Chem 278(33): 30525-33) As the effect of TTA on plasma triacylglycerol is directed towards PPARα activation, which has been demonstrated by the absence of this effect in PPARα knockout mice, reducing fish oil plasma triacylglycerol levels even in knockout mice (Dallongeville J et al. (2001) J Biol Chem 276: 4634-4639).
Tilsetning med dietarisk n-3 poly umettede fettsyrer, så som finnes i fiskeolje, stimulerer hepatisk peroksimal acyl- CoA oksidase aktivitet og således fettsyreoksidasjon i leveren og i mindre grad i skjelettmuskelen (Ukropec J et al. Supplementation with dietary n-3 polyunsaturated fatty acids, as found in fish oil, stimulates hepatic peroximal acyl-CoA oxidase activity and thus fatty acid oxidation in the liver and to a lesser extent in skeletal muscle (Ukropec J et al.
(2003) Lipids 38(10): 1023-9). En fiskeoljerik diett har blitt vist å øke både aktiviteten og mRNA nivåene av hepatiske mitokondriene og peroksimale fettsyreoksiderende enzymer (Hong DD et al. (2003) Biochim Biophys Acta: Mol Cell Biol Lipids 1635 (1): 29-36). Fiskeolje induserte en økning i forekomst av peroksimal acyl- CoA oksidase i lever, men ikke muskelen i rotter, og forfatternes hypotese er at dette skyldes n-3 fettsyrer som beskytter mot fettindusert insulin resistens ved å fungere som PPARa-ligander, inkluderende hepatisk (ikke intramuskulær) peroksisom proliferering. PPARa- genekspresjon forandres ikke. (Neschen S et al. (2002) Am J Physiol Endocrinol Metab 282: E395-E401). (2003) Lipids 38(10): 1023-9). A fish oil-rich diet has been shown to increase both the activity and mRNA levels of hepatic mitochondrial and peroximal fatty acid oxidizing enzymes (Hong DD et al. (2003) Biochim Biophys Acta: Mol Cell Biol Lipids 1635 (1): 29-36). Fish oil induced an increase in peroximal acyl-CoA oxidase in liver but not muscle in rats, and the authors' hypothesis is that this is due to n-3 fatty acids that protect against fat-induced insulin resistance by acting as PPARα ligands, including hepatic (not intramuscular) peroxisome proliferation. PPARα gene expression is not changed. (Neschen S et al. (2002) Am J Physiol Endocrinol Metab 282: E395-E401).
Som det fremgår fra avsnittene ovenfor, de biokjemiske detaljer på eksakt hvordan TTA og fiskeolje påvirker fettmetabolismen er ikke kjent i detalj. Enda mindre er kjent om hvordan planteoljer positivt påvirker fettmetabolismen som beskrevet ifølge foreliggende oppfinnelse (Rustan AC, Christiansen EN, Drevon CA (1992) biochem J 283(2): 333-339). Effektene kan, eller trenger ikke være, gjennom de samme reaksjonsveier, både TTA og oljer kan for eksempel fungere som PPARa- ligander, eller virke uavhengig av PPARa. Dersom de virker gjennom samme reaksjonsvei vil man ikke forvente at TTA potensieres av oljer, på grunn av at TTA er en sterk PPARa- aktivator som man ville kunne forvente ville fullstendig mette PPARa-aktiveringen. As can be seen from the paragraphs above, the biochemical details of exactly how TTA and fish oil affect fat metabolism are not known in detail. Even less is known about how plant oils positively influence fat metabolism as described according to the present invention (Rustan AC, Christiansen EN, Drevon CA (1992) biochem J 283(2): 333-339). The effects may or may not be through the same reaction pathways, both TTA and oils can, for example, act as PPARa ligands, or act independently of PPARa. If they work through the same reaction pathway, one would not expect TTA to be potentiated by oils, due to the fact that TTA is a strong PPARα activator which one would expect would completely saturate PPARα activation.
Å kunne oppnå en additiv effekt av TTA pluss effekten av planteoljen eller fiskeoljen med å kombinere de to vil således være uventet. For å oppnå en synergistisk effekt langt over den additive effekt, slik det spesielt ses for TTA og soyaolje i alle tester ifølge oppfinnelsen, men også i mindre grad i TTA og fiskeolje eller solsikkeolje i Being able to achieve an additive effect of TTA plus the effect of the plant oil or fish oil by combining the two would thus be unexpected. To achieve a synergistic effect far above the additive effect, as is particularly seen for TTA and soybean oil in all tests according to the invention, but also to a lesser extent in TTA and fish oil or sunflower oil in
senking av triacylglyserolnivået, og olivenolje og solsikkeolje i senking av kolesterolnivået, er enda mer overraskende. 6-oksiderbare fettsyreanaloger har mange effekter, og vi vet ikke hvordan alle disse bringes frem, men basert på de uventede resultater av foreliggende oppfinnelse vil vi forvente at de potensieres av planteoljer og fiskeoljer, uten at vi bindes til en bestemt teori. lowering triacylglycerol levels, and olive oil and sunflower oil in lowering cholesterol levels, is even more surprising. 6-oxidizable fatty acid analogues have many effects, and we do not know how all of these are brought about, but based on the unexpected results of the present invention, we would expect them to be potentiated by plant oils and fish oils, without being bound to a particular theory.
PPAR- ligander påvirker proliferasjon av forskjellige cancercellelinjer. TTA har spesielt blitt funnet å redusere proliferasjon av mange cancercellelinjer (Berge K et al. (2001) Carcinogenesis 22:1747-1755), Abdi-Dezfuli F et al. (1997) Breast Cancer Res Treat 45: 229-239; Tronstad KJ et al. (2001) Biochem Pharmacol 61: 639-649; Tronstad KJ et al. (2001) Lipids 36: 305-313). Denne reduksjon er relatert til reduksjon i triacylglyserolnivåer (Tronstad KJ et al. (2001) Biochem Pharmacol 61: 639-649), og er mediert av både PPAR- avhengige og uavhengige reaksjonsveier (Berge K et al. (2991) Carcinogenesis 22: 1747-1755). Siden oljer forbedrer TTAs evne til å senke triacylglyserolnivåer og er en PPAR- ligand, er det således sannsynlig at den vil forbedre de antiproliferative effekter av TTA også, noe som gjør dette til en forbedring i TTAs cancerhindrende og behandlende egenskaper. TTA kan anvendes for å hindre og/eller behandle cancer inkluderende inhibering av primær og sekundær neoplasmer, vekst av tumorer, invasjon av en primær tumor inn i bindevev, og dannelse av sekundære tumorer (NO 2002 5930). PPAR ligands affect proliferation of various cancer cell lines. In particular, TTA has been found to reduce proliferation of many cancer cell lines (Berge K et al. (2001) Carcinogenesis 22:1747-1755), Abdi-Dezfuli F et al. (1997) Breast Cancer Res Treat 45: 229-239; Tronstad KJ et al. (2001) Biochem Pharmacol 61: 639-649; Tronstad KJ et al. (2001) Lipids 36: 305-313). This reduction is related to a reduction in triacylglycerol levels (Tronstad KJ et al. (2001) Biochem Pharmacol 61: 639-649), and is mediated by both PPAR-dependent and independent pathways (Berge K et al. (2991) Carcinogenesis 22: 1747 -1755). Since oils enhance TTA's ability to lower triacylglycerol levels and are a PPAR ligand, it is thus likely to enhance the antiproliferative effects of TTA as well, making this an improvement in TTA's cancer prevention and treatment properties. TTA can be used to prevent and/or treat cancer including inhibition of primary and secondary neoplasms, growth of tumors, invasion of a primary tumor into connective tissue, and formation of secondary tumors (NO 2002 5930).
Generelt vil PPAR- agonister og polyumettede fettsyrer modulere den inflammatoriske respons. TTA modulerer inflammatorisk respons ved å redusere frigivelse av inflammatorisk cytokin interleukin-2 og undertrykke PHA- stimulert proliferasjon av perifere mononukleære celler (Aukrust P et al. (2003) Eur J Clin Invest 33(5): 426-33). Moduleringen av cytokiner ved TTA kan være PPAR- mediert, eller gjennom forandrede protaglandinnivåer, eller ved modifisering av lipidmediert signal transaksjon, hvor den siste mekanisme og er den foreslåtte mekanisme for polyumettede fettsyrer, så som de som finnes i planteoljer og fiskeoljer. Nå når oppfinnerne har funnet de uventede resultater vist i foreliggende oppfinnelse, vil de derfor forvente at planteoljer og/ eller fiskeoljer i kombinasjon med ikke-B-oksiderbare fettsyreanaloger vil potensiere effekten av fettsyreanaloger på inflammentoriske forstyrrelser, inkluderende immunmedierte forstyrrelser så som reumatoid artritt, systemisk vaskulitt, systemisk lupus erytematøs, systemisk sklerose, dermatomyositt, polymyositt, forskjellige autoimmune endokrine forstyrrelser (for eksempel tyrioditt og adrenalititt), forskjellige immunmedierte neurologiske forstyrrelser (for eksempel multippel sklerose og myastenia gravis), forskjellige karidovaskulære forstyrrelser (for eksempel myokarditt, kognitiv hjertesvikt, arteriosklerose og stabil og ustabil angina, og Wegeners granulomatose), inflammatoriske tarmforstyrrelser, Chrons forstyrrelser, ikke- spesifikk kolikk, pankreatitt, nefrititt, kolestatitt/ fibrose i lever, og akutt og kronisk allograft avvisning etter organtransplantasjon, og likeledes proliferative hudforstyrrelser, så som psoriasis, atopisk dermatitt, ikke- spesifikk dermatitt, primær irriterende kontaktdermatitt, allergisk kontaktdermatitt, lamellær ichtyose, epidermolyttisk hyperkeratose, premalign sol-indusert keratose, og seborrea, og sykdommer som har en inflammatorisk komponent så som for eksempel Alzheimers sykdom eller nedsatt/ forbedrbar kognitiv funksjon. In general, PPAR agonists and polyunsaturated fatty acids will modulate the inflammatory response. TTA modulates inflammatory response by reducing release of inflammatory cytokine interleukin-2 and suppressing PHA-stimulated proliferation of peripheral mononuclear cells (Aukrust P et al. (2003) Eur J Clin Invest 33(5): 426-33). The modulation of cytokines by TTA may be PPAR-mediated, or through altered protaglandin levels, or by modification of lipid-mediated signal transduction, where the latter mechanism is the proposed mechanism for polyunsaturated fatty acids, such as those found in plant oils and fish oils. Now that the inventors have found the unexpected results shown in the present invention, they will therefore expect that vegetable oils and/or fish oils in combination with non-B-oxidizable fatty acid analogues will potentiate the effect of fatty acid analogues on inflammatory disorders, including immune-mediated disorders such as rheumatoid arthritis, systemic vasculitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, various autoimmune endocrine disorders (for example, thyroiditis and adrenalitis), various immune-mediated neurological disorders (for example, multiple sclerosis and myasthenia gravis), various caridovascular disorders (for example, myocarditis, cognitive heart failure, arteriosclerosis and stable and unstable angina, and Wegener's granulomatosis), inflammatory bowel disorders, Chron's disorders, non-specific colic, pancreatitis, nephritis, cholestatitis/fibrosis of the liver, and acute and chronic allograft rejection after organ transplantation tation, and likewise proliferative skin disorders, such as psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun-induced keratosis, and seborrhea, and diseases that have an inflammatory component such as for example Alzheimer's disease or impaired/improvable cognitive function.
Således vedrører den forleggende oppfinnelsen et materiale kjennetegnet ved at nevnte materiale omfatter Thus, the present invention relates to a material characterized by said material comprising
i) en planteolje og/eller en fiskeolje, og i) a vegetable oil and/or a fish oil, and
ii) en ikke-B-oksiderbare fettsyreanalog, hvor nevnte ikke-B-oksiderbare fettsyreanalog har følgende generelle formel (I) ii) a non-B-oxidizable fatty acid analog, wherein said non-B-oxidizable fatty acid analog has the following general formula (I)
R1-[xl-CH2]„-COOR2R1-[x1-CH2]„-COOR2
- hvor Ri er et CrC24 alkyl, alkenyl eller alkynyl, og - where R 1 is a CrC 24 alkyl, alkenyl or alkynyl, and
- hvor R2 representerer hydrogen eller C1-C4 alkyl, og - where R2 represents hydrogen or C1-C4 alkyl, and
- hvor n er et heltall fra 1 til 12, og - where n is an integer from 1 to 12, and
- hvor / er et oddetall og indikerer posisjonen i forhold til COOR2, og - where / is an odd number and indicates the position in relation to COOR2, and
- hvor X, uavhengig av hverandre er valgt fra gruppen omfattende O, S, SO, S02, Se og CH2, og - where X is independently selected from the group comprising O, S, SO, SO 2 , Se and CH 2 , and
- med den forutsetning at minst en av X, ikke er CH2, - with the proviso that at least one of X, is not CH2,
- eller et salt, prodrug eller kompleks derav. - or a salt, prodrug or complex thereof.
Ytterligere utførelser av materialet er beskrevet i underkrav 24-36. Further embodiments of the material are described in subclaims 24-36.
Videre vedrører den forleggende oppfinnelsen anvendelse av materialet Furthermore, the present invention relates to the use of the material
for fremstilling av et farmasøytisk eller ernæringsmessig materiale for å hindre og/eller behandle insulin resistens obesitet, diabetes, fettlever, hyperkolesterolemi, dyslepidemi, aterosklerose, koronar hjertesykdom, trombose, stenose, sekundær stenose, myokardisk infarkt, slag, høyt blodtrykk, endotelisk dysfunksjon, prokoagulent tilstand, polysistisk eggstokksyndrom, metabolsk syndrom, cancer, inflammatorisk forstyrrelse og proliferative hudforstyrrelser. for the production of a pharmaceutical or nutritional material to prevent and/or treat insulin resistance obesity, diabetes, fatty liver, hypercholesterolemia, dyslipidemia, atherosclerosis, coronary heart disease, thrombosis, stenosis, secondary stenosis, myocardial infarction, stroke, high blood pressure, endothelial dysfunction, procoagulant condition, polycystic ovary syndrome, metabolic syndrome, cancer, inflammatory disorder and proliferative skin disorders.
Ytterligere utførelser av materialet er beskrevet i underkrav 2, 4 og 6-22. Further embodiments of the material are described in subclaims 2, 4 and 6-22.
FIGURER FIGURES
Fig. 1 viser at økningen i fettacyl- CoA aktivitet for TTA potensieres med soyaolje, olivenolje og fiskeolje. Fig. 2 viser at den fosfolipidsenkende effekt av TTA potensieres med solsikkeolje, soyaolje og fiskeolje. Fig. 3 viser at den kolesterolsenkende effekt av TTA potensieres med olivenolje, solsikkeolje, soyaolje og fiskeolje. Fig. 4 viser at den triacylglyserolsenkende effekt av TTA potensieres med olivenolje, solsikkeolje, soyaolje og fiskeolje. Fig. 1 shows that the increase in fatty acyl-CoA activity for TTA is potentiated with soya oil, olive oil and fish oil. Fig. 2 shows that the phospholipid-lowering effect of TTA is potentiated with sunflower oil, soya oil and fish oil. Fig. 3 shows that the cholesterol-lowering effect of TTA is potentiated with olive oil, sunflower oil, soya oil and fish oil. Fig. 4 shows that the triacylglycerol-lowering effect of TTA is potentiated with olive oil, sunflower oil, soya oil and fish oil.
DEFINISJONER ANVENDT I SØKNADEN DEFINITIONS USED IN THE APPLICATION
Dyr Animals
I denne forbindelse inkluderer termen "dyr" som angitt her "pattedyr" så som mennesker og husdyr (agrikulturelle), spesielt dyr av økonomisk viktighet så som In this context, the term "animal" as defined herein includes "mammals" such as humans and livestock (agricultural), especially animals of economic importance such as
hønsefugler, bovine, ovine, kaprine og porsine pattedyr, spesielt de som produserer produkter egnet for menneskelig konsumpsjon, så som kjøtt, egg og melk. Videre er termen tenkt å inkludere fisk og skalldyr, så som laks, torsk, tilapia, musling, østers, hummer eller krabber. Termen inkluderer også husdyr, så som hunder og katter. fowl, bovine, ovine, caprine and porcine mammals, especially those that produce products suitable for human consumption, such as meat, eggs and milk. Furthermore, the term is intended to include fish and shellfish, such as salmon, cod, tilapia, clams, oysters, lobsters or crabs. The term also includes domestic animals, such as dogs and cats.
Planteoljer og/ eller fiskeoljer Plant oils and/or fish oils
Disse inkluderer alle oljer av planteopprinnelse eller marin opprinnelse, inkluderende, men ikke begrenset til fettaktige eller faste oljer og likeledes essensielle eller flyktige oljer, og enhver kombinasjon derav. De trenger ikke nødvendigvis være i væskeform. Solsikkeolje, som ble anvendt i foreliggende oppfinnelse, er faktisk olje fra solsikkefrøet, ikke selve blomsten. These include all oils of plant or marine origin, including but not limited to fatty or fixed oils and likewise essential or volatile oils, and any combination thereof. They do not necessarily have to be in liquid form. Sunflower oil, which was used in the present invention, is actually oil from the sunflower seed, not the flower itself.
Behandling Treatment
I relasjon til de farmasøytiske applikasjoner av oppfinnelsen angir termen "behandling" reduksjon av alvorligheten av sykdommen. In relation to the pharmaceutical applications of the invention, the term "treatment" denotes the reduction of the severity of the disease.
Prevensjon Contraception
Termen "prevensjon" angir prevensjon av en gitt sykdom, det vil si en forbindelse ifølge foreliggende oppfinnelse administreres før utvikling av tilstand. Dette betyr at forbindelsen ifølge foreliggende oppfinnelse kan anvendes som et profylaktisk middel eller som en ingrediens i et ernæringsmateriale for å hindre risiko eller utbrudd av en gitt sykdom. The term "contraception" denotes prevention of a given disease, that is, a compound according to the present invention is administered before the development of the condition. This means that the compound according to the present invention can be used as a prophylactic agent or as an ingredient in a nutritional material to prevent the risk or outbreak of a given disease.
Ernæringsmessig materiale Nutritional material
Denne term er ment å inkludere ethvert spisbart materiale, inkluderende, men ikke begrenset til ernæringsmessige tilsetningsstoffer, functional food, urtetilsetninger for eksempel for human eller animalsk forhold. Termen inkluderer også næringsprodukter for humant forbruk og dyrefor, hvor materialet ifølge foreliggende oppfinnelse er et tilsetningsstoff, og ikke hovedingrediensen. Dette gjelder spesielt dyref6r, hvor ethvert for kan tilsettes med materialet ifølge oppfinnelsen, for å oppnå de biologiske effekter derav. This term is intended to include any edible material, including but not limited to nutritional additives, functional food, herbal additives for example for human or animal conditions. The term also includes nutritional products for human consumption and animal feed, where the material according to the present invention is an additive, and not the main ingredient. This particularly applies to animal feed, where any feed can be added with the material according to the invention, in order to achieve the biological effects thereof.
Prodru<g>Prodru<g>
Termen "prodrug" benyttes vanligvis innen feltet for å beskrive et medikament som har blitt modifisert slik at det har ingen effekt in vitro, men aktiveres in vivo. Vanligvis er denne modifisering tilsetning av en forbindelse til mormedikamentet, som den naturlige mekanisme i kroppen vil fjerne, og gi den nå aktive (opprinnelige) morforbindelse. Således er termen "prodrug", rent biologisk, identisk i dets effekter til morforbindelsen og inkludering av termen "prodrug" i forbindelsesbeskrivelsen utvider ikke rammen av forbindelsene inkludert i patentet. The term "prodrug" is usually used in the field to describe a drug that has been modified so that it has no effect in vitro, but is activated in vivo. Usually this modification is the addition of a compound to the parent drug, which the natural mechanism in the body will remove, leaving the now active (original) parent compound. Thus, the term "prodrug", purely biologically, is identical in its effects to the parent compound and inclusion of the term "prodrug" in the compound description does not expand the scope of the compounds included in the patent.
ADMINISTRERING AV FORBINDELSENE IFØLGE FORELIGGENDE OPPFINNELSE ADMINISTRATION OF THE COMPOUNDS ACCORDING TO THE PRESENT INVENTION
Som et farmasøytisk medikament kan materialet ifølge foreliggende oppfinnelse administreres direkte til dyret ved enhver egnet teknikk, inkluderende parenteralt, intranasalt, oralt eller ved absorpsjon gjennom hud/ skinn. De kan administreres lokalt eller systemisk. Den spesifikke administrasjonsrute på hvert middel vil avhenge for eksempel på den medisinske historie til det mottakene dyr eller menneske. As a pharmaceutical drug, the material according to the present invention can be administered directly to the animal by any suitable technique, including parenterally, intranasally, orally or by absorption through the skin. They can be administered locally or systemically. The specific route of administration of each agent will depend, for example, on the medical history of the recipient animal or human.
Eksempler på parenteral administrering inkluderer subkutanøs, intramuskulær, intravenøs, intraarteriell og intraperitoneal administrering. Examples of parenteral administration include subcutaneous, intramuscular, intravenous, intraarterial and intraperitoneal administration.
Som et generelt forslag kan den totale farmasøytiske effektive mengde av hver av de ikke- B-oksiderbare fettsyreanaloger administrert parenteralt per dosering fortrinnsvis være i området av cirka 1 mg/ kg/ dag til 200 mg/ kg/ dag til pasientens kroppsvekt for mennesker, selv om, som angitt ovenfor, så vil dette underlegges en stor del av terapeutisk vurdering. En dosering av 5 - 50 mg/ kg/ dag er mest foretrukket. En dosering av 1 - 300 mg/ kg/ dag av olje er foretrukket, og en dosering av 10 - 150 mg/ kg/ dag er mest foretrukket. As a general suggestion, the total pharmaceutically effective amount of each of the non-B-oxidizable fatty acid analogs administered parenterally per dosage may preferably be in the range of about 1 mg/kg/day to 200 mg/kg/day of the patient's body weight for humans, even if, as indicated above, this will be subject to a large part of therapeutic assessment. A dosage of 5 - 50 mg/kg/day is most preferred. A dosage of 1 - 300 mg/kg/day of oil is preferred, and a dosage of 10 - 150 mg/kg/day is most preferred.
Dersom de gis kontinuerlig administreres forbindelsene ifølge foreliggende oppfinnelse typisk med 1-4 injeksjoner per dag eller ved kontinuerlig subkutanøs infusjon, for eksempel ved anvendelse av en minipumpe. En intravenøs poseløsning kan også benyttes. Nøkkelfaktoren i å utvelge en egnet dosering er resultatet som skal oppnås, som målt med nedgang i total kroppsvekt eller forhold av fett til kjøttmasse, eller ved andre kriterier for å måle regulering og hindring av obesitet eller for å hindre obesitets- relaterte tilstander, slik det er hensiktsmessig for den praktiserende. If they are given continuously, the compounds according to the present invention are typically administered with 1-4 injections per day or by continuous subcutaneous infusion, for example using a mini pump. An intravenous bag solution can also be used. The key factor in selecting a suitable dosage is the result to be achieved, as measured by a decrease in total body weight or the ratio of fat to meat mass, or by other criteria to measure the regulation and prevention of obesity or to prevent obesity-related conditions, such as is appropriate for the practitioner.
For parenteral administrering, formuleres, i en utførelse, forbindelsene ifølge foreliggende oppfinnelse generelt ved å blande hver med den ønskede grad av renhet, i enhets doserings injiserbare former (løsning, suspensjon eller emulsjon), med en farmasøytisk akseptabel bærer, det vil si en som er ikke- toksisk til mottakerne av doseringen og konsentrasjonene som benyttes, og som er kompatibel med andre ingredienser i formuleringen. For parenteral administration, in one embodiment, the compounds of the present invention are generally formulated by mixing each with the desired degree of purity, in unit dosage injectable forms (solution, suspension or emulsion), with a pharmaceutically acceptable carrier, that is, one which is non-toxic to the recipients of the dosage and concentrations used, and is compatible with other ingredients in the formulation.
Generelt, formuleringene kan fremstilles ved å sette forbindelsene ifølge foreliggende oppfinnelse i forbindelse med, uniformt og intimt, væskebærer eller finfordelt stoffbærere eller begge deler. Deretter, dersom nødvendig, formes produktet til ønsket formulering. Fortrinnsvis er bæreren en parenteral bærer, mer fortrinnsvis en løsning som er isotonisk med blod til mottakeren. Eksempler på slike bærer vehikler inkluderer vann, saltløsning, Ringers løsning og dekstroseløsning. Ikke- vandige vehikler, så som faste oljer og etyl oleat er også nyttige heri, og likeledes liposomer. In general, the formulations can be prepared by bringing the compounds of the present invention into contact, uniformly and intimately, with liquid carriers or finely divided material carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably, the carrier is a parenteral carrier, more preferably a solution isotonic with the blood of the recipient. Examples of such carriers include water, saline, Ringer's solution and dextrose solution. Non-aqueous vehicles, such as solid oils and ethyl oleate are also useful herein, and likewise liposomes.
Bæreren kan hensiktsmessig inneholde mindre mengde av tilsetningsstoffer så som substanser som forbedrer isotonisitet og kjemisk stabilitet. Slike materialer er ikke-toksiske for mottakeren av doseringene og konsentrasjonene som benyttes, og inkluderer buffere, så som fosfat, sitrat, sukinat, eddiksyre og andre organiske syrer eller deres salter, antioksidanter så som askorbinsyre, immunoglobuliner, hydrofyliske polymerer, så som polyvinylpyrrolidon; aminosyrer, så som glysin, glutamisk syre, aparaginsyre eller aginin; monosakkarider, disakkarider og andre karbohydrater inkluderende cellulose eller dets derivater, glukose, mannose eller dekstriner; kjelaterende midler så som EDTA; sukkeralkoholer så som mannitol eller sorbitol; motion så som natrium; og/ eller ikke-ioniske surfaktanter så som polysorbater, poloksamere eller PEG. The carrier can appropriately contain a smaller amount of additives such as substances that improve isotonicity and chemical stability. Such materials are non-toxic to the recipient at the dosages and concentrations used and include buffers such as phosphate, citrate, succinate, acetic acid and other organic acids or their salts, antioxidants such as ascorbic acid, immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aparagic acid or aginine; monosaccharides, disaccharides and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; exercise such as sodium; and/or non-ionic surfactants such as polysorbates, poloxamers or PEG.
For orale farmakologiske materialer kan slike bærematerialer som for eksempel vann, gelatin, gummier, laktose, stivelser, magnesium stearat, talk, olje, polyalken glykol, vaselin og lignende anvendes. Slike farmasøytiske materialer kan være i enhets doseringsform og kan ytterligere inneholde andre terapeutisk verdifulle substanser eller konvensjonelle farmasøytiske adjuvanser så som konserveringsmidler, stabiliserende midler, emulsifiserende midler, buffere og lignende. De farmasøytiske preparater kan være i konvensjonelle væskeformer, så som tabletter, kapsler, drageer, ampuller og lignende, i konvensjonelle doseringsformer så som ampuller og stikkpiller og lignende. For oral pharmacological materials, such carrier materials as, for example, water, gelatin, gums, lactose, starches, magnesium stearate, talc, oil, polyalkene glycol, petroleum jelly and the like can be used. Such pharmaceutical materials may be in unit dosage form and may further contain other therapeutically valuable substances or conventional pharmaceutical adjuvants such as preservatives, stabilizing agents, emulsifying agents, buffers and the like. The pharmaceutical preparations can be in conventional liquid forms, such as tablets, capsules, dragees, ampoules and the like, in conventional dosage forms such as ampoules and suppositories and the like.
I tillegg kan forbindelsen ifølge foreliggende oppfinnelse, det vil si de ikke- B-oksiderbare fettsyreanaloger og planteoljer og/eller fiskeoljer, anvendes i ernæringsmessige preparater, som definert tidligere, i hvilket tilfelle doseringsformen av ikke- B-oksiderbar fettsyreanalog fortrinnsvis er som beskrevet for farmasøytika eller mindre, idet mengden av planteoljer og/eller fiskeoljer fortrinnsvis er egnet for fremstilling av mat og formaterialer. Som en del av et ernæringsmessig materiale, og spesielt dyrefor, kan planteoljer og/eller fiskeoljer være en vesentlig del av foret, og således ha en ernæringsverdi og likeledes for å potensiere effekten av ikke- B-oksiderbare fettsyreanaloger. In addition, the compound according to the present invention, i.e. the non-B-oxidizable fatty acid analogues and plant oils and/or fish oils, can be used in nutritional preparations, as defined previously, in which case the dosage form of the non-B-oxidizable fatty acid analogue is preferably as described for pharmaceuticals or less, as the amount of vegetable oils and/or fish oils is preferably suitable for the production of food and raw materials. As part of a nutritional material, and especially animal feed, plant oils and/or fish oils can be a significant part of the feed, and thus have a nutritional value and likewise to potentiate the effect of non-B-oxidizable fatty acid analogues.
Olje ifølge foreliggende oppfinnelse kan omfatte opptil alt av fettet i en ernærings-sammenblanding. I dyrefor, kan mengden av ikke- B-oksiderbare fettsyreanalog være opptil 10 ganger relatert til produkter for human konsumpsjon, det vil si opptil 2 g/ kg/ dag av dyrets kroppsvekt. Oil according to the present invention can comprise up to all of the fat in a nutritional mixture. In animal feed, the amount of non-B-oxidizable fatty acid analogue can be up to 10 times related to products for human consumption, i.e. up to 2 g/kg/day of the animal's body weight.
De eksperimentelle resultater gitt nedenfor har vist at planteoljer og/eller fiskeoljer i vesentlig grad potensierer de biologiske effekter av ikke- B-oksiderbare fettsyreanaloger. The experimental results given below have shown that plant oils and/or fish oils significantly potentiate the biological effects of non-B-oxidizable fatty acid analogues.
En foretrukket utførelse av foreliggende oppfinnelse vedrører således et materiale omfattende i) en planteolje og/eller fiskeolje og ii) en ikke- B-oksiderbar fettsyreanalog. A preferred embodiment of the present invention thus relates to a material comprising i) a plant oil and/or fish oil and ii) a non-B-oxidizable fatty acid analogue.
Den ikke- B-oksiderbare fettsyreanalog har den følgende generelle formel (I): The non-B-oxidizable fatty acid analogue has the following general formula (I):
- hvor Ri er et C1-C24 alkyl, alkenyl eller alkynyl, og - where R 1 is a C1-C24 alkyl, alkenyl or alkynyl, and
- hvor R2 representerer hydrogen eller C1-C4 alkyl, og - where R2 represents hydrogen or C1-C4 alkyl, and
- hvor n er et heltall fra 1 til 12, og - where n is an integer from 1 to 12, and
- hvor /' er et oddetall og indikerer posisjonen i forhold til COOR2, og - where /' is an odd number and indicates the position in relation to COOR2, and
- hvor X, uavhengig av hverandre er valgt fra gruppen omfattende O, S, SO, S02, Se og CH2, og - where X is independently selected from the group comprising O, S, SO, SO 2 , Se and CH 2 , and
- med den forutsetning at minst en av X, ikke er CH2, - with the proviso that at least one of X, is not CH2,
- eller et salt, prodrug eller kompleks derav. - or a salt, prodrug or complex thereof.
For å blokkere oj- oksidasjon ved innsetting av et substitutt i Ri, kan alkyl være en C1-C24 alkyl substituert i en eller flere posisjoner med en eller flere forbindelser valgt fra gruppen omfattende fluorid, klorid, hydroksy, Ci-C4 alkoksy, CM-C4 alkyltio, C2-C5 acyloksy eller C1-C4 alkyl. To block oj- oxidation by insertion of a substituent in Ri, alkyl may be a C1-C24 alkyl substituted in one or more positions with one or more compounds selected from the group comprising fluoride, chloride, hydroxy, C1-C4 alkoxy, CM- C4 alkylthio, C2-C5 acyloxy or C1-C4 alkyl.
De ikke- B-oksiderbare fettsyreanaloger bør fortrinnsvis være like i lengde til fettsyrene de er analoge av, og derfor er det totale antall karbonatomer i fettsyre backbone fortrinnsvis mellom 8 og 30, mer fortrinnsvis mellom 12 og 26. The non-B-oxidizable fatty acid analogues should preferably be equal in length to the fatty acids of which they are analogues, and therefore the total number of carbon atoms in the fatty acid backbone is preferably between 8 and 30, more preferably between 12 and 26.
Foretrukne utførelser av ikke- P-oksiderbare fettsyrer er tetradesyltioeddiksyre, tetradesylseleneddiksyre og 3-Tia-15-heptadesyn. Preferred embodiments of non-β-oxidizable fatty acids are tetradecylthioacetic acid, tetradecylselenoacetic acid and 3-Thia-15-heptadesyne.
En foretrukket utførelse av oljekomponenten omfatter polyumettede fettsyrer. Foretrukne utførelser av oljekomponenten er solsikkeolje, soyaolje og olivenolje. A preferred embodiment of the oil component comprises polyunsaturated fatty acids. Preferred versions of the oil component are sunflower oil, soya oil and olive oil.
Oppfinnelsen kan anvendes som et farmasøytisk materiale og/ eller ernæringsmateriale for hindring og/ eller behandling av insulin resistens, obesitet, diabetes, fettlever, hyperkolesterolemi, dyslepidemi, aterosklerose, koronar hjertesykdom, trombose, stenose, sekundær stenose, myokardisk infarkt, slag, forhøyet blodtrykk, endotelisk dysfunksjon, prokoagulent tilstand, polysistisk eggstokksyndrom, metabolsk syndrom og cancer. The invention can be used as a pharmaceutical material and/or nutritional material for the prevention and/or treatment of insulin resistance, obesity, diabetes, fatty liver, hypercholesterolemia, dyslipidemia, atherosclerosis, coronary heart disease, thrombosis, stenosis, secondary stenosis, myocardial infarction, stroke, high blood pressure , endothelial dysfunction, procoagulant condition, polycystic ovary syndrome, metabolic syndrome and cancer.
Videre, oppfinnelsen kan anvendes for fremstilling av et farmasøytisk eller ernæringsmessig materiale for hindring og/ eller behandling av en inflammatorisk forstyrrelse. Furthermore, the invention can be used for the production of a pharmaceutical or nutritional material for the prevention and/or treatment of an inflammatory disorder.
Videre, oppfinnelsen kan anvendes for fremstilling av et farmasøytisk eller ernæringsmessig materiale for hindring og/ eller behandling av en proliferativ hudforstyrrelse. Furthermore, the invention can be used for the production of a pharmaceutical or nutritional material for the prevention and/or treatment of a proliferative skin disorder.
EKSPERIMENTELL SEKSJON EXPERIMENTAL SECTION
Eksempel 1 Example 1
Toksisitetsforsøk for TTA Toxicity test for TTA
En 28 dagers toksisitetsforsøk i hunder i samsvar med GLP guidelines har blitt utført ved (Corning Hazleton (Europe), England). Oral administrering av TTA i doseringsnivåer opptil 500 mg/ kg/ dag ble generelt godt tolerert. Noen lipidrelaterte parametere ble senket i dyrene som blir gitt høye doseringer. Dette er i samsvar med den farmakologiske aktivitet for TTA. A 28 day toxicity test in dogs in accordance with GLP guidelines has been carried out at (Corning Hazleton (Europe), England). Oral administration of TTA at dosage levels up to 500 mg/kg/day was generally well tolerated. Some lipid-related parameters were lowered in the animals given high doses. This is consistent with the pharmacological activity of TTA.
Doseringsnivået for 500 mg/ kg/ dag ga også tap av kroppsvekt. Der var ingen bevis på toksisitet i doseringsnivået på 50 eller 500 mg/ dag/ kg. The dosage level of 500 mg/kg/day also produced a loss of body weight. There was no evidence of toxicity at the 50 or 500 mg/day/kg dose level.
Tester for mutagenisk aktivitet har blitt utført ved (Covance Laboratories Limited, England). Det ble konkludert at TTA og TSA ikke induserte mutasjoner i stammer av Salmonella thyphimurium og Escherichia coli. Videre var TTA ikke mutagenisk idet de ble testet i muselymfoma celler og L5178Y. Tests for mutagenic activity have been carried out at (Covance Laboratories Limited, England). It was concluded that TTA and TSA did not induce mutations in strains of Salmonella thyphimurium and Escherichia coli. Furthermore, TTA was not mutagenic when tested in mouse lymphoma cells and L5178Y.
Konsentrasjonen av forbindelsene testet i S. typhimuhum og E. coli 3-1000 mg/ plate/ (TTA) 2-5000 mg/ plate (TSA). I muselymfoma celler, L5178Y, var konsentrasjonen 2,5-50 mg/ ml. The concentration of the compounds tested in S. typhimuhum and E. coli 3-1000 mg/ plate/ (TTA) 2-5000 mg/ plate (TSA). In mouse lymphoma cells, L5178Y, the concentration was 2.5-50 mg/ml.
TTA og TSA ble funnet å ikke være mutagenisk i disse tester. TSA og TTA har blitt testet for kromosomale avvik i dyrkede Chinese hamster eggstokkceller og ingen abberasjon ble indusert med doseringene som ble testet (12-140 mg/ ml). TTA and TSA were found not to be mutagenic in these tests. TSA and TTA have been tested for chromosomal abnormalities in cultured Chinese hamster ovary cells and no aberration was induced with the dosages tested (12-140 mg/ml).
Forbindelsene ifølge foreliggende oppfinnelse er derfor potensielt nyttige for farmakologiske forbindelser i denne sammenheng. The compounds according to the present invention are therefore potentially useful for pharmacological compounds in this context.
Eksempel 2 Example 2
Fremstilling og karakterisering av ikke- B- oksiderbare fettsyreanaloger: Preparation and characterization of non-B-oxidizable fatty acid analogues:
A) Syntese av 3- substituerte fettsyreanaloger: A) Synthesis of 3-substituted fatty acid analogues:
Forbindelsene anvendt i samsvar med foreliggende oppfinnelse hvor substituenten X, = 3 er et svovelatom eller selenatom kan fremstilles i samsvar med generelle prosedyre: The compounds used in accordance with the present invention where the substituent X, = 3 is a sulfur atom or selenium atom can be prepared in accordance with the general procedure:
X er et svovelatom: X is a sulfur atom:
Den tio-substituerte forbindelse anvendt i samsvar med foreliggende oppfinnelse kan fremstilles ved den generelle prosedyre angitt nedenfor: The thio-substituted compound used in accordance with the present invention can be prepared by the general procedure indicated below:
Svovelforbindelsen, nemlig tetradesyltioeddiksyre (TTA), (CH3-(CH2)i3-S-CH2-COOH ble fremstilt som vist i EP-345.038. The sulfur compound, namely tetradecylthioacetic acid (TTA), (CH 3 -(CH 2 )i 3 -S-CH 2 -COOH) was prepared as shown in EP-345,038.
X er selenatom: X is selenium atom:
Den selen-substituerte forbindelse anvendt i samsvar med foreliggende oppfinnelse kan fremstilles med følgende generelle prosedyre The selenium-substituted compound used in accordance with the present invention can be prepared by the following general procedure
Forbindelsen ble renset med forsiktig krystallisering fra etanol eller metanol. The compound was purified by careful crystallization from ethanol or methanol.
Den finale forbindelse, for eksempel idet alkyl er tetradesyl, (CH3-(CH2)i3-Se-CH2-COOH (tetradesylseleneddiksyre (TSA)) kan renses med krystallisering fra dietyl, eter og heksan. B) Syntese av ikke- B-oksiderbar fettsyreanalog omfattende karbon-karbon trippel binding: Syntese av en forbindelse i samsvar med foreliggende oppfinnelse er representativt beskrevet med henvisning til syntese av 3-tia-15-heptadekyn: KOH (2,76 g, 49,0 mmol) var oppløst i metanol (30 ml), og tioglykolisk syre (2,04g, 22,1 mmol) i metanol (25 ml) ble tilsatt dråpe for dråpe. Etter 10 minutter ble 14-brom-2-tetradesyn (5,5 g, 20,1 mmol) forsiktig tilsatt dråpe for dråpe, og blandingen ble oppvarmet til 50 °C natten over. Blandingen ble avkjølt til 0 °C, og 30 ml HCI ble tilsatt (pH = 1). Presipetatet ble filtrert og vasket med vann (2x). Faststoffmaterialet ble oppløst i kloroform (100 ml) og vasket med vann (1x), tørket (MgS04) og løsemiddelet ble evaporert av. Utbyttet av forbindelsen 14-brom-2-tetradesyn var 4,4 9 (77%). The final compound, for example where the alkyl is tetradecyl, (CH3-(CH2)i3-Se-CH2-COOH (tetradecylselenoacetic acid (TSA)) can be purified by crystallization from diethyl, ether and hexane. B) Synthesis of non-B-oxidizable fatty acid analogue comprising a carbon-carbon triple bond: Synthesis of a compound in accordance with the present invention is representatively described with reference to the synthesis of 3-thia-15-heptadekyne: KOH (2.76 g, 49.0 mmol) was dissolved in methanol ( 30 mL), and thioglycolic acid (2.04 g, 22.1 mmol) in methanol (25 mL) was added dropwise. After 10 min, 14-bromo-2-tetradecyne (5.5 g, 20.1 mmol) was carefully added dropwise and the mixture was heated to 50 °C overnight. The mixture was cooled to 0 °C and 30 mL of HCl was added (pH = 1). The precipitate was filtered and washed with water (2x). The solid material was dissolved in chloroform (100 mL) and washed with water (1x), dried (MgSO 4 ) and the solvent was evaporated. The yield of the compound 14-bromo-2-tetradecyne was 4.49 (77%).
Syntese av ovenfor nevnte ikke- B-oksiderbare fettsyreanaloger ble gitt som eksempler, og ikke for å illustrere syntese av alle forbindelser av formel (I). Andre forbindelser i samsvar med foreliggende oppfinnelse kan syntesefiseres som angitt i søkers patentsøknader PCT/NO99/00135 og NO 20001123. Synthesis of the above-mentioned non-B-oxidizable fatty acid analogues was given as examples, and not to illustrate the synthesis of all compounds of formula (I). Other compounds in accordance with the present invention can be synthesized as indicated in the applicant's patent applications PCT/NO99/00135 and NO 20001123.
Eksempel 3 Example 3
Biologiske effekter av materialene ifølge oppfinnelsen Biological effects of the materials according to the invention
Kjemikalier Chemicals
Kjemikaliene var tilgjengelige fra vanlige kommersielle kilder og var av reagent gradering. Fiskeoljen var fra Hordafor, mens planeoljene var fra Mills. Karboksymetylcellulose (CMC) ble anvendt som en kontroll (negativ). The chemicals were available from common commercial sources and were of reagent grade. The fish oil was from Hordafor, while the planing oils were from Mills. Carboxymethylcellulose (CMC) was used as a control (negative).
Dyr Animals
Hankjønn Wistar rotter, veiende fra 250 til 358 gram, ble innkjøpt fra AnLab Ltd. Male Wistar rats, weighing from 250 to 358 grams, were purchased from AnLab Ltd.
(Prahg, Tsjekkia) og ble holdt i trådbur med en temperatur på 22 ± 1 °C og lysregulert (lys fra 7 am til 7 pm). Der var ingen restriksjoner på ernærings- og (Prahg, Czech Republic) and were kept in wire cages with a temperature of 22 ± 1 °C and light-regulated (light from 7 am to 7 pm). There were no restrictions on nutrition and
vanninntak. Tre rotter ble holdt i hvert bur. Økning i vekt og næringsinntak ble monitorert daglig. water intake. Three rats were kept in each cage. Increase in weight and nutrient intake were monitored daily.
Dietter Diets
Rottene ble foret en standard Chow ST1 diett (fra [Velaz, Prahg, Tsjekkia]). The rats were fed a standard Chow ST1 diet (from [Velaz, Prahg, Czech Republic]).
Behandlinger Treatments
Hankjønn Wistar rotter fikk akklimatisere seg til de nye omgivelsene før initiering av eksperimentet. De ble deretter behandlet daglig i 10 dager med gavage. CMC ble anvendt som en bærer og negativ kontroll. Hver behandlingsgruppe talte 4 rotter. Gruppene som ble behandlet med TTA ble gitt 150 mg/ kg kroppsvekt/ dag oppløst i CMC eller oljer. Gruppene som ble behandlet med oljer (solsikkeolje, soyaolje, olivenolje eller fiskeolje) ble gitt 3 ml (cirka 2,5 kg)/ kg kroppsvekt/ dag. Gruppene som ble behandlet med oljer (solsikkeolje, soyaolje, olivenolje eller fiskeolje) ble gitt 3 ml (ca. 2,5 g)/ kg kroppsvekt/ dag. CMC ble anvendt som en bærer og negativ kontroll. Dagen etter siste behandling ble rottene ofret. Male Wistar rats were allowed to acclimatize to the new environment before initiation of the experiment. They were then treated daily for 10 days by gavage. CMC was used as a vehicle and negative control. Each treatment group counted 4 rats. The groups treated with TTA were given 150 mg/kg body weight/day dissolved in CMC or oils. The groups treated with oils (sunflower oil, soya oil, olive oil or fish oil) were given 3 ml (about 2.5 kg)/kg body weight/day. The groups treated with oils (sunflower oil, soybean oil, olive oil or fish oil) were given 3 ml (approx. 2.5 g)/kg body weight/day. CMC was used as a vehicle and negative control. The day after the last treatment, the rats were sacrificed.
Ofring og opptak av vev Tissue sacrifice and uptake
Rottene ble anastatisert med 1:1 blanding av Hypnorm™ (fentanyl sitrat 0,315 mg/ ml og fluanison 10 mg/ ml, Janssen Animal Health) og Dormicum<®> (midasolam 5 mg/ ml, F. Hoffmann-La Roche) injisert subkutanøst. Blod ble trukket direkte fra hjertet ved anvendelse av en heparin-skylt sprøyte. Lever ble umiddelbart fjernet, veid og delt i to deler, som deretter umiddelbart ble avkjølt på is eller frosset i væskeformig nitrogen, respektivt. Plasma og vev ble lagret ved - 80 °C inntil analyse. Protokollen var godkjent av [Norwegian State Board of Biological Experiments with Living Animals]. The rats were anesthetized with a 1:1 mixture of Hypnorm™ (fentanyl citrate 0.315 mg/ml and fluanisone 10 mg/ml, Janssen Animal Health) and Dormicum<®> (midazolam 5 mg/ml, F. Hoffmann-La Roche) injected subcutaneously . Blood was drawn directly from the heart using a heparin-flushed syringe. Livers were immediately removed, weighed and divided into two parts, which were then immediately chilled on ice or frozen in liquid nitrogen, respectively. Plasma and tissue were stored at - 80 °C until analysis. The protocol was approved by the [Norwegian State Board of Biological Experiments with Living Animals].
Fremstilling av hepatiske subcellulære fraksjoner Preparation of hepatic subcellular fractions
Lever fra rottene ble homogenisert individuelt i iskald sukroseløsning (0,25 mol/ L sukrose i 10 mmol/L HEPES buffer pH 7,4 og 1 mmol/ L EDTA) ved anvendelse av en homogeniserer av typen Potter-Elvehjem. Subcellulær fraksjonering av leverne ble utført som tidligere beskrevet (Berge RK et al. (1984) Eur J Biochem 141: 637-44). Prosedyren ble utført ved 0-4 °C, og fraksjonene ble lagret ved -80 °C. Protein ble analysert med BioRad protein analyse kit ved anvendelse av bovin serum albumin som standard. Livers from the rats were homogenized individually in ice-cold sucrose solution (0.25 mol/L sucrose in 10 mmol/L HEPES buffer pH 7.4 and 1 mmol/L EDTA) using a homogenizer of the Potter-Elvehjem type. Subcellular fractionation of the livers was performed as previously described (Berge RK et al. (1984) Eur J Biochem 141: 637-44). The procedure was performed at 0-4 °C, and the fractions were stored at -80 °C. Protein was analyzed with the BioRad protein analysis kit using bovine serum albumin as a standard.
Enzym analyse Enzyme analysis
Fettacyl-CoA oksidase aktivitet ble målt i peroksimale leverfraksjon som tidligere beskrevet (Small GM, Burdett K, Connock MJ (1985) Biochem J 227:205-10). Resultatene ble gitt som fettacyl- CoA oksidase aktivitet per total protein, baselinje-aktivitet (aktivitet av kontroll) ble subtrahert, og dataene som er presentert i figur 1 ble normalisert til aktiviteten av TTA. Fatty acyl-CoA oxidase activity was measured in peroximal liver fractions as previously described (Small GM, Burdett K, Connock MJ (1985) Biochem J 227:205-10). The results were given as fatty acyl-CoA oxidase activity per total protein, baseline activity (activity of control) was subtracted, and the data presented in Figure 1 were normalized to the activity of TTA.
Lipidanalvse Lipid analysis
Plasma og leverlipider ble målt enzymatisk på Technocon Axon system (Miles, Tarrytown, NY) ved anvendelse av triglyserid kit fra Bayer, Total kolesterol (Bayer, Tarrytown, NY), og PAP150 kit for kolin- inneholdende fosfolipider fra bioMerieux. Resultatene ble gitt per total protein, og data som er presentert i figurene 2-4 ble normalisert til aktiviteten av den positive kontroll (intet tilsatt TTA eller oljer; det vil si "normale" nivåer). Plasma and liver lipids were measured enzymatically on the Technocon Axon system (Miles, Tarrytown, NY) using the triglyceride kit from Bayer, Total cholesterol (Bayer, Tarrytown, NY), and the PAP150 kit for choline-containing phospholipids from bioMerieux. Results were given per total protein, and data presented in Figures 2-4 were normalized to the activity of the positive control (no added TTA or oils; that is, "normal" levels).
Claims (1)
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| CN2005800298221A CN101010101B (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizable fatty acid entities |
| RU2007105885/15A RU2394598C2 (en) | 2004-07-19 | 2005-07-19 | Composition containing protein material and compounds which contain unoxidisable structural elements of fatty acids |
| US10/550,129 US20070009608A1 (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and compounds comprising non-oxidizable fatty acid entities |
| AU2005264782A AU2005264782B2 (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizable fatty acid entities |
| PCT/NO2005/000271 WO2006009464A2 (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities |
| NZ553261A NZ553261A (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities |
| KR1020077003854A KR20070054637A (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities |
| JP2007522458A JP2008506774A (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizing fatty acid body |
| ES10183765.6T ES2660700T3 (en) | 2004-07-19 | 2005-07-19 | Composition comprising vegetable and / or fish oils and non-oxidizable fatty acid entities |
| RU2007105886/15A RU2388490C2 (en) | 2004-07-19 | 2005-07-19 | Composition containing vegetable or cod-liver oil and compounds which contain non-oxidising structural elements of fatty acids |
| EP05772070A EP1773397A2 (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities |
| DK10183765.6T DK2275140T3 (en) | 2004-07-19 | 2005-07-19 | Composition, comprising plant and / or fish oils and non-oxidizable fatty acid units |
| EP05772164A EP1784223A2 (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities |
| EP10183765.6A EP2275140B1 (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities |
| NZ553260A NZ553260A (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizable fatty acid entities |
| CN2005800298236A CN101010102B (en) | 2004-07-19 | 2005-07-19 | Composition comprising non-oxidizable fatty acid analogoues and plant and/or fish oils |
| CA2574381A CA2574381C (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizable fatty acid entities |
| AU2005264781A AU2005264781B2 (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities |
| JP2007522457A JP2008506773A (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizing fatty acid body |
| CA002574366A CA2574366A1 (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and compounds comprising non-oxidizable fatty acid entities |
| MX2007000816A MX2007000816A (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizable fatty acid entities. |
| PCT/NO2005/000272 WO2006009465A2 (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizable fatty acid entities |
| MX2007000813A MX2007000813A (en) | 2004-07-19 | 2005-07-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities. |
| KR1020077003855A KR20070046866A (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and non-oxidizable fatty acid entities |
| US10/550,033 US7659242B2 (en) | 2004-07-19 | 2005-07-19 | Composition comprising protein material and compounds comprising non-oxidizable fatty acid entities |
| NO20070924A NO20070924L (en) | 2004-07-19 | 2007-02-19 | Material, as well as the use of the same. |
| NO20070923A NO20070923L (en) | 2004-07-19 | 2007-02-19 | Material, as well as the use of the same. |
| HK07109601.5A HK1101555A1 (en) | 2004-07-19 | 2007-09-04 | Composition comprising protein material and non-oxidizable fatty acid entities |
| US13/423,884 US20120276212A1 (en) | 2004-07-19 | 2012-03-19 | Composition comprising plant and/or fish oils and non-oxidizable fatty acid entities |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO20043093A NO324534B1 (en) | 2004-07-19 | 2004-07-19 | Material prepared from a combination of non-β-oxidizable fatty acid analogues and a plant oil or fish oil and uses thereof |
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| Publication Number | Publication Date |
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| NO20043093D0 NO20043093D0 (en) | 2004-07-19 |
| NO20043093L NO20043093L (en) | 2006-01-20 |
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| NO (1) | NO324534B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO20171033A1 (en) * | 2017-06-23 | 2018-12-24 | Olivita As | Combination of oils |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999058120A1 (en) * | 1998-05-08 | 1999-11-18 | Rolf Berge | USE OF NON-β-OXIDIZABLE FATTY ACID ANALOGUES FOR TREATMENT OF SYNDROME-X CONDITIONS |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO20171033A1 (en) * | 2017-06-23 | 2018-12-24 | Olivita As | Combination of oils |
| NO344004B1 (en) * | 2017-06-23 | 2019-08-12 | Olivita As | Combination of oils |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101010102A (en) | 2007-08-01 |
| CN101010102B (en) | 2013-02-27 |
| NO20043093D0 (en) | 2004-07-19 |
| NO20043093L (en) | 2006-01-20 |
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