WO2005018632A1 - Treatment of neurodegenerative conditions - Google Patents
Treatment of neurodegenerative conditions Download PDFInfo
- Publication number
- WO2005018632A1 WO2005018632A1 PCT/GB2004/003524 GB2004003524W WO2005018632A1 WO 2005018632 A1 WO2005018632 A1 WO 2005018632A1 GB 2004003524 W GB2004003524 W GB 2004003524W WO 2005018632 A1 WO2005018632 A1 WO 2005018632A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acid
- linolenic acid
- lipid
- dihomo
- disease
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/62—Halogen-containing esters
- C07C69/65—Halogen-containing esters of unsaturated acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
- C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
Definitions
- the present invention relates to a method for treating neurodegenerative conditions, particularly those in which increase in transforming growth factor ⁇ (TGF- ⁇ ) is beneficial, particularly TGF- ⁇ l. More particularly the present invention provides treatment for neurodegenerative conditions, particularly those such as demyelinating diseases, such as multiple sclerosis, Alzheimer's and Parkinsons diseases and the degenerative sequelae associated with head trauma, stroke and intracranial bleeds, whereby neuronal function may be improved or restored from an impaired condition, eg. by remyeleination.
- TGF- ⁇ transforming growth factor ⁇
- the present invention provides treatment for neurodegenerative conditions, particularly those such as demyelinating diseases, such as multiple sclerosis, Alzheimer's and Parkinsons diseases and the degenerative sequelae associated with head trauma, stroke and intracranial bleeds, whereby neuronal function may be improved or restored from an impaired condition, eg. by remyeleination.
- TGF- ⁇ l and PGE 2 production has been shown to be increased non-specifically in ⁇ -linolenic acid fed mice ex vivo.
- TGF- ⁇ 1 has been reported to protect in acute and relapsing EAE ((Racke et al (1993); Santambrogio et al (1993)), and PG inhibitors such as indomethacin augment, and thus worsen, the disease (Ovadia & Paterson (1982)).
- Cytokines are implicated in the pathogenesis of MS, with many studies showing an increase in myelinotoxic inflammatory cytokines (TNF- ⁇ , IL-1 ⁇ and LFN- ⁇ ) coinciding with the relapse phase of the disease.
- TGF- ⁇ l cytokine transforming growth factor-betal
- TGF- ⁇ l is expressed in the CNS and, in oral-tolerance-induced protection in EAE, TGF- ⁇ and PGE are expressed in the brain (Karpus & Swanborg (1991); Khoury et al (1992)). Harbige ((1998) concluded that dietary ⁇ -linolenic acid effects on EAE are mediated through Th 3 -like mechanisms involving TGF- ⁇ l and possibly through superoxide dismutase antioxidant activity.
- T cell depleters and modulators such as cyclophosphamide
- T-cells indeed produce beneficial cytokines, such as TGF- ⁇ l, as well as deleterious ones in man.
- David Baker of Institute of Neurology UK summed up the disparity between what is effective in the EAE and in MS with a paper entitled 'Everything stops EAE, nothing stops MS' at the 10 th May 2004 UK MS Frontiers meeting of the UK MS Society. It is clear that immunosuppression alone cannot cure MS.
- MS patients in addition to the autoimmune disease, that leads to membrane abnormality, cytokine dysregulation and subsequent immune attack and lesioning.
- the 'gold standard' treatment for MS remains interferon, such as with ⁇ - Avonex ®, Rebif ® and other interferon preparations.
- This gold standard treatment only addresses needs of some, eg 30%, of the patients and even in these symptom improvement is restricted to reduced severity of relapses. Whilst symptoms may be reduced in a proportion of patients, the disease tends to progress to further disability and death due to underlying degeneration.
- PBMC peripheral blood mononuclear cell production
- pro-inflammatory cytokines TNF- ⁇ and IL-l ⁇ were significantly and markedly ( ⁇ 70%) reduced and they either maintained or increased the PBMC membrane long chain omega-6 fatty acids dihomo- ⁇ -linolenic acid (DHLA) and arachidonic acid (AA) in contrast to patients taking placebo who demonstrated loss of these fatty acids over the course of the trial period.
- DHLA dihomo- ⁇ -linolenic acid
- AA arachidonic acid
- MOG myelin oligodendrocyte glycoprotein
- blackcurrant seed oil 72 % w/w 18:3n-6, GLA
- blackcurrant seed oil has a low sn-2 GLA with most of the GLA in the sn-1 and sn-3 positions (Lawson and Hughes 1988).
- TG-GLA structured triacylgcerol containing three GLA moieties
- the present inventors now set out, in view of their results for high sn-2- ⁇ - linolenic acid Borage Oil, to demonstrate that it is indeed the presence of an sn-2- ⁇ - linolenic acid, dihomo- ⁇ -linolenic acid or arachidonic acid residue in a glyceride, particularly a triglyceride, that gives it efficacy in treating EAE, CREAE and the human disease MS.
- the present invention provides a method of treating a patient in need of therapy for a neurodegenerative disease comprising administering to that patient a therapeutically effective dose of a defined structure lipid glyceride comprising a glycerol moiety esterifed with one or more fatty acid moieties, characterised in that the lipid has a fatty acid moiety at the sn-2 position selected from the group of residues consisting of residues of ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid and arachidonic acid.
- Particularly advantageously treated neurodegenerative diseases are those involving demyelination.
- the present method specifically arrests underlying neurodegeneration and restores neuronal function.
- the method normalises neuronal membrane composition, and restores healthy PBMC spontaneuosly released TGF- ⁇ l/TNF ⁇ ratios and the ratios of TGF- ⁇ l with other PBMC released cytokines.
- the method arrests neurodegeneration in multiple sclerosis of all types but particularly relapsing remitting, primary progressive and chronic progressive MS and the restoration, in part or completely, of neuronal function such as measured, eg. By MRI or CAT scan or by EDSS score.
- Such method may also be used in treatment of cerebral impairment after stroke, head trauma and intracranial bleeding where there is demyelination or neuronal damage.
- the lipid is administered for a duration and at a dose sufficient to maintain or elevate TGF- ⁇ levels in the patient to therapeutic levels.
- therapeutic levels is meant levels at least consistent with healthy subjects.
- the dose is such as to produce a TGF- ⁇ 1/TNF- ⁇ ratio spontaneously released from peripheral blood mononuclear cells (PBMCs) isolated from blood of a patient, after 18 months of daily dosing, of 0.4 to 3.0, at least 0.5, more preferably at least 0.75 and most preferably at least 1.
- PBMCs peripheral blood mononuclear cells
- the dose is such as to produce a TGF- ⁇ 1/IL-l ⁇ ratio in blood of a patient, after 18 months of daily dosing, of at least 0.5, more preferably at least 0.75 and most preferably at least 1.
- said levels are produced after 12 months and more preferably after 6 months.
- the amount of lipid administered daily will be between 0.5 and 30 grams, orally dosed, still more preferably between 1 and 20 grams and most preferably between 1 and 18 grams, typically 3 to 5 grams.
- the sn-2 moiety is that of a ⁇ -linolenic acid residue
- the dose may be toward the higher end of these ranges, particuarly where the sn-1 and sn-3 moieties are relatively inert, eg.
- the lipid is a monoglyceride, diglyceride or triglyceride containing the at least one sn-2 ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid or arachidonic acid moiety of general Formula I below:
- R and R are independently selected from hydrogen and acyl groups, and R 2 is selected from the group consisting of ⁇ -linolenic acid, dihomo- ⁇ - linolenic acid and arachidonic acid residues.
- acyl groups are defined as comprising at least one carbonyl group on the end of an optionally substituted hydrocarbyl chain selected from alkyl and alkenyl chains, the carbonyl group being directly attached by its carbon to the oxygen of the glycerol residue shown in Formula 1.
- Preferred acyl groups R 1 and R 3 are saturated fatty acid moities of formula - CO-(CH 2 ) n -CH 3 , wherein n is an integer selected from 1 to 22, more preferably being 4 to 16, still more preferably being from 5 to 12, most preferably being from 6 to 10.
- Particularly preferred acyl groups are those of caprylic and capric acids, particularly being 1,3-dicaprylic or 1,3-dicapric glycerols having the ⁇ -linolenic acid, dihomo- ⁇ - linolenic acid or arachidonic acid moiety at the sn-2 position.
- Preferred glycerides for use in the invention are triglycerides.
- US 4701469 describes some potential triglycerides for nutraceutical use that the present inventors have determined may be used in the method of the invention, although it only specifically describes 1,3-dioctanyl triglycerides wherein the sn-2 acid is of an EFA, only 1,3-dioctanoyl eicosapenta glycerol is described as having been prepared. These are said to useful in inter alia immunomodulation, but although a number of diseases are specified, use in immunosuppresion in neurodegeneration and MS are not listed.
- R 1 to R 3 for inclusion in the compound of formula I are simple saturated fatty acids or naturally occurring fatty acids with structural or metabolic function, such as medium chain or long chain fatty acids, there are other possibilities. Particularly preferred fatty acids are those that are utilised primarily by the metabolism for producing energy. Where fatty acids are structural, that is utilised in membranes, they are conveniently such as ⁇ -linolenic acid, linoleic acid, dihomo- ⁇ -linolenic acid and arachidonic acid residues. By residue is meant the moiety that remains after the fatty acid carboxyl group esterifies to one of the hydroxy groups of the glycerol molecule.
- sn-1 and sn-3 are selected from fatty acids that are metabolised in the human to yield energy as opposed to a fatty acid that is primarily directed to the structural membrane pool: such preferred acids include oleic acid and palmitic acid.
- sn-1 and sn-3 fatty acid chain (R and R ) is unsaturated it may also be that of other essential fatty acids, such as the n-3 acids such as stearidonic acid, eicosapentanoic acid and docosahyexanoic acid.
- the fatty acid is optionally substituted these will preferably be by hydroxy, oxo, carboxyl, alkyl, alkenyl and alkoxy groups.
- the hydrocarbyl chain is preferably one of from 1 to 30 carbon atoms in length, more preferably from 4 to 28 carbon atoms in length, still more preferably 4 to 24 carbon atoms in length. Most preferably the hydrocarbyl chain is that of a fatty acid, more particularly a mono or polyunsaturated fatty acid.
- a fatty acid more particularly a mono or polyunsaturated fatty acid.
- Many of the preferred lipids for use in the method of the invention are known and may be prepared by chemical process known in the art. For example, many are commercially available, such as trigamma-linolenin, known as TLG, but herein referred to as GGG, reflecting the identity of groups R R R where G represents ⁇ - linolenic acid residues. GGG is commercially available from Nu-Check-Prep Inc.
- EP 0300844 describes its synthesis using a base-catalysed trans-esterification of triacetin with methyl gamma linolenate to give a mixture containing 80% GGG, unreacted methyl ⁇ - linolenate and 10% mono- and di-glycerides.
- Triarachidin is known and small quantities can be obtained commercially eg. from Sigma AAA has been synthesised from arachidonic acid by using immobilised lipase patented for angiogenisis-enhancing activity US 4888324.
- the present inventors prefer the use of the mono- ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid or arachidonic acid sn-2 ester triglycerides because they administer less of the immunomodulatory and proinflammatory fatty acids ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid or arachidonic acid whilst retaining the enhanced activity that the sn-2 ⁇ -linolenic acid, dihomo- ⁇ - linolenic acid or arachidomc acid moiety provides with regard to the desired membrane normalising and disease modifying effect.
- Novel lipids which are preferred are accessible by processes and methods set out in the Examples herein. Most preferred lipids are those where there is just a single ⁇ -linolenic acid, dihomo- ⁇ -linolenic acid or arachidonic acid moiety esterified to the glycerol at sn-2, with the flanking sn-1 and sn-3 acids being unsaturated medium chain or long chain acids.
- novel lipids disclosed herein including compounds of formula II
- R 1 and R 3 are the same and are -C(O)(CH 2 ) n CH 3 wherein n is selected from 4 to 14, more preferably 6 to 10 and most preferably 7, 8 or 9 and R 2 is selected from ⁇ -linolenyl, dihomo- ⁇ -linolenyl and arachidonyl.
- a further aspect of the present invention provides a method for synthesis of a compound of general formula III
- R 1 and R 3 are the same and are -C(O)(CH 2 ) n CH 3 wherein n is selected from 4 to 14, more preferably 6 to 10 and most preferably 7, 8 or 9 and R 2 is ⁇ - linolenyl residue, dihomo- ⁇ -linolenyl residue or arachidonyl residue comprising reacting 1,3-dihydroxyacetone with a compound of formula X-C(O)(CH 2 ) n CH 3 wherein X is selected from Cl, Br and I, to give the corresponding l,3-di-( C(O)(CH 2 ) n CH 3 ) 2-keto compound reducing the keto group to the corresponding l,3-di-( C(O)(CH 2 ) n CH 3 ) 2-ol and reacting that with ⁇ -linolenyl chloride or dihomo- ⁇ -linolenyl chloride or arachidonyl chloride.
- n is selected from 4 to
- R 1 to R 3 are the same and selected from ⁇ -linolenyl residue, dihomo- ⁇ -linolenyl residue or arachidonyl residue comprising reacting the corresponding ⁇ -linolenyl chloride, dihomo- ⁇ - linolenyl chloride or arachidonyl chloride with glycerol.
- Synthesis of some of these compounds is described below and schemes shown in the figures below. For example, a single-step esterification of glycerol using GLA and a coupling agent, such as DCCI/DMAP (1.1-Dicylcohexylcarbodiimide/ 4- dimethylaminopyridine) coupling reagents may be carried out.
- DCCI/DMAP 1.1-Dicylcohexylcarbodiimide/ 4- dimethylaminopyridine
- GLA-C1 prepared from ⁇ -linolenic acid and oxalyl chloride
- glycerol in dichloromethane/pyridine with good yields at scale-up to 250 g purified by column chromatography.
- Yukiki Watanebe, Yoichi, Takagi, Yoshiaki (Nisshin Oil Mills Ltd, Japan) describes a related but different technique for purification of tri- ⁇ -linolenin
- the applicant further provides an improved process which allows glycerol to react with more than 3 equivalents of decanoyl chloride and purified the tricaprin product by recrystallisation.
- Further aspects of the present invention provide use of triglyceride oils as described above for the manufacture of a medicament for the treatment of neurodegenerative diseases as set out for the method of the invention.
- Particularly preferred medicaments are for the arresting and reversing of neurodegeneration in multiple sclerosis of all types but particularly relapsing remitting, primary progressive and chronic progressive and the restoration, in part or completely, of neuronal integrity function such as measured, eg. By MRI or CAT scan or by EDSS score.
- TGF- ⁇ l responsive diseases may be treated as set out previously.
- the lipids for use in the present invention may be administered by any of the conventional vehicles known in pharmacy. Most conveniently they are administered as neat oils or in admixture with foodstuffs, in the form of capsules containing such oils, or in enterically coated forms. Other forms will occur to those skilled in the art but Remington Pharmaceutical Sciences 19 Edition. It will be realised by those skilled in the art that other beneficial agents may be combined with the lipids for use in the present invention or otherwise form part of a treatment regime with the lipids. These might be ion channel blockers, eg. sodium chamiel blockers, interferons ( ⁇ , ⁇ , or ⁇ ), T-cell depleters, steroids or other palliative agents.
- ion channel blockers eg. sodium chamiel blockers, interferons ( ⁇ , ⁇ , or ⁇ )
- T-cell depleters steroids or other palliative agents.
- Table 1 Shows the compositional % Total fatty acid content of various triglyceride oils and protective effect in EAE.
- Table 2 Shows the parameters of the three treatment groups in high sn-2 GLA Borage Oil trial described in PCT/GB04/002089.
- Table 3 Shows the effect of various forms of GLA on EAE incidence and clinical score in SJL mice: lower score indicating improved therapeutic effect.
- Table 4 Shows the failure of enriched Blackcurrent oil, a high GLA, but low sn-2- GLA, plant oil, to match fungal and Borage oils in EAE.
- Figure 1 Shows spontaneous peripheral blood mononuclear cell cytokine production in placebo and high sn-2 ⁇ -linolenic acid, PCT/GB04/002089 trial oil treated human MS patients at 18 months.
- Figure 2 Shows the effect of placebo and low dose (5g/day) high sn-2 GLA Borage oil on human MS patient EDSS score as compared to high dose (15g/day) displayed as a histogram with months treatment on the x axis.
- Figure 3 Shows the effect of placebo, low dose and high dose high sn-2 GLA Borage oil on human MS patient Mean Relapse rate (%) as histogram with months on x axis.
- Figure 4 Shows the reaction scheme for synthesis of a single fatty acid triacylglyceride for use in the method and use of this invention.
- Figure 5 Shows the reaction scheme for synthesis of control compound tricaprin.
- Figure 6 Shows the reaction scheme for synthesis of CGC, a mixed fatty acid triacylglyceride of the invention.
- Figure 7 Shows the reaction scheme for synthesis of C-DHGLA-C, a mixed fatty acid triacylglyceride of the invention.
- Figure 8 Shows the reaction scheme for synthesis of control compound GCG, 1,3- dicapryl, 2- ⁇ -linolenic acid.
- Figure 9 Shows the reaction scheme for synthesis of C-AA-C, a mixed fatty acid traiacylglyceride of the invention.
- High sn-2 Borage oil (PCT/GB04/002089) trial. Twenty-eight active relapsing-remitting (two relapses in the preceding 18 months) multiple sclerosis patients (ages ranging from 18 to 65 yrs) were entered into a double-blind placebo controlled trial to investigate the effects of encapsulated borage oil on clinical activity and laboratory parameters over 18 months.
- This oil was of high sn-2 ⁇ -linolenic (GLA) content (>40% of sn-2 residues being ⁇ -linolenic acid ) with low monene (eg. erusic acid) content and had no added Vitamin E, a known immunomodulator.
- GLA high sn-2 ⁇ -linolenic
- Exclusion criteria include any form of steroid or immunosuppressive drug treatment, pregnancy, hyperlipidemia, regular use of aspirin or related drugs and vitamin or fatty acid supplementation within the previous three months.
- Results are shown in Tables 1 and 2 and Figures 1 to 5.
- the primary outcome parameter was the number of clinical relapses between baseline (Month 0) and the end of treatment (Month 18).
- Secondary outcome parameters included: the time to first clinical relapse; severity of relapses, as assessed by EDSS score and the use of steroid treatment; and changes in EDSS at Month 3, 6, 9, 12, and 18 compared to baseline and defined as at least 1.0 point increase in the EDSS that is sustained for 3 months or at least 1.5 point increase on the EDSS from the baseline EDSS that is sustained for 3 months.
- Eleven patients were in the placebo group seven patients had been taking low- dose Borage oil, and ten patients had been taking high-dose Borage oil.
- the study drug was well-tolerated, and there were no serious adverse events during the 18- month trial.
- TNF- ⁇ , IL-l ⁇ and IFN- ⁇ in cell culture supernatants and plasma were detected using commercially available paired antibodies enabling cytokine detection in an ELISA format (R&D systems Ltd, Abingdon, UK).
- the sensitivities for the TNF- ⁇ and IFN- ⁇ ELISAs were 15.6-lOOOpg/ml and 3.9-250 ⁇ g/ml for IL-l ⁇ .
- Patient 1 The first patient was a 48 year old woman who had had a clinically active, relapsing remitting MS for 9 years. She had originally worked as a full-time administrator at the local Health Authority, but she was unable to perform her duties because of her severe MS. Therefore, she later worked as a part-time secretary, but still had difficulties in mobilization because of muscles stiffness and sensory disturbances. She was also experiencing severe clinical relapses at an average of one relapse every nine months. Most of these relapses had resulted in hospital admissions for steroid therapy. In view of her active MS, she was recruited into the Borage oil trial.
- Patient 2 The second case was a 46-year old woman who also had a clinically active relapsing remitting MS for 8 years. She had originally worked as a shop assistant, but became unemployed after MS was diagnosed. Her symptoms included difficulty with mobilisation and painful sensory symptoms in both legs. She had experienced three clinical relapses in the two years preceding the clinical trial, and had been admitted to hospital twice for steroid therapy. Consequently, she was recruited into the Borage oil trial, but her walking continued to deteriorate. Six months into the trial, she need to use a walking stick and also received treatment with Baclofen to reduce low limb spasticity. Approximately ten months after starting the Borage oil trial, she was admitted to hospital because of severe clinical relapse, which was treated with steroids.
- the DCM was dried over magnesium sulphate, filtered and concentrated in vacuo to a brown oil ( ⁇ 21 g).
- the oil was purified on a silica column using 5% ether in hexane at first and then 10%. 15.6g (77% yield) of a clear oil was obtained. By tic this material contained a small amount of free GLA. (This material was repurified at a later date)
- glycerol tri-6,9,12-linolenate (gamma linolenic acid triglyceride, trigammalinolenin, GGG) was prepared from 96.2 % GLA by a two-step acid chloride route. It is a clear, pale yellow oil and was stored under nitrogen in the freezer. The GLA content was 97.1 % and no C20:l, C22:l, or C24:l acids were detected). The HPLC purity was 93.6 %.
- the precipitated pyridine hydrochloride was removed by filtration and washed with dichloromethane. The combined washing and filtrate was then washed with aqueous solutions (20 ml) of 5% sodium chloride, 5% sodium bicarbonate, 0.1N hydrochloric acid, and 5% sodium chloride. The dichloromethane layer was then dried over MgSO 4 and the solvent removed in vacuo. The residual oil crystallised on standing. This material was recrystallised from isopropanol (40 ml) to give 15.6 g (86% yield) of a waxy white solid.
- the precipitated pyridine hydrochloride was removed by filtration and washed with dichloromethane. The combined washing and filtrate was then washed with aqueous solutions (300 ml) of 5% sodium chloride, 5% sodium bicarbonate, 0. IN hydrochloric acid, and 5% sodium chloride. The dichloromethane layer was then dried over MgSO 4 and the solvent removed in vacuo. The residual oil crystallised on standing. This material was recrystalhsed from isopropanol (400 ml) to give 228 g (86% yield) of a waxy white solid.
- glycerol tridecanoate (tricaprin, CCC) was been prepared from decanoyl chloride (98 %) by a one-step process (scheme given below). It is a white, low-melting solid and was stored under nitrogen in the freezer. The C content was 99.9 % of fatty acid content and the HPLC purity was 97.9 %.
- CGC was prepared by reaction of 1,3-Dicaprin with GLA-chloride in dichloromethane-pyridine.
- 1,3-Dicaprin was prepared by sodium borohydride reduction of l,3-didecanoyloxypropan-2-one, which was in turn prepared by reaction of decanoyl chloride with 1,3-dihydroxyacetone.
- the intermediate 1,3-dicaprin must be handled with care since it can undergo acyl migration on exposure to acids , bases and heat.
- the residual oily acid chloride (GLA-Cl) was then added dropwise over 15 min (ice /water cooling) to a stirred solution of 1,3-dicaprin (11.2g, 0.028 mol), DCM (50 ml), pyridine (2.42 ml, 2.37 g, 0.03 mol) and 4- dimethylaminopyridine (0.10 g, 0.0008 mol, 0.03 equiv) at 10-15°C .
- the temperature was maintained by ice-water cooling.
- the reaction mixture was stirred at RT under nitrogen overnight. Pyridine hydrochloride was removed by filtration and washed with DCM.
- 1,3-Dicaprin The above ketone (158 g, 0.40 mol) was dissolved in tetrahydrofuran (THF, 2.25 L). Water (50 ml) was then added, the solution cooled to 5°C, and sodium borohydride (5.66 g, 1.5eq) added portionwise below 10°C. The reaction mixture was monitored by HPLC (C18, eluted with ACN at lml min ⁇ 210nm) (Note: only about 4.5g of the borohydride was in fact added, as all SM had reacted). The reaction mixture was stirred at RT for lh and then concentrated in vacuo to remove THF.
- THF tetrahydrofuran
- CGC 1,3-Dicaprin 2-gammalinolenoate
- GLA95 1,3-Dicaprin 2-gammalinolenoate
- DCM dichloromethane
- oxalyl chloride 55.7 ml, 82.3 g, 0.65 mol, 1.5eq
- the mixture was stirred at RT overnight and then concentrated in vacuo to remove DCM and excess oxalyl chloride.
- the residual oily acid chloride (GLA-Cl) was then added dropwise over 30-40 min at 10-15 °C (ice /water cooling) to a stirred solution of 1,3-dicaprin (164.7g, 0.41 mol), DCM (650 ml), pyridine (33.3 ml, 32.5 g, 0.41 mol) and 4-dimethylaminopyridine (1.50 g, 0.012 mol, 0.03 equiv) at 10-15°C .
- the reaction mixture was stirred at RT under nitrogen overnight. Pyridine hydrochloride was removed by filtration and washed with DCM.
- DHLA (3.93g, 12.8 mmol, 1 eq) was dissolved in dichloromethane (DCM, 20 ml) and stirred at room temperature under a nitrogen atmosphere.
- Oxalyl chloride (1.69 ml, 2.46 g, 19.4 mmol, 1.5 eq) was added dropwise over 1-2 min, and left stirring at room temperature overnight. The resulting solution was concentrated in vacuo to remove DCM and excess oxalyl chloride.
- DHLA-C1 The residual oily acid chloride (DHLA-C1) was then added dropwise over 5 min at 25°C to a stirred mixture of 1,3-dicaprin (4.91 g, 12.2 mmol, 0.95 eq), pyridine (0.98 ml, 0.96 g 12.1 mmol, 0.95 eq) and 4-dimethylam inopyridine (DMAP, 8 mg, 0.07 mmol, 0.03 eq).
- DMAP 4-dimethylam inopyridine
- the residual oily acid chloride (A-Cl) was then added dropwise over 15 min to a pre- warmed (25 °C) stirred mixture of glycerol (5.11 g, 0.055 mol, 1 eq), pyridine (13.5 ml, 13.2 g, 0.17 mol, 3 eq) and 4-dimethylamino pyridine (DMAP, 0.20 g, 0.002 mol, 0.03 eq).
- DMAP 4-dimethylamino pyridine
- the temperature of the reaction mixture rose to 42 °C during the addition and a gentle reflux was observed.
- the mixture was stirred at 30-40 °C and monitored by HPLC. After 2 h, no further product formation was observed.
- the precipitated pyridine hydrochloride was filtered off and washed with DCM.
- a second batch (17.8 g) was produced from 39.8 g of arachidonic acid, The two batches were combined and residual solvents removed under vacuo to give 40.5 g (43%) of a mobile pale yellow oil. HPLC purity 84.8% GLC analysis 94.3% AA (arachidonic acid).
- the residual oily acid chloride (GLA-Cl) was then added dropwise over 20 min at 25°C to a stirred mixture of 1,3-dihydroxyacetone dimer (28.99 g, 0.32 mol, 1.0 equiv), pyridine (52 ml, 50.9 g 0.64 mol, 2.0 equiv), 4-dimethylaminopyridine (2.36 g, 0.02 mol, 0.06 equiv) and dichloromethane (DCM, 600 ml) at room temperature under nitrogen. The temperature of the reaction mixture was allowed to rise to 40°C and the mixture was stirred for a further 2 h under nitrogen (monitored by HPLC).
- 1,3-dihydroxyacetone dimer 28.99 g, 0.32 mol, 1.0 equiv
- pyridine 52 ml, 50.9 g 0.64 mol, 2.0 equiv
- 4-dimethylaminopyridine (2.36 g, 0.02 mol, 0.06 equiv
- 1,3-Di- ⁇ -linolenin 2-decanoate (Glycerol l,3-dioctadeca-(6Z,9ZJ2Z -trienoate 2- decanoate or GCG)
- Decanoyl chloride (13.5 ml, 12.4 g, 0.065 mol, 1.1 eq) was added to a stirred solution of 1,3-di- ⁇ -linolenin (36.1 g, 0.059 mol, leq), dry pyridine (5.7 ml, 5.6 g, 0.07 mol, l.leq), 4-dimethylaminopyridine (0.2 g, 0.002 mol, 0.03 eq) and dichloromethane (DCM, 150 ml) over ca.
- DCM dichloromethane
- 1,3-Dicaprin 2-arachidonate Glycerol 1,3-didecanoate 2-eicosatetra-(5-Z,8-Z,ll- ZJ4-Z)enoate or CAP
- This triglyceride is known.
- CAC has been identified as a constituent of lymph lipids following administration of safflower oil to rats.
- WO 03 013,497 describing an arachidonic acid containing triglyceride (produced by culturing Mortierella alpina) useful for diseases caused by brain hypofunction, but specifically for cognition enhancement.
- the two intermediates used in the synthesis of CAC are known.
- the synthesis of CAC from 1,3-dicaprin, and the purification of this are all novel.
- CAC was prepared by reaction of 1 ,3-Dicaprin with arachidonyl chloride in dichloromethane-pyridine.
- 1,3-Dicaprin was prepared by sodium borohydride reduction of l,3-didecanoyloxypropan-2-one, which was in turn prepared by reaction of decanoyl chloride with 1,3-dihydroxyacetone.
- the intermediate 1,3-dicaprin must be handled with care since it can undergo acyl migration on exposure to acids , bases and heat.
- An older method 6 of making 1,3-dicaprin, by catalysed addition of decanoic acid to a glycidol ester (from epichlorohydrin) was deemed less attractive because of more severe reaction conditions and acyl migration problems.
- the final product, CAC was purified by careful column chromatography on silica which removed byproducts.
- the residual oily acid chloride (GLA-Cl) was then added dropwise over 15 min (ice /water cooling) to a stirred solution of 1,3-dicaprin (11.2g, 0.028 mol), DCM (50 ml), pyridine (2.42 ml, 2.37 g, 0.03 mol) and 4- dimethylammopyridine (0.10 g, 0.0008 mol, 0.03 equiv) at 10-15°C .
- the temperature was maintained by ice-water cooling.
- the reaction mixture was stirred at RT under nitrogen overnight. Pyridine hydrochloride was removed by filtration and washed with DCM.
- the pyridine hydrochloride formed was removed by filtration and washed with DCM. The combined filtrate and washings were then washed with 1 x 150ml portions of 5%NaCl, 5%NaHCO 3 , 0.1N HCl, 5%NaCl. The solution was then dried over MgSO 4 and concentrated in vacuo to a yellowish semi-solid. This was then crystallised from methanol (500ml) to give a white solid. The yield was 158 g (60%). 1,3-Dicaprin The above ketone (158 g, 0.40 mol) was dissolved in tetrahydrofuran (THF, 2.25 L).
- the residual oily acid chloride (GLA-Cl) was then added dropwise over 30-40 min at 10-15°C (ice /water cooling) to a stirred solution of 1,3-dicaprin (94.2 g, 0.24 mol), DCM (450 ml), pyridine (19.1 ml, 18.6 g, 0.24 mol) and 4-dimethylaminopyridine (1.72 1.50 g, 0.014 mol, 0.06 equiv) at 10-15°C .
- the reaction mixture was stirred at RT under nitrogen overnight. Pyridine hydrochloride was removed by filtration and washed with DCM.
- glycerol l,3-didecanoate-2-arachidonate (l,3-dicaprin-2-AA, CAC) has been prepared from decanoyl chloride (98 %) and Arachidonic acid (95%) by a three-step process (scheme given below). It is a very pale yellow oil and was stored under nitrogen in the freezer. The HPLC purity is 95.8 %.
- OGO was here prepared by reaction of 1,3-Doleoin with GLA-chloride in dichloromethane-pyridine.
- 1,3-Diolein was prepared by sodium borohydride reduction of l,3-dioleoylpropan-2-one, which was in turn prepared by reaction of oleoyl chloride with 1,3-dihydroxyacetone.
- the intermediate 1,3-dioleolin must be handled with care since it can undergo acyl migration on exposure to acids , bases and heat.
- Older methods 7 ' 8 of making 1,3-dioleoin, via mono-tritylglycerols or glycidyl esters was deemed less attractive because of more steps and acyl migration problems.
- the final product, OGO was purified by careful column chromatography on silica which removed by-products.
- 1,3-Diolein 2-gammalinolenoate (O-G-O) ⁇ -Linolenic acid (GLA95, 41.2 g, 0.15 mol, 1.1 equiv) was dissolved in dichloromethane (DCM, 250 ml). The resulting solution was stirred at RT under nitrogen and oxalyl chloride (19.1 ml, 28.2 g, 0.22 mol, 1.65 equiv) added dropwise over 5 mins. The mixture was stirred at RT overnight and then concentrated in vacuo to remove DCM and excess oxalyl chloride.
- DCM dichloromethane
- the residual oily acid chloride (GLA-Cl) was then added dropwise over 15 min (ice /water cooling) to a stirred solution of 1,3- diolein (83.5g, 0.13 mol), DCM (250 ml), pyridine (10.9 ml, 10.6 g, 0.14 mol) and 4- dimethylaminopyridine (0.49 g, 0.004 mol, 0.15 equiv) at 10-15°C .
- the temperature was maintained by ice-water cooling.
- the reaction mixture was stirred at RT under nitrogen overnight. Pyridine hydrochloride was removed by filtration and washed with DCM.
- glycerol l,3-oleoate-2-gammalinolenoate (l,3-dioleate-2-GLA, OGO) was prepared from oleoyl chloride (98 %) by a three-step process (scheme given below). It was an almost colourless oil (slight yellow tinge) and is being stored under nitrogen in the freezer. The HPLC purity was 89.4 %.
- the proton-decoupled 13 C NMR spectra with suppressed NOE were collected at 21 °C in a 5-mm broadband probe on a Joel 500 MHz spectrometer operating at 125.728 MHz.
- Waltz decoupling was the chosen mode of decoupling and was gated on only during the 14.89s acquisition time.
- the relaxation delay was set at 30 sees and the pulse angle was 90°.
- the spectral window used was ca.35 ppm (from 173.5 to 172.6 ppm) with a 170 ppm offset.
- the spectra were internally referenced to CDC1 at 77.0 ppm.
- the approximate number of scans collected for adequate signal-to- noise ranged from 300 to 1200 scans depending on the concentration and purity of the sample.
- the total acquisition time for the experiments ranged between 2-8h e.g
- CREAE Chronic Relapsing Experimental Autoimmune Encephalomyelitis
- CREAE was induced in C57B1/6 and SJL mice.
- Animals were injected subcutaneously with 100 ⁇ g of the neuroantigen peptide MOG 35-55 (amino acid sequence MEVGWYRSPFSRVVHLYRNGK Genemed Synthesis, hie) or 1 mg of mouse spinal cord homogenate (SCH), in phosphate buffered saline (PBS), emulsified by sonication for 10 min at room temperature, in incomplete Freund's adjuvant (DIFCO, Detroit, USA) supplemented with 480 ⁇ g of mycobacteria tuberculosis and 60 ⁇ g of Mycobacteria butyricium (DIFCO, Detroit, USA) on days 0 and 7 as described previously (Morris-Downes, MM., et al 2002).
- PBS phosphate buffered saline
- DIFCO incomplete Freund's adjuvant
- mycobacteria tuberculosis 60 ⁇ g of Myco
- MOG EAE in C57BL mice Treatment was from Days 5 to 21 inclusive except C-DHLA-C group where treatment was from days 5 to 15 inclusive. Animals were culled on PSD 25. [Five animals from an untreated group, 3 animals from control CCC treatment group, 5 animals from GGG 150ul treatment group and 2 animals from GGG 350ul treatment group were sampled for histological analysis on PSD 20].
- Treatment was from Days 6 to 20 inclusive.
- C-A-C are all capable of reducing severity of CREAE whereas compounds G-C-G and C-C-C failed to treat the condition.
- Compound O-G-O is believed to work if the dose is adjusted.
- the arachidnoic acid compounds are effective, but lead to death of some animals. Surviving animals had much reduced disease. It is believed that the dose of these compounds may be reduced still further to provide survival with satisfactory treatment.
- Some of the studies show a bell shaped response curve for compounds C-G-C and G-G-G, suggesting that very high doses are not optimal, as set out above. Such dosing can be conveniently determined by those skilled art, eg.
- Genain CP. Cannella B., hauser SL and Raine CS. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nature Med 1999:5,170-175.
- Transforming growth factor beta I reduces infarct size after experimental cerebral ischemia in a rabbit model .Stroke 24,558-562.
- TGF-beta I protects hippocampal neurons against degeneration caused by transient global ischaemia. Dose-response relationship and potential neuroprotective mechanisms. Stroke, 27, 1609-1614.
- Hollifield RD Harbige LS, PhM-Dinh D, Sharief M.
- Evidence for cytokine Dysregulation in Multiple Sclerosis Peripheral Blood Mononuclear cell production of pro-inflammmatory and anti-inflammatory cytokines during relapse and remission. Autoimmunity, 2003 36(3):133-141.
- Schiefer HB Hancock DS, Loew FM. Long-term effects of partially hydrogenated herring oil on the rat myocardium. Drug Nutr Interact. 1982;1(2):89-102.
- Schluesener HJ Lider O. Transforming growth factors beta 1 and beta 2: cytokines with identical immunosuppressive effects and a potential role in the regulation of autoimmune T cell function. J Neuroimmunol 1989; 24:249-58.
- FGO Fungal Oil
- BOO Borage Oil
- EPO Evening Primrose Oil
- SAF Safflower Oil
Abstract
Description
Claims
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0603646A GB2422373B (en) | 2003-08-18 | 2004-08-13 | Treatment of neurodegenerative conditions |
JP2006523678A JP2007502805A (en) | 2003-08-18 | 2004-08-13 | Treatment of neurodegenerative conditions |
AU2004266480A AU2004266480B2 (en) | 2003-08-18 | 2004-08-13 | Treatment of neurodegenerative conditions |
CH00249/06A CH698539A8 (en) | 2003-08-18 | 2004-08-13 | Compounds with unsaturated fatty acid residues for the preparation of medicaments for the treatment of multiple sclerosis. |
EP04768085A EP1660071A1 (en) | 2003-08-18 | 2004-08-13 | Treatment of neurodegenerative conditions |
DE112004001520T DE112004001520B4 (en) | 2003-08-18 | 2004-08-13 | Use of a lipid glyceride of specified structure for the manufacture of a medicament for the treatment of multiple sclerosis |
CA2534202A CA2534202C (en) | 2003-08-18 | 2004-08-13 | Lipid glycerides for the treatment of neurodegenerative conditions involving demyelination |
CN200480030644XA CN1867328B (en) | 2003-08-18 | 2004-08-13 | Use of lipid glyceride in preparing medicine for treatment of neurodegenerative conditions |
US10/567,778 US7964641B2 (en) | 2003-08-18 | 2004-08-13 | Treatment of neurodegenerative conditions |
IS8246A IS8246A (en) | 2003-08-18 | 2006-01-19 | Treatment of neurodegenerative conditions |
FI20060154A FI20060154A (en) | 2003-08-18 | 2006-02-17 | Treatment of neurogenerative conditions |
NO20061232A NO20061232L (en) | 2003-08-18 | 2006-03-17 | Treatment of neurodegenerative conditions |
US12/654,780 US20100113810A1 (en) | 2003-08-18 | 2009-12-31 | Treatment of neurodegenerative conditions |
US12/654,779 US20100113595A1 (en) | 2003-08-18 | 2009-12-31 | Treatment of neurodegenerative conditions |
US13/363,705 US20120142775A1 (en) | 2003-08-18 | 2012-02-01 | Treatment of neurodegenerative conditions |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0319358.8 | 2003-08-18 | ||
GB0319358A GB0319358D0 (en) | 2003-08-18 | 2003-08-18 | Treatment of neurodegenerative conditions |
GB0410846A GB0410846D0 (en) | 2004-05-14 | 2004-05-14 | Treatment of neurodegenerative conditions |
GB0410846.0 | 2004-05-14 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/654,780 Division US20100113810A1 (en) | 2003-08-18 | 2009-12-31 | Treatment of neurodegenerative conditions |
US12/654,779 Continuation US20100113595A1 (en) | 2003-08-18 | 2009-12-31 | Treatment of neurodegenerative conditions |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005018632A1 true WO2005018632A1 (en) | 2005-03-03 |
Family
ID=34219616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2004/003524 WO2005018632A1 (en) | 2003-08-18 | 2004-08-13 | Treatment of neurodegenerative conditions |
Country Status (13)
Country | Link |
---|---|
US (4) | US7964641B2 (en) |
EP (2) | EP2324828A1 (en) |
JP (1) | JP2007502805A (en) |
AU (1) | AU2004266480B2 (en) |
CA (1) | CA2534202C (en) |
CH (1) | CH698539A8 (en) |
DE (1) | DE112004001520B4 (en) |
ES (1) | ES2304094B2 (en) |
FI (1) | FI20060154A (en) |
GB (1) | GB2422373B (en) |
IS (1) | IS8246A (en) |
NO (1) | NO20061232L (en) |
WO (1) | WO2005018632A1 (en) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006092623A1 (en) * | 2005-03-02 | 2006-09-08 | Btg International Limited | Cytokine modulators using cyclic glycerides of essential polyunsaturated fatty acids |
WO2006092622A1 (en) * | 2005-03-02 | 2006-09-08 | Btg International Limited | Treatment of cytokine dysregulation by using sn-2 gamma-linolenoyl, gamma-dihomolinolenoyl or arachidonoyl patty acid glycerol monoesters |
US20080004909A1 (en) * | 2005-11-30 | 2008-01-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational systems related to nutraceuticals |
WO2008081989A1 (en) * | 2006-12-28 | 2008-07-10 | Suntory Holdings Limited | Nerve regeneration agent |
US7935729B2 (en) | 2003-05-14 | 2011-05-03 | Btg International Limited | Use of triglyceride oils containing γ-linolenic acid residues and linoleic acid residues for the treatment of neurodegenerative disease |
US7964641B2 (en) | 2003-08-18 | 2011-06-21 | Btg International Limited | Treatment of neurodegenerative conditions |
US8202907B2 (en) | 2004-09-17 | 2012-06-19 | Suntory Holdings Limited | Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders |
US8372812B2 (en) | 2009-02-26 | 2013-02-12 | Aker Biomarine Asa | Phospholipid and protein tablets |
US8697138B2 (en) | 2007-03-28 | 2014-04-15 | Aker Biomarine As | Methods of using krill oil to treat risk factors for cardiovascular, metabolic, and inflammatory disorders |
US8793141B2 (en) | 2005-11-17 | 2014-07-29 | The Invention Science Fund I, Llc | Assistance related to health |
US9028877B2 (en) | 2007-03-28 | 2015-05-12 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9168241B2 (en) | 2005-06-30 | 2015-10-27 | Suntory Holdings Limited | Compositions ameliorating a reduced diurnal activity and/or depressive symptoms |
US9867856B2 (en) | 2014-01-10 | 2018-01-16 | Aker Biomarine Antarctic As | Phospholipid compositions and their preparation |
US10042980B2 (en) | 2005-11-17 | 2018-08-07 | Gearbox Llc | Providing assistance related to health |
US10296720B2 (en) | 2005-11-30 | 2019-05-21 | Gearbox Llc | Computational systems and methods related to nutraceuticals |
US10456412B2 (en) | 2015-02-11 | 2019-10-29 | Aker Biomarine Antarctic As | Lipid extraction processes |
US10704011B2 (en) | 2013-06-14 | 2020-07-07 | Aker Biomarine Antarctic As | Lipid extraction processes |
US10744146B2 (en) | 2001-08-02 | 2020-08-18 | Suntory Holdings Limited | Composition having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction |
US10864223B2 (en) | 2015-02-11 | 2020-12-15 | Aker Biomarine Antarctic As | Lipid compositions |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2535966C2 (en) * | 2008-09-12 | 2014-12-20 | Криопрашис Криобиоложия Лтда. | Cell-based therapy of ischemic tissue |
TR201808471T4 (en) | 2010-07-05 | 2018-07-23 | Beth Israel Deaconess Medical Ct Inc | Sn-2-monoacylglycerols and lipid malabsorption. |
JP2016023163A (en) * | 2014-07-22 | 2016-02-08 | 出光興産株式会社 | AGENT FOR REDUCING OXIDATIVE STRESS ON NERVE CELLS COMPRISING γ-LINOLENIC ACID |
CN105468156A (en) * | 2015-11-25 | 2016-04-06 | 新乡医学院 | Novel asynchronous brain-computer interface system based on alpha wave control |
KR102054401B1 (en) * | 2018-03-26 | 2019-12-10 | 주식회사 엔지켐생명과학 | 1,2-diacylglycerol compound, method for preparing the same and immunomodulating agent including the same as active ingredient |
CN113164377A (en) * | 2018-10-18 | 2021-07-23 | Ds生物制药有限公司 | DGLA and/or 15-HETRE for the treatment of inflammatory, fibrotic and proliferative conditions |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4701469A (en) * | 1983-04-15 | 1987-10-20 | Roussel Uclaf | Triglycerides, process for therapeutical applications and compositions containing them |
WO2001097793A2 (en) * | 2000-06-23 | 2001-12-27 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | 2-arachidonylglycerol (2-ag) - an inhibitor of tumor necrosis factor -alfa and neuroprotector of brain in closed head injury |
WO2003013497A1 (en) * | 2001-08-02 | 2003-02-20 | Suntory Limited | Compositions having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction |
Family Cites Families (132)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2077371A (en) | 1937-04-13 | Synthetic drx | ||
US655579A (en) * | 1900-02-27 | 1900-08-07 | Draper Co | Lease-forming mechanism. |
US2617791A (en) | 1949-09-15 | 1952-11-11 | Trojan Powder Co | Recovery of valuable products from pentaerythritol mother liquor |
US3158541A (en) | 1959-12-18 | 1964-11-24 | Escambia Chem Corp | Product for reduction of blood cholesterol concentration |
US3082228A (en) | 1959-12-18 | 1963-03-19 | Escambia Chem Corp | Method for producing monoesters of polyunsaturated fatty acids |
FR2003425A1 (en) | 1968-03-07 | 1969-11-07 | Unilever Nv | EDIBLE PLASTIC FAT COMPOSITIONS AND PROCESS FOR PREPARING THEM |
US3558656A (en) | 1968-04-19 | 1971-01-26 | Smith Kline French Lab | Glycerol trichloroethyl carbonate and derivatives |
US3671563A (en) | 1968-04-19 | 1972-06-20 | Smith Kline French Lab | Glycerol 3-(2,2,2-trichloroethyl) carbonate |
US3676472A (en) | 1969-07-28 | 1972-07-11 | American Home Prod | Certain linoleic and linolenic acid ester fractions of vegetable oils and derivatives thereof |
US3748348A (en) | 1970-07-27 | 1973-07-24 | Lever Brothers Ltd | Directed-interesterified glyceridic oils having a high linoleic acid content and process for their production |
US3671557A (en) | 1970-09-17 | 1972-06-20 | Smith Kline French Lab | 1,2-diacylglycerol 3-(2,2,2-trichloroethyl) carbonates |
GB1370021A (en) | 1971-03-25 | 1974-10-09 | Unilever Ltd | Process for preparing usaturated carboxylic acids |
US3855254A (en) | 1972-03-31 | 1974-12-17 | Lever Brothers Ltd | Interesterification process |
GB1506563A (en) | 1974-04-25 | 1978-04-05 | Williams J | Immunosuppressive agents |
US4058594A (en) * | 1974-04-25 | 1977-11-15 | John Williams | Immuno-suppressive agents |
US3988446A (en) | 1974-11-07 | 1976-10-26 | Abbott Laboratories | Glycerides with anti-inflammatory properties |
US3972907A (en) | 1975-03-24 | 1976-08-03 | G. D. Searle & Co. | Anti-hyperlipidemic fatty acids and esters |
US4048202A (en) | 1975-04-11 | 1977-09-13 | G. D. Searle & Co. | 3-O-Alkanoylglyceric acids |
US4178299A (en) | 1978-03-27 | 1979-12-11 | Abbott Laboratories | Process for preparing 1,3-diacyl glycerols |
DE2967049D1 (en) * | 1978-04-11 | 1984-07-19 | Efamol Ltd | Pharmaceutical and dietary composition comprising gamma-linolenic acids |
US4181670A (en) | 1978-12-11 | 1980-01-01 | G. D. Searle & Co. | Phenyl 5Z,8Z,11Z,14Z-eicosatetraenoate and congeners |
EP0092076B1 (en) | 1982-04-16 | 1986-12-17 | Societe Des Produits Nestle S.A. | Lipid composition for oral, enteral or parenteral feeding |
US4607052A (en) | 1983-04-15 | 1986-08-19 | Roussel-Uclaf | Triglycerides, dietetic and therapeutical applications and compositions containing them |
US4701468A (en) * | 1983-04-15 | 1987-10-20 | Roussel-Uclaf | Oxidized triglycerides having therapeutic utility |
GB8404463D0 (en) | 1984-02-21 | 1984-03-28 | Efamol Ltd | Microbiological production of essential fatty acids |
AT383130B (en) | 1984-05-15 | 1987-05-25 | Chemie Linz Ag | METHOD FOR THE PRODUCTION OF PHOSPHATIDYLCHOLINES AND PHOSPHATIDYLETHANOLAMINES SUBSTITUTED DIFFERENTLY AT C1 AND C2 OVER THE NEW COMPOUNDS 1-0-TRITYLGLYCEROPHOSPHOCHOLIN OR RELATED (1-0, N-DITYHOHOLINE) |
US5077312A (en) | 1984-07-08 | 1991-12-31 | Oncogen | Biologically active lipids binding membrane receptors |
GB2178752B (en) | 1985-07-12 | 1989-10-11 | Unilever Plc | Substitute milk fat |
US4888324A (en) | 1985-10-01 | 1989-12-19 | Angio-Medical Corporation | Method for enhancing angiogenesis with lipid containing molecules |
GB8524275D0 (en) | 1985-10-02 | 1985-11-06 | Efamol Ltd | Pharmaceutical & dietary compositions |
US5151291A (en) | 1985-12-27 | 1992-09-29 | Nisshin Flour Milling Co., Ltd. | Glycerides of eicosapentaenoic acid, processes for preparing the same and oil and fat products containing the same |
US5306730A (en) | 1986-02-03 | 1994-04-26 | Kabushiki Kaisha Yakult Honsha | Botulinum toxin neutralizer |
US5227403A (en) | 1986-10-01 | 1993-07-13 | The Nisshin Oil Mills, Ltd. | Fats and oils having superior digestibility and absorptivity |
US4867965A (en) | 1986-10-02 | 1989-09-19 | Revlon, Inc. | Fatty acid diesters |
FR2617161B1 (en) | 1987-06-29 | 1989-10-27 | Azar Robert | NOVEL UNSATURATED FATTY ACID GLYCERIDES AND PROCESS FOR OBTAINING SAME |
US4832975A (en) | 1987-09-29 | 1989-05-23 | The Procter & Gamble Company | Tailored triglycerides having improved autoignition characteristics |
DK565288D0 (en) * | 1988-10-11 | 1988-10-11 | Novo Industri As | PROCEDURE FOR THE PREPARATION OF TRIGLYCERIDES, APPLICATION OF SUCH TRIGLYCERIDES, AND AN EMULSION CONTAINING SUCH TRIGLYCERIDES |
US5008126A (en) | 1989-06-27 | 1991-04-16 | Nabisco Brands, Inc. | Long chain diol diesters as low calorie fat mimetics |
GB9026648D0 (en) | 1990-12-07 | 1991-01-23 | Efamol Holdings | Nutrition |
US5922345A (en) | 1990-12-07 | 1999-07-13 | Scotia Holdings Plc | Nutrition |
US5658767A (en) | 1991-01-24 | 1997-08-19 | Martek Corporation | Arachidonic acid and methods for the production and use thereof |
PH11992043811B1 (en) | 1991-01-24 | 2002-08-22 | Martek Corp | Arachidonic acid and methods for the production and use thereof |
IT1247165B (en) | 1991-03-15 | 1994-12-12 | Fidia Spa | THERAPEUTIC USE OF PHOSPHATIDYLSERINE AND DERIVATIVES IN DEGENERATIVE PATHOLOGIES, ALSO ASSOCIATED WITH IMMUNITARY DYSFUNCTIONS. |
JPH04328199A (en) | 1991-04-26 | 1992-11-17 | Nisshin Oil Mills Ltd:The | Concentration of alpha-linolenic acid-containing triglyceride |
GB9111900D0 (en) | 1991-06-03 | 1991-07-24 | Efamol Holdings | Fatty acid compositions |
US5674901A (en) | 1995-06-01 | 1997-10-07 | Wisconsin Alumni Research Foundation | Methods of treating animals to maintain or increase CD-4 and CD-8 cell populations |
JPH05310638A (en) | 1992-05-01 | 1993-11-22 | Idemitsu Petrochem Co Ltd | Production of unsaturated fatty acid triglyceride |
JPH06172263A (en) | 1992-08-14 | 1994-06-21 | Agency Of Ind Science & Technol | High-purity arachidonic acid triglyceride and its production |
US5618955A (en) | 1992-11-30 | 1997-04-08 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Fatty acid derivatives and pharmaceutical compositions containing same |
WO1994015464A1 (en) | 1993-01-15 | 1994-07-21 | Abbott Laboratories | Structured lipids |
GB9301446D0 (en) | 1993-01-26 | 1993-03-17 | Scotia Holdings Plc | Internal radiation damage |
GB9301629D0 (en) | 1993-01-27 | 1993-03-17 | Scotia Holdings Plc | Formulations containing unsaturated fatty acids |
JPH06279311A (en) | 1993-03-26 | 1994-10-04 | Sagami Chem Res Center | Activation agent for protein kinase c isozyme |
JPH0741421A (en) | 1993-05-28 | 1995-02-10 | Suntory Ltd | Preventive agent or improver for medical symptom using leukotriene b4 (ltb4) |
US20050027004A1 (en) | 1993-06-09 | 2005-02-03 | Martek Biosciences Corporation | Methods of treating senile dementia and Alzheimer's diseases using docosahexaenoic acid and arachidonic acid compositions |
US5663450A (en) | 1993-08-17 | 1997-09-02 | Cv Therapeutics | Macrophage lipid chemoattractant |
EP0734723A4 (en) | 1993-12-29 | 2001-04-11 | Kowa Tekuno Sachi Co Ltd | Therapeutic composition for hyperparathyroidism of patient subjected to artificial dialysis |
JPH07309773A (en) | 1994-05-16 | 1995-11-28 | Sagami Chem Res Center | Acetylcholine release promoter |
FR2722410B1 (en) | 1994-07-15 | 1996-10-04 | Grinda Jean Robert | PROCESS FOR THE STABILIZATION OF POLYUNSATURATED FATTY ACIDS AND THE USE OF THESE STABILIZED ENTHERAPEUTIC PRODUCTS |
JP3770628B2 (en) | 1994-08-09 | 2006-04-26 | サントリー株式会社 | Prevention and amelioration of medical symptoms through delayed allergic reaction |
EP0707850A1 (en) | 1994-09-21 | 1996-04-24 | Scotia Holdings Plc | Use of polyunsaturated fatty acids for the manufacture of a medicament for the treatment of brest pain |
EP0711503A3 (en) | 1994-11-14 | 1997-11-26 | Scotia Holdings Plc | Milk fortified with GLA and/or DGLA |
US5990163A (en) | 1995-01-13 | 1999-11-23 | The Salk Institute For Biological Studies | Selective modulation of processes mediated by retinoid X receptors, and compounds useful therefor |
US6410078B1 (en) | 1995-04-28 | 2002-06-25 | Loders-Croklaan B.V. | Triglycerides, rich in polyunsaturated fatty acids |
US6765020B2 (en) | 1995-08-07 | 2004-07-20 | Suntory Limited | Drugs for prevention and treatment of diseases caused by abnormalities in cartilage tissues |
GB9519661D0 (en) | 1995-09-27 | 1995-11-29 | Scotia Holdings Plc | Fatty acid treatment |
US6015798A (en) | 1995-10-10 | 2000-01-18 | Colgate Palmolive Company | Method for reducing the damaging effects of radiation therapy on animal skin and mucosa |
US5776913A (en) | 1995-10-10 | 1998-07-07 | Colgate Palmolive Company | Therapeutic diet for metabolic abnormalities found in animals with lymphoma |
WO1997038688A1 (en) | 1996-04-12 | 1997-10-23 | Peptide Technology Pty. Limited | Methods of treating immunopathologies using polyunsaturated fattyacids |
US5753702A (en) | 1996-05-22 | 1998-05-19 | University Of Vermont | Arachidonic acid metabolite, 16-hete |
CA2271166C (en) | 1996-06-03 | 2006-08-29 | Croda International Plc | Compositions and uses thereof |
US6340485B1 (en) | 1996-06-03 | 2002-01-22 | Croda International Plc | Compositions and uses thereof |
CA2259330C (en) | 1996-06-29 | 2003-03-18 | The Scottish Agricultural College | Improvement of male fertility with antioxidants and/or polyunsaturated fatty acids |
GB9617847D0 (en) | 1996-08-27 | 1996-10-09 | Scotia Holdings Plc | Fatty acid treatment |
CZ293704B6 (en) | 1996-10-11 | 2004-07-14 | Scarista Limited | Pharmaceutical preparation for the treatment of schizophrenia and/or tardive dyskinesia comprising eicosapentaenoic acid and/or stearidonic acid as well as process for preparing a medicament for treating schizophrenia and/or tardive dyskinesia |
US6080787A (en) | 1997-02-21 | 2000-06-27 | Abbott Laboratories | Methods for reducing the incidence of necrotizing enterocolitis |
DK1039892T3 (en) | 1997-02-21 | 2004-08-30 | Univ Tennessee Res Foundation | Use of polyunsaturated fatty acids to reduce the incidence of necrotizing enterocolitis |
US6201022B1 (en) | 1997-03-27 | 2001-03-13 | Myorx, Inc. | Methods for treating neurotransmitter-mediated pain syndromes by topically administering an omega fatty acid |
US6051754A (en) | 1997-04-11 | 2000-04-18 | Abbott Laboratories | Methods and compositions for synthesis of long chain poly-unsaturated fatty acids in plants |
US6432684B1 (en) | 1997-04-11 | 2002-08-13 | Abbott Laboratories | Human desaturase gene and uses thereof |
US5968809A (en) | 1997-04-11 | 1999-10-19 | Abbot Laboratories | Methods and compositions for synthesis of long chain poly-unsaturated fatty acids |
US20020037876A1 (en) | 1998-06-25 | 2002-03-28 | Yissum Research Development Company Of Hebrew University Of Jerusalem | Carboxylic acids and derivatives thereof and pharmaceutical compositions containing them |
GB9715444D0 (en) | 1997-07-22 | 1997-09-24 | Scotia Holdings Plc | Therapeutic and dietary compositions |
US6369252B1 (en) | 1998-02-26 | 2002-04-09 | The University Of Georgia Research Foundation, Inc. | Structured lipids |
EP1066235B1 (en) | 1998-04-03 | 2003-10-01 | Yissum Research And Development Company Of The Hebrew University Of Jerusalem | Synthetic endogenous cannabinoid analogues and uses thereof |
US7101914B2 (en) | 1998-05-04 | 2006-09-05 | Natural Asa | Isomer enriched conjugated linoleic acid compositions |
US6696584B2 (en) | 1998-05-04 | 2004-02-24 | Natural Asa | Isomer enriched conjugated linoleic acid compositions |
US6214372B1 (en) | 1998-05-04 | 2001-04-10 | Con Lin Co., Inc. | Method of using isomer enriched conjugated linoleic acid compositions |
ATE375712T1 (en) | 1998-08-04 | 2007-11-15 | Cargill Inc | PROMOTERS OF FATTY ACID DESATURASE FROM PLANTS |
KR100325581B1 (en) | 1998-08-07 | 2002-08-24 | 오우택 | Analgesic compositions containing substances that result from lipoxygenase metabolism of arachidonic acid |
US6555579B2 (en) | 1998-08-13 | 2003-04-29 | The Wistar Institute | Methods for reducing atherosclerotic plaques |
GB9901809D0 (en) | 1999-01-27 | 1999-03-17 | Scarista Limited | Highly purified ethgyl epa and other epa derivatives for psychiatric and neurological disorderes |
JP3779505B2 (en) | 1999-08-24 | 2006-05-31 | 花王株式会社 | Oil composition |
US6426367B1 (en) | 1999-09-09 | 2002-07-30 | Efa Sciences Llc | Methods for selectively occluding blood supplies to neoplasias |
US6340705B1 (en) | 1999-09-10 | 2002-01-22 | Monsanto Technology, Llc | Use of α-linolenic acid metabolites for treatment or prevention of cancer |
PT1088552E (en) | 1999-09-30 | 2006-06-30 | Loders Croklaan Bv | COMPOSITIONS CONTAINING PINOLENIC ACID AND ITS UTILIZATION AS A COMPONENT IN HEALTH |
GB9923738D0 (en) | 1999-10-07 | 1999-12-08 | Nestle Sa | Nutritional composition |
US20010047036A1 (en) | 1999-12-17 | 2001-11-29 | Vanderhoof Jon A. | Composition for improving the proliferative response during adaptation of the gastrointestinal tract and use in short bowel syndrome |
EG22407A (en) | 2000-02-17 | 2003-01-29 | Iams Company | Method for improving bone modeling and chondrocyte functioning in growing canines |
US6361806B1 (en) | 2000-02-23 | 2002-03-26 | Michael P. Allen | Composition for and method of topical administration to effect changes in subcutaneous adipose tissue |
EP1129711B1 (en) | 2000-02-24 | 2004-01-28 | Unilever N.V. | Pinolenic acid against diabetes |
GB0016045D0 (en) | 2000-06-29 | 2000-08-23 | Laxdale Limited | Therapeutic combinations of fatty acids |
JP2002047176A (en) | 2000-08-04 | 2002-02-12 | Idemitsu Technofine Co Ltd | Ige production suppressing agent |
US6664230B1 (en) | 2000-08-24 | 2003-12-16 | The Regents Of The University Of California | Orally administered peptides to ameliorate atherosclerosis |
FR2815227B1 (en) | 2000-10-17 | 2003-04-11 | Schwartz Laboratoires Robert | ANTI-STRESS COMPOSITION FOR PRIMARY INCORPORATION IN NUTRITIONAL VEHICLES |
NO20005718A (en) | 2000-11-13 | 2001-06-05 | Ethics Cosmeceuticals Ab | Composition for skin containing chitosan-conjugated CLA and chitosan-conjugated vitamin A or a <beta> -cyclodextrin-conjugated vitamin A and methods for its preparation and use |
US6528040B1 (en) | 2001-01-18 | 2003-03-04 | Maurine Pearson | EMU oil-based formulations for use as an analgesic, anesthetic and antipruritic |
WO2002069964A1 (en) | 2001-03-05 | 2002-09-12 | Ernest Stephen P | Enteral formulation |
JP2004531568A (en) | 2001-05-30 | 2004-10-14 | ラクスデイル リミテッド | Coenzyme Q and eicosapentaenoic acid (EPA) |
CA2452401C (en) * | 2001-07-02 | 2013-02-26 | Suntory Limited | Process for producing fat comprising triglyceride containing highly unsaturated fatty acid |
EP1285590A1 (en) | 2001-08-08 | 2003-02-26 | Société des Produits Nestlé S.A. | Lipid blends |
AU784852B2 (en) | 2001-08-10 | 2006-07-06 | Mars, Incorporated | Canine support diet |
US20030032674A1 (en) * | 2001-08-13 | 2003-02-13 | Hwang Daniel H. | Use of unsaturated fatty acids to treat severe inflammatory diseases |
NL1019368C2 (en) | 2001-11-14 | 2003-05-20 | Nutricia Nv | Preparation for improving receptor performance. |
US6677470B2 (en) | 2001-11-20 | 2004-01-13 | Natural Asa | Functional acylglycerides |
ITMI20012732A1 (en) | 2001-12-20 | 2003-06-20 | Health Pharma S R L | FOOD SUPPLEMENT FOR NEUROPATHICS |
AUPS082102A0 (en) | 2002-03-01 | 2002-03-21 | Women's And Children's Hospital | Therapeutic properties of oils |
CN101072509A (en) | 2002-03-08 | 2007-11-14 | 孟山都技术有限公司 | Treatment and prevention of inflammatory disorders |
US20040048926A1 (en) | 2002-03-15 | 2004-03-11 | Hoffman Dennis Robert | Use of docosahexaenoic acid and arachidonic acid to enhance the visual development of term infants breast-fed up to the age of six months |
WO2003097034A1 (en) | 2002-05-17 | 2003-11-27 | Nikken Chemicals Co., Ltd. | TGF-α EXPRESSION INHIBITORS |
US7335481B2 (en) | 2002-07-24 | 2008-02-26 | Christer Owman | Methods of identifying compounds that affect a fatty acid cell-surface receptor |
AU2003304108B2 (en) | 2002-10-30 | 2007-03-22 | Spherics, Inc. | Nanoparticulate bioactive agents |
US7074418B2 (en) | 2002-11-18 | 2006-07-11 | Changaris David G | Conjugated fatty acid based emulsion and methods for preparing and using same |
US20040229950A1 (en) | 2002-11-26 | 2004-11-18 | Vanderhoek Jack Y. | Method and composition with conjugated linoleic acid esters |
US6841573B2 (en) | 2002-11-27 | 2005-01-11 | Molecular Nutrition | Use of arachidonic acid as a method of increasing skeletal muscle mass |
US20040209953A1 (en) | 2002-12-06 | 2004-10-21 | Wai Lee Theresa Siu-Ling | Glyceride compositions and methods of making and using same |
US20040208939A1 (en) | 2003-04-18 | 2004-10-21 | Barry Sears | Novel dietary compositions to reduce inflammation |
GB0311081D0 (en) * | 2003-05-14 | 2003-06-18 | Btg Internat Limted | Treatment of neurodegenerative conditions |
EP1651169A4 (en) * | 2003-08-01 | 2008-02-27 | Medarex Inc | Combination therapies for multiple sclerosis |
CA2534202C (en) | 2003-08-18 | 2012-01-17 | Btg International Limited | Lipid glycerides for the treatment of neurodegenerative conditions involving demyelination |
EP1711173A2 (en) | 2003-12-31 | 2006-10-18 | Igennus Limited | Formulation containing an eicosapentaenoic acid or an ester thereof and a triterpene or ester thereof |
GB0504362D0 (en) * | 2005-03-02 | 2005-04-06 | Btg Int Ltd | Cytokine modulators |
-
2004
- 2004-08-13 CA CA2534202A patent/CA2534202C/en not_active Expired - Fee Related
- 2004-08-13 DE DE112004001520T patent/DE112004001520B4/en not_active Expired - Fee Related
- 2004-08-13 EP EP11157375A patent/EP2324828A1/en not_active Withdrawn
- 2004-08-13 CH CH00249/06A patent/CH698539A8/en not_active IP Right Cessation
- 2004-08-13 GB GB0603646A patent/GB2422373B/en not_active Expired - Fee Related
- 2004-08-13 WO PCT/GB2004/003524 patent/WO2005018632A1/en active IP Right Grant
- 2004-08-13 ES ES200650014A patent/ES2304094B2/en not_active Expired - Fee Related
- 2004-08-13 EP EP04768085A patent/EP1660071A1/en not_active Withdrawn
- 2004-08-13 JP JP2006523678A patent/JP2007502805A/en active Pending
- 2004-08-13 AU AU2004266480A patent/AU2004266480B2/en not_active Ceased
- 2004-08-13 US US10/567,778 patent/US7964641B2/en not_active Expired - Fee Related
-
2006
- 2006-01-19 IS IS8246A patent/IS8246A/en unknown
- 2006-02-17 FI FI20060154A patent/FI20060154A/en not_active Application Discontinuation
- 2006-03-17 NO NO20061232A patent/NO20061232L/en not_active Application Discontinuation
-
2009
- 2009-12-31 US US12/654,780 patent/US20100113810A1/en not_active Abandoned
- 2009-12-31 US US12/654,779 patent/US20100113595A1/en not_active Abandoned
-
2012
- 2012-02-01 US US13/363,705 patent/US20120142775A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4701469A (en) * | 1983-04-15 | 1987-10-20 | Roussel Uclaf | Triglycerides, process for therapeutical applications and compositions containing them |
WO2001097793A2 (en) * | 2000-06-23 | 2001-12-27 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | 2-arachidonylglycerol (2-ag) - an inhibitor of tumor necrosis factor -alfa and neuroprotector of brain in closed head injury |
WO2003013497A1 (en) * | 2001-08-02 | 2003-02-20 | Suntory Limited | Compositions having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction |
Cited By (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10744146B2 (en) | 2001-08-02 | 2020-08-18 | Suntory Holdings Limited | Composition having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction |
US7935729B2 (en) | 2003-05-14 | 2011-05-03 | Btg International Limited | Use of triglyceride oils containing γ-linolenic acid residues and linoleic acid residues for the treatment of neurodegenerative disease |
US7964641B2 (en) | 2003-08-18 | 2011-06-21 | Btg International Limited | Treatment of neurodegenerative conditions |
US8367729B2 (en) | 2004-09-17 | 2013-02-05 | Suntory Holdings Limited | Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders |
US8202907B2 (en) | 2004-09-17 | 2012-06-19 | Suntory Holdings Limited | Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders |
US8114903B2 (en) | 2005-03-02 | 2012-02-14 | Btg International Limited | Cytokine modulators using cyclic glycerides of essential polyunsaturated fatty acids |
WO2006092622A1 (en) * | 2005-03-02 | 2006-09-08 | Btg International Limited | Treatment of cytokine dysregulation by using sn-2 gamma-linolenoyl, gamma-dihomolinolenoyl or arachidonoyl patty acid glycerol monoesters |
WO2006092623A1 (en) * | 2005-03-02 | 2006-09-08 | Btg International Limited | Cytokine modulators using cyclic glycerides of essential polyunsaturated fatty acids |
US9168241B2 (en) | 2005-06-30 | 2015-10-27 | Suntory Holdings Limited | Compositions ameliorating a reduced diurnal activity and/or depressive symptoms |
US10042980B2 (en) | 2005-11-17 | 2018-08-07 | Gearbox Llc | Providing assistance related to health |
US8793141B2 (en) | 2005-11-17 | 2014-07-29 | The Invention Science Fund I, Llc | Assistance related to health |
US20080004909A1 (en) * | 2005-11-30 | 2008-01-03 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational systems related to nutraceuticals |
US10296720B2 (en) | 2005-11-30 | 2019-05-21 | Gearbox Llc | Computational systems and methods related to nutraceuticals |
KR101578498B1 (en) * | 2006-12-28 | 2015-12-18 | 산토리 홀딩스 가부시키가이샤 | Nerve regeneration agent |
KR20140117705A (en) * | 2006-12-28 | 2014-10-07 | 산토리 홀딩스 가부시키가이샤 | Nerve regeneration agent |
WO2008081989A1 (en) * | 2006-12-28 | 2008-07-10 | Suntory Holdings Limited | Nerve regeneration agent |
EP3593797A1 (en) * | 2006-12-28 | 2020-01-15 | Suntory Holdings Limited | Nerve-regenerating agent |
US8383677B2 (en) | 2006-12-28 | 2013-02-26 | Suntory Holdings Limited | Nerve-regenerating agent |
US10543237B2 (en) | 2007-03-28 | 2020-01-28 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9889163B2 (en) | 2007-03-28 | 2018-02-13 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US8697138B2 (en) | 2007-03-28 | 2014-04-15 | Aker Biomarine As | Methods of using krill oil to treat risk factors for cardiovascular, metabolic, and inflammatory disorders |
US9220735B2 (en) | 2007-03-28 | 2015-12-29 | Aker Biomarine Antarctic As | Methods of using krill oil to treat risk factors for cardiovascular, metabolic, and inflammatory disorders |
US9320765B2 (en) | 2007-03-28 | 2016-04-26 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9375453B2 (en) | 2007-03-28 | 2016-06-28 | Aker Biomarine Antarctic As | Methods for producing bioeffective krill oil compositions |
US9644169B2 (en) | 2007-03-28 | 2017-05-09 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9644170B2 (en) | 2007-03-28 | 2017-05-09 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9730966B2 (en) | 2007-03-28 | 2017-08-15 | Aker Biomarine Antartic As | Method of reducing appetite in a human subject comprising administering krill oil composition |
US9816046B2 (en) | 2007-03-28 | 2017-11-14 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US11865143B2 (en) | 2007-03-28 | 2024-01-09 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9119864B2 (en) | 2007-03-28 | 2015-09-01 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US10010567B2 (en) | 2007-03-28 | 2018-07-03 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9078905B2 (en) | 2007-03-28 | 2015-07-14 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9034388B2 (en) | 2007-03-28 | 2015-05-19 | Aker Biomarine Antartic As | Bioeffective krill oil compositions |
US9028877B2 (en) | 2007-03-28 | 2015-05-12 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US9072752B1 (en) | 2007-03-28 | 2015-07-07 | Aker Biomarine Antarctic As | Bioeffective krill oil compositions |
US8372812B2 (en) | 2009-02-26 | 2013-02-12 | Aker Biomarine Asa | Phospholipid and protein tablets |
US10704011B2 (en) | 2013-06-14 | 2020-07-07 | Aker Biomarine Antarctic As | Lipid extraction processes |
US11578289B2 (en) | 2013-06-14 | 2023-02-14 | Aker Biomarine Antarctic As | Lipid extraction processes |
US9867856B2 (en) | 2014-01-10 | 2018-01-16 | Aker Biomarine Antarctic As | Phospholipid compositions and their preparation |
US10456412B2 (en) | 2015-02-11 | 2019-10-29 | Aker Biomarine Antarctic As | Lipid extraction processes |
US10864223B2 (en) | 2015-02-11 | 2020-12-15 | Aker Biomarine Antarctic As | Lipid compositions |
US11819509B2 (en) | 2015-02-11 | 2023-11-21 | Aker Biomarine Antarctic As | Lipid compositions |
Also Published As
Publication number | Publication date |
---|---|
GB2422373B (en) | 2008-05-21 |
AU2004266480A1 (en) | 2005-03-03 |
GB0603646D0 (en) | 2006-04-05 |
US20100113595A1 (en) | 2010-05-06 |
AU2004266480B2 (en) | 2011-03-03 |
US20080194684A1 (en) | 2008-08-14 |
IS8246A (en) | 2006-01-19 |
US7964641B2 (en) | 2011-06-21 |
US20120142775A1 (en) | 2012-06-07 |
EP2324828A1 (en) | 2011-05-25 |
ES2304094A1 (en) | 2008-09-01 |
CH698539A8 (en) | 2009-10-15 |
JP2007502805A (en) | 2007-02-15 |
EP1660071A1 (en) | 2006-05-31 |
CA2534202A1 (en) | 2005-03-03 |
US20100113810A1 (en) | 2010-05-06 |
CA2534202C (en) | 2012-01-17 |
DE112004001520T5 (en) | 2006-07-06 |
NO20061232L (en) | 2006-05-15 |
GB2422373A (en) | 2006-07-26 |
FI20060154A (en) | 2006-02-17 |
ES2304094B2 (en) | 2010-10-14 |
CH698539B1 (en) | 2009-08-31 |
DE112004001520B4 (en) | 2008-04-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20100113810A1 (en) | Treatment of neurodegenerative conditions | |
CA2524036C (en) | Treatment of neurodegenerative conditions | |
US9796658B2 (en) | Production and purification of esters of polyunsaturated fatty acids | |
US20100130608A1 (en) | Compositions and methods for reducing triglyceride levels | |
JP2010509204A (en) | Fatty acid alcohol | |
US20090023807A1 (en) | Treatment of Cytokine Dysregulation by Using Sn-2 Gamma-Linolenoyl, Gamma-Diho-Molinolenoyl or Arachidonoyl Patty Acid Glycerol Monoesters | |
US8114903B2 (en) | Cytokine modulators using cyclic glycerides of essential polyunsaturated fatty acids | |
US20090036410A1 (en) | Structured Phospholipids | |
GB2442164A (en) | Treatment of neurodegenerative conditions | |
GB2442161A (en) | Treatment of neurodegenerative conditions | |
CN1867328B (en) | Use of lipid glyceride in preparing medicine for treatment of neurodegenerative conditions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200480030644.X Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2534202 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004266480 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1120040015200 Country of ref document: DE Ref document number: 20060154 Country of ref document: FI Ref document number: 2006523678 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 0603646.1 Country of ref document: GB Ref document number: 0603646 Country of ref document: GB |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004768085 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2004266480 Country of ref document: AU Date of ref document: 20040813 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004266480 Country of ref document: AU |
|
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
WWP | Wipo information: published in national office |
Ref document number: 2004768085 Country of ref document: EP |
|
RET | De translation (de og part 6b) |
Ref document number: 112004001520 Country of ref document: DE Date of ref document: 20060706 Kind code of ref document: P |
|
WWE | Wipo information: entry into national phase |
Ref document number: 112004001520 Country of ref document: DE |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8607 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10567778 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 200650014 Country of ref document: ES Kind code of ref document: A |
|
WWG | Wipo information: grant in national office |
Ref document number: 200650014 Country of ref document: ES Kind code of ref document: A |