EP2405773A1 - Stigmasterol for the treatment of alzheimer's disease - Google Patents

Stigmasterol for the treatment of alzheimer's disease

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Publication number
EP2405773A1
EP2405773A1 EP10708409A EP10708409A EP2405773A1 EP 2405773 A1 EP2405773 A1 EP 2405773A1 EP 10708409 A EP10708409 A EP 10708409A EP 10708409 A EP10708409 A EP 10708409A EP 2405773 A1 EP2405773 A1 EP 2405773A1
Authority
EP
European Patent Office
Prior art keywords
weight
stigmasterol
composition
nutritional
beta
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10708409A
Other languages
German (de)
English (en)
French (fr)
Inventor
Marcus Otto Walter Grimm
Tobias Hartmann
Petra FRIEß-JAVORKOVÅ
Ulrich Laufs
Oliver WEINGÄRTNER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nutricia NV
Original Assignee
Nutricia NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nutricia NV filed Critical Nutricia NV
Publication of EP2405773A1 publication Critical patent/EP2405773A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention is directed to the use of stigmasterol for the treatment of amyloidosis, in particular amyloidosis of the beta-amyloid peptide (A ⁇ ), and for the treatment of Alzheimer's disease.
  • stigmasterol for the treatment of amyloidosis, in particular amyloidosis of the beta-amyloid peptide (A ⁇ ), and for the treatment of Alzheimer's disease.
  • amyloidosis refers to a variety of conditions in which amyloid proteins are abnormally deposited in organs and/or tissues.
  • a protein or peptide is described as being amyloid if, due to an alteration in its secondary structure, it takes on a particular aggregated insoluble form similar to the beta-pleated sheet.
  • Symptoms vary widely depending upon the site of amyloid deposition.
  • Cerebral amyloidosis is a significant aspect of Alzheimer's disease, for which there is currently no cure and that affects a considerable part of the human population, in particular of elderly people.
  • Several publications have reported in general terms that subjects suffering from various age-related disorders may benefit from specific classes of compounds, e.g., originating from plants.
  • WO 00/30666 relates to a composition comprising plant matter from a plant of the genus Uncaria.
  • the composition may amongst others be used for a variety of brain stimulating uses, such as improving mental alertness, for reducing or preventing amyloid protein deposits or for promoting or supporting pancreatic function in a patient.
  • the composition may contain a mixture of the plant sterols beta- sitosterol, stigmasterol and campesterol.
  • the effectiveness of a specific phytosterol, in particular stigmasterol for treatment of amyloidosis is not shown, nor are disclosed the relative proportions of the various phytos- terols in the claimed compositions
  • the use of phytosterols in the treatment of cardiovascular diseases has also been reported in WO 2007/124597.
  • compositions comprising one or more free (unesterified) phytosterols and/or phy- tostanols which are substantially completely dissolved in one or more esteri- fied phytosterols and/or phytostanols.
  • the compositions may be used for treatment of dementia (including Alzheimer's disease).
  • dementia including Alzheimer's disease
  • WO 99/32097 discloses phytosterol compositions comprising ⁇ - sitosterol, campesterol and stigmastanol (sitostanol), and optionally campestanol and analogs/derivatives thereof for preventing and delaying the onset of Alzheimer's disease.
  • the presence of stigmasterol and a therapeutic effect thereof in the treatment of amyloidosis is not disclosed.
  • WO 06/121558 describes a composition allegedly suitable for treatment of a variety of age-related disorders, e.g. Alzheimer's disease.
  • the composition comprises one or more of a variety of active components, including statins, bisphonoates, polyphenolic compounds and omega-3 fatty acids. It is men- tioned that the composition may also comprise phytosterols for inhibiting cholesterol absorption. The use of stigmasterol (or another specific phytosterol) specifically for treatment of amyloidosis is not shown.
  • WO 01/03712 discloses the use of certain phytosterol-containing pharmaceutical compositions (oil, gelatine capsule, topical cream) comprising at most 37 weight % of stigmasterol with good anti-hypersensitivity and antiinflammatory effects. A therapeutic effect of in stigmasterol the treatment of amyloidosis is not disclosed.
  • WO 2005/094610 discloses a coating agent comprising a sterol, such as stigmasterol, with a relative amount of 33.3 weight% used in an orange juice drink.
  • EP 2 036 444 discloses a liquid nutritional preparation containing free plant sterols, comprising 45 to 80 weight% of ⁇ -sitosterol, 8 to 40 weight% of campesterol and not more than 30 weight% of a sterol, such as stigmasterol and brassicasterol.
  • phytosterols and phytostanols are considered 'Novel Food Ingredients' in Europe and several novel food applications have been filed with the European Commission (see the internet site : http://ec.europa.eu/food/food/bio- technology/novelfood/authorisations_en.htm) . It is submitted that these applications are directed to a phytosterol composition comprising ⁇ 80 weight % ⁇ - sitosterol, ⁇ 15 weight% ⁇ -sitostanol, ⁇ 40 weight% campesterol, ⁇ 5 weight% campestanol, ⁇ 30 weight % stigmasterol, ⁇ 3 weight % brassicasterol and ⁇ 3 weight% other sterols and stanols.
  • phytosterol composi- tions in commercial food products may only contain ⁇ 30 weight % of stigmasterol, relative to the total amount of phytosterols.
  • phytosterols have different effects on a specific pathology, namely on pathologic aggregation of a beta amyloid peptide (A ⁇ ), cleaved from Amyloid Precursor Protein (APP) via a cascade of beta-secretase activity and gamma-secretase activity.
  • a ⁇ beta amyloid peptide
  • APP Amyloid Precursor Protein
  • phytosterols may in fact have an adverse effect on at least some forms of amyloidosis, in particular on amyloidosis of beta-amyloid peptide (A ⁇ ) in a mammal.
  • amyloidosis in particular on amyloidosis of beta-amyloid peptide (A ⁇ ) in a mammal.
  • a ⁇ beta-amyloid peptide
  • Another common type of amyloid can be found in the pancreas of patients with type 2 diabetes (amylin),
  • the present invention relates to the use of stigmasterol in the manufacture of a nutritional or pharmaceutical composition for prophylactic or therapeutic treatment of amyloidosis of beta- amyloid peptide (A ⁇ ), in a mammal, in particular in the nervous system of a mammal, more in particular the cerebral part of the nervous system of a mammal.
  • a ⁇ beta- amyloid peptide
  • the present invention relates to the use of stigmasterol in the manufacture of a nutritional or pharmaceutical composition for prophylactic or therapeutic treatment of amyloidosis of beta- amyloid peptide (A ⁇ ) in a mammal, wherein stigmasterol is used in the relative absence of one or more phytosterols selected from the group of ergosterol, beta-sitosterol, brassi- casterol, and campesterol.
  • the invention further relates to the use of stigmasterol in the manufacture of a nutritional or pharmaceutical composition for prophylactic or therapeutic treatment of Alzheimer's disease.
  • the invention further relates to the use of stigmasterol in the manufacture of a nutritional or pharmaceutical composition as a gamma- secretase inhibitor , as a beta- secretase inhibitor or as a combination of both.
  • Phytosterols also called plant sterols
  • Phytosterols are a group of steroid alcohols, phytochemicals naturally occurring in plants. Common phytosterols are stigmasterol, ergosterol, beta- sitosterol, campesterol and brassicasterol. Commercially available phytosterols are often available as mixtures thereof.
  • Phy- tosterols are sterols that are extracted from plants and may be presented as free sterols or esterified with food grade fatty acids.
  • Amyloidosis is a group of diseases characterised by deposition of amyloids in a mammal.
  • Amyloid is a generic term referring to a group of diverse, but specific extracellular protein deposits which all have common prop- erties, staining characteristics, and x-ray diffraction spectra. Regardless of the nature of the amyloid protein deposited all amyloids have the following characteristics: 1) an amorphous appearance at the light microscopic level and appear eosinophilic using hematoxylin and eosin stains; 2) typically stain with Congo red and demonstrate a red/green birefringence as viewed under polar - ized light. 3) typically contain a predominant beta-pleated sheet secondary structure, and 4) ultrastructurally amyloid usually consist of non-branching fibrils of indefinite length and with a diameter of 7 to 10 nm.
  • amyloidosis forms include the amyloid associated with Alzheimer's disease, Down's syndrome and Hereditary cerebral hemorrhage with amyloidosis of the Dutch type (wherein the specific amyloid is referred to as beta-amyloid protein or AB), the amyloid associated with chronic inflammation, various forms of malignancy and Familial Mediterranean Fever (wherein the specific amyloid is referred to as AA amyloid or inflammation-associated amyloidosis), the amyloid associated with multiple myeloma and other B-cell dyscrasias (wherein the specific amyloid is referred to as AL amyloid), the amyloid associated with type 11 diabetes (wherein the specific amyloid is referred to as amylin or islet amyloid), the amyloid associated with the prion diseases including Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, kuru and animal scrapie (wherein the specific amyloid is referred to as PrP amyloid),
  • amyloid and amyloidosis reference is made to WO 00/30666, page 17-line 17- page 22 line 11, of which the contents are incorporated herein by reference.
  • stigmasterol was considered effective in reducing gamma-secretase activity.
  • Other phytosterols campesterol, beta-sitosterol and ergosterol
  • cholesterol a sterol of animal origin
  • the amount of such other phytosterols preferably a phytosterol selected from the group of ergosterol, beta- sitosterol, brassicasterol, and campesterol, and optionally also comprising cholesterol is relatively low, or even that these other compounds are absent from any nutritional or pharmaceutical composition for prophylactic or therapeutic treatment of amyloidosis, in particular of beta- amyloid peptide (A ⁇ ) in a mammal and/or for the prophylactic or therapeutic treatment of Alzheimer's disease.
  • a phytosterol selected from the group of ergosterol, beta- sitosterol, brassicasterol, and campesterol, and optionally also comprising cholesterol is relatively low, or even that these other compounds are absent from any nutritional or pharmaceutical composition for prophylactic or therapeutic treatment of amyloidosis, in particular of beta- amyloid peptide (A ⁇ ) in a mammal and/or for the prophylactic or therapeutic treatment of Alzheimer's disease.
  • a ⁇ beta- amyloid peptide
  • the concentration of stigmasterol in a composition of the invention as a weight percentage of the sum of phytosterols, in particular stigmasterol, ergosterol, beta-sitosterol, brassicasterol, and campesterol, and optionally also including cholesterol is more than 30 weight%, in particular 35 to 100 weight%, preferably 50 to 100 weight%, more preferably 75 to 100 weight%, most preferably 90 to 100 weight%, in particular 95 to 100 weight%, more in particular 98 to 100 weight%, relative to the total amount of phytosterols in the composition, in particular the sum of stigmasterol, ergos- terol, beta- sitosterol, brassicasterol and campesterol, and optionally also including cholesterol.
  • the concentration of stigmasterol in a composition of the invention as a weight percentage of the sum of phytos- terols, in particular stigmasterol, ergosterol, beta- sitosterol, brassicasterol and campesterol, and optionally also including cholesterol is more than 30 weight%, in particular 35 to 100 weight%, preferably 50 to 100 weight%, more preferably 75 to 100 weight%, most preferably 90 to 100 weight %, in particular 95 to 100 weight%, more in particular 98 to 100 weight%.
  • the stigmasterol is used for the treatment of a human, in particular an elderly person.
  • an elderly person is a person of the age of 50 or more, in particular of the age of 55 or more, more in particular of the age of 60 or more, more in particular of the age of 65 or more.
  • This rather broad definition takes into account the fact that the average age varies between different populations, on different continents, etc.
  • Most developed world countries have accepted the chronological age of 65 years as a definition of 'elderly' or older person (associated with the age at which one may begin to receive pension benefits), but like many westernized concepts, this does not adapt well to e.g. the situation in Africa.
  • U United Nations
  • a composition of the present invention usually contains stigmasterol in an amount sufficient to administer to a subject (in particular a human adult (average weight about 70 kg)) a daily dosage of at least 0.5 mg/day , at least 5 mg/day, at least 25 mg/day, at least 50 mg/day, at least 100 mg/day, at least 200 mg/day, at least 400 mg/day, or at least 800 mg/day.
  • the daily dosage may be 4000 mg/day or less, 2000 mg/day or less, 1000 mg/day or less, 500 mg/day or less, or 250 mg/day or less.
  • the daily dosage is 0.5 to 2000 mg/day, in particular of 5 to 1000 mg/day, more in particular 25 to 500 mg/day of stigmasterol.
  • the amount of stigmasterol contained therein is suitably present in the composition in a quantity to provide the daily dosage in a single serving.
  • serving denotes an amount of food or beverage normally ingested by a human adult with a meal at a time and may range, e.g., from about 1 g (such as a nutritional shot) to about 500 g.
  • stigmasterol may be used in a pharmaceutical composition comprising one or more pharmaceutically acceptable carrier materials.
  • stigmasterol may be used as a nutritional supplement, e.g., as an additive to a multi- vitamin preparations comprising vitamins and minerals which are essential for the maintenance of normal metabolic function but are not synthesized in the body, especially for the treatment or prevention of age-related decline in brain neuronal function and/or cognitive functioning in a mammal.
  • the pharmaceutical composition preferably for enteral application, may be solid or liquid galenical formulation. Examples of solid galenical formulations are tablets, capsules ⁇ e.g. hard or soft shell gelatine capsules), pills, sachets, powders, granules and the like which contain the active ingredient together with conventional galenical carriers. Any conventional carrier material can be utilized.
  • the carrier material can be organic or inorganic inert carrier material suitable for oral administration.
  • Suitable carriers include water, gelatine, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, and the like. Additionally, additives such as flavouring agents, preservatives, stabilizers, emulsifying agents, buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding. While the individual active ingredients are suitably administered in a single composition they may also be administered in individual dosage units.
  • composition may contain the daily dosage in one or more dosage units.
  • the dosage unit may be in a liquid form or in a solid form, wherein in the latter case the daily dosage may be provided by one or more solid dosage units, e.g. in one or more capsules or tablets.
  • stigmasterol may be used in a nutritional composition comprising at least one component se- lected from the group of fats, proteins, and carbohydrates.
  • a nutritional composition differs from a pharmaceutical composition by the presence of nutrients which provide nutrition to the subject to which the composition is administered, in particular the presence of protein, fat, digestible carbohydrates and dietary fibres. It may further contain ingredients such as minerals, vitamins, organic acids, and flavouring agents.
  • the term "nutraceutical composition” is often used in literature, it denotes a nutritional composition with a pharmaceutical component or pharmaceutical purpose.
  • the nutritional composition according to the invention may also be denoted a neutraceutical composition.
  • the nutritional composition according to the invention may comprise protein, preferably intact protein.
  • the nutritional composition according to the invention comprises milk protein.
  • the nutritional composition according to the invention comprises a protein selected from the group consisting of whey protein, casein or caseinate.
  • the nutritional composition according to the invention comprises caseinate, more preferably the nutritional composition according to the invention comprises at least 70 weight%, more preferably at least 90 weight% casein and/or caseinate, based on total protein.
  • the proteins are included in intact (unhydrolyzed) form, in order to have a palatable product.
  • Such high molecular weight proteins increase the viscosity of the heat-treated liquid product, compared to the hydrolyzed forms.
  • the present inventors were able to make an acceptable product, with good palatability and limited viscosity, by applying the measures according the invention, still avoiding precipitation.
  • the nutritional composition according to the invention comprises between 0.2 and 16 gram protein per 100 ml, preferably between 0.2 and 10 gram protein per 100 ml, more preferably between 1 and 6 grams pro- tein per 100 ml, more preferably between 2 and 5 grams protein per 100 ml.
  • the nutritional composition according to the invention may comprise fat.
  • the fat may be a solid, a semi-solid or a liquid (oil) at room temperature (25 0 C).
  • the fat may include one or more medium chain triglycerides (MCT), , one or more long chain triglycerides or any combination of the two types.
  • MCT or MCT's may in particular be selected from MCT's having a triglyceride chain that is 6, 7, 8, 9 or 10 carbon atoms long.
  • the LCT or LCT's typically are at least 12 carbon atoms long. MCTs are beneficial because they are easily absorbed and metabolized. Moreover, the use of MCTs will reduce the risk of nutrient malabsorption.
  • LCT sources such as rapeseed oil, more in particular rapeseed oil low in erucic acid, sunflower oil, corn oil, palm kernel fat, coconut fat, palm oil, or mixtures thereof are preferred because they provide more energy per unit of fat.
  • the nutritional composition according to the invention comprises one or more polyunsaturated fatty acids (PUFA' s) , in particular one or more PUFA's selected from docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and eicosapentaenoic acid (EPA).
  • PUFA' s polyunsaturated fatty acids
  • the fat comprises 30 to 60 weight % of animal or algal fat, 40 to 70 weight % of vegetable fat and optionally 0 to 20 weight % of MCTs based on total fat of the nutritional composition according to the invention.
  • the animal fat preferably comprises none or a low amount of milk fat, i.e. lower than 6 weight%, especially lower than 3 weight%.
  • a mixture comprising one or more oils selected from the group of corn oil, egg oil, canola oil and marine oil may be present.
  • Egg oils, fish oils and algal oils are a preferred source of non- vegetable fats.
  • Marine oils containing DHA and/or EPA are preferably present in the nutritional composition accord- ing to the invention for obtaining a positive health effect, such as, for instance, the prevention of cardiovascular risks.
  • the concentration preferably is 25 weight% or less, more preferably 15 weight% or less of the fat.
  • the amount of EPA ranges preferably between 4 weight% and 15 weight%, more preferably between 8 weight% and 13 weight% of the fat.
  • the nutritional composition according to the invention comprises a phospholipid, preferably 0.1 to 50 weight% phospholipids, based on total weight of lipids, more preferably 0.5 to 20 weight%, more preferably between 1 and 5 weight%, based on total weight of lipids.
  • the nutritional composition according to the invention contains at least one selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol.
  • the total amount of lipids is preferably between 10 and 30 weight% on dry matter, and/or between 2 and 6 g lipid per 100 ml for a liquid composition. Inclusion of phospholipids improve the stability of the nutritional composition according to the invention.
  • the nutritional composition according to the invention comprises one or more digestible carbohydrates.
  • the digestible carbohydrates positively influence the operational skills of a subject, and add to the advantageous effect of the nutritional composition according to the invention.
  • the total amount of digestible carbohydrates is preferably between 25 and 80 weight % on dry matter basis, preferably 40 to 80 weight.
  • the composition preferably contains between 1 and 50 gram digestible carbohydrates per 100 ml of a liquid product, more preferably between 5 and 30 grams per 100 ml, more preferably 10 to 30 grams of digestible carbohydrates per 100 ml.
  • digestible carbohydrates are digestible pentoses, digestible hexoses and digestible oligosaccharides, e.g. digestible disaccharides and digestible trisaccharides. More specifically one or more digestible carbohydrates may be chosen selected from the group of galactose, mannose, ribose sucrose, trehalose, palatinose, lactose, maltodextrose, maltose and glucose.
  • a nutritional composition according to the invention comprises one or more non-digestible carbohydrates (dietary fibres) such as oligosaccharides.
  • oligosaccharides in particular refers to saccharides comprising 3 to 25 monosaccharide units per molecule.
  • the oligosaccharide ⁇ ) may in particular be selected from the group of fructo- oligosaccharides (FOS), galacto-oligo ⁇ saccharides (GOS), trans-galacto- oligosaccharides (TOS), xylo-oligosaccharides (XOS), soy oligosaccharides, and the like.
  • composition according to the invention comprises a mixture of neutral and acid oligosaccharides, such as disclosed in WO 2005/039597 (N.V. Nutricia); compositions disclosed therein are incorporated herein by reference.
  • taurine taurine
  • cystein manganese
  • molybdenum zinc
  • selenium magnesium
  • chromium iron
  • copper vitamin A
  • vitamin Bl vitamin B2
  • vitamin B3 vitamin B5
  • vitamin B6 folic acid
  • vitamin B12 vitamin C
  • vitamin D vitamin D
  • vitamin E biotin
  • the nutritional composition for use in a accordance with the invention may in particular be selected from the group of spreads ; yoghurts, cus- tards, ice-creams, butter, and other dairy products; dairy- substitute products; fruit drinks; candy bars, and cookies.
  • the nutritional or neutraceutical composition according to the invention is a liquid, preferable a dairy-based liquid nutritional compo- sition for medical purposes.
  • a liquid nutritional composition of the invention has an energy density of 80 to 450 kcal per 100 ml of the composition, more preferably between 90 and 250 kcal per ml of the liquid nutritional composition. This is in particular considered advantageous because persons suffering from neu- ropathies or neurological problems often experience problems with eating.
  • a liquid nutri- tional composition is relatively easy to administer, and by having an energetic value in the specified range, such people can relatively easily obtain sufficient caloric intake.
  • Liquid nutritional compositions preferably have a long shelf life.
  • increasing shelf life by heat treatments often results in destabilisa- tion of the products and/or palatability, leading to a product which is undesirable.
  • a nutritional composition according to the invention can be subjected to a heat treatment without major adverse effects on the palatability.
  • the nutritional composition according to the invention is preferably heat-treated, more preferably the composition is subjected to a sterilization treatment.
  • the nutritional composition according to the invention is subjected to an ultra-high temperature treatment (UHT-treatment).
  • UHT-treatment ultra-high temperature treatment
  • Such UHT-treatment is preferably applied in line, i.e. before the liquid final product is filled in the package of the unit.
  • the invention is further directed to a specific composition compris- ing stigmasterol, namely a nutritional composition, comprising stigmasterol, wherein the stigmasterol concentration in the composition as a weight percentage of the sum of phytosterols, in particular stigmasterol, ergosterol, beta- sitosterol, brassicasterol, and campesterol, and optionally also including cholesterol is more than 30 weight%, preferably 35 to 100 weight%, preferably 50 to 100 weight%, more preferably 75 to 100 weight%, most preferably 90 to 100 weight%, in particular 95 to 100 weight %, more in particular 98 to 100 weight%.
  • the stigmasterol concentration as percentage of the total dry weight can be chosen within wide limits.
  • the concentration may be at least 0.05 weight%, at least 0.1 weight%, at least 0.25 weight%, at least 0.5 weight%, at least 1 weight% or at least 2.5 weight% based on the total dry weight of the composition.
  • the concentration may be 90 weight % or less, 75 weight % or less, 50 weight% or less , 25 weight% or less, 10 weight% or less or 5 weight% or less, based on the total dry weight of the composition.
  • the composition is in a dosage unit form, e.g. in a packaging such as a bottle, a carton, a cup, in a strip (in case of a pharmaceutical or nutritional supplement), or the like.
  • the dosage unit form may provide 0.5 to 2000 mg, in particular 5 to 1000 mg, more in particular 25 to 500 mg stigmasterol.
  • the invention is further directed to a pharmaceutical composition
  • a pharmaceutical composition comprising stigmasterol, comprising stigmasterol, wherein the stigmasterol concentration in the composition as a weight percentage of the sum of phytosterols, in particular stigmasterol, ergosterol, beta- sitosterol, brassicasterol, and campesterol, and optionally also including cholesterol is more than 37 weight%, preferably 40 to 100 weight%, preferably 50 to 100 weight%, more preferably 75 to 100 weight%, most preferably 90 to 100 weight %, in particular 95 to 100 weight%, more in particular 98 to 100 weight%.
  • the invention is further directed to prophylactic or therapeutically treating amyloidosis , preferably of beta-amyloid peptide (A ⁇ ) in a mammal, the method comprising administering an effective dose of stigmasterol to the mammal, either as a nutritional or pharmaceutical composition according to the invention.
  • amyloidosis preferably of beta-amyloid peptide (A ⁇ ) in a mammal
  • stigmasterol administering an effective dose of stigmasterol to the mammal, either as a nutritional or pharmaceutical composition according to the invention.
  • the invention is further directed to prophylactic or therapeutically treating Alzheimer's disease, the method comprising administering an effective dose of stigmasterol to a mammal suffering from Alzheimer's disease or having a risk of developing Alzheimer's disease.
  • a mammal suffering from Alzheimer's disease or having a risk of developing Alzheimer's disease is considered to have a risk.
  • mammals are considered to have a risk of developing Alzheimer's disease in case they have an increased genetic risk or in case they are elderly.
  • the administration may in particular be an enteral administration, although in principle any other form of administration may be used, depending upon the form in which the stigmasterol is to be administered.
  • Alternative forms of administration are known in the art and include injection, admini- stration as a suppository, etc.
  • Campesterol, ergosterol, beta-sitosterol, stigmasterol and cholesterol were obtained from SIGMA ALDRICH.
  • stock solutions of 10 mM in ethanol were prepared and stored at -20 0 C under non oxidizing conditions.
  • D EMEM Dulbecco's Modified Eagle's Medium
  • FCS foetal calf serum
  • MEM Ix Non-essential Amino Acid Solution
  • SH-SY5Y-wt cells were scraped and cracked in a buffer, containing 10 mM Tris- HCl pH 7.4. After separation of total membranes via ultracentrifugation, re- suspended membranes were incubated with 100 ⁇ M of sterol and gamma- secretase activity was measured by detecting the fluorescence-generating cleavage product of a specific gamma-secretase-substrate. Experiments were reproduced three times.
  • any pharmaceutical or nutritional composition comprising a phytosterol mixture comprising stigmasterol should be depleted in or devoid of any phytosterol and optionally cholesterol, with a gamma-secretase stimulation effect, since the latter sterols would counteract the desired gamma- secretase inhibition effect of stigmasterol.
  • Beta-amyloid is formed out of the amyloid precursor protein (APP) by the successive action of two secretases, beta- secretase and gamma-secretase.
  • the APP protein is a normal occurring protein in humans and animals and exerts normal biological functions.
  • the processing by beta- and gamma- secretases is increased, leading to build-up of toxic amyloid-beta.
  • gamma- secretase will reduce the formation of beta- amyloid.
  • stigmasterol could affect the activity of gamma-secretase in brain tissue of mice.
  • mice were fed either a diet containing stig- masterol (ST) or a diet without stigmasterol (ctrl).
  • ST stig- masterol
  • ctrl stigmasterol
  • the diets were provided to the mice for 4 weeks and brain tissue was collected thereafter. Brains were homogenized and gamma- seer etase activity was determined with a fluorescent assay using a gamma- secretase specific peptide. The rate of fluorescent signal increase caused by peptide breakdown was taken as a measure of gamma- secretase activity.
  • mice fed the stigmasterol (ST) diet showed a significant (p ⁇ 0.008) decrease of 26.6 % in gamma-secretase activity, compared to mice fed the control diet (ctrl) as can be seen in Figure 1.
  • Stigmasterol effectively reduces the activity of gamma-secretase. This reduction is an important step in the reduction of amyloid-beta formation.

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EP10708409A 2009-03-12 2010-03-12 Stigmasterol for the treatment of alzheimer's disease Withdrawn EP2405773A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
NL2009050121 2009-03-12
PCT/NL2009/050315 WO2010104375A1 (en) 2009-03-12 2009-06-08 Stigmasterol for the treatment of alzheimer's disease
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CN109793783A (zh) * 2017-11-16 2019-05-24 西双版纳华坤生物科技有限责任公司 一种用于阿尔兹海默症预防与治疗物质的应用及制备方法
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BRPI1009814A2 (pt) 2015-08-25

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