WO2003053456A1 - Utilisation d'hyperforine ou d'extraits de millepertuis pour traiter des etats de choc anaphylactique et pour maintenir et ameliorer la sante des os - Google Patents

Utilisation d'hyperforine ou d'extraits de millepertuis pour traiter des etats de choc anaphylactique et pour maintenir et ameliorer la sante des os Download PDF

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WO2003053456A1
WO2003053456A1 PCT/EP2002/014207 EP0214207W WO03053456A1 WO 2003053456 A1 WO2003053456 A1 WO 2003053456A1 EP 0214207 W EP0214207 W EP 0214207W WO 03053456 A1 WO03053456 A1 WO 03053456A1
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acid
hyperforin
bone
john
hci
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PCT/EP2002/014207
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German (de)
English (en)
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Oliver Werz
Dana Albert
Dieter Steinhilber
Andreas Bock
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Phenion Gmbh & Co. Kg
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Priority to AU2002358698A priority Critical patent/AU2002358698A1/en
Publication of WO2003053456A1 publication Critical patent/WO2003053456A1/fr

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    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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

Definitions

  • the present invention relates to the use of hyperforin or extracts from St. John's wort (Hypericum) for the prophylactic and / or therapeutic treatment of anaphylactic shock conditions and for maintaining and improving the health of bones, in particular for the treatment of osteoporosis; as well as food supplements and pharmaceutical preparations containing hyperforin or St. John's wort extract.
  • Hypericum perforatum L is a medicinal plant whose use can be traced back to ancient times.
  • the origin of the botanical name is derived from the Greek hyper (over) and eikon (picture). Plants of the genus Hypericum are said to have been fixed above god figures or images to ward off evil spirits. Hypericum was used in various cultures to deter ghosts.
  • the type designation perforatum refers to the translucent dotted leaves. These are oil tanks of lysigenic or schizogenic origin.
  • the German name and their synonyms indicate the flowering period around St. Johannis (St. John's wort, Walpurgiskraut, Clarwendkraut), the red dyes (Herrgottsblut, Blutkraut) and the sometimes heavily wooded stems (Tüfpel-hartheu, Hartheu).
  • St. John's wort was also used to flavor the beer similar to hops (forest hop herb, field hop herb).
  • One reason for this use is the chemical relationship of Hyperforin to the bitter hop substances (Humulon, Lupulon), which are said to give the beer durability and taste.
  • Hypericum perforatum L. is a representative of the family Hypericaceae (hard hay family), the term Guttiferae (lat .: gutta, drops), which is no longer used, indicates the family's peculiarity for the formation of excretory containers.
  • the genus Hypericum L. is widespread worldwide and so far comprises 378 known species. It represents a peculiarity within the order of the Theales in that it also shows herbaceous, non-tropical representatives.
  • Hypericum perforatum L. can be described as follows:
  • the stems have two longitudinal edges and are covered with glands towards the tip.
  • the leaves have an elliptical-egg-shaped to oblong or linear shape, whereby the shape and size of the leaves may differ slightly depending on the position on the plant. They are translucent dotted and show mostly black glands on the edge.
  • the flowers are arranged in an umbel and provided with bare, black glandular stems.
  • the sepals are about 6 mm long and finely pointed, sawn or with entire margins.
  • the petals are crooked-elliptical and notched on one side with a length of 10-13 mm, of golden yellow color with black dots or lines.
  • Hypericin and hyperforin are known as therapeutically important ingredients.
  • the hypericin content in an extract can be an important indicator of the amount of flower components contained in the original drug, since the hypericin content is particularly high there.
  • the derivatives of phloroglucin, hyperforin and adhyperforin are characteristic of Hypericum perforatum L. Other phloroglucin derivatives have been detected in other species of the genus Hypericum. Hyperforin is present in the dried plant at an average content of about 1% to 2.5%. Hyperforin is considered to be extremely sensitive to oxidation and unstable in certain solvents.
  • a hyperforin-containing ointment or cream is known from DE-A-198 54 446, which may contain pure hyperforin or St. John's wort extract and which is used for the treatment of inflammatory skin diseases.
  • WO 00/30660 describes the use of hyperforin as a cytostatic.
  • Hyperforin can also be effective against Alzeimer disease. Molecular and cell biological studies would have shown that hyperforin can help prevent Alzheimer's plaques from developing.
  • the amyloid precursor molecule is cleaved in such a way that fragments are formed which are rapidly broken down and therefore cannot accumulate.
  • These two enzymes are, on the one hand, the alpha secretase, which correctly breaks down the precursor molecule, and, on the other hand, the protein kinase C, which in turn activates the alpha secretase.
  • Hyperforin inhibits the growth of resistant Gram-positive bacteria. This is based on the effect of Hyperforin on several staphylococcal and streptococcal strains - also on Staphylococcus aureus strains that were resistant to penicillin and methicillin - or to Corynebacterium diphtheriae. Hyperforin, on the other hand, is said to have no effect on gram-negative bacteria such as Pseudomonas aeruginosa or Candida albicans.
  • hyperforin and St. John's wort extract can also be effective against anaphylactic shock conditions and for maintaining and improving bone health, in particular for the treatment of osteoporosis.
  • the present invention therefore relates to the use of hyperforin or St. John's wort extract for anaphylactic shock conditions or for maintaining and improving bone health, in particular for the treatment of osteoporosis.
  • Anaphylactic shock is defined as a shock due to an acute, severe and generalized intolerance reaction. In a narrow sense, anaphylactic shock is based on an immediate-type hypersensitivity reaction. Today we know that other mechanisms can trigger the intolerance reaction.
  • drugs such as antibiotics, anesthetics, analgesics, colloids, contrast agents
  • foreign proteins and polysaccharides such as insect and snake venoms, serums, vaccines, organ extracts or allergen solutions for desensitization.
  • mediators In the case of anaphylactic shock, mediators (histamine, leukotrienes (LTs ⁇ PAF)) are released by immunological as well as non-immunological reactions, which cause vasodilation, increased capillary permeability with plasma exudation, bronchoconstriction, etc.
  • mediators histamine, leukotrienes (LTs ⁇ PAF)
  • LTs ⁇ PAF leukotrienes
  • Leukotrienes which are essential mediators in the development of anaphylactic shock, are - like the prostaglandins - formed by the so-called arachidonic acid cascade.
  • PGs prostaglandins
  • 5-lipoxygenase 5-lipoxygenase
  • LTs are pro-inflammatory and bronchoconstrictive.
  • LTs mediate effects of the platelet activating factor (PAF), e.g. systemic drop in blood pressure and anaphylactic shock.
  • PAF platelet activating factor
  • a major effect of PAF is the strong systemic lowering of blood pressure, which is linked to the pathogenesis of anaphylactic shock.
  • Wild-type mice succumb to the lethal effects of PAF (systemic drop in blood pressure and reduced cardiac output) while 5-LO-Knockout (KO) mice are more or less resistant to these PAF effects. It is assumed that the KO mice are spared the PAF effects due to the lack of LT. This suggests that the pharmacological inhibition of LT synthesis could protect against the PAF-induced systemic drop in blood pressure associated with the pathogenesis of anaphylactic shock.
  • Hyperforin is an inhibitor of 5-LO. Based on these properties, extracts of H. perforatum or isolated hyperforin, in addition to their known anti-inflammatory activity, have considerable potential for the treatment of PAF-induced systemic blood pressure drop and anaphylactic shock.
  • hyperforin or St. John's wort extracts for maintaining and improving the health of bones and in particular for treating osteoporosis is based on the surprising property of this active substance or mixture of active substances to positively influence the bone metabolism.
  • Hyperforin or St. John's wort extracts can therefore also be used according to the invention to prevent calcium metabolism diseases or to treat them.
  • the following clinical applications are to be subsumed under this central term: hypercalcaemia, tumor osteolysis, ossifications, ostitis deformans Paget.
  • Osteoporosis is defined as a loss or decrease in bone mass, bone structure and bone function associated with fractures.
  • the osteoporosis can be reduced according to the decrease in bone mass and the deterioration in the microarchitecture of the bone, causing the bone overall brittle and more prone to fractures, divide into several stages:
  • osteoopenia Age-related loss of bone mass
  • osteoporosis is based on morphological and functional changes in the bone structure.
  • the strength of the bone is largely dependent on the existing bone mass. During the growth phase there is an increase in the total bone mass. The maximum bone mass is reached around the age of 30 to 35. Then there is a slow but steady loss of bone mass.
  • Osteoporosis usually develops in the mature skeleton because the natural balance between bone growth and bone loss is disturbed
  • the bone consists of two parts: the cortex, which makes up 80% of the bone in the human skeleton, and the cancellous bone.
  • the alignment of the cancellous trabeculae takes place under the influence of bending stress and compressive stress. As a result, tension bundles and cancellous pressure bundles are formed, which contribute to the stability of the bone.
  • the majority of the bone matrix consists of type I collagen.
  • the collagen units each consisting of two alpha-1 and one alpha-2 chain
  • the hydroxylation of proline and lysine follows as a post-translational modification.
  • the hydroxylysine and hydroxyproline released during collagen breakdown cannot be used by the organism to build new protein structures. Hydroxylysine and hydroxyproline are excreted in the urine. The excretion of hydroxylysine and hydroxyproline in the urine therefore gives an insight into bone breakdown or bone turnover.
  • hydroxylysine and hydroxyproline are not specific bone markers, since about 20% of the collagen is found in the organism, for example in the skin.
  • crosslinks are certain proteins that ensure the cross-linking of the collagen fibrils. When the collagen molecule is broken down, these proteins are released.
  • Desoxypyridinolines are specific for bone collagen. Their determination is therefore particularly suitable to get an insight into the bone metabolism. They are excreted in the urine in a free and peptide-bound form in a ratio of approximately 40:60. Their determination has proven to be a specific and sensitive method for bone loss
  • Bone metabolism disorders are best recognized where the bone offers the largest exchange area, i.e. in the trabecular system. Therefore, in metabolic bone diseases such as osteoporosis, the cancellous bone is first broken down.
  • the trabeculae are rarefied, which are used for cross-linking and are therefore responsible for the rigidity of the overall system.
  • the structures subject to direct tensile and compressive stress are preserved longer, so that the osteoporotic bone impresses as a structure with longitudinally arranged trabeculae. Bone build-up and breakdown are caused by osteoblasts and osteoclasts.
  • osteoblasts The task of osteoblasts is the production of collagen type I and osteocalcin as components of the bone matrix, the production of growth factors and the regulation of bone resorption.
  • the osteoblast receptors for PTH and calcitriol In contrast to the osteoclasts, the osteoblast receptors for PTH and calcitriol.
  • PTH does not directly stimulate osteoclasts; rather, the osteoclasts are stimulated by paracrine hormones of the osteoblasts. Only an orderly interaction of osteoblasts and osteoclasts guarantees a physiological bone remodeling.
  • Calcium and vitamin D are used as the so-called basic therapy for osteoporosis.
  • the enteral calcium absorption decreases postmenopausally due to the lack of estrogen and the calcium requirement increases as a result, the increased calcium requirement must either be covered by a suitable change in diet (lots of milk and milk products) or a corresponding medication must be taken.
  • the need for vitamin D is not adequately covered, at least in north, central and western Europe, especially during the winter months. Due to the insufficient sun exposure from November to March and the insufficient intake of vitamin D with food, additional medication measures are recommended. You can choose between vitamin D preparations and the active vitamin D metabolites.
  • fluorine salts have an anabolic effect on the bones. They induce growth factors in the osteoblasts. If fluorine preparations are administered long-term, they can reinforce existing trabeculae by bone apposition. The activity of the osteoclasts is not inhibited, so the risk of fracture decreases.
  • 5-LO metabolites such as 5-HETE, LTB 4 and the cysteinyl LTs
  • 5-LO metabolites stimulate the formation and activity of the osteoclasts [Gallwitz, WE, Mundy, GR, Lee, CH, Qiao, M., Roodman, GD, Raftery, M ., Gaskell, SJ, Bonewald, LF (1993)
  • 5-Lipoxygenase metabolites of arachidonic acid stimulate isolated osteoclasts to resorb calcified matrices.
  • LTB 4 or LTD 4 stimulates bone resorption in vitro and in vivo
  • Leukotriene B4 stimulates osteoclastic bone absorption both in vitro and in vivo.
  • 5-LO KO mice have a significantly higher cortical bone density and strength than WT mice and lose far less bone mass after ovariotomy [Bonewald, L.F., Flynn, M., Qiao, M., Dallas, M.R., Mundy, G.R., Boyce, B.F. (1997) Mice lacking 5-lipoxygenase have increased cortical bone thickness. Adv Exp Med Biol 433, 299-302].
  • 5-LO metabolites are considered negative regulators of bone formation and it is believed that elevated LT levels favor postmenopausal osteoporosis.
  • 5-LO inhibitors could therefore be important for the therapy of postmenopausal osteoporosis.
  • the anti-osteoporotic effects of various dual inhibitors of 5-LO and COX are noteworthy [Rajendran, KG, Chen, SY, Sood, A., Spielvogel, BF, Hall, IH (1995) The anti-osteoporotic activity of amine-carboxyboranes in rodents.
  • Hyperforin is a dual inhibitor of COX and 5-LO. Based on these properties, extracts of H. perforatum or isolated hyperforin, in addition to their known anti-inflammatory effects, have considerable potential for the therapy of osteoporosis. Experiments by the applicant also show that hyperforin induces the apoptosis of osteoclast macrophages, as a result of which bone degradation could be suppressed in vivo (example 3).
  • hyperforin or extracts from St. John's wort for the prophylactic and / or therapeutic treatment of anaphylactic shock or osteoporosis and of pharmaceutical preparations containing hyperforin or St. John's wort extract is preferred in humans, but can also be done in animals.
  • Hyperforin or extracts from St. John's wort are preferably used intraperitoneally, orally, nasally, buccally, rectally, intramuscularly, topically, subcutaneously, by inhalation, intra-articularly or intravenously.
  • the use according to the invention takes the form of tablets, dragées, capsules, solutions, emulsions, ointments, creams, inhalation preparations, aerosols or suppositories.
  • Another object of the present invention is the use of Hyperforin or extracts from St. John's wort (Hypericum) for the production of a food supplement which, in the prophylactic sense, supports the maintenance and improvement of bone health.
  • Another object of the present invention is a nutritional supplement containing hyperforin or extracts from St. John's wort (Hypericum), which in the prophylactic sense supports the maintenance and improvement of bone health.
  • the nutritional supplement according to the invention can also contain other substances which are beneficial to bone health, in particular fluorine salts, calcium salts and vitamin D.
  • the nutritional supplement according to the invention can be taken directly in the form of tablets, dragees, capsules, solutions or emulsions or can be incorporated into foods, in particular calcium-containing foods such as milk or milk products. Foods enriched in this way enable a healthy bone density to be maintained even at an advanced age.
  • the nutritional supplement according to the invention can be used in particular in the sports, fitness and wellness sector and can be taken in the form of tablets, dragees, capsules, solutions or emulsions or incorporated into sports, fitness and wellness supplements, in particular in protein powder, vitamin preparations or mineral preparations. It is particularly preferred to combine the food supplement according to the invention with compounds which are selected from: "Branched chain amino acids" (BCAA),? -Hydroxy-?
  • creatine is a dietary supplement that is often used in weight training and is said to have muscle and bone-strengthening effects, particularly strong synergistic effects can be expected from the combined administration.
  • Another object of the present invention is the use of Hyperforin or extracts from St. John's wort (Hypericum) for the production of a pharmaceutical preparation or a medicament for the prophylactic and / or therapeutic treatment of anaphylactic shock conditions or for maintaining and improving the health of bones, in particular for Treatment of osteoporosis.
  • Another object of the present invention is a pharmaceutical preparation for the prophylactic and / or therapeutic treatment of anaphylactic shock states or for maintaining and improving the health of bones, in particular for the treatment of osteoporosis, which contains hyperforin or St. John's wort extract as active ingredient.
  • the preparation of the preparation according to the invention is carried out in a manner known to the person skilled in the art, eg. B., as in WO 00/30660, or in Kaul, R. "St. John's wort, botany, ingredients, quality control, pharmacology, toxicology and clinic", Wiss. Verl.-Gesell., 2000, described, whereupon in full Reference is made.
  • the concentration of the active ingredient in the pharmaceutical preparation according to the invention can be adapted and varied by the person skilled in the art depending on the intended use.
  • the dosage of the H. perforatum extract can, for example, be about 300 to 600 mg (e.g. as a coated tablet) about 3 times a day. This would correspond to a dosage of the Hyperforin of about 5 - 25 mg.
  • the dosage and duration of use of the hyperforin or St. John's wort extract to be used according to the invention or the pharmaceutical preparation containing hyperforin or St. John's wort extract can also be adapted and varied by the person skilled in the art depending on the intended use.
  • the pharmaceutical preparations according to the invention can contain at least one further auxiliary or additive, such as. B. contain oils, protective colloids, plasticizers, antioxidants and / or emulsifiers.
  • a physiologically compatible oil such as, for example, sesame oil, corn oil, cottonseed oil, soybean oil or peanut oil, esters of medium-chain vegetable fatty acids or fish oils such as, for example, mackerel, sprat or To use salmon oil.
  • stabilizers such as a-tocopherol, t-butylhydroxy-toluene, t-butylhydroxyanisole, ascorbic acid or ethoxyquine. It is also preferred, because of the photosensitivity of the hyperforin, to pack and store the preparations according to the invention in an opaque manner.
  • hyperforin or extracts from St. John's wort can take place together with other, preferably chemically pure, medicinal substances and / or herbal medicinal products, or the pharmaceutical preparation according to the invention can contain such other, preferably chemically pure, medicinal substances or medicinal products.
  • Suitable drugs or drugs are listed in WO 00/30660 and DE-A-42 01 903, to which reference is hereby made in full.
  • Antipsoriatics, non-steroidal anti-inflammatory drugs are examples of antipsoriatics, non-steroidal anti-inflammatory drugs.
  • Nonsteroidal anti-inflammatory drugs Pyrazole derivatives:
  • Flufenamic acid mefenamic acid, niflumic acid.
  • Naproxen, piroxicam, pirprofen, tiaprofenic acid Naproxen, piroxicam, pirprofen, tiaprofenic acid.
  • Oxicame tenoxicam
  • LT inhibition of synthesis To determine the LT inhibition of synthesis, freshly isolated granulocytes from human blood were incubated with Hyperforin or H. perforatum extract (light weir) and then stimulated with ionophore A23187 in the presence and absence of arachidonic acid. A dose-dependent inhibition of 5-LO product formation (5-HETE, LTB and its trans-isomers) was observed in each case.
  • the IC 50 values are around 1 ⁇ M Hyperforin or 8.5 - 14.2 ⁇ g / ml extract. From 3 ⁇ M Hyperforin (or 28.4 ⁇ g / ml extract) the LT synthesis is almost completely ( ⁇ 3%) suppressed.
  • J774 cells in particular are accepted as osteoclast models and have been used as test models for the screening of bisphosphonates (Luckman et al., 1998: Heterocycle-containing bisphosphonates cause apoptosis and inhibit bone resorption by preventing protein prenylation: Evidence from structure-activity relationships in J774 macrophages. Journal of Bone and Mineral Research 13 (11): 1668-1678; Rogers et al., 1996: Bisphosphonates induce apoptosis in mouse macrophage-like cells in vitro by a nitrite oxide-independent mechanism. Journal of Bone and Mineral Research 11 (10): 1482-1491).

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Abstract

La présente invention concerne l'utilisation d'hyperforine ou d'extraits de millepertuis (Hypericum) pour prévenir et/ou traiter des états de choc anaphylactique et pour maintenir et améliorer la santé des os, en particulier pour traiter l'ostéoporose. L'invention concerne également des compléments alimentaires et des préparations pharmaceutiques contenant de l'hyperforine ou de l'extrait de millepertuis.
PCT/EP2002/014207 2001-12-21 2002-12-13 Utilisation d'hyperforine ou d'extraits de millepertuis pour traiter des etats de choc anaphylactique et pour maintenir et ameliorer la sante des os WO2003053456A1 (fr)

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AU2002358698A AU2002358698A1 (en) 2001-12-21 2002-12-13 Use of hyperforin or st john's wort extracts against anaphylactic states of shock and for maintaining and improving bone health

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DE10163676A DE10163676A1 (de) 2001-12-21 2001-12-21 Verwendung von Hyperforin oder Extrakten aus Johanniskraut gegen anaphylaktische Schockzustände oder Osteoporose
DE10163676.8 2001-12-21

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WO2007075605A3 (fr) * 2005-12-19 2008-06-26 Abbott Lab Procede d'utilisation de ?-hydroxy-?-methylbutyrate
WO2009046801A1 (fr) * 2007-10-09 2009-04-16 Merck Patent Gmbh Compositions pharmaceutiques contenant de la benfotiamine et un ou plusieurs agents pharmaceutiquement actifs pour le traitement d'états de douleur d'origine névropathique
WO2010133707A1 (fr) * 2009-05-18 2010-11-25 Asac Compañía De Biotecnología E Investigación Sa Solutions d'hyperphorines stabilisées pour administration par voie orale
KR101039053B1 (ko) * 2008-10-06 2011-06-07 대한민국(농촌진흥청장) 물레나물 추출물을 유효성분으로 하는 골질환 예방 및 치료용 조성물
US8217077B2 (en) 2004-03-26 2012-07-10 Abbott Laboratories HMB uses thereof
US8916217B2 (en) 2010-01-29 2014-12-23 Abbott Laboratories Aseptically packaged nutritional liquids comprising HMB
US9241508B2 (en) 2010-01-29 2016-01-26 Abbott Laboratories Nutritional emulsions comprising calcium HMB
US9521859B2 (en) 2010-06-10 2016-12-20 Normanella T. Dewille Substantially clear nutritional liquids comprising calcium HMB and soluble protein
CN106511336A (zh) * 2016-12-16 2017-03-22 常州南京大学高新技术研究院 Harrisotone A衍生物的组合物在抗骨质疏松药物中的应用
US9693577B2 (en) 2010-01-29 2017-07-04 Abbott Laboratories Method of preparing a nutritional powder comprising spray dried HMB
EP3760203A1 (fr) * 2019-07-03 2021-01-06 Medizinische Universität Graz Médicament pour la prévention ou le traitement d'un trouble métabolique

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AMERICAN FAMILY PHYSICIAN. UNITED STATES 1 JUL 2002, vol. 66, no. 1, 1 July 2002 (2002-07-01), pages 129 - 134, ISSN: 0002-838X *
DATABASE MEDLINE [online] 1 July 2002 (2002-07-01), MORELLI VINCENT ET AL: "Alternative therapies for traditional disease states: menopause.", XP002231103, Database accession no. NLM12126027 *
DATABASE WPI Section Ch Week 200129, Derwent World Patents Index; Class B04, AN 2001-274144, XP002231104 *
PATENT ABSTRACTS OF JAPAN vol. 016, no. 156 (C - 0930) 16 April 1992 (1992-04-16) *

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WO2007075605A3 (fr) * 2005-12-19 2008-06-26 Abbott Lab Procede d'utilisation de ?-hydroxy-?-methylbutyrate
AU2008310114B2 (en) * 2007-10-09 2014-01-16 Merck Patent Gmbh Pharmaceutical compositions containing benfotiamine and one or more pharmaceutically active agents for the treatment of pain conditions of neuropathic origin
JP2010540668A (ja) * 2007-10-09 2010-12-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング ベンフォチアミンと１または２種以上の医薬活性剤とを含む神経因性の疼痛状態の処置のための医薬組成物
WO2009046801A1 (fr) * 2007-10-09 2009-04-16 Merck Patent Gmbh Compositions pharmaceutiques contenant de la benfotiamine et un ou plusieurs agents pharmaceutiquement actifs pour le traitement d'états de douleur d'origine névropathique
KR101039053B1 (ko) * 2008-10-06 2011-06-07 대한민국(농촌진흥청장) 물레나물 추출물을 유효성분으로 하는 골질환 예방 및 치료용 조성물
WO2010133707A1 (fr) * 2009-05-18 2010-11-25 Asac Compañía De Biotecnología E Investigación Sa Solutions d'hyperphorines stabilisées pour administration par voie orale
US8916217B2 (en) 2010-01-29 2014-12-23 Abbott Laboratories Aseptically packaged nutritional liquids comprising HMB
US9241508B2 (en) 2010-01-29 2016-01-26 Abbott Laboratories Nutritional emulsions comprising calcium HMB
US9693577B2 (en) 2010-01-29 2017-07-04 Abbott Laboratories Method of preparing a nutritional powder comprising spray dried HMB
US9521859B2 (en) 2010-06-10 2016-12-20 Normanella T. Dewille Substantially clear nutritional liquids comprising calcium HMB and soluble protein
CN106511336A (zh) * 2016-12-16 2017-03-22 常州南京大学高新技术研究院 Harrisotone A衍生物的组合物在抗骨质疏松药物中的应用
EP3760203A1 (fr) * 2019-07-03 2021-01-06 Medizinische Universität Graz Médicament pour la prévention ou le traitement d'un trouble métabolique
WO2021001518A1 (fr) 2019-07-03 2021-01-07 Medizinische Universität Graz Ligands de pxr pour la prévention ou le traitement de troubles métaboliques

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