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WO2009120214A1 - Compositions comprenant des inhibiteurs d’arnox pour l’inhibition d’espèces d’oxygène réactif - Google Patents

Compositions comprenant des inhibiteurs d’arnox pour l’inhibition d’espèces d’oxygène réactif Download PDF

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Publication number
WO2009120214A1
WO2009120214A1 PCT/US2008/058683 US2008058683W WO2009120214A1 WO 2009120214 A1 WO2009120214 A1 WO 2009120214A1 US 2008058683 W US2008058683 W US 2008058683W WO 2009120214 A1 WO2009120214 A1 WO 2009120214A1
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WO
WIPO (PCT)
Prior art keywords
arnox
extract
salicaceae
aging
skin
Prior art date
Application number
PCT/US2008/058683
Other languages
English (en)
Inventor
Dale Kern
Christiaan Meadows
Original Assignee
Nu Skin International, Inc.
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
Priority to AU2008353441A priority Critical patent/AU2008353441A1/en
Priority to CN2008801290521A priority patent/CN102014930A/zh
Priority to EA201001558A priority patent/EA201001558A1/ru
Priority to JP2011501769A priority patent/JP2011515466A/ja
Priority to EP08744616A priority patent/EP2280714A1/fr
Priority to PCT/US2008/058683 priority patent/WO2009120214A1/fr
Priority to MX2010010668A priority patent/MX2010010668A/es
Priority to KR1020107023951A priority patent/KR20110000745A/ko
Priority to CA2719833A priority patent/CA2719833A1/fr
Priority to NZ588182A priority patent/NZ588182A/xx
Application filed by Nu Skin International, Inc. filed Critical Nu Skin International, Inc.
Publication of WO2009120214A1 publication Critical patent/WO2009120214A1/fr
Priority to IL208324A priority patent/IL208324A0/en
Priority to ZA2010/07247A priority patent/ZA201007247B/en

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/609—Amides, e.g. salicylamide
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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)
    • A61K36/35—Caprifoliaceae (Honeysuckle family)
    • A61K36/355—Lonicera (honeysuckle)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/602—Glycosides, e.g. rutin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the invention relates to extracts of natural products useful in sequestering serum aging factors that may be administered internally or topically. More particularly, the invention relates to agents and compositions thereof for use cosmetically to inhibit or ameliorate aging-related oxidation and methods for their use as skin care products.
  • NOX The plasma membrane NADH oxidase
  • NADH hydroquinone
  • CLOX hydroquinone
  • tNOX A hormone-insensitive and drug-responsive form of the NOX designated tNOX has been described that is specific for cancer cells. For example, see U.S. Patent No. 5,605,810, which is incorporated herein by reference in its entirety.
  • arNOX NADH oxidase
  • the aging-related isoform of NADH oxidase (arNOX) is a member of this family of proteins.
  • the circulating form of arNOX increases markedly in human sera and in lymphocytes of individuals, especially between the ages of 30 to 65.
  • the arNOX protein is uniquely characterized by an ability to generate superoxide radicals, which may contribute significantly to aging-related changes including atherogenesis and other action-at-a-distance aging phenomena.
  • Activity of arNOX in aging cells and in sera has been described previously. See, for example, PCT Pub. App. No. WO 00/57871, which is incorporated by reference in its entirety herein.
  • ROS reactive oxygen species
  • the skin in particular is vulnerable to damage by reactive oxygen species.
  • the skin is composed of two major layers.
  • the stratum corneum, or epidermis is the top layer and forms a protective covering for the skin and controls the flow of water and substances in and out of the skin.
  • the dermis is the lower level of the skin and provides the strength, elasticity and the thickness to the skin.
  • the main cell type of the dermis is fibroblasts, which are responsible for synthesis and secretion of all the dermal matrix components such as collagen, elastin and glycosaminoglycans. Collagen provides the strength, elastin the elasticity, and glycosaminoglycans the moistness and plumpness of the skin.
  • the skin In addition to being damaged by reactive oxygen species the skin is subject to various damaging stressors.
  • the skin may be damaged or abused by many factors in the environment. Some are naturally occurring such as UV radiation from the sun, wind and even mechanical insults such as cuts, scrapes and the like. Other, man-made insults also occur daily. These include the use of soaps, emulsifier-based cosmetics, hot water, organic solvents, air conditioning and central heating. Further, other insults to the skin may result from or be part of dermatological disorders or the normal aging process (chronoaging), which may be accelerated by exposure of skin various external stressors (e.g. photoaging).
  • Symptoms of aging skin include dryness, itchiness, thinning or thickening of the skin, wrinkles and fine lines, areas of hyperpigmentation commonly referred to as liver spots and areas underneath the skin where blood vessels have ruptured (telangietasias).
  • Anti-aging cosmetic and medical products which treat or delay the visible signs of actual aging and weathered skin such as wrinkles, lines, sagging, hyperpigmentation and age spots are desirable.
  • most cosmetic or medicinal products do not address the bases of such symptoms, e.g., the production and buildup of arNOX related radicals derived from ROS. Accordingly, there is a demand for effective natural skin treatments and preventative compositions and methods for using the same.
  • the invention relates to agents for sequestering serum aging factors, and methods for using the same. More particularly, the invention relates to agents termed herein "Naractin" to denote any one of several naturally-occurring arNOX inhibitors either present in N. tazetta powder or capable of augmenting TV. tazetta powder to an inhibitory level comparable to that of the fresh N. tazetta extracts, and to methods for using "Naractins" to prevent or treat disorders and complications of disorders resulting from cell damage caused by an aging-related isoform of NADH oxidase (arNOX).
  • the agents of the invention comprise at least one naturally occurring Naractin. Such naturally occurring naratins are also capable of augmenting the anti-arNOX effect of other naturally occurring arNOX inhibitory agents.
  • the invention includes a topical composition useful for ameliorating the effects of aging comprising an effective amount of at least one arNOX inhibitory agent.
  • the arNOX inhibitory agent is a naractin, the naractin being effective in decreasing the effects of aging.
  • the naractin is extracted and/or purified from N. tazetta, willow, maize, crepis, poplar, vibumam, mold- especially Aspergillus, alangium, birch, bupleurum, colchicum, spurge, filipendulum, gardenia, lithospermum, tobacco or mistletoe.
  • the naractin is a salicylate or a derivative thereof.
  • the salicylate is salicylate is salicin, salicylic acid, salicyl hydroxamate, derivatives or combinations thereof.
  • the naractin is derived from Alangium chinense, A. platanifolium, A. premnifolium, Aspergillus niger, Betula alba, Bupleurum falcatum, Catharanthus roseus, Chosenia bracteosa, Colchicum autumnale, Crepis foetida, C.
  • rhoeadifolia Datura inoxia, Duboisia myoporoides, Eleutherococcus setchuensis, Euphorbia salicifolia, Filipendula ulmaria, Foeniculum vulgare, Gardenia jasminoides, Lithospermum erythrorhizon, Nicotiana tabacum, Populus alba, P. balsamifera, P. davidiana, P. deltoides, P. euphratica, P. grandidentata, P. heterophylla, P. lasiocarpa, P. maximowiczii, P. nigra, P. sieboldii, P. simonii, P. tacamahaca, P.
  • tomentosa P. tremula, P. tremuloides, P. trichocarpa, Salix acutifolia, S. alba, S. americana, S. arctica, S. aurita, S. babylonica, S. basfordiana, S. caesia, S. calodendron, S. capitata, S. caprea, S. chaenomeloides, S. cinerea, S. daphnoides, S. fragilis, S. geminata, S. gracilis, S. gracilistyla, S. gracilistyloides, S. gymnolepis, S. hastata, S. herbacea, S. incana, S.
  • the naractin is a salicylate or a derivative thereof.
  • the salicylate is salicylate is salicin, salicylic acid, salicyl hydroxamate, derivatives or combinations thereof
  • the composition further includes a cosmetically or pharmaceutically acceptable carrier.
  • the naractin inhibitory agent is present together with other arNOX inhibitors derived from naturally occurring sources including but not limited to broccoli, shitake, coleus rosemary, lotus, artichoke, sea rose tangerine, Oenothera biennis, astaxanthin, red orange, Schisandra chinensis, Lonicera, Fagopyrum, carrot or olive.
  • the naractin augments the effects of the additional arNOX inhibitory agents.
  • arNOX inhibitory compositions described herein can be administered in any convenient manner.
  • forms of administration include a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap, a shampoo or a sunscreen.
  • the effects of aging ameliorated by the instant invention include, but are not limited to lines, wrinkles, hyperpigmentation, dehydration, loss of elasticity, angioma, dryness, itching, telangietasias, actinic purpura, seborrheic keratoses, lack of hydration, decrease in collagen or actinic keratoses.
  • the arNOX inhibitory agent is provided at a concentration of between about 5 ⁇ g/ml to about 500 ⁇ g/ml.
  • the invention comprises a method to inhibit the generation of reactive oxygen species by aging-related isoform of NADH oxidase, to ameliorate the effects of aging comprising: administering a therapeutically effective amount of a composition comprising at least one of salicin, salicylic acid, salicyl hydroxamate to a patient in need thereof, such that generation of reactive oxygen species by aging-related isoform of NADH oxidase, is inhibited and wherein an effect of aging is ameliorated.
  • he method further comprises an extract, or purified extract, from least one of broccoli, shitake, coleus rosemary, lotus, artichoke, sea rose tangerine, Oenothera biennis, astaxanthin, red orange, Schisandra chinensis, Lonicera, Fagopyrum, carrot, Narcissus tazetta, olive, willow, oat or maize.
  • the composition is applied as a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap, a shampoo or a sunscreen.
  • the effects of aging include, but are not limited to, lines, wrinkles, hyperpigmentation, dehydration, loss of elasticity, angioma, dryness, itching, telangietasias, actinic purpura, seborrheic keratoses, lack of hydration, decrease in collagen or actinic keratoses.
  • the invention includes a cosmetic method for ameliorating the effects of aging comprising applying to the skin a cosmetic composition comprising: an effective amount of a naractin sufficient to inhibit arNOX, wherein at least one arNOX mediated effect of aging is inhibited.
  • the naractin is a salicylate a salt or a derivative thereof.
  • the salicylate is salicin, salicyl hydroxamte, or salicylic acid.
  • the cosmetic composition further includes a plant extract comprising: carrot extract, olive extract, broccoli extract, shitake extract, coleus, extract rosemary extract, lotus extract, artichoke extract, sea rose extract tangerine extract, Oenothera biennis extract, red orange extract, Schisandra chinensis extract, Lonicera extract, Fagopyrum extract, willow extract, maize, oat or Narcissus tazetta extract.
  • the naractin is provided together with a cosmetically acceptable carrier.
  • the effects of aging ameliorated by the method according to the invention include lines, wrinkles, hyperpigmentation, dehydration, loss of elasticity, angioma, dryness, itching, telangietasias, actinic purpura, seborrheic keratoses, lack of hydration, decrease in collagen or actinic keratoses.
  • the naractin is applied at least once a day.
  • the naractin is provided in a cosmetic preparation at a concentration of between about 5 ⁇ g/ml to about 500 ⁇ g/ml.
  • the cosmetic composition according to the invention is administered as a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap, a shampoo or a sunscreen.
  • the invention comprises a kit for applying a cosmetic useful in ameliorating the effects of aging comprising: at least one naractin; and instruction for use.
  • the kit further comprises a cosmetic preparation suitable as a carrier for the at least one arNOX inhibitory plant extract.
  • Figure Ib is the same as Ia except that instead of SHAM the inhibitory effect of the N. tazetta powder was augmented with salicin (Naractin 3).
  • the Naractins form reddish complexes with iron with spectral properties similar to the reddish colors that characterize portions of TV. tazetta bulb parts and extracts that contain arNOX-inhibitory substances as shown in Figure 2.
  • Figures 2a-f illustrate regions of the TV. tazetta bulb and extracts that contain substances inhibitory to arNOX activity. Inhibitory substances are absent from the parts of the bulbs and/or extracts that do not become red or pink in color.
  • Figure 2a is a drawing of a bulb divided into the region comprised of leaves and the stem region.
  • Figure 2b is a photograph showing that the red- colored compounds associated with arNOX inhibition are localized in the stem region.
  • Figure 2c show different regions of the bulb from which extracts were made and have from different regions have different levels of red color development as shown in Figures 2d, 2e and 2f. Color development is rapid. Bulbs of TV. tazetta varieties where extracts do not inhibit arNOX activity also fail to develop the red color.
  • Figure 3 illustrates a similar reddish color of the vasculature of maize steeles (the central water conducting tissues of the root) after addition of iron chloride. The substance resulting in the red color is a naturally-occurring hydroxamate.
  • Figure 4 shows inhibition of arNOX activity of saliva (72 y/o M) in the base line (BL) panel and inhibition by addition of a homogenate prepared from maize steeles. Maize sheaths (the tissue surrounding the steeles) neither became colored upon addition of iron nor inhibited arNOX activity.
  • Figure 5 shows examples from analyses by thin layer chromatography of methanol extracts of TV. tazetta bulbs (B) compared to the commercial TV. tazetta powder (A).
  • the plates with blue (UV) background show ultraviolet fluorescence.
  • the plates with light background (BB) were stained with Berlin blue.
  • the TLC system was dichloromethane:methanol:NH 4 OH (10:1 :0.2).
  • a reddish component just above but clearly separated from the material at the origin and suggestive of the presence of hydroxamates was much more evident in the laboratory-extracted sample than in the commercial powder. This was evident for both methanol (Figure 5a) and water (Figure 5b) extracts.
  • the putative hydroxamate was seen also in the commercial powder but at much lower levels than in the laboratory- extracted sample once again correlating with levels of arNOX inhibitory activity.
  • Figure 6 shows a spectral analyses of TV. tazetta bulb and maize Steele and sheath extracts compared to a known hydroxamate (SHAM) following addition of ferric chloride to form red-colored ferric hydroxamates.
  • SHAM hydroxamate
  • arNOX inhibitory-extracts of TV. tazetta bulbs were red and exhibited an absorbance maximum around 550 run. Extracts of TV. pseudo narcissus bulbs which lacked inhibitory activity were colorless and showed no absorbance at 550 nm.
  • Maize root Steele (active) and maize root sheath (inactive) fractions were largely uncolored in the absence of added ferric chloride (-FeCl 2 ).
  • Figure 7 is a graph of the arNOX activity of ferri cytochrome c as a function of SHAM dilution (log).
  • the graph illustrates the dose-dependent inhibition of arNOX activity of saliva (72 y/o M) by a commercially available preparation of SHAM (Sigma-Aldrich, St. Louis, MO). Inhibition is largely complete at 11 mg/ml.
  • Figure 8 is a graph of the arNOX activity of ferri cytochrome c as a function of salicylic acid dilution (log). The graph illustrates the dose-dependent inhibition of arNOX activity of saliva (72 y/o M) as a function of salicylic acid concentration. Salicylic acid at a concentration of lmg/ml inhibits about 50%.
  • Figure 9 is a graph of the arNOX activity of ferricytochrome c as a function of salicin dilution (log). The graph illustrates the dose-dependent inhibition of arNOX activity of saliva (72 y/o M) as a function of salicin concentration. Maximum inhibition of arNOX activity is achieved at a concentration of 1 mg/ml.
  • Figures 10a and 10b are graphs showing the arNOX inhibition of various "Naractin" combinations.
  • Figure 10a illustrates salicin augmentation of arNOX inhibition of a mixture of 4 mg/ml Schizandra powder plus N. tazetta extract (20 ⁇ l) in the presence of 1 mg/ml salicin.
  • Figure 10b illustrates the arNOX inhibition by a mixture of 4 mg/ml Schizandra powder plus 1 mg/ml N. tazetta powder in the presence of 1 mg/ml salicin. Of the mixture, 60 ⁇ l was added to at total of three ml of assay mixture containing saliva (72 y/o M) as the arNOX activity source.
  • the invention relates to agents for sequestering serum aging factors, and methods for using the same. More particularly, the invention relates to agents termed herein "Naractin" to denote any one of several naturally-occurring arNOX inhibitors either present in N. tazetta powder or capable of augmenting N. tazetta powder to an inhibitory level comparable to that of the fresh N. tazetta extracts, and to methods for using "Naractins" to prevent or treat disorders and complications of disorders resulting from cell damage caused by an aging-related isoform of NADH oxidase (arNOX).
  • the agents of the invention comprise at least one naturally occurring Naractin.
  • Non-aractin is used herein to denote any one of several naturally-occurring arNOX inhibitors either present in TV.
  • tazetta powder commercially available from, for example, Xian Aojing Science and Technology Developing CO., LTD, Xi' an, Shaanxi, CN
  • tazetta powder capable of augmenting TV.
  • tazetta powder to an inhibitory level comparable to that of the fresh TV. tazetta extracts.
  • the inventors have currently identified three known substances, chemically pure, with "Naractin" activity.
  • Naractins have been herein identified from TV. tazetta extract they may be present from other natural sources such as, for example, willow, maize and oat and, of course, the invention encompasses Naractins regardless of their source.
  • cosmetic refers to a substance intended to be applied to the body for cleansing, beautifying, promoting attractiveness, or altering the appearance.
  • extract refers to a solution obtained by steeping or soaking a substance in a solvent and removing the active ingredient.
  • the solvent can be any suitable solvent including but not limited to alcohol, water or the like.
  • the extract is concentrated or the solvent can be evaporated and the active ingredient resuspended or solubilized in a different solvent.
  • the TV. tazetta extract is made by separating the stem region from the bulb and homogenizing one stem region in 3ml of distilled water.
  • disorder refers to any condition of a living animal or plant body or of one of its parts that impairs normal functioning comprising any ailment, disease, illness, clinical condition, pathological condition, weakened condition, unsound condition, and any abnormal or undesirable physical condition.
  • reactive oxygen species refers to oxygen derivatives from oxygen metabolism or the transfer of free electrons, resulting in the formation of free radicals (e.g., superoxides or hydroxyl radicals).
  • the term “antioxidant” refers to compounds that neutralize the activity of reactive oxygen species or inhibit the cellular damage done by said reactive species.
  • pharmaceutically acceptable carrier refers to a carrier medium that does not interfere with the effectiveness of the biological activity of the active ingredient, is chemically inert, and is not toxic to the patient to whom it is administered.
  • the term "pharmaceutically acceptable derivative” refers to any homolog, analog, or fragment corresponding to the formulations described in this application, which exhibit antioxidant activity, and is relatively non- toxic to the subject.
  • therapeutic agent refers to any molecule, compound, or treatment, preferably an antioxidant, which assists in the prevention or treatment of the disorders, or complications of disorders caused by reactive oxygen species.
  • agent that sequesters arNOX refers to any molecule, compound, or treatment that interacts with arNOX, thus decreasing the reaction of arNOX with other substrates and inhibits the ability of arNOX to generate reactive oxygen species.
  • salicylates refers to salts, conjugates or derivatives of salicin whether derived from naturally occurring sources or synthesized de novo. Such salicylates include, for example, salicylic acid, salicin hydroxamate and salicin itself, their derivatives, salts and conjugates.
  • tazetta bulbs are in dormancy.
  • the theory being that at the growth stage the bulbs produce quantities of unidentified compounds referred to as "dormins". Such “dormins” are further hypothesized to elicit a state of dormancy in cells or tissues.
  • N. tazetta "dormin” is not the same agent as the herein identified as “Naractins.”
  • N. tazetta powder The most readily available hydroxamate for evaluation was salicyl hydroxamate (Naractin 1), also known as SHAM, a known inhibitor of the alternate oxidase of plants. SHAM was tested and was found to augment the arNOX inhibitory response of N. tazetta powder. A level of inhibition of greater than 90% was obtained with N. tazetta powder augmented with low levels of SHAM. While there were insufficient N. tazetta bulbs to complete the characterization of the active component but the work was continued with N. tazetta powder (extract) (Xi'an Aojing Science and Technology Developing Co., LTD., Xi'an, Shaanxi, China; 20:1 available in both bulb and flower extract). N. tazetta powder does appear to contain low levels of a naturally-occurring hydroxamate but at levels much less than extracts prepared from N. tazetta bulbs.
  • Salicylic acid (Naractin 2) of itself is a very potent arNOX inhibitor which also gives a red color when reacted with ferric iron. Esters of salicylic acid or aspirin do not inhibit arNOX.
  • the invention includes a topical composition useful for ameliorating the effects of aging comprising an effective amount of at least one arNOX inhibitory agent.
  • the arNOX inhibitory agent is a naractin, the naractin being effective in decreasing the effects of aging.
  • the naractin is purified from N. tazetta, willow, maize, crepis, poplar, viburnam, mold- especially Aspergillus, alangium, birch, bupleurum, colchicum, spurge, filipendulum, gardenia, lithospermum, tobacco or mistletoe.
  • the naractin is a salicylate or a derivative thereof.
  • the salicylate is salicylate is salicin, salicylic acid, salicyl hydroxamate, derivatives or combinations thereof.
  • the naractin is derived from Alangium chinense, A. platanifolium, A. premnifolium, Aspergillus niger, Betula alba, Bupleurum falcatum, Catharanthus roseus, Chosenia bracteosa, Colchicum autumnale, Crepis foetida, C.
  • rhoeadifolia Datura inoxia, Duboisia myoporoides, Eleutherococcus setchuensis, Euphorbia salicifolia, Filipendula ulmaria, Foeniculum vulgare, Gardenia jasminoides, Lithospermum erythrorhizon, Nicotiana tabacum, Populus alba, P. balsamifera, P. davidiana, P. deltoides, P. euphratica, P. grandidentata, P. heterophylla, P. lasiocarpa, P. maximowiczii, P. nigra, P. sieboldii, P. simonii, P. tacamahaca, P.
  • tomentosa P. tremula, P. tremuloides, P. trichocarpa, Salix acutifolia, S. alba, S. americana, S. arctica, S. aurita, S. babylonica, S. basfordiana, S. caesia, S. calodendron, S. capitata, S. caprea, S. chaenomeloides, S. cinerea, S. daphnoides, S. fragilis, S. geminata, S. gracilis, S. gracilistyla, S. gracilistyloides, S. gymnolepis, S. hastata, S. herbacea, S. incana, S.
  • the naractin is a salicylate or a derivative thereof.
  • the salicylate is salicylate is salicin, salicylic acid, salicyl hydroxamate, derivatives or combinations thereof
  • the composition further includes a cosmetically or pharmaceutically acceptable carrier.
  • the naractin inhibitory agent is present together with other arNOX inhibitors derived from naturally occurring sources including but not limited to broccoli, shitake, coleus rosemary, lotus, artichoke, sea rose tangerine, Oenothera biennis, astaxanthin, red orange, Schisandra chinensis, Lonicera, Fagopyrum, carrot, or olive,.
  • the naractin augments the effects of the additional arNOX inhibitory agents.
  • arNOX inhibitory compositions described herein can be administered in any convenient manner.
  • forms of administration include a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap, a shampoo or a sunscreen.
  • the effects of aging ameliorated by the instant invention include, but are not limited to lines, wrinkles, hyperpigmentation, dehydration, loss of elasticity, angioma, dryness, itching, telangietasias, actinic purpura, seborrheic keratoses, lack of hydration, decrease in collagen or actinic keratoses.
  • the arNOX inhibitory agent is provided at a concentration of between about 5 ⁇ g/ml to about 500 ⁇ g/ml.
  • the invention comprises a method to inhibit the generation of reactive oxygen species by aging-related isoform of NADH oxidase, to ameliorate the effects of aging comprising: administering a therapeutically effective amount of a composition comprising at least one of salicin, salicylic acid, salicyl hydroxamate to a patient in need thereof, such that generation of reactive oxygen species by aging-related isoform of NADH oxidase, is inhibited and wherein an effect of aging is ameliorated.
  • the method further comprises an extract, or purified extract, from least one of broccoli, shitake, coleus rosemary, lotus, artichoke, sea rose tangerine, Oenothera biennis, astaxanthin, red orange, Schisandra chinensis, Lonicera, Fagopyrum, carrot, Narcissus tazetta, olive, willow, oat , maize, crepis, poplar, viburnam, mold- especially Aspergillus, alangium, birch, bupleurum, colchicum, spurge, filipendulum, gardenia, lithospermum, tobacco or mistletoe..
  • the composition is applied as a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap, a shampoo, an elixir or a sunscreen.
  • the effects of aging include, but are not limited to, lines, wrinkles, hyperpigmentation, dehydration, loss of elasticity, angioma, dryness, itching, telangietasias, actinic purpura, seborrheic keratoses, lack of hydration, decrease in collagen or actinic keratoses.
  • the invention includes A cosmetic method for ameliorating the effects of aging comprising applying to the skin a cosmetic composition comprising: an effective amount of a naractin sufficient to inhibit arNOX, wherein at least one arNOX mediated effect of aging is inhibited.
  • the naractin is a salicylate a salt or a derivative thereof.
  • the salicylate is salicin, salicyl hydroxamte, or salicylic acid.
  • the cosmetic composition further includes a plant extract comprising: carrot extract, olive extract, broccoli extract, shitake extract, coleus, extract rosemary extract, lotus extract, artichoke extract, sea rose extract tangerine extract, Oenothera biennis extract, red orange extract, Schisandra chinensis extract, Lonicera extract, Fagopyrum extract, willow extract, maize, crepis, poplar, viburnam, mold- especially Aspergillus, alangium, birch, bupleurum, colchicum, spurge, filipendulum, gardenia, lithospermum, tobacco, mistletoe., oat or Narcissus tazetta extract.
  • the naractin is provided together with a cosmetically acceptable carrier.
  • the effects of aging ameliorated by the method according to the invention include lines, wrinkles, hyperpigmentation, dehydration, loss of elasticity, angioma, dryness, itching, telangietasias, actinic purpura, seborrheic keratoses, lack of hydration, decrease in collagen or actinic keratoses.
  • the naractin is applied at least once a day.
  • the naractin is provided in a cosmetic preparation at a concentration of between about 5 ⁇ g/ml to about 500 ⁇ g/ml.
  • the cosmetic composition according to the invention is administered as a cream, a milk, a lotion, a gel, an elixir, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap, a shampoo or a sunscreen.
  • the invention comprises a kit for applying a cosmetic useful in ameliorating the effects of aging comprising: at least one naractin; and instruction for use.
  • the kit further comprises a cosmetic preparation suitable as a carrier for the at least one arNOX inhibitory plant extract.
  • the antioxidants, cellular components, and target proteins defined herein are abbreviated as follows: mitochondrial DNA mtDNA nicotinamide adenine dinucleotide NADH cell surface hydroquinone (NADH) oxidase with protein disulfide-thiol isomerase activity NOX
  • NOX specific to cancer cells tNOX low density lipoprotein LDL plasma membrane oxido-reductase chain PMOR ubiquinone or coenzyme Q CoQ coenzyme Q 10 CoQio reactive oxygen species ROS
  • the present invention is directed to naturally occurring agents identified and purified from the Narcissus tazetta bulb and maize and may be administered either internally or topically. These agents specifically inhibit arNOX and ameliorate some of its aging related effects. Such agents can take the form of isolated agents or plant extracts. Further, while arNOX inhibitory agents can be used alone, they may also be used as compositions comprising multiple arNOX inhibitory agents and/or formulations including compounds having other beneficial effects on the body. In particular, the inventors have found that by adding arNOX inhibitors to cosmetics, the inhibitors can have beneficial effects that augment the normal skin care regimen.
  • the invention comprises a cosmetic composition for ameliorating the effects of aging comprising a cosmetically effective amount of at least one arNOX inhibitory agent wherein the arNOX inhibitory agent is effective in decreasing the effects of aging upon the skin.
  • the invention includes a cosmetically acceptable carrier.
  • the carrier may include powders, emollients, lotions, creams, liquids and the like.
  • the arNOX inhibitory agent is derived from a plant.
  • the plant is selected from broccoli, shitake, coleus, rosemary, lotus, artichoke, sea rose, tangerine, Oenothera biennis, astaxanthin, red orange, Schisandra chinensis, Lonicera, Fagopyrum, carrot, Narcissus tazetta, willow, maize, , maize, crepis, poplar, viburnam, mold- especially Aspergillus, alangium, birch, bupleurum, colchicum, spurge, filipendulum, gardenia, lithospermum, tobacco, mistletoe, oat or olive.
  • the cosmetic composition according to this exemplary embodiment can be administered in any exemplary manner.
  • the cosmetic composition according to the invention is applied topically, orally, parenterally, transdermally or rectally.
  • the composition is formulated as a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap or a shampoo.
  • the invention includes a cosmetic method for ameliorating the effects of aging comprising applying to the skin a cosmetic composition comprising an effective amount of an arNOX inhibitor, wherein at least one arNOX mediated effect of aging is inhibited.
  • the arNOX inhibitor is a plant extract.
  • the arNOX inhibitor is purified from a plant extract.
  • the arNOX inhibitory agent is present in a concentration of between about 5 ⁇ g/ml to about 500 ⁇ g/ml.
  • the concentration of the active agent is present in a concentration of between about 15 to 100 ⁇ g/ml.
  • the cosmetic composition according to the invention is applied topically, orally, parenterally, transdermally, rectally or by any effective method.
  • the composition is formulated as a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap or a shampoo.
  • the invention comprises a kit.
  • the kit may include a volume of an arNOX inhibitory agent and instruction for use.
  • the kit may further include a cosmetic preparation such that the arNOX inhibitory agent can be added to the cosmetic preparation prior to use.
  • one arNOX inhibitory agent is used, in other exemplary embodiments more than one extract or arNOX inhibitory agent are used together.
  • the one or various arNOX inhibitory agents may be applied or administered in various ways. Such as, for example, topical administration, in the form of a cream, a milk, a lotion, a gel, a suspension of lipid or polymeric microspheres or nanospheres or vesicles, a soap, a shampoo or a sunscreen and in the form of a tea or capsule or any other effective manner.
  • NADH oxidase is a unique cell surface protein with hydroquinone (NADH) oxidase and protein disulfide-thiol interchange activities that normally responds to hormone and growth factors.
  • a hormone insensitive and drug-responsive form of the activity designated tNOX also has been described, which is specific for cancer cells.
  • SHAM was tested for inhibition of arNOX activity and greater than 90% inhibition of arNOX activity of saliva from a 72 y/o male was obtained at a concentration of 1 mg/ml (Figure 7). SHAM was also found to augment the inhibition of arNOX activity of partially active TV. tazetta powders ( Figure 1). The commercially available TV. tazetta powder does appear to contain low levels of a naturally-occurring hydroxamate possibly similar to SHAM but at levels much less than that found in extracts prepared from fresh N. tazetta bulbs ( Figures 5a and 5b).
  • salicylic acid (Naractin 2, commercially available from, for example, Sigma-Aldrich, St Louis, Mo. was tested as an inhibitor of arNOX activity of saliva (72 y/o M) and was found to inhibit arNOX (Figure 8).
  • Salicylic acid also gave a red color when reacted with ferric iron similar to that given by the hydroxamates. Esters of salicylic acid and/or aspirin did not inhibit arNOX.
  • Salicin (Sigma-Aldrich, St Louis, Mo) (designated herein as Naractin 3), the major salicylate of willow bark, was subsequently tested and found to be active at a ten-fold lower concentration than either SHAM (Naractin 1) or salicylic acid (Naractin 2) ( Figure 9).
  • the characteristics of aged cells includes those that express and/or shed arNOX, and include, but are not limited to, those exhibiting one or more of the following characteristics: an age-related PMOR system, the ability to generate reactive oxygen species, and have functionally defective mitochondria.
  • One embodiment of the invention is the utilization of agents to reduce the negative effects of aging cells.
  • the symptoms of aging skin include dryness, itchiness, thinning or thickening of the skin, wrinkles and fine lines, areas of hyperpigmentation (called age or liver spots), and a mottled appearance.
  • Aging skin has been shown to have a decrease in collagen and a concomitant decrease in elasticity.
  • aging skin has increased amounts of cleaved collagen and cross-linked proteins. Superoxide radicals have been indicated in these processes.
  • the skin may take more time to heal when injured. Blood vessels are easier to see through the thinning skin, also because they become dilated with age. These blood vessels may be visible as red dome-like formations on the skin (cherry angiomas), or as broken capillaries on the face (telangietasias).
  • senile or actinic purpura which are purplish spots or patches on the skin created by small hemorrhages in the skin. Older skin has less protection against sun damage because protective cells called melanocytes decrease with age. Aging skin is also more likely to develop a variety of benign and pre-cancerous growths, such as seborrheic and actinic keratoses. Seborrheic keratoses often have a rough, brown appearance, and look like a wart. They are benign. Actinic keratoses are small, scaly growths on areas of the skin that have received sun exposure. They are an early sign of skin cancer
  • the invention encompasses the use of topical administration of natural plant extracts, alone or in the form of a cream emollient, lotion, gel, emollient or the like, to maintain skin vitality.
  • a preferred embodiment of the invention comprises the topical administration of a cream, which comprises an arNOX inhibiting extract, to the skin of patients to maintain and improve skin vitality.
  • the present invention provides compositions comprising active agent(s), which prevent and/or ameliorates skin damage and associated conditions, particularly those resulting from aging and associated with arNOX. Further, the invention encompasses methods for utilizing said compositions.
  • the stratum corneum is the layer of the skin that forms the top surface layer and serves to protect the skin while controlling moisture and the flow of substances in and out of the skin. As this barrier function is broken down, the skin suffers damaging effects, thus further contributing to premature aging. These damaging effects causing premature aging of the skin are a concern for many individuals wishing to maintain healthy, youthful looking and feeling skin. Reactive oxygen species participate in a number of destructive reactions potentially lethal to cells.
  • a preferred embodiment of the invention provides naturally occurring active agents from plants for the treatment of arNOX related damage to tissue, especially skin.
  • the active agents prevent and/or ameliorate skin damage and associated conditions.
  • the processed plant products sequester arNOX activity.
  • the processed plant products inhibit reactive oxygen species.
  • agents and methods of the invention prevent and/or improve the health of the skin.
  • the agents may improve, tautness of skin, color and appearance of pores, elasticity, hydration and/or help diminish the appearance of fine lines and visible signs of aging.
  • the agents positively affect the body's natural production of collagen and elastin.
  • the agents of the invention minimize the effects of environmental agitators such as pollution, sun, free radicals and stress.
  • One embodiment of the invention provides a composition for preventing and reducing the effects of the production of reactive oxygen species and methods for using the same.
  • the invention encompasses the use of active agents derived from plants to at least partially sequester or inhibit arNOX activity. Further, the invention contemplates the use of other synthetic and natural compounds to sequester arNOX activity.
  • the present invention discloses compositions, which treat the skin and delay the visible signs of actual aging and weathered skin such as wrinkles, lines, sagging, hyperpigmentation and age spots.
  • the present invention also decreases the appearance and condition of sensitive, dry and/or flaky skin, serves to soothe red, and/or irritated skin, and treats spots, pimples, blemishes, and other skin irregularities.
  • the invention provides pharmaceutical or cosmetic compositions, methods of use, and pharmaceutical or cosmetic kits for the treatment of disorders resulting from oxidative changes in cells that result in aging by targeting an aging-related isoform of NADH oxidase (arNOX), shed into the sera by aging cells.
  • the compositions may contain agents extracted from plants.
  • the compositions of the invention may comprise at least one extract shown to inhibit arNOX activity, whether alone or with other inhibition agents and, at least partially, inhibit or block the activity of an aging-related isoform of NADH oxidase shed into the sera by aging cells.
  • the composition may comprise ubiquinones, natural extracts or agents derived therefrom known to comprise active agents useful in inhibiting arNOX, together with other compounds known in the art to make creams, lotions, emollients, gels and the like.
  • Such other compounds may comprise gums, fillers, preservatives and the like.
  • Vehicles other than, or in addition to water can include liquid or solid emollients, solvents, humectants, thickeners and powders.
  • the vehicle may be from 0.1% to 99.9%, preferably from 25% to 80% by weight of the composition, and can, in the absence of other cosmetic adjuncts, form the balance of the composition.
  • the vehicle is at least 80% water, by weight of the vehicle.
  • water comprises at between about 50% to 85% of the composition by weight.
  • water is present between about 0.1% to 55%, by weight of the composition.
  • other vehicles are used in the above recited concentrations.
  • An oil or oily material may be present, together with an emulsifier to provide either a water-in-oil emulsion or an oil-in-water emulsion, depending largely on the average hydrophilic- lipophilic balance (HLB) of the emulsifier employed.
  • HLB hydrophilic- lipophilic balance
  • the inventive compositions may also include sunscreens.
  • Sunscreens include those materials commonly employed to block ultraviolet light.
  • Illustrative compounds are the derivatives of PABA, cinnamate and salicylate.
  • octyl methoxycinnamate and 2- hydroxy-4-methoxy benzophenone also known as oxybenzone
  • Octyl methoxycinnamate and 2-hydroxy-4-methoxy benzophenone are commercially available under the trademarks, Parsol MCX and Benzophenone-3, respectively.
  • the exact amount of sunscreen employed in the emulsions can vary depending upon the degree of protection desired from the sun's UV radiation.
  • Emollients may further be incorporated into cosmetic compositions of the present invention. Levels of such emollients may range from 0.5% to 50%, preferably between 5% and 30% by weight of the total composition. Emollients may be classified under such general chemical categories as esters, fatty acids and alcohols, polyols and hydrocarbons.
  • Esters may be mono- or di-esters.
  • Acceptable examples of fatty di-esters include dibutyl adipate, diethyl sebacate, diisopropyl dimerate, and dioctyl succinate.
  • Acceptable branched chain fatty esters include 2-ethyl-hexyl myristate, isopropyl stearate and isostearyl palmitate.
  • Acceptable tribasic acid esters include triisopropyl trilinoleate and trilauryl citrate.
  • Acceptable straight chain fatty esters include lauryl palmitate, myristyl lactate, and stearyl oleate.
  • Preferred esters include coco-caprylate/caprate (a blend of coco-caprylate and coco-caprate), propylene glycol myristyl ether acetate, diisopropyl adipate and cetyl octanoate.
  • Suitable fatty alcohols and acids include those compounds having from 10 to 20 carbon atoms. Especially preferred are such compounds such as cetyl, myristyl, palmitic and stearyl alcohols and acids.
  • polyols which may serve as emollients are linear and branched chain alkyl polyhydroxyl compounds.
  • propylene glycol, sorbitol and glycerin are preferred.
  • polymeric polyols such as poly-propylene glycol and polyethylene glycol.
  • Butylene and propylene glycol are also especially preferred as penetration enhancers.
  • Exemplary hydrocarbons which may serve as emollients are those having hydrocarbon chains anywhere from 12 to 30 carton atoms. Specific examples include mineral oil, petroleum jelly, squalene and isoparaff ⁇ ns.
  • compositions of the present invention comprise thickeners.
  • a thickener will usually be present in amounts anywhere from 0.1 to 20% by weight, preferably from about 0.5% to 10% by weight of the composition.
  • Exemplary thickeners are cross-linked polyacrylate materials available under the trademark CARBOPOL® from the B. F. Goodrich Co. Gums may be employed such as xanthan, carrageenan, gelatin, karaya, pectin and locust beans gum. Under certain circumstances the thickening function may be accomplished by a material also serving as a silicone or emollient. For instance; silicone gums in excess of 10 centistokes and esters such as glycerol stearate have dual functionality.
  • Powders may be incorporated into the cosmetic composition of the invention.
  • These powders include chalk, talc, kaolin, starch, smectite clays, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, aluminum starch octenyl succinate and mixtures thereof.
  • adjunct minor components may also be incorporated into the cosmetic compositions. These ingredients may include coloring agents, opacifiers and perfumes. Amounts of these other adjunct minor components may range anywhere from 0.001% up to 20% by weight of the composition.
  • composition of the invention may be used for topical application to human skin, as an agent for conditioning, moisturizing and smoothing the skin, increasing the flexibility and elasticity and preventing or reducing the appearance of wrinkled, lined or aged skin.
  • Formulations of the present invention offer a response to the loss of skin tone and promotes benefits to effectively boost hydration and firmness of the surface layer of the skin, all while working to repair the underlying layers of the skin with antioxidants and other beneficial ingredients to help diminish the appearance of fine lines and wrinkles and to restore visible tone and elasticity.
  • such anti-oxidants are specifically directed to inhibit arNOX.
  • a small quantity of the composition comprised of from about 1 to 1000 ml of active agent, is applied to the skin.
  • a quantity of composition comprising from about 1 to 100 ml of active agent is applied to the skin. This process may be repeated several times daily for any period of time. Preferably, the composition is applied to the skin once in the morning and once in the evening.
  • the topical skin care composition of the invention can be formulated as a lotion, a cream, a gel or the like.
  • the composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer.
  • a lotion or a cream can be packaged in a bottle or a roll-ball applicator, or a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation.
  • the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar.
  • the invention accordingly also provides a closed container containing a cosmetically acceptable composition as herein defined.
  • the following examples are offered by way of illustration and not by way of limitation.
  • N. tazetta may have arNOX inhibitory agents
  • bulbs of paper white ⁇ Narcissus tazetta) narcissus were obtained from a commercial provider (Brent and Becky's Bulbs, Gloucester, VA).
  • Water and ethanolic extracts were prepared which inhibited arNOX activity and augmented the inhibition when combined with Narcissus tazetta powder (Xian Aojing Science and Technology Developing CO., LTD, Xian, CN) of low activity.
  • Narcissus tazetta powder Xian Aojing Science and Technology Developing CO., LTD, Xian, CN
  • Augmentation of the powder derived from N tazetta bulbs with SHAM Sigma- Aldrich, St. Louis, MO is shown in Figure Ia.
  • SHAM a known inhibitor of the alternative oxidase activity of plants, was tested for inhibition of arNOX activity and greater than 90% inhibition of arNOX activity of saliva from at 72 y male was obtained at a concentration of 1 mg/ml (Figure 7). SHAM was also found to augment the inhibition of arNOX activity of partially active Narcissus tazetta powder ( Figure 1).
  • the commercially available Narcissus tazetta powder (IBR-DORMIN®, Israel) does appear to contain low levels of a naturally-occurring hydroxamate possibly similar to SHAM but at levels much less than that found in extracts prepared from fresh Narcissus tazetta bulbs ( Figures 5 a and 5b).
  • salicylic acid (Naractin 2) was tested as an inhibitor of arNOX activity of saliva from a 72 y/o male and was found to inhibit arNOX activity (Figure 8). Salicylic acid also gave a red color when reacted with ferric iron similar to that given by the hydroxamates. Esters of salicylic acid and/or aspirin did not inhibit arNOX activity. An aqueous extract of willow bark, a natural source of salicylates, was tested and found to inhibit arNOX as well.
  • balsamifera ⁇ salicaceae dried bark + twigs USA-WI
  • P. balsamifera ⁇ salicaceae dried buds France
  • P. davidiana ⁇ salicaceae dried bark china
  • deltoides ⁇ salicaceae) dried bark USA-WI P. deltoides ⁇ salicaceae) fresh bark USA-WI, P. deltoides ⁇ salicaceae) fresh leaf USA-WI, P. deltoides var. deltoides ⁇ salicaceae) dried bark Canada (cult), P. deltoides var. occidentalis ⁇ salicaceae) dried bark Canada (cult), P. euphratica ⁇ salicaceae) dried bark china, P. euphratica ⁇ salicaceae) dried buds turkey, P. grandidentata ⁇ salicaceae) dried bark USA-WI, P.
  • tacamahaca ⁇ salicaceae) dried bark USA-WI P. tomentosa ⁇ salicaceae) dried bark china, P. tomentosa ⁇ salicaceae) entire plant china, P. tomentosa ⁇ salicaceae) dried leaf china, P. tremula ⁇ salicaceae) dried bark Germany, P. tremula ⁇ salicaceae) dried leaf Switzerland, P. tremula (salicaceae) oven dried leaf Finland, P. tremula ⁇ salicaceae) fungus infected stem bark France, P. tremula ⁇ salicaceae) dried twig Finland, P.
  • tremuloides ⁇ salicaceae) dried bark USA P. tremuloides ⁇ salicaceae) dried bark USA-WI, P. tremuloides ⁇ salicaceae) young entire plant, P. tremuloides ⁇ salicaceae) freeze-dried internodes USA-AK, P. tremuloides ⁇ salicaceae) dried leaf USA-WI, P. tremuloides triploid ⁇ salicaceae) fresh leaf USA-WI, P. tremuloides triploid type ⁇ salicaceae) dried bark USA-WI, P. trichocarpa ⁇ salicaceae) dried bark USA-WA, P.
  • alba ⁇ salicaceae dried bark USA-UT, S. alba ⁇ salicaceae) oven dried leaf England, S. alba ⁇ salicaceae) oven dried leaf Finland(cult), S. alba cv. cardinalis ⁇ salicaceae) dried leaf England, S. alba sex female ⁇ salicaceae) dried bark Germany, S. alba sex male ⁇ salicaceae) dried bark Germany, S. alba x s. babylonica (s. sepula ⁇ salicaceae) oven dried leaf England, S. alba x s.fragilis ⁇ s. russellia ⁇ salicaceae) oven dried leaf England, S.
  • alba x s. pentadra ⁇ s.ehrhardt ⁇ salicaceae) oven dried leaf England S. alba x S. babylonica ⁇ salicaceae) entire plant USSR, S. americana ⁇ salicaceae) dried leaf England, S. arctica ⁇ salicaceae) dried leaf Iceland, S. aurita ⁇ salicaceae) dried bark Germany, S. aurita ⁇ salicaceae) oven dried leaf Finland, S. aurita sex female ⁇ salicaceae) dried bark Germany, S. babylonica ⁇ salicaceae) dried leaf India, S. babylonica ⁇ salicaceae) oven dried leaf England, S.
  • caprea sex male ⁇ salicaceae) dried bark Germany S. caprea var. lanata ⁇ salicaceae) dried leaf England
  • S. caprea x s. viminalis s. serican ⁇ salicaceae) oven dried leaf England
  • S. chaenomeloides salicaceae dried leaf Japan
  • S. cinerea salicaceae
  • S. cinerea ⁇ salicaceae dried bark Switzerland
  • S. cinerea ⁇ salicaceae) oven dried flowers Finland S.
  • phylicifolia (salicaceae) dried twig Finland, S. phylicifolia x S. myrsinifolia (salicaceae) oven dried leaf Finland, S. purpurea (salicaceae) dried bark, S. purpurea (salicaceae) dried bark Germany, S. purpurea (salicaceae) dried bark Switzerland, S. purpurea (salicaceae) dried leaf Germany, S. purpurea (salicaceae) dried leaf Germany(cult), S. purpurea (salicaceae) dried leaf Switzerland, S. purpurea (salicaceae) fresh leaf, S.
  • purpurea (salicaceae) fresh leaf England, S. purpurea (salicaceae) frozen leaf, S. purpurea (salicaceae) oven dried leaf England, S. purpurea sex female (salicaceae) dried bark Germany, S. purpurea sex female (salicaceae) dried leaf Germany, S. purpurea sex male (salicaceae) dried bark Germany, S. purpurea var. goldstones (salicaceae) dried leaf England, S. purpurea x s.triandra (s. leiophyl (salicaceae) oven dried leaf England, S.
  • tetrasperma (salicaceae) dried stem bark Thailand, S. tremuloides ⁇ salicaceae) dried bark USA, S. triandra (salicaceae) dried bark Germany, S. triandra ⁇ salicaceae) oven dried leaf England, S. triandra cv. black maul ⁇ salicaceae) dried leaf England, S. triandra sex female ⁇ salicaceae) dried bark Germany, S. triandra sex male ⁇ salicaceae) dried bark Germany, S. triandra x. s. viminalls ⁇ s. hippopha ⁇ salicaceae) oven dried leaf England, S.
  • viminalis ⁇ salicaceae dried bark Germany, S. viminalis ⁇ salicaceae) dried leaf England, S. viminalis ⁇ salicaceae) oven dried leaf England, S. viminalis ⁇ salicaceae) oven dried leaf Finland(cult), S. viminalis ⁇ salicaceae) dried twig Finland(cult), S. viminalis cv. aquatica ⁇ salicaceae) oven dried twig Finland(cult), S.
  • Buffy coats a mixture of lymphocytes and platelets. Such buffy coats are commercially available from, for example, Rockland Immunochemicals (Gilbertsville, PA). The blood samples were maintained at 4 0 C prior to collection and assay. Ca. 10 7 cells were added to each assay. Cell numbers were determined using a hemocytometer.
  • the assay consists of 150 ⁇ l serum or 40 ⁇ l buffy coats in PBSG buffer (8.06 g NaCl, 0.2 g KCl, 0.18 g Na 2 HPO 4 , 0.26 g KH 2 PO 4 , 0.13 g CaCl 2 , 0.1 g MgCl 2 1.35 g glucose dissolved in 1000 ml deionized water, adjusted to pH 7.4, filtered and stored at 4 0 C) Rates were determined using an SLM Aminco DW-2000 spectrophotometer (Milton Roy, Rochester, NY, USA) in the dual wave length mode of operation with continuous measurements over 1 min every 1.5 min. After 45 min, test compounds were added and the reaction was continued for 45 min. After 45 min. a millimolar extinction coefficient of 19.1 cm "1 was used for reduced ferri cytochrome c. The results of the test compounds are provided in Table 1. Extracts were made of the compounds in water unless otherwise indicated.
  • Table 1 provides the results of some arNOX inhibition experiments.
  • Subjects were clinically graded on the right and left sides of the face for objective irritation parameters (erythema, edema, scaling) and subjective irritation parameters (burning, stinging, itching, tightness, tingling).
  • Skin luminance measurements were made in triplicate using a Chroma Meter CR400 (Konica-Minolta, Japan) skin luminance analyzer and were taken on pigmented lesions (selected by the investigator) on the right and left sides of the face to instrumentally assess changes in skin color/tone. An additional Skin luminance measurement was taken on a non-pigmented (normal) area on one side of the face.
  • Chroma Meter CR400 Konica-Minolta, Japan
  • a single visco-elasticity measurement was taken using the Cutometer ® SEM 575 (Courage + Khazaka, Germany) visco-elasticity meter. Measurements were taken on the center of each subject's right and left cheeks in order to assess the visco-elastic properties of the skin.
  • test material 1 arNOX Control Gel A w/Schizandra (non-encapsulated), TV. tazetta extract and Salicin (green label) JZ- 91-39 and test material 3.
  • Table 2 provides a summary of the demographic information (age, ethnicity, and Fitzpatrick skin classification) for all subjects. For ethnicity and Fitzpatrick skin type, the number of subjects in each category is listed with the percentage of the subject population in parentheses. Ethnicity information was obtained from each subject's Eligibility and Health Questionnaire.
  • the Fitzpatrick Skin Classification is based on the skin's unprotected response to the first 30-45 minutes of sun exposure after a winter season without sun exposure.
  • the categories of the skin types are as follows:
  • Type I always burns easily; never tans;
  • Type II always burns easily; tans minimally;
  • Type III Burns moderately; tans gradually; Type I V. Burns minimally; always tans well; Type V.Rarely bums; tans profusely; Type VI.Never burns; deeply pigmented;
  • Fitzpatrick reported an alternative classification system that is useful in assessing the degree of perioral and periorbital (periocular) wrinkles (rhytidosis): Class I - Fine wrinkles; Class II - Fine-to-moderately deep wrinkles and moderate number of wrinkle lines;
  • Skin surface hydration measurements were taken using the Corneometer CM 825 (Courage + Khazaka, Germany) hydration analyzer. Measurements were made in triplicate and were taken on the lower center of the left and right cheeks in order to quantify the moisture content of the stratum corneum.
  • the measuring principle of the Corneometer is based on capacitance measurement of a dielectric medium. Any change in the dielectric constant due to skin surface hydration variation alters the capacitance of a precision measuring capacitor. These measurements can detect very slightest changes in the hydration level of the skin with very high reproducibility. Readings are directly proportional to the skin's electrical capacitance and measurements increase as the skin becomes more hydrated.
  • Chroma Meter CR400 Konica-Minolta, Japan
  • the Chroma Meter instrumentally (and objectively) assesses changes in skin color/tone.
  • An additional Chroma Meter measurement was taken on a non-pi gmented (normal) area on one side of the face.
  • the Chroma Meter is a sensitive colorimeter that allows the setting and calibration of color-difference target colors.
  • the Chroma Meter has a detachable head for easy and independent analysis of selected areas. The following values were recorded:
  • L* Describes the relative brightness on a gray scale from black to white; values increase as the skin becomes brighter and lighter
  • a* Describes the color hue ranging from red to green; values increase with improvements in skin vascularization, increased blood flow, and improved skin tone
  • b* Describes the color hue ranging from blue to yellow; values typically decrease with skin lightening
  • a single visco-elasticity measurement was taken using the Cutometer SEM 575 (Courage + Khazaka, Germany) visco-elasticity meter. Measurements were taken on the center of each subject's right and left cheeks in order to assess the visco-elastic properties of the skin.
  • the measuring principle is based on suction. Negative pressure is created in the device and the skin is drawn into the aperture of the probe. Inside the probe, the penetration depth is determined by a non-contact optical measuring system. The light intensity varies due to the penetration depth of the skin. The resistance of the skin to be sucked up by the negative pressure (firmness and its ability to return into its original position (elasticity) are displayed on the instrument as curves at the end of each measurement.
  • Three-hundred (300) mbar of negative pressure was applied and released through an 8-millimeter (mm) probe.
  • the movement of the skin into and out of the probe was recorded during the application and release of suction, and resiliency and extensibility were calculated.
  • Salicin yellow label
  • TL-90-58 contains glycerin
  • Moisturizers and make-up products may be applied after test material applications.
  • Subjects were provided with written usage instructions, a calendar of future visits, and a daily diary to record test material application times and comments.
  • Subjects returned to the clinic at Week 4 (Visit 2) and Week 8 (Visit 3), having washed their face and removed all make-up at least 30 minutes prior to each visit.
  • the daily diaries and test materials were returned to the clinic and checked for usage compliance; new diaries (and test materials, if needed) were distributed at Week 4.
  • Subjects received clinical grading and bio-instrumentation measurements (Chroma Meter, Corneometer and Cutometer) in accordance with the Baseline procedures.
  • Each subject also completed a Subject Skin Change Evaluation Questionnaire and a Subject Evaluation Questionnaire regarding test material attributes, tolerance, and improvements in skin condition on the right and left sides of the face.
  • Subjects were provided with written usage instructions, a calendar of future visits, and a daily diary to record test material application times and comments.
  • Subjects also completed a Subject Skin Change Evaluation Questionnaire and a Subject Evaluation Questionnaire regarding test material attributes, tolerance, and improvements in skin condition parameters on the right and left sides of the face.
  • ⁇ 0- Indicates a statistically significant (p ⁇ 0 05) decrease compared to Baseline ft Indicates a statistically significant (p > 0 05) increase compared to Baseline
  • ⁇ 0- Indicates a statistically significant (p ⁇ 0 05) decrease compared to Baseline ft Indicates a statistically significant (p > 0 05) increase compared to Baseline
  • ⁇ 0- Indicates a statistically significant (p ⁇ 0 05) decrease compared to Baseline
  • ⁇ Q" Indicates a statistically significant (p > 0 05) increase compared to Baseline
  • ⁇ 0- Indicates a statistically significant (p ⁇ 0 05) decrease compared to Baseline ft Indicates a statistically significant (p > 0 05) increase compared to Baseline
  • Table 5 provides comparisons of the average change from the baseline for the clinical grading and instrumentation studies.
  • Subjects were graded for erythema, edema, scaling, burning, stinging, itching, tightness, and tingling on the right and left side of the face.
  • Skin luminance was measured in triplicate using a skin luminance analyzer (Chroma Meter CR400, Konica-Minolta, Japan). Measurements were taken over pigmented lesions (selected by the Investigator) on the right and left sides of the face in order to instrumentally assess changes in skin color/tone. An additional skin luminance measurement was taken on a non-pi gmented (normal) area on one side of the face.
  • a single visco-elasticity measurement was taken using a Cutometer MPA 580 (Courage + Khazaka, Germany). The measurement was taken on the center of each subject's right and left cheeks in order to assess the visco-elastic properties of the skin.
  • test material 1 arNOX Control Gel A w/Schizandra (non-encapsulated), N.
  • test material 1 (arNOX Control Gel A w/Schizandra (non-encapsulated), Narcissus tazetta extract and Salicin (green label) JZ-91-39) and test material 2, (arNOX Control Gel A w/Schizandra (blue label) TL-90-59) were superior to control A, (arNOX Control Gel A (no label) AB-87-04A) and control B, (arNOX Control Gel B (red label) JZ-91-40 (contains glycerin)) at improving overall discoloration at Week 4.
  • test material 1 and 2 were superior to control B, (arNOX Control Gel B (red label) JZ-91-40 (contains glycerin)) at Week 8.
  • Test material 2 (arNOX Control Gel A w/Schizandra (blue label) TL-90-59), test material 3, (arNOX Control Gel B w/Schizandra (non-encapsulated), Narcissus tazetta extract and Salicin (yellow label) TL-90-58 (contains glycerin)), and test material 4, (arNOX Control Gel B w/Salicin (half yellow, half black label) KK-89-49 (contains glycerin)) were superior to control A, (arNOX Control Gel A (no label) AB-87-04A) and control B, (arNOX Control Gel B (red label) JZ-91-40 (contains glycerin)) at improving the appearance of at Week 8.

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Abstract

La présente invention concerne des agents destinés à séquestrer des facteurs de vieillissement de sérum, et des procédés d’utilisation de ceux-ci. Plus particulièrement, l’invention concerne des agents appelés ici « naractin » afin de désigner l’un quelconque des nombreux inhibiteurs arNOX naturels présents dans la poudre de N. tazetta ou capables d’élever le niveau d’inhibition de la poudre de N. tazetta à un niveau comparable à celui des extraits de N. tazetta frais. L’invention concerne également des procédés d’utilisation de « naractins » destinés à empêcher ou à traiter des troubles et des complications de troubles résultant de lésions cellulaires provoquées par un isoforme lié au vieillissement de l’oxydase NADH (arNOX). Dans un mode de réalisation exemplaire, les agents de la présente invention comprennent au moins un naractin naturel. De tels naractins naturels sont également capables d’augmenter l’effet anti-arNOX d’autres agents d’inhibition d’arNOX naturels.
PCT/US2008/058683 2008-03-28 2008-03-28 Compositions comprenant des inhibiteurs d’arnox pour l’inhibition d’espèces d’oxygène réactif WO2009120214A1 (fr)

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CA2719833A CA2719833A1 (fr) 2008-03-28 2008-03-28 Compositions comprenant des inhibiteurs d'arnox pour l'inhibition d'especes d'oxygene reactif
EA201001558A EA201001558A1 (ru) 2008-03-28 2008-03-28 КОМПОЗИЦИИ, СОДЕРЖАЩИЕ anr NOX-ИНГИБИТОРЫ ДЛЯ ПОДАВЛЕНИЯ АКТИВНЫХ ФОРМ КИСЛОРОДА
JP2011501769A JP2011515466A (ja) 2008-03-28 2008-03-28 反応性酸素種の阻害のためのａｒｎｏｘ阻害物質を含む組成物
EP08744616A EP2280714A1 (fr) 2008-03-28 2008-03-28 Compositions comprenant des inhibiteurs d arnox pour l inhibition d espèces d oxygène réactif
PCT/US2008/058683 WO2009120214A1 (fr) 2008-03-28 2008-03-28 Compositions comprenant des inhibiteurs d’arnox pour l’inhibition d’espèces d’oxygène réactif
AU2008353441A AU2008353441A1 (en) 2008-03-28 2008-03-28 Compositions comprising arnox-inhibitors for the inhibition of reactive oxygen species
KR1020107023951A KR20110000745A (ko) 2008-03-28 2008-03-28 활성산소종의 억제를 위한 ａｒＮＯＸ-억제제를 포함하는 조성물
MX2010010668A MX2010010668A (es) 2008-03-28 2008-03-28 Composiciones que comprenden inhibidores de nadh oxidasa relacionada con el envejecimiento para la inhibicion de especies reactivas de oxigeno.
NZ588182A NZ588182A (en) 2008-03-28 2008-03-28 Compositions comprising arnox-inhibitors for the inhibition of reactive oxygen species
CN2008801290521A CN102014930A (zh) 2008-03-28 2008-03-28 用于抑制活性氧物质的包含arnox-抑制剂的组合物
IL208324A IL208324A0 (en) 2008-03-28 2010-09-21 Compositions comprising arnox-inhibitors for the inhibition of reactive oxygen species
ZA2010/07247A ZA201007247B (en) 2008-03-28 2010-10-11 Compositions comprising arnox-inhibitors for the inhibition of reactive oxygen species

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CN102641223A (zh) * 2011-02-18 2012-08-22 株式会社爱茉莉太平洋 用于改善肤色或增加皮肤弹性的化妆品组合物
CN103561718A (zh) * 2010-12-30 2014-02-05 雅芳产品公司 皮肤中动力蛋白的调节
JP2014505026A (ja) * 2010-12-03 2014-02-27 アラーガン インコーポレイテッド 薬学的クリーム組成物および使用法
US9750682B2 (en) 2015-07-30 2017-09-05 Elc Management, Llc Methods and compositions for improving the appearance of skin
US10251832B2 (en) 2017-05-26 2019-04-09 Mary Kay Inc. Cosmetic compositions and methods
WO2021091284A3 (fr) * 2019-11-06 2021-07-01 한국생명공학연구원 Composition cosmétique destinée à prévenir le vieillissement de la peau et à réduire les rides cutanées, comprenant un extrait de viburnum stellato-tomentosum

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JP6912771B2 (ja) * 2017-04-11 2021-08-04 学校法人立命館 脂漏性角化症の予防又は改善剤
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JP2014505026A (ja) * 2010-12-03 2014-02-27 アラーガン インコーポレイテッド 薬学的クリーム組成物および使用法
CN103561718A (zh) * 2010-12-30 2014-02-05 雅芳产品公司 皮肤中动力蛋白的调节
CN102440927A (zh) * 2011-02-10 2012-05-09 漳州市格莱雅化妆品有限公司 一种水仙花美白爽肤水化妆品
CN102641223A (zh) * 2011-02-18 2012-08-22 株式会社爱茉莉太平洋 用于改善肤色或增加皮肤弹性的化妆品组合物
US9750682B2 (en) 2015-07-30 2017-09-05 Elc Management, Llc Methods and compositions for improving the appearance of skin
US10251832B2 (en) 2017-05-26 2019-04-09 Mary Kay Inc. Cosmetic compositions and methods
US10881603B2 (en) 2017-05-26 2021-01-05 Mary Kay Inc. Cosmetic compositions and methods
US11534391B2 (en) 2017-05-26 2022-12-27 Mary Kay Inc. Cosmetic compositions and methods
US12233151B2 (en) 2017-05-26 2025-02-25 Mary Kay Inc. Cosmetic compositions and methods
WO2021091284A3 (fr) * 2019-11-06 2021-07-01 한국생명공학연구원 Composition cosmétique destinée à prévenir le vieillissement de la peau et à réduire les rides cutanées, comprenant un extrait de viburnum stellato-tomentosum

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