WO2013169291A2 - Method for inducing udp-glucuronosyltransferase activity using pterostilbene - Google Patents

Method for inducing udp-glucuronosyltransferase activity using pterostilbene Download PDF

Info

Publication number
WO2013169291A2
WO2013169291A2 PCT/US2012/064993 US2012064993W WO2013169291A2 WO 2013169291 A2 WO2013169291 A2 WO 2013169291A2 US 2012064993 W US2012064993 W US 2012064993W WO 2013169291 A2 WO2013169291 A2 WO 2013169291A2
Authority
WO
WIPO (PCT)
Prior art keywords
pterostilbene
cancer
ugt
effective amount
therapeutically effective
Prior art date
Application number
PCT/US2012/064993
Other languages
English (en)
French (fr)
Other versions
WO2013169291A3 (en
Inventor
Jeremy BARTOS
Ryan DELLINGER
Original Assignee
ChromaDex Inc.
The Regents Of The University Of California
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 CN201280074486.2A priority Critical patent/CN104768543A/zh
Priority to EP12876092.3A priority patent/EP2846785A4/en
Priority to CA2872623A priority patent/CA2872623A1/en
Priority to AU2012379655A priority patent/AU2012379655B2/en
Priority to KR20147034337A priority patent/KR20150027081A/ko
Priority to JP2015511433A priority patent/JP2015523963A/ja
Application filed by ChromaDex Inc., The Regents Of The University Of California filed Critical ChromaDex Inc.
Priority to BR112014027646A priority patent/BR112014027646A2/pt
Priority to MX2014013503A priority patent/MX2014013503A/es
Priority to IN9990DEN2014 priority patent/IN2014DN09990A/en
Publication of WO2013169291A2 publication Critical patent/WO2013169291A2/en
Priority to ZA2014/08893A priority patent/ZA201408893B/en
Publication of WO2013169291A3 publication Critical patent/WO2013169291A3/en

Links

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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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

  • a process for increasing or inducing UDP-glucuronosyltransferase (UGT) activity using an effective amount of pterostilbene is described in connection with methods of treatment for cellular proliferative disorders.
  • Pharmaceutical and nutraceutical formulations containing pterostilbene suitable for administration to an individual for inducing UDP- glucuronosyltransferase (UGT) activity are described.
  • Phase II metabolism an endogenous or exogenous substrate is rendered more hydrophilic through the covalent attachment of an endogenous molecule.
  • Phase II is also referred to as conjugative metabolism, since conjugating moieties such as sulfonates, glucuronates, glutathiones, glycinates, acetates, and methylates, can be formed.
  • conjugating moieties such as sulfonates, glucuronates, glutathiones, glycinates, acetates, and methylates.
  • Phase II metabolism is used by the body to increase the hydrophilicity of the substrate molecule, which facilitates transport and elimination of the conjugate product.
  • Phase II glucuronidation reactions are catalyzed by the UDP- glucuronosyltransferase (UGT) family of enzymes.
  • the glucuronidation reaction consists of the transfer of the glucuronosyl group from uridine 5'-diphospho-glucuronic acid (UDP-GA) to substrate molecules that contain oxygen, nitrogen, sulfur or carboxyl functional groups.
  • UGT enzymes represent a highly responsive defense system against the mutagenicity of carcinogens and the toxicity of both xenobiotics and endogenous metabolic intermediates.
  • PPARs peroxisome proliferator-activated receptors
  • Glucuronidation plays a physiological role in the modulation of biologically active endogenous hormones and metabolic intermediates.
  • One important endogenous UGT substrate is bilirubin, the metabolism of which is tightly controlled by UGT1A1 , thus forming the elimination product bilirubin diglucuronide.
  • Another isoform, UGT2B4 is known to be the major bile acid conjugating UGT enzyme in human liver, catalyzing glucuronidation of hyodeoxycholic acid.
  • UGT2B4 is known to be the major bile acid conjugating UGT enzyme in human liver, catalyzing glucuronidation of hyodeoxycholic acid.
  • PPARs serve an important role in the regulation of UGTs (Barbier, et al, J. Biol. Chem. (2003) 278:32852-32860).
  • the PPAR nuclear receptor network represents a central determinant of cellular energy balance.
  • RXR retinoid X receptor
  • PPAR forms a ligand-activated nuclear receptor transcription factor that is capable of integrating the expression of a wide spectrum of target genes (including UGTs) involved in cellular lipid metabolism, energy homeostasis, and inflammation.
  • PPAR-alpha isoform expression is most prominent in the liver, kidney, and heart where it is engaged in the regulation of fatty acid oxidation.
  • PPAR-alpha can also mediate induction of biotransformation enzymes.
  • fatty acids represent a major source of cellular energy and are important physiological activators of PPAR-alpha.
  • the aforementioned PPAR-RXR heterodimer in association with other co-activators, binds to DNA sequences called peroxisome proliferator response elements (PPREs) in the regulatory region of a target gene, initiating transcription and translation of enzymes, such as UGTs, and the like.
  • PPREs peroxisome proliferator response elements
  • UGT inducers in humans are known, such as clofibrate, which is a PPAR-alpha agonist (Barbier, loc. cit.).
  • UGT1A1 is a PPAR-alpha target gene, and exposure to certain inducers such as PPAR-alpha agonists can increase mRNA expression of this UGT in the liver (Shelby, et al, Drug Metab. and Disposition (2006) 34:1772-1778).
  • UGTs have been shown to glucuronidate and inactivate 12-hydroxyeicosatetraenoic acid, or 12(S)-HETE ("12-HETE").
  • 12-HETE 12-hydroxyeicosatetraenoic acid
  • AA arachidonic acid
  • LOX lipoxygenases
  • 5 -LOX is responsible for the production of leukotrienes and 5-HETE, while 12-LOX yields 12-HETE.
  • lipoxygenase converts AA to the unstable hydroperoxy-eicosatetraenoic acid (HPETE), which is then hydrolyzed by peroxidase into HETE.
  • HPETE hydroperoxy-eicosatetraenoic acid
  • 5-LOX and 12-LOX metabolites promote carcinogenesis through resistance to apoptosis as well as increased proliferation, angiogenesis and cell migration.
  • Both 5-LOX and 12-LOX which are largely absent from normal epithelia, are often constitutively expressed in various epithelial cancers.
  • 12-LOX mR A Elevated levels of 12-LOX mR A has also been linked to late stage cancer and poor prognosis. Additionally, 12-LOX has been demonstrated to play a direct role in skin carcinogenesis in mouse models, and 12-HETE has been detected at elevated levels in skin tumors compared to normal skin in mice. Specifically, levels of 12-HETE were 50-fold higher in papillomas and squamous cell carcinomas than in normal skin from the same mouse (Virmani, J., et ah, Cancer Lett. (2001) 162(2): 161-165; Krieg, P., et ah, Mol. Carcinog. (1995) 14(2): 118-129).
  • an enzyme inducer or agonist that can activate or induce expression of UGTs by administration of said inducer to an individual, animal or human. Further, it is expected that an enzyme inducer or agonist that can activate or induce expression of UGTs would also reduce levels of 12-HETE, which would serve as a useful contribution to the art.
  • a method of treating an individual for a cellular proliferative disorder comprising administering to the individual in need of such treatment a therapeutically effective amount of the compound pterostilbene wherein UDP-glucuronosyltransferase (UGT) activity is increased.
  • UDP-glucuronosyltransferase UDP-glucuronosyltransferase
  • a method of preventing or inhibiting the UV- induced loss of UDP-glucuronosyltransferase (UGT) activity in an individual comprising administering to the individual in need of such treatment a therapeutically effective amount of the compound pterostilbene wherein UDP-glucuronosyltransferase (UGT) activity is increased.
  • UDP-glucuronosyltransferase UDP-glucuronosyltransferase
  • 12-HETE levels in pre-cancerous actinic keratoses (AK) lesions can be reduced by administration of pterostilbene.
  • 12-LOX expression levels in pre-cancerous, proliferating cells, or malignant cells may be reduced by administration of pterostilbene.
  • FIG. 1 describes a proposed metabolic pathway in an embodiment of the present invention, in which UGTs can inactivate 12-HETE.
  • FIG. 2 depicts UV-B downregulation of UGTs in normal human melanocytes exposed to a single dose of UV-B at 25 mJ/cm 2 .
  • Solid bar untreated cells; diagonally-line bars: UV-B treated cells at 4 hr and 24 hr, left to right, respectively.
  • FIG. 3 depicts in one embodiment UV-B induced loss of UGT2 isoforms in normal human melanocytes, and prevention of said loss with pterostilbene (Ptero).
  • UV-B dose 25 mJ/cm 2 .
  • Solid bar untreated cells; diagonally-line bar: UV-B treated cells; vertically-lined bar: UV-B treated and pterostilbene treated ( ⁇ ).
  • FIG. 4 depicts in another embodiment UGT mRNA expression in primary culture normal human keratinocytes by RT-PCR analysis of total mRNA for UGT isoform family members (GAPDH as positive control).
  • FIG. 5 depicts in another embodiment UV-B induced loss of UGT2B17 isoform in normal human keratinocytes, and prevention of said loss with pterostilbene.
  • UV-B dose 25 mJ/cm 2 .
  • Solid bar untreated cells; diagonally-line bar: UV-B treated cells; vertically-lined bar: UV-B treated and pterostilbene treated ( ⁇ ).
  • FIG. 6 depicts in another embodiment 12-LOX expression by Western blot after treatment of SKmel28 human melanoma cells with pterostilbene (Ptero) or resveratrol (Res) at 50 ⁇ (B-actin as loading control).
  • a safe and effective dietary supplement has been provided containing pterostilbene, which can be administered in a therapeutically effective amount to an individual for treatment of a cellular proliferative disorder.
  • a method of treating an individual for a cellular proliferative disorder comprises the step of administering to the individual in need of such treatment a therapeutically effective amount of the compound pterostilbene wherein UDP-glucuronosyltransferase (UGT) activity is increased.
  • UDP-glucuronosyltransferase (UGT) activity is increased.
  • said safe and effective dietary supplement containing pterostilbene will cause regression of actinic keratoses (AKs) and other precancerous changes associated with UV-induced photodamage of the skin. Furthermore, said dietary supplement containing pterostilbene will be used for the treatment, suppression and/or prevention of non- melanoma skin cancers (NMSCs).
  • NMSCs non- melanoma skin cancers
  • a method of inhibiting the loss of UDP- glucuronosyltransferase (UGT) activity an individual afflicted with a cellular proliferative disorder comprises the step of administering to the individual in need of such treatment a therapeutically effective amount of the compound pterostilbene wherein UDP- glucuronosyltransferase (UGT) activity is increased.
  • UDP-glucuronosyltransferases catalyze the transfer of glucuronic acid from a high-energy cofactor, UDP-glucuronic acid, to a xenobiotic, drug, or endogenous substrate containing an available reactive or nucleophilic center such as a hydroxyl, carboxyl, amino, or thiol group.
  • the UGTs are Phase II biotransformation enzymes predominantly expressed in liver and intestine, and are membrane-bound enzymes localized on the luminal surface of the endoplasmic reticulum. Relative to the parent substrate, the end-products of glucuronidation are typically more polar and better suited for excretion and elimination through the urine or bile.
  • Endogenous UGT substrates include bilirubin, neutral steroids, bile acids, fatty acids, and retinoids.
  • Xenobiotic UGT substrates range from environmental toxicants such as benzo[a]pyrene to common pharmaceuticals such as acetaminophen and other NSAIDs.
  • Individual UGT isoforms display distinctive patterns of substrate specificity and inducible regulation. Different UGTs are expressed in a species- and tissue-specific manner. The two major UGT gene families are UGT1 and UGT2.
  • PPARs are known to be involved in the regulation of UGTs.
  • the UGTs are targets of PPAR-alpha, as opposed to PPAR-gamma.
  • Resveratrol a known PPAR- gamma activator, has shown some induction of UGTs, but is not an activator of PPAR-alpha.
  • pterostilbene activated PPAR-alpha, in a manner similar to ciprofibrate (Rimando, et al., J. Agric. Food Chem. (2005) 53:3403-3407).
  • Pterostilbene is not thought to be an activator of PPAR-gamma. This sub-type selectivity is thought to be advantageous in the present approach to activate or induce expression of UGTs using pterostilbene.
  • UGTs have been shown to glucuronidate and inactivate 12-hydroxyeicosatetraenoic acid (12-HETE), which is produced by the enzyme 12-LOX during the process of UV -induced skin carcinogenesis, for example. It has been discovered that pterostilbene, and nutraceutical formulations thereof, can induce UGT activity, thus reducing 12-HETE levels in the skin.
  • 12-HETE 12-hydroxyeicosatetraenoic acid
  • Figure 1 shows a model of arachidonic acid (AA) metabolism and UGT conjugative metabolism. Cyclooxygenses can also play a role in inflammatory processes, but are not discussed herein. Overall, Figure 1 shows the proposed role of AA metabolism in UV-induced skin cancer progression (or other types of UV-induced skin damage, e.g., sunburn), including production and metabolism of 12-HETE.
  • AA arachidonic acid
  • Non-melanoma skin cancer is by far the most common cancer that plagues man. The incidence of NMSC is nearly as great as all other forms of cancer combined. For 2007, the American Cancer Society estimated that more than one million new cases of non-melanoma skin cancers were diagnosed in the United States, and that there were approximately 2,700 deaths related to non-melanoma skin cancer. However, these estimates are low given that squamous cell carcinoma and basal cell carcinoma of the skin are not required to be reported and, thus, the number of actual cases annually is probably over three million. There are two primary types of NMSC: basal cell carcinoma accounts for approximately 80% of the cases, while squamous cell carcinoma accounts for approximately 20%.
  • NMSC neuronal senor
  • NMSC NMSC
  • squamous cell carcinoma NMSC
  • sun exposure with resultant photocarcinogenesis.
  • Treatment for NMSC is surgical, often resulting in scarring and other morbidities.
  • Actinic keratoses AKs
  • NMSC cutaneous neoplasms
  • UV light from tanning booths or arc welding, x-irradiation, or exposure to certain chemicals.
  • AKs are extremely common lesions and are present in more than 10 million Americans.
  • the yearly rate of progression of an AK in an average-risk person in Australia is between 8 and 24 per 10,000.
  • High-risk individuals (those with multiple AKs) have progression rates as high as 12-30 percent over 3 years.
  • Two percent of squamous cell cancers originating in AKs may metastasize, and 7 percent recur locally.
  • Actinic keratoses are treated most commonly with liquid nitrogen or a topical chemotherapeutic, such as, for example, 5-fluorouracil. Less commonly they are treated with other topical agents (diclofenac and imiquimod), photodynamic therapy, chemical peels or non-fractionated or fractionated ablative laser resurfacing.
  • actinic keratosis is the proliferative disorder that produces AKs.
  • An ideal chemopreventive agent could achieve regression of precancerous changes, prevent development of NMSC and minimize ultraviolet light associated damage with minimal or no side effects.
  • topical agents that can remove actinic keratoses but they generally result in significant inflammation at the treatment site. A novel approach is required.
  • Human skin comprises a top epidermal layer (epidermis) which rests on a lower dermal layer (dermis).
  • the epidermis is made up primarily of keratinocytes, which develop at the bottom, move toward the top, and are constantly replaced. As old dead cells are shed, they are replaced, so this layer is constantly renewing itself.
  • the epidermis also contains melanocytes, located generally near the bottom of the layer, which produce the pigment melanin, contributing to skin color, and also providing UV-protection.
  • the epidermis also contains dendritic (Langerhans) cells, which are involved in the immune system, and basal cells found at the bottom of the layer.
  • the epidermis also includes squamous cells.
  • the epidermal and dermal layers also contain stem cells and hair follicles. In mammals, melanocytes are also distributed in the brain, eye, ear, and heart, among other tissues.
  • the skin cells as described are susceptible to UV light-induced damage, DNA damage, and carcinogenesis.
  • Pterostilbene (3,5-dimethoxy-4'-hydroxy-trans-stilbene) is an orally bioavailable compound with a half life t of about 105 minutes in blood.
  • resveratrol has poor bioavailability, and is readily metabolized by UGTs leading to a much shorter half life (t 2 about 14 minutes in blood), which hinders its effectiveness as a chemopreventive agent.
  • Resveratrol has also been shown to induce UGT activity (Chow, H.H., et al, "Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study,” Cancer Prev. Res. (Phila. Pa.), (2010) 3(9): 1168-75).
  • UGT activity Chow, H.H., et al, "Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study," Cancer Prev. Res. (Phila. Pa.), (2010) 3(9): 1168-75.
  • Resveratrol is well tolerated in humans, but is readily metabolized (by the UGTs ironically) leading to a short half-life which hinders its effectiveness as a chemopreventative agent.
  • Pterostilbene is found in grapes and berries. It is a naturally occurring dimethylated analog of resveratrol, but has a longer half-life most likely due to the methyl groups which may dramatically reduce its metabolism by UGTs (Hougee, S., et al, "Selective COX-2 inhibition by a Pterocarpus marsupium extract characterized by pterostilbene, and its activity in healthy human volunteers," Planta Med. (2005) 71(5): 387- 92).
  • Pterostilbene has been shown to be equally or significantly more potent than resveratrol in several biological assays in mice including inhibition of NF-KB, AP-1 and iNOS activation in mouse skin (Cichocki, M., et al., "Pterostilbene is equally potent as resveratrol in inhibiting 12-O-tetradecanoylphorbol- 13 -acetate activated NFkappaB, AP-1, COX-2, and iNOS in mouse epidermis," Mol. Nutr. Food Res. (2008) 52 Suppl 1 : S62-70).
  • a nutraceutical formulation comprising pterostilbene or a derivative thereof can be used to advantageously increase the activity of, or induce the in vivo expression of UDP-glucuronosyltransferases (UGTs).
  • UGTs UDP-glucuronosyltransferases
  • This up-regulation of UGTs can inhibit or prevent the loss of UGTs caused by certain factors, including down-regulation in response to UV radiation observed in human keratinocytes or melanocytes, for example. See Figure 1.
  • Useful therapeutic dosages of pterostilbene can range, but are not limited to, from about 5 mg to about 1000 mg in a human individual. Another suitable dose range is from about 20 mg to about 250 mg.
  • Pterostilbene may be formulated as a pharmaceutical or nutraceutical composition, including a pharmaceutically or nutraceutically acceptable carrier, respectively.
  • a suitable level of pterostilbene may range from about 0.1% by weight to about 10%> by weight, based on the total weight of the composition.
  • nutraceutical compositions of the present invention may be administered in combination with a nutraceutically acceptable carrier.
  • the active ingredients in such formulations may comprise from 1% by weight to 99% by weight, or alternatively, 0.1% by weight to 99.9% by weight.
  • Nutraceutically acceptable carrier means any carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the user.
  • Useful excipients include microcrystalline cellulose, magnesium stearate, calcium stearate, any acceptable sugar (e.g., mannitol, xylitol), and for cosmetic use an oil-base is preferred.
  • compositions of the present invention may be administered in combination with a pharmaceutically acceptable carrier.
  • the active ingredients in such formulations may comprise from 1% by weight to 99% by weight, or alternatively, 0.1% by weight to 99.9% by weight.
  • “Pharmaceutically acceptable carrier” means any carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the user.
  • Pterostilbene can be provided in daily dosages of from about 50 mg to about 250 mg, in a human patient, for example. Another suitable dosage range is from about 50 mg to about 150 mg daily. Another suitable dosage range is from about 50 mg to about 100 mg daily. A particularly suitable dosage is about 100 mg administered daily.
  • levels of 12-HETE in AK lesions can be determined to assess induction of expression of UGTs in an individual both prior to and after receiving pterostilbene supplementation.
  • the following is a general study design for a Phase II clinical trial to assess efficacy of pterostilbene to induce expression and/or increase activity of UGTs, and to decrease levels of 12-HETE and/or inhibit expression of 12-LOX, amongst other measurable endpoints.
  • the study provides the opportunity to evaluate a novel method for suppression or prevention of NMSC. It utilizes a variety of endpoints from analysis of molecular markers to standard clinical assessment to state of the art compositional imaging. This design allows for an economy of effort, testing the putative agent first clinically, with associated key endpoint biomarkers for which valuable validation data can be obtained.
  • Eligible subjects can receive pterostilbene orally at a dose in a range of about 50 mg to about 250 mg. In one embodiment a patient will receive 100 mg of pterostilbene orally, on a daily basis.
  • Pterostilbene can be provided in an appropriate nutraceutical formulation in combination with, or co-administered with, a nutraceutically acceptable carrier.
  • pterostilbene can be provided in an appropriate pharmaceutical formulation in combination with, or co-administered with, a pharmaceutically acceptable carrier.
  • Duration of therapy can be up to about 12 weeks. Subjects will be evaluated at 4, 8 and 12 weeks of the study therapy, and then post-treatment, at weeks 16 and 20 of the study.
  • Imaging of AK lesions can be carried out using wide-field functional imaging (WiFI) technology to measure changes in blood flow, fat and water content, for example, prior to and after pterostilbene supplementation.
  • Wide-field Functional Imaging is the integration of two wide-field imaging modalities: spatially modulated reflectance/fluorescence imaging (MI) and laser speckle imaging (LSI). WiFI can simultaneously measure tissue blood flow and biochemical composition (i.e. oxy- and deoxy- hemoglobin, water and lipid content) in turbid tissues.
  • MI spatially modulated reflectance/fluorescence imaging
  • LSI laser speckle imaging
  • An initial screening visit is to be performed for each patient, including, but not limited to, a dermatology review, i.e. complete skin exam of arms, limbs, and other skin areas for AKs and/or sun damage.
  • a dermatology review i.e. complete skin exam of arms, limbs, and other skin areas for AKs and/or sun damage.
  • the following tests can also be run: blood testing (CBC with differential), comprehensive metabolic panel, lipid panel, and urinalysis.
  • a skin biopsy site can be designated as pre-treatment AK (pre-AK). If biopsy results reveal no AK but atypical cell structures, the subject may continue treatment and be monitored.
  • pre-AK pre-treatment AK
  • the skin study area will be examined, photographed, and imaged. Specifically, AKs on bilateral forearm(s) of each patient are photographed and counted. Post-treatment biopsy specimens of suspected NMSCs and post-treatment AK sites (post-AK) are then collected and analyzed, along with blood and urine testing as above. [0060] In an embodiment, at 16 and 20 weeks post-treatment (or at some other scheduled time point before or after), the skin study area will be mapped, examined, photographed, and imaged, as above.
  • Arachidonic acid metabolite (12-HETE and PGE 2 ) levels will be determined from actinic keratoses pre-treatment and then compared to post treatment levels using liquid chromatography coupled to a triple quad mass spectrometer (LC/MS/MS) following established protocols. Assay requires tissue extraction, sonication, centrifugation and protein content determination to prepare samples followed by LC/MS/MS. It is expected that levels of 12-HETE and PGE 2 in AK will be significantly reduced after pterostilbene treatment or pterostilbene supplementation.
  • Protein levels of COX-2, 12-LOX, UGT and 15-PGDH will be measured semi- quantitatively by Western blot normalized to actin following established protocols. Changes in expression levels from AK following pterostilbene treatment will be compared to pre- treatment levels and reported as fold changes following densitometry. It is expected that COX-2 and 12-LOX expression will be significantly reduced after pterostilbene treatment. Conversely, it is expected that UGT and 15-PGDH protein levels will be significantly increased in AK following pterostilbene supplementation.
  • Secondary endpoints include PGE 2 (pg/mg protein) and enzyme protein levels of UGT, COX-2, 15-PDGH, and 12-LOX. Additional secondary endpoints include blood flow, fat and water content measured in AK lesions, number of original AK lesions, number of new AK lesions, and number of non-melanoma skin cancers (NMSCs).
  • PGE 2 pg/mg protein
  • enzyme protein levels of UGT COX-2
  • 15-PDGH 15-PDGH
  • 12-LOX 12-LOX
  • Additional secondary endpoints include blood flow, fat and water content measured in AK lesions, number of original AK lesions, number of new AK lesions, and number of non-melanoma skin cancers (NMSCs).
  • Suitable dosage forms include tablets, capsules, solutions, suspensions, powders, gums, and confectionaries.
  • Sublingual delivery systems include, but are not limited to, dissolvable tabs under and on the tongue, liquid drops, and beverages.
  • Edible films, hydrophilic polymers, oral dissolvable films or oral dissolvable strips can be used.
  • Other useful delivery systems comprise oral or nasal sprays or inhalers, and the like.
  • pterostilbene may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, pills, powders, granules or other suitable dosage forms.
  • the active agent may be combined with at least one excipient such as fillers, binders, humectants, disintegrating agents, solution retarders, absorption accelerators, wetting agents, absorbents, or lubricating agents.
  • excipients include magnesium stearate, calcium stearate, mannitol, xylitol, sweeteners, starch, carboxymethylcellulose, microcrystalline cellulose, silica, gelatin, silicon dioxide, and the like.
  • the compounds may be administered by any route, including but not limited to oral, sublingual, buccal, ocular, pulmonary, rectal, and parenteral administration, or as an oral or nasal spray (e.g. inhalation of nebulized vapors, droplets, or solid particles).
  • Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, intravaginal, intravesical (e.g., to the bladder), intradermal, transdermal, topical, or subcutaneous administration.
  • parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, intravaginal, intravesical (e.g., to the bladder), intradermal, transdermal, topical, or subcutaneous administration.
  • the instillation of pterostilbene in the body of the patient in a controlled formulation with systemic or local release of the drug to occur at a later time.
  • the drug may
  • the treatment may be carried out for as long a period as necessary, either in a single, uninterrupted session, or in discrete sessions.
  • the treating physician will know how to increase, decrease, or interrupt treatment based on patient response.
  • treatment is carried out for from about four to about twelve weeks.
  • the treatment schedule may be repeated as required.
  • Pterostilbene, and nutraceutical formulations thereof is believed to be effective against a range of cancers and tumor types, including skin cancers, including, but not limited to basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Kaposi's sarcoma, Merkel cell carcinoma, cutaneous lymphoma, moles, dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and psoriasis.
  • skin cancers including, but not limited to basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Kaposi's sarcoma, Merkel cell carcinoma, cutaneous lymphoma, moles, dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and psoriasis.
  • Skins cancers may be solid tumors that may or may not be metastatic.
  • tumor cell includes a cell afflicted by any one of the above identified disorders.
  • Other cellular proliferative disorders are susceptible to treatment by the pterostilbene formulations described herein, including, but not limited to, cancers selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, colorectal cancer, lung cancer, renal cancer, liver cancer, brain cancer, stomach cancer, bronchial cancer, pancreatic cancer, bladder cancer, and bone cancer.
  • cancers selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, colorectal cancer, lung cancer, renal cancer, liver cancer, brain cancer, stomach cancer, bronchial cancer, pancreatic cancer, bladder cancer, and bone cancer.
  • Pterostilbene, and nutraceutical formulations thereof is also believed to be useful in the treatment of non-cancer cellular proliferative disorders, that is cellular proliferative disorders which are characterized by benign indications. Such disorders may also be known as cytoproliferative or hyperproliferative in that cells are made by the body at an atypically elevated rate.
  • Non-cancer cellular proliferative disorders believed treatable by pterostilbene formulation include actinic keratoses (AKs) and other pre-cancerous lesions.
  • UV-B irradiation was performed as previously described (Liu, F., et al, "MiTF links Erkl/2 kinase and p21 CIP1/WAF1 activation after UVC radiation in normal human melanocytes and melanoma cells, " Mol. Cancer (2010) 9: 214). Cells were grown to about 70% confluence and media was removed completely for UV-B radiation treatment. UVB irradiation was performed in a Stratalinker UV crosslinker apparatus (Stratagene, La Jolla, California) with peak wavelength at 312 nm. The UV intensity was measured by a radiometer with proper probes. The culture media was replaced immediately after radiation treatment and cells were returned to a 37°C incubator to recover. For chronic exposures, this process was repeated every hour for a total of five exposures. Times indicated herein always reflect time following first exposure.
  • UGT2B7, UGT2B10 and UGT2B15 were found to be expressed in human melanocytes isolated from de -identified neonatal foreskins. Further, no UGT expression was observed in 4 of 5 melanoma cell lines examined. This raises the intriguing possibility that loss of UGT expression is part of melanoma etiology.
  • UV-B could regulate UGT expression in melanocytes, once again melanocytes were isolated from de-identified neonatal foreskins and cultured. These cells were then exposed to a single dose of UV-B at 25 mJ/cm 2 , which is approx. equivalent to a sunburn dose.
  • NADPH dehydrogenase quinone 1 (NQOl) is used as a control since its expression did not change following UV-B exposure. This was the first demonstration that UGT expression can be regulated by UV-B exposure and is consistent with an increased risk of melanoma associated with acute UV exposure.
  • Keratinocytes are the predominant type of cell in the epidermis (about 95% of the cells in the epidermis). NMSC can arise from these cells.
  • UGT1A4, UGT1A6 and UGT2B17 were shown to be expressed in primary culture human keratinocytes (normal) isolated from neonatal foreskin. Bands of the expected sizes were excised and sequenced using standard methods to confirm their identities as the indicated UGT. This was the first characterization of UGT expression in human keratinocytes.
  • FIG. 4 shows UGT mRNA expression in primary culture human keratinocytes. RT-PCR analysis of total mRNA from human keratinocytes for the indicated UGT family members was performed. GAPDH primers were used as a positive control (+). No other UGT family member was detected.
  • pterostilbene substantially blocked 12- LOX activity in vitro, testing by known methods.
  • B-actin was used as a loading control. It was observed that pterostilbene inhibited 12-LOX expression better than resveratrol in vitro.
  • 12-LOX produces 12-HETE
  • reduction of 12-LOX expression by pterostilbene in proliferating or pre-cancerous cells will prevent or reduce 12-HETE formation and/or pterostilbene will be effective to restore 12-HETE to normal levels in damaged skin (both by inhibiting 12-LOX and by upregulating UGTs).
  • treatment of proliferating or pre-cancerous cells will result in regression or reversion of AKs (and optionally NMSCs).
  • a patient (or each member of a patient cohort) is treated with a daily dosage of 100 mg pterostilbene formulated in an acceptable nutraceutical carrier, administered orally as follows.
  • 100 mg pterostilbene and 150 mg micro crystalline cellulose are combined in a vegetable capsule.
  • identifying AKs (and optionally NMSCs) from a skin test area on the forearm of the patient (8 cm 2 ), and mapping, photographing, imaging, and taking biopsies of the lesions a clinical study is carried out as detailed above. After 12 weeks of study monitoring, it is expected that an individual human subject will exhibit regression of AKs identified in the skin test area.
  • a patient (or each member of a patient cohort) is treated with a daily dosage of 100 mg pterostilbene formulated in an acceptable nutraceutical carrier, administered orally.
  • a daily dosage of 100 mg pterostilbene formulated in an acceptable nutraceutical carrier administered orally.
  • a clinical study is carried out as detailed above. It is expected that in the course of the study over 12 weeks, UGT expression in the pre- cancerous tissue samples as a function of mR A or protein will be significantly increased.
  • a patient (or each member of a patient cohort) is treated with a daily dosage of 100 mg pterostilbene formulated in an acceptable nutraceutical carrier, administered orally.
  • a daily dosage of 100 mg pterostilbene formulated in an acceptable nutraceutical carrier administered orally.
  • a clinical study is carried out as detailed above. It is expected that in the course of the study over 12 weeks, 12-HETE levels in the precancerous tissue samples will be significantly reduced.
  • a patient (or each member of a patient cohort) is treated with a daily dosage of 100 mg pterostilbene formulated in an acceptable nutraceutical carrier, administered orally as follows.
  • 100 mg pterostilbene and 150 mg micro crystalline cellulose are combined in a vegetable capsule.
  • a clinical study is carried out as detailed above. After 12 weeks of study monitoring, it is expected that the treatment will prevent progression of pre-cancerous AKs into NMSC identified in the skin test area, and/or suppress formation of new NMSC in the individual human subject.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Oncology (AREA)
  • Physiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Reproductive Health (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Nutrition Science (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
PCT/US2012/064993 2012-05-08 2012-11-14 Method for inducing udp-glucuronosyltransferase activity using pterostilbene WO2013169291A2 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP12876092.3A EP2846785A4 (en) 2012-05-08 2012-11-14 METHOD OF INDUCING UDP-GLUCURONOSYLTRANSFERASE ACTIVITY BY PTEROSTILS
CA2872623A CA2872623A1 (en) 2012-05-08 2012-11-14 Method for inducing udp-glucuronosyltransferase activity using pterostilbene
AU2012379655A AU2012379655B2 (en) 2012-05-08 2012-11-14 Method for inducing UDP-glucuronosyltransferase activity using pterostilbene
KR20147034337A KR20150027081A (ko) 2012-05-08 2012-11-14 프테로스틸벤을 사용한 udp-글루쿠로노실 전이 효소 활성 유도 방법
JP2015511433A JP2015523963A (ja) 2012-05-08 2012-11-14 プテロスチルベンを使用してｕｄｐ−グルクロノシルトランスフェラーゼ活性を誘導する方法
CN201280074486.2A CN104768543A (zh) 2012-05-08 2012-11-14 用于使用蝶芪诱导udp-葡萄糖醛酸转移酶活性的方法
BR112014027646A BR112014027646A2 (pt) 2012-05-08 2012-11-14 método para tratar um indivíduo quanto a um distúrbio proliferativo celular, e método para prevenir ou inibir a perda induzida por uv da atividade de udp-glucuronosiltransferase (ugt) em um indivíduo
MX2014013503A MX2014013503A (es) 2012-05-08 2012-11-14 Metodo para inducir actividad udp-glucuronosiltransferasa utilizando pterostilbeno.
IN9990DEN2014 IN2014DN09990A (forum.php) 2012-05-08 2012-11-14
ZA2014/08893A ZA201408893B (en) 2012-05-08 2014-12-04 Method for inducing udp-glucuronosyltransferase activity using pterostilbene

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13/466,827 2012-05-08
US13/466,827 US8841350B2 (en) 2011-05-11 2012-05-08 Method for inducing UDP-glucuronosyltransferase activity using pterostilbene

Publications (2)

Publication Number Publication Date
WO2013169291A2 true WO2013169291A2 (en) 2013-11-14
WO2013169291A3 WO2013169291A3 (en) 2015-06-18

Family

ID=47142275

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/064993 WO2013169291A2 (en) 2012-05-08 2012-11-14 Method for inducing udp-glucuronosyltransferase activity using pterostilbene

Country Status (12)

Country Link
US (2) US8841350B2 (forum.php)
EP (1) EP2846785A4 (forum.php)
JP (1) JP2015523963A (forum.php)
KR (1) KR20150027081A (forum.php)
CN (1) CN104768543A (forum.php)
AU (1) AU2012379655B2 (forum.php)
BR (1) BR112014027646A2 (forum.php)
CA (1) CA2872623A1 (forum.php)
IN (1) IN2014DN09990A (forum.php)
MX (1) MX2014013503A (forum.php)
WO (1) WO2013169291A2 (forum.php)
ZA (1) ZA201408893B (forum.php)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017525738A (ja) * 2014-09-04 2017-09-07 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 皮膚におけるバリア機能のｕｖ誘導性喪失の処置に使用される局所プテロスチルベン組成物
CN107849083A (zh) * 2015-06-10 2018-03-27 益力舒健康公司 用于治疗皮肤病症的烟酰胺核苷和紫檀芪组合物和方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016037007A1 (en) * 2014-09-04 2016-03-10 The Regents Of The University Of California Topical pterostilbene compositions for use in treating uv-induced skin damage and hyperplasia
US12134956B2 (en) 2022-10-11 2024-11-05 Halliburton Energy Services, Inc. Liner hanger system
US12398624B2 (en) 2023-07-11 2025-08-26 Halliburton Energy Services, Inc. Self-energizing seal for expandable liner hanger

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6623724B2 (en) * 1996-09-18 2003-09-23 Applied Genetics Incorporated Dermatics Dermatological compositions and methods
US6414037B1 (en) * 1998-01-09 2002-07-02 Pharmascience Pharmaceutical formulations of resveratrol and methods of use thereof
DE10161253A1 (de) 2001-12-13 2003-06-26 Dragoco Gerberding Co Ag Verwendung von Dihydropinosylvin und dessen Derivaten als Inhibitoren
FR2869229B1 (fr) 2004-04-26 2006-08-25 Sederma Soc Par Actions Simpli Utilisation d'un inducteur des ugt par voie topique
ES2246165B1 (es) 2004-07-20 2006-12-01 Universitat De Valencia Uso combinado del pteroestilbeno y la quercetina para la fabricacion de medicamentos utiles en el tratamiento del cancer.
US8426369B2 (en) 2006-12-07 2013-04-23 Rutgers, The State University Of New Jersey Prevention and treatment of colon cancer
US8509879B2 (en) 2007-11-06 2013-08-13 The Regents Of The University Of California Apparatus and method for widefield functional imaging (WiFI) using integrated structured illumination and laser speckle imaging
US20090175984A1 (en) 2008-01-08 2009-07-09 David Rubin Method and compositions for preserving wine
US20090324740A1 (en) 2008-06-13 2009-12-31 Albritton Iv Ford D Novel nasal spray
US20100240767A1 (en) 2009-03-23 2010-09-23 Muhammed Majeed Melanogenesis inhibitiuon by 3,5-dimethoxy-4'-hydroxystilbenes and cosmeceutical compositions thereof
ES2798254T3 (es) 2009-06-22 2020-12-10 Indus Biotech Private Ltd Proceso para la obtención de pteroestilbeno purificado y métodos de uso del mismo
US20110136751A1 (en) 2009-10-06 2011-06-09 Green Molecular Use of Polyphenols in the Treatment of Cancer
EP2322159A1 (en) 2009-10-30 2011-05-18 Green Molecular, S.L. Use of pterostilbene (pter) as medicament for prevention and/or treatment of skin diseases, damages or injures or as cosmetic
US8415507B2 (en) * 2010-02-03 2013-04-09 Laurus Labs Private Limited Pterostilbene cocrystals
US8883218B2 (en) * 2010-03-26 2014-11-11 The Board Of Trustees Of The University Of Arkansas Anti-cancer nanoparticle compositions and methods of use
WO2012103457A2 (en) 2011-01-28 2012-08-02 University Of Kentucky Stilbene analogs and methods of treating cancer
WO2013051459A1 (ja) * 2011-10-02 2013-04-11 キユーピー 株式会社 ＲＮＡ干渉によるｍＲＮＡ発現の抑制を促進する促進剤およびその用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of EP2846785A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017525738A (ja) * 2014-09-04 2017-09-07 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 皮膚におけるバリア機能のｕｖ誘導性喪失の処置に使用される局所プテロスチルベン組成物
CN107849083A (zh) * 2015-06-10 2018-03-27 益力舒健康公司 用于治疗皮肤病症的烟酰胺核苷和紫檀芪组合物和方法
US11426398B2 (en) 2015-06-10 2022-08-30 Elysium Health, Inc. Nicotinamide riboside and pterostilbene compositions and methods for treatment of skin disorders
US12109206B2 (en) 2015-06-10 2024-10-08 Elysium Health, Inc. Nicotinamide riboside and pterostilbene compositions and methods for treatment of skin disorders

Also Published As

Publication number Publication date
US10039725B2 (en) 2018-08-07
EP2846785A4 (en) 2016-06-15
CA2872623A1 (en) 2013-11-14
WO2013169291A3 (en) 2015-06-18
AU2012379655A1 (en) 2014-11-20
US20150011650A1 (en) 2015-01-08
MX2014013503A (es) 2015-11-13
KR20150027081A (ko) 2015-03-11
IN2014DN09990A (forum.php) 2015-08-14
EP2846785A2 (en) 2015-03-18
US8841350B2 (en) 2014-09-23
ZA201408893B (en) 2016-08-31
JP2015523963A (ja) 2015-08-20
US20120289605A1 (en) 2012-11-15
AU2012379655B2 (en) 2018-01-18
BR112014027646A2 (pt) 2017-06-27
CN104768543A (zh) 2015-07-08

Similar Documents

Publication Publication Date Title
Shang et al. Sulforaphane attenuation of experimental diabetic nephropathy involves GSK-3 beta/Fyn/Nrf2 signaling pathway
US10039725B2 (en) Method for treating non-melanoma skin cancer by inducing UDP-glucuronosyltransferase activity using pterostilbene
Mittal et al. Ameliorative potential of rutin in combination with nimesulide in STZ model of diabetic neuropathy: targeting Nrf2/HO-1/NF-kB and COX signalling pathway
Hsu et al. Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway
Sun et al. aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2
US20130245110A1 (en) Use for cannabinoids
Zheng et al. Improvement of retinal vascular injury in diabetic rats by statins is associated with the inhibition of mitochondrial reactive oxygen species pathway mediated by peroxisome proliferator–activated receptor γ coactivator 1α
Chun-Bin et al. The main active components of Curcuma zedoaria reduces collagen deposition in human lung fibroblast via autophagy
Wang et al. Geraniol improves endothelial function by inhibiting NOX-2 derived oxidative stress in high fat diet fed mice
WO2009014624A2 (en) Nrf2 inducers for treating epidermolysis bullosa simplex
Chen et al. Selenoprotein P is elevated in individuals with obesity, but is not independently associated with insulin resistance
Goswami et al. Pharmacological inhibition of soluble epoxide hydrolase or genetic deletion reduces diclofenac-induced gastric ulcers
Panieri et al. NRF2, a crucial modulator of skin cells protection against vitiligo, psoriasis, and cancer
Otterson et al. EUK-207 protects human intestinal microvascular endothelial cells (HIMEC) against irradiation-induced apoptosis through the Bcl2 pathway
Canovai et al. Preventive efficacy of an antioxidant compound on blood retinal barrier breakdown and visual dysfunction in streptozotocin-induced diabetic rats
Sutham et al. Ovariectomy and obesity have equal impact in causing mitochondrial dysfunction and impaired skeletal muscle contraction in rats
Li et al. Effects of arsenic on wnt/β-catenin signaling pathway: a systematic review and meta-analysis
Kwak et al. The cardioprotective effects of zileuton, a 5-lipoxygenase inhibitor, are mediated by COX-2 via activation of PKCδ
Schmidt et al. Regulation of heme oxygenase-1 expression by dopamine in cultured C6 glioma and primary astrocytes
Lương et al. The roles of vitamin D in seborrhoeic keratosis: possible genetic and cellular signalling mechanisms
Jung et al. Antidiabetic effect of SN158 through PPARα/γ dual activation in ob/ob mice
Yalçın et al. Comparative in vitro and in silico evaluation of the toxic effects of metformin and/or ascorbic acid, new treatment options in the treatment of Melasma
Abdull Razis et al. Characterization of the temporal induction of hepatic xenobiotic-metabolizing enzymes by glucosinolates and isothiocyanates: Requirement for at least a 6 h exposure to elicit complete induction profile
US20070270501A1 (en) Medicaments for Treating Barrett's Eesophagus
Meijin et al. A3081 VDR agonist prevents diabetic endothelial dysfunction through inhibition of prolyl isomerase-1 mediated mitochondrial oxidative stress and inflammation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12876092

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase in:

Ref document number: 2872623

Country of ref document: CA

Ref document number: 2015511433

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2014/013503

Country of ref document: MX

NENP Non-entry into the national phase in:

Ref country code: DE

ENP Entry into the national phase in:

Ref document number: 2012379655

Country of ref document: AU

Date of ref document: 20121114

Kind code of ref document: A

ENP Entry into the national phase in:

Ref document number: 20147034337

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2012876092

Country of ref document: EP

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112014027646

Country of ref document: BR

ENP Entry into the national phase in:

Ref document number: 112014027646

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20141105