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
  • A61K31/12—Ketones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/02—Algae
  • A61K36/05—Chlorophycota or chlorophyta (green algae), e.g. Chlorella
• • 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a method of inhibiting the expression of inflammatory cytokines and chemokines in an animal or man, and to the use of a xanthophyll, e.g. astaxanthin, for the preparation of a medicament for the prophylactic and/or therapeutic inhibition of the expression of inflammatory cytokines and chemokines.
• a xanthophyll e.g. astaxanthin
• the nuclear factor- ⁇ B (NF- ⁇ B) is a conditionally regulated transcription factor that plays a key role in the expression of a variety of genes involved in inflammation, cell survival, apoptosis, cell differentiation and cancer. It was first identified as a regulator of K light chain expression in murine B-lymphocytes, but has now been shown to be expressed ubiquitously and to be a master regulator of several important processes.
• the NF- ⁇ B family consists of structurally related proteins of the Rel family, including p50, p52, p65/RelA, c-Rel and RelB (reviewed in Rothwarf and Karin, 1999).
• NF- ⁇ B is bound to the inhibitor protein I ⁇ B, which masks the nuclear localisation signal of NF-KB and retains it in the cytoplasm.
• I ⁇ B inhibitor protein
• Activation of the cell with various stimuli initiates signalling pathways involving activation of a whole series of protein kinases. This results in phosphorylation of I ⁇ B, targeting the protein for degradation (Rothwarf and Karin, 1999).
• the I ⁇ B/NF- ⁇ B complex dissociates, NF- ⁇ B translocates to the nucleus and binds to its cognate sites.
• Nuclear translocation of NF- ⁇ B is activated by various stimuli, including the inflammatory cytokines TNF- ⁇ and IL-1, UN-irradiation, mitogens, viruses, bacterias, double stranded D ⁇ A, ionizing radiation and hydrogen peroxide, in accordance with the important role played by ⁇ F- ⁇ B in various tissues (Rothwarf and Karin, 1999).
• NF- ⁇ B The functional importance of NF- ⁇ B in acute and chronic inflammation is based on its ability to regulate the promoters of a variety of genes.
• the products of such genes are e.g. cytokines, adhesion molecules and acute phase proteins, which are critical for inflammatory processes (Baeuerle et al., 1995, Shakov et al., 1990, Libermann et al., 1990).
• the present invention provides a method to inhibit the expression of inflammatory cytokines and chemokines in an animal or man.
• the method of the invention comprises administration to an animal or man of at least one type of xanthophyll in an amount inhibiting the expression of inflammatory cytokines and chemokines in said animal or man.
• inflammatory cytokines are TNF- ⁇ and IL-1
• chemokines are MIP-2, CXC 5 and CXC 6.
• the daily doses of the xanthophyll for inhibiting the expression of inflammatory cytokines and chemokines will normally be in the range of 0.01 to 50 mg per kg body weight of an animal or human, but the actual dose will be decided based on the recommendations of the manufacturer of the medicament comprising the xanthophyll.
• the type of xanthophyll is astaxanthin.
• the astaxanthin may be selected from the group consisting of astaxanthin from a natural source, such as a culture of the alga Haematococcus sp., synthetic astaxanthin and mixtures thereof.
• Astaxanthin from other natural sources than algae such as from fungi and crustaceans, and other xanthophylles as well, are expected to be similarly useful for the purposes of the invention.
• An advantage of using astaxanthin from algae may be that the astaxanthin exists in a form esterif ⁇ ed with fatty acids, which esterified astaxanthin thereby is more stable during handling and storage than free astaxanthin.
• Another aspect of the invention is directed to the use of at least one type of xanthophyll for the preparation of a medicament for the prophylactic and/or therapeutic inhibition of the expression of inflammatory cytokines and chemokines in an animal or man.
• the type of xanthophyll is astaxanthin.
• the astaxanthin may be selected from the group consisting of astaxanthin from a natural source, such as a culture of the alga Haematococcus sp., synthetic astaxanthin and mixtures thereof.
• Yet another aspect of the invention is directed to a commercial package containing a medicament comprising at least one type of xanthophyll and written and/or data carrier instructions for administration to an animal or man of the medicament for the prophylactic and/or therapeutic inhibition of the expression of inflammatory cytokines and chemokines.
• the medicament preferably comprises astaxanthin, selected from the group consisting of astaxanthin from a natural source, such as a culture of the alga Haematococcus sp., synthetic astaxanthin and mixtures thereof.
• the commercial package of the invention may additionally contain a water soluble antioxidant, such as glutathione and/or ascorbic acid (vitamin C) and/or a fat soluble antioxidant other than the xanthophyll, such as tocopherol (vitamin E).
• the commercial package and/or the medicament comprised by the present invention may comprise additional ingredients which are pharmacologically acceptable inactive or active in prophylactic and/or therapeutic use, such as excipients and flavouring agents.
• Fig 1 is a diagram which shows that Astaxanthin inhibits the activation of NF- KB effected by UN exposure.
• HeLa cells were transfected with a ⁇ F- ⁇ B -dependent reporter gene and exposed to UN-C 24 hours after transfection. Pretreatment with Astaxanthin was done 3 hours prior to irradiation, where indicated. Cells were harvested and luciferase activity was measured 14-18 hours following exposure. The ratio between Firefly and Renilla luciferase activity is represented as fold activation over the activity in unstimulated control cells. The standard error is based on two identical experiments.
• the human fibroblast cell line Hela Tet/off was cultured in MEM alpha medium supplemented with 10% fetal calf serum, penicillin and streptomycin (Gibco Grand Island, NY). The day before transfection, cells were plated on 6 cm dishes in a medium containing 2.5% fetal calf serum. On the day of transfection, the cell culture medium was changed to fresh medium (2.5% fetal calf serum).
• a stock solution of Astaxanthin was prepared by dissolving synthetic Astaxanthin (Sigma) in 99.6% ethanol.
• the concentration of Astaxanthin was measured by spectrophotometry, and the absorbance maximum at 474-479 nm was used to calculate the concentration, according to the formula: Abs max /210.
• the 6x ⁇ B-Luc plasmid contains a firefly luciferase reporter gene driven by 6 NF- ⁇ B binding sites cloned upstream of a TK promoter (Meyer et al. 1993).
• the pRL-TK plasmid contains a Renilla luciferase reporter gene driven by the TK promoter and is used as a control for transfection efficiency (Promega). Transfection, UV irradiation and reporter gene analysis
• Plasmid DNA (l ⁇ g of the 6x ⁇ B-Luc reporter gene plasmid and 200 ng of pRL- TK control plasmid) was added to a mixture of 4 ⁇ l fuGENE 6 transfection reagent
• Extracts were prepared 14-18 hours following exposure, and luciferase assays were performed using components of the luciferase assay system (Promega). Results
• NF- ⁇ B has been shown to be responsive to UN-irradiation (reviewed in Pitette et al., 1997).
• UN-C induces expression of a transfected ⁇ F- ⁇ B-dependent reporter gene (Fig. 1).
• pretreatment of the cells with Astaxanthin at the highest concentration repressed this activation almost 3-fold.
• Astaxanthin has an inhibitory effect on NF- ⁇ B, DNA binding activity of NF- ⁇ B and/or translocation of the NF- ⁇ B across the nuclear membrane by interfering with at the signalling components in the NF- ⁇ B activation pathway.
• NF- ⁇ B activation pathway A paradigm in information transfer from membrane to nucleus. Available at www.stke.org/cgi/content/full/OC_sigtrans; 1999/5/re 1.
• ⁇ B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor a gene in primary macrophages. J. Exp. Med. 171, 35-47.
• H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant- responsive factor. EMBO J. 12, 2005-2015.

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• 2000
  • 2000-03-27 SE SE0001071A patent/SE0001071D0/xx unknown
• 2001
  • 2001-03-21 WO PCT/SE2001/000600 patent/WO2001072296A1/en not_active Ceased
  • 2001-03-21 JP JP2001570257A patent/JP2003528139A/ja active Pending
  • 2001-03-21 DE DE60126591T patent/DE60126591D1/de not_active Expired - Fee Related
  • 2001-03-21 EP EP01916022A patent/EP1267857B1/en not_active Expired - Lifetime
  • 2001-03-21 CA CA2405479A patent/CA2405479C/en not_active Expired - Fee Related
  • 2001-03-21 AU AU2001242965A patent/AU2001242965A1/en not_active Abandoned
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