WO2004087128A1 - Methyl-β-orcinolcarboxylate from lichen (everniastrum cirrhatum) for use for the treatment of fungal infections and cancer - Google Patents
Methyl-β-orcinolcarboxylate from lichen (everniastrum cirrhatum) for use for the treatment of fungal infections and cancer Download PDFInfo
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- WO2004087128A1 WO2004087128A1 PCT/IN2003/000097 IN0300097W WO2004087128A1 WO 2004087128 A1 WO2004087128 A1 WO 2004087128A1 IN 0300097 W IN0300097 W IN 0300097W WO 2004087128 A1 WO2004087128 A1 WO 2004087128A1
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- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 230000031068 symbiosis, encompassing mutualism through parasitism Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 235000015961 tonic Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960000716 tonics Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- ICTZCAHDGHPRQR-UHFFFAOYSA-N usnic acid Natural products OC1=C(C)C(O)=C(C(C)=O)C2=C1C1(C)C(O)=C(C(=O)C)C(=O)C=C1O2 ICTZCAHDGHPRQR-UHFFFAOYSA-N 0.000 description 1
- 229940004858 usnic acid Drugs 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
-
- 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
- A61K36/09—Lichens
-
- 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
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the new use of an already known biomolecule methyl- ⁇ -orcinol carboxylate of formula 1 isolated from a lichen (Everniastrum cirrhatum), for treating pathogenic fungal infections of humans that are resistant to polyene and azole antibiotics such as amphotericin B, nystatin, clotrimazole etc.
- Lichens are symbiotic associations between fungi, green algae and/or cyanobacteria. They have a varied chemistry and produce many polyketide-derived compounds, including some, such as depsides and depsidones that are rarely reported elsewhere. Depsides are a class of compounds, which appear to be unique to the lichens. These compounds are dimeric esters of variously substituted orsellinic acids and are the major source of the so-called lichen acids. Although lichens have been appreciated in traditional medicines, their value has largely been ignored by the modern pharmaceutical industry because difficulties in establishing axenic cultures and conditions for rapid growth preclude their routine use in most conventional screening processes.
- the association between fungi and algae is specific and selective.
- the name of the fungal component is given to the whole lichen and there are >13500 described species, including almost one-fifth of all known fungi (Hawcksworth and Hill, 1984; The Lichen Forming Fungi, Mecorquodale Ltd).
- the individual mycobionts and photobionts are small and nondescript if cultured in a laboratory dish, the symbiotic components together in nature present a full range of varied and beautiful forms, and some such as Ramalina menziesii (the 'fishnet' lichen) can drape entire trees, creating a prominent display (Arvis,W.O.,2000; Lichens, Smithsonian Situation Press). They perform a variety of ecological roles such as colonizing marginal habitat in Antarctica, stabilizing soil in the semi-arid desert of Australia and contributing to nitrogen turnover in the northern pacific forests of North America.
- Lichens produce a wide range of chemical compounds, among which approximately 350 secondary metabolites have been identified.
- These mycobiont derived products usually accumulate as extra cellular crystals on the cell walls of the symbionts, and account for up to 10% (in exceptional cases, up to 40%) of thallus dry mass (Galun, M. and Shomer-llan, A. (1988) in CRC Handbook of Lichenology, Vol. Ill; Galun, M., ed.), pp,3- 8.CRC Press); many are unique to lichens.
- lichen secondary compounds are formed by the polyketide pathway, while others derive from the shikimic acid and mevalonic acid pathways these are key routes for secondary metabolism in all organisms.
- Several lichen extracts have been used for various remedies in folk medicine, and screening test with lichens have indicated the frequent occurrence of metabolites with antibiotic, antimycobacterial, antiviral, analgesic, and antipyretic properties.
- lichen metabolites are formed by condensation of two or more hydroxybenzoic acids whereby the carboxyl group of one molecule is este ⁇ fied with a phenolichydroxyl group of a second molecule. Owing to the phenolic nature of their chemical structures, these molecules are interesting candidates for evaluating their effects on leukotriene biosynthesis, as a major class of inhibitors often contains a hydroxylated aromatic ring (Fitzsimmons et al 1989).
- two small-molecule lichen-derived metabolites protolichesterinic acid and lobaric acid, have been reported to inhibit 5-LO from porcine leukocytes (Ogmundsdottir et al 1998). The latter has also been shown to inhibit peptide leukotriene formation (Gissurarson et al 1997). Lichen depsides have also been described to inhibit prostaglandin biosynthesis (Sankawa et al 1982).
- antifungal agents such as greseofulvine, amphotericin and nystatin are available in the market, although the available antibacterials are replete. Most of these antifungals are synthetic derivatives with known side effects to human and animals. Compounding this problem is the development of resistance towards commonly used drugs thus rendering the chemotherapy less useful. Therefore new antifungal substances from natural sources have to be generated to counter the resistance phenomenon.
- the world market for antifungals was over US $ 1500 millions representing 1.5% of the total global anti-infective market.
- anti-fungals both topical and systemic represent more than 6% of the total anti-infective agents.
- the main object of the present invention to identify Lichen extract, which can specifically kill the polyene drug resistant fungal infections of humans.
- Still another object of the invention is to test the ergosterol binding ability of the bioactive molecule using in-vitro assays.
- an antifungal/anticancer composition comprising a pharmaceutically effective amount of methyl- ⁇ -orcinol carboxylate of formula I and a pharmaceutically acceptable carrier
- the composition is anti-fungal and the methyl- ⁇ - orcinol carboxylate of formula I is present in a concentration in the range of 10-400 ⁇ g/ml.
- the composition is anticancer and the methyl- ⁇ -orcinol carboxylate of formula I is present in concentration in range of 1-10 ⁇ g/ml.
- the fungus is from the group of yeasts comprising of Candida sp, exemplified by Candida albicans.
- the cancer is liver, colon, ovarian or mouth (oral) cancer of humans.
- the invention also relates to a method of treatment of fungal infections in a subject comprising administering to the subject an anti-fungal composition comprising a pharmaceutically effective amount of methyl- ⁇ -orcinol carboxylate of formula I and a pharmaceutically acceptable carrier.
- the methyl- ⁇ -orcinol carboxylate of formula I is isolated from lichen Everniastrum cirrhatum.
- the fungus comprises a multiple or single drug resistant strain.
- the methyl- ⁇ -orcinol carboxylate of formula I is present in a concentration in the range of 10-400 ⁇ g/ml.
- the fungus is from the group of yeasts comprising of Candida sp, exemplified by Candida albicans.
- the fungus is a polyene drug resistant strain, the polyene drug being exemplified by nystatin and anphotericin
- the fungus comprises an azole resistant strain, the azole drug being exemplified by clotrimazole, flucanoazole, itracanoazole and micanazole.
- the fungus is simultaneously resistant to both polyene and azole classes of antibiotics.
- the subject is preferably human.
- the present invention also provides a method for the treatment of cancer in a subject such as a human being, the cancer being either of liver, colon, ovarian and mouth (oral) cancer comprising administering to the subject a pharmaceutically effective amount of methyl- ⁇ -orcinol carboxylate of formula I and a pharmaceutically acceptable carrier.
- the concentration of methyl- ⁇ -orcinol carboxylate of formula I is in the range of 1-10 ⁇ g/ml.
- the present invention also relates to the use of methyl- ⁇ -orcinol carboxylate of formula I
- the present invention relates to the use of a biomolecule methyl- ⁇ -orcinolcarboxylate of formula I isolated from a lichen (Everniastrum cirrhatum),
- Formula I for treating pathogenic fungal infections of humans that are resistant to polyene antibiotics such as amphotericin B, nystatin etc.
- the biomolecule does not possess ergosterol- binding property.
- Candida sp Infections due to Candida sp account for about 80% of all major systemic fungal infections.
- Candida is now the fourth most prevalent organism found in bloodstream infections and is the most common cause of fungal infections in immuno-compromised people.
- Vaginal candidiasis commonly affects women, including those with normal immunity, especially after antibiotic use.
- the active compound could be crystallized from 96% hexane: 4% ethyl acetate fraction.
- the purified compound was analyzed by spectroscopic techniques using 1H & 13 C NMR, LC-MS etc to decipher the chemical structure.
- Ccompound was identified as methyl- ⁇ -orcinolcarboxylate, of formula I.
- the compound is a colorless crystal with melting temperature of 137°C.
- Caccamese et al (1985) have already found that the methyl- ⁇ -orcinolcarboxylate inhibit the growth of yeast strains such as Saccharomyces cerevisiae.
- the present invention therefore provides an antifungal/anticancer composition comprising a pharmaceutically effective amount of methyl- ⁇ -orcinol carboxylate of formula I and a pharmaceutically acceptable carrier.
- a concentration of methyl- ⁇ -orcinol carboxylate of formula I in the range of 10-400 ⁇ g/ml provides antifungal activity against the group of yeasts comprising of Candida sp, exemplified by Candida albicans.
- a concentration of methyl- ⁇ -orcinol carboxylate of formula I in the range of 1-10 ⁇ g/ml provides anticancer activity against liver, colon, ovarian or mouth (oral) cancer of humans.
- the methyl- ⁇ -orcinol carboxylate of formula I is isolated from lichen Everniastrum cirrhatum.
- the fungus can be either a multiple drug resistant or single drug resistant strain.
- the fungus can be from the group of yeasts comprising of Candida sp, exemplified by Candida albicans.
- the drugs in question can be a polyene drug exemplified by nystatin and anphotericin or a azole drug exemplified by clotrimazole, flucanoazole, itracanoazole and micanazole.
- C. albicans was grown to log phase in Sabouraud's dextrose broth (5 ml) for 48 hrs at 37°C in a shaker at 250rpm.
- the cells were pelleted by centrifugation at 5000rpm at 4°C and the pellet was dissolved in 5 ml phosphate buffered saline PBS (6.8pH).
- the culture was divided in to five groups of 1 ml each in eppendrof tubes.
- Ethyl methane sulfonate was added to each of the culture tube @ 0.1% (v/v) and allowed to grow for 40 min. Then the mutagen was completely washed off thrice by repeatedly pelleting the cells and re-dissolving in PBS. The mutagenized stocks was then diluted in Sabouraud's dextrose broth two folds and allowed to grow for 6 hrs at 37°C in a shaker at 250rpm. Titre of the cells before treatment with EMS and immediately after treatment with EMS was calculated to obtain the killing percentage in each of the five tubes. The mutagenized and fixed cultures were then plated in Sabouraud's dextrose agar containing different concentration of amphotericin, nystatin and clotrimazole.
- the drug resistance property of the mutants was studied by standardized disc diffusion assay (Bauer at al 1966, American Journal of Clinical Pathology 45: 493-496) with slight modifications.
- the discs were prepared (5 mm diameter made of Whatman #3 filter paper) by impregnating 8 ⁇ l of test compound and placing them on pre-inoculated agar surface.
- a disc containing only the solvent was used as the control.
- a zone of growth inhibition surrounding the disc is indicative of the resistant nature of the strains to antibiotics.
- the results indicate that all the mutant strains were highly resistant to amphotericin and nystatin as the zone of growth inhibition was far less in mutants than that of the wild type parent strain.
- Amph C7R, Amph C6R, Clo 31R and Clo 28R were only resistant to clotrimazole indicating of less zone of growth inhibition.
- Ethanol extract was filtered using Whatman filter paper No.l and concentrated at the 60°C under reduced pressure. The ethanolic extract was then lyophilized to obtain 15.5 g of crude extract. Stock of 100 mg/ml was made in DMSO and tested for bio-activity. 4. Bioactivity guided fractionation of the lichen materials
- hexane and ethyl acetate fractions thus obtained are mixed together and further fractionated in a glass column having an internal diameter of 3.0 cm and length of 72.0 cm.
- Hexane was used as the initial mobile phase and silica gel (particle size 60-120 mesh) as the stationary phase.
- Different fractions of approximately 100 ml were collected and dried under vacuum. Concentrated fractions were then run on TLC plates and fractions of similar TLC pattern were pooled together. After about 3 liter of hexane fraction collected the polarity of the mobile phase was slightly increased from fraction No. 36 by adding ethyl acetate to hexane (4% of ethyl acetate in final volume).
- fractions No.64 to 78 were combined together based on identical 7-spot bands as appeared in TLC. Above fractions were dissolved in 50 ml of acetone and kept at room temperature (25-30°C) for crystallization of compounds. Crystals thus obtained were again properly washed with acetone and TLC of crystals was carried out by using a mobile phase of benzene 98% plus acetone 2%. TLC plates showed a single spot on exposing to iodine fume. These TLC plates exhibited a single dark red colored spot when dipped in bacopa reagent (vaniline 3.5 g, H 2 SO 4 17.8 g, absolute alcohol 332.5 ml) and heated at 120 ° C for 5 minutes. About 40 mg of the crystal could be collected from the above run. The melting temperature of crystal thus obtained was found to be 137 ° C.
- the active spot obtained by TLC was further purified by repetitive column chromatography, which can be performed by a person skilled in the art and then analyzed by H & C NMR, LC-MS to determine the structure of the active pure compound. On the basis of spectroscopic data the compound isolated was identified as Methyl- ⁇ -orcinolcarboxylate. 6. Specific anticandidial activity of methyl- ⁇ -orcinolcarboxylate acid against polyene and azole resistant strains
- Cytotoxicity testing in vitro was done by the method of Woerdenbag et al.,1993; J.Nat.Prod. 56 (6): 849-856). 2x10 3 cells/well were incubated in the 5% CO 2 incubator for 24h to enable them to adhere properly to the 96 well polysterene microplate (Grenier, Germany). Test compounds dissolved in 100% DMSO (Merck,Germany) in atleast five doses were added and left for 6h after which the compound plus media was replaced with fresh media and the cells were incubated for another 48h in the CO 2 incubator at 37°C. The concentration of DMSO used in our experiments never exceeded 1.25%, which was found to be non-toxic to cells.
- IC 90 is the concentration ⁇ g/mL required for 90% inhibition of cell growth as compared to that of untreated control.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IN2003/000097 WO2004087128A1 (en) | 2003-03-31 | 2003-03-31 | Methyl-β-orcinolcarboxylate from lichen (everniastrum cirrhatum) for use for the treatment of fungal infections and cancer |
GB0522200A GB2415379B (en) | 2003-03-31 | 2003-03-31 | Methyl-ß-orcinolcarboxylate from lichen (everniasrum cirrhatum) for use for the treatment of cancer |
DE10394214T DE10394214T5 (en) | 2003-03-31 | 2003-03-31 | Lichen methyl B-orcinol carboxylate (Everniastrum cirrhatum) for use in the treatment of fungal infections and cancer |
JP2004570066A JP4498930B2 (en) | 2003-03-31 | 2003-03-31 | Methyl-β-orcinol carboxylate from lichen plant (Everniastrum cirrhatum) for use in the treatment of fungal infections and cancer |
CA002521055A CA2521055A1 (en) | 2003-03-31 | 2003-03-31 | Methyl-.beta.-orcinolcarboxylate from lichen (everniastrum cirrhatum) for use for the treatment of fungal infections and cancer |
AU2003226628A AU2003226628A1 (en) | 2003-03-31 | 2003-03-31 | METHYL-Beta-ORCINOLCARBOXYLATE FROM LICHEN (EVERNIASTRUM CIRRHATUM) FOR USE FOR THE TREATMENT OF FUNGAL INFECTIONS AND CANCER |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IN2003/000097 WO2004087128A1 (en) | 2003-03-31 | 2003-03-31 | Methyl-β-orcinolcarboxylate from lichen (everniastrum cirrhatum) for use for the treatment of fungal infections and cancer |
Publications (1)
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WO2004087128A1 true WO2004087128A1 (en) | 2004-10-14 |
Family
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PCT/IN2003/000097 WO2004087128A1 (en) | 2003-03-31 | 2003-03-31 | Methyl-β-orcinolcarboxylate from lichen (everniastrum cirrhatum) for use for the treatment of fungal infections and cancer |
Country Status (6)
Country | Link |
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JP (1) | JP4498930B2 (en) |
AU (1) | AU2003226628A1 (en) |
CA (1) | CA2521055A1 (en) |
DE (1) | DE10394214T5 (en) |
GB (1) | GB2415379B (en) |
WO (1) | WO2004087128A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006137172A1 (en) * | 2005-06-24 | 2006-12-28 | Taiyo Kagaku Co., Ltd. | Pest control agent of fungi or parasites for fish |
CN115989072A (en) * | 2020-07-27 | 2023-04-18 | 兽医医药动力学有限责任公司 | Lichen extract-based formulation for cervidae animals |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010202562A (en) * | 2009-03-03 | 2010-09-16 | Ogawa & Co Ltd | Phenol-based antimicrobial agent |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05271064A (en) * | 1991-11-27 | 1993-10-19 | Dainippon Jochugiku Co Ltd | Antibacterial agent for methicillin-resistant staphylococcus aureus and infection preventing method using the agent |
-
2003
- 2003-03-31 CA CA002521055A patent/CA2521055A1/en not_active Abandoned
- 2003-03-31 WO PCT/IN2003/000097 patent/WO2004087128A1/en active Application Filing
- 2003-03-31 JP JP2004570066A patent/JP4498930B2/en not_active Expired - Fee Related
- 2003-03-31 DE DE10394214T patent/DE10394214T5/en not_active Withdrawn
- 2003-03-31 GB GB0522200A patent/GB2415379B/en not_active Expired - Fee Related
- 2003-03-31 AU AU2003226628A patent/AU2003226628A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH05271064A (en) * | 1991-11-27 | 1993-10-19 | Dainippon Jochugiku Co Ltd | Antibacterial agent for methicillin-resistant staphylococcus aureus and infection preventing method using the agent |
Non-Patent Citations (4)
Title |
---|
CACCAMESE S ET AL: "METHYL BETA ORCINOLCARBOXYLATE AND DEPSIDES FROM PARMELIA-FURFURACEA", JOURNAL OF NATURAL PRODUCTS (LLOYDIA), vol. 48, no. 1, 1985, pages 157 - 158, XP009024129, ISSN: 0163-3864 * |
CACCAMESE S ET AL: "METHYL-BETA-ORCINOLCARBOXYLATE AND ATRANOL FROM THE LICHEN STEREOCAULON-VESUVIANUM", JOURNAL OF NATURAL PRODUCTS (LLOYDIA), vol. 49, no. 6, 1986, pages 1159 - 1160, XP009024140, ISSN: 0163-3864 * |
DATABASE WPI Section Ch Week 199346, Derwent World Patents Index; Class B05, AN 1993-365135, XP002267625 * |
SHAHI SUSHIL K ET AL: "Use of lichen as antifungal drug against superficial fungal infections", JOURNAL OF MEDICINAL AND AROMATIC PLANT SCIENCES, vol. 22-23, no. 4A-1A, 2000, pages 169 - 172, XP009024139 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006137172A1 (en) * | 2005-06-24 | 2006-12-28 | Taiyo Kagaku Co., Ltd. | Pest control agent of fungi or parasites for fish |
CN115989072A (en) * | 2020-07-27 | 2023-04-18 | 兽医医药动力学有限责任公司 | Lichen extract-based formulation for cervidae animals |
Also Published As
Publication number | Publication date |
---|---|
CA2521055A1 (en) | 2004-10-14 |
DE10394214T5 (en) | 2006-03-16 |
GB2415379B (en) | 2007-10-31 |
AU2003226628A1 (en) | 2004-10-25 |
GB0522200D0 (en) | 2005-12-07 |
JP4498930B2 (en) | 2010-07-07 |
JP2006514969A (en) | 2006-05-18 |
GB2415379A (en) | 2005-12-28 |
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