WO2000048447A2 - Composition for treatment of external secretion disorders except hypolacrimation - Google Patents
Composition for treatment of external secretion disorders except hypolacrimation Download PDFInfo
- Publication number
- WO2000048447A2 WO2000048447A2 PCT/JP2000/000810 JP0000810W WO0048447A2 WO 2000048447 A2 WO2000048447 A2 WO 2000048447A2 JP 0000810 W JP0000810 W JP 0000810W WO 0048447 A2 WO0048447 A2 WO 0048447A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- treatment
- composition
- aldose reductase
- reductase inhibitor
- hypolacrimation
- Prior art date
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
-
- 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
- A61P1/04—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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- 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
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- This invention relates to a composition for treatment of external secretion disorders except hypolacrimation, and more particularly to a composition for treatment of hyposalivation and a so-called "dry mouth syndrome".
- External secretions are discharges that are discharged directly by way of a glandular cell, or through an excretory duct or the like onto a body surface or into a lumen.
- One of well-known external secretions is saliva, and the others are secretion from nasal mucous membranes and mucous membranes of a respiratory tract, secretion from a stomach and an intestine, discharges from a vagina, perspiration, etc..
- Some of diseases resulting from disorder of the above-mentioned external secretion are: dryness of various parts of body such as so-called “dry mouth syndrome” (xerostomia), “dry nose syndrome” (xeromycteria), “dry skin” (xeroderma), “dry vagina syndrome” (symptom of vaginal dryness); and chronic pancreatitis, chronic gastritis, and chronic bronchitis due to depression of external secretion.
- Sj ⁇ gren's syndrome an autoimmune disease.
- Sjogren's syndrome is characterized by a symptom of dryness due to infiltration of phlogocyte onto an acinus of an exocrine gland and around an excretory duct, and destruction and atrophy of the acinus and an epithelial cell of the excretory duct that follows.
- One of the characteristic symptoms is eye and mouth dryness, as well as dryness of skin, nose, throat, bronchia, vulva, and vagina.
- the dry mouth syndrome causes various disorders such as feeling of thirst, xerosis of tunica mucosa oris, urtication, dysmaesesis, dyspepsia because of dryness of lip and inside the mouth due to decrease of secretion of saliva resulting from some cause. Also, the dry mouth syndrome may allow stay of food remnants inside the mouth, which may lead to dental caries. There are various factors of causing the dry mouth syndrome.
- febrile diseases As generalized factors, the followings are known: febrile diseases, dehydration, endocrinopathy (myxedema, Basedow's disease, diabetes insipidus, etc.), dysbolism (diabetes, uremia, liver cirrhosis, etc.), deficiency of vitamin-A, B, autoimmune diseases (Sjogren's syndrome, progressive scleroderma, etc.), anemia, bleeding, aging, various medications (sedatives, parasympatholytic drugs, antihistamines, etc.). As local factors, sialadenitis, atrophy of salivary gland, sequela of radiotherapy, malformation (ectodermal dysplasia, etc.) and so forth are known.
- the causes of the dry mouth syndrome vary including ones which still remain unidentified.
- As a therapy for the dry mouth syndrome there have been conducted several treatments such as drinking liquid all day long little by little, chewing gum or the like, and using artificial saliva. All these treatments are, however, symptomatic treatments, and providing a medicament that can establish a fundamental measures to improve decrease of saliva secretion has been strongly demanded.
- a healthy person discharges 1 to 1.5 litter of saliva a day through a pair of left and right grand salivary glands (parotid gland, submandibular gland, sublingual gland) and small salivary glands (labial glands, lingual glands, palatine glands, buccal glands).
- Saliva is discharged in response to a stimulant that may harm a human body to dilute the same or maintain the physiological pH value thereof, as well as helping mastication and deglutition of foods.
- saliva dissolves the food, makes a person taste the food, and helps him smoothly utter a word by keeping a wet state inside the mouth.
- saliva secretion is one of essential physiological functions, and hence, improving decreased saliva secretion is particularly significant in treating the dry mouth syndrome.
- This invention intends to solve the problems described above, and one of the objects is to provide a composition for treatment that is effective in external secretion disorders except hypolacrimation, and more particularly effective in at least one of diseases selected from hyposalivation and dry mouth syndrome.
- Another object of this invention is to provide a method for treating a disease of a subject that suffers from external secretion disorders except hypolacrimation, and more particularly at least one of diseases selected from hyposalivation and dry mouth syndrome.
- Still another object of this invention is to provide a use of pharmaceutical composition for treatment of external secretion disorders except hypolacrimation, and more particularly to treat at least one of diseases selected from hyposalivation and dry mouth syndrome.
- composition for treatment that solves the above problems and is effective in external secretion disorders except hypolacrimation (for instance, hyposalivation and dry mouth syndrome) has a feature that the composition comprises an aldose reductase inhibitor as an active ingredient.
- the aldose reductase inhibitor may preferably comprise a compound represented by the general formula ( I ):
- a and B are independently lower alkylene
- X, Y, and Z are independently halogen, or a pharmacologically acceptable salt thereof.
- a and B are independently methylene, X is chlorine, Y is bromine, and Z is fluorine.
- composition for treatment may preferably be in the form of preparation for oral local administration, and more preferably in the form of preparation for sublingual administration.
- the method that solves the above problems and treats external secretion disorders except hypolacrimation has a feature that an aldose reductase inhibitor of an effective amount is administered to a subject in need of a treatment of external secretion disorders except hypolacrimation (for instance, hyposalivation and dry mouth syndrome).
- composition for treatment of external secretion disorders except hypolacrimation which comprises, as an active ingredient, an aldose reductase inhibitor; (2) the composition for treatment described in (1) that is used for treatment of hyposalivation;
- the aldose reductase inhibitor is a compound represented by the above general formula ( I ) (wherein A, B, X, Y, and Z are independently defined above, or a pharmacologically acceptable salt thereof;
- composition for treatment described in any of (1) to (5) that is in the form of preparation for oral local administration;
- composition for treatment described in (6) that is in the form of preparation for sublingual administration
- a method of treating external secretion disorders except hypolacrimation which comprises administering an effective amount of an aldose reductase inhibitor to an object that needs treatment for the external secretion disorders except hypolacrimation;
- Aldose reductase inhibitors included in this invention as the active ingredient are not specified if they can inhibit aldose reductase, being exemplified in the concrete by the compounds represented by the above general formula ( I ), particularly the compound of the formula (II ):
- a and B are independently lower alkylene.
- Lower alkylene as used in this specification mean straight or branched alkylene groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. In the concrete, they are methylene, ethylene, trimethylene, propylene groups, and the like, among which methylene and ethylene groups are desirable.
- X, Y, and Z are independently halogen (chlorine, bromine, fluorine, iodine), and it is particularly desirable when X is chlorine, Y is bromine, and Z is fluorine.
- the compound and pharmacologically acceptable salts thereof included in this invention as the active ingredient are publicly known compounds, which can be produced for example with the method described in the Japanese Published Unexamined Patent Publication No. Sho 62-96476 or a method based on this method.
- Pharmacologically acceptable salts of the compound in this invention include salts with basic compounds such as inorganic bases (e.g. sodium, potassium, calcium, magnesium, aluminum, ammonium, etc.), and organic bases (e.g. primary amines such as ethanolamine; secondary amines such as diethylamine, diethanolamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, etc.; tertiary amines such as trimethylamine, triethylamine, pyridine, picoline, triethanolamine, etc.; and so on) and the like.
- basic compounds such as inorganic bases (e.g. sodium, potassium, calcium, magnesium, aluminum, ammonium, etc.), and organic bases (e.g. primary amines such as ethanolamine; secondary amines such as diethylamine, diethanolamine, dicyclohexylamine, N,N'- dibenzylethylenediamine, etc.; tertiary amines such as tri
- the aldose reductase inhibitor used in this invention is effective in treating external secretion disorders except hypolacrimation, and particularly dry mouth syndrome and improving hyposalivation in mammals including man, ox/cow, horse, dog, mouse, and rat etc., being the active ingredient in the treatment of external secretion disorders except hypolacrimation and particularly in the treatment of dry mouth syndrome and/or hyposalivation in the mammals.
- the external secretion disorder except hypolacrimation in this invention means a state where an external secretion function is decreased because of some factor, e.g., Sj ⁇ gren's syndrome.
- Some of the diseases resulting from the above external secretion disorder are: dry syndrome such as "dry mouth syndrome” (xerostomia), “dry nose syndrome” (xeromycteria), “dry skin” (xeroderma), “dry vagina syndrome” (symptom of vaginal dryness); and chronic pancreatitis, chronic gastritis, and chronic bronchitis due to depression of external secretion.
- Saliva secretion disorder in this specification means an anomalous state (depression or suppression) of saliva secretion caused by some factor.
- Treatment with the composition for treatment of this invention includes all controls, including prevention, cure, relief or decrement of symptom, suppression of progress, etc.
- composition for treatment of this invention may be administered orally or parenterally, but local administration (for instance, mouth) onto parts required is particularly desirable when the avoidance of the influence on other areas of the cardiovascular system and the significance of their actual effectiveness, etc. are taken into account.
- sublingual tablets, troches, chewable tablets, collutoriums, sprays, ointments, powders, granules, tablets, capsules, injections, ophthalmic solutions are some of the forms for preparations, and preferably, the form of sublingual tablet, troches, sprays and ointments is suitable. These preparations can be manufactured according to known art.
- ingredients having pharmacological activity different from that of the ingredient of this invention may be added as needed to the pharmaceutical preparations of this invention if they are compatible to the purpose of the invention.
- the dose and dosing frequency of the active ingredient of this invention vary according to the symptoms of the disease to be treated, age and body weight of the patient, dosage form, treatment duration, therapeutic effect desired, etc.
- oral dosage of several times, preferably 1 to 6 times a day brings about a satisfactory effect for an adult.
- one active ingredient alone or two or more active ingredients in combination may be contained in the preparation.
- the amount of each ingredient may be determined appropriately according to the therapeutic effect and safety of each ingredient.
- the 0.3% eye drops was instilled to a diabetic patient (female, 43 years old) four times a day. On the sixth day after the administration has started, an obvious sthenia of saliva secretion of the patient was observed.
- the aldose reductase inhibitor is effective in improvement of hyposalivation or dry mouth syndrome.
- the aldose reductase inhibitor is effective in improvement of hyposalivation or dry mouth syndrome, since the aldose reductase inhibitor has a significant effect on increasing of saliva secretion.
- composition for treatment of this invention including an aldose reductase inhibitor as an active ingredient is effective in improvement of external secretion disorders except hypolacrimation, particularly hyposalivation and dry mouth syndrome. Therefore, the composition for treatment of this invention is suggested to be useful for treatment of external secretion disorders except hypolacrimation.
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Gynecology & Obstetrics (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BR0005010-5A BR0005010A (en) | 1999-02-18 | 2000-02-15 | Composition for the treatment of external secretion disorders except hypolacrimation and its use |
MXPA00010193A MXPA00010193A (en) | 1999-02-18 | 2000-02-15 | Composition for treatment of external secretion disorders except hypolacrimation. |
CA002328877A CA2328877A1 (en) | 1999-02-18 | 2000-02-15 | Composition for treatment of external secretion disorders except hypolacrimation |
JP2000599253A JP2003516309A (en) | 1999-02-18 | 2000-02-15 | Agents for treating exocrine disorders except tear secretion disorders |
AU24624/00A AU2462400A (en) | 1999-02-18 | 2000-02-15 | Composition for treatment of external secretion disorders except hypolacrimation |
IL13907100A IL139071A0 (en) | 1999-02-18 | 2000-02-15 | A composition containing an aldose reduction inhibitor for treatment of external secretion disorders |
EP00902961A EP1073666A1 (en) | 1999-02-18 | 2000-02-15 | Composition for treatment of external secretion disorders except hypolacrimation |
US09/673,563 US6339088B1 (en) | 1999-02-18 | 2000-02-15 | Composition for treatment of external secretion disorders except hypol acrimation |
NO20005216A NO20005216D0 (en) | 1999-02-18 | 2000-10-17 | Composition for the treatment of external secretion disorders except hypolacrimation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12072599P | 1999-02-18 | 1999-02-18 | |
US60/120,725 | 1999-02-18 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2000048447A2 true WO2000048447A2 (en) | 2000-08-24 |
WO2000048447A3 WO2000048447A3 (en) | 2001-01-25 |
Family
ID=22392173
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2000/000810 WO2000048447A2 (en) | 1999-02-18 | 2000-02-15 | Composition for treatment of external secretion disorders except hypolacrimation |
Country Status (11)
Country | Link |
---|---|
US (1) | US6339088B1 (en) |
EP (1) | EP1073666A1 (en) |
JP (1) | JP2003516309A (en) |
AR (1) | AR029335A1 (en) |
AU (1) | AU2462400A (en) |
BR (1) | BR0005010A (en) |
CA (1) | CA2328877A1 (en) |
IL (1) | IL139071A0 (en) |
MX (1) | MXPA00010193A (en) |
NO (1) | NO20005216D0 (en) |
WO (1) | WO2000048447A2 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1064965A2 (en) * | 1999-06-30 | 2001-01-03 | Pfizer Products Inc. | Combinations of aldose reductase inhibitors and selective cyclooxygenase-2 inhibitors |
JP2002265375A (en) * | 2001-03-13 | 2002-09-18 | Inabata Koryo Kk | Salivation promoter and food composition and composition for oral cavity each containing the same |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003243603A1 (en) * | 2002-06-13 | 2003-12-31 | Board Of Regents, The University Of Texas System | Methods and compositions involving aldose reductase inhibitors |
WO2006013914A1 (en) * | 2004-08-06 | 2006-02-09 | Daiichi Pharmaceutical Co., Ltd. | Preparation for administration to mouth mucosa |
US20110092566A1 (en) * | 2004-11-19 | 2011-04-21 | Srivastava Satish K | Treatment of cancer with aldose reductase inhibitors |
EP2848252A3 (en) | 2007-03-23 | 2015-06-17 | The Board of Regents of the University of Texas System | Aldose reductase inhibitors for use in treating uveitis |
US20090270490A1 (en) * | 2008-04-24 | 2009-10-29 | The Board Of Regents Of The University Of Texas System | Methods involving aldose reductase inhibition |
ITUB20152695A1 (en) * | 2015-07-31 | 2017-01-31 | Metis Healthcare S R L | COMPOSITION FOR THE INCREASE OF HUMOR SECRATIONS |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4734419A (en) * | 1985-10-07 | 1988-03-29 | Fujisawa Pharmaceutical Co., Ltd. | Quinazoline derivatives, compositions thereof and their use in treating diabetic complications |
EP0301466A2 (en) * | 1987-07-29 | 1989-02-01 | Fujisawa Pharmaceutical Co., Ltd. | Uricosuric composition |
EP0331059A2 (en) * | 1988-02-29 | 1989-09-06 | Fujisawa Pharmaceutical Co., Ltd. | Antihypertensive composition containing a dioxoquinazoline derivative |
WO2000001676A1 (en) * | 1998-07-02 | 2000-01-13 | Neurosearch A/S | Potassium channel blocking agents |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000043015A1 (en) * | 1999-01-25 | 2000-07-27 | Fujisawa Pharmaceutical Co., Ltd. | Eye drops |
-
2000
- 2000-02-15 US US09/673,563 patent/US6339088B1/en not_active Expired - Fee Related
- 2000-02-15 CA CA002328877A patent/CA2328877A1/en not_active Abandoned
- 2000-02-15 EP EP00902961A patent/EP1073666A1/en not_active Withdrawn
- 2000-02-15 AU AU24624/00A patent/AU2462400A/en not_active Abandoned
- 2000-02-15 IL IL13907100A patent/IL139071A0/en unknown
- 2000-02-15 JP JP2000599253A patent/JP2003516309A/en active Pending
- 2000-02-15 BR BR0005010-5A patent/BR0005010A/en not_active Application Discontinuation
- 2000-02-15 MX MXPA00010193A patent/MXPA00010193A/en unknown
- 2000-02-15 WO PCT/JP2000/000810 patent/WO2000048447A2/en not_active Application Discontinuation
- 2000-02-17 AR ARP000100686A patent/AR029335A1/en unknown
- 2000-10-17 NO NO20005216A patent/NO20005216D0/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4734419A (en) * | 1985-10-07 | 1988-03-29 | Fujisawa Pharmaceutical Co., Ltd. | Quinazoline derivatives, compositions thereof and their use in treating diabetic complications |
EP0301466A2 (en) * | 1987-07-29 | 1989-02-01 | Fujisawa Pharmaceutical Co., Ltd. | Uricosuric composition |
EP0331059A2 (en) * | 1988-02-29 | 1989-09-06 | Fujisawa Pharmaceutical Co., Ltd. | Antihypertensive composition containing a dioxoquinazoline derivative |
WO2000001676A1 (en) * | 1998-07-02 | 2000-01-13 | Neurosearch A/S | Potassium channel blocking agents |
Non-Patent Citations (3)
Title |
---|
AO S ET AL: "Effect of instillation of aldose reductase inhibitor FR74366 on diabetic cataract." INVESTIGATIVE OPHTHALMOLOGY AND VISUAL SCIENCE, (1991 NOV) 32 (12) 3078-83., XP000951485 * |
DATABASE WPI Section Ch, Week 200042 Derwent Publications Ltd., London, GB; Class B02, AN 2000-482892 XP002149309 & WO 00 43015 A (FUJISAWA PHARM CO LTD), 27 July 2000 (2000-07-27) * |
KANAMARU, MITSUTAKA ET AL: "Aldose reductase inhibitory and uricosuric activities of FK366 in healthy volunteers" J. CLIN. PHARMACOL. (1993), 33(11), 1122-31, XP000951478 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1064965A2 (en) * | 1999-06-30 | 2001-01-03 | Pfizer Products Inc. | Combinations of aldose reductase inhibitors and selective cyclooxygenase-2 inhibitors |
EP1064965A3 (en) * | 1999-06-30 | 2003-02-12 | Pfizer Products Inc. | Combinations of aldose reductase inhibitors and selective cyclooxygenase-2 inhibitors |
JP2002265375A (en) * | 2001-03-13 | 2002-09-18 | Inabata Koryo Kk | Salivation promoter and food composition and composition for oral cavity each containing the same |
Also Published As
Publication number | Publication date |
---|---|
IL139071A0 (en) | 2001-11-25 |
WO2000048447A3 (en) | 2001-01-25 |
BR0005010A (en) | 2002-03-19 |
EP1073666A1 (en) | 2001-02-07 |
MXPA00010193A (en) | 2002-04-17 |
AR029335A1 (en) | 2003-06-25 |
CA2328877A1 (en) | 2000-08-24 |
US6339088B1 (en) | 2002-01-15 |
NO20005216D0 (en) | 2000-10-17 |
AU2462400A (en) | 2000-09-04 |
JP2003516309A (en) | 2003-05-13 |
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