EP1085886A1 - Protection des neurones contre l'ischemie - Google Patents

Protection des neurones contre l'ischemie

Info

Publication number
EP1085886A1
EP1085886A1 EP99931068A EP99931068A EP1085886A1 EP 1085886 A1 EP1085886 A1 EP 1085886A1 EP 99931068 A EP99931068 A EP 99931068A EP 99931068 A EP99931068 A EP 99931068A EP 1085886 A1 EP1085886 A1 EP 1085886A1
Authority
EP
European Patent Office
Prior art keywords
bilobalide
patient
effective amount
disease
need
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP99931068A
Other languages
German (de)
English (en)
Inventor
Krish Chandrasekaran
Katy Drieu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ipsen Pharma SAS
Original Assignee
Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
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
Application filed by Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS filed Critical Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Publication of EP1085886A1 publication Critical patent/EP1085886A1/fr
Withdrawn legal-status Critical Current

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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention is directed to the use of EGb 761®, more particularly bilobalide, in protecting neurons from ischemic insults associated with stimulation of mitochondrial gene expression.
  • Ischemia is caused by reduced or severely blocked blood flow, resulting in inadequate supply and loss of function of the affected tissues.
  • the brain is very sensitive to ischemia because it has a high metabolic rate and low oxygen stores and small reserves of high-energy phosphates or carbohydrates.
  • a brief period of global brain ischemia causes cell death in hippocampal CA1 pyramidal neurons days after perfusion (Pulsinelli, W.A., et al., 1982, Ann.
  • COX 1 cytochrome c oxidase subunit 1
  • mtDNA mitochrondriai DNA
  • the extract contains 24% ginkgo-flavone glycosides, 6% terpene lactones (ginkgolides and bilobalide), about 7% proanthocyanidins and several other constituents.
  • ginkgo-flavone glycosides 6% terpene lactones (ginkgolides and bilobalide)
  • proanthocyanidins and several other constituents.
  • Bilobalide accounts for about 3% of the total extract. See Drieu, K., Presse Med, 1986, 15, 1455-1457.
  • a protective role by bilobalide on mitochondrial respiration has been shown (Spinnewyn, B., Blavet, N. and Drieu, K.
  • Ginkgo biloba extract (EGb 761®) on oxygen consumption by isolated cerebral mitochondria
  • EGb 761® Ginkgo biloba extract
  • In vivo administration of EGb 761® was shown to increase mitochondrial respiration after cerebral ischemia in gerbils.
  • the principal component in Ginkgo biloba extract that increased 'state 3' respiration was identified to be bilobalide.
  • this invention is directed to a method of protecting neurons from ischemic insult in a patient in need thereof, which comprises administering to said patient an effective amount of bilobalide.
  • this invention is directed to a pharmaceutical composition useful for protecting neurons from ischemic insult in a patient in need thereof, which comprises a pharmaceutically acceptable carrier and an effective amount of bilobalide.
  • this invention is directed to a pharmaceutical composition useful for protecting neurons from ischemic insult in a patient in need thereof, which comprises a gingko biloba extract comprising an effective amount of bilobalide.
  • this invention is directed to a method of stimulating mitochondrial gene expression in a patient in need thereof, which comprises administering to said patient an effective amount of bilobalide.
  • this invention is directed to a pharmaceutical composition useful for stimulating mitochondrial gene expression in a patient in need thereof, which comprises a pharmaceutically acceptable carrier and an effective amount of bilobalide.
  • this invention is directed to a pharmaceutical composition useful for stimulating mitochondrial gene expression in a patient in need thereof, which comprises a gingko biloba extract comprising an effective amount of bilobalide.
  • this invention is directed to a method of protecting neurons from ischemic insult in a patient in need thereof, which comprises administering to said patient a gingko biloba extract comprising an effective amount of bilobalide.
  • this invention is directed to a pharmaceutical composition useful for protecting neurons from ischemic insult in a patient in need thereof, which comprises a pharmaceutically acceptable carrier and an effective amount of bilobalide.
  • this invention is directed to a pharmaceutical composition useful for protecting neurons from ischemic insult in a patient in need thereof, which comprises a gingko biloba extract comprising an effective amount of bilobalide.
  • this invention is directed to a method of stimulating mitochondrial gene expression in a patient in need thereof, which comprises administering to said patient a gingko biloba extract comprising an effective amount of bilobalide.
  • this invention is directed to a pharmaceutical composition useful for stimulating mitochondrial gene expression in a patient in need thereof, which comprises a pharmaceutically acceptable carrier and an effective amount of bilobalide.
  • this invention is directed to a pharmaceutical composition useful for stimulating mitochondrial gene expression in a patient in need thereof, which comprises a gingko biloba extract comprising an effective amount of bilobalide.
  • This invention is also directed to a method of treating stroke, head trauma, spinal cord trauma, traumatic brain injury, multiinfarct dementia, Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, drug addictions, or an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised, which comprises administering to a patient in need thereof an effective amount of bilobalide.
  • This invention is also further directed to a pharmaceutical composition useful for treating stroke, head trauma, spinal cord trauma, traumatic brain injury, multiinfarct dementia, Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, drug addictions, or an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised, which comprises a pharmaceutically acceptable carrier and an effective amount of bilobalide.
  • This invention is furthermore directed to, a pharmaceutical composition useful for treating stroke, head trauma, spinal cord trauma, traumatic brain injury, multiinfarct dementia, Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, drug addictions, or an ischemic event arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised, which comprises a gingko biloba extract comprising an effective amount of bilobalide.
  • the gingko biloba extract comprising bilobalide is EGb 761®.
  • ginkgo terpenoid as used herein includes all of the naturally occurring terpenes which are derived from the gymnosperms tree Ginkgo biloba as well as synthetically produced ginkgo terpenoids and pharmaceutically active derivatives and salts thereof and mixtures thereof.
  • examples of ginkgo terpenoids include ginkgolides and bilobalide.
  • Examples of ginkgo terpenoids are disclosed in Ginkgolides, Chemistry, Biology, Pharmacology, and Clinical Perspectives, J.R. Provs. Science Publishers, Edited by P. Braguet (1988); F.V. DeFeudis, Ginkgo Biloba Extract (EGb 761®); Pharmacological Activities and Clinical Applications, Elsevier, Chapter II (1991).
  • Bilobalide has the following structure:
  • ginkgolide and bilobalide herein include the various ginkgolides and bilobalide disclosed in the books cited above as well as non-toxic pharmaceutically active derivatives thereof.
  • examples of ginkgolide and bilobalide derivatives include tetrahydro derivatives, acetyl derivatives, and alkyl esters such as the monoacetate derivatives and triacetate derivatives disclosed in Okabe, et al., J. Chem. Soc. (c), pp. 2201-2206 (1967).
  • ginkgo biloba extract includes a collection of natural molecules, including terpenoids, derived from the ginkgo biloba tree.
  • the extract is the ginkgo biloba extract EGb 761®.
  • Bilobalide can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant
  • nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • bilobalide is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of steriie solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.
  • Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • the dosage of bilobalide in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the dose can be administered as a single dose or divided into multiple doses.
  • Bilobalide may be administered in an amount of 0.05 to 2 mg/kg body weight of the patient or, preferably, administered in an amount of 0.1 to 1 mg/kg body weight of the patient.
  • a pharmaceutical composition of bilobalide includes within its meaning an extract of ginkgo biloba which contains bilobalide, such as EGb 761®. It should be noted that not all extracts of ginkgo biloba contains bilobalide, however, EGb 761® (which is also known as TANAKAN®, R_KAN®, TEBONIN®, TANAKENE®, and TEBOFORTAN®) does.
  • EGb 761® which is also known as TANAKAN®, R_KAN®, TEBONIN®, TANAKENE®, and TEBOFORTAN®
  • PC12S rat pheochromocytoma PC12 cells
  • NGF nerve growth factor
  • PC12S a morphological variant of rat pheochromocytoma PC12 cells, called PC12S, that retains the ability to grow attached to plastic tissue culture dish, is used.
  • PC12S cells are grown in DMEM medium (Bio Fluids, Rockville, Maryland) containing 2 mM glutamine, 7.5% heat inactivated fetal calf serum, and 7.5% heat inactivated horse serum, with penicillin-streptomycin (Bio Fluids, Rockville, Maryland).
  • Nerve growth factor (NGF) (Life Technologies, MD, USA) was added at a concentration of 50 ng/ml. Two days after addition of NGF, PC12S cells demonstrate prominent neurite outgrowth, and after 5 days, their morphology resembles that of sympathetic neurons. All experiments are done on cells that are maintained in the presence of
  • Bilobalide was obtained from Dr. Katy Drieu, (IPSEN, France), it is also available from Sigma (St. Louis, Missouri). Ouabain is dissolved in water, whereas, bilobalide is dissolved in 95% ethanol. When ethanol is used as a solvent, appropriate control experiments are conducted using vehicle alone. Ethanol concentrations are always ⁇ 0.1 %. In studies related to the effect of pretreatment of bilobalide, cells are treated with 10 ⁇ g/ml for about 24 hours and then ouabain is added and total RNA is isolated at various time periods.
  • PC12S cells grown in presence of NGF are used. Cells are treated with drugs for various periods of time, 0, 1 , 3, 6, 12, 24 and 48 hours after addition of drug. Cells are then washed once with DPBS (Dulbecco's Phosphate Buffered Saline; Bio-Fluids, Rockville, Maryland) without calcium and magnesium and total RNA is isolated using the TRIzol reagent (Life Technologies, MD, USA). One ml of TRIzol reagent is added directly to the dish and placed in a rocker for about 5 min. The suspension is then transferred to a 2 ml eppendorf centrifuge tube containing 0.2 ml of chloroform.
  • DPBS Dynabecco's Phosphate Buffered Saline
  • Bio-Fluids Rockville, Maryland
  • the tube is vortexed for about 15 seconds and is centrifuged for about 15 min at about 4 °C.
  • the aqueous phase is removed and total RNA is precipitated with half-volume of isopropanol.
  • the total RNA is pelleted by centrifugation of about 13,000 g for about 15 min at about 4 ° C, the pellet is washed once with 70% ethanol, dried and suspended in 100 ⁇ l of DEPC (diethyl pyrocarbonate; Sigma, St. Louis, Missouri) treated water.
  • DEPC diethyl pyrocarbonate
  • Northern blot analysis Ten ⁇ g of total RNA is run on a 1.2% formaldehyde agarose gel and transferred onto a GeneScreen membrane as described by the manufacturer (Dupont, New England Nuclear, Massachusetts, USA).
  • Prehybridization is done by about 16 hours at about 42 °C using the hybridizol reagent (Oncor, MD, USA; Hybridizol I and Hybridizol II mixed in the ratio of 4:1 ). Hybridization is done by about 48 hours at about 42 °C in the same solution with the addition of [ 32 P] labeled cytochrome oxidase subunit III (COX III) probe.
  • Blots are exposed to X-ray film (Biomax MS, Kodak, Rochester, NY, USA) with an intensifying screen for about 45 min to about 2 days at about -70 °C. The probe is removed form the blots by placing the blots in boiling DEPC-treated water for about 10 min.
  • RNA hybridized is quantified using an image analysis program (NIH image 1.54) from autoradiograms of lower exposure than is used for photography. Ratios of COX III mRNA to ⁇ actin mRNA are calculated.
  • Cytochrome oxidase subunit III probe is prepared by poiymerase chain reaction (PCR) using rat genomic DNA and primers corresponding to rat mtDNA sequence.
  • the PCR conditions are as follows: 30 cycles for about 1 min at about 94 °C, about 30 sec at about 55 °C, and about 1 min at about 72 °C.
  • the PCR product (565 bp) is purified by agarose gel electrophoresis separation, elution and alcohol precipitation (Quiagen, CA, USA), ⁇ actin probe is prepared by isolating the cDNA insert from the plasmid clone (ATCC-# 78554, American Type Culture Collection, MD, USA).
  • the probes are labeled using the random primer method and purified by gel-filtration (Pharmacia, NJ, USA).
  • PC12S cells were differentiated with NGF for 10 days. The cells were treated with the vehicle for various periods of time and total RNA was isolated. The total RNA samples were subjected to northern blot analysis with a probe for the mtDNA-encoded COX III gene and with a probe for ⁇ actin gene.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Vascular Medicine (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un extrait de ginko biloba, comprenant un bilobalide utilisé pour protéger les neurones contre les agressions ischémiques, et pour stimuler une expression génique mitochondriale.
EP99931068A 1998-06-11 1999-06-10 Protection des neurones contre l'ischemie Withdrawn EP1085886A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US9686998A 1998-06-11 1998-06-11
US8912698P 1998-06-11 1998-06-11
US89126P 1998-06-11
US96869 1998-06-11
PCT/EP1999/004098 WO1999064028A1 (fr) 1998-06-11 1999-06-10 Protection des neurones contre l'ischemie

Publications (1)

Publication Number Publication Date
EP1085886A1 true EP1085886A1 (fr) 2001-03-28

Family

ID=26780277

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99931068A Withdrawn EP1085886A1 (fr) 1998-06-11 1999-06-10 Protection des neurones contre l'ischemie

Country Status (8)

Country Link
EP (1) EP1085886A1 (fr)
JP (1) JP2002517456A (fr)
KR (1) KR20010078734A (fr)
AU (1) AU4772099A (fr)
CA (1) CA2331918A1 (fr)
IL (1) IL140196A0 (fr)
NO (1) NO20006243L (fr)
WO (1) WO1999064028A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7226916B1 (en) 2000-05-08 2007-06-05 N.V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
US7585523B2 (en) * 2002-08-27 2009-09-08 Targeted Medical Pharma Composition and method to augment and sustain neurotransmitter production
KR100623164B1 (ko) * 2004-07-22 2006-09-19 재단법인서울대학교산학협력재단 뇌신경 보호효과를 갖는 신규한 은행잎 엑스를 정제하는방법 및 이를 함유하는 조성물
KR100723609B1 (ko) * 2006-04-28 2007-06-04 주식회사 유유 신규한 조성의 알츠하이머형 치매 및 파킨슨씨병 예방 또는 치료용 은행잎 추출물, 그리고 은행잎으로부터의 추출 및 정제 방법
FR2904222A1 (fr) 2006-07-27 2008-02-01 Sod Conseils Rech Applic Utilisation d4extraits de ginkgo biloba pour le traitement de maladies mitochondriales
RU2464977C2 (ru) * 2006-08-23 2012-10-27 Тзе Юнивесити Оф Монтана Способ снижения частоты поражения или гибели нервных клеток
WO2012047063A2 (fr) * 2010-10-08 2012-04-12 제일약품주식회사 Composition pharmaceutique pour aider au traitement de la démence ou pour traiter la démence, contenant seulement un extrait d'angelica gigas nakai, seulement un extrait de feuille de ginkgo, ou un mélange d'extrait d'angelica gigas nakai et d'extrait de feuille de ginkgo
CN105125897A (zh) * 2015-10-05 2015-12-09 南京多宝生物科技有限公司 一种含天麻的植物组合物提取方法和应用
CN110893183A (zh) * 2018-09-13 2020-03-20 成都百裕制药股份有限公司 银杏萜内酯在制备预防、缓解或治疗肌萎缩侧索硬化药物中的应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3338995A1 (de) * 1983-10-27 1985-05-09 Dr. Willmar Schwabe GmbH & Co, 7500 Karlsruhe Bilobalid enthaltende arzneimittel
DE3940094A1 (de) * 1989-12-04 1991-06-06 Montana Ltd Wirkstoffkonzentrate und neue wirkstoff-kombinationen aus blaettern von ginkgo biloba, ein verfahren zu ihrer herstellung und die wirkstoff-konzentrate bzw. die wirkstoff-kombinationen enthaltenden arzneimittel
IT1238684B (it) * 1990-02-09 1993-09-01 Indena Spa Derivati del bilobalide,loro usi e formulazioni che li contegono

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9964028A1 *

Also Published As

Publication number Publication date
JP2002517456A (ja) 2002-06-18
KR20010078734A (ko) 2001-08-21
IL140196A0 (en) 2002-02-10
NO20006243L (no) 2001-02-08
WO1999064028A1 (fr) 1999-12-16
NO20006243D0 (no) 2000-12-08
CA2331918A1 (fr) 1999-12-16
AU4772099A (en) 1999-12-30

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