EP1268849A2 - Systemes de reactifs pour detecter la presence d'un cofacteur reduit dans un echantillon et leurs procedes d'utilisation - Google Patents

Systemes de reactifs pour detecter la presence d'un cofacteur reduit dans un echantillon et leurs procedes d'utilisation

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Publication number
EP1268849A2
EP1268849A2 EP01916527A EP01916527A EP1268849A2 EP 1268849 A2 EP1268849 A2 EP 1268849A2 EP 01916527 A EP01916527 A EP 01916527A EP 01916527 A EP01916527 A EP 01916527A EP 1268849 A2 EP1268849 A2 EP 1268849A2
Authority
EP
European Patent Office
Prior art keywords
signal producing
electron transfer
reagent
transfer agent
analyte
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Withdrawn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
EP01916527A
Other languages
German (de)
English (en)
Inventor
Tianmei Ouyang
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.)
LifeScan Inc
Original Assignee
LifeScan Inc
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 LifeScan Inc filed Critical LifeScan Inc
Publication of EP1268849A2 publication Critical patent/EP1268849A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/26—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase
    • C12Q1/32—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving oxidoreductase involving dehydrogenase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/902—Oxidoreductases (1.)
    • G01N2333/90212—Oxidoreductases (1.) acting on a sulfur group of donors (1.8)

Definitions

  • the field of this invention is analyte detection, particularly reagent systems for use in analyte detection
  • Analyte detection in physiological fluids is of ever increasing importance to today's society
  • Analyte detection assays find use in a variety of applications, including clinical laboratory testing, home testing, etc , where the results of such testing play a prominent role in diagnosis and management in a variety of disease conditions
  • Analytes of interest include alcohol, formaldehyde, glucose, glutamic acid, glycerol, beta-hydroxybutyrate, L-lactate, leucine, malic acid, pyruvic acid, steroids, etc
  • a variety of analyte detection protocols and devices for both clinical and home use have been developed
  • Many of the protocols and devices that have been developed to date employ a signal producing system to identify the presence of the analyte of interest in a physiological sample, such as blood
  • One type of signal producing system that finds use in the detection of a variety of different analytes is one in which a dehydrogenase oxidize
  • U S Patents of interest include 4,629,697, 5, 126,247 and 5,902,731 See also Raap et al , Histochem J (1983) 15 881-893 SUMMARY OF THE INVENTION
  • Signal producing systems, reagent compositions, test strips and kits of the same, as well as methods for their use in the detection of an analyte in a sample are provided
  • the subject signal producing systems are characterized by having at least a first and second electron transfer agent and a redox indicator, where in many preferred embodiments the systems include a proteinaceous and non-proteinaceous electron transfer agent, e g a phenazine compound and a diaphorase
  • the subject systems and kits further include both an enzyme cofactor and an enzyme having an analyte oxidizing activity, e g an analyte dehydrogenase
  • the subject systems, reagent compositions, test strips and kits find use in the detection of a wide variety of analytes in a sample
  • FIGURES Fig 1 provides a graphical representation of the observed rate of reaction in a test strip according to the subject invention vs the theoretical expected rate of reaction for a test strip that includes both PMS and a diaphorase, clearly demonstrating that the use of both a non-proteinaceous and proteinaceous electron transfer agent, e g PMS and a diaphorase, provides for an unexpected increase in the rate of reaction
  • the subject signal producing systems are characte ⁇ zed by having at least a first and second electron transfer agent and a redox indicator, where in many preferred embodiments the systems include a proteinaceous and non-proteinaceous electron transfer agent, e g a phenazine compound and a diaphorase
  • the subject systems and kits further include both an enzyme cofactor and an enzyme having an analyte oxidizing activity, e g an analyte dehydrogenase
  • the subject systems, reagent compositions, test strips and kits find use in the detection of a wide variety of analytes in a sample, such as a physiological sample, e g blood or a fraction thereof
  • the subject invention provides a signal producing system that is capable of detecting the presence of a reduced enzyme cofactor in a sample
  • signal producing system is meant a collection of two or more compounds or molecules which are capable of acting in concert, when combined, to produce a detectable signal that is indicative of the presence of, and often amount of, a particular analyte in a given sample
  • the term signal producing system is used broadly to encompass both a mixture of all of the reagent constituents of the signal producing system as well as a system in which one or more of the reagent constituents are separated from the remainder of the reagent constituents, e g as is present m a kit
  • a feature of the subject signal producing systems is the presence of two distinct electron transfer agents
  • electron transfer agent is meant a compound or molecule that can transfer an electron, m the form of a hydride ion, from a reduced enzyme cofactor to a redox indicator
  • the first of the distinct electron transfer agents is a low molecular weight molecule
  • the second electron transfer agent is a high molecular weight molecule
  • low molecular weight means a molecular weight that does not exceed about 2000 daltons, usually about 1000 daltons and m many embodiments about 500 daltons
  • High molecular weight means a molecular weight of at least about 5000 daltons and in many embodiments 10,000 or 20,000 daltons or higher
  • the molecular weight of the high molecular weight electron transfer agent often will not exceed about 100,000 daltons
  • the low molecular weight electron transfer agent is a non-proteinaceous compound while the high molecular weight electron transfer agent is a proteinaceous compound
  • proteinaceous is meant a
  • a variety of low molecular weight non-proteinaceous electron transfer agents are of interest These agents include flavins such as riboflavin (RBF), alloxazine (ALL) and lumichrome (LC), phenazines such as phenazine, phenazine methosulfate (PMS), phenazine ethosulfate, methoxyphenazine methosulfate and safranine, methyl- 1, 4-naphthol (menadione), phenothiazines such as PT and its radical cation, PT+, thionin (TH), azure A (AA), azure B (AB), azure C (AC), methylene blue (MB), methylene green (MG) and toluidine blue O (TOL), phenoxazines such as phenoxazine (POA), basic blue 3 (BB3), and brilliant cresyl blue ALD (BCBA), benzo- -phenazo
  • the high molecular weight proteinaceous electron transfer agent is an enzyme that is capable of oxidizing a reduced cofactor, e g NAD(P)H, and concomitantly reducing a redox indicator.
  • this electron transfer enzyme is a diaphorase, such as lipoic dehydrogenase, ferredoxin-NADP reductase, lipoamide dehydrogenase, NADPH dehydrogenase, etc
  • diaphorases are available and may be employed, where representative commercially available diaphorases that may be present in the subject signal producing systems include bacillus diaphorase, clostridium diaphorase, vibrio diaphorase, porcine diaphorase, and the like
  • the ratio of the first to the second electron transfer agent is chosen to provide for an accelerated reaction rate as compared to a control, e g a comparable signal producing system with a single electron transfer agent, e g only PMS or a diaphorase
  • the ratio of the first to the second electron transfer agent in the subject systems ranges from about 0 001 to 10, usually from about 0 01 to 1 0 and more usually from about 0 05 to 0 5 (nmole/U), respectively
  • the subject signal producing systems also include a redox indicator
  • redox indicator is meant a compound that is capable of being reduced by the electron transfer agents to produce a detectable, e g chromogemc, product Where the redox indicator produces a chromogenic product, i.e.
  • the redox indicator is a chromogen
  • suitable chromogens are any compound capable of changing color upon reduction by one or more electrons, where suitable chromogens are generally ones that accept electrons from the electron transfer agents, described above.
  • a variety of different redox indicator compounds are of interest.
  • Compounds of interest include: oxazines, thiazines, and tetrazolium salts.
  • tetrazolium salts which are capable of accepting the captured hydride from the electron transfer agents to form a colored formazan product.
  • these salts have the advantageous feature of being faint yellow in the oxidized form, but turn bright visible colors upon electron reduction and conversion to formazan dyes.
  • Tetrazolium compounds or salts that are of particular interest include: 2-(2' benzothiazolyl)-5-styryl-3- (4'-phthalhydrazidyl) tetrazolium (BSPT); 2-benzothiazolyl-(2)-3,5-diphenyl tetrazolium (BTDP); 2,3-di(4-nitrophenyl) tetrazolium (DNP); 2,5-diphenyl-3-(4-styrylphenyl) tetrazolium (DPSP); distyryl nitroblue tetrazolium (DS-NBT); 3,3'-[3,3'-dimethoxy-(l,l - biphenyl)-4,4'-diyl]-bis[2-(4-nitrophenyl)-5- phenyl(-2H tetrazolium (NBT); 3-(4,5- dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium (MTT);
  • WST-5 is preferred in many embodiments because it readily dissolves in an aqueous medium, which is most compatible with biological samples. Furthermore, the resulting formazan compound exhibits strong spectral absorption at the purple-blue region, thus reducing the need for correcting the background signal from hemoglobin.
  • Other useful tetrazolium salts are disclosed in U.S. Pat. Nos.
  • the above described signal producing systems are capable of detecting the presence of a reduced enzyme cofactor in a sample, particularly an aqueous sample and more particularly a physiological sample, e.g. whole blood or a fraction or derivative thereof.
  • a variety of different reduced enzyme cofactors may be detected using the subject signal producing systems, where representative reduced enzyme cofactors include the reduced forms of the following cofactors beta-nicotinamide ademne dinucleotide (beta-NAD), beta- nicotinamide ademne dinucleotide phosphate (beta-NADP), thiomcotinamide ademne dinucleotide, thiomcotinamide ademne dinucleotide phosphate, mcotinamide 1,N6- ethenoademne dmucleotide, mcotinamide l,N6-ethenoademne dinucleotide phosphate, and pyrrolo-quinohne quinone (PQQ)
  • the subject signal producing systems are particularly suited for use in the detection of NADH or NAD(P)H
  • the reduced enzyme cofactor is one that is produced following the oxidation of an analyte of interest in a sample
  • the subject signal producing systems also include the enzyme cofactor and an analyte oxidizing enzyme that is capable of oxidizing the analyte of interest and concomitantly reducing the enzyme cofactor
  • Enzyme cofactors of interest include those desc ⁇ bed above, I e beta-nicotinamide ademne dinucleotide (beta-NAD), beta-nicotinamide ademne dinucleotide phosphate (beta-NADP), thiomcotinamide ademne dmucleotide, thiomcotinamide ademne dinucleotide phosphate, mcotinamide 1 ,N6-ethenoaden ⁇ ne dinucleotide, mcotinamide l,N6-ethen
  • reagent compositions for use in detecting at least a reduced enzyme cofactor, and in many embodiments and analyte, in a sample
  • the reagent compositions may be fluid, e g aqueous, or dry compositions, where in many embodiments the reagent compositions are dry compositions
  • the subject reagent compositions are ones that include the first and second electron transfer agent and the redox indicator, where these components are described above
  • Such reagent compositions are suitable for use in the detection of reduced enzyme cofactors, e g
  • the reagent compositions further include an enzyme cofactor and an analyte oxidizing enzyme, where these components are described above
  • the subject invention provides dry strips for assaying for a particular analyte in whole blood, e g in beta-hydroxybutyrate, glucose, etc
  • the reagent test strip includes a solid support and a dry reagent composition present thereon, where the dry reagent composition is made up of all of the reagent compounds necessary to produce a detectable signal in the presence of the analyte of interest
  • the dry reagent composition present on the subject test strip is one that includes the following members an analyte oxidizing enzyme, an enzyme cofactor, first and second electron transfer agents and a redox indicator, where each of these constituent members are described in greater detail supra.
  • the subject test strips include a membrane test pad that is affixed to a solid support
  • the support may be a plastic - e g , polystyrene, nylon, or polyester - or metallic sheet or any other suitable material known in the art
  • the test pad preferably comprises a bibulous, such as filter paper or polymer membrane Associated with the test pad, e g coated onto the test pad, incorporated into the test pad, etc , is the reagent composition
  • the strip may also be configured in more complex arrangements, e g where the test pad is present between the support and a surface layer, where one or more reagents employed in sample processing may be present on the surface layer
  • flow paths or channels may be present on the test strip, as is known in the art Of interest in many embodiments are the test strip configurations disclosed in U S Patent No 5,902,731. the disclosure of which is herein incorporated by reference
  • the subject test strips may be fabricated employing any convenient protocol
  • One convenient protocol is to contact at least the test pad portion of the strip with an aqueous composition that includes all of the members of the reagent composition that is to be associated with the test pad in the final reagent test st ⁇ p
  • the test pad may be immersed m the aqueous composition, maintained therein for a sufficient pe ⁇ od of time and then d ⁇ ed, whereby the test pad of the reagent test st ⁇ p which has associated therewith the reagent composition is produced
  • the aqueous composition will include the va ⁇ ous members of the reagent composition to be associated with the test pad of the reagent test st ⁇ p, where the va ⁇ ous members are present in amounts sufficient to provide for the desired amounts in the reagent composition that is produced on the test pad
  • the concentration of non-proteinaceous electron transfer agent present in this aqueous composition typically ranges from about 1 ⁇ M to 1000 ⁇ M, usually from about 10 ⁇ M to
  • the analyte oxidizing agent enzyme ranges in concentration from about 100 U to 2000 U, and usually from about 200 U to 1000 U when present
  • Other components that may be present in this aqueous composition employed to prepare the reagent test st ⁇ p include sodium chlo ⁇ de, magnesium chlo ⁇ de, T ⁇ s, PSSA, Tetromc 1307, Crotein-SPA, sucrose, oxamic acid, sodium salt, and the like See the expe ⁇ mental section, infra, for a more detailed desc ⁇ ption of a representative method for prepa ⁇ ng the subject reagent test st ⁇ ps
  • the above desc ⁇ bed signal producing systems, reagent compositions and test st ⁇ ps find use in methods of detecting the presence of, and often the amount of, an analyte in a sample
  • a va ⁇ ety of different analytes may be detected using the subject methods, where representative analytes include those desc ⁇ bed above, e g alcohol, formaldehyde, glucose, glutamic acid, glycerol, beta-hydroxybutyrate, L-lactate, leucine, malic acid, pyruvic acid, steroids, etc
  • the subject methods may be used to determine the presence, and often concentration, of an analyte in a variety of different physiological samples, such as u ⁇ ne, tears, saliva, and the like, they are particularly suited for use in determining the concentration of an analyte in blood or blood fractions, e g blood de ⁇ ved samples, and more particularly in whole blood
  • An important feature of the subject methods is that use of the subject signal producing systems that include
  • the sample and the signal producing system are combined into a reaction mixture, the reaction is allowed to proceed for a sufficient period to time to generate a signal indicative of the presence of (and often amount of) analyte in the sample, and the resultant signal is detected and related to the presence of (and often amount of) analyte in the sample.
  • the reaction mixture may be produced in any convenient environment, such as a cuvette or other fluid containment means.
  • the above steps take place on a reagent test strip as described supra
  • the subject methods are now discussed further in terms of methods in which a reagent test strip is employed
  • the first step is to apply a quantity of the physiological sample to the test strip, where the test strip is described supra
  • the amount of physiological sample, e g blood, that is applied to the test strip may vary, but generally ranges from about 2 ⁇ L to 40 ⁇ L, usually from about 5 ⁇ L to 20 ⁇ L
  • the blood sample size that is applied to the test strip may be relatively small, ranging in size from about 2 ⁇ L to 40 ⁇ L, usually from about 5 ⁇ L to 20 ⁇ L
  • blood samples of a variety of different hematocrits may be assayed with the subject methods, where the hematocrit may range from about 20% to 65%, usually from about 25% to 60%
  • the sample is allowed to react with the members of the signal producing system to produce a detectable product that is present in an amount proportional to the initial amount of the analyte of interest present in the sample
  • kits for use in practicing the subject methods at least include a signal producing system as described above, where the signal producing system components may be combined into a single reagent composition or separated, e g present in separate containers
  • the signal producing system will be present in the kits in the form of a reagent test strip, as described supra
  • the subject kits may further include a means for obtaining a physiological sample
  • the subject kits may further include a means for obtaining a blood sample, such as a lance for sticking a finger, a lance actuation means, and the like
  • the subject kits may include a control solution or standard, e g an analyte control solution that contains a standardized concentration of analyte
  • the kits also include an automated instrument, as described above, for detecting the amount of product produced on the st ⁇ p following sample application and relating the detected product to the amount of analyte in the sample
  • the kits also include an automated instrument, as described above, for detecting the amount of product produced on the st ⁇ p
  • Table 3 provides a comparison of the observed rate and the expected or theoretical rate for the above described assays.
  • Fig 1 provides a graph of the observed rate vs the theoretical rate
  • the reaction rate of the signal producing system of the test strip is accelerated by the presence of both PMS and Diaphorase, where the magnitude of the observed acceleration is unexpectedly greater than the predicted amount of acceleration based on the sum of the reaction rates of systems having PMS or Diaphorase individually
  • the subject invention provides for a significant and unexpected enhancement in the rate of reaction observed in an analyte detection protocol based on the oxidation of an analyte and the concomitant reduction of a redox indicator
  • the subject invention provides for a more economical manner of analyte detection, as compared to certain prior art methods, e g ones that rely solely on diaphorase as the electron transfer agent. As such, the subject invention represents a significant contribution to the art.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Analytical Chemistry (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)

Abstract

L'invention concerne des systèmes de production de signal, des compositions de réactifs, des bandes d'essai ainsi que des matériels composés de ceux-ci, de même que leur procédé d'utilisation dans la détection d'un analyte dans un échantillon. Les systèmes de production de signal de l'invention sont caractérisés en ce qu'ils présentent au moins un premier et un second agent de transfert d'électrons et un indicateur d'oxydoréduction, dans de nombreux modes de réalisation préférés. Les systèmes contiennent un agent de transfert d'électrons protéiniques et non protéiniques, par exemple un composé de phénazine et une diaphorase. Dans de nombreux modes de réalisation préférés, les systèmes et les matériels de l'invention comprennent également au moins un cofacteur enzymatique ou une enzyme et souvent l'un et l'autre présentant une activité d'oxydation d'analyte, par exemple, une déhydrogénase d'analyte. Les systèmes, les compostions de réactifs, les bandes d'essai ainsi que les matériels de l'invention trouvent une utilisation dans la détection d'une large variété d'analytes dans un échantillon, tel qu'un échantillon physiologique, par exemple le sang ou une fraction de celui-ci.
EP01916527A 2000-03-28 2001-03-08 Systemes de reactifs pour detecter la presence d'un cofacteur reduit dans un echantillon et leurs procedes d'utilisation Withdrawn EP1268849A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US53720300A 2000-03-28 2000-03-28
US537203 2000-03-28
PCT/US2001/007619 WO2001073114A2 (fr) 2000-03-28 2001-03-08 Systemes de reactifs pour detecter la presence d'un cofacteur reduit dans un echantillon et leurs procedes d'utilisation

Publications (1)

Publication Number Publication Date
EP1268849A2 true EP1268849A2 (fr) 2003-01-02

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EP01916527A Withdrawn EP1268849A2 (fr) 2000-03-28 2001-03-08 Systemes de reactifs pour detecter la presence d'un cofacteur reduit dans un echantillon et leurs procedes d'utilisation

Country Status (13)

Country Link
EP (1) EP1268849A2 (fr)
JP (1) JP2003528623A (fr)
KR (1) KR20020089412A (fr)
CN (1) CN1419604A (fr)
AR (1) AR027726A1 (fr)
AU (1) AU2001243542A1 (fr)
CA (1) CA2404421A1 (fr)
HK (1) HK1050030A1 (fr)
IL (1) IL151262A0 (fr)
MX (1) MXPA02009469A (fr)
PL (1) PL357180A1 (fr)
RU (1) RU2266543C2 (fr)
WO (1) WO2001073114A2 (fr)

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EP2542887B1 (fr) * 2010-03-01 2013-06-19 System Biologie AG Bandelette réactive pour la détection d'équol
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CN102520150A (zh) * 2011-12-08 2012-06-27 上海高丰医疗电器有限公司 一种伽马-羟基丁酸的测定诊断试纸及其制备方法
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Also Published As

Publication number Publication date
MXPA02009469A (es) 2003-02-24
KR20020089412A (ko) 2002-11-29
PL357180A1 (en) 2004-07-26
WO2001073114A2 (fr) 2001-10-04
AU2001243542A1 (en) 2001-10-08
AR027726A1 (es) 2003-04-09
CA2404421A1 (fr) 2001-10-04
RU2002123839A (ru) 2004-03-10
CN1419604A (zh) 2003-05-21
HK1050030A1 (zh) 2003-06-06
JP2003528623A (ja) 2003-09-30
WO2001073114A3 (fr) 2002-03-28
RU2266543C2 (ru) 2005-12-20
IL151262A0 (en) 2003-04-10

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