EP1481416A1 - Mass spectrometry method for analysing mixtures of substances - Google Patents
Mass spectrometry method for analysing mixtures of substancesInfo
- Publication number
- EP1481416A1 EP1481416A1 EP03711878A EP03711878A EP1481416A1 EP 1481416 A1 EP1481416 A1 EP 1481416A1 EP 03711878 A EP03711878 A EP 03711878A EP 03711878 A EP03711878 A EP 03711878A EP 1481416 A1 EP1481416 A1 EP 1481416A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mass
- ionization
- quadrupole
- analysis
- substances
- 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.)
- Granted
Links
Classifications
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/004—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn
- H01J49/0045—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn characterised by the fragmentation or other specific reaction
- H01J49/005—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn characterised by the fragmentation or other specific reaction by collision with gas, e.g. by introducing gas or by accelerating ions with an electric field
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/26—Mass spectrometers or separator tubes
- H01J49/34—Dynamic spectrometers
- H01J49/42—Stability-of-path spectrometers, e.g. monopole, quadrupole, multipole, farvitrons
- H01J49/4205—Device types
- H01J49/421—Mass filters, i.e. deviating unwanted ions without trapping
Definitions
- the present invention relates to a mass spectrometric method for analyzing substance mixtures using a triple quadrupole mass spectrometer.
- the samples can be used for the aforementioned analyzes and individual substances in selected samples can be identified and quantified.
- HTS high-throughput screening
- the advantage of very precise methods such as NMR or IR spectroscopy is that they provide information about both the structure and, if appropriate, the quantity of a substance.
- High molecular weight materials such as coal tar, humic acid, fulvic acid or kerogens can also be analyzed (Zenobie and Knochenmuss, Mass Spec. Rev., 1998, 17, 337 - 366). Both the identity and the structure of substances can be determined, although the structural analysis is not always clear, so that it has to be confirmed using other methods, for example NMR.
- G. Hopfgartner and F. Vilbois describe a method for screening with the aid of LC / MS of metabolites of structurally known compounds which are formed in vitro or in vivo and which are known as Active ingredients are in different phases of drug development. This process takes place in two steps. In the first search step, interesting ions are detected in a rapid "fill scan mode", which can be considered as candidates for further investigations. men. These can be ions which correspond to ions of particularly high intensity or can be considered as candidates for possible degradation products or metabolites of the active ingredients. These ions are used in a second scan to identify the chemical structure of these ions or compounds after fragmentation in a collision chamber of the mass spectrometer.
- the collision chamber constantly contains collision gas in order to enable a rapid elucidation of the ion or metabolite structure.
- a disadvantage of the structure determination is that a known mass of a precursor ion, a fragment or an ion adduct is required.
- the starting structure of the substance to be investigated for HPLC / MS should advantageously be known in these experiments. Since HPLC / MS alone is not suitable for the absolute structure determination. However, if the structure of the parent compound is known, statements can be made about the structure of any metabolites. Since the structure of the substance to be developed as an active ingredient is known, statements about the structure of the unknown metabolites of the active ingredient can be made with some certainty. However, the statement is made more difficult or prevented by possible superimposition of compounds of the same mass other than impurities. A quantification of the compounds is not possible with this method.
- steps (a) to (c) and step (d) can also be carried out in the reverse order.
- Substance mixtures in the sense of the invention are in principle all mixtures which contain more than one substance, for example complex reaction mixtures of chemical syntheses such as synthesis products from combinatorial chemistry or mixtures of substances of biological origin such as fermentation broths of an aerobic or anaerobic fermentation, body fluids such as blood, lymph, Urine or stool, reaction products a biotechnological synthesis with one or more free or bound enzymes, extracts of animal material such as extracts from various organs or tissues or plant extracts such as extracts of the entire plant or individual organs such as roots, stems, leaves, flowers or seeds or their mixtures.
- Mixtures of substances of biological origin, such as extracts of animal or vegetable origin, advantageously of vegetable origin are advantageously analyzed in this method.
- the mass spectrometers that can be used in the method usually consist of a sample inlet system, an ionization chamber, an interface, ion optics, one or more mass filters and a detector.
- ion sources known to the person skilled in the art can be used to generate ions in the process.
- these ion sources are coupled via a so-called interface to the following components of the mass spectrometer, for example the ion optics, the mass filter (s) or the detector.
- Interposing an interface has the advantage that the analysis can be carried out without delay.
- the ion source cannot volatile and / or volatile, preferably non-volatile substances are brought directly into the gas phase.
- pre-purifications of substance mixtures can also be carried out via an advantageous chromatographic separation, which have material flows of different widths in the analysis, since these material flows can be processed via the interface.
- the samples to be analyzed or the substances contained therein can also be enriched as a result.
- a wide range of solvents can be processed with the least loss of sample.
- EI electron impact ionization
- CI chemical ionization
- Typical reactant gases are, for example, methane, isobutane, ammonium, argon or hydrogen.
- the substance mixtures are vibrationally excited by incident energy-rich particles (radioactive decay, UV, IR photons, Ar + or Cs + ions, laser beams) in a collision cascade and thereby ionized.
- incident energy-rich particles radioactive decay, UV, IR photons, Ar + or Cs + ions, laser beams
- Electrospray ionization is a very gentle method. Ions are continuously formed at ESI. This continuous ion formation has the advantage that it can be easily connected to almost any type of analyzer and that it can be easily combined with a chromatographic see separation such as separation via capillary electrophoresis (CE), liquid chromatography (LC) or high pressure liquid chromatography (HPLC), since it has a good tolerance for high flow rates up to 2 ml / min eluate.
- CE capillary electrophoresis
- LC liquid chromatography
- HPLC high pressure liquid chromatography
- the spraying of the eluent is pneumatically supported by a so-called nebulizing gas, for example nitrogen.
- the gas is blown out of a capillary under a pressure of up to 4 bar, advantageously up to 2 bar, which encloses the inlet capillary of the eluent.
- so-called normal phase e.g. silica gel, aluminum oxide, aminodeoxyhexite, aminodeoxy-d-glucose, triethylenetetramine, polyethylene oxide or aminodicarboxy columns
- / or reversed-phase columns are preferably reversed-phase columns
- Columns such as columns with a C 4 Cg or Cis stationary phase are preferred.
- the electrospray technique leads to the (quasi) molecular ion due to the extremely gentle ionization. These are usually adducts with ions already present in the sample solution (eg protons, alkali and / or ammonium ions). Another advantage is that multiply charged ions can also be detected, so that ions with a molecular weight of up to a hundred thousand daltons can be detected. In the method according to the invention, molecular weights in a range from 1 to 10,000 daltons, preferably in a range, can advantageously be detected from 50 to 8000 daltons, particularly preferably in a range from 100 to 4000 daltons. Ion spray ionization, atmospheric pressure ionization (APCI) or thermoset ionization may be mentioned as further exemplary methods.
- APCI atmospheric pressure ionization
- thermoset ionization may be mentioned as further exemplary methods.
- the ionization process takes place under atmospheric pressure and is essentially divided into three phases:
- the solution to be analyzed is in a strong electrostatic field, which is advantageous by generating a potential difference of 2-10 kV, 2-6 kV , is generated between the inlet capillary and a counter electrode.
- An electrical field between the inlet capillary tip and the mass spectrometer penetrates the analyte solution and separates the ions in an electrical field.
- Positive ions are drawn to the surface of the liquid in the so-called positive mode, negative ions in the opposite direction or vice versa in measurements in the so-called positive mode.
- the positive ions accumulated on the surface are then pulled further towards the cathode.
- An aerosol is formed, which consists of analyte and solvent.
- the desolvation of the drops formed takes place in the following stage, which leads to the successive reduction in the drop size.
- the evaporation of the solvent is controlled by thermal action, e.g. by supplying hot inert gas. Evaporation in conjunction with the electrostatic forces increases the charge density on the surface of the sprayed substance mixture droplets. If the charge density or its charge repulsion forces then exceeds the surface tension of the droplets (so-called Raleigh limit), these droplets explode (Coulomb explosion) into smaller partial droplets. This process "solvent evaporation / Coulomb explosion” is repeated several times until the ions finally pass into the gas phase. To good ones
- the gas flow in the interface, the heating temperature applied, the flow rate of the heating gas, the pressure of the nebulizing gas and the capillary voltage must be precisely monitored and controlled.
- the different ionization processes can be used to generate single or multiple charged ions.
- ES electrospray
- APCI atmospheric pressure chemical ionization
- the ionization takes place in a so-called coronna discharge.
- the thermospray or electrospray method is preferred, and the electrospray method is particularly preferred.
- the ionization space is connected to the following mass spectrometer via an interface, that is to say via a micro-opening (100 ⁇ m).
- curtain gas for example nitrogen
- curtain gas for example nitrogen
- the nitrogen collides with the ions generated, for example, by electrospray, which were generated in the substance mixture.
- Blowing in the curtain gas advantageously prevents neutral particles from being sucked into the high vacuum of the subsequent mass spectrometer. Furthermore, the desolvation of the ions is supported by the curtain gas.
- the method according to the invention can be carried out with all quadrupole mass spectrometers known to the person skilled in the art, such as the triple quadrupole mass spectrometers.
- Triple quadrupole instruments are the standard instruments for low-energy collision activation studies.
- These devices usually consist of a first quadrupole, which is suitable for analyzing the mass / charge quotient (m / z) of the ions contained in the substance mixture after ionization in high vacuum (approx. 10 ⁇ 5 Torr), the mass ( n) individual ions, several or all ions can be measured.
- so-called "cones" lenses or lens systems can also be used to focus and introduce the ions into the first analytical quadrupole. Combinations of quadrupoles and cones can also be implemented and used.
- the ions are advantageously fragmented in it by applying a fragmentation voltage.
- ionization potentials in the range of 5-11 electron volts (eV), preferably 8-11 electron volts (eV), are applied.
- Q2 is also filled with a collision gas such as a noble gas such as argon or helium or another gas such as CO or nitrogen or mixtures of these gases such as argon / helium or argon / nitrogen for the fragmentation in the process according to the invention.
- Argon and / or nitrogen is preferred for reasons of cost.
- the collision gas is present in the process according to the invention with a pressure of 1 ⁇ 10 -5 to 1 ⁇ 10 -1 Torr, preferably 10 ⁇ 2 . Nitrogen is particularly preferred. Even without the application of a fragmentation voltage, the ions in the collision chamber may be fragmented in the presence of a collision gas. Between the qua- drupol Q1 and Q2 may have additional quadrupoles or cones for guiding the ions.
- this Q3 either the m / z quotients of individually selected fragments, several or all of the m / z quotients present in the substance mixtures after ionization (for the sake of simplicity referred to as mass or masses in this application) can be determined 10. Additional quadrupoles or cones can also be present between the quadrupole Q2 and Q3 to direct the ions.
- Collection of ions can also be operated as ion traps
- the ions generated can be held or directed. They usually consist of 4, 6 or 8 rods or rods with the help of which an oscillating electric field is generated, with opposite rods being electrically connected.
- the designations quadrupole the designations hexa-
- the mass of at least one ion present in the substance mixture after ionization in Ql is analyzed and selected.
- This selected ion is then fragmented in Q2 in the presence of collision gas and a fragmentation voltage and then one of the fragment ions formed is identified in a further analytical quadrupole Q3 and advantageously also quantified.
- the fragment ion to be analyzed is selected in such a way that this ion is advantageous has a high intensity, an easily identifiable characteristic mass and, in an advantageous embodiment of the method, enables easy quantification.
- process step (d) the masses of all ions present in the substance mixture after ionization are analyzed, the quadrupole Q2 used as the collision chamber being always filled with collision gas, but in process step (d) no fragmentation voltage being present at Q2.
- this analysis can be carried out both with Q1 and with Q3, but it is more advantageous to carry out the analysis with Q3, since Q2 lies between Q1 and the quadrupole Q2 used as a collision chamber as a collision chamber. If a fragmentation occurs in Q2 despite the absence of a fragmentation voltage, this has no influence on a possible detection of the ion masses at the detector. In the case of a mass analysis with Q1, such a question in Q2 would lead to incorrect conclusions in the detection. Mass detection with Q3 is therefore preferred because possible sources of error are eliminated or are negligible.
- FIG. 1 shows the sequence of the method according to the invention.
- process steps (b) to (d) and (e) are advantageously carried out at least once within 0.1 to 10 seconds, preferably at least once within 0.2 to 6 seconds, particularly preferably within 0.2 to 2 Seconds, very particularly preferably at least once within 0.3 to less than 2 seconds.
- the process steps are carried out two to three times, preferably three times, within 0.2 to 6 seconds.
- the quadrupole Q2 which acts as a collision chamber, is constantly filled with collision gas in order to enable measurements of this type which follow one another rapidly and quickly. As our own measurements showed, this has no negative impact on the reproducibility of the measurements.
- At least 20 m / z quotients, preferably at least 40 m / z quotients, particularly preferably at least 60 m / z quotients, very particularly preferably at least 80 m / z quotients, are advantageous different ions or more identified and / or quantified.
- chromatographic methods Purification by methods known to those skilled in the art, such as chromatographic methods, is, however, advantageous.
- a purification and / or pre-purification of the substance mixtures can be coupled very easily to the mass spectrometric analysis, for example by means of chromatography.
- All separation methods known to the person skilled in the art, such as LC, HPLC or capillary electrophoresis, can be used as the chromatographic method. Separation methods based on adsorption, gel permeation, ion pair, ion exchange, exclusion, affinity, normal phase or reversed phase chromatography, to name just a few, can be used.
- Chromatographs based on normal phase and / or reversed phase, preferably reversed-phase columns with different hydrophobic modified materials such as C 4 -, Cs ⁇ or C ⁇ s ⁇ phases are advantageously used.
- a coupling of purification methods is advantageous from chromatography methods with a flow rate of the eluent (analyte + solvent) advantageously between 1 ⁇ l / min to 2000 ⁇ l / min, preferably between 5 ⁇ l / min to 600 ⁇ l / min, particularly preferably between 10 ⁇ l / min up to 500 ⁇ l / min possible, for example.
- a flow rate of the eluent analyte + solvent
- protic or aprotic polar or non-polar solvents can be used as solvents for the purification process, which can be used with the subsequent analysis. are compatible.
- Suitable solvents are, for example, solvents that carry little or no charges, such as aprotic apolar solvents, which have a low dielectric constant (E ⁇ ⁇ 15), low dipole moments ( ⁇ ⁇ 2.5D) and low E T N values (0.0 - 0.5) are characterized.
- Dipolar organic solvents or mixtures thereof are also suitable as solvents for the process according to the invention.
- suitable solvents are methanol, ethanol, acetonitrile, ether and heptane.
- Weak acidic solvents such as 0.01-0.1% formic acid, acetic acid or trifluoroacetic acid are also suitable.
- Weakly basic solvents such as 0.01-0.1% triethylamine or ammonia are also suitable.
- Strongly acidic or strongly basic solvents such as 5% HCL or 5% triethylamine are also suitable in principle as solvents. Mixtures of the abovementioned solvents are also advantageous.
- the buffers customary in biochemistry are also suitable as solvents, advantageously buffers ⁇ 200 mM, preferably ⁇ 100 mM, particularly preferably ⁇ 50 mM, very particularly preferably ⁇ 20 mM. It is also advantageous, if buffers> 100 mM are used for the preparation of the substance mixture, that the buffers are completely or partially removed, for example by dialysis. Acetate, formate, phosphate, tris, MOPS, HEPES or mixtures thereof may be mentioned as buffers. High buffers and / or salt concentrations negatively influence the ionization processes and should be avoided if necessary.
- the substance mixtures for the method according to the invention which are otherwise only poorly or not at all detectable, can be derivatized before the analysis and thus ultimately analyzed.
- Derivatization is particularly advantageous in cases in which hydrophilic groups are introduced into hydrophobic or volatile compounds, such as esters, amides, lactones, aldehydes, ketones, alcohols, etc., which advantageously also carry an ionizable functionality.
- Examples of such derivatizations are reactions of aldehydes or ketones to oximes, hydrazone or their derivatives or alcohols to esters, for example with symmetrical or mixed anhydrides.
- an internal standard such as e.g. Peptides, amino acids, coenzymes, sugars, alcohols, conjugated alkenes, organic acids or bases are added.
- This internal standard advantageously enables the quantification of the compounds in the mixture. In this way, substances contained in the substance mixture can be more easily analyzed and ultimately quantified.
- Labeled substances are advantageously used as the internal standard, but in principle non-labeled substances are also suitable as the internal standard.
- Such similar chemical compounds are advantageously used as the internal standard, but in principle non-labeled substances are also suitable as the internal standard.
- 15 bonds are, for example, so-called compounds of a homologous series, the members of which differ only by, for example, an additional methylene group.
- at least one isotope is preferably selected from the group 2 H, "c, 15 N ,” 0, 18 0, 33 S, 3 S, 36 S, 35 cl, 37 C1, 2 S ⁇ ,
- a substance is selected that has the highest possible homology to the substances to be analyzed in the mixture, that is to say structural similarity, to the chemical compound to be measured.
- structural similarity to the chemical compound to be measured. The higher the structural similarity, the better the knife
- a ratio of analyte to is advantageous
- the substance mixture samples in the method according to the invention can be prepared manually or advantageously automatically using conventional laboratory robots. Analysis with the mass spectrometer after any chromatographic separation can also be carried out manually or advantageously be carried out automatically.
- mass spectrometry can advantageously be used for the rapid screening of various substance mixtures, for example plant extracts, in what is known as high-throughput screening.
- the method according to the invention is characterized by high sensitivity, good quantifiability, excellent reproducibility, and the lowest sample consumption.
- mixtures of biological origin for example, new mutants of known or unknown enzymatic activities can be quickly obtained after a mutagenesis, for example after a classic mutagenesis with chemical agents such as NTG, radiation such as UV radiation or X-rays or after a so-called site-directed mutagenesis, PCR Mutagenesis, transposon mutagenesis or the so-called gene shuffling.
- FIG. 2 shows the total ion chromatogram of an MRM + fill scan measurement
- MRM multiple reaction monitoring
- FS fill scan
- TIC total ion chromatogram
- XIT sum of several total ion chromatograms.
- the representation of the measurement selected in FIG. 2 shows the summation of the intensities (y-axis) measured on the detector at the respective times (x-axis) from the two mass spectrometric experiments of multiple reaction monitoring (MRM). and the fill scan (FS).
- MRM multiple reaction monitoring
- FS fill scan
- FIG. 3 shows the total ion chromatogram of the MRM experiment from an MRM + FS measurement.
- the representation of the MRM measurement selected in FIG. 3 shows the summation of the intensities (y axis) measured on the detector at the respective times (x axis) from all predefined mass transitions of the MRM experiment.
- the representation selected in FIG. 4 shows the respective measurement results of each individual mass transition (here 30 pieces) in a coordinate cross.
- the FS experiment measured in alternation to the MRM experiment is shown in the TIC in FIG. 5.
- FIG. 6 shows the TIC of the FS experiment.
- FIG. 8 A total ion chromatogram of an MRM + fill scan measurement is shown in FIG. 8 as in FIG. A calibration sample was measured.
- the representation of the measurement selected in FIG. 8 shows the summation of the intensities (y-axis) measured on the detector at the respective times (x-axis) from the mass spectrometric experiment of multiple reaction monitoring.
- FIG. 9 shows an extracted chromatogram in which coenzyme Q 10 was identified.
- FIG. 10 and FIG. 11 show the identification of capsanthin and bixin, respectively.
- FIG. 12 shows a total ion chromatogram of a filling scan of a plant extract.
- FIGS. 13 to 15 show the masses of different analytes in the extracted chromatogram, the assignment of which to a specific structure still has to be made.
Landscapes
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Electron Tubes For Measurement (AREA)
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10208626 | 2002-02-28 | ||
DE10208625 | 2002-02-28 | ||
DE2002108626 DE10208626A1 (en) | 2002-02-28 | 2002-02-28 | Triple quadrupole mass spectrometer, for the analysis of a mixture of substances, especially biological, comprises using structured mass/charge quotients after ionizing |
DE2002108625 DE10208625A1 (en) | 2002-02-28 | 2002-02-28 | Triple quadrupole mass spectrometer, for the analysis of a mixture of substances, especially biological, comprises using structured mass/charge quotients after ionizing |
PCT/EP2003/001274 WO2003073464A1 (en) | 2002-02-28 | 2003-02-10 | Mass spectrometry method for analysing mixtures of substances |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1481416A1 true EP1481416A1 (en) | 2004-12-01 |
EP1481416B1 EP1481416B1 (en) | 2016-06-15 |
Family
ID=27766685
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03711878.3A Expired - Lifetime EP1481416B1 (en) | 2002-02-28 | 2003-02-10 | Mass spectrometry method for analysing mixtures of substances |
Country Status (9)
Country | Link |
---|---|
US (1) | US7196323B2 (en) |
EP (1) | EP1481416B1 (en) |
JP (3) | JP2005526962A (en) |
AU (1) | AU2003218649B2 (en) |
CA (1) | CA2476597C (en) |
ES (1) | ES2590759T3 (en) |
IL (1) | IL163290A (en) |
NO (1) | NO20043943L (en) |
WO (1) | WO2003073464A1 (en) |
Families Citing this family (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7368728B2 (en) * | 2002-10-10 | 2008-05-06 | Universita' Degli Studi Di Milano | Ionization source for mass spectrometry analysis |
AU2006268776B2 (en) * | 2005-07-08 | 2011-07-14 | Metanomics Gmbh | System and method for characterizing a chemical sample |
EP1910959A1 (en) * | 2005-07-25 | 2008-04-16 | Metanomics GmbH | Means and methods for analyzing a sample by means of chromatography-mass spectrometry |
ES2522816T3 (en) | 2006-03-24 | 2014-11-18 | Metanomics Gmbh | Procedure to predict type II diabetes |
US20090194679A1 (en) * | 2008-01-31 | 2009-08-06 | Agilent Technologies, Inc. | Methods and apparatus for reducing noise in mass spectrometry |
DE112009001703T5 (en) | 2008-07-15 | 2011-05-19 | Inserm Institute National De La Sante Et De La Recherche Medicale | Means and methods for diagnosing gastric bypass and related conditions |
EP2350287A2 (en) | 2008-10-23 | 2011-08-03 | BASF Plant Science GmbH | A method for producing a transgenic cell with increased gamma-aminobutyric acid (gaba) content |
CA2690487A1 (en) * | 2009-01-21 | 2010-07-21 | Schlumberger Canada Limited | Downhole mass spectrometry |
WO2010139711A1 (en) | 2009-06-04 | 2010-12-09 | Metanomics Health Gmbh | Means and methods for diagnosing prostate carcinomas |
CA2782415A1 (en) | 2009-12-01 | 2011-06-09 | Metanomics Health Gmbh | Means and methods for diagnosing multiple sclerosis |
EP3502707A1 (en) | 2010-01-29 | 2019-06-26 | metanomics GmbH | Means and methods for diagnosing heart failure in a subject |
US20130140452A1 (en) | 2010-06-01 | 2013-06-06 | Beate Kamlage | Means and methods for diagnosing pancreatic cancer in a subject |
BR112012031232A2 (en) | 2010-06-10 | 2016-10-25 | Metanomics Health Gmbh | method, device and use |
JP6258707B2 (en) | 2010-12-28 | 2018-01-10 | クエスト ダイアグノスティックス インヴェストメンツ インコーポレイテッド | Determination of insulin by mass spectrometry |
CA2834455A1 (en) | 2011-05-31 | 2012-12-06 | Metanomics Health Gmbh | Methods for diagnosing multiple sclerosis |
JP6185464B2 (en) | 2011-07-28 | 2017-08-23 | メタノミクス ゲーエムベーハー | Means and methods for diagnosing and monitoring heart failure in a subject |
WO2013079594A1 (en) | 2011-11-30 | 2013-06-06 | Metanomics Health Gmbh | Device and methods to diagnose pancreatic cancer |
JP2015509603A (en) * | 2012-03-09 | 2015-03-30 | ビーエーエスエフ ソシエタス・ヨーロピアBasf Se | Means and methods for assessing liver disease |
WO2013132460A2 (en) * | 2012-03-09 | 2013-09-12 | Basf Se | Means and methods for assessing disorders related to impaired iron adsorption or energy metabolism |
JP6421118B2 (en) | 2012-10-02 | 2018-11-07 | メタノミクス ヘルス ゲーエムベーハー | Means and method for diagnosis of recurrence of prostate cancer after prostatectomy |
ES2686542T3 (en) | 2012-10-18 | 2018-10-18 | Metanomics Gmbh | Means and procedures for determining a standard amount of clearance of a biomarker of metabolic disease in a sample |
KR101590573B1 (en) * | 2013-07-31 | 2016-02-01 | 주식회사 엘지화학 | Method for evaluating characteristics of a mixture using the combination of pure substances and system using the same |
EP3084443B1 (en) | 2013-12-20 | 2018-08-22 | Metanomics Health GmbH | Means and methods for diagnosing pancreatic cancer in a subject based on a metabolite panel |
GB2531336B (en) * | 2014-10-17 | 2019-04-10 | Thermo Fisher Scient Bremen Gmbh | Method and apparatus for the analysis of molecules using mass spectrometry and optical spectroscopy |
US10324082B2 (en) | 2015-03-03 | 2019-06-18 | Quest Diagnostics Investments Llc | Methods for quantitation of insulin levels by mass spectrometry |
RU2613897C1 (en) * | 2015-12-21 | 2017-03-21 | Федеральное государственное автономное образовательное учреждение высшего образования "Национальный исследовательский Томский политехнический университет" | Volt-ammetric method for determination of coenzyme q10 in cosmetic creams |
WO2017149603A1 (en) * | 2016-02-29 | 2017-09-08 | 株式会社島津製作所 | Mass spectrometer |
WO2018007394A1 (en) | 2016-07-08 | 2018-01-11 | Basf Plant Science Company Gmbh | Method for the calibration of a biological sample |
JP6739080B2 (en) * | 2016-11-17 | 2020-08-12 | 学校法人東京理科大学 | Vitamin D quantification method, mass spectrometer and vitamin D quantification reagent kit |
JP6422525B2 (en) * | 2017-03-29 | 2018-11-14 | 一般財団法人石油エネルギー技術センター | Method and program (CSA1) for approximately specifying the molecular structure of a multicomponent mixture |
EP3602071B1 (en) | 2017-03-31 | 2022-12-07 | Quest Diagnostics Investments LLC | Methods for quantitation of insulin and c-peptide |
JP7090863B2 (en) * | 2017-06-30 | 2022-06-27 | 株式会社サンセイアールアンドディ | Pachinko machine |
EP3502699A1 (en) | 2017-12-20 | 2019-06-26 | Metanomics Health GmbH | Methods for diagnosing pancreatic cancer |
EP3502703A1 (en) | 2017-12-22 | 2019-06-26 | Metanomics Health GmbH | Method for the assessment of nafld |
EP3696822A1 (en) | 2019-02-18 | 2020-08-19 | Metanomics Health GmbH | Means and methods for determining a personalized cutoff value for a biomarker |
US20240230676A1 (en) | 2021-04-30 | 2024-07-11 | Roche Diagnostics Operations, Inc. | Esm1 marker panels for early detection of sepsis |
JP2024516680A (en) | 2021-04-30 | 2024-04-16 | エフ. ホフマン-ラ ロシュ アーゲー | IL6 Marker Panel for Early Detection of Sepsis |
EP4330688A2 (en) | 2021-04-30 | 2024-03-06 | Roche Diagnostics GmbH | Pct marker panels for early detection of sepsis |
CN117321419A (en) | 2021-04-30 | 2023-12-29 | 豪夫迈·罗氏有限公司 | Presepsin marker panel for early detection of sepsis |
US20240230675A1 (en) | 2021-04-30 | 2024-07-11 | Roche Diagnostics Operations, Inc. | Sflt1 marker panels for early detection of sepsis |
CN117280218A (en) | 2021-04-30 | 2023-12-22 | 豪夫迈·罗氏有限公司 | STREM1 marker panel for early detection of sepsis |
US20240230673A1 (en) | 2021-04-30 | 2024-07-11 | Roche Diagnostics Operations, Inc. | Gdf15 marker panels for early detection of sepsis |
WO2022229422A2 (en) | 2021-04-30 | 2022-11-03 | Roche Diagnostics Gmbh | Igfbp7 marker panels for early detection of sepsis |
EP4330685A2 (en) | 2021-04-30 | 2024-03-06 | Roche Diagnostics GmbH | Ngal marker panels for early detection of sepsis |
WO2023052446A1 (en) | 2021-09-29 | 2023-04-06 | F. Hoffmann-La Roche Ag | Mr-proadm marker panels for early detection of sepsis |
WO2023156655A1 (en) | 2022-02-21 | 2023-08-24 | F. Hoffmann-La Roche Ag | Dll1 marker panels for early detection of sepsis |
WO2023175152A1 (en) | 2022-03-18 | 2023-09-21 | Roche Diagnostics Gmbh | Troponin marker combinations for early discrimination of type 2 versus type 1 acute myocardial infarction |
WO2023175176A1 (en) | 2022-03-18 | 2023-09-21 | Roche Diagnostics Gmbh | Cmybpc marker combinations for early discrimination of type 2 versus type 1 acute myocardial infarction |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4540884A (en) * | 1982-12-29 | 1985-09-10 | Finnigan Corporation | Method of mass analyzing a sample by use of a quadrupole ion trap |
US5397894A (en) * | 1993-05-28 | 1995-03-14 | Varian Associates, Inc. | Method of high mass resolution scanning of an ion trap mass spectrometer |
US6093929A (en) * | 1997-05-16 | 2000-07-25 | Mds Inc. | High pressure MS/MS system |
US6140638A (en) * | 1997-06-04 | 2000-10-31 | Mds Inc. | Bandpass reactive collision cell |
US6331702B1 (en) * | 1999-01-25 | 2001-12-18 | University Of Manitoba | Spectrometer provided with pulsed ion source and transmission device to damp ion motion and method of use |
US6428956B1 (en) * | 1998-03-02 | 2002-08-06 | Isis Pharmaceuticals, Inc. | Mass spectrometric methods for biomolecular screening |
AU3489900A (en) * | 1999-02-11 | 2000-08-29 | Maxygen, Inc. | High throughput mass spectrometry |
US6504148B1 (en) * | 1999-05-27 | 2003-01-07 | Mds Inc. | Quadrupole mass spectrometer with ION traps to enhance sensitivity |
WO2001015201A2 (en) * | 1999-08-26 | 2001-03-01 | University Of New Hampshire | Multiple stage mass spectrometer |
BR0111473A (en) * | 2000-06-07 | 2004-01-13 | Univ Duke | Methods for screening an individual for glycogen storage disease, for screening an individual for pomp disease, for monitoring the clinical condition of an individual with pomp disease, to estimate the efficacy of a therapeutic regimen for an individual with disease pompe and to determine the concentration of an oligosaccharide in a biological sample |
CA2340150C (en) * | 2000-06-09 | 2005-11-22 | Micromass Limited | Methods and apparatus for mass spectrometry |
US6586727B2 (en) * | 2000-06-09 | 2003-07-01 | Micromass Limited | Methods and apparatus for mass spectrometry |
US20060141632A1 (en) * | 2000-07-25 | 2006-06-29 | The Procter & Gamble Co. | New methods and kits for sequencing polypeptides |
US7034292B1 (en) * | 2002-05-31 | 2006-04-25 | Analytica Of Branford, Inc. | Mass spectrometry with segmented RF multiple ion guides in various pressure regions |
-
2003
- 2003-02-10 EP EP03711878.3A patent/EP1481416B1/en not_active Expired - Lifetime
- 2003-02-10 US US10/505,154 patent/US7196323B2/en not_active Expired - Lifetime
- 2003-02-10 AU AU2003218649A patent/AU2003218649B2/en not_active Ceased
- 2003-02-10 WO PCT/EP2003/001274 patent/WO2003073464A1/en active Application Filing
- 2003-02-10 ES ES03711878.3T patent/ES2590759T3/en not_active Expired - Lifetime
- 2003-02-10 JP JP2003572064A patent/JP2005526962A/en active Pending
- 2003-02-10 CA CA2476597A patent/CA2476597C/en not_active Expired - Fee Related
-
2004
- 2004-07-29 IL IL163290A patent/IL163290A/en not_active IP Right Cessation
- 2004-09-21 NO NO20043943A patent/NO20043943L/en not_active Application Discontinuation
-
2009
- 2009-09-24 JP JP2009218884A patent/JP2010019848A/en active Pending
-
2013
- 2013-10-11 JP JP2013213955A patent/JP2014041142A/en active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO03073464A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2476597A1 (en) | 2003-09-04 |
US7196323B2 (en) | 2007-03-27 |
AU2003218649B2 (en) | 2007-09-06 |
NO20043943L (en) | 2004-09-21 |
JP2014041142A (en) | 2014-03-06 |
WO2003073464A1 (en) | 2003-09-04 |
EP1481416B1 (en) | 2016-06-15 |
CA2476597C (en) | 2011-05-17 |
JP2010019848A (en) | 2010-01-28 |
ES2590759T3 (en) | 2016-11-23 |
IL163290A (en) | 2014-01-30 |
US20050103991A1 (en) | 2005-05-19 |
AU2003218649A1 (en) | 2003-09-09 |
JP2005526962A (en) | 2005-09-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1481416B1 (en) | Mass spectrometry method for analysing mixtures of substances | |
DE69936168T2 (en) | Mehrfachprobeninlassmassenspektrometer | |
DE10392706B4 (en) | Fast combination multi-mode ionization source for mass spectrometers | |
DE60306355T2 (en) | MICROMATRIX SAMPLE READER BY MEANS OF ELECTROSPRAYMASS SPECTROMETRY | |
DE60120337T2 (en) | Method and apparatus for mass spectrometry | |
DE20122885U1 (en) | mass spectrometry | |
DE112014002710B4 (en) | Procedure for calibrating ion signals | |
DE112014006538T5 (en) | Method of targeted mass spectrometric analysis | |
DE102017000240A1 (en) | IRMS sample introduction system and method | |
DE112014001961T5 (en) | Method for screening samples | |
DE112019003143T5 (en) | Structure analysis of ionized molecules | |
DE102017011423B4 (en) | Method and apparatus for isotope ratio mass spectrometry | |
DE112015000644B4 (en) | Methods of mass spectrometry and mass spectrometer | |
DE112015000977B4 (en) | Ambient ionization with an impactor spray source | |
DE112013006178B4 (en) | Process for ion production | |
DE10292304B4 (en) | Separation of components of an analytical sample in an ion mobility spectrometer by supplying selectively interacting gaseous particles | |
DE3887922T2 (en) | Discharge ionization source for analyzing the atmosphere. | |
DE102018112349B4 (en) | 2Analysis device and method for the analysis of substances by ion mobility spectrometry | |
DE112015004694T5 (en) | ion source | |
DE112015001516B4 (en) | Synchronized variation of source conditions of a chemical ionization mass spectrometer at atmospheric pressure coupled to a chromatograph to improve stability during analysis | |
DE102004033993B4 (en) | Ion source for a mass spectrometer | |
EP0738000B1 (en) | Intermediary storage of ions for spectrometric investigations | |
DE10208625A1 (en) | Triple quadrupole mass spectrometer, for the analysis of a mixture of substances, especially biological, comprises using structured mass/charge quotients after ionizing | |
WO2001094924A2 (en) | Method for analysing enzyme-catalysed reactions using maldi-tof mass spectrometry | |
DE10208626A1 (en) | Triple quadrupole mass spectrometer, for the analysis of a mixture of substances, especially biological, comprises using structured mass/charge quotients after ionizing |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20040928 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK RO |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: DOSTLER, MARTIN Inventor name: WALK, TILMANN, B. |
|
17Q | First examination report despatched |
Effective date: 20100709 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R079 Ref document number: 50315487 Country of ref document: DE Free format text: PREVIOUS MAIN CLASS: H01J0049420000 Ipc: H01J0049000000 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: H01J 49/00 20060101AFI20151207BHEP Ipc: H01J 49/42 20060101ALI20151207BHEP |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
INTG | Intention to grant announced |
Effective date: 20160122 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT SE SI SK TR |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP Ref country code: GB Ref legal event code: FG4D Free format text: NOT ENGLISH |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D Free format text: LANGUAGE OF EP DOCUMENT: GERMAN |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 806864 Country of ref document: AT Kind code of ref document: T Effective date: 20160715 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 50315487 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20160615 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2590759 Country of ref document: ES Kind code of ref document: T3 Effective date: 20161123 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160916 Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 15 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20161017 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 50315487 Country of ref document: DE |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20170316 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170228 Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170210 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20170228 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 16 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170210 Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170210 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MM01 Ref document number: 806864 Country of ref document: AT Kind code of ref document: T Effective date: 20170210 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170210 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20180706 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20170211 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CH Payment date: 20190225 Year of fee payment: 17 Ref country code: GB Payment date: 20190227 Year of fee payment: 17 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20190227 Year of fee payment: 17 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20030210 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20190426 Year of fee payment: 17 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: CY Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20160615 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: TR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20160615 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R119 Ref document number: 50315487 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20200210 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20200229 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20200229 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20200210 Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20200229 Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20200901 |