WO1988007684A2 - Dosage immunologique infrarouge - Google Patents
Dosage immunologique infrarouge Download PDFInfo
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- WO1988007684A2 WO1988007684A2 PCT/FR1988/000161 FR8800161W WO8807684A2 WO 1988007684 A2 WO1988007684 A2 WO 1988007684A2 FR 8800161 W FR8800161 W FR 8800161W WO 8807684 A2 WO8807684 A2 WO 8807684A2
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- MCMSPRNYOJJPIZ-UHFFFAOYSA-N cadmium;mercury;tellurium Chemical compound [Cd]=[Te]=[Hg] MCMSPRNYOJJPIZ-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 150000001804 chlorine Chemical class 0.000 description 1
- 208000012482 complete androgen insensitivity syndrome Diseases 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- PJQCANLCUDUPRF-UHFFFAOYSA-N dibenzocycloheptene Chemical compound C1CC2=CC=CC=C2CC2=CC=CC=C12 PJQCANLCUDUPRF-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000000469 dry deposition Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- DLLJVQNYBYOKGS-UHFFFAOYSA-N ethoxyethane;pentane Chemical compound CCCCC.CCOCC DLLJVQNYBYOKGS-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009615 fourier-transform spectroscopy Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000001469 hydantoins Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000013390 scatchard method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
- C07D223/24—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom
- C07D223/28—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom having a single bond between positions 10 and 11
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/5302—Apparatus specially adapted for immunological test procedures
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/531—Production of immunochemical test materials
- G01N33/532—Production of labelled immunochemicals
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N2021/3595—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using FTIR
Definitions
- the present invention relates to a new type of immunoassay and a new type of Fourier transform infrared spectroscopy device useful for said assays.
- Urmunological methods are powerful, very selective analytical techniques which allow the determination of very small quantities of analyte. Their use holds a preponderant place in clinical analysis. Indeed, the interaction between an antigen and corresponding antibodies can be extremely specific.
- the invention therefore relates to a new immunological assay called IRIA ("INFRA / RED IMMUNOASSAY”), characterized in that a marker is used carrying carbonyl functions linked to a metal.
- the antigen is therefore marked with the marker.
- the antigen can be directly complexed with the carbonyl metal complex, in particular when the antigen comprises an unsaturated carbonaceous organic site, such as an aromatic nucleus, a cyclopentadienic cycle or a double or triple c-c bond.
- An advantageous alternative from the point of view of stability consists in binding the antigen to a molecule comprising an unsaturated organic site, in particular a carbon unsaturation, such as an aromatic nucleus, a cyclopentadienic cycle or a double or triple cc bond, which is then complexed with a complex of carbonyl metals.
- the marker then consists of this molecule complexed by a complex of carbonyl metals.
- carbonyl metal complex is understood to mean an organometallic complex of formula M x L y , L y representing the ligands linked to one or more metals M, at least one of the ligands being a carbonyl function.
- the dosing principle is as follows.
- the labeled antigen (Ag-M (CO)) and the unlabeled assay antigen (Ag) are put in competition in variable proportions in the presence of a small amount of anticoros (Ac).
- the tracer is evaluated in one of the two fractions by measuring the intensity of the signals corresponding to the frequencies characteristic of the carbonyl groups. The determination of an unknown sample is made by comparison with a standard curve carried out with pure unlabeled antigen.
- This immunoassay method makes it possible to quantitatively determine very small quantities of drugs in various biological media (plasma, urine, saliva, etc.) in humans, animals or plants.
- the detection is carried out by an infrared spectroscopy device with Fourier transform which makes it possible to detect the CO ligands. This technique retains the specific characteristics of the immunological reaction and appears to be sensitive enough to be applied to the dosage of many drugs.
- Fourier transform spectroscopy allows the immunological assay of substances that the metallo immunological test, also using metallic markers, could not detect.
- tricyclic antidepressants marked with a cyclopentadienylmanganese andricarbonyl fragment are made possible.
- antidepressants mention may be made of the tricyclics: desipramine, imipramine, nortriptyline, amitriptyline, clomipramine, maprotiline, and atypicals: nomifensine, mianserine, amineptine, zimelidine.
- barbiturate antiepileptics phenobarbital, mephobarbital
- hydantoin derivatives phenytoin, mephenytoin
- tranquilizers derived from benzodiazepines (diazepam, nitrazepam) or tricyclic neuroleptics (chlorpromazine, trifluoperazine), as well as neuroleptics (haloperidol, fluspirilene) or antitumor drugs (methotrexate, 5-fluorouracil, azathioprine), alkaloids antibiotics, cardiotonics.
- Suitable markers are shown below: cymantrene derivatives of the type
- markers carrying a COOH function at the end of the R chain are particularly suitable for being coupled to an antigen carrying an amino function (primary or secondary), which is the case for most drugs, via a amide bond between the two functions.
- an antigen carrying an amino function primary or secondary
- markers Another type of marker can be cited according to the present invention, these markers have the formula
- M x L y represents an organometallic compound in which
- M x represents one or more metals from groups VI to IX of the periodic table which may be different and L y represents one or more ligands of which at least one ligand is the CO ligand, this (these) ligand (s) comprising the metals, this (s) ligand (s) can be very varied (s), in particular cyclopentadienyl Cp or even CS.
- M x L y is chosen from Mo 2 Cp 2 (CO) 4 , Co 2 (CO) 6 and Os 3 (CO) 9 .
- these markers can be coupled to the antigen by an alkylation reaction, the complexation of the carbonyl metal complex M x L y on the triple bond being able to take place before or after said coupling.
- D represents the antigen
- This alkylation can be done via the complexed carbocation:
- the marker can be coupled to a COOH function of the antigen, but this type of marker is also suitable when the antigen has an amide function.
- the tracer is then prepared from an antigen derivative for which the amide function is changed to the amino function which is reacted with phosgene and the amino marker. In general, then, an alkylation is obtained on the antigen, the tracer having the formula
- the drug to be assayed does not have an NH 2 function
- such a function can be created, for example thereby reducing a nitrated NO 2 function which is easy to introduce. Consequently, the markers mentioned above can be coupled to any drug with a view to their infrared immunoassay according to the invention whether it has an NH 2 function or whether it is introduced.
- the use of IR-FT spectroscopy requires that all instrumental parameters are optimized to obtain the maximum sensitivity of the spectrometer, i.e. the lowest possible level of background noise in the specific region that interests us, namely 2200-1800 cm-1.
- the IR spectroscopy device with Fourier transform, useful for immunological assays using markers M x (L) y according to the invention is characterized by a low level of noise in the region 2200-1800 cm- 1 not exceeding 0.002% absorbance units.
- the device according to the invention will advantageously include the following elements taken separately or in combination:
- a liquid sample to be dosed with a solvent which does not absorb or little in the region 2200-1800 cm-1 a liquid sample to be dosed with a solvent which does not absorb or little in the region 2200-1800 cm-1.
- the use of an InSb detector rather than an MCT detector increases the signal-to-noise ratio (SNR) in the region 2200-1850 cm-1 by a factor of 40. In this region, the reduction of the spectral window increases the dynamic range of the detector and reduces the noise reaching the detector.
- the reduction of the spectral window can be obtained by means of a narrow band optical filter.
- the spectral window can be reduced, for example, to 50 cm-1.
- optical filters have certain drawbacks, since they do not transmit all the energy in the region where they are transparent.
- small variations in the ambient temperature cause oscillations of the order of
- the filter consists of a paste deposited on the surface of the detector, which is refrigerated with liquid nitrogen and under vacuum.
- a disadvantage of using optical filters is that one must avoid making measurements near their cut-off zones.
- the present invention proposes two devices limiting the frequencies around 1800-2300 cm-1 including the specific region of carbonyl metals: 1. a sandwich type detector composed of an MCT element (mercury-cadmium-telluride) limiting the high energies to 2300 cm-1 and an InSb element (indiumantimony) limiting the low energies to 1300 cm-1. 2. an InSb detector, cutting at low energies around 1800 cm-1, coupled with a broadband optical filter cutting high energies at 2300 cm-1.
- MCT element cury-cadmium-telluride
- InSb element indiumantimony
- the absorbance is proportional to the path of the infrared ray passing through the solution. It is therefore desirable to use long-range cells, but this can lead to saturation of the detector by absorption of the solvent leading to a loss of sensitivity in detection.
- the absorption of the solvent in the region of interest should preferably not exceed 0.5-0.7 absorbance units. This element should be considered when choosing the cell route.
- any solvent, including water can be used provided that its length is carefully controlled.
- the suitable solvents can be alkanes (pentane, hexane, etc.) or halogenated alkanes of low molecular weight (CH 2 Cl 2 , CHCl 3 , CCI, etc.). Indeed, these have no absorption or very low absorption in the region v (CO).
- IR-FT infrared spectra of these solvents were produced in 5 to 30 mm path cells. It is noted that, even with a path of 30 mm, which represents a path a hundred times longer than the path of cells of conventional solutions, such a cell can be effectively used without degrading the energy transmission in the region v (CO ) in a significative way.
- the infrared spectroscopy device can therefore comprise a path cell of the order of 30 mm.
- the diameter of the cell does not exceed 1 mm and can even drop to 0.1 mm. This characteristic makes it possible to reduce the volume of solutions required.
- the device of the present invention it is possible to use a detection element of 0.25 mm (diameter or side if it is a square) instead of 1 mm, the reduction in the surface of the detector leading to an increase in SNR.
- FIG. 1 represents the ratio of two emission spectra 0 with a DA 3 spectrometer in which a vacuum has been made (SNR);
- FIG. 2 represents an emission spectrum with an optical filter placed on an InSb detection element and then cooled with liquid nitrogen and under vacuum (with the same DA 3 spectrometer);
- FIG. 3 represents the ratio of two emission spectra with the spectrometer DA 3 after having placed an optical filter on the detection element as fig. 2;
- FIG. 4 represents an emission spectrum of an optical filter which cuts the high energies towards
- FIG. 5 represents a spectrum of CH 2 Cl 2 in an infrared cell with a path of 7 mm
- FIG. 6 represents the ratio of two emission spectra of CH 2 Cl 2
- FIG. 7 represents a spectrum of CHCl 3 in an infrared cell with a path of 7 mm
- FIG. 8 represents the ratio of two emission spectra of CHCl 3
- FIG. 9 represents a spectrum of n-pentane in an infrared cell with a path of 7 mm
- FIG. 10 represents the ratio of two emission spectra of n-pentane
- FIG. 5 represents a spectrum of CH 2 Cl 2 in an infrared cell with a path of 7 mm
- FIG. 6 represents the ratio of two emission spectra of CH 2 Cl 2
- FIG. 7 represents a spectrum of CHCl 3 in an infrared cell with a path of 7 mm
- FIG. 8 represents the ratio of two emission spectra of CHCl 3
- FIG. 9 represents a spectrum of
- FIG. 11 represents the infrared absorption of CCL 4 between 2200-1800 cm-1 using a 30 mm cell covered with gold;
- FIG. 12 represents an IR-FT spectrum (recorded with a 30 mm cell) of the carbonyl bands of the complex marked notriptyline-CpMn (CO) 3 after subtracting the bands of solvent CCl 4 ;
- FIG. 13 represents an IR-FT spectrum (recorded in a microcell of 1 mm in travel, with CClu as solvent) of the carbonyl bands of the complex labeled nortriptyline-CpMn (CO) 3 after subtracting the bands of the CCI 4 solvent;
- BSA bovine serum albumin
- DCC dicyclohexylcarbodiimide
- the dialyzed solution is then distributed in glass jars, then lyophilized.
- the immunogen is thus obtained in the form of a powdery bright white solid, the rate of coupling of which will be controlled according to the method described by ERLANGER and coll. (1957) based on the UV absorption of the drug.
- the calculation of the molecular extinction coefficients at 250 nm allowed us to estimate at 44 the number of desipramine molecules coupled to a SAB molecule.
- Desipramine base (600 mg; 2.25 mmol) is extracted from the hydrochloride, then dissolved in 50 ml of freshly distilled THF. Add 2 ml of pyridine, then with stirring add dropwise 600 mg (2.25 mmol) of CyCOCl dissolved in 20 ml of THF.
- the first injection 250 ⁇ g of immunogen per rabbit is carried out with the complete FREUND adjuvant (GIBCO product) and the booster injections with incomplete adjuvant. Blood is taken around ten days after each booster injection, from the marginal vein in the ear. The serum is then frozen at -20 ° C in fractions of 100 ⁇ l.
- the total radioactivity (T) is evaluated, thus ⁇ ue the non-specific binding (LNS).
- the percentage of bound antigen (B) is calculated for each point with respect to T after deduction of the non-specific binding.
- the antibody titers are then defined by the greatest dilution which binds 50% of the tracer.
- the specificity is evaluated from inhibition curves obtained according to the same protocol as for the calibration curves by replacing the cold antigen, with the molecule to be studied.
- the percentage of cross-reaction is then calculated according to the method of ABRAHAM (1969) compared to IMIPRAMINE. If X pg and Y pg are the quantities of imipramine and of the substance respectively necessary to displace 50% of tritiated imipramine bound to the antibodies, the percentage expressing the cross-reaction of the substance will be equal to X / Y x 100.
- H of HCG 4.52-4.3 (multiplet) and 4.47 (singlet).
- IR-FT BOMEM Michelson 100 RMN H1: BRUKER 250 MHz
- a transparent filter in the infrared region between 2030 and 2080 cm-1 was bonded to the surface of an InSb detector and the assembly was brought to a pressure below 10 -1 torr.
- the detector was then supplied with liquid nitrogen, it was cooled for 40 to 50 min. A displacement of the filter response was observed of the order of 50 cm-1, thus displacing the new frequency domain between 2080 and 2130 cm-1.
- Figures 1, 2 and 3 show that a significant stabilization of the optical filter is observed when it is cooled with liquid nitrogen with only slight residual oscillations of the order of 10 -5 units of absorbance.
- the spectra of FIGS. 5 to 10 show that the solvents chosen from alkanes or halogenated alkanes exhibit very low absorption in the v (CO) region.
- the device 2 on page 7 was used (see window in Figure 4), thus combining an InSb detector coupled with a broadband optical filter cutting the high energies around 2300 cm-1.
- FIG. 14 represents the calibration curve obtained using the device of example V- (1), by measuring the carbonyl strip at 2030 cm-1.
- the range was made from a solution of nortriptyline, HC1 at 2 ⁇ g / ml, ie values from 0 to 1000 picomoles per tube.
- This table presents the values which made it possible to establish the IRIA calibration curve for the nortriptyline shown in FIG. 14.
- New type of immunological dosing designated IRIA, employing a tag bearing carbonyl functions linked to at the one metal.
- a means of detecting the tag in the form of an infrared spectroscopie device with a Fourier transform. so an IR spectroscopy device with a Fourier transform, comprising, separately or in combination, the following element an InSb detector; a reduced spectral window; a cell with a long light trajectory and ofsmall diameter; a liquid dosing s ple with preferably one solvent which absorbs little or nothing in the region 2200-1800 cm-1.
- the invention relates to a new type of immunoassay called "IRIA".
- IRIA immunoassay
- the invention also relates to a detection of the marker which is carried out by an infrared spectroscopy device with Fourier transform.
- the invention also relates to a Fourier transform IR spectroscopy device which comprises the following elements separately or in combination: the InSb detector; a reduced spectral window; a long diameter light path cell; a liquid sample to be dosed with, preferably, a solvent which does not absorb or little in the 2200-1800 cm-1 regi.
- New type ofimmunological dosing designated IRIA, employing a tag bearing carbonyl functions linked to at l one metal. Also a means ofdetecting the tag, in the form ofan infrared spectroscopie device with a Fourier transform. so an IR spectroscopy device with a Fourier transform, comprising, separately or in combination, the following element an InSb detector; a reduced spectral window; a cell with a long lighttrajectory and ofsmall diameter; a liquid dosing s ple with preferably one solvent which absorbs little or nothing in the region 2200-1800 cm-1.
- the invention relates to a new type of immunoassay called "IRIA".
- IRIA immunoassay
- the invention also relates to a marker definition which is carried out by a Fourier transform infrared spectroscopy device.
- the invention also relates to an IR spectroscopy device with Fourier transform which comprises the following elements separately or in combination: the InSb detector; a reduced spectral window; a long diameter light path cell; a liquid sample to be dosed with, preferably, a solvent which does not absorb or little in the reg 2200-1800 cm-1.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR87/04698 | 1987-04-03 | ||
FR8704698A FR2613490A1 (fr) | 1987-04-03 | 1987-04-03 | Dosage immunologique infrarouge |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1988007684A2 true WO1988007684A2 (fr) | 1988-10-06 |
WO1988007684A3 WO1988007684A3 (fr) | 1988-12-15 |
Family
ID=9349757
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1988/000161 WO1988007684A2 (fr) | 1987-04-03 | 1988-03-31 | Dosage immunologique infrarouge |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0308473A1 (fr) |
FR (1) | FR2613490A1 (fr) |
WO (1) | WO1988007684A2 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2630547A1 (fr) * | 1988-04-22 | 1989-10-27 | Centre Nat Rech Scient | Marquage froid de molecules de nature peptidique ou proteique |
US5468644A (en) * | 1991-05-09 | 1995-11-21 | British Technology Group Limited | Spectroscopic investigation using organometallic compounds |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2353854A1 (fr) * | 1976-05-31 | 1977-12-30 | Technion Res & Dev Foundation | Methode et reactif d'analyse par liaison specifique |
-
1987
- 1987-04-03 FR FR8704698A patent/FR2613490A1/fr not_active Withdrawn
-
1988
- 1988-03-31 EP EP19880903268 patent/EP0308473A1/fr not_active Withdrawn
- 1988-03-31 WO PCT/FR1988/000161 patent/WO1988007684A2/fr not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2353854A1 (fr) * | 1976-05-31 | 1977-12-30 | Technion Res & Dev Foundation | Methode et reactif d'analyse par liaison specifique |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2630547A1 (fr) * | 1988-04-22 | 1989-10-27 | Centre Nat Rech Scient | Marquage froid de molecules de nature peptidique ou proteique |
WO1989010372A1 (fr) * | 1988-04-22 | 1989-11-02 | Centre National De La Recherche Scientifique (Cnrs | Marquage froid de molecules de nature peptidique ou proteique |
US5468644A (en) * | 1991-05-09 | 1995-11-21 | British Technology Group Limited | Spectroscopic investigation using organometallic compounds |
Also Published As
Publication number | Publication date |
---|---|
FR2613490A1 (fr) | 1988-10-07 |
WO1988007684A3 (fr) | 1988-12-15 |
EP0308473A1 (fr) | 1989-03-29 |
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