WO1991005255A1 - Diagnosis of lung diseases by analysis of non-volatile and volatile constituents of respiratory air - Google Patents

Diagnosis of lung diseases by analysis of non-volatile and volatile constituents of respiratory air Download PDF

Info

Publication number
WO1991005255A1
WO1991005255A1 PCT/EP1990/001638 EP9001638W WO9105255A1 WO 1991005255 A1 WO1991005255 A1 WO 1991005255A1 EP 9001638 W EP9001638 W EP 9001638W WO 9105255 A1 WO9105255 A1 WO 9105255A1
Authority
WO
WIPO (PCT)
Prior art keywords
substances
volatile
analysis
air
methods
Prior art date
Application number
PCT/EP1990/001638
Other languages
German (de)
French (fr)
Inventor
Lutz Scheideler
Hugo Hämmerle
Otto Inacker
Original Assignee
Nmi Naturwissenschaftliches Und Medizinisches Institut An Der Universität Tübingen In Reutlingen
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 Nmi Naturwissenschaftliches Und Medizinisches Institut An Der Universität Tübingen In Reutlingen filed Critical Nmi Naturwissenschaftliches Und Medizinisches Institut An Der Universität Tübingen In Reutlingen
Publication of WO1991005255A1 publication Critical patent/WO1991005255A1/en

Links

Classifications

    • 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
    • G01N33/483—Physical analysis of biological material
    • G01N33/497—Physical analysis of biological material of gaseous biological material, e.g. breath
    • 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

Definitions

  • lung cell types e.g. of the various cell types of the lung epithelium (pneumocytes type I and II) or of the interstitial s.
  • the first indicators at the cellular level can be the impairment of specific metabolic performance of certain cells (e.g. surfactant release of pneumocytes type II) or the activation of the body's own defense mechanisms (release of mediators).
  • the object of the present application is therefore on the one hand to obtain sample material for the determination of diagnostically relevant constituents of the broncho-alveolar boundary fluid under conditions which are not stressful for the patient and possibly also reasonable within the framework of a preventive examination.
  • analytical methods should be provided for the qualitative and quantitative discontinuous and continuous determination of these components.
  • Breathing gas analyzes e.g. using mass spectrometric methods have so far only been used on volatile, low molecular weight, mostly organic compounds, such as Acetone, methyl ethyl ketone, propanol (Gordon 1985), pyridine (Kostelc 1980), dichloromethane, toluene, styrene (Wilson 1981), ammonia, acetaldehyde and ethanol (Lovett 1979).
  • organic compounds such as Acetone, methyl ethyl ketone, propanol (Gordon 1985), pyridine (Kostelc 1980), dichloromethane, toluene, styrene (Wilson 1981), ammonia, acetaldehyde and ethanol (Lovett 1979).
  • the invention thus relates to a method for diagnosing the
  • the non-volatile components from approx. 750 l i.e. from 250 breaths
  • the non-volatile components from approx. 750 l were enriched by condensation in a cold trap at -196 ° C and subsequent freeze-drying.
  • biochemical methods protein separation by two-dimensional SDS gel electrophoresis (sodium dodecyl sulfate) followed by silver staining
  • proteins up to a molecular weight of 60,000 D could be found (Dalton) can be detected.
  • non-volatile substances e.g. Macromolecules, in particular proteins
  • Macromolecules in particular proteins
  • test person's saliva sample (approx. 300 ⁇ l) was also first freeze-dried, then taken up in buffer and electrophoresed.
  • the separation of the proteins from the air and saliva contained in the applied substance was carried out by two-dimensional polyacrylamide gel electrophoresis (see Fig. 3).
  • Sheets I - IV are accompanied by illustrations that have the following meaning:
  • Fig. 1 Secondary ion mass spectra of breathed sample plates. About 1 cm 2 large, freshly vaporized silver indium plates were placed on a cooling table (-196 ° C) and a) breathed through a glass tube with 6 breaths or b) exposed to the ambient air for the same time. The samples were freeze-dried on the cryotable by applying an ultra-high vacuum and then measured in the secondary ion mass spectrometer.
  • Fig. 2 Freeze-dried substance f t of approximately 750 1 Atemlu.
  • the non-volatile components of the breathing air were first frozen out from 250 breaths of a subject in a cold trap at -196 ° C. ( ⁇ 15 ml of aqueous condensate) and then freeze-dried.
  • Fig. 3 Gel electrophoresis diagrams of breathing air and saliva samples of a subject after separation of the proteins
  • Fig. 4 Comparison of the protein pattern (2D-SDS gels, Fig. 3) of breath and saliva samples. literature

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Hematology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Urology & Nephrology (AREA)
  • Food Science & Technology (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)

Abstract

The film of fluid lining the lungs and respiratory passages (alveolar fluid or bronchial secretion, spittle) contains volatile and non-volatile metabolic products and mediators some of which are of considerable diagnostic value. Primary non-volatile substances in aerosol form can enter the exhaled air. The determination of these substances in human exhaled air can be used, possibly together with volatile substances, to diagnose diseases.

Description

Diagnose von Lungenkrankheiten durch Analyse von nicht-flüchtigen und flüchtigen Bestandteilen der Atemluft Diagnosis of lung diseases through analysis of non-volatile and volatile components of the air we breathe
Mit zunehmender Umweltbelastung kommt dem Problem der Früh¬ erkennung von Schädigungen der Lunge und der Atemwege wach¬ sende Bedeutung zu. Die frühen Stadien einer pathologischen Veränderung des Gewebes sind diagnostisch schwer faßbar, chronische Erkrankungen werden oft erst in einem relativ späten Stadium, wenn bereits eine eindeutige Funktionsstö¬ rung vorliegt, diagnostiziert.With increasing environmental pollution, the problem of early detection of damage to the lungs and the respiratory tract becomes increasingly important. The early stages of a pathological change in the tissue are difficult to diagnose, chronic diseases are often diagnosed only at a relatively late stage when there is already a clear functional disorder.
Am Anfang eines derartigen Krankheits- oder Entzündungspro- zesses steht die Schädigung einzelner Lungenzelltypen, z.B. der verschiedenen Zelltypen des Lungenepithels (Pneumocyten Typ I und II) oder des Interstitiu s.At the beginning of such a disease or inflammation process there is damage to individual lung cell types, e.g. of the various cell types of the lung epithelium (pneumocytes type I and II) or of the interstitial s.
Erste Indikatoren auf zellulärer Ebene können dabei die Be¬ einträchtigung spezifischer Stoffwechselleistungen bestimm¬ ter Zellen (z.B. Surfactant-Ausschüttung von Pneumocyten Typ II) oder die Aktivierung körpereigener Abwehrmechanismen (Ausschüttung von Mediatoren) sein.The first indicators at the cellular level can be the impairment of specific metabolic performance of certain cells (e.g. surfactant release of pneumocytes type II) or the activation of the body's own defense mechanisms (release of mediators).
In der klinischen Diagnostik wird daher unter anderem ver¬ sucht, Veränderungen des Lungenstatus durch die Bestimmung der Konzentration einzelner Stoffwechselprodukte und Media¬ toren (z.B. Immunglobuline, Lymphokine) in der broncho-al- veolären Grenzflüssigkeit zu erfassen. Zur Gewinnung von Probenmaterial wird dabei zur Zeit in der Klinik die Technik der broncho-alveolären Lavage (BAL) eingesetzt. Dabei werden die Patienten narkotisiert und mit Hilfe eines Bronchoskops werden ganze Lungensegmente mehrmals mit Wasser oder physiologischer Kochsalzlösung (bis zu 300 ml) durchgespült. Die Spülflüssigkeiten werden anschließend analysiert (Re¬ view, s. Reynolds, 1987) .In clinical diagnostics, attempts are therefore made, inter alia, to change the status of the lungs by determining the concentration of individual metabolic products and mediators (eg immunoglobulins, lymphokines) in the broncho-al- to record the veolar boundary fluid. The technique of broncho-alveolar lavage (BAL) is currently used in the clinic to obtain sample material. Patients are anesthetized and whole lung segments are flushed several times with water or physiological saline (up to 300 ml) using a bronchoscope. The rinsing liquids are then analyzed (Review, see Reynolds, 1987).
Dieses Verfahren belastet den Patienten in erheblichem Maße und ist daher nicht präventiv einsetzbar. Eine on-line-Mes- sung ist nicht möglich, die Probennahme ist nur bedingt re¬ produzierbar, aufgrund der Irritation des Gewebes kann nur unter Vorbehalt auf die Verhältnisse in situ rückgeschlossen werden.This procedure puts a considerable strain on the patient and can therefore not be used preventively. An on-line measurement is not possible, the sampling can only be reproduced to a limited extent. Due to the irritation of the tissue, it is only possible to draw conclusions about the conditions in situ.
Die Aufgabe der vorliegenden Anmeldung besteht somit einer¬ seits darin, Probenmaterial für die Bestimmung diagnostisch relevanter Bestandteile der broncho-alveolären Grenzflüssig¬ keit unter Bedingungen zu gewinnen, die für den Patienten nicht belastend und gegebenenfalls auch im Rahmen einer Vor¬ sorgeuntersuchung zumutbar sind. Andererseits sollten Analy¬ senmethoden für die qualitative und quantitative diskonti¬ nuierliche und kontinuierliche Bestimmung dieser Bestand¬ teile bereitgestellt werden.The object of the present application is therefore on the one hand to obtain sample material for the determination of diagnostically relevant constituents of the broncho-alveolar boundary fluid under conditions which are not stressful for the patient and possibly also reasonable within the framework of a preventive examination. On the other hand, analytical methods should be provided for the qualitative and quantitative discontinuous and continuous determination of these components.
Überraschenderweise wurde gefunden, daß hochmolekulare, nicht-flüchtige Biopolymere, wie z.B. Proteine aus der bron¬ cho-alveolären Grenzflüssigkeit in der Atemluft nachweisbar sind und für die Diagnose von Krankheiten genutzt werden können.Surprisingly, it has been found that high molecular weight, non-volatile biopolymers, such as e.g. Proteins from the bron-cho-alveolar boundary fluid are detectable in the breathing air and can be used for the diagnosis of diseases.
Damit wird in vielen Fällen ein Ersatz der aufwendigen und den Patienten belastenden Probennahme mit Hilfe der broncho- alveolären Lavage durch ein nicht-invasives, den Patienten nicht belastendes Verfahren möglich. Die Analyse kann entwe¬ der direkt durch on-line-Analyse der Exspirationsluft oder aber nach vorhergehender Anreicherung der Substanzen aus einem größeren Volumen Exspirationsluft erfolgen.In many cases this makes it possible to replace the time-consuming and stressful sampling with the help of bronchoalveolar lavage by a non-invasive method that does not burden the patient. The analysis can either be carried out directly by on-line analysis of the expiratory air or but after previous enrichment of the substances from a larger volume of expiratory air.
Atemgasanalysen, z.B. mit Hilfe massenspektrometrischer Me¬ thoden, sind bisher lediglich an flüchtigen, niedermolekula¬ ren, zumeist organischen Verbindungen, wie z.B. Aceton, Me- thylethylketon, Propanol (Gordon 1985) , Pyridin (Kostelc 1980), Dichlormethan, Toluol, Styrol (Wilson 1981), Ammo¬ niak, Acetaldehyd sowie Ethanol (Lovett 1979) , durchgeführt worden.Breathing gas analyzes, e.g. using mass spectrometric methods have so far only been used on volatile, low molecular weight, mostly organic compounds, such as Acetone, methyl ethyl ketone, propanol (Gordon 1985), pyridine (Kostelc 1980), dichloromethane, toluene, styrene (Wilson 1981), ammonia, acetaldehyde and ethanol (Lovett 1979).
Die Bestimmung hochmolekularer Substanzen, die in Form von z.B. Tröpfchen, Aerosolen oder Clustern in der Atemluft transportiert werden, eröffnet zusätzlich zur Analyse von flüchtigen, niedermolekularen Verbindungen (Barkley 1980, Benoit 1983, 1985, Wilson 1986) ein völlig neues Potential in der Atemluftanalytik.The determination of high molecular substances, which in the form of e.g. Droplets, aerosols or clusters transported in the air we breathe opens up a completely new potential in breath air analysis in addition to the analysis of volatile, low-molecular compounds (Barkley 1980, Benoit 1983, 1985, Wilson 1986).
Somit betrifft die Erfindung ein Verfahren zur Diagnose desThe invention thus relates to a method for diagnosing the
Gesundheitszustandes sowie zur Therapieüberwachung und zurHealth status as well as for therapy monitoring and for
Verlaufskontrolle von Krankheiten gemäß den Ansprüchen 1 bis 8.Monitoring the course of diseases according to claims 1 to 8.
Die Beispiele erläutern die Erfindung.The examples illustrate the invention.
Beispiel 1example 1
Sechs Atemstöße eines Probanden wurden auf ein auf -196 "C gekühltes, l cm2 großes Probenträgerplättchen aufgehaucht. Die Probe wurde auf dem Cryotisch durch Anlegen eines Ul¬ trahochvakuums gefriergetrocknet und anschließend mit Sekun- därionenmassenspektrometrie (SIMS) vermessen. Bereits bei diesen geringen Probenmengen konnten mit dieser empfindli¬ chen Meßmethode neben anorganischen Ionen auch spezifische organische Gruppen nachgewiesen werden (s. Abb. 1) . Beispiel 2Six breaths of a subject were breathed onto a 1 cm 2 sample plate which was cooled to -196 "C. The sample was freeze-dried on the cryotable by applying an ultra high vacuum and then measured with secondary ion mass spectrometry (SIMS). Even with these small sample amounts With this sensitive measuring method it was possible to detect not only inorganic ions but also specific organic groups (see Fig. 1). Example 2
Die nicht-flüchtigen Bestandteile aus ca 750 1 (d.h. aus 250 Atemstößen) der Atemluft eines gesunden Probanden wurden durch Auskondensieren in einer Kühlfalle bei -196 °C und an¬ schließende Gefriergetrocknung angereichert. Bei der Analyse der so gewonnenen Substanz (s. Abb. 2) mit biochemischen Me¬ thoden (Proteinauf rennung durch zweidimensionale SDS-Gel- elektrophorese (sodium dodecyl Sulfate) mit anschließender Silberfärbung) konnten Proteine bis zu einem Molekularge¬ wicht von 60 000 D (Dalton) nachgewiesen werden.The non-volatile components from approx. 750 l (i.e. from 250 breaths) of the breath of a healthy subject were enriched by condensation in a cold trap at -196 ° C and subsequent freeze-drying. When analyzing the substance obtained in this way (see Fig. 2) using biochemical methods (protein separation by two-dimensional SDS gel electrophoresis (sodium dodecyl sulfate) followed by silver staining), proteins up to a molecular weight of 60,000 D could be found (Dalton) can be detected.
Beispiel 3Example 3
Dieses Beispiel belegt, daß in der Ausatemluft nicht-flüch¬ tige Stoffe, z.B. Makromoleküle, insbesondere Proteine, nachweisbar sind, die nicht der Mundhöhle, sonderen tieferen Regionen des Respirationstraktes (Lunge, Bronchien) entstam¬ men.This example shows that non-volatile substances, e.g. Macromolecules, in particular proteins, can be detected which do not originate from the oral cavity, but from deeper regions of the respiratory tract (lungs, bronchi).
Die gemäß Beispiel 2 in einer Kühlfalle bei -196 °C ausge¬ frorenen und anschließend gefriergetrockneten Substanzen aus der Exspirationsluft wurden in Lysispuffer (9M Harnstoff, 4 % N0NIDETR P40, 5 % Ampholyte pH 7-9 (LKB) ) aufgenommen und auf ein Polyacrylamid-Gel aufgetragen.The substances from the expiration air which were frozen out in a cold trap at -196 ° C. and then freeze-dried according to Example 2 were taken up in lysis buffer (9M urea, 4% NOIDET R P40, 5% ampholyte pH 7-9 (LKB)) Polyacrylamide gel applied.
Die Speichelprobe des Probanden (ca. 300 μl) wurde ebenfalls zunächst gefriergetrocknet, anschließend in Puffer aufgenom¬ men und elektrophoretisiert.The test person's saliva sample (approx. 300 μl) was also first freeze-dried, then taken up in buffer and electrophoresed.
Die Auftrennung der in der aufgetragenen Substanz enthalte¬ nen Proteine aus Atemluft und Speichel erfolgte durch zwei¬ dimensionale Polyacrylamid-Gelelektrophorese (s. Abb. 3) .The separation of the proteins from the air and saliva contained in the applied substance was carried out by two-dimensional polyacrylamide gel electrophoresis (see Fig. 3).
1. Dimension, horizontal: Isoelektrische Fokussierung1st dimension, horizontal: Isoelectric focusing
2. Dimension, vertikal: SDS-Elektrophorese.2nd dimension, vertical: SDS electrophoresis.
Oberes Gel: Exspirationsluft; Unteres Gel: Speichel. Beispiel 4Upper gel: expiratory air; Lower gel: saliva. Example 4
Die im Proteinmuster nach Gelelektrophorese gemäß Beispiel 3 auftretenden Proteine aus Speichel und Atemluft wurden ver¬ glichen.The proteins from saliva and breathing air appearing in the protein pattern after gel electrophoresis according to Example 3 were compared.
Diejenigen in der Atemluft auftretenden Proteine, die im Speichel nicht oder nur in geringerer Konzentration nach¬ weisbar sind, wurden schwarz hervorgehoben (s. Abb. 4) . Die weitgehende Übereinstimmung der Gele im Bereich um 50 000 D und pH 5,5 könnte auf das Mitreißen von Aerosolpar- tikeln aus dem Mundbereich zurückzuführen sein. Es ist je¬ doch auch denkbar, daß der Flüssigkeitsfil über den Schleimhäuten der Atemwege und des Mundes die gleichen Hauptkomponenten enthält, die dann in Proben unterschiedli¬ cher Herkunft nachgewiesen werden. Those proteins occurring in the air we breathe that are not detectable in saliva or can only be detected in lower concentrations were highlighted in black (see Fig. 4). The extensive agreement of the gels in the range around 50,000 D and pH 5.5 could be due to the entrainment of aerosol particles from the mouth area. However, it is also conceivable that the liquid film above the mucous membranes of the respiratory tract and the mouth contains the same main components, which are then detected in samples of different origins.
Auf den Blättern I - IV werden Abbildungen beigelegt, die folgende Bedeutung haben:Sheets I - IV are accompanied by illustrations that have the following meaning:
Abb. 1: Sekundärionen-Massenspektren behauchter Probenträ- gerplättchen. Ca 1 cm2 große, frisch mit Silber be¬ dampfte Indiumplättchen wurden auf einen Kühltisch (-196 °C) gebracht und a) durch ein Glasrohr mit 6 Atemstößen behaucht bzw. b) für die gleiche Zeit der Umgebungsluft ausgesetzt. Die Proben wurden auf dem Cryotisch durch Anlegen eines Ultrahochvakuums ge¬ friergetrocknet und anschließend im Sekundärionen- Massenspektrometer vermessen.Fig. 1: Secondary ion mass spectra of breathed sample plates. About 1 cm 2 large, freshly vaporized silver indium plates were placed on a cooling table (-196 ° C) and a) breathed through a glass tube with 6 breaths or b) exposed to the ambient air for the same time. The samples were freeze-dried on the cryotable by applying an ultra-high vacuum and then measured in the secondary ion mass spectrometer.
(Rotes Spektrum: Exspirationsluft; blaues Spektrum: Umgebungsluft)(Red spectrum: expiratory air; blue spectrum: ambient air)
Abb. 2: Gefriergetrocknete Substanz aus ca. 750 1 Atemluft. Die nicht-flüchtigen Bestandteile der Atemluft wur¬ den aus 250 Atemstößen eines Probanden zunächst in einer Kühlfalle bei -196 °C ausgefroren (→ 15 ml wäßriges Kondensat) und anschließend gefriergetrock¬ net.Fig. 2: Freeze-dried substance f t of approximately 750 1 Atemlu. The non-volatile components of the breathing air were first frozen out from 250 breaths of a subject in a cold trap at -196 ° C. (→ 15 ml of aqueous condensate) and then freeze-dried.
Abb. 3: Gelelektrophorese-Diagramme von Atemluft- und Spei¬ chelproben eines Probanden nach Trennung der Pro¬ teineFig. 3: Gel electrophoresis diagrams of breathing air and saliva samples of a subject after separation of the proteins
Abb. 4: Vergleich der Proteinmuster (2D-SDS-Gele, Abb. 3) von Atemluft- und Speichelproben. LiteraturFig. 4: Comparison of the protein pattern (2D-SDS gels, Fig. 3) of breath and saliva samples. literature
Barkley, J. ; Bunch, J.; Bursey, J.T.; Caεtillo, N. ; Cooper, S.D.; Davis, J.M. ; Erickson, M.D.; Harris III, B.S.H.; Kir- patrick, M. ; Michael, L.C.; Parks, S.P.; Pellizzari, E.D.; Ray, M. ; Smith, D. ; Tomer, K.B.; Wagner, R. ; and Zweidinger,Barkley, J.; Bunch, J .; Bursey, J.T .; Caεtillo, N.; Cooper, S.D .; Davis, J.M. ; Erickson, M.D .; Harris III, B.S.H .; Kir- patrick, M.; Michael, L.C .; Parks, S.P .; Pellizzari, E.D .; Ray, M.; Smith, D.; Tomer, K.B .; Wagner, R.; and Zweidinger,
"Gas chromatography mass spectrometry, Computer analysis of volatile halogenated hydrocarbons in man and his environment a multimedia environmental study." Biomedical Mass Spectrometry, Vol. 7, No. 4, (1980), 139 - 147"Gas chromatography mass spectrometry, computer analysis of volatile halogenated hydrocarbons in man and his environment a multimedia environmental study." Biomedical Mass Spectrometry, Vol. 7, No. 4, (1980), 139-147
Benoit, F.M. ; Davidson, W.R. ; Lovett, A.M. ; Nacson, S.; and Ngo, A. :Benoit, F.M. ; Davidson, W.R. ; Lovett, A.M. ; Nacson, S .; and Ngo, A.:
"Breath analysis by API/MS - human exposure to volatile or¬ ganic solvents." International Archives of Occupational and Enviromental Health, 55 (1985) , 113 - 120"Breath analysis by API / MS - human exposure to volatile organic solvents." International Archives of Occupational and Enviromental Health, 55 (1985), 113-120
Benoit, F.M. :Benoit, F.M. :
"Breath analysis by atmospheric pressure ionization mass spectrometry." Analytical Chemistry, Vol. 55, No. 4, (1983), 805 - 807"Breath analysis by atmospheric pressure ionization mass spectrometry." Analytical Chemistry, Vol. 55, No. 4, (1983), 805-807
Gordon, S.M. ; Szidon, J.P. ; Krotoszynski, B.K. ; Gibbons, R.D.; and O'Neill, H.O.:Gordon, S.M. ; Szidon, J.P. ; Krotoszynski, B.K. ; Gibbons, R.D .; and O'Neill, H.O .:
"Volatile organic compounds in exhaled air from patients with lung cancer." Clinical Chemistry, Vol. 31, No. 8 (1985) , 1278 - 1282"Volatile organic compounds in exhaled air from patients with lung cancer." Clinical Chemistry, Vol. 31, No. 8 (1985), 1278-1282
Kostelc, J.G.; Preti, G. ; Zelson, P.R. ; Stoller, N.H. ; and Tonzetich, J. :Kostelc, J.G .; Preti, G.; Zelson, P.R. ; Stoller, N.H. ; and Tonzetich, J.:
"Salivary Volatiles as Indicators of Periodontitis. " Journal of Periodontic Research 15, (1980), 185 - 192 Lovett, A.M. ; Reid, N.M. ; and Buckley, J.A. :"Salivary Volatiles as Indicators of Periodontitis." Journal of Periodontic Research 15, (1980), 185-192 Lovett, AM; Reid, NM; and Buckley, JA:
"Real-time analysis of breath using an atmosperic pressure ionization mass spectrometer." Biomedical Mass Spectrometry, Vol. 6, No. 3, (1979), 91 - 97"Real-time analysis of breath using an atmosperic pressure ionization mass spectrometer." Biomedical Mass Spectrometry, Vol. 6, No. 3, (1979), 91-97
Reynolds, H.Y. :Reynolds, H.Y. :
"Broncho-alveoläre Lavage." American Review of Respir. Di- seases 135, (1987), 250 - 263"Broncho-alveolar lavage." American Review of Respir. Diseases 135, (1987), 250-263
Wilson, H.K. ; and Ottley, T.W.:Wilson, H.K. ; and Ottley, T.W .:
"The use of a transportable mass spectrometer for the direct measurement of industrial solvents in breath. Biomedical Mass Spectrometry, Vol. 8, No. 12, (1981), 606 - 610"The use of a transportable mass spectrometer for the direct measurement of industrial solvents in breath. Biomedical Mass Spectrometry, Vol. 8, No. 12, (1981), 606-610
Wilson, H.K. :Wilson, H.K. :
"Breath analysis - Physiological basis and sampling techni- ques." Scand. J. Work Environ. Health 12 (1986), 174 - 192 "Breath analysis - Physiological basis and sampling techniques." Scand. J. Work Environ. Health 12 (1986) 174-192

Claims

Patentansprüche Claims
1. Verfahren zur Diagnose des Gesundheitszustandes sowie zur Therapieüberwachung und zur Verlaufskontrolle von Krankheiten, speziell der Lunge und der Atemwege, da¬ durch gekennzeichnet, daß nicht-flüchtige Substanzen - gegebenenfalls zusammen mit endogenen und exogenen flüchtigen Stoffen - in der menschlichen Atemluft analy¬ siert werden.1. A method for diagnosing the state of health and for monitoring the therapy and monitoring the course of diseases, especially the lungs and the respiratory tract, characterized in that non-volatile substances - optionally together with endogenous and exogenous volatile substances - are analyzed in the human breathing air become.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die Exspirationsluft unmittelbar, ohne vorhergehende An¬ reicherung der nachzuweisenden Substanzen, dem Detektor¬ system zugeführt wird.2. The method according to claim 1, characterized in that the expiratory air is supplied directly to the detector system without prior enrichment of the substances to be detected.
3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die Substanzen aus der Atemluft angereichert werden.3. The method according to claim 1, characterized in that the substances from the breathing air are enriched.
4. Verfahren nach Anspruch 1 und 3, dadurch gekennzeichnet, daß zur Anreicherung die Kondensation auf gekühlten Oberflächen, die auf einer Temperatur unterhalb des Ge¬ frierpunktes der gesuchten Substanzen gehalten werden, verwendet wird.4. The method according to claim 1 and 3, characterized in that the enrichment, the condensation on cooled surfaces, which are kept at a temperature below the freezing point of the substances sought, is used.
5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß zur Kühlung flüssiger Stickstoff eingesetzt wird.5. The method according to claim 4, characterized in that liquid nitrogen is used for cooling.
6. Verfahren nach Anspruch 1 und 2, dadurch gekennzeichnet, daß die Exspirationsluft dem Analysensystem direkt oder aber über ein Molekularstrahlsystem ohne Gas-Wand-Wech¬ selwirkung zugeführt wird.6. The method according to claim 1 and 2, characterized in that the expiratory air is supplied to the analysis system directly or via a molecular beam system without gas-wall interaction.
7. Verfahren nach Anspruch 1, 2 und 6, dadurch gekennzeich¬ net, daß in der Exspirationsluft enthaltene Cluster oder Aerosole gegebenenfalls vor Erreichen des Detektorsy- stems durch Energiezufuhr in ihre molekularen Bestand¬ teile überführt werden, z.B. durch Beheizung, Ultra¬ schallanregung, Bestrahlung mit elektromagnetischen Wel¬ len wie Mikrowellen, kohärentem oder divergierendem Licht bzw. Infrarot-Licht.7. The method according to claim 1, 2 and 6, characterized gekennzeich¬ net that clusters or aerosols contained in the expiratory air, if necessary, before reaching the detector system Stems are converted into their molecular components by supplying energy, for example by heating, ultrasound excitation, radiation with electromagnetic waves such as microwaves, coherent or diverging light or infrared light.
8. Verfahren nach Anspruch 1 bis 7, dadurch gekennzeichnet, daß zur Analyse der Substanzen spezielle, auch für den Nachweis höherer Massen (> MW 1000) geeignete massen- spektrometrische Verfahren (z.B. Time of Flight - Mas- senspektrometrie) , Infrarot-spektroskopische Verfahren, spezifische Sensoren und andere Verfahren verwendet wer- ■ den. 8. The method according to claim 1 to 7, characterized in that for the analysis of the substances special, also for the detection of higher masses (> MW 1000) suitable mass spectrometric methods (eg time of flight - mass spectrometry), infrared spectroscopic methods , specific sensors and other methods are used.
PCT/EP1990/001638 1989-09-30 1990-09-28 Diagnosis of lung diseases by analysis of non-volatile and volatile constituents of respiratory air WO1991005255A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19893932784 DE3932784C3 (en) 1989-09-30 1989-09-30 Process for the extraction of non-volatile substances as analytical sample material from the human breath
DEP3932784.1 1989-09-30

Publications (1)

Publication Number Publication Date
WO1991005255A1 true WO1991005255A1 (en) 1991-04-18

Family

ID=6390625

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1990/001638 WO1991005255A1 (en) 1989-09-30 1990-09-28 Diagnosis of lung diseases by analysis of non-volatile and volatile constituents of respiratory air

Country Status (2)

Country Link
DE (1) DE3932784C3 (en)
WO (1) WO1991005255A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0669531A1 (en) * 1994-02-24 1995-08-30 Kraft Foods, Inc. Method and apparatus for measuring volatiles released from food products
WO1995031721A1 (en) * 1994-05-13 1995-11-23 Filt Forschungsgesellschaft Für Lungen- Und Thoraxerkrankungen Mbh Process and device for collecting expired breath condensate
WO1997004310A1 (en) * 1995-07-24 1997-02-06 Medium - Sensor Gmbh Device for recovering substances present in exhaled air
WO1999028743A1 (en) * 1997-12-03 1999-06-10 Ufz-Umweltforschungszentrum Leipzig-Halle Gmbh Device for investigating respiratory tract diseases and diagnostic agents
DE102005026933A1 (en) * 2005-06-06 2006-12-07 Filt Lungen- Und Thoraxdiagnostik Gmbh Analysis of markers in exhaled respiratory gases to diagnose respiratory conditions comprises comparing changes in markers in gases with theoretical values for constant flow or stenosis respiration and extrapolating actual values
DE19717717B4 (en) * 1997-04-18 2007-08-02 InViTek Gesellschaft für Biotechnik & Biodesign mbH Method for the non-invasive detection of malignant tumors of the lung

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19920233C2 (en) * 1999-05-03 2002-11-07 Siemens Ag Device for optimizing the treatment of kidney problems
DE19951204C2 (en) * 1999-10-15 2002-08-08 Filt Forschungsgesellschaft Fu Procedure for analyzing the ingredients in exhaled air
DE10232849A1 (en) * 2002-07-19 2004-02-12 Abb Patent Gmbh Gas analyzer, e.g. for field detection of odorless, invisible toxic agents and pollutants, has self-contained sampling and detector, and sample is transferred to detector under action of force field
DE10232850A1 (en) * 2002-07-19 2004-02-12 Abb Patent Gmbh Mobile analysis facility
DE102006039140B4 (en) * 2006-08-16 2013-02-21 Aerocrine Ab Device, its use and method for fractionating the expiratory volume
DE102008030158A1 (en) * 2008-06-27 2010-02-11 Dina Levina Device for extracting condensate from breathable air of humans and animals, has pipe-shaped line with approximately U-formed curved distribution, which is passed from exhaled air and is connected at outer side with cooling device

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3649199A (en) * 1970-03-26 1972-03-14 Varian Associates Method for detecting trace quantities of an organic drug material in a living animal
GB2045930A (en) * 1979-03-19 1980-11-05 Draegerwerk Ag Breath test device
US4772559A (en) * 1985-10-10 1988-09-20 Monell Chemical Senses Center Method of detecting the presence of bronchogenic carcinoma by analysis of expired lung air

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2034468B (en) * 1978-11-03 1983-02-09 Jones T Gas sampling devices
JP2620787B2 (en) * 1987-07-31 1997-06-18 株式会社ジャルコ Odor measuring instrument

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3649199A (en) * 1970-03-26 1972-03-14 Varian Associates Method for detecting trace quantities of an organic drug material in a living animal
GB2045930A (en) * 1979-03-19 1980-11-05 Draegerwerk Ag Breath test device
US4772559A (en) * 1985-10-10 1988-09-20 Monell Chemical Senses Center Method of detecting the presence of bronchogenic carcinoma by analysis of expired lung air

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Analytical Chemistry, Band 55, Nr. 4, April 1983, American Chemical Society, F.M. Benoit et al.: "Breath analysis by atmospheric pressure ionization mass spectrometry", Seiten 805-807 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0669531A1 (en) * 1994-02-24 1995-08-30 Kraft Foods, Inc. Method and apparatus for measuring volatiles released from food products
WO1995031721A1 (en) * 1994-05-13 1995-11-23 Filt Forschungsgesellschaft Für Lungen- Und Thoraxerkrankungen Mbh Process and device for collecting expired breath condensate
WO1997004310A1 (en) * 1995-07-24 1997-02-06 Medium - Sensor Gmbh Device for recovering substances present in exhaled air
DE19717717B4 (en) * 1997-04-18 2007-08-02 InViTek Gesellschaft für Biotechnik & Biodesign mbH Method for the non-invasive detection of malignant tumors of the lung
WO1999028743A1 (en) * 1997-12-03 1999-06-10 Ufz-Umweltforschungszentrum Leipzig-Halle Gmbh Device for investigating respiratory tract diseases and diagnostic agents
DE102005026933A1 (en) * 2005-06-06 2006-12-07 Filt Lungen- Und Thoraxdiagnostik Gmbh Analysis of markers in exhaled respiratory gases to diagnose respiratory conditions comprises comparing changes in markers in gases with theoretical values for constant flow or stenosis respiration and extrapolating actual values
EP1731095A2 (en) 2005-06-06 2006-12-13 FILT Lungen- und Thoraxdiagnostik GmbH Measurement and analysis of components of exhaled respiratory gas
DE102005026933B4 (en) * 2005-06-06 2010-09-23 Filt Lungen- Und Thoraxdiagnostik Gmbh Method and use of a device for carrying out the method for measuring and analyzing components of exhaled respiratory gas

Also Published As

Publication number Publication date
DE3932784C3 (en) 2002-08-01
DE3932784A1 (en) 1991-04-11
DE3932784C2 (en) 1997-05-15

Similar Documents

Publication Publication Date Title
WO1991005255A1 (en) Diagnosis of lung diseases by analysis of non-volatile and volatile constituents of respiratory air
EP2194867B1 (en) Collection and measurement of exhaled particles
DE69826117T2 (en) DETECTION OF MEDICAL CONDITIONS BY ANALYSIS OF EXHAUSTED GAS OR STEAM
EP0759169B1 (en) Process and device for collecting expired breath condensate
EP2729801B1 (en) Device and method for analyzing volatile organic compounds in gaseous samples
EP1217643B1 (en) Method and apparatus for the determination of the state of organisms and natural products and for the analysis of gaseous mixtures having main components and secondary components
DE19951204C2 (en) Procedure for analyzing the ingredients in exhaled air
Kootker et al. The effects of decomposition and environment on antemortem H-Pb-Sr isotope compositions and degradation of human scalp hair: Actualistic taphonomic observations
EP2066236B1 (en) Device for fractionating expiration volume
Hunt The estimation of magnesium in plasma, muscle and bone, by atomic absorption spectrophotometry
DE19718924A1 (en) Apparatus to recover component fractions from exhaled air
EP1036322B1 (en) Device for investigating respiratory tract diseases and diagnostic agents
DE102006039140B4 (en) Device, its use and method for fractionating the expiratory volume
DE102005026933B4 (en) Method and use of a device for carrying out the method for measuring and analyzing components of exhaled respiratory gas
Kubáň et al. Capillary electrophoretic analysis of exhaled breath condensate in the diagnosis of gastroesophageal reflux disease
DE19528158A1 (en) Device for extracting the contents of the exhaled air
DE10114141A1 (en) Rapid testing for tuberculosis analyzes exhaled patient breath for tuberculosis-specific molecules followed by ion drift findings in calibrated apparatus
DE10137564A1 (en) Screening for drugs in a human or animal, comprises taking the condensation from exhaled breath, to be prepared for quantitative and qualitative analysis on site or to give a sample for a laboratory
Cherednikova et al. Study of exhaled air composition during recovery after respiratory disease by mass spectrometric analysis, St
DE10339015A1 (en) Diagnosing a disease, comprises that matter is analyzed in a gas or aerosol phase from the patient's skin by an ion mobility spectrometer, for rapid detection by gas chromatography
SK CAPILLARY ELECTROPHORETIC ANALYSIS OF EXHALED BREATH CONDENSATE IN THE DIAGNOSIS OF GASTROESOPHAGEAL REFLUX
JPS5965251A (en) Measurement of lactic acid contained in sweat or the like
DE10137566A1 (en) Quantification of respiratory exchange process, useful e.g. for defining sources of biomolecules in breath, comprises analysis of breath condensate after administering a marker
DE19921764A1 (en) Detecting coma conditions for ensuring more specific therapy, comprises using gas analysis on patient's breath or volatile part of patient's secretions and comparing with data profiles of different coma conditions
DE202006012837U1 (en) System for analyzing breathing, especially lung function, with monitoring of inhaling and exhaling cycles and with sampling of exhaled gasses

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB IT LU NL SE