Surgery – Diagnostic testing – Respiratory
Reexamination Certificate
2001-09-18
2003-04-01
Nasser, Robert L. (Department: 3736)
Surgery
Diagnostic testing
Respiratory
C073S023300, C422S084000
Reexamination Certificate
active
06540691
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the diagnosis of disease in mammals and more particularly to a method employing breath testing for the detection of particular diseases in humans.
2. Brief Description of Related Art
Volatile Organic Compounds in Human Breath
Alveolar breath is a distinctive gas whose chemical composition differs markedly from inspired air. Volatile organic compounds (VOCs) are either subtracted from inspired air (by degradation and/or excretion in the body) or added to alveolar breath as products of metabolism. Some features of this transformation have been well understood for many years: e.g. oxygen is subtracted and carbon dioxide is added by the oxidative metabolism of glucose (Phillips M., Breath tests in medicine, Scientific American 1992:267(1):74-79).
Pauling et al, in 1971, employed cold trapping to concentrate the VOCs in breath and found that normal human breath contained several hundred different VOCs in low concentrations (Pauling L. Robinson A B, Teranishi R and Cary P: Quantitative analysis of urine vapor and breath by gas-liquid partition chromatography, Proc Nat Acad Sci USA 1971:68:2374-6). This observation has been subsequently confirmed in many different laboratories, employing progressively more sophisticated and sensitive assays. More than a thousand different VOCs have been observed in low concentrations in normal human breath (Phillips M: Method for the collection and assay of volatile organic compounds in breath, Analytical Biochemistry 1997;247:272-278).
Reactive oxygen species (ROS) are toxic byproducts of energy production in the mitochondria. “Oxidative stress” is the constant barrage of oxidative damage which ROS inflict upon DNA, proteins, lipids and other biologically important molecules Fridovich I. The biology of oxygen radicals. Science 201:875-880;1978; Pryor W A: Measurement of oxidative stress status in humans. Cancer Epidemiol Biomarkers Prev 2 (3):289-292; 1993 (FIG.
1
). Oxidative stress has been implicated as a pathologic mechanism in aging and several diseases. Ashok B T; Ali R: The aging paradox: free radical theory of aging Exp Gerontol 1999 34(3):293-303; Saretzki G and von Zglinicki T: (Replicative senescence as a model of aging: the role of oxidative stress and telomere shortening—an overview) Z Gerontol Geriatr 1999;32(2):69-75; Halliwell B, Gutteridge J M C, Cross C E: Free radicals, antioxidants, and human disease: Where are we now? J Lab Clin Med 119: 598-620;1992. Consequently, oxygen is now recognized as both beneficial and harmful: it is essential to sustain mammalian life because it is the final acceptor of electrons in oxidative metabolism, but in this process it also causes oxidative stress and tissue damage.
Breath Alkanes as Markers of Disease
Analysis of VOCs in inspired air and alveolar breath is a useful research tool with potential applications in clinical medicine. Breath analysis opens a non-invasive window on normal metabolic pathways, and also illustrates how these pathways are altered in disease.
Alkanes in breath are markers of oxygen free radical (OFR) activity in vivo. OFR's degrade biological membranes by lipid peroxidation, converting polyunsaturated fatty acids (PUFAs) to alkanes which are excreted through the lungs as volatile organic compounds (VOCs); (Kneepkens C M F, Ferreira C. Lepage G and Roy C C: The hydrocarbon breath test in the study of lipid peroxidation; principles and practice, Clin Invest Med 1992; 15(2):163-186;
Kneepkens C M F, Lepage G and Roy C C: The potential of the hydrocarbon breath test as a measure of lipid peroxidation, Free Radic Biol Med 1994;17:127-60) (FIG.
5
). Increased pentane in the breath has been reported as a marker of oxidative stress in several diseases including breast cancer (Hietanen E, Bartsch H, Beireziat J-C, Camus A-M, McClinton S. Eremin O, Davidson L and Boyle P: Diet and oxidative stress in breast, colon and prostate cancer patients: a case control study, European Journal of Clinical Nutrition 1994;48:575-586), heart transplant rejection (Sobotka P A, Gupta D K, Lansky D M, Costanzo M R and Zarling E J: Breath pentane is a marker of acute cardiac allograft rejection. J. Heart Lung Transplant 1994; 13:224-9), acute myocardial infarction (Weitz Z W, Birnbaum A J, Sobotka P A, Zarling E J and Skosey J L: High breath pentane concentrations during acute myocardial infarction. Lancet 1991;337:933-35), schizophrenia (Kovaleva E. S, Orlov O. N, Tsutsul'kovskaia Mia, Vladimirova T. V, Beliaev B. S: Lipid peroxidation processes in patients with schizophrenia. Zh Nevropatol Psikiatr 1989:89(5): 108-10), rheumatoid arthritis (Humad S. Zarling E. Clapper M and Skosey J L: Breath pentane excretion as a marker of disease activity in rheumatoid arthritis, Free Rad Res Comms 198;5(2):101-106) and bronchial asthma (Olopade C O, Zakkar M, Swedler W I and Rubinstein I: Exhaled pentane levels in acute asthma, Chest 1997;111(4):862-5). Analysis of breath alkanes could potentially provide a new and non-invasive method for early detection of some of these disorders (Phillips M: Breath tests in medicine, Scientific American 1992;267(1):
74-79).
Alkanes are degraded to other VOCs such as alkyl alcohols and possibly to methyl alkanes (Phillips M: Method for the collection and assay of volatile organic compounds in breath, Analytical Biochemistry 1997; 247:272-78) but there is little information about the excretion of these compounds in the breath, where they might also provide clinically useful markers of disease.
Breath testing for VOC markers of oxidative stress is a comparatively new field of research, and published information is scanty in a number of areas: First, studies of breath alkanes have focused near-exclusively on ethane and pentane which are degradation products of n-3 and n-6 PUFAs respectively. Hexane and octane have also been observed in the breath of animals, but there is little information about longer chain VOCs in normal human breath. Second, most studies have taken little or no account of the presence of alkanes in the inspired ambient air, where they appear to be near-universal contaminants. Cailleux and Allain questioned whether pentane was a normal constituent of human breath, because the concentrations in breath and inspired air, were frequently so similar. (Cailleux A & Allain P: Free Radicals Res Commun 1993; 18:323-327). This problem may be resolved by determination of the alveolar gradient of a VOC, the difference between its concentration in the breath and in the ambient air. (Phillips M. Sabas M & Greenberg J: Free Radical Res Commun. 1994; 20:333-337).
Breath Alkanes As Markers of Breast Cancer
Breast cancer is a common disease which now affects approximately one in every ten women in the United States. Early detection by periodic screening mammography can reduce mortality by 20-30%. However, mammography is expensive, frequently requires painful breast compression, entails exposure to radiation, and generates false-positive results in one third of all women screened over a 10 year period (Elmore J G, Barton M B, Moceri V M, Polk S, Arena P J and Fletcher S W: Ten-year risk of false positive screening mammograms and clinical breast examinations). There is a clinical need for a screening test for breast cancer which is at least as sensitive and specific as mammography, but is simpler, safer, less painful and less expensive.
The cytochrome P450 (CYP) system comprises a group of mixed function oxidase enzymes which metabolize drugs and other xenobiotics. This system also metabolizes alkanes to alcohols e.g. n-hexane to 2- and 3-hexanol (Crosbie S J, Blain P G and Williams F M: Metabolism of n-hexane by rat liver and extrahepatic tissues and the effect of cytochrome P
40
inducers. Hum Exp Toxicol 1997; 16(3):131-137). Rats treated with a potent cytochrome P-450 inhibitor exhibited a ten-fold increase in hexane and other breath VOCs with no increase in hepatic lipid peroxidation, demonstrating the significance of this pathway for VOC clearance (Mathews J M, Raymer J H, Ethe
Nasser Robert L.
Pitney Hardin Kipp & Szuch LLP
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