Surgery – Diagnostic testing – Respiratory
Reexamination Certificate
1999-11-08
2001-07-03
Winakur, Eric F. (Department: 3736)
Surgery
Diagnostic testing
Respiratory
C600S543000, C600S529000, C436S064000, C436S813000, C436S900000
Reexamination Certificate
active
06254547
ABSTRACT:
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.
BACKGROUND OF THE INVENTION
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 (1,2) (FIG.
1
). Oxidative stress has been implicated as a pathologic mechanism in aging and several diseases (3,4,5). 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.
Although the significance of oxidative stress in disease is well recognized, it has proved difficult to measure its intensity in vivo. Various markers have been proposed, including malonaldehyde and conjugated dienes in the blood, and hydrocarbons and hydrogen peroxide in the breath (6,7). Breath markers of oxidative stress have attracted attention because breath tests are intrinsically non-invasive and painless (8). Increased breath alkanes, particularly ethane and pentane, have demonstrated increased oxidative stress in breast cancer (9), rheumatoid arthritis (10), heart transplant rejection (11), acute myocardial infarction (12), schizophrenia (13) and bronchial asthma (14).
However, breath tests for ethane and pentane have limited value in screening for these disorders because their sensitivity and specificity are poor, resulting in large numbers of false positive and false negative results.
Oxidative stress produces many different degradation products, so that ethane and pentane are only one-dimensional markers of a larger process. Phillips et al recently reported a two-dimensional marker of oxidative stress, the breath alkane profile (U.S. application Ser. No. 09/229,020: A breath test for the detection of various diseases). This marker comprises the alveolar gradient (concentration in breath minus concentration in air) of a spectrum of alkanes from C4 to C20. The alveolar gradient varies with the difference between the rate of synthesis and the rate of clearance of a volatile organic compound (VOC) in the body. In a group of normal humans, the breath alkane profile was found to rise significantly with age.
Phillips et al also previously observed that methylated alkanes are common components of the breath in normal humans as well as in those suffering from lung cancer (15,16). These VOCs appeared to provide additional markers of oxidative stress.
SUMMARY OF THE INVENTION
A new marker of oxygen free radical (OFR) activity in the body was developed: the breath alkane profile. This comprised the alveolar gradients of a wide spectrum of VOCs ranging from C2 to C20 alkanes plotted as a function of carbon chain length. Similar profiles were developed for two alkane metabolites in breath: alkyl alcohols and 2-methyl alkanes. These profiles provide a new and non-invasive probe of human metabolism by demonstrating the relative predominance of synthesis versus clearance of a VOC in vivo. In the present inventive method, methylated alkanes were combined with the breath alkane profile in order to construct the breath methylated alkane contour (BMAC), a new three-dimensional marker of oxidative stress.
This technique has been refined herein by determining the alveolar gradient of methylated alkanes and incorporating this data into a three dimensional plot. That is, where alveolar gradient versus the carbon chain length of n-alkanes was previously plotted, a third dimension has been added to the plot, which is the location of methylation along the carbon chain of the n-alkane. The information obtained from identifying the methylation site, in addition to the alveolar gradient and the carbon chain length of the n-alkane, has produced a new and uniquely sensitive marker of oxidative stress in humans. In the data presented herein, collected in tests upon normal human beings and in those suffering form heart transplant rejection, it is shown that
1. Oxidative stress was greater in heart transplant recipients than in age-matched normal controls;
2. Oxidative stress increased with the severity of heart transplant rejection; and
3. The breath test was sensitive and specific for clinically significant rejection.
REFERENCES:
patent: 5996586 (1999-12-01), Phillips
Natnithithadha Navin
Pitney Hardin Kipp & Szuch LLP
Winakur Eric F.
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