Surgery – Diagnostic testing – Respiratory
Reexamination Certificate
1999-08-27
2001-06-19
O'Connor, Cary (Department: 3736)
Surgery
Diagnostic testing
Respiratory
C600S532000, C600S543000, C073S023300
Reexamination Certificate
active
06248078
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to analysis of hepatic disorders in a mammal. For example, in one aspect, the invention relates to test systems and methods for detecting and/or staging hepatic disorders in a human patient. The present invention is useful for a variety of applications including use in the diagnosis or treatment of liver disease.
BACKGROUND
There is recognition that a variety of methods can be used to detect hepatic disorders particularly in human patients. The methods are generally dominated by fluid-based tests that monitor liver-related molecules in blood, plasma and urine. See e.g.,
Handbook of Clinical Laboratory Data
(1997) (CRC Press, Inc. West Palm Beach, Fla.)
However, many of the fluid-based tests for hepatic dysfunction are believed to be associated with significant drawbacks. For example, most of the tests are optimized to provide only an indirect measure of liver function. That is, the tests provide little or no information about how the liver functions in real-time. Significant patient follow-up and testing is often needed to achieve desired results. Additionally, there has been some concern that fluid-based tests may not always provide enough sensitivity or selectivity to detect mild hepatic disorders. Nearly all of the tests require handling of body fluids, thereby posing a biohazard risk to personnel conducting the tests.
Several attempts have been made to provide more effective methods for detecting hepatic disorders. For example, in one approach, a biopsy is taken from the patient to more precisely evaluate liver function. However, biopsy procedures are often costly, time-intensive and extremely painful. Biopsy procedures may also be unsuitable for patients suffering from specific hepatic disorders or patients who have received a liver transplant.
In another approach, it has been reported that it is possible to relate presence of certain volatile molecules in human breath to specific conditions. Several tests have been designed to detect these molecules. See e.g., Phillips, M.,
Sci. Am.,
(1992), 267: 74; Perman, J. A.,
Canad. J Physiol. Pharmac.,
(1991); 69: 111; Risby et al.,
Surgery,
(1994), 115, 94; and Kazui et al.,
Free Radic Biol. Med.,
(1992), 13, 509; for disclosure relating to the prior breath tests.
More specific breath tests have been disclosed. For example, U.S. Pat. No. 5,386,832 discloses assays for measuring liver function by analyzing specific labeled molecules in human breath.
More particularly, it has been reported that specific sulfurous compounds such as volatile sulfides can be detected in the breath of some cirrhotic patients. It has been proposed that at least some of the compounds may arise from liver dysfunction. See e.g., Chen et al.,
J. Lab Clin. Med.,
(1970), 75: 628; Kaji et al.,
Clin. Chim. Acta,
(1978), 85: 279; Tangernan et al.,
J. Lab Clin. Med.,
(1985), 106: 175 and Husamura, M.,
Nippon Naisa Gakkai Zasshi,
(1979), 68: 1284.
However, the breath tests mentioned have been associated with problems which have tended to restrict use. For example, practically none of the tests are formatted to classify and/or stage a hepatic disorder. That is, the tests are not optimized to provide information as to what liver disorder is manifested by a patient and to what extent that disorder has progressed In addition, the tests usually cannot discriminate between different or closely related hepatic disorders. These shortcomings can negatively impact patient care in a variety of ways, e.g., by complicating diagnoses and/or delaying implementation of a life-saving therapy. The inability of the prior breath tests to stage hepatic disorders has made it especially difficult to evaluate patients in real-time.
Additionally, several of the prior breath tests have been reported to require administration of carbon 14 or other nuclides. Release of radioactive respiratory gas by patients may not be desirable for several reasons.
Many of the prior breath tests suffer from additional drawbacks and disadvantages. For example, as disclosed, the tests often require substantial breath samples, thereby restricting use to patients that can safely provide a substantial volume of breath. However, in many situations, patients may not be able to provide a large breath volume. Several specific breath tests require nearly all of the patient's breath sample, thereby eliminating opportunities to re-test the breath samples after analysis. In instances where more breath is needed, it can be very inconvenient or even impossible for patients to provide another breath sample. In cases where a patient's breath sample is exhausted, follow-up tests and statistical analyses can be difficult or impossible to perform, which compromises the accuracy of the analysis.
It has been disclosed that human breath includes perhaps hundreds of volatile organic molecules. However, only a fraction of these molecules are believed to relate to hepatic disorders. Accordingly, there is a need in the field to develop effective tests that can reliably characterize the disorders. In particular, it would be desirable to have test systems and methods that can facilitate reliable detection and preferably staging of hepatic disorders in a human patients.
SUMMARY OF THE INVENTION
The present invention generally relates to test systems and methods for characterizing a hepatic disorder in a mammal, and particularly a human patient. In general, the test systems and methods detect at least one volatile organic molecule in respiratory gas and relate the organic molecule to the presence and preferably the stage of the hepatic disorder in the mammal. The present invention has several important applications including use in the diagnosis and/or treatment of hepatic disorders in human patients.
More particularly, we have discovered that certain volatile organic molecules in respiratory gas can be used to detect and preferably stage a variety of hepatic disorders. Sometimes the volatile organic molecules will be referred to herein as breath “biomarkers” or a similar term to denote a physiological origin for these molecules. Preferred use of the invention generally involves detection and quantitation of biomarkers that have been found to be indicative of the presence and stage of certain hepatic disorders. For example, it has been found that the presence and stage of specific hepatic disorders can be determined with high sensitivity and selectivity by detecting and quantifying the biomarkers. Preferred use of the invention typically requires minimal breath volumes, thereby facilitating testing of sick, infirm or very young patients including children and infants. Patient inconvenience with respect to providing substantial breath samples is reduced or eliminated by the invention. The test systems and methods described herein are non-invasive and are well-suited for safe and reliable handling of a large numbers of breath samples.
The present invention has additional important uses and advantages. For example, it can be used to provide a reliable indicator of liver function at an early stage of disease progression and in real-time. Opportunities for early medical intervention are therefore increased. The invention can be used to monitor liver function in patients having or suspected of having a family history of liver disease. Alternatively, the invention can be used to evaluate liver function as part of a routine medical check-up. As a specific illustration, the invention can be used as part of a pre-natal care program to provide real-time analysis of liver function in a mother and her fetus. Other applications of the invention include use in veterinary settings to monitor liver function in domesticated or wild animals.
Accordingly, in one aspect, the present invention features test systems for detecting and preferably staging a hepatic disorder in a mammal such as a human patient.
In one embodiment, the invention features a test system that includes at least one and preferably all of the following components:
a) a chamber for receiving respira
Burdick James F.
Jiang Long
Risby Terence H.
Sehnert Shelley
Buchanan Robert L.
Buckley Linda M.
Edwards & Angell LLP
Johns Hopkins University
Natnithithadha Navin
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