Reagent for evaluating a hepatic operation

Details Reagent for evaluating a hepatic operation Reagent for evaluating a hepatic operation

1998-09-11

2001-01-16

Warden, Jill (Department: 1743)

Chemistry: analytical and immunological testing

Peptide, protein or amino acid

C436S811000, C436S034000, C436S900000, C600S532000, C128S898000

Reexamination Certificate

active

06174730

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a reagent for evaluating a hepatic operation with which the actual liver excision ratio by the operation, the liver regeneration/increase ratio or the liver weight of a patient after the hepatic operation can be measured safely and simply.
2. Description of the Prior Art
In liver excision which is one of the representative treating methods for liver cancer, the liver excision ratio (i.e. the ratio by weight of the excised liver to the total liver before the excision) and the weight of the remaining liver are important as numerical values representing objectively the evaluation of the excision and the degree of invasion by the excision. Together with the results of the liver function test, these values provide useful information for prognosis.
In order to know the liver excision ratio and the weight of the remaining liver mentioned above, measurement by weighing is most accurate. However, it is practically impossible to weigh the remaining liver though it is possible to weigh the excised liver.
At present, in order to determine the scope of a liver to be excised, it is possible to measure the ratio of this planned scope of excision from a total liver CT slice using an area measuring instrument prior to a hepatic operation [Ogasawara et al., Jpn. J. Surg. 25:43 (1995); Okamoto et al., Surgery 95:586 (1984); Yamanaka et al., Hepatology 18:79 (1993)]. After the operation, however, the patient is in an invaded state being connected with a plurality of tubes for transfusion or the like, and thus CT will impose a great burden on the patient. Besides, CT requires a high cost. Therefore, it is not realistic to practice this method in a large number of patients.
Besides, the system to calculate a liver volume from a total liver CT slice has spread little since the system is useful only for that purpose and very expensive. Furthermore, in the use of that system, a contrast medium is often administered to a patient to trace a liver slice from a CT image with a high sensitivity, which may cause the patient a shock.
On the other hand, the liver is an organ with a vigorous ability to regenerate. It regenerates and increases rapidly if the postoperative course is good after a liver excision or a liver transplantation operation, or a hepatic operation for various therapies such as embolization therapy, alcohol injection treatment and microwave coagulation therapy. Thus, it is thought that information concerning the liver regeneration/increase ratio and the liver weight after the regeneration is useful for judging unfavorable postoperative course and for managing treatment and nutrition [Hymsfield et al., Ann. Int. Med. 90:185 (1979)].
At present, what is commonly used as a parameter for the prognosis of a hepatic operation is a test method generically named the “liver function test”, in which the ability to synthesize proteins such as serum albumin, the amounts of enzymes leaking from the liver, and the ability to include/excrete organic substances and drugs are measured (Merck Manual 16th Edition (1992)]. As one of the liver function test, there is the sugar tolerance test in which fructose or galactose is loaded to a subject and the ratio of its removal from the blood and the ratio of its retention in the blood are measured. However, these test results do not necessarily correlate with the liver regeneration/increase ratio.
Although determination by weighing is the most accurate way to know the liver regeneration/increase ratio and the liver weight of a patient, it is actually impossible to weigh the liver of a patient after a hepatic operation. To date, scintigraphy using 198Au or 99mTc [MacDermott and Weber, Surgery 54:56 (1963); Parker and Siemsen, Radiology 88:342 (1967); Barrett et al., Cancer 22:268 (1968); Aronsen et al., Ann. Surg. 171:567 (1970)] and the determination of a liver volume by CT [Hymsfield et al., Ann. Int. Med. 90:185 (1979); Yamanaka et al., Hepatology 18:79 (1993)]. However, these methods have various problems such as heavy physical burden imposed on patients, exposure to radiation and a very high price of the system.
The liver is a major organ which metabolizes aromatic amino acids; in particular, phenylalanine and tyrosine are metabolized in the liver for the most part [Essential of Human Metabolism, W. C. McMurray Harper & Row Publishers, N.Y., (1983)]. A liver function test method noting this point has been reported recently. This method comprises administering
13
C-labelled phenylalanine to a subject, measuring
13
CO
2
discharged into the exhalation and evaluating the phenylalanine metabolizing ability of the liver from the degrees of increase of the
13
CO
2
[U.S. Pat. No. 5,386,832; Burke et: al., Am J. Surgery 173:270 (1997)]. However, correlation with liver regeneration/increase ratios has not been examined at all.
Since the liver is also a major metabolic organ for methionine, alanine and galactose [Essential of Human Metabolism, W. C. McMurray Harper & Row Publishers, N.Y., (1983)], methods for evaluating liver functions by administering to a subject
13
C-labelled methionine or alanine [Japanese Patent No. 2680861] or
13
C-labelled galactose [Mion F. et al., Life Sciences 54:2093 (1994); Walton W. et al., Gastroenterology 71:98 (1976)] and measuring the degrees of increase of
13
CO
2
discharged into the exhalation have been reported. However, correlation with liver regeneration/increase ratios has not been examined at all in these methods.
As described above, although the liver excision ratio, the liver regeneration/increase ratio or the liver weight of a patient after a hepatic operation is important for evaluating the operation, there has been no effective means to obtain such information. Thus, almost nothing is done to obtain such information at present.
Under circumstances, it is desired to provide a means to measure safely and simply the liver excision ratio, the liver regeneration/increase ratio or the liver weight of a patient after a hepatic operation which would be an important parameter for evaluating the operation.
OBJECTS AND SUMMARY OF THE INVENTION
It is an object of the present invention to provide a reagent for evaluating a hepatic operation, with which the liver excision ratio, the liver regeneration/increase ratio or the liver weight of a patient after the hepatic operation can be measured safely and simply regardless of the conditions of the patient.
Toward the solution of this problem, the present inventors have made intensive and extensive researches. As a result, the inventors have found that it is possible to accurately measure the liver excision ratio, the liver regeneration/increase ratio or the liver weight of a patient after a hepatic operation by administering to the patient once or a plurality of times an aromatic amino acid, methionine, alanine, fructose or galactose labelled with
13
C and measuring degrees of increase of
13
C level in the exhaled CO
2
. Thus, the present invention has been achieved.
The present invention relates to a reagent for evaluating a hepatic operation, comprising an aromatic amino acid, methionine, alanine, fructose or galactose labelled with
13
C at least at one position.


REFERENCES:
patent: 5302520 (1994-04-01), Goux
patent: 5386832 (1995-02-01), Wagner et al.
patent: 5413917 (1995-05-01), Malloy et al.
patent: 5961470 (1999-10-01), Wagner et al.
patent: 5962335 (1999-10-01), Katzman
patent: WO9201937 (1992-02-01), None
patent: WO9205270 (1992-04-01), None
Derwent Abstract XP-002089103, 1992.
“Test for Alcoholic Cirrhosis by Conversion of [14C]-or [13C]Galactose To Expired CO2,” Walton W. Shreeve, M.D., et al., vol. 71, No. 1, Gastroenterology 71:96-101, 1976.
“In Vivo Oxidation of [13C]Galactose in Patients with Galactose-1-Phosphate Uridyltrasferase Deficiency,” Gerard T. Berry et al., Biochemical and Molecular Medicine 56, 158-165 (1995).
“Breath tests: concepts, applicatio

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