Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Reexamination Certificate
1999-09-23
2001-07-03
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
C424S001110, C424S001650, C424S009100, C549S223000
Reexamination Certificate
active
06254851
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds useful as diagnostic agents for pancreatic exocrine function and their use.
2. Background of the Invention
“Pancreatic exocrine function tests” are useful for the diagnosis of pancreatic diseases such as chronic and acute pancreatitis and pancreatic cancer. They are also useful to assess the condition and prognosis of patients and to control the medication: The general descriptions are found in Arvanitakis and Cooke, Gastroenterology, 74:932 (1978); Niederau and Grendell, Gastroenterology, 88:1973 (1985); Goldberg, Bull. Mol. Biol. Med., 15:1 (1990); Lankisch, Int. J. Pancreatology, 14:9 (1993); Bank and Chow, Gastroenterologist, 2:224 (1994); and Steer et al., New Eng. J. Med., 332:1482 (1995).
At present, “Gold standard” of the pancreatic exocrine function test involves inserting a tube through the mouth to the duodenum to collect the duodenal juice. Now, the secretin test is generally utilized wherein secretin is intravenously administered to stimulate the secretion of the pancreatic juice prior to the collection. This method is highly accurate since the amount and components of the pancreatic juice are directly analyzed. However, this method can not be used repeatedly or used for screening because of the very strong stress caused on the subjects. It is available at only a relatively small number of medical centers having highly skilled physicians. Further, since this method requires fluoroscopic tube placement during the collection of the duodenal juice, there is the problem of X ray exposure.
On the other hand, a test for quantifying pancreatic exocrine enzymes from the pancreas into the blood is clinically employed for screening pancreatic diseases (The Merck Manual 16th edition). However, the increase of the pancreatic exocrine enzymes in the blood is only observed at the initial stage of acute pancreatitis or at the recrudescent stage of chronic pancreatitis and does not always reflect the ability of the pancreas to secrete pancreatic exocrine enzymes. Further, the increase of pancreatic exocrine enzymes in the blood may sometimes not be detected due to serum turbidity in pancreatitis accompanied by hyperlipemia.
Accordingly, simple methods which require no insertion of a tube are utilized for repetition and screening tests. One of them is the pancreolauryl test (PLT) wherein a synthetic substrate FDL (fluorescein diraulate, dilaurylfluorescein) for cholesterol ester hydrolase, esterase, secreted from the pancreas is orally administered and urine is accumulated for 10 hours followed by measuring the amount of a degradation product fluorescein excreted into the urine: U.S. Pat. No. 3,917,812; Barry et al., Lancet (1982) October 2, p. 742; Scharpe and Iliano, Clin. Chem., 33:5 (1987). However, this method requires a long time to carry out the test and therefore can not often be performed on outpatients and is not suitable in physical examinations.
Under these circumstances, there is a need for the development of a simple method for testing the pancreatic exocrine function which imparts low stress on subjects and gives accurate results soon.
On the one hand, the
13
C-breath test wherein a
13
C-labeled starch is administered has been recently considered to be employed in the test for the pancreatic exocrine function: Hiele et al., Gastroenterology, 96:503 (1989); Dewit et al., Pediatric Res., 32:45 (1992); and Z. Gastroenterol., 35:187 (1997). In the enteric tract, starch is degraded efficiently to glucose by the cleavage at any internal &agr;-1,4 glucoside linkage with &agr;-amylase secreted from the pancreas and by the action of enzymes such as &agr;-glucosidase (maltase) of mucosal epithelial cells of the small intestine and absorbed: Essentials of Human Metabolism, 2nd ed., W. C. McMurray, Harper & Row Publishers, NY. The
13
C-breath test wherein a
13
C-labeled starch is administered utilizes the phenomenon that after the
13
C-labeled starch is degraded in the digestive tract, it is absorbed and decarboxylated by metabolic action in the body to generate
13
CO
2
which is excreted into the breath, and it is a safe and simple method. However, any
13
C-labeled oligosaccharide or polysaccharide other than
13
C-labeled starch has not yet been studied.
Since there is an &agr;-glucosidase (maltase) in mucosal epithelial cells of the small intestine, which cleaves a non-reducing terminal &agr;-1,4-glucoside linkage (Enzyme Handbook, Springer-Verlag, Berlin), starch is degraded into glucose sequentially from the non-reducing terminal and absorbed only by the action of enzymes such as the &agr;-glucosidase (maltase), even without the action of &agr;-amylase. Thus, starch is subject to the action of a non-pancreatic-exocrine enzyme &agr;-glucosidase (maltase) of mucosal epithelial cells of the small intestine and therefore the
13
C-labeled starch breath test does not reflect the pancreatic exocrine function only. Accordingly, it would be more preferred if a substrate compound specific for &agr;-amylase in the digestive tract is selected.
Accordingly, an object of the present invention is to provide a diagnostic agent for pancreatic exocrine function which leads to a test for the pancreatic exocrine function imparting low stress on subjects and yields the results in a short period of time.
It is another object of the present invention to provide a diagnostic agent for pancreatic exocrine function which is specific to the &agr;-amylase secretion ability.
It is a further object of the present invention to provide a novel compound usable in the pancreatic exocrine function test.
SUMMARY OF THE INVENTION
The present inventors have found that the pancreatic exocrine function test can be carried out by orally administering a
13
C-labeled oligosaccharide or a
13
C-labeled inclusion complex or a
13
C-labeled fluorescein ester compound to a rat with chronic pancreatitis and measuring the
13
C concentration in the exhaled CO
2
after administration. Thus, the present invention has been completed.
Accordingly, the present invention provides a
13
C-labeled oligosaccharide or polysaccharide or a salt thereof or a derivative thereof or a C
13
C-labeled inclusion complex other than U-
13
C-maltose,
13
C-starch, 1-
13
C-maltotetraose and 1-
13
C-amylose.
Also, the present invention provides a diagnostic agent for pancreatic exocrine function comprising a
13
C- or
14
C-labeled oligosaccharide or polysaccharide or a salt or a derivative thereof, or a
13
C- or
14
C-labeled inclusion complex or a salt thereof other than
13
C-starch.
Moreover, the present invention provides a diagnostic agent for pancreatic exocrine function comprising a compound which is degraded with &agr;-amylase but not degraded with &agr;-glucosidase.
Furthermore, the present invention provides a
13
C- or
14
C-labeld fluorescein ester compound or a salt thereof.
Also, the present invention provides a diagnostic agent for pancreatic exocrine function comprising a
13
C- or
14
C-labeled fluorescein ester compound or a pharmaceutically acceptable salt thereof.
The subject matters of the present invention are as follows.
(1) A
13
C-labeled oligosaccharide or polysaccharide or a salt thereof excluding U-
13
C-maltose,
13
C-starch, 1-
13
C-maltotetraose and 1-
13
C-amylose.
(2) The
13
C-labeled oligosaccharide or polysaccharide or salt thereof according to (1), which is hydrolyzed with &agr;-amylase.
(3) The
13
C-labeled oligosaccharide or polysaccharide or salt thereof according to (2), which is not hydrolyzed with &agr;-glucosidase.
(4) The
13
C-labeled oligosaccharide or polysaccharide or salt thereof according to any one of (1) to (3), wherein at least one sugar molecule constituting the oligosaccharide or polysaccharide is
13
C-labeled.
(5) The
13
C-labeled oligosaccharide or polysaccharide or salt thereof according to any one of (1) to (3), wherein at least one sugar molecule constituting the oligosaccharide or polysaccharide is modified with at least one
13
C-labeled modifying group.
(6) The
13
Hosoi Isaburo
Ito Asuka
Kohno Tadashi
Ohshima Junko
Shibata Kunihiko
Fish & Richardson P.C.
Jones Dameron L.
Tokyo Gas Company Limited
LandOfFree
Diagnostic agents for pancreatic exocrine function does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Diagnostic agents for pancreatic exocrine function, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Diagnostic agents for pancreatic exocrine function will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2559500