Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-10-16
2004-02-10
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S198100, C530S350000, C530S399000, C530S388220
Reexamination Certificate
active
06689745
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/JP00/02264 which has an International filing date of Apr. 7, 2000, which designated the United States of America and was not published in English.
TECHNICAL FIELD
The present invention relates to an agent for protecting pancreatic cells or an agent for ameliorating hypofunction of pancreatic cells, or an agent for protecting pancreatic tissues or an agent for ameliorating hypofunction of pancreatic tissues, these agent comprising as the active ingredient a neurotrophic factor.
BACKGROUND ART
Pancreas is an organ consisting of the endocrine gland tissues called pancreatic islet (Langerhans islet) and the exocrine gland tissues secreting digestive enzymes such as amylase, lipase, protease, etc. In the Langerhans islet, B cells (&bgr; cells) synthesizing and secreting insulin, etc., A cells (&agr; cell) synthesizing and secreting glucagon, etc., D cells (&dgr; cells) synthesizing and secreting somatostatin, and pancreatic polypeptide cells (hereinafter, referred to as PP cells) synthesizing and secreting pancreatic polypeptide, etc. exist, and they greatly affect the control of blood glucose and metabolism. Disorders of these endocrine glands and exocrine glands may induce abnormalities of controlling blood glucose level (e.g., diabetes mellitus, hypoglycemia, insulin shock, etc.) and decreased digestion (e.g., steatorrhea, etc.), respectively.
Pancreatic function disorders are induced by various causes, and representative underlying diseases thereof are, for example, pancreatitis or diabetes mellitus. Pancreatitis is clinically classified into acute pancreatitis and chronic pancreatitis, and the former is mono-pancreatitis or repetitive pancreatitis being characterized by acute bellyache attack accompanied by increase in pancreatic enzyme level in blood or urine. Serious acute pancreatitis further induces necrosis and hemorrhage of pancreatic substratum, serious renal failure, or respiratory failure, and may results in shock to death. The treatment thereof is usually carried out by inhibiting pancreatic exocrine by fasting and an H2 blocker, and further by preventing complications by administering a protease inhibitor, an antibiotic, or an analgesic.
Chronic pancreatitis is mainly induced by over-uptake of alcohol, and characterized by repetitive or persistent bellyache. Morphologically, it is characterized by immethodical sclerosis accompanied by destruction and permanent dissipation of pancreatic exocrine tissues, and it induces symptoms caused by pancreatic exocrine grand failure such as steatorrhea. In chronic pancreatitis, it is observed that about 50% of the patients produce a complication of diabetes mellitus due to pancreatic endocrine disorder (pancreatic diabetes). The characteristic of the secondary diabetes of this chronic pancreatitis is the lack of both insulin and glucagon, and the treatment thereof is mostly carried out by administration of insulin. About half of the causes of death for chronic pancreatitis are concerned with diabetes mellitus, and hypoglycemia after insulin injection (i.e., insulin shock) caused by the lack of glucagon or diabetic complications such as nephropathy or infections are pointed out as a cause of death.
In addition, sulfonylurea derivatives having an insulin secretion promoting activity have been used in the treatment of diabetes mellitus, but they may occasionally induce pancreatic cell dysfunction or pancreatic tissue dysfunction, due to excessive burden on the pancreas by forcing the pancreas to secrete insulin.
At present, a method for promoting a spontaneous recovery of pancreatic function has been used in the treatment of pancreatic function disorder, by eliminating diseases or factors that are a cause therefor (cf., “Learning of Pancreatopathy”, edited by Tadashi TAKEUCHI, published by Nankodo Co. Ltd., Aug. 1, 1993), but there in have not been known or used any method or agent for aggressively recovering the decreased pancreatic function.
On the other hand, neurotrophic factors are a generic name for proteins, which are provided from target cells or neurons and glia cells and Schwann cells in the living body. They show activities of maintaining the survival and differentiation of neurons, and are classified into many types according to the kinds of nerves or receptors to function. Among them, proteins being known as neurotrophins have high structural homology with each other and form a family. The typical examples thereof are neurotrophins such as nerve growth factor (hereinafter, abbreviated as NGF), brain-derived neurotrophic factor (hereinafter, abbreviated as BDNF), neurotrophin 3 (hereinafter, abbreviated as NT-3), neurotrophin 4 (hereinafter, abbreviated as NT-4), neurotrophin 5 (hereinafter, abbreviated as NT-5), or neurotrophin 6 (NT-6); ciliary neurotrophic factor (hereinafter, abbreviated as CNTF); glia cell-derived neurotrophic factor (hereinafter, abbreviated as GDNF), etc. In addition, neurotrophins are known to act as a specific ligand of receptors (trkA, trkB and/or trkC), which are the products of p-75 and trk genes (cf. Takeshi NONOMURA, Hiroshi HATANAKA; Jikken Igaku, vol. 13, p. 376 (1995)).
Neurotrophic factors have been studied with respect to their medical use as a therapeutic agent for treating a patient of neurodegenerative diseases. For example, Society for Neuroscience, vol. 21, p. 1535 (1995), A. P. Mizisin et al. discloses the pharmacological activity of BDNF on diabetic peripheral neuropathy, but this literature merely suggests the possible pharmacological activity of BDNF on neuropathy based on the finding that BDNF improves the reduction of motor nerve conduction in vivo. WO 98/32458 discloses that neurotrophic factors such as BDNF can normalize the blood glucose level of diabetic animal models, and applications thereof onto the treatment of diabetes mellitus are disclosed therein.
DISCLOSURE OF INVENTION
As mentioned above, an agent for protecting pancreatic cells or an agent for ameliorating damaged pancreatic cells, an agent for protecting pancreatic cell function or an agent for ameliorating pancreatic cell hypofunction, or an agent for protecting pancreatic tissues or an agent for ameliorating damaged pancreatic tissues, or an agent for protecting pancreatic tissue function or an agent for ameliorating pancreatic tissue hypofunction has been desired in the medical field.
The present inventors have an interest in that the insulin secretion of BDNF-treated type 2 diabetic animal models is kept at high level, and have studied pancreatic function ameliorating activities by using type 2 diabetic animal models. As a result, they have found that BDNF can (1) increase the decreased insulin content in pancreas of type 2 diabetes animal models, (2) reduce the increased glucagon content in pancreas, (3) normalize the localization of A cells and D cells in the pancreatic Langerhans islet, (4) promote the re-granulation of insulin secretory granules of B cells in the pancreatic Langerhans islet, and normalize the organellae. Based on the finding of these pancreatic function ameliorating activity and pancreatic cell protecting activity of BDNF, the present inventors have further studied and have accomplished the present invention.
More particular, the present invention relates to the following:
1. An agent for protecting pancreatic cells or an agent for ameliorating damaged pancreatic cells, which comprises as the active ingredient a neurotrophic factor;
2. An agent for protecting pancreatic cell function or an agent for ameliorating pancreatic cell hypofunction, which comprises as the active ingredient a neurotrophic factor;
3. An agent for protecting pancreatic tissues or an agent for ameliorating damaged pancreatic tissues, which comprises as the active ingredient a neurotrophic factor;
4. An agent for protecting pancreatic tissue function or an agent for ameliorating pancreatic tissue hypofunction, which comprises as the active ingredient a neurotrophic factor;
5. The agent for protection or ameliorat
Itakura Yasushi
Taiji Mutsuo
Birch & Stewart Kolasch & Birch, LLP
Kemmerer Elizabeth
Sumitomo Pharmaceuticals Company Limited
Wegert Sandra
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