Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-07-31
2001-07-17
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S236100, C424S239100
Reexamination Certificate
active
06261572
ABSTRACT:
BACKGROUND
The present invention relates to a method for treating a pancreatic disorder. In particular the present invention relates to a method for treating a pancreatic disorder by in vivo administration of a neurotoxin to the body of the pancreas of a patient.
Exocrine Pancreas
The human pancreas is a gland comprised of both exocrine and endocrine tissues. Anatomically, the pancreas consists of unicate process, head, neck, body and tail regions. The acinar cells of the exocrine pancreas secret digestive enzymes, for digesting ingested food. The ductal cells of the exocrine pancreas secret an electrolyte solution comprising bicarbonate for the neutralization of the acidic chyme produced in the stomach. Together the digestive enzymes and the electrolyte fluid make up the pancreatic juice which flows past the sphincter of Oddi into the duodenum via the pancreatic ducts. The exocrine pancreas can make up to three liters per day of pancreatic juice containing about 20 different enzymes and zymogens, such as amylase, lipase, trypsin and trypsinogen. The secretion of pancreatic juice is stimulated by the presence of chyme in the upper portions of the small intestine, and the precise composition of pancreatic juice appears to be influenced by the types of compounds (carbohydrate, lipid, protein, and/or nucleic acid) in the chyme. Gastric acid made by the stomach stimulates the release of secretin. Secretin in turn stimulates the secretion of a pancreatic juice rich in water and electrolytes. Gastric acid, long chain fatty acids and certain amino acids trigger the release of cholecystokinin (CCK) from the duodenum and jejunum. CCK stimulates the secretion of an enzyme rich secretion from the pancreas.
The constituents of pancreatic juice includes proteases (trypsin, chymotrypsin, carboxypolypeptidase), nucleases (RNAse and DNAse), pancreatic amylase, and lipases (pancreatic lipase, cholesterol esterase and phospholipase). Many of these enzymes, including the proteases, are initially synthesized by the acinar cells in an inactive form as zymogens. Thus trypsin is synthesized as trypsinogen, chymotrypsin as chymotypsinogen, and carboxypolypeptidase as procarboxypolypeptidase. These enzymes are activated according to a cascade, wherein, in the first step, trypsin is activated through proteolytic cleavage by the enzyme enterokinase. Trypsinogen can also be autoactivated by trypsin. Once activation has begun, the activation process proceeds rapidly. Trypsin, in turn, activates both chymotypsinogen and procarboxypolypeptidase to form their active protease counterparts.
The exocrine pancreatic enzymes are normally activated only when they enter the intestinal mucosa in order to prevent autodigestion of the pancreas. To prevent premature activation, the acinar cells also co-secrete a trypsin inhibitor that normally prevents activation of the proteolytic enzymes within the secretory cells and in the ducts of the pancreas. Inhibition of trypsin activity also prevents activation of the other proteases.
Pancreatitis is an inflammation of the pancreas and can be chronic or acute. Acute pancreatitis can be edematous or the more severe necrotizing or hemorrhagic pancreatitis. About five thousand new cases of pancreatitis occur each year in the United States and the mortality rate is about ten percent. Pancreatitis is frequently secondary to alcohol abuse or biliary tract disease. Pancreatitis can also be caused by drugs, trauma, gallstones or viral infection. One theory states that pancreatitis is due to autodigestion of the pancreas by proteolytic enzymes activated in the pancreas instead of in the intestinal lumen. Hence, pancreatitis is believed to manifest when an excess amount of trypsin saturates the supply of trypsin inhibitor. Excess trypsin can be due to underproduction of trypsin inhibitor, or the overabundance of trypsin within the cells or ducts of the pancreas. In the latter case, pancreatic trauma or blockage of a duct can lead to localized overabundance of trypsin. Under acute conditions large amounts of pancreatic zymogen secretion can pool in the damaged areas of the pancreas. If even a small amount of free trypsin is available activation of all the zymogenic proteases rapidly occurs, leading to autodigestion of the pancreas and the symptoms of acute pancreatitis. Pancreatitis can be fatal.
Some forms of acute pancreatitis, such as those triggered by excessive use of alcohol, scorpion sting, or intoxication by anti acetylcholine esterase containing insecticides, can be the result of excessive cholinergic stimulation of the exocrine cells of the pancreas. This excessive cholinergic stimulation can result from a symptomatic decrease in the number of pancreatic muscarinic acetylcholine receptors in pancreatitis.
Exp Toxicol Pathol April
1994; 45(8): 503-5.
Unfortunately, chronic pancreatitis is believed to be irreversible. Berger et al.,
The Pancreas,
page 720, infra. In Western countries, chronic pancreatitis appears to affect predominantly men aged 25 to 50 years, most of whom are alcoholics.
There are many drawbacks and deficiencies in current therapies for pancreatitis. Treatment of acute pancreatitis can include nasogastric suction to decrease gastrin release from the stomach and thereby prevent gastric contents from entering the duodenum and stimulating pancreatic exocrine secretions. Nasogastric suction is unpleasant and can be ineffective to arrest the course of pancreatitis.
Treatment of chronic pancreatitis can be by surgical resection of from 50% to 95% of the pancreas followed by oral enzyme replacement upon alimentation, clearly a suboptimal form of therapy.
Pancreatitis can be accompanied by constriction of pancreatic ducts leading to the duodenum resulting in a deficiency of pancreatic enzymes in the intestinal lumen, referred to as pancreatic exocrine insufficiency.
Pancreatic exocrine secretion can be regulated by both hormonal and nervous mechanisms. Thus, during the gastric phase of stomach secretion, parasympathetic nerve impulses to the pancreas result in acetylcholinergic stimulation of and release of enzymes by the cholinergically innervated acinar cells.
Significantly, cholinergic innervation dominates neuronal control of the exocrine pancreas. (Berger et al.,
The Pancreas,
volume 1, chapter 5, pages 65-66, Blackwell Science Ltd. (1998), which publication (two volumes) is incorporated herein by reference in its entirety) and it is known that cholinergic stimulation promotes secretion of pancreatic enzymes. Notably, pancreatic acinar cells have acetylcholine receptors. Ibid, pages 83-84. Extrinsic nervous control of the exocrine pancreas is parasympathetic, through vagal input. Ibid, page 66. Intrinsic nervous control of the pancreas refers to that part of the enteric nervous system which is within the pancreas (the intrapancreatic nervous system). The intrapancreatic nervous system comprises an interconnecting plexus of small ganglia supplied by preganglionic vagal fibers and postganglionic sympathetic fibers. Importantly, intrinsic cholinergic neurons (i.e. those with their cell bodies in intrapancreatic ganglia) dominate in the intrapancreatic nervous system. Ibid, page 67.
While intravenous anticholinergics may not significantly influence exocrine pancreatic digestive fluid secretion (see e.g. Dig Dis Sci February 1997; 42(2): 265-72 and
Am J Surg January
1996; 171(1): 207-11), extensive literature exists to support the hypothesis of significant cholinergic influence upon exocrine pancreatic cell secretory activity: See e.g.
Exp Toxicol Pathol April
1994; 45(8): 503-5,
Dig Dis
1992; 10(1):38-45,
Dig Dis
1992; 10(6): 326-9,
Arch Surg December
1990; 125(12): 1546-9, and
Ann Surg April
1982; 195(4): 424-34.
Endocrine Pancreas
The endocrine pancreas comprises the pancreatic islets of Langerhan which are aggregations of polypeptide hormone producing cells scattered widely throughout the acinar tissue and which are most numerous in the tail portion of the pancreas. Typically, total islet tissue constitutes only about 1 or 2 percent of the pancr
Allergan Sales Inc.
Baran Robert J.
Fisher Carlos A.
Jague Donna
Krass Frederick
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