Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-01-26
2002-01-08
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, C424S832000, C514S866000
Reexamination Certificate
active
06337075
ABSTRACT:
BACKGROUND
The present invention relates to methods for treating diabetes. In particular the present invention relates to methods for treating diabetes by administration of a neurotoxin to a patient.
Diabetes
The human pancreas is a gland comprised of both exocrine and endocrine tissues. The acinar cells of the exocrine pancreas secret digestive enzymes while the ductal cells of the exocrine pancreas secret an electrolyte solution.
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 pancreatic mass.
Islet tissue contains at least three functionally different types of cells. These three cell types are A cells which can make glucagon, B (or &bgr;) cells which make insulin and D cells which can make a third islet hormone, somatostatin. The B cells are the most abundant of the three types of islet cells. Insulin promotes the uptake of glucose by cells, especially muscle cells and prevents an excessive breakdown of glycogen stored in liver and muscle. As an antidiabetic hormone essential for lowering blood sugar, insulin is a powerful hypoglycemic agent. In most instances, the actions of glucagon are contrary to those of insulin. Thus, glucagon is a hyperglycemic factor which causes blood sugar to increase.
Glucose is the major factor which promotes release of insulin from islet B cells. Glucose also reduces glucagon secretion from islet A cells. Like glucose, glucagon (from islet A cells) also promotes insulin secretion from the islet B cells.
Diabetes mellitus is the most common endocrine disorder and is a chronic condition. It is estimated that in 1999 there were 100 million people worldwide with diabetes and the number of diabetics worldwide is expected to reach 300 million within the next ten years, that is by the year 2009.
Type
2
Diabetes Prediction and Prevention,
edited by Graham A. Hitman, John Wiley & Sons publisher, preface (1999), the entire contents of which publication are incorporated herein by reference. Unfortunately, diabetic retinopathy is a leading cause of blindness and other complications of diabetes include renal disease, foot problems and neuropathic conditions. Of the major forms of diabetes mellitus, type 2 diabetes cases outnumber type 1 diabetes cases by a ratio of about ten to one.
In type 1 or insulin dependent diabetes mellitus (IDDM) the B cells of the pancreas, and hence the capacity to make insulin, are destroyed by what is probably an autoimmune disease. Insulin replacement is the preferred therapy. Whereas at most about 20% of the cases of diabetes mellitus are type 1 or IDDM, typically about 80% to 90% of the cases of diabetes mellitus are type 2 or non insulin dependent diabetes mellitus (NIDDM). Although NIDDM is more prevalent than IDDM, its pathogenesis is not well understood. It has though been determined that NIDDM is the result of both a beta cell defect and insulin resistance. Thus, patients with type 2 NIDDM have the two physiological defects of hypersecretion of insulin (during at least the early phase of type 2 diabetes) and resistance to insulin in target tissues. There is support for the belief that hyperinsulinemia is the primary defect and it is known that in the early stages of type 2 diabetes, B cell production of insulin increases.
Type
2
Diabetes Prediction and Prevention,
supra, pages 199 and 311. Thus, in the first phase (new onset) of NIDDM, the plasma glucose level is normal despite demonstrable insulin resistance with elevated insulin levels. In the second phase insulin resistance worsens so that postprandial hyperglycemia develops despite elevated insulin. In the third or late phase of type diabetes, insulin resistance does not change but declining insulin secretion causes fasting hyperglycemia and overt diabetes. It is possible that early phase hypersecretion of insulin causes the insulin resistance. Thus, the primary defect can be due to disfunctional islet cells cause insulin hypersecretion which leads to insulin resistance. In support of this theory, one can note that B cell mass is intact in type 2 NIDDM, while most beta cells have been destroyed in type 1 IDDM. Interestingly, the alpha cell population is increased in type 2 NIDDM, resulting in an elevated ratio of alpha to beta cells and excess glucagon production.
Harrison's Principles of Internal Medicine
14
th
Edition (1998), pages 2064-65.
Unfortunately, high insulin levels, such as can occur in early phase type 2 diabetes have recently been linked to an increased risk of blood clots. Thus, patients with elevated insulin also have impaired ability to dissolve blood clots (impaired fibrinolysis). Significantly, blood clot formation is a major cause of heart attack and is the cause of the most common type of stroke.
J Am Med Assoc,
2000;283:221-228.
There is clearly therefore a need to treat hyperinsulinemia, such as can occur during, at least, the early phase of type 2 diabetes. Unfortunately, there are many drawbacks and deficiencies with known treatments for type 2 NIDDM. Thus, current therapy for type 2 NIDDM can include administration of an oral agent such as a sulfonylurea (for example acetohexamide, chlorpropamide, tolazamide, glimeripiride, glyburide or glibornuride) which acts by stimulating B cell secretion of insulin, in an attempt to overcome the insulin resistance of early phase type 2 diabetes or to address the declining insulin production by B cells in late phase, type 2 diabetes. Unfortunately, sulfonylureas increase extrapancreatic insulin receptors. Additionally, severe and prolonged hypoglycemia can follow sulfonylurea administration, which can necessitate a need for massive glucose infusions. Furthermore, oral sulfonylureas can have undesirable systemic effects. Finally, sulfonylureas typically have a duration of action of only about 12-60 hours per dose of sulfonylurea administered. Thus, a need exists for a more effective anti-diabetic drug.
Endocrine pancreatic innervation of the islets of Langerhan is through both sympathetic and parasympathetic nerve fibers which terminate on or near islet cells. Thus, sympathetic nerve fibers appear to inhibit insulin secretion, probably by acting via &agr;
2
adrenergic receptors on B islet cells. Contrarily, vagal (parasympathetic) stimulation causes the release of insulin from B cells. Berger et al.,
The Pancreas,
volume 1, page 110, published by Blackwell Science (1998), the entire contents of which publication (2 volumes) are incorporated herein by reference. Thus, stimulation of the dorsal vagus or the pancreatic nerve increases the output of insulin and glucagon and this response is abolished by atropine, a muscarinic acetylcholine receptor antagonist. Additionally, the parasympathetic neurotransmitter acetylcholine stimulates release of insulin from B cells in vivo and in vitro.
Thus, endocrine pancreatic activity appears to be stimulated by cholinergic fibers since, as indicated, parasympathetic innervation of islet cells can apparently increase insulin secretion, and to a lesser extent, may also increase glucagon secretion. See e.g.
Amer J. Physiol
July 1999; 277 (1 Pt 1): E93-102,
Regul Pept
Jun. 30, 1999; 82(1-3): 71-9,
J Physiol
(Lond) Mar. 1, 1999; 515 (Pt 2): 463-73,
Pfluger Arch
August 1996; 432(4):589-96, and
J Surg Res
April 1990; 48(4): 273-8.
A possible physiological function of the cholinergic system in relation to insulin secretion is to contribute to the rapid insulin release seen during the cephalic phase after food intake. Significantly, B islet cells are more sensitive to cholinergic stimulation than are A islet cells, since it appears that cholinergic control is more significant over insulin secretion than it is over glucagon secretion.
J Surg Res
April 1990; 48(4):273-8, at 277
Botulinum Toxin
The anaerobic, gram positive bacterium
Clostridium botulinum
produces a potent polypeptide
Allergan Sales Inc.
Baran Robert J.
Fisher Carlos A.
Jagoe Donna A.
Voet Martin A.
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