Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-11-02
2004-02-10
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C451S472000, C451S482000, C451S486000, C451S489000
Reexamination Certificate
active
06689385
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention is in the field of pharmacology, and relates to single-component or multi-component formulations used to enhance the efficiency and safety in the clinical use of the biguanide metformin, the sulfonylureas or combinations of sulfonylurea-metformin, in the pharmacological treatment of insulin resistance and type 2 diabetes mellitus.
2. Description of the Prior Art
Insulin resistance and non-insulin-dependent diabetes are prevalent in up to 35% of the population depending upon the age and nature of the subset. In the United States alone, 16 million people have type 2 diabetes and 13 million have impaired glucose tolerance. In fact type 2 diabetes has reached epidemic proportions worldwide. By 2025, an estimated 300 million people will have diabetes, most of whom will inhabit China, India, and the United States. Because of an aging and increasingly sedentary, obese population with changing, unhealthy diets, insulin resistance is also increasing alarmingly (it is already two to three times more prevalent than type 2 diabetes). This apparent increase in the prevalence of insulin resistance and type 2 diabetes occurs in all ethnic populations, but especially in those that have migrated from their native lands to more urbanized and westernized regions of the world.
Insulin resistance and type 2 diabetes exist not merely as part of the aging process, but also as a process that advances aging. Diabetes affects metabolism in totality: carbohydrate, lipid and protein. Its causes and its management are very, very complex and strikingly nonlinear.
Patients with diabetes of all types have considerable morbidity and mortality from microvascular (retinopathy, neuropathy, nephropathy) and macrovascular (heart attacks, stroke, peripheral vascular disease) pathology, all of which carry an enormous cost. For example: a) Proliferative retinopathy (the leading cause of blindness in the United States) and/or macular edema occur in about 50% of patients with type 2 diabetes, as do peripheral and/or autonomic neuropathy. b) The incidence of diabetic renal disease is 10% to 50% depending on ethnicity. c) Diabetics have heart attacks, strokes and peripheral vascular disease at about triple the rate of non-diabetics. The cost of treating diabetes and its complications exceeds $100 billion annually. In addition to these dreadful data, insulin resistance (a prelude to type 2 diabetes in about 50% of those effected) with its associated hypertension, coagulopathy, dyslipidemia and obesity substantially adds to these morbidity, mortality and cost statistics.
There are two clinical forms of diabetes, each with a different pathogenesis: type 1, insulin dependent diabetes mellitus and type 2, non-insulin dependent diabetes mellitus. The latter represents 90% of all diabetics. In type 2 diabetes, cellular resistance to the functional effectiveness of insulin results in above normal levels of insulin secretion. When this compensatory increase of insulin production cannot be maintained, and/or when cellular insulin resistance increases further, blood sugar rises, lipid and protein metabolism are disturbed, and the insidious processes of vascular complications of long-term diabetes begin.
The fasting hyperglycemia of type 2 diabetes exists in the presence of hyperinsulinemia; this reflects the presence of insulin resistance in the liver with resultant glycogenolysis and gluconeogenesis. In addition to the impaired insulin suppression of hepatic glucose production, a decrease of insulin-mediated glucose uptake by muscle cells contributes (about 50%) to the resultant hyperglycemia.
After ingestion of glucose, the maintenance of normal blood sugar therefore depends upon: 1) stimulation of insulin secretion; 2) insulin-mediated suppression of hepatic glycogenolytic and gluconeogenic glucose production, and 3) insulin-mediated glucose uptake by muscle. Although hyperglycemia has an independent, direct effect in suppressing hepatic gluconeogenesis and stimulating muscle glucose uptake, these effects are modest compared to those of insulin and are inadequate to compensate for the countering effects of insulin resistance.
The congeries of micro and macro pathologies from hyperinsulinemia and/or hyperglycemia have as causative mechanisms: free radical damage, nonenzymatic protein glycation, lipoprotein disturbances, disturbances of physiological NO effects, reduced synthesis of heparan sulfate and disorders of sorbitol and myoinositol metabolism.
Free radical generation and induced nitric oxide synthase (iNOS) production secondary to the hyperglycemia of type 2 diabetes can lead to pancreatic &bgr;-cell destruction, and the production of diagnostic enzymatic indicators characteristic of type 1 diabetes. This fact has introduced the term “type 1.5 diabetes”. In this scenario, &bgr;-cells are not only “exhausted” by the progression of pathology from insulin resistance to type 2 diabetes, but may also undergo destruction induced by chronic hyperglycemia.
Hypertension, dyslipidemia, coagulopathy, obesity and development of type 2 diabetes—all of which may follow chronic insulin resistance—are largely preventable, as are the eventual diabetic micro- and macrovascular complications. In those patients with insulin resistance who do progress to type 2 diabetes, successful treatment requires maintenance of blood glucose at a normal preprandial level (or at a postprandial level below 180 dl) and a hemoglobin A1c level below 7.0%. This degree of glucose control is often not consistently attainable over long periods of time.
Likewise, good glycemic control avoids the impaired synthesis of the basement membrane proteoglycan, heparan sulfate, which accompanies hyperglycemia. Heparan sulfate is an essential component of the basement membrane of many cells. Most importantly, it supports many of the normal functions of endothelial cells by maintaining the integrity of the basement membrane and its anionic charge, both of which are critical in maintaining physiologic membrane impermeability: It is the predominant glycosaminoglycan produced by the glomerular epithelial cells. Microproteinuria, due to its inadequacy in the glomerular basement membrane, is one of the earliest, most consistent early signs of diabetes, and diabetic nephropathy is invariably associated with progressive proteinuria. Reductions of heparan sulfate in the basement membrane of retinal and renal capillaries also leads to the increased capillary permeability that occurs at both sites significantly contributing to diabetic retinopathy and nephropathy.
Glucose tolerance declines with age because of: 1) increased cell receptor resistance to insulin; 2) intracellular post receptor disturbances and 3) diminished pancreatic islet &bgr;-cell sensitivity to insulin and glucose. Insulin resistance, with secondary hyperinsulinemia and/or hyperglycemia, contributes to many disorders associated with aging, i.e., hypertension, obesity, atherosclerosis, lipid abnormalities, coagulopathies and chronic metabolic perturbations including type 2 diabetes.
Although insulin resistance and type 2 diabetes each have an inherited pathogenic component, they both are substantially influenced by inappropriate diet and inadequate exercise.
In aging, as in diabetes, elevated circulating glucose reacts nonenzymatically with proteins and nucleic acids to form products that: 1) disturb the functionality of the cellular phospholipid membrane; 2) diminish tissue elasticity and 3) secondary to free radical formation, increase lipid peroxidation.
The ingestion of sugars, fats, and sodium have been linked to insulin resistance, while caloric restriction, exercise, ingestion of chromium, vanadium, magnesium, and certain antioxidants are associated with greater insulin sensitivity. Lifespan may favorably be affected, and the incidence of many chronic disorders commonly associated both with aging and with diabetes can be reduced, by manipulating the diet and its influence upon the glucose/insulin system.
Diabetes—Pertinent Anatomy and Physiolo
Pearson Don C.
Richardson Kenneth T.
Chronorx LLC
Sheikh Humera N.
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