Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-08-15
2001-07-17
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06262062
ABSTRACT:
BACKGROUND OF THE INVENTION
Coronary Heart Disease Risk Factors (CHDRFs) are major causes of death in the industrialized world. CHD risk factors include Type 2 Diabetes (and its precursor, Impaired Glucose Tolerance (IGT)), hyperlipidemia or dislipidemia, overweight, obesity and essential hypertension, i.e., a form of hypertension that occurs without a discoverable organic cause. The CHDRF syndrome may, therefore, be defined as a group of interrelated disorders: Type 2 Diabetes, IGT, Dislipidemia, Overweight, Obesity and essential hypertension. It has also become apparent that Type 2 Diabetes, by itself, represents a syndrome of various, in part sequential, disease states which interact with other components of the CHDRF syndrome. However, the exact interrelationships between the disease states that make up these syndromes is not fully understood. A wide variety of chemical and physical abnormalities associated with these syndromes exist. They include elevations in fasting blood glucose and gluconeogenesis in spite of significant increases in fasting insulin and C-peptide concentrations and increases in lipogenesis. Typically associated with lipogenesis are increases in levels of fasting Free Fatty Acid (FFA), fasting triglycerides (TG) and total cholesterol concentrations, increases in levels of fasting Low Density Lipoprotein (LDL)-cholesterol, decreases in levels of fasting High Density Lipoprotein (HDL)-cholesterol, an increased LDL/HDL ratio, increases in body weight and increases in systolic and diastolic blood pressure.
Although these syndromes are interrelated and typically result from derangements in nutrient metabolism, all the associated symptoms may not be present in individual patients. Accordingly, in some patients lipid metabolism problems may predominate, while in others, carbohydrate metabolism problems may be predominant. While these factors, which lend one aspect of the syndrome to dominate over another, are not well understood, it is clear that each portion of the syndrome, or combinations of portions of the syndrome, represents risk factors in coronary heart disease.
Insulin Resistance/Type 2 Diabetes/CHDRF Syndrome
A common denominator in the etiology of the syndromes of Type 2 Diabetes and the CHDRFs appears to be Insulin Resistance (IR). IR is characterized as a state in which a normal amount of insulin produces a subnormal biological response in carbohydrate metabolism. This may be the case for subjects afflicted with the non-insulin-dependent diabetes form of Type 2 Diabetes and in pre-diabetic subjects affected by Impaired Fasting Glucose (IFG) or Impaired Glucose Tolerance (IGT). These subjects require (and endogenously produce) higher than normal levels of insulin to compensate for their insulin resistance and to normalize their blood glucose levels. Traditionally, IR has been expressed as the insulin/glucose ratio (I/G). More recently, several more complex models have been proposed to define Insulin Resistance or the Insulin Sensitivity Index. Only recently have other biological functions of insulin become the focus of more intense scientific interest, e.g. the role of insulin in endogenous lipogenesis. Although an interaction between insulin resistance and the CHDRF components has been established, the cause and effect relationship between insulin resistance, obesity, dislipidemia and IGT/Type 2 Diabetes is still subject to debate. IR increases FFA levels, which further contributes to IR, thereby creating a vicious circle. Therapeutic modalities for lowering any one of the lipid fractions in dislipidemia have not proven capable of correcting the entire hyperlipidemic complex with a single therapeutic agent.
Compared to Type 1 (juvenile) Diabetes, the Type 2 Diabetes syndrome, particularly its non-insulin-dependent mellitus (NIDDM) forms, is characterized by relatively inadequate endogenous insulin concentrations. However, insulin concentrations in Type 2 diabetics may, in fact, be higher than in the normal population. A possible explanation for this apparent discrepancy is that Type 2 diabetics, as well as subjects afflicted with IFG or IGT, typically require more insulin to control their blood sugar levels. Temporary increases in certain diabetogenic mediators, such as glucagon, growth hormones and catecholamines may initially cause the requirement for more insulin. These mediators communicate their specific control functions as agonists to target tissue or cells through compatible cell bound receptors. Continued, long term agonist load eventually leads to ‘down-regulation’ of such receptors, i.e. the receptor response and/or sensitivity are decreased. Depending on the agonist involved, this mechanism can lead to tolerance or addiction. As a result, increasing doses are required to achieve the same effect. Antagonists have equivalent receptor specificity as their agonist counterparts, but do not convey any agonist-type control message. In contrast to agonists, prolonged exposure of such receptors to their specific antagonists can restore receptor response or sensitivity, a process called receptor ‘up-regulation’.
As long as any agonists load by mediators, such as hormones, neuro-transmitters or neuro-modulators prevails for infrequent, short durations, the respective receptors for such mediators can ‘up-regulate’ between such temporary agonist loads. In other words, the receptors can resume their normal sensitivity between ‘receptor-ligand’ interactions. The early stage of IR may be characterized by temporary increases in diabetogenic mediators such as catecholamines and/or glucagon. However, resistance to the action of insulin on the control of glucose may not carry over to the action of insulin on lipogenesis. Even though the individual is resistant to the action of insulin in controlling glucose, the response of lipid metabolism to insulin may remain at the normal level. As temporary agonist ‘loads’ become more frequent or sustained, the affected receptors will down-regulate. As a result, IR may become a permanent metabolic burden and, with additional diabetogenic factors, such as cortisol, may accelerate progressive increases in hepatic gluconeogenesis (GNG) and glucose production (GP). The IR dependent insulin excess in the face of hyper-gluconeogenesis caused hyperglycemia then becomes a blueprint for hyper- or dislipidemia, overweight and obesity. Gradually, the &bgr;-cells' secretory capacity to produce and secrete insulin will diminish, resulting in a slow but steady rise in fasting glucose levels until, eventually, such secretory capacity will be exhausted, at which time the subject becomes ‘insulin dependent’, i.e. dependent on exogenous insulin injections.
Dislipidemia
Dislipidemia is characterized by any of the following, and combinations thereof: elevated levels of total and LDL-cholesterol, elevated levels of TG, a high LDL/HDL ratio and elevated levels of FFA and low levels of HDL-cholesterol. Lipid metabolism is rather complex. While it is clear that dislipidemia is associated with the development of coronary heart disease, there is no clear understanding of the pathogenic causes and pathways leading up to the manifestation of the various lipid disorders. The relative roles of lipid ingestion versus endogenous lipogenesis in the etiology of lipid abnormalities have not been fully understood.
Overweight/Obesity
Obesity is a disease of major proportions and severe economic consequences. No longer is obesity considered merely a physical or cosmetic inconvenience. Obesity is second only to cigarette smoking as a preventable cause of premature death, and its complications add in excess of $100 billion to U.S. health care costs. Obesity can not be treated effectively by willpower alone, and currently available pharmaceutical drugs are only marginally effective. Moreover, several obesity drugs have recently been withdrawn from the market because of their risk of potentially fatal side-effects, e.g. pulmonary hypertension or heart defects in connection with dexfenfluramin or fenfluramine.
Six out of ten people (approximately 130 m
CPD, LLC
Henley III Raymond
Michael Best & Friedrich
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