Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-11
2003-03-04
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
06528520
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 dyslipidemia, 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, Dyslipidemia, 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/Beta-Cell Dysfunction/Type 2 Diabetes/CHDRF Syndrome
Common denominators in the etiology of the syndromes of Type 2 Diabetes and the CHDRFs appear to be Insulin Resistance (IR) and Beta-Cell Dysfunction. 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, in pre-diabetic subjects affected by Impaired Fasting Glucose (IFG) or Impaired Glucose Tolerance (IGT), and in overweight and obese subjects. These subjects require (and endogenously produce) higher than normal levels of insulin to compensate for their insulin resistance and Beta-Cell Dysfunction 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, dyslipidemia and IGT/Type 2 Diabetes is still subject to debate. IR increases FFA and Triglyceride (TG) levels, which further contribute to IR, thereby creating a vicious circle. Therapeutic modalities for lowering any one of the lipid fractions in dyslipidemia 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, IGT, Overweight or Obesity 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, endogenous opiates, cortisol and/or glucagon.
Another early pathophysiologic indicator of the emergence of the CHDRF Syndrome is a condition called Beta-Cell Dysfunction. Non-diabetics experience a bi-phasic insulin response to an oral glucose challenge, i.e. an acute, first phase governed by a rise in blood glucose, and second, proportional phase characterized by a more sustained insulin release, following, in a quasi proportional manner, the post-prandial glucose excursion. Overweight and IGT subjects already have a significantly reduced first phase insulin release, which virtually disappears altogether once the subject becomes obese and or diabetic. This condition exaggerates the Insulin Resistance related hyperglycemia and hyperinsulinemia and accelerates the severity of the CHDRF Syndrome.
A pharmacologic restoration of the vitally important first phase insulin release has, to this date, been an elusive scientific undertaking.
Resistance to the action of insulin in 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 dyslipidemia, 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.
Dyslipidemia
Dyslipidemia 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 dyslipidemia is associated with
CPD, LLC
Hartwig Gregory J.
Henley III Raymond
Michael & Best & Friedrich LLP
Welch Teresa J.
LandOfFree
Method of treating the syndrome of coronary heart disease... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of treating the syndrome of coronary heart disease..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of treating the syndrome of coronary heart disease... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3005617