Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-05-07
2002-11-05
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S464000, C424S422000, C424S435000, C514S866000, C514S909000
Reexamination Certificate
active
06476071
ABSTRACT:
RELATED PATENT APPLICATION BY THE SAME INVENTORS
Methods And Pharmaceutical Preparations For Normalizing Blood Pressure With (−)-Hydroxycitric Acid
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to pharmaceutical compositions containing (−)-hydroxycitric acid useful for correcting Polymorphic Metabolic Dysfunction (PMD) in individuals in need thereof by influencing the metabolism of insulin, glucocorticoids and leptin and the relationship of these to the resistin-peroxisome proliferator-activated receptor &ggr; (PPAR&ggr;) axis.
2. Description of Prior Art
According to the National Heart, Lung, and Blood Institute (1999), an estimated 97 million adults in the United States are overweight or obese, conditions which substantially raise their risks of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, respiratory problems, and endometrial, breast, prostate, and colon cancers. The percentage of overweight and obese men and women as a fraction of the populace at large has risen dramatically since 1960; in 1999, the estimated percentage of people in these categories has increased to approximately 55 percent of adults aged 20 years or older. The World Health Organization and the National Heart, Lung and Blood Institute of the National Institutes of Health have classified obesity as an epidemic inasmuch as the incidence of obesity in children and adults has increased by nearly 50% in the past decade. Significantly, it is increasingly recognized that unwanted weight often is indicative of intractable metabolic changes which are poorly treated over the long term with simple anorectic agents and which are substantially aggravated by bouts of dieting. As this suggests, the traditional focus upon weight loss and the treatment of obesity per se very commonly has been and remains nonproductive.
Leptin is the best known of the primary signals for the communication of body fat information to the central nervous system. Identification of this peptide in 1994 provided major new insights into the regulation of food intake, energy expenditure and body fat maintenance. It is now clear that this compound, which is derived primarily from fat cells, reduces food intake and increases the activity of the thermogenic components of the sympathetic nervous system in metabolically normal individuals.
Leptin production is stimulated by insulin and glucocorticoids, but inhibited by beta-adrenergic stimulation. Circulating levels of leptin are correlated with the level of body fat. The peptide exerts its effects through leptin receptors in the central nervous system. Modulation of neurons by leptin results in a reduction in the secretion of neuropeptide Y (NPY), a reduction in the secretion agouti-related protein (AGRP), and an increase in the secretion of proopiomelanocortin (POMC), the precursor of alpha-melanocyte-stimulating hormone (alpha-MSH), which reduces food intake. When researchers have examined the role of leptin in weight loss, injections in lean and obese subjects have had a dose-related effect upon weight and fat loss. However, there was significant discomfort at the injection site. For leptin to be clinically acceptable, the route of delivery must be improved. Alternatively, a solution would include indirect methods of influencing leptin secretion and/or sensitivity.
The use of a leptin-controlling alternative is all the more crucial because although injected leptin has shown some promise in reducing unwanted weight, its effects are not well understood and may be negative. A surprising and disappointing finding in one study was that some 30 percent of all the leptin-treated subjects actually gained weight during this trial, in comparison with one half of the placebo subjects. Moreover, inasmuch as leptin levels in the obese are already high—the obese may have three to five times as much leptin in their blood as do normal weight individuals, but only 20 percent more leptin in their brains—overcoming leptin resistance via exogenous leptin may require the continuous use of quite large amounts of the compound and bring its own array of side effects. As is the case of with insulin, which is taken by diabetics to overcome insulin resistance, excessive levels of leptin may not be innocuous. Indeed, studies have shown a strong correlation between elevated leptin levels and the insulin resistance syndrome. A causal model for leptin's role in insulin resistance has been offered by several teams of researchers. (Girard J. Is leptin the link between obesity and insulin resistance? Diabetes Metab. September 1997;23 Suppl 3:16-24; Spiegelman B M, Flier J S. Adipogenesis and obesity: rounding out the big picture. Cell. Nov. 1, 1996;87(3):377-89; Cohen B, Novick D, Rubinstein M. Modulation of insulin activities by leptin. Science. Nov. 15, 1996;274(5290): 1185-8.) Conversely, it might be argued that the initial issue is that of insulin resistance itself and that this metabolic syndrome or Syndrome X blunts the normal physiologic effects of leptin. (Boden G, Chen X, Kolaczynski J W, Polansky M. Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects. J Clin Invest. Sep. 1, 1997;100(5):1107-13.)
Adrenal glucocorticoids, such as cortisol and corticosterone, play an important role in the neuroendocrine control of food intake and energy expenditure. Experimental evidence demonstrates that glucocorticoids are critical for the development and maintenance of obesity, that is, obesity is linked to increases in glucocorticoid production and/or to hyperresponsiveness to glucocorticoids in the hypothalaniic-pituitary-adrenal axis. Glucocorticoids have been shown to be necessary if the chronic intracerebroventricular infusion of neuropeptide Y is to produce obesity and related abnormalities. Obversely, adrenalectomy in animals with a lesion to the ventromedial hypothalamus will reverse obesity. In humans, excess production of glucocorticoids produces modest obesity, and destruction of the adrenal glands is associated with a loss of body fat. Significantly, it has been found that glucocorticoids inhibit the body weight-lowering effect of leptin. (Zakrzewska KE, Cusin I, Sainsbury A, Rohner-Jeanrenaud F, Jeanrenaud B. Glucocorticoids as counterregulatory hormones of leptin: toward an understanding of leptin resistance. Diabetes April 1997;46(4):7 17-9.)
Both neuropeptide Y and leptin act within the hypothalamus, yet the effects of the glucocorticoids in promoting weight gain may be realized peripherally as well as centrally. In an animal experiment, a continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion, which was sufficient to abolish endogenous corticosterone output, produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities typical of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and a decrease in the expression of UCP-3 in muscle, i.e., infusion resulted in a marked decrease in the expression of the “thermogenic” proteins. Chronic central glucocorticoid administration increased hypothalamic levels of neuropeptide Y. (Zakrzewska K E, Cusin I, Stricker-Krongrad A, Boss 0, Ricquier D, Jeanrenaud B, Rohner-Jeanrenaud F. Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat. Diabetes February 1999;48(2):365-70.) Through perhaps unrelated means, glucocorticoids induce insulin resistance. (Weinstein SP, Paquin T, Pritsker A, Haber R S. Glucocorticoid-induced insulin resistance: dexamethasone inhibits the activation of glucose transport in rat skeletal muscle by both insulin- and non-insulin-related stimuli. Diabetes. April 1995;44(4):441-5.)
Closely related to the physiologic actions of insulin and leptin are the linked actions of resistin and peroxisome pr
Clouatre Dallas L.
Dunn James M.
Channavajjala Lakshmi
Page Thurman K.
LandOfFree
Correcting polymorphic metabolic dysfunction with... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Correcting polymorphic metabolic dysfunction with..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Correcting polymorphic metabolic dysfunction with... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2985888