Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-09-23
2003-03-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S464000, C424S450000, C424S458000, C424S488000, C424S489000, C424S486000, C424S401000, C424S439000, C424S045000, C424S725000, C424S736000, C514S323000
Reexamination Certificate
active
06534085
ABSTRACT:
1. INTRODUCTION
The present invention relates to compositions and methods for promoting weight loss and/or preventing weight gain in mammals by administering phytochemicals. Among the phytochemicals useful in the compositions and methods of the invention are dietary indole, Diindolylmethane (DIM), as well as its precursor, Indole-3-carbinol (I3C), and cogener, 2-(Indol-3-ylmethyl)-3,3′-diindolylmethane (LTR-1). When used as described, these natural substances, alone and in combination with other substances, facilitate weight loss as part of a nutritional system targeting release and metabolism of stored fat.
2. BACKGROUND OF THE INVENTION
The term “overweight” describes an excessive accumulation of body fat or “adiposity”. “Overweight” is defined as an elevation in the Body Mass Index (BMI) beyond desirable standards due to increased body fat. The BMI expresses an individual's degree of overweight independent of height by dividing weight in kilograms (Kg) by height squared (m
2
). In overweight men a BMI above 25 Kg/m
2
and in overweight women a BMI above 26 Kg/m
2
defines a level of adiposity which negatively impacts health (Simopoulos, A.P., Body Weight Reference Standards, In Van Itallie, T.B. and Simopoulos, A.P. (Eds), Obesity: New Directions in Assessment and Management, The Charles Press, Inc., Philadelphia, Pa., 1995). The increasing prevalence of overweight is one of the major health problems of industrialized countries. Overweight occurs as a result of an imbalance between energy intake as food and energy expenditure through physical activity. Most importantly, the trend to increased consumption of sugar and refined carbohydrate in excess of energy needs results in a metabolic and hormonal status favoring the formation and storage of fat. Weight loss depends on mobilization and metabolism of fat at the cellular level. This requires the metabolic process of lipolysis and encompasses the release of stored fat from fat cells. In all mammals the process and rate of lipolysis are highly regulated by the system of catecholamine hormones.
Increased carbohydrate consumption in modern society is the result of the introduction of refined sugar and processed carbohydrate in various forms. The addition of high fructose corn syrup in 1967 is a prime example of this shift in dietary composition which has contributed to the further increase of the sugar component of the average diet to about 8% of total calories (Raper, N., and Marston, R., “Content of the U.S. food supply (tables of nutrients and foods)”, Human Nutrition Information Service: Washington, D.C., U.S. Department of Agriculture, 1988). The presence of sugar and other “high glycemic” processed carbohydrates found in bread and pasta, increases blood insulin levels, inhibits lipolysis, and promotes new fat synthesis. This raises serum triglycerides, serum cholesterol, and increases the risk of atherosclerosis and coronary heart disease. Strategies to decrease our daily intake of processed carbohydrate and increase the release and metabolism of stored fat are clearly needed.
Interventions to decrease appetite have focused on supporting brain levels of the neurotransmitter serotonin which is derived from the amino acid tryptophan. However, simply providing increased dietary sources of tryptophan have in themselves not proven successful at reducing appetite. Use of drugs such as fluoxetine and fenfluramine, which raise brain serotonin levels, have proven effective in promoting weight loss. Unfortunately, this pharmacologic approach has been recently associated with serious cardiovascular side effects (Kolanowski, J., “A risk-benefit assessment of anti-obeisity drugs”,
Drug Safety
20(2):119-131, 1999). Use of the serotonin precursor, L-5-hydroxy-tryptophan (5HTP) may represent a safer approach to reducing appetite for carbohydrates. Other safe and effective means to promote weight loss are clearly needed.
With regard to increasing fat metabolism, both caloric restricted dieting and increased exercise promote a more active catecholamine system which favors active lipolysis. Increasing the efficiency of this process has been the object of much of the pharmacotherapy of obesity.
The process of lipolysis is regulated primarily by the system of catecholamine hormone receptors present on the surface of fat cells. These catecholamine receptors consist of a family of membrane bound proteins with differerent structure and activity known as the &agr; and &bgr; receptors. The &agr; and &bgr; receptors have opposing action on the rate of lipolysis. Predominance of activity from the &bgr; receptors favors active lipolysis and translates into weight loss. Predominance of &agr; receptor activity inhibits lipolysis and favors continued fat storage. Nature has provided for an adaptive mechanism by which activity and number of the a receptors increase with caloric restriction. This slows continued lipolysis during periods of fasting and results in the increased loss of muscle tissue in addition to fat during dieting. The increased presence and activity of &agr; receptors and decreased overall metabolic rate which occur during fasting has been call the “starvation response”. The starvation response reduces the efficiency of lipolysis during weight loss.
Much of modern obesity research has concerned methods for maintaining a hormonal balance which favors &bgr; over &agr; receptor activity to promote more efficient and active lipolysis. The objective is to facilitate continued lipolysis or fat loss while preserving muscle or “lean body mass”. This is achieved with exercise, a restricted calorie but protein supplemented diet, and with the administration of substances which mimic the &bgr; receptor activity of the catecholamine hormones. The most popular &bgr; stimulating substance in use since antiquity is ephedrine, originally discovered in the Chinese herb “Ma Huong”. Ephedrine resembles the catecholamine hormone, epinephrine, and effectively increases the rate of lipolysis. However, like epinephrine, ephedrine produces serious side effects related to overstimulation of the sympathetic nervous system, including tachycardia, hypertension, nervousness, tremor and insomnia (Cupp, M. J., “Herbal remedies: adverse effects and drug interactions”,
American Family Physician
59(5):1239-45, 1999). To offer alternatives to the use of ephedrine and related drugs like amphetamines, the pharmaceutical industry has attempted with little success to develop &bgr; receptor stimulants with more specific action limited to the promotion of lipolysis in fat cells.
Another attractive approach, to increasing rates of lipolysis has been blockade of the catecholamine &agr; receptor system Lafontan, M., Berlan, M., et al., “Alpha-2-adrenoceptors in lipolysis: &agr;2 antagonists and lipid mobilizing strategies”,
Am. J. Clinical Nutrition
55:219S-227S, 1992). This has been possible with oral use of yohimbine, another natural compound which blocks &agr; receptors allowing the epinephrine and norepinephrine already present to have unopposed action at the &bgr; receptors. While theoretically an attractive approach, and successful in promoting weight loss in dogs (Berlan, M., Galittzky, J., et al., “Anorectic effect of alpha2-antagonists in Dog: effect of acute and chronic treatment”,
Pharmacology Biochemistry & Behavior
39:313-320, 1991), the use of yohimbine has only inconsistently promoted increased weight loss in placebo controlled studies in humans (Sax, L., “Yohimbine does not affect fat distribution in men”,
International Journal of Obesity
15:561-565, 1991, and Berlin, I., Stalla-Bourdillon, A., et al., “Lack of efficacy of yohimbine in the treatment of obesity”,
J. of Pharmarmocologie
(Paris) 3:343-347, 1986).
The need thus remains to develop other approaches and applications of safe natural substances to effectively promote lipolysis and facilitate weight loss.
Diindolylmethane (DIM), as well as its precursor, Indole-3-carbinol (I3C), and cogener, 2-(Indol-3-ylmethyl)-3,3′-diindolylmethane (LTR-1) are natural phytochemicals and part of
BioResponse L.L.C.
DiNola-Baron Liliana
Page Thurman K.
Pennie & Edmonds LLP
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