Methods and compositions for producing weight loss

Details Methods and compositions for producing weight loss Methods and compositions for producing weight loss

2000-10-04

2002-11-05

Weber, Jon P. (Department: 1651)

Drug, bio-affecting and body treating compositions

Plant material or plant extract of undetermined constitution...

C424S078010

Reexamination Certificate

active

06475530

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods and compositions for producing weight loss in mammals.
One of the greatest problems confronting modem society in economically successful countries today is obesity. Unfortunately, obesity brings with it the conditions that are ripe for the more serious disease of diabetes.
Among the many possible solutions for treating obesity are formulations of weight loss products that work with some of the basic biochemical processes involved in fat metabolism. This process has been exploited through pharmaceutical intervention at the neurocrine level as well as at the level of fat cells themselves, or the way fat cells metabolize fats in brown adipose tissue.
The term thermogenisis has been coined to describe the process whereby food intake is converted to body heat through the metabolic process of caloric conversion. In obese people, certain metabolic defects associated with the thermogenic process begin to appear. These metabolic predispositions manifest in a number of identifiable biochemical syndromes that can be attacked through therapeutic intervention with agents that over-ride the cascade of events leading to obesity.
One of the more natural approaches to starting artificial thermogenisis, that is, thermogenisis that is unrelated to food consumption, is the use of plant derived substances that contain ephredine or ephedrine like compounds such as ma-haung or ephedra. Ephedra is an herb that grows wild in parts of the western United States. Ephedra contains ephedrine, an alkaloid that stimulates the production of catecholamines such as norepinephrine. Norepinephrine or noradrenaline is presumed to start the thermogenic process by stimulating metabolism in fat cells via the neurocrine axis that involves beta-adrenergic receptors. This in turn results in lipolysis, or the liberation of fat in fat cells via an increase in the basal metabolic rate. This pharmacological intervention results in weight loss in lean, obese, and post-obese human subjects and has been demonstrated in clinical studies (Dulloo, A G & Miller D S, Wrld Rev Nutr Diet 50: 1-56 ;1987).
Ephedra (also known by its Chinese name, MaHuang) has also been combined with methylxanthines such as caffeine, and the prostaglandin inhibitor aspirin, in a three component weight loss formula (U.S. Pat. No. 5055460). Caffeine and aspirin have been shown to potentiate the thermogenic action of ephedrine (Dulloo A. G., Intl. Jour. Obes.; 1993, 17 (Suppl. 1), S35-S40). An increase in catecholamine release as a result of pharmacological intervention with thermogenic agents leads to a blunted response on metabolism because of negative feedback systems associated with biochemical phenomena that take place in the synaptic junction. These negative feedback control systems involve adenosine, free fatty acids, and prostaglandins. The methylxanthines such as caffeine work to overcome the negative feedback related to adenosine, and the aspirin inhibits cyclooxygenase, the enzyme responsible for synthesizing prostaglandins, and a new element has been added in the instant invention by the optional inclusion of nicotinic acid to lower free fatty acids. By inhibiting these negative feedback controls, the thermogenic or up-regulated metabolic effect produced by exogenous administration of agents capable of increasing nor-adrenaline can be potentiated.
One example of the magnitude of potentiation that can be achieved by combining a nor-adrenaline increasing agent such as ephedra, with a prostaglandin inhibitor such as aspirin to reduce feedback inhibition is the study conducted by Dulloo and Miller (Am J Clin Nutr 1987;45:564-9). In this study, aspirin and ephedra together more than doubled the weight loss in mice when compared to the effect of ephedra alone. Aspirin by itself resulted in no weight loss. Ephedra alone resulted in reduced body fat and weight and reduced obesity, but did not reverse obesity, whereas aspirin and ephedra together actually reversed obesity.
The use of aspirin to inhibit cyclooxygenase and thereby reduce prostaglandins is believed to be the mechanism of action that explains its anti-inflammnatory activity. Aspirin is one of the class of compounds known as non-steroidal anti-inflammatory drugs, otherwise known as NSAIDs. These drugs work by inhibiting cyclooxygenase 1, the enzyme that synthesis prostaglandins from arachidonic acid. Prostaglandin E-2 is a pro-inflammatory prostaglandin. But a single large dose of aspirin only inhibits cyclooxygenase partially, but not completely. Prostaglandin levels return to baseline levels within the next 6 hours. In U.S. Pat. No. 5055460, the preferred range for the dose of aspirin is from 200-1000 mg., with the particularly preferred unit dose being 300 mg. of aspirin. This amount of aspirin, with caffeine, and ephedra, is recommended to be taken 1-6 times per day. Yet even a single dose of 300 mg. per day of aspirin is capable of causing gastric erosion in healthy young adults in 5-7 days. Even more serious gastric bleeding would occur if up to six doses per day of this amount of aspirin were to be consumed. The use of aspirin to potentiate the thermogenic effects of ephedra or any other nor-adrenaline, catacholamine stimulating compound is therefore dangerous.
There is a definite need for a safer thermogenic triad that can inhibit the negative feedback produced by prostaglandins, without the side-effects of gastric erosion produced by the NSAID drugs like aspirin. There is also a need for a prostaglandin inhibitor formula that is more effective at suppressing cyclooxygenase and reducing prostaglandins with a single dose, and provide long term reduction of prostaglandins over an 8-24 hour period. There is also a need for a prolonged activity thermogenic formula that increases metabolism all day from a single dose, while at the same time prostaglandin's are being suppressed in parallel over the same time period. There is also a need for a more complete suppression of the negative feedback produced by catecholamine stimulated free fatty acid release.
One attempt to over come the side-effects associated with the use of aspirin in the thermogenic triad has been to substitute white willow bark, which contains salicylic acid, for the aspirin component. Chemically, aspirin is acetylsalicylic acid, which is effective at inhibiting cyclooxygenase, and thereby lowers prostaglandin levels, whereas salicylic acid or white willow bark minimally effective at inhibiting cyclooxygenase, and therefore is not as effective as aspirin at potentiating the thermogenic effects of compounds such as ephedra.
A much safer and more effective composition for the thermogenic triad would be the use of a COX inhibitor other than aspirin. COX-2, or cyclooxygenase-2 inhibitors inhibit cyclooxygenase and reduce prostaglandins without producing the degree of gastric erosion associated with NSAID drugs such as aspirin. However, many COX-2 inhibitors have a short half-life, and do not keep prostagladins suppressed completely or in a prolonged fashion over a 6-24 hour period. In addition, the turnover rate for cyclooxygenase is fairly short.
Another attempt to formulate a weight loss product is described in U.S. Pat. No. 5798101. This patent is directed to herbal compositions to reduce weight and help suppress appetite consisting of St. John's Wort and ephedra with or without caffeine. These formulations do not include a prostaglandin inhibitor such as aspirin or a COX-2 inhibitor, so the thermogenic component (the ephedra) would be less effective at driving metabolism because of the negative feedback from prostaglandins. The St John's Wort is present to produce an effect on serotonin, a neurotransmitter involved in mood and carbohydrate craving. Thus, its function in the formulations described in this patent is as an appetite suppressant, not as a component in the thermogenic triad of ephedra, aspirin, and caffeine.
Growth hormone (GH) has been implicated in a number of metabolic effects. Administration of exogenous growth hormone by injection has b

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