Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-22
2004-04-20
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S043000, C514S045000, C514S046000, C514S058000, C514S054000, C514S060000, C514S909000, C424S464000, C424S468000, C424S474000, C424S479000, C424S480000, C424S475000, C536S026260
Reexamination Certificate
active
06723737
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the chronic elevation of endogenous adenosine levels by the use of stable adenosine 5′-triphosphate (ATP) compositions, which are taken orally over a period of time. The elevated levels of adenosine, produced by the in vivo degradation of ATP, act in decreasing the sensitivity (desensitization) of adenosine receptors. The decrease in sensitivity can materialize through a decrease in numbers of receptors (density) or through a reduction in the receptor's coupling activity (intracellular signal transduction). The reduced sensitivity of certain adenosine receptors towards their natural agonist—adenosine, can be useful by itself or in combination with adenosine antagonists, which are much more active towards desensitized adenosine receptors. Examples for utilization of these methods are in the treatment of disorders or diseases, which are controlled by biochemical mechanisms regulated by adenosine receptors. One such case is in the treatment of obesity, which can be treated by the metabolic stimulation of weight loss. Lipolysis, the degradation of fat (triglycerides) in adipose tissue to free fatty acids and glycerol, is known to be inhibited by the interaction of adenosine with A
1
adenosine receptors of the adipocyte (fat cell). The interaction of adenosine with adipose tissue A
1
adenosine receptors was shown to stimulate lipogenesis—the buildup of triglycerides (fat) in fat cells. Methods for desensitization of A
1
adenosine receptors in a human in vivo, thus significantly diminishing the activity of endogenous adenosine, are disclosed and taught and are utilized for the effective reduction of weight in humans. Effective weigh loss in humans can be achieved either by the desensitization of the adipose tissue adenosine A
1
receptors by themselves, or by desensitization in combination with adenosine antagonists such as caffeine or theophylline, which are much more effective in blocking the action of adenosine once its receptors became desensitized. The use of chronic administration of adenosine for the purpose of desensitization of adipose tissue A
1
adenosine receptors in the induction of weight loss in humans, demonstrates the utility of the present invention. Obesity is the costliest disease in industrialized countries. It is associated with a variety of chronic life-threatening diseases such as type II diabetes, hypertension, stroke, and heart disease. The definition of obesity is an excessive accumulation of fat in the body. Obesity in terms of a disease is defined if body weight is 20% or more above the desirable weight (Council on Scientific Affairs, J. Amer. Med. Assoc. 1988). Overweight is defined if body weight exceeds the desirable weight by less than 20%. Desirable weight in humans has been well-defined (council on scientific affairs, JAMA 1988). Weight loss in overweight or obese humans can be achieved by diet, physical activity and behavior modification or by treatment with drugs. There are three main ways for the pharmaceutical treatment of overweight or obesity: 1. Inhibition of absorption of nutrients in the intestine; 2. Modulation of the activities of the metabolic and central nervous system (hypothalamic) satiety and food consumption (hunger) signals; and 3. Induction of energy dissipation in tissues, especially adipose tissue (thermogenesis). The methods disclosed here of the chronic administration of adenosine by the oral delivery of the pro-drug ATP, deal with the induction of energy dissipation, in the form of degradation of fats in adipose tissue.
BACKGROUND OF INVENTION
The physiological activities of adenosine triphosphate and adenosine were first discovered in 1929 (for a review, see Williams and Bumstock 1997). It is now known that adenosine exerts its physiological effects by interacting with specific receptors, several subtypes of which (A
1, A
2A
, A
2B
and A
3
) have been characterized and shown to regulate specific physiological processes. Adenosine triphosphate in turn, exerts its physiological activities by interacting with another family of receptors termed P
2
receptors (Bumstock 1990). The A
1
adenosine receptors were shown to regulate significant brain (Williams and Bumstock 1997); heart and adipose tissue functions (van der Graaf et al. 1999) by their in vivo interactions with endogenous, extracellular adenosine in animals and humans. The function of these A
1
adenosine receptors is to transmit regulatory signals from adenosine, which is the product of extracellular metabolism, to the inside of the cells. This signal transduction is in turn achieved by a family of G proteins-linked to cell membrane A
1
adenosine receptors (Linden 1991). The G
i
protein, which interacts with the A
1
adenosine receptors, acts in inhibiting the intracellular activity of adenyl cyclase, the enzyme catalyzing the synthesis of cyclic AMP (cAMP) inside the cell. Thus, upon interaction of extracellular adenosine with A
1
adenosine receptors, the G
i
proteins coupled to this receptor inhibit the synthesis of cAMP, resulting in lower cellular levels of cAMP and in the case of adipose A
1
adenosine receptors, overall inhibition of lipolysis (LaNoue and Martin 1994). Because signaling from the adipose tissue A
1
adenosine receptors inhibit the degradation of triglycerides to free fatty acids and glycerol (lipolysis), the possibility of excessive activity of the adipose tissue A
1
adenosine receptors was considered as a genetic factor in obesity. This indeed turned out to be the case in genetically obese mice and rats as well as in humans. In these cases the adipose tissue A
1
adenosine receptors were found to be extremely active in transmitting their signal to the G
i
proteins with little dependence on the presence of extracellular adenosine (LaNoue and Martin 1994).
Therefore, the inhibition of the activity of adipose tissue A
1
adenosine receptors via antagonism of adenosine or a mediated reduction of the efficacy of the receptors'coupling to G
i
proteins would constitute a reasonable approach to weight control or obesity in humans. Methods utilizing the administration of A
1
adenosine receptor antagonists, such as caffeine (1,3,7-trimethylxanthine), theophylline (1,3-dimethylxanthine) or synthetic A
1
adenosine receptor antagonists, did not produce weight loss in genetically obese experimental animals (Xu et al. 1998). However, Caffeine, which is an established non-specific A
1
adenosine receptor antagonist (Jacobson and van Rhee 1997), was shown effective in inducing weight loss in humans as part of a variety of regimens discussed in several issued U.S. patents.
U.S. Pat. No. 5,422,352 discloses a combination of caffeine and ephedrine in a ratio of about 12:1 as a composition for reducing weight in humans. U.S. Pat. No. 5,480,657 discloses a composition of caffeine, chromium and fructose for the treatment of obesity. U.S. Pat. No. 5,679,358 discloses compositions containing caffeine, theophylline or their derivatives along with other ingredients for the purpose of reduction of superfluous fat of any origin by topical application. For example, this patent refers to caffeine, theophylline or pentoxifylline as lipolytic agents, though no mechanism is discussed in the specifications. U.S. Pat. No. 5,798,101 discloses compositions and methods for reducing weight consisting of St. John's Wart herbal extracts with or without caffeine. Caffeine and theophilline have been established as non-specific antagonists of adenosine receptors, namely, they interact with both A
1
and A
2A
adenosine receptors with moderate affinity (Jacobson and van Rhee 1997). All of the issued U.S. Patents discussed above refer to caffeine as a “stimulator of metabolism” or in one case a “lipolytic agent”.
A published placebo-controlled double blind human clinical study has demonstrated that caffeine ingestion increased the levels of free fatty acids (the products of lipolysis) in young men in a statistically significant manner. The increase in free fatty acids after caffeine challenge was not related t
Connolly Bove & Lodge & Hutz LLP
Krass Frederick
Ostrup Clinton
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