Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-05-08
2002-07-16
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S052000, C514S249000, C514S561000, C514S565000
Reexamination Certificate
active
06420342
ABSTRACT:
The invention is related to nutritional, pharmaceutical or dietetic preparations that comprise ribose or folic acid or functional analogs thereof and the use of these compositions in the prevention or treatment of specific diseases that are related to disorders or insufficiencies of total nucleotide metabolism.
BACKGROUND OF THE INVENTION
Nucleotides are heterocyclic compounds that occur in all mammals. Nucleotides consist of a purine or pyrimidine base, a sugar unit and one to three phosphate groups. The major purine bases that occur in the human body are adenine (6-aminopurine), guanine (2-amino-6-hydroxypurine), hypoxanthine (6-hydroxypurine) and xanthine (2,6-dihydroxypurine); the major pyrimidines are uracil (2,4-dihydroxypyrimidine), cytosine (2,4-dihydroxy-5-methylpyrimidine) and thymine (4-amino-2-hydroxypyrimidine). The sugar moiety can be ribose (in ribonucleosides) or 2-deoxyribose. The sugar moiety is connected to the base through a &bgr;-N-glycosidic bond at N9 of the base; the phosphate groups are connected to the sugar moiety through the 3′ or 5′ position. When the phosphate groups are split from nucleotides compounds called nucleosides are formed.
For the purpose of this document, total nucleotide netabolism (TNM), is defined as the combination of all biochemical pathways in which nucleotides, their precursors and metabolites are directly involved as main ingredients and that occur in the body of mammals. The pathways include the synthetic routes for purines and pyrimidines, both de novo and salvage pathways, starting from carbamoyl phosphate and 5-phosphoribosyl-1-pyrophosphate (PRPP), respectively. They also include the interconversions of the various nucleotides into each other, the phosphorylation and dephosphorylation reactions of respectively nucleosides and nucleotides and the catabolic pathways of nucleotides to the compounds that are cleared from the body. They do not include the further reactions of phosphoric groups thus split off from the phosphorylated nucleotides.
Nucleotides and their related metabolites play a key role in life, as has been described in the biochemical literature. Triphosphorylated forms, and especially adenosine triphosphate (ATP), are the main forms of chemical energy in mammal's body. This type of energy is for example required to allow desirable biochemical reactions to occur at a substantial rate, to maintain ionic gradients over membranes and to allow transport of some important, components over membranes. Nucleotides also can provide phosphate in a lot of biochemical reactions Nucleotides (bases) can form building blocks for DNA and RNA. Nucleotides and their derivatives can serve as mediators or regulators of many metabolic processes; for example the cyclic form of the monophosphates of adenosine and guanosine function as a second messenger after activation of receptors in the membrane. Due to allosteric effects they regulate many pathways. ADP is involved in platelet aggregation. Adenosine is a potent vasodilator and receptors have been described for other nucleic acid bases as well. Nucleotides are also part of many key cofactors such as NAD, FAD and CoA.
Nucleotides also activate intermediates in many reactions. Interconversion reactions of monosaccharides require activation by means of various nucleotides; there monosaccharides form important constituents of glycoproteins. Ethanolamine also requires activation before it can be modified intocholine, and ATP is needed to activate methionine in order to have if function as a methyl donor.
Nucleotides or precursors thereof can be formed in the body or be consumed from the diet. Nucleotides from diet can be broken drown in the digestive tract to nucleotides and nucleic acid bases, which can be rapidly absorbed by the gut and can be reassembled to nucleotides and related metabolites. Xanthines occur widely in drinks and chocolate.
Nucleotides can be synthesized de novo in several tissues using a pathway that requires the presence of much energy (ATP) and many reactants. That is way the human body is equipped with salvage systems that allow effective reuse of catabolic products of nucleotides.
Under certain conditions, e.g. when an unbalanced diet was consumed or when (severe) tissue damage has occurred in a short period of time, the body is temporarily exposed to large amounts of nucleic acids. Pyrimidines are in this case catabolized to beta-aminoisobutyric acid (thymine) or beta-alanine (e.g. uracil) that can be cleared through the urine. Beta-alamine can also be used for biosynthesis of carnosine and anserine by reaction with histidine or 1-methyl histidine. Excess purines are metabolized to xanthine (2,6-dihydroxypurine) and finally uric acid (2,6,8-trihydroxypurine).
Uric acid is mainly synthesized in the liver and thereafter released in the circulation. In extra-cellular fluids (e.g., synovial fluid or blood plasma) it occurs in the ionized form. Normal levels in blood serum are three to 6-7 mg/100 ml. The latter concentration is similar to or above the solubility product of monosodium urate at 37° C., which indicates the risk for (local) precipitation of urate crystals. Urate is normally predominantly (>⅔) cleared via the urine.
Hyperuricemia is defined as that situation when serum urate is bove 7.0 mg/100 ml in men and above 6.0 mg/100 ml in women. The occurrence of hyperuricemia is associated with disorders like obesity, hypertension, alcohol abuse, and congestive heart failure, though it is not considered to be a cause of these disorders. Nevertheless hyperuricemia may lead to diseases like gouty arthritis, tric acid urolithiasis and even nephropathies and also occurs in the syndrome of Lesch-Nyhan. Therefore it is important to ensure that at all times urate levels in serum and urine remain at normal magnitudes.
Uric acid contributes under normal conditions significantly to the total antioxidant (radical scavenging) capacity of blood plasma. It has been reported that total antioxidant capacity can be important for detoxifying reactive species, such as free radicals, e.g. these that are released during uncontrolled inflammatory conditions, and toxic (exogenous) compounds. It is also reported that scavenging of free radicals is important to prevent damage to membranes of cells.
Compounds that are normally used as antioxidants such as ascorbic acid and tocopherols have to be administered in huge amounts in order to have them contribute to the same extent to the total antioxidant capacity of blood plasma. This would lead to undesirable side effects in the product, and, on the longer term, also in persons who consume such a product, due to the prooxidaant effect of these components. Administration of other redox-active compounds to meet the same antioxidant capacity at urate may lead to undesirable side-effects such as interaction with other circulating antioxidants/radical scavengers such as serum albumin.
Urate is normally produced from xanthine by the enzyme xanthine dehydrogenase. Under certain conditions these enzyme is converted to xanthine oxidase. In this form the enzym uses oxygen as oxydant and hydrogen peroxyde is formed. It is important that the latter compound is neutralized before it can cause harm.
Therefore a need exists to develop a preparation that ensures a constant and sufficiently high antioxidant capacity of extracellular fluids such as blood plasma without undesirable side effects in both product and patients.
Due to their importance for life, nucleotides are rapidly metabolized and a high turnover rate exists. Some metabolites can interconvert using well-described pathways. There pathways are highly regulated and interdependent. Under normal conditions these pathways occur rapidly. This ensures a rather constant concentration of all nucleotides and/or related metabolites, whose magnitude depends on the requirements that are set by the condition of the various tissues and cells and on local concentrations of many components that are involved in TNM.
Under several conditions the human body is not able to maintain homeos
Hageman Robert Johan Joseph
Smeets Rudolf Leonardus Lodewijk
Verlaan George
Henley III Raymond
N.V. Nutricia
Young & Thompson
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