Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-09-24
2001-04-17
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
Reexamination Certificate
active
06218366
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compositions and methods for raising the hypoxic threshold in mammals experiencing a hypoxic condition. Such mammals include humans with cardiovascular or peripheral vascular disease, or humans undergoing chronic or transient hypoxia.
BACKGROUND OF THE INVENTION
It is well known that the energy coinage of the cell is adenosine triphosphate (ATP). During anabolism, the energy derived from the metabolism of nutrients is transferred to high energy phosphate bonds of ATP. The energy in these bonds is expended during the energy consumption phase. An important and “costly” expenditure, in which ATP is rapidly cycled, is that required for muscular contraction.
The energy buildup steps occur within the muscle cell during two basic processes. Oxidative phosphorylation replenishes ATP by the breakdown of circulating fatty acids, glucose and intramuscular glycogen and triglycerides. Anaerobic phosphorylation provides ATP from creatine phosphate, circulating glucose and intramuscular glycogen via kinase reactions such as the myokinase reaction.
In the synthesis of ATP via the nucleotide salvage pathway, the nucleotide precursors that may be present in the tissue are converted to AMP and further phosphorylated to ATP. Adenosine is directly phosphorylated to AMP, while xanthine and inosine are first ribosylated by 5-phosphoribosyl-1-pyrophosphate (PRPP) and then converted to AMP. Ribose is found in the normal diet only in very low amounts, and is synthesized within the body by the pentose phosphate pathway. In the de novo synthetic pathway, ribose is phosphorylated to PRPP, and condensed with adenine to form the intermediate adenosine monophosphate (AMP.) AMP is further phosphorylated via high energy bonds to form adenosine diphosphate (ADP) and ATP. During energy consumption, ATP loses one high energy bond to form ADP, which can be hydrolyzed to AMP. AMP and its metabolites adenine, hypoxanthine and inosine are freely diffusible from the muscle cell and may not be available for resynthesis to ATP via the salvage pathway.
In U.S. Pat. No. 4,719,201, it is disclosed that when ATP is hydrolyzed to AMP in cardiac muscle during ischemia, the AMP is further metabolized to adenosine, inosine and hypoxanthine, which are lost from the cell upon reperfusion. In the absence of AMP, rephosphorylation to ADP and ATP cannot take place. Since the precursors were washed from the cell, the nucleotide salvage pathway is not available to replenish ATP levels. It is disclosed that when ribose is administered via intravenous perfusion into a heart recovering from ischemia, recovery of ATP levels is enhanced.
The availability of PRPP appears to control the activity of both the salvage and de novo pathways, as well as the direct conversion of adenine to ATP. Production of PRPP from glucose via the pentose phosphate pathway appears to be limited by the enzyme glucose-6-phosphate dehydrogenase (G6PDH). Glucose is converted by enzymes such as G6PDH to ribose-5-phosphate and further phosphorylated to PRPP, which augments the de novo and salvage pathways, as well as the utilization of adenine. The addition of ribose bypasses this rate limiting enzymatic step.
Many conditions produce hypoxia. Such conditions include acute or chronic ischemia when blood flow to the tissue is reduced due to coronary artery disease or peripheral vascular disease where the artery is partially blocked by atherosclerotic plaques. Transient hypoxia frequently occurs in individuals undergoing anesthesia and/or surgical procedures in which blood flow to a tissue is temporarily interrupted. Peripheral vascular disease can be mimicked in intermittent claudication where temporary arterial spasm causes similar symptoms. Finally, persons encountering high altitudes may become hypoxic.
Thus, a continuing need exists for methods to raise the hypoxic threshold of cardiac and skeletal muscle.
SUMMARY OF THE INVENTION
The present invention provides compositions for, and methods to raise the hypoxic threshold in a mammal. It is believed that the present compositions and methods allow mammals to tolerate situations in which, absent the present compositions and methods, the mammal would experience the onset of symptoms and consequences of hypoxia. The preferrred compositions include D-Ribose alone or, optionally, in combination with vasodilators and/or inotropic agents in pharmaceutically acceptable carriers. Hypoxia may be chronic, as in mammals with congestive heart failure, coronary artery disease or peripheral vascular disease. Hypoxia may also be transient, as in mammals undergoing anesthesia and surgical procedures, experiencing high altitudes, or exposed to toxic substances that interfere with oxygen utilization.
It is here shown that the administration of ribose will raise the hypoxic threshold of a mammal such as a human or domestic animal, thereby enabling such mammals to better tolerate the situation causing hypoxia. It is further disclosed that in mammals in which the hypoxia is caused by reduced blood flow due to arterial occlusion or spasm, the administration of ribose plus a vasodilator will enhance the raising of the hypoxic threshold.
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Tan, Z.T
Cyr John St.
Johnson Clarence A.
MacCarter Dean J.
Sawada Stephen G.
Bioenergy Inc.
Reamer James H.
Schwegman Lundberg Woessner & Kluth P.A.
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