Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Patent
1995-03-20
1999-11-09
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
514675, A61K 3112
Patent
active
059816015
DESCRIPTION:
BRIEF SUMMARY
The present invention relates generally to therapeutic compositions comprising one or more redox compounds. The therapeutic compositions of the present invention are useful in enhancing cellular ATP production thereby ameliorating the effects of reduced bioenergy capacity such as occurring during aging, systemic or vascular disease or in conjunction with chemical therapy.
Cells unable to meet their biological energy (bioenergy) demand from intracellular produced ATP become non-functional and generally die. The bioenergy threshold is different for various cell types and tissues of the body. For example, brain, skeletal muscle and cardiac muscle have a high oxygen demand and are highly dependent on mitochondrial oxidative phosphorylation. Other tissues with lower bioenergetic demand contain comparatively few mitochondria and rely to a greater extent on glycolysis as a source of ATP.
The two basic mechanisms responsible for cellular ATP production are cytosolic glycolysis and mitochondrial respiration. ATP synthesis via glycolytic processes involves the oxidation of glucose to pyruvate, coupled to the reduction of NAD.sup.+ to NADH. In order for this pathway to be maintained, the supply of NAD.sup.+ must continually be regenerated through a redox sink. For example, in muscle tissue the re-oxidation of NADH can be achieved by the conversion of pyruvate to lactate by lactate dehydrogenase. In this case muscle lactate may be regarded as a redox sink for that tissue. ATP production by oxidative phosphorylation in functionally respiring mitochondria is integrated with the re-oxidation of NADH via the activity of the electron transport system In this case a supply of reduced pyridine nucleotides is needed. In addition to NADH generated by glycolysis, further amounts of "reducing power" (both pyridine and flavin nucleotides) are generated by the activities of the TCA cycle as well as oxidation of fatty acids in mitochondria. Another significant cell system involved in the maintenance of cellular NAD.sup.+ /NADH redox balance is the plasma membrane oxidoreductase enzyme system (Crane et al, J. Bioenergy Biomember 23, 773-803, 1991). In cases where the mitochondrial electron transport chain is impaired (such as in mitochondrial disease and the ageing process), a decline in ATP production and under certain conditions concomitant build up of NADH is proposed to ensue. The metabolic consequence of such mitochondrial dysfunction would be an increasing reliance by the cell on cytosolic glycolysis to generate the ATP required for cellular maintenance and growth, acting in concert with the plasma membrane NADH oxidoreductase system. A key feature of cellular bioenergetics is, therefore, the balance that must be maintained between the oxidised and reduced forms of these nucleotide co-enzymes (exemplified by the NAD.sup.+ /NADH ratio), by the interaction of the glycolytic pathway, mitochondrial respiratory and plasma membrane oxidoreductase enzyme system.
Cells may become unable to meet their bioenergy threshold as a result of mitochondrial poisons which directly or indirectly disrupt mitochondrial respiratory chain function; certain degenerative diseases which are caused by mutations in mitochondrial DNA (mtDNA); and aging which may result in a high rate of somatic gene mutation in the mtDNA. The mitochondrial genome is subjected to a high mutation rate mainly because of its close proximity to the major source of cellular free radicals (the mitochondrial electron transport chain) and because the mitochondrial organelle lacks an efficient DNA repair system. The mitochondrial genome (16,569 bp) essentially encodes only genes concerned with energy production. It contains the structural genes for seven proteins of complex I of the respiratory chain, a single sub-unit protein of complex III, three sub-units of complex IV and two sub-units of ATP synthase (complex V); the rest of the mitochondrial DNA codes for the organellar rRNA's and tRNA's specific to mitochondrial protein synthesis. Given the paucity of spacer regions between
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Linnane Anthony William
Martinus Ryan Dennis
Nagley Phillip
Vaillant Francois
Badio Barbara
Centre for Molecular Biology and Medicine
Dees Jos,e G.
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