Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-05-23
2002-07-09
Henley, Jr., Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S560000, C514S689000
Reexamination Certificate
active
06417233
ABSTRACT:
This is A371 of PCT/IT99/00331 filed Oct. 19, 1999.
The present invention relates to a pharmaceutical
utritional composition for supporting and/or providing therapy to individuals at risk and/or under treatment for dysfunctions of energy metabolism, and specifically, for mitochondrial diseases.
More specifically, the present invention relates to a composition comprising (a) an amount of a lipid-soluble benzoquinone selected from the group consisting of ubiquinone (Coenzyme Q
10
, CoQ
10
), its reduced form, ubiquinol-10 (CoQ
10
H
2
) or mixtures thereof, effective for performing a therapeutical and/or preventive and/or nutritional activity, and (b) at least a further component suitable for stimulating and enhancing the intramitochondrial transportation of component (a), the resulting composition being potently effective for the prevention and/or treatment of mitochondriopathies.
Accordingly the composition may take the form and exert the action of a dietary or nutritional supplement or of an actual medicine, depending upon the support or preventive action, or the strictly therapeutic action, which the composition is intended to exert in relation to the particular individuals it is to be used in. Depending on the actual circumstances, the composition of the present invention need not or, alternatively, should be taken under the supervision of an attending physician.
In the publication by the United Mitochondrial Disease Foundation, “About Mitochondria and Disease” (http:/ibiochemgen.ucsd.edu/umdf/AboutMitoDisease.htm), which is incorporated herein by reference, the following definition of what a mitochondrial disease is, and what the triggering, sub-cellular causes are, is given:
“The mitochondria produce adenosine triphosphate (ATP), the body's mobile energy source. When mutations occur which affect the mitochondria, the vital supply of ATP is disrupted, less and less energy is generated within the cell. When this process is repeated on a large scale throughout the body, whole systems begin to fail, and the life of the person in whom this is happening can be compromised, changed or even ended. The cells that require the most energy, like the brain, heart and skeletal muscles, are the most vulnerable”.
This reference also provides a detailed list and description of mitochondrial diseases, which encompasses, inter alia, Co-enzyme Q
10
deficiency; Complex III deficiency (Ubiquinone—cytochrome c oxidoreductase deficiency) whose symptoms include pigmentary retinopathy; Complex IV deficiency/COX deficiency (cytochrome c oxidase deficiency) whose symptoms include optic atrophy and ophthalmoplegia; CPEO (Chronic Progressive External Ophthalmoplegia Syndrome) whose symptoms include visual myopathy and retinis pigmentosa; ARMD (Age-Related Macular Degeneration); NARP (Neuropathy, Ataxia and Retinis pigmentosa) and many others.
Since CoQ
10
is indispensable to cellular bionergetics, its deficiency may bring about a host of pathologies.
Indeed, CoQ
10
is known to play an essential role as an electron (redox) carrier in the mitochondrial electron transport chain of the cell. However, it also protects membrane phospholipids and those in LDL from peroxidation as well as protects and/or regenerates vitamin E. CoQ
10
is synthesized in the body from precursors of cholesterol synthesis and therefore is not classed as a vitamin. However, the ability to synthesize CoQ
10
decreases with age and there may be an increasing dependence on food to supply the nutrient. The most abundant sources are fresh unprocessed foods, particularly meats, fish, nuts and seed oils. The average daily intake of CoQ
10
is approximately 2 mg.
Ubiquinol-10 or CoQ
10
H
2
, the reduced form of CoQ
10
, plays a second role as a potent lipid-soluble antioxidant and its activity at physiological concentrations in the lipid components of cells has recently been shown.
CoQ
10
's antioxidative, electron transport, and membrane-stabilizing properties have widely been investigated aiming at prevention of and/or treatment of various cardiovascular diseases, including prevention of cellular damage during reperfusion, angina pectoris, hypertension, myocardial ischemia, and congestive heart failure.
In patients with mitochondrial encephalomyopathy, CoQ
10
treatment increases mitochondrial functions and exercise performance, and reduces the acidosis associated with exercise. This finding is consistent with CoQ
10
participation in electron transport and mitochondrial membranes, and in the biological oxidation of cellular fuels for energy generation.
CoQ
10
deficiency was also reported to be associated with viral infections, and supplementation of CoQ
10
in acquired immune deficiency syndrome (AIDS) patients resulted in enhanced macrophage activity and increased serum level of IgG. CoQ
10
treatment has been reported to provide some benefits in cancer patients, and enhanced hematopoietic activity in malnourished children. All the evidence suggests that CoQ
10
may play essential roles in maintaining and promoting health, under normal and abnormal conditions.
It has become more and more apparent that individuals at risk and/or under treatment for mitochondriopathies are in need of increased supplementation of ubiquinones with respect to the normal intake of these substances through the diet, since particularly CoQ
10
deficiency may cause the onset, precipitate or aggravate the symptoms of a serious mitochondriopathy.
Many efforts have been made over the last decade in order to find formulations that would increase the bioavailability of CoQ
10
or anyhow enhance its efficacy at the cellular organelle sites of action. For instance, M. Weis et al in “Bioavailability of four oral Coenzyme Q
10
formulations in healthy volunteers (Molec. Aspects Med. Vol. 15 [supplement] pps 273-s 280, 1994) report on a four-way randomised cross-over trial wherein the bioavailability of four different CoQ
10
formulations was compared. The study results suggest that a soy bean oil suspension of CoQ
10
(Bioquinon®, 100 mg CoQ
10
with 400 mg of soy bean oil in soft gelatine capsules) exhibits the highest bioavailability.
However, in spite of all these efforts, no satisfactory formulations able to provide a therapeutical or preventive effective concentration of ubiquinons and particularly of CoQ
10
at their intracellular sites of action, have been developed to-date.
Polyunsaturated fatty acids (PUFA) are subdivided in classes based on the location of the first double bond counting from the methyl end of the fatty acid molecule: &ohgr;-3 (or n-3) fatty acids have their first double bond between the third and fourth carbon atoms, and the (&ohgr;-6 (or n-6) fatty acids have their first double bond between the sixth and seventh carbon atoms. Particularly importante are the &ohgr;-3 fatty acids and, specifically, linolenic acid (18:3 &ohgr;3) (LNA), eicosapentaenoic acid (20:5 &ohgr;3) (EPA), and docosahexaenoic acid (22:6 &ohgr;3) (DHA), wherein the first number (before the colon) gives the number of carbon atoms in the molecule and the second gives the number of double bonds.
In the last two decades, epidemiologic studies, clinical investigations and animal experiments have expanded our knowledge of the properties of dietary fatty acids in health and disease, growth and development. As a recent result of these investigations, the focus is on the ratio of &ohgr;-6/&ohgr;-3 fatty acids in the diet; the essentiality of &ohgr;-3 fatty acids and their metabolic effect in the prevention and treatment of chronic diseases. These biological and functional effects of &ohgr;-3 fatty acid exert profound beneficial metabolic changes in coronary heart disease, hypertension, non-insulin-dependent diabetes mellitus, inflammatory and autoimmune disorders, and possibly cancer. For a detailed account on the sources, metabolism, biological and functional effects and dietary aspects of &ohgr;-3 fatty acids see e.g. “Functional Food” edited by Israel Goldberg, Chapman & Hall (1994), Chapter 16: “Fatty Acids” by Artemis P. Simopoulos, pp 355-392, which i
Feher Janos
Sears Grazia
Henley, Jr. Raymond
Nixon & Vanderhye
Sigma-Tau HealthScience S.p.A.
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