CA2291959A1 - A nutriceutical composition of l-carnitine, ubiquinone, n-3 polyunsaturated fatty acids and vitamins specifically formulated at pharmacological doses for the amelioration of the risk factors and symptoms of atherosclerosis-related illnesses - Google Patents

Abstract

A nutriceutical composition wherein the individual vitamins and other food components are formulated at pharmacological doses is proposed for the treatment of occlusive vascular diseases.
Each component has been chosen based on its proven utility, in isolation, in human subjects with established coronary heart disease, cerebrovascular disease and have suffered at least one stroke, and peripheral vascular disease and suffer from intermittent claudication, and based on the component's particular mode, or modes, of action targeting the individual stages of the disease such that the total composition provides a novel mixture of agents which act additively and in concert with each other in a manner specific to the disease. The composition consists of the metabolic enhancers, L-carnitine and coenzyme Q (ubiquinone); the homocysteine-lowering vitamins, folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin); a LDL cholesterol-lowering amount of nicotinic acid, or any slow release form, esterified or otherwise; the antioxidants, vitamin C
(ascorbic acid), vitamin E
(.alpha.-tocopherol), and selenium; and omega-3 polyunsaturated fatty acids.

Description

A NUTRICEUTICAL COMPOSITION OF L-CARNITINE, UBIQUINONE, N-3 POLYUNSATURED FATTY ACIDS AND VITAMINS SPECIFICALLY FORMULATED AT
PHARMACOLOGICAL DOSES FOR THE AMELIORATION OF THE RISK FACTORS AND
SYMPTOMS OF ATHEROSCLEROSIS-RELATED ILLNESSES
SPECIFICATION
Technical Field of the Invention This invention is related to the occlusive vascular diseases which are characterized by narrowed arteries caused by atherosclerosis. Atherosclerosis is the coating of the internal epidermal walls of arterial blood vessels with plaques which consist of oxidized LDL (low density lipid) cholesterol S contained within foam cells. This results in the narrowing of the arterial lumen and the restriction of the supply of blood to the cells of the organs and tissues fed by the arteries, thus compromising the metabolism of the cells through oxygen starvation {ischaemia). (In advanced atherosclerosis there is also fibrosis and calcification {"hardening"), and this reduces the elasticity of the epidermal tissue thereby making the vasculature poorly responsive to vasodilation.) The narrowing of the blood vessels also renders the passageway susceptible to sudden thrombosis (clotting) with complete blockage of blood flow bringing about the death of the cells fed by them.
Three main types of occlusive vascular disease exist: coronary heart disease which affects the heart muscles and can lead ultimately to a heart attack, cerebrovascular occlusive disease which affects brain cells and can lead to a stroke, and peripheral vascular disease affecting usually the muscles of the leg causing intermittent claudication (attacks of pain and lameness in the leg).
The development of atherosclerosis is a mufti-factorial, mufti-staged process.
This invention is the result of investigations into the risk factors for atherosclerosis at its various stages of development and of seeking "natural product" remedies that have been proven, singly, to reduce these risk factors and to halt the further development of atherosclerosis in persons with established occlusive vascular disease, and, in some cases, to bring about regression of atherosclerosis.
Further, this invention is also the result of seeking "natural products", which, when they were tested by themselves, counteracted some of the life threatening effects of atherosclerotic diseases.
The invention, hence, is a novel combination therapy wherein each component ha.s demonstrated utility in humans in double-blinded, placebo-controlled clinical trials, but has never been heretofore been applied in standard medical practice and, particularly, never in combination with each other.
The rationale of combination therapy is threefold. When a malady can potentially be caused by any one of several independent factors, but, in the patient under consideration, the particular factor causing the illness is not known - then a combination of remedies, where each component in the combination is targeted to all of the various causative factors, will have a better chance of succeeding. This is because the combination treatment "covers all the bases".
Secondly, if a malady is caused by several independent factors, all of them together contributing to the illness but by different mechanisms, then the combination treatment can be described as being complete, and the effect of the combination treatment is additive. Thirdly, if the malady is caused by several linked factors, all of them contributing to illness through a single mechanism or biochemical cycle, then the combination therapy will act synergistically, acting on the linked causative factors; and the effect of the combination treatment will be multiplicative and therefore significantly more potent.
Theoretically, synergy can exist, say, when two substrates are required for some biochemical reaction. The kinetics of the biochemical reaction is therefore proportional to the product of the concentration of the two substrates. Empirically, synergy between two components can be demonstrated when the dose-response curve for one component has a larger slope in the presence of the second component than in its absence. If the dose-response curve has the same slope in the presence of the second substance, but is only raised up the y-axis, synergy is absent, but the observations indicates that the two components operate additively.

Background Art There is virtually no "natural remedy" prescribed by physicians for their patients who have coronary heart disease, who have suffered a stroke, or who have intermittent claudication. Many "natural remedies" have, however, been experimentally investigated and have been reported in the peer-reviewed biomedical literature, but have not become recommended and incorporated into standard practice. An exception to this is the established use of niacin, in the form of nicotinic acid, at a daily dose of 1.5 grams per day to reduce blood cholesterol (Compendium of Pharmaceuticals and Specialties, 34"' edition, 1999, published by Canadian Pharmacists Association, pg. 1169). Very recently the American Academy of Family Physicians have made the recommendation of large doses of vitamins E and C for heart disease (Can Vitamins Help with Heart Disease", Patient Information Handout from the American Academy of Family Physicians: in American Family Physician, 59(6):1464-5, Mar. 15, 1999). The use of vitamin E and vitamin C may be considered now to be part of the prior art. Otherwise, vitamins are generally prescribed only when deficiencies in the diet are recognized, and Recommended Dietary Allowances have been established to determine what are the daily dosages to correct these deficiencies (The Merck Manual, Chapter 7:
Nutritional and Metabolic Disorders). However, pharmacological doses, that is, doses which are significantly above RDA values and which are effective in correcting disease states or risk factors are not generally and widely recognized in standard medical practice, with the abovementioned exceptions. Further, specific combinations of vitamins, minerals and other food components targeted at specific illnesses is not part of established medicine.

Disclosure of the Invention The development of occlusive arterial disease at its various stages, and the natural compounds that have been determined to remedy each stage can be summarized in the following chart:
DISEASE-CAUSING EVENT NATURAL COMPOUNDS THAT OPPOSE

THE DISEASE-CAUSING EVENT

1 Damage to arterial walls,Omega-3 polyunsaturated fatty acids believed to decrease to be caused by high blood pressure;
blood pressure and high homocysteineFolic Acid, Vitamins B6 and B1z to lower homocysteine.

2 Deposition of oxidized, Antioxidants - Vitamins C and E, and low- Selenium - to density cholesterol (LDL)prevent the oxidation of low-density at the cholesterol;

sites of arterial wall Nicotinic acid to decrease low-density damage cholesterol produces plaques. level.

3 Narrowing of the arteriesOmega-3 unsaturated fatty acids to caused decrease blood by the plaques restrictsviscosity and promote vasodilation blood whereby blood flow and oxygen deliveryflow in plaque-coated arteries is to the eased;

tissues fed by them (ischaemia).Coenzyme Q and carnitine to enhance the heart's metabolic energy thereby counteracting low oxygen delivery to ischaemic tissues.

4 Sudden rupture of plaqueVitamin E to inhibit platelet aggregation;
material in the artery (as a consequenceOmega-3 fatty acids to inhibit platelet of adhesion, rapid blood flow during vasoconstriction, ventricular arrhythmia physical and exertion, for example) fibrillation in the heart;
and platelet aggregation Coenzyme Q (ubiquinone) and L-carnitine at the site of to the rupture causes obstructionenhance the metabolic efficiency of of the infarcted blood flow and kills and weakened heart muscles after a those cells heart attack.

whose oxygen supply has subsequently been cut ofI'.

The invention is a selected composition of vitamins, and other food components, each one of which has demonstrated on subjects with diagnosed coronary artery disease, cerebrovascular, or peripheral vascular disease in secondary intervention clinical trials a reduction in mortality and/or recurrence of events, efficacy in reducing some of the risk factors associated with atherosclerosis, or benefit in ameliorating the effects of occlusive vascular disease, particularly those of coronary artery disease.
The dosages are at the pharmacological levels that were used in these clinical trials. These dosages are large enough to elicit physiological reactions, to shift the equilibrium of a biochemical pathway if the component is a substrate of one of its reactions, or, if the component is an enzyme cofactor precursor, to increase the concentrations of active, cofactor-bound enzyme as compared to inactive, apoenzyme thereby favouring the biochemical pathway in which the enzyme plays a key part.
Each component is discussed below separately:
Ni in (slow release form: inositol hexanicotinate) Nicotinic acid, but not its amide, has long been known for its hypolipidaemic properties, lowering triglyceride and LDL cholesterol while increasing HILL cholesterol in most types of hyperlipidaemia ( 1 ). In addition to its action at the early stages of atherogenesis, it has clinically been demonstrated in subjects with established coronary heart disease to be effective in halting the progression, and occasionally bringing about regression of atherosclerosis. Secondary intervention trials lasting between 2 and 6 years with niacin have shown reductions in additional cardiovascular events (2).
The esterified form, as in inositol hexanicotinate, releases nicotinic acid slowly thereby avoiding the side effects of flushing and itching ( 1 ).
( 1 ) Compendium of Pharmaceuticals and Specialties, 34'~ edition, 1999, published by Canadian Pharmacists Association, pg. 1169.
(2) "Effect of Niacin on Atherosclerotic Cardiovascular Disease" by Guyton, J.R. in The American Journal of Cardiology 82(12A):18U-23U, Dec. 17, 1998.

Antioxidants' Vitamin E (a-toconherol), Vitamin C Ascorbic Acid,, Selenium and Coenzyme O
According to the Antioxidant Theory of Cardiovascular Disease, LDL cholesterol particles enter the subendothelial interstices of the arterial wall, where they undergo oxidation by the oxygen radicals and peroxides produced consequent to oxidative metabolism or prostaglandin and leukotriene biosynthesis.(1,2) These sites attract monocytes which migrate into the subendothelial interstices, differentiate into macrophages which in turn engulf the oxidized LDL
particles, and then transform into immobilized foam cells, the dominant material of the atherogenic plaque.
The site becomes a focal point for additional macrophage and oxidized LDL accumulation. The final result of this self propagating cascade is plaque formation and narrowing of the arterial lumen.
Oxidized LDL also stimulates arterial wall cells to produce cytokines that promote the proliferation of smooth muscle cells and the synthesis of fibre protein, a process that adds to plaque development. Additionally, oxidized LDL inhibits the production of endothelium-dependent relaxation factor which is a stimulant of vasodilation. Thus, by opposing vasodilation, oxidized LDL
exacerbates the narrowing of the arterial passageway.
In view of the above, the expectation that long-term, high dietary intake of antioxidants, such as vitamin C, a-tocopherol, ~i-carotene and selenium, which are known from in vitro experiments to inhibit LDL oxidation, should reduce the risk of cardiovascular disease and stroke, was borne out by retrospective epidemiological surveys.(1,2) However, prospective primary prevention trials failed to show cardioprotection for vitamin C, showed inconclusive benefit with vitamin E and demonstrated a statistically-insignificant increased mortality risk with (3-carotene.
Prospective secondary intervention trials lasting from 1 to 8 years, on the other hand, on subjects with known cardiovascular disease demonstrated significant cardioprotection with vitamin E supplementation.(3-5) This invention contains vitamins E and C in accordance with the recommendation of the American Academy of Family Physicians (6) and American Heart Association (7) for individuals with established cardiovascular disease. Vitamin C was justified for inclusion in spite of the absence of direct experimental benefit but because of its known protection from oxidation of the fat-soluble LDL antioxidants (primarily vitamin E) and because of its innocuousness. In addition to its antioxidant activity, vitamin E has other beneficial effects. Plasma from subjects supplemented with vitamin E at 400-1600 IU/d showed in ex-vivo flow-shear measurements significant diminishing of platelet adhesion to glass surfaces coated with fibrinogen, fibronectin, and collagen.(8) This invention contains a source of selenium justified by the evidence that subjects who are deficient in selenium are at high risk for cardiovascular disease (2) and by animal model studies showing antioxidant synergy with vitamin E (9). Supplementation with selenium, through a post-mRNA
transcriptional positive feedback mechanism, increases the synthesis of the selenium-based enzyme, glutathione peroxidase, which carries out the reduction of hydroperoxides.(10) The dosage of selenium required for secondary intervention in cardiovascular patients (as opposed to primary prevention using nutritional doses (11)) is as yet undetermined; however, an amount has been established for the protection against dialysis-induced atherosclerosis.(10) Coenzyme Q is a known antioxidant; however, there is no evidence for effective in-vivo antioxidant activity, and its inclusion is based on its known metabolic enhancement activity. See below.
( 1 ) "Antioxidant Vitamins and Prevention of Cardiovascular Disease:
Laboratory, Epidemiological and Clinical Trial Data" by Marchioli, R. in Pharmacological Research 40(3):227-238, 1999.
(2) "Lipoprotein Oxidation, Antioxidants and Cardiovascular Risk:
Epidemiologic Evidence" by van de Vijver, L.P.L. et al. in Prostaglandins, Leukotrienes and Essential Fatty Acids, 57(4&5):479-487, 1997.
(3) "Free Radicals and Antioxidants in Cardiovascular Disease" by Maxwell, S.R.J. and Lip, G.Y.H.
in Br. J. Clin. Pharmacol. 44:307-317, 1999.
(4) "Antioxidant Vitamins and the Prevention of Coronary Heart Disease" by Adams, A.K., Wermuth, E.O. and McBride, P.E. in American Family Physician 60(3):895-902, Sept. 1, 1999.
(5) "Dietary Supplementation with n-3 Polyunsaturated Fatty Acids and Vitamin E after Myocardial Infarction: Results of the GISSI-Prevenzione Trial" by Marchioli, R. et al. in The Lancet 354:447-455, Aug., 1999.
(6) "Can Vitamins Help with Heart Disease", Patient Information Handout from the American Academy of Family Physicians: in American Family Physician, 59(6):1464-5, Mar.
15, 1999.
_7_ (7 ) "Antioxidant Consumption and Risk of Coronary Heart Disease: Emphasis on Vitamin C, Vitamin E, and (3-Carotene: A Statement for Healthcare Professionals From the American Heart Association" in Circulation 99:591-595, Feb. 2, 1999.
(8) "Reduction of Platelet Adhesiveness by Vitamin E Supplementation in Humans" by Jandak, J., Steiner, M. and Richardson, P.D. in Thrombosis Res. 49:393-404, 1988.
(9) "Vitamin E Combined with Selenium Inhibits Atherosclerosis in Hypercholesterolemic Rabbits Independently of Effects on Plasma Cholesterol Concentrations" by Schwenke, D.C. and Behr, S.R. in Circ. Res. 83(4): 366-377, Aug. 24, 1998.
(10) "Dietary Selenium Increases Cellular Glutathione Peroxidase Activity and Reduces the Enhanced Susceptibility to Lipid Peroxidation of Plasma and Low-density Lipoprotein in Kidney Transplant Recipients" by Hussein, O. et al. in Transplantation 63(5):679-685, Mar.
15, 1997.
( 11 ) "Background and Rationale Behind the SU. VLMAX Study, A Prevention Trial Using Nutritional Doses of a Combination of Antioxidant Vitamins and Minerals To Reduce Cardiovascular Diseases and Cancers" by Hercberg, S. et al. in Food Chem Toxicol, 37(9-10):925-930, Sept.-Oct., 1999.
Folic Acid, Vitamin B~ fPvridoxinel and Vitamin B,2 lCobalamin) Hyperhomocyst(e)inaemia (or, more directly, deficiencies in folic acid and vitamin B6 which cause hyperhornocyst(e)inaemia) has been established in epidemiological and prospective case-control studies as an independent risk factor for occlusive vascular disease and a predictor for disease progression.( 1-3) Plasma homocysteine is believed to be responsible for the initial event of arterial wall damage and subsequent plaque growth, and, at the late stages of atherosclerosis, for thrombogenesis.(4) Statistical measures of risk suggest that there is no threshold homocysteine plasma concentration that is atherogenic, but rather that all concentrations carry risk in a graded, dose-dependent manner. In a small, 2-year secondary prospective trial using patients with peripheral occlusive vascular disease and with high initial baseline homocysteine that had been lowered with vitamin therapy, it was shown that the incidence of expected coronary and cerebral vascular events _g-was reduced by the vitamin supplementation.(5) Several large prospective secondary intervention trials are currently underway to confirm the value of homocysteine lowering using folic acid and vitamin B6 in coronary heart disease and stroke.(2) Homocysteine is an amino acid intermediate in the transformation of methionine into cysteine.
The enzyme methionine synthase (5-methyltetrahydrofolate:homocysteine methyltransferase), using cobalamin as a cofactor and 5-methyltetrahydrofolate (5-MTHF) as a methyl group donor, transforms homocysteine back into methionine (remethylation). The methyl donor, 5-methyltetrahydrofolate is synthesized from folic acid in a multi-step enzymatic pathway. In addition, homocysteine is transformed into cysteine by the transtranssulfuration pathway which is catalyzed by the enzyme cystathionine (3-synthase which uses pyridoxal phosphate as a cofactor. Pyridoxal phosphate is synthesized from its vitamin precursor, pyridoxine (vitamin B6).
Hyperhomocysteinemia may be caused by mutations in the genes for methionine synthase or cystathione (3-synthase, by low vitamin status, renal disease and by some drugs such as methotrexate. These factors and some forms of the genetic defects can be compensated for by increased intake of folic acid and vitamin B6.
This invention contains all of folic acid (which is the most powerful reverser of hyperhomocyst(e)imia), vitamin B6 and vitamin B12 at dosages used in the clinical trials on patients with established arterial vascular disease (2). Although vitamin B1z has limited effectiveness in lowering homocysteine, it is added in order to prevent the masking of pernicious anemia caused by vitamin B12 deficiency.
(1) "Homocysteine: Update On a New Risk Factor" by Banal, R.S., Jacobsen, D.W.
and Robinson, K. in Cleveland Clinic Journal of Medicine, 64(10): 543-549, Nov./Dec., 1997.
(2) "Homocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiological Evidence" by Eikelboom, J.W. et al. in Ann. Intern. Med. 131(5):363-375, Sept.

7, 1999.
(3) "Prospective Blinded Study of the Relationship Between Plasma Homocysteine and Progression of Symptomatic Peripheral Arterial Disease" by Taylor, L.M. et al. in J. of Vascular Surgery, 29(1):8-21, Jan., 1999.
(4) "Putative Mechanisms for Vascular Damage by Homocysteine" by Bellamy, M.F.
and McDowell, LF.W. in J. Inner. Metab. Dis. 20:307,315, 1997.
(5) "Normohomocysteinaemia and Vitamin-Treated Hyperhomocysteinaemia Are Associated With Similar Risks of Cardiovascular Events in Patients With Premature Peripheral Arterial Occlusive Disease. A Prospective Cohort Study" by de Jong, S.C. et al. in J.
Internal Medicine 246:87-96, 1999.
Omega-3 Polyunsaturated Fattv Acids Historically, it was the epidemiological observation that those communities in which fish was a main dietary component had low incidences of cardiovascular disease that alerted researchers to the beneficial effects of fish oil and omega-3 polyunsaturated fatty acids (PLJFA) in particular. The possible mechanisms by which this benefit is achieved include (a)decreases in blood pressure, plasma triglycerides, blood viscosity, vasoconstriction, platelet adhesion, ventricular arrhythmia and ventricular fibrillation, and (b)increases in fibrinolysis, endothelial derived relaxation factor and vasodilation. Hence, these effects play their part at the various stages of cardiovascular disease from the beginning of plaque formation to ischaemia and to clot formation. ( 1 ) A 3.5 year prospective intervention trial on subjects recruited less than 3 months since their first myocardial infarction indicated significant decrease of mortality at a daily dose of 1 gm of omega-3 PUFA. (2) (1) "Omega-3 Fatty Acids: Current Status in Cardiovascular Medicine" by Schmidt, E.B. and Dyerberg, J. in Drugs 47(3):405-424, 1994.
(2) "Dietary Supplementation with n-3 Polyunsaturated Fatty Acids and Vitan>in E after Myocardial Infarction: Results of the GISSI-Prevenzione Trial" by Marchioli, R. et al. in The Lancet 354:447-455, Aug., 1999.

Coenzyme (Ubiauinonel Double-blind studies on patients with chronic heart failure showed significant improvement in clinical status, myocardial function, and exercise capacity in the group taking coenzyme Q,o. Patients with S stable angina pectoris tested in a double-blind trial which measured exercise tolerance demonstrated lower anginal frequency and nitroglycerin consumption. The beneficial action of coenzyme Qlo is attributed to its role in oxidative phosphorylation and ATP production which counteracts the energy-starved state of weakened and ischaemic hearts. ( 1 ) (1) "Perspectives On Therapy of Cardiovascular Diseases With Coenzyme Q,o" by Mortensen, S.A.
in Clinical Investigator, 71: S 116-S 123, 1993.
L-Carnitine From a number of different exercise studies with controls on patients with coronary ischaemia, it was shown that carnitine administration could increase maximal heart rate, rate-pressure product, the duration of pacing, and the exercise time until angina; and decrease the degree of ST-segment depression at maximal work load and left ventricular end diastolic pressure.
Myocardial metabolism was improved by various measures. Patients who had suffered acute myocardial infarction and were treated with L-carnitine within eight hours of the onset of chest pain showed less release of the MB
isoenzyme of creatinine phosphokinase than did the control group. This suggests that L-carnitine can protect cardiac muscle from infarct-induced necrosis.(1,2) Subjects with peripheral vascular disease who demonstrated impaired carnitine metabolism were able to increase the walking time to claudication pain after carnitine administration. (3) There are two mechanisms by which L-carnitine is believed to enhance metabolic energy output.
One, which promotes glucose energetics, is localized at the entry of pyruvate into the Citric Acid Cycle. Pyruvate can either be shunted to anaerobic lactate production or acetyl-CoA synthesis, the latter entering the Citric Acid Cycle which precedes ATP production by oxidative phosphorylation.

The enzyme that converts pyruvate into acetyl-CoA,' pyruvate dehydrogenase, is controlled in a feedback loop by the ratio of free CoA to acetyl-CoA. An excess of carnitine promotes acetyl-carnitine production by the enzyme, CoA:carnitine acetyltransferase, which uses acetyl-CoA as the source of acetyl groups, thereby leaving an excess of free CoA. Through positive feedback control by free CoA on pyruvate dehydrogenase, pyruvate is thereby directed preferentially into the Citric Acid Cycle and eventual ATP production.
The second proposed mechanism involves the promotion of fatty acid oxidation, which is the major energy source in myocardial tissue. The Carnitine Transport System is the means by which fatty-acylCoA is transported from the cytosol and into the mitochondria) matrix. The fatty-acyl moiety is transferred from acylCoA to L-carnitine by the enzyme, carnitine acyltransferase, thereby forming free CoA and fatty-acylcarnitine, the latter being translocatable across the mitochondria) membrane.
Inside the mitochondrion the reverse acyltransferase reaction occurs and regenerates free L-carnitine and fatty-acylCoA. The fatty-acylCoA, now in the mitochondria) matrix, undergoes ~3-oxidation ultimately producing acetylCoA which enters into the Citric Acid Cycle and ultimate ATP
production.
(1) "The Therapeutic Potential of Carnitine in Cardiovascular Disorders" by Pepine, C.J. in Clinical Therapeutics, 13(1):2-21, 1991.
(2) "Carnitine - From Cellular Mechanisms to Potential Clinical Applications in Heart Disease" by Atar, D, et al. in Europ. J. Clin. Invest. 27: 973-976, 1997.
(3) "Carnitine-Related Alterations in Patients With Intermittent Claudication -Indication for a Focused Carnitine Therapy" by Brevetti, G. et al. in Circulation 93, no. 9, 1685-1689, 1996.
It should be stated emphatically that, with the exception of nicotinic acid and with the possible exceptions vitamins E and C, none of the above-mentioned natural product compounds in the invention are prescribed as part of traditional medical practice. They are just now emerging from the research literature bearing empirical proof of their utility in human subjects with atherosclerotic occlusive vascular diseases, and, therefore, their use 'should be considered novel. Furthermore, the use of the combination of these compounds, wherein they operate in concert with each other in an additive manner and, for some ingredient pairings, such as that of vitamins E
and C and that of vitamin E and selenium, in a synergistic manner, must also be, a fortiori, novel.
A Preferred Mode of Executing the Invention The following chart puts forth a preferred, but not limiting, embodiment of the invention, including the Recommended Daily Allowances for comparison.
COMPOUND FORMULA DOSAGE RDA VALUES
(per day) malelfemale Folic acid 2.5 mg 0.20 mg/0.18 mg Vitamin B6 (pyridoxine)50 mg 2.0 mg/1.6 mg Vitamin B,z (cobalamin)1 mg 0.0020 mg/0.0020mg Nicotinic acid (as 1.5 gram (niacin 15 mg/13 mg (as niacin) inositol equivalents) hexanicotinate, or = 1.65 gram inositol other slow hexanicotinate release form) Vitamin C 1 gram 60 mgI60 mg Vitamin E {as the 400 mg (= 400 IU) 10 mg/8 mg (10 IUI8 IU) water-soluble a-tocopherol acetate) Selenomethionine 0.20 mg as elemental0.070 mg10.055 mg as selenium Sodium Selenate Coenzyme Q,o (ubiquinone)100 mg no RDA values exist L-carnitine 2.0 gram no RDA values exist Omega-3 fatty acids 1 gram of fish oil no RDA values exist ("fish oil") Other embodiments may omit nicotinic acid, to allow for those who are taking, and who wish to continue taking, inhibitors of the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) reductase (i.e.
the "statin" drugs, such as lovastatin) to lower their LDL cholesterol. Such an alternative embodiment which lacks niacin would be recommended for those susceptible to complications of high dose niacin, namely, subjects with liver disease, diabetes mellitus, gout, peptic ulcer, severe hypotension or arterial bleeding.
Another embodiment of the invention may omit or lower the amount of omega-3 polyunsaturated fatty acids because of the possibility of losing glucose regulation in subjects with diabetes mellitus.

Claims (17)

1. A nutriceutical composition intended for the treatment of atherosclerotic occlusive vascular diseases wherein the components are present at pharmacological doses consisting of the metabolic enhancers L-carnitine and coenzyme Q (ubiquinone) or any of their functionally equivalent structural derivatives or variants; and the vitamins folic acid or its salt or its functionally equivalent structural derivatives or their salts, vitamin B6 (pyridoxine) or any functionally equivalent structural derivative, vitamin B12 (cobalamin) or any of its functionally equivalent structural variants or derivatives, vitamin C (ascorbic acid) or any of its salts, vitamin E (.alpha.-tocopherol) in any of its functionally equivalent structural variants or derivatives, a source of selenenium; and may include or not include nicotinic acid, either as a free acid or as a salt, or in a slow release form; and may include or not include a source of omega-3 polyunsaturated fatty acids.

2. The claim of 1 wherein the functionally equivalent structural derivatives of L-carnitine include, but are not limited to, acetyl-L-carnitine, propanoyl-L-carnitine, butyryl-L-carnitine, their sodium or potassium salts, or their free acid forms.

3. The claim of 1 wherein the functionally equivalent structural derivatives or variants of coenzyme Q
may have 6, 8 or 10 isoprene units, and the oxidation states may be the quinone, semiquinone or the hydroquinone forms.

4. The claim of 1 wherein folic acid may be in its reduced derivatives, dihydro- or tetrahydrofolic acid, as well as their sodium or potassium salts.

5. The claim of 1 wherein the structural derivative of vitamin B6 includes the 5' phosphorylated form (pyridoxine-5'-phosphate).

6. The claim of 1 wherein the structural variants of vitamin B12 include the oxidations states for the cobalt atom of the corrin ring being +1, +2 or +3; and the group co-ordinated to the cobalt atom (opposite to the dimethylbenzimidazole) being either a -CH3, -OH, or a 5'-deoxyadenosyl group.

7. The claim of 1 wherein the structural variants of vitamin E include the d or 1 or a racemic mixture of .alpha.-tocopherol, and the structural derivatives include its esters with, but not limited to, acetic acid and succinic acid.

8. The claim of 1 wherein the source of selenium is, but not limited to, selenomethionine or selenocysteine.

9. The claim of 1 wherein the slow-release form of nicotinic acid includes inositol hexanicotinate.

10. The claim of 1 wherein the source of omega-3 polyunsaturated fatty acids consists substantially of eicosapentaenoic and/or docosahexaenoic and/or .alpha.-linolenic acids, or their alkoyl esters.

11. The claim of 1 and 10 wherein the source of the omega-3 polyunsaturated fatty acids is, but not limited to, any one or a combination of fish oil from mackerel, herring, salmon, tuna, trout, cod or flounder.

12. The claim of 1 wherein the daily dosage of L-carnitine or its functionally equivalent structural variants or derivatives ranges from about 0.1 gram to about 4.0 grams, the daily dosage of coenzyme Q (ubiquinone) or its structural variants or derivatives ranges from about 50 milligrams to about 200 milligrams, the daily dosage of folic acid or its salts or its derivatives or their salts ranges from about 0.4 milligram to about 5.0 milligrams, the daily dosage of vitamin B6 (pyridoxine) or its functionally equivalent structural derivatives ranges from about to about 100 milligrams, the daily dose of vitamin B12 (cobalamin) or its functionally equivalent structural variants or derivatives ranges from about 0.2 milligram to about 1 milligram, the daily dose of ascorbic acid or its salts ranges from about 100 milligrams to about 2 grams, the daily dose of vitamin E or its functionally equivalent structural variants or derivatives ranges from about 30 milligrams to about 800 milligrams, the daily dose of selenium as elemental selenium ranges from about 0.05 milligram to about 0.2 milligram, the daily dose of nicotinic acid or nicotinate salts or nicotinic acid equivalents in the slow release form ranges from about 1.0 gram to about 2.0 grams, and the daily dose of omega-3 polyunsaturated fatty acids or their esters ranges from about 1 gram to about 6 grams.

13. The claim of 1 and 12 wherein the daily dose of L-carnitine or its functionally equivalent structural variants or derivatives is at or about 2.0 grams, the daily dose of coenzyme Q
(ubiquinone) or its structural variants or derivatives is at or about 100 milligrams, the daily dose of folic acid or its salts or its derivatives or their salts is at or about 2.5 milligrams, the daily dose of vitamin B6 or its functionally equivalent structural derivative is at or about 50 milligrams, the daily dose of vitamin B12 or its functionally equivalent structural variants or derivatives is at or about 1 milligram, the daily dose of vitamin C or its salts is at or about 1 gram, the daily dose of vitamin E or its functionally effective structural variants or derivatives is at or about 400 milligrams, the daily dose of selenium as elemental selenium is at or about 0.2 milligram, the daily dose of nicotinic acid or its salts or of nicotinic acid equivalents in the slow release form is at or about 1.5 gram, and the daily dose of omega-3 polyunsaturated fatty acids is at or about 1 gram.

14. The claims of 1, 12 and 13 wherein the ingredients of the composition are presented for consumption in, but limited to, tablet, capsule, loose powder, aqueous suspension or "nutrition bar" dosage delivery formats.

15. The claims of 1, 12, 13 and 14 wherein the ingredients of the composition are packaged together in a substantially unitary package but wherein a portion of the ingredients of the composition is present for consumption in one dosage delivery format as listed in claim 14 and the remaining ingredient or ingredients is (are) present in another one of these formats.

16. The claim of 1, 12, 13, 14 and 15 wherein the ingredients are presented either in a single dose form providing the daily dosage in one unit of the dosage delivery format of those in claim 14, or in a number of dosage delivery units of claim 14 wherein a fraction of the daily dosage is contained within one unit, wherein the ratios of the ingredients as detailed in claims 12 and 13 are maintained and preserved, and several dosage delivery units must be taken per day.

17. The claim of 1, where the atherosclerotic occlusive vascular diseases are coronary heart disease manifest as, but not limited to, post-myocardial infarction, post-coronary arterial bypass graft surgery, stable angina pectoris, myocardial ischaemia; cerebrovascular disease after at least a first stroke, and peripheral vascular disease manifest as intermittent claudication.